Chemistry of Heterocyclic Compounds

vol.22

OxO- and thioxo-1,3-thiazines (review)
1-13
Mass-spectrometric study of the cyclization reactions of diazoketones. 8. 1-Diazo-3,4-epoxy-4-
arylbutan-2-ones
13-18
Synthesis of 2-, 6-, and 7-aminomethyl derivatives in the 4,5-dihydroxybenzofuran series
18-22
Conversion of trans, trans-1-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes into
hemidithioacetals and 4H-thiopyrans. Structure of trans, trans-1-mercapto-3-phenyl-5-(4-
methoxyphenyl)-2-thiabicyclo[4.4.0] dec-3-ene
23-28
Study of kinetics and mechanism of sulfonation of thiophene and its derivatives by complex
compounds of sulfuric anhydride
28-33
Synthesis of heterocyclic analogs of prostaglandins from pyrrole and indole
33-36
New synthesis of indole-7-carboxylic acid
36-37
Synthesis of heterocycles from 1,5-diketones. 3. Alicyclic 1,5-diketones in reaction with
phenylhydrazine
38-44
Synthesis of derivatives of 4-imino-2-amino-2-imidazoline. New example of a multicomponent
condensation involving isonitriles
45-51
New derivatives of imidazoline 3-oxide and thiazoline with 2,6-dialkylphenol fragments
52-56
Spectroscopic study of the structure of N-(2-benzimidazolyl)-O-methylcarbamate
57-63
Reactivity of methyl derivatives of nitrogenous heterocycles in vapor-phase catalytic oxidation
63-66
Synthesis and ring-chain isomerism of n-monosubstituted 4-benzoylnicotinamides and 3-
benzoylisonicotinamides
67-70
Acetals of lactams and acid amides. 46. Unusual reactions of α-cyano-β-
dimethylaminocrotonamide with anthranilic acid derivatives
70-73
Synthesis of 5-oxoindeno[1,2-b]pyridinium salts
73-76
Azaindole derivatives. 67. Synthesis of N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-
azaindoles
76-80
Synthesis and some reactions of 4-nitro derivatives of imidazo[4,5-c]pyridin-2-ones
80-85
Synthesis of N6-substituted adeninyl-9-β-D-glucofuranuronosides
85-88
Synthesis and properties of symm-triazine derivatives. 4. Synthesis of 2,4,6-trisubstituted symm-
triazines containing sterically-hindered phenol fragments
89-94
Structure and some properties of tetrazole 5-methylpyrimido[4,5-e]-[1,2,4]triazine-6,8-dione and
its azide in different phase states
95-100
10-Alkenylphenothiazines. 1. Synthesis and cis,trans-isomerization of 10-propenylphenothiazines
100-103
New type of recyclization of 2-benzopyrylium salts

104-105
Reaction of flavylium perchlorate with carbon monoxide
105
Unusual reaction of N,N-dimethylacetamide diethyl acetal with 2-aminomethylene-5,5-
dimethylcyclohexane-1,3-dione. Synthesis of coumarin and carbostyril derivatives
106-107
1-Thiocarbamoyl-5-oxy- and 5-thiosemicarbazido-2-pyrazolines
107-108
Methods for the synthesis of azoles containing indole substituents (review)
109-133
Quantum-chemical treatment of recyclization reactions. 9. Photoisomerization of five-membered
heterocycles
133-140
Synthesis of 5-substituted cyanofurans and their reaction with hydrazine
140-145
Chlorination of 1,3-dioxolan-4-ones
145-147
Reaction of 2-methyl-5,6-dihydro-2H-pyran with dichlorocarbene
147-148
Chemistry of isoflavone heteroanalogs. 11. Benzodioxane analogs of chalcone, flavone, and
isoflavone
149-154
An unusual product of the reaction of 1-phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-1-
propanone with hydrogen sulfide and acids: 2α-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-1-
thiadecalin
155-161
Reactions of azirines with sulfur nucleophiles. 4. Treatment of 2H-azirine with
mercaptosubstituted acids. reactions of aziridinyl alkyl sulfides with carboxylic acids and acyl
chloride derivatives
161-166
New derivatives of meso-(tetra-4-pyridyl)porphine and their reactions
167-171
Tetracyanoethylation and fischer rearrangement of some 4-oxo-4,5,6,7-tetrahydroindoles
172-175
Chemistry of the pyrazolidines. 26. Alkylation of 4-benzyliden-1-phenyl-3.5-dioxopyrazolidines
176-180
Reaction of 4-aminoimadazo[4.5-c]pyridin-2-ones with α-bromomethylketones
180-186
Effects of acids on orientation in the reaction of 5-formyl-4-(1-pyridino)azole 2-oxides with
aromatic amines
186-192
Reaction of pyrido[1,2-a]benzimidazole and tetrahydropyrido[1,2-a]benzimidazole with
acetylenedicarboxylic ester
192-194
Mass spectrometric study of the stereoisomers of 2-furyl- and 2-phenyldecahydro-4-quinolinone
and their tertiary alcohols
195-199
Arylidenehydrazono-2(4)-azafluorenes
200-205
Synthesis and dynamic stereochemistry of 1,5-disubstituted 2,3,4,5-tetrahydro-1H-1,5-
benzodiazepin-2-ones
206-210
Homolytic addition of 1,3-oxathiolane to unsaturated hydrocarbons
210-214
Effect of substituents on the relative stability of furoxan isomers
214-217
Mass spectra and 13C NMR spectra of the adducts of epoxyenamines with sulfene

217-221
Fragmentation of substituted 2-sila-1,3-dioxacycloalkanes under electron impact
221-224
Synthesis of 2-(diazomethyl)-3-methyl-5H-furan-4-one from 1,5-bis(diazo)-3-methylpentane-2,4-
dione
225
Thermal isomerization of α-arylideneisochromenes into α-naphthols
226
Addition of isocyanates and isothiocyanates to 2-amino-3-phenylcarbamoylazirines
227-228
First synthesis of ethylenebisporphyrins
228-229
Synthesis of N-heterocyclic analogues of 2,5-diaryloxazoles
229
Synthesis of 2-benzoyl(thenoyl)benzo-1,4-thiazines
230
Electrophilic heterocyclization of unsaturated sulfur and phosphorus compounds (review)
231-242
Hydrogenation of furfural on polymer-containing catalysts
243-246
Interaction of ethoxyacetaldehyde with 1,3-dicarbonyl compounds
247-250
Acid-base properties and stability of pyrylium polymethine dyes in chlorohydrocarbon solutions
250-253
Electrochemical reduction of N-vinylazoles
253-257
Studies of 1-azabicyclics. 23. Nitration of 1,2-dihydropyrrolizine and its homologs
257-261
Synthesis of derivatives of indole and quinoline by the intramolecular catalytic cyclization of
allylanilines
262-264
Nucleophilic substitution reactions in 4-halonitro-pyrazolecarboxylic acids
265-267
Reaction of 1,2-hydroxylaminooximes with 1,2-diketones. Conversion of 2-acyl-1-hydroxy-3-
imidazoline 3-oxides to pyrazine 1,4-dioxides
268-275
Studies of imidazo[1,2-a]benzimidazole derivatives. 21. Synthesis of haloketones in the
imidazo[1,2-a] benzimidazole series
275-282
Reaction of N-aminobenzimidazolium cations with aromatic aldehydes. Synthesis of 2,4-diaryl-as-
triazino[1,6-a] benzimidazoles
282-287
Formation of 4,5-dihydro-1,2,4-triazoles during rearrangement of O-acetyl derivatives of 1,2-
hydroxylaminohydrazones and thiosemicarbazones
287-291
Quantum-chemical interpretation of recyclization reactions. 10. Photoisomerization of six-
membered heterocycles
291-297
Reaction of 5-bromo-6-amino-3-(4-methylaminobutyl)pyridine with potassamide
297-300
Rearrangement of 2-hetarylalkylpyridinium salts
300-303
New method of synthesis of 3-alkyl-4-piperidones
304-306
Mass spectrometry of stereoisomeric 3-hydroxy-4-piperidones
306-310

Synthesis of 5-arylpyrimidine-2-carboxylic acids and the liquid-crystal characteristics of their aryl
esters
310-318
Reactions of azinium ions. 4. Reactions of quinoxalinium salts with nitroalkanes — Single-stage
path to tetraazaheterocycles with bridged and framework structures
318-328
Preparation of some substituted 1,2,4-triazines
328-330
Purinenucleoside analogs. 2. 9-(1-Alkoxyethyl-1)-6-substituted purines
331-334
Configuration of 2-(4-pyridyl)-5-aryloxazole molecules in various states of aggregation
334-339
Macroheterocycles. 24. Synthesis of new derivatives of diaza-18-crown-6
340-342
Reaction of phthalimide with diethylene triamine and triethylene tetramine
343
5-Amino-6-mercaptopyrimidines in the synthesis of derivatives of 5-amino-1,2,3-thiadiazole
344-345
2-Selenoxoquinazolones-4, a new kind of quinazolone
345-346
Alkylation of 6-substituted purines in conditions of interphase catalysis
346-347
Synthesis of condensed tetrahydropteridines by the cyclization of the 8-ethylpteridinium cation
with dinucleophiles
348-349
Synthesis of 2,3-diphenyl-5,6-dihydro-1,3-oxazinium hexachloroantimonate from 2-phenyl-1,3-
dioxane
349-350
Acidic transformation of 2-(2-hydroxyphenylamino)-1,4-naphthoquinone-4-phenylimines into N-
phenylbenzo[a]-phenoxazimes
350-351
Synthesis of heterocycles on the basis of aliphatic nitro compounds (review)
353-370
Some reactions of 3,7-dimethyl-2,3-epoxyoctanal and its derivatives
370-372
Synthesis of the diastereomeric 2-aryl-1-cyclohexyl-3-(2,3-epoxypropionyl)aziridines
372-375
Quantum-chemical treatment of recyclization and cyclization reactions. 11. Formation of a
pyrylium ring
376-380
Synthesis of 4-methyl-2,3,4-trichlorotetrahydropyran and several features of the stereochemistry
of the nucleophilic substitution of the α-chlorine atom
380-386
Structure of the products of the o-monoalkylation of pyrocatechol by α-bromoketones
386-389
X-ray structural investigation of novel azabicyclic systems containing aziridine rings
390-393
New examples of the vinylation of NH-heterocycles with acetylene at atmospheric pressure in the
KOH-DMSO system
393-396
Synthesis of tetraphenylporphins with reactive groups in the benzene rings. 3. Use of
diazotization for the preparation of substituted tetraphenylporphins
397-401
Ethyl 1,4-dihydropyridinecarbodithioates and the electronic effects of sulfur-containing ester
substituents
401-410

Formation of a derivative of 3,3,5-tricarbonyl-1,2,3,4-tetrahydropyridine under the conditions of
the hantzsch synthesis
410-414
Synthesis and reactions of 8-benzylidene-2-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylic acid
arylamides
415-416
Preparation of derivatives of 1,2-dihydro- and 1,2,3,6-tetrahydropyrazinones from acylated 1,2-
hydroxylamino ketones
417-421
Synthesis of 1-alkyl(aralkyl)-4-acyl-2-piperazinones
421-424
Analogs of purine nucleosides. 3. Alkoxyalkylation of hypoxanthine by the silyl method
425-431
Alkyliminomalonic acid and 2-alkyloxaziridine-3, 3-dicarboxylic acid esters
431-437
Oxazolidines. 1. Basic catalytic disproportionation of cyclohexanospiro-2-oxazolidines: Synthesis
of N-substituted 4,5,6,7-tetrahydroindoles
437-439
Oxazolidines. 2. Synthesis of 2-methyloxazolidines by cyclization of vinyl ethers of 1, 2-amino
alcohols
440-442
Mass spectrometric study of 1,2,4- and 1,3,4-oxadiazoles containing indole substituents
442-446
NMR spectral study of the structure of 2-amino-4-thiazolinones
447-451
Synthesis of isomeric 4- and 5-hydroxylaminothiazolidin-2-thiones
451-455
Benzazolin-2-thiones in the michael reaction. 1. Reaction of benzothiazolin- and benzoxazolin-2-
thiones with acrylonitrile, acrylamide, and methylacrylate in the presence of acid catalysts
456-459
PMR study of the conformational behavior of 2,5,5-trisubstituted 1,3,2-dioxaborinanes
459-462
Synthesis of furan derivatives from 1,3-alkadiynes
463
A new reaction in the series of 4,5,5-trimethyl-Δ3-butenolides
464
Addition of indole to fervenulin-3-one and its 4-N-oxide
465-466
New synthesis of pyrrolo[1,2-a] pyrrole derivatives
466-467
Homolytic alkylation of 2-methylquinoline by benzodioxolane and benzodioxane
467-468
Reaction of 4-methoxy(methylthio)-5-amino-6-mercaptopyrimidines with ω, ω-
dibromoacetophenone
468-469
New synthesis of 1-vinyl- and 1,3-divinyluracils
469-470
Reaction of 8-bromo-3-methylxanthine with amines in DMFA
470
Analogues of prostacyclin (PGI2) modified in the 2-oxabicyclo[3.3.0]octane fragment (review)
471-485
Reaction of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines with boron trifluoride etherate
in methanol
485-489
Formation of 2-phenyl-γ-benzpyrone (flavone) in nucleophilic thiylation of 1-(2′-hydroxyphenyl)-3-
phenylprop-1-yn-1-one by potassium p-thiocresolate
490-491

Synthesis of tetra(1,4-dithiacyclohexene)porphyrazine and its metal complexes
492-494
Asymmetrical alkylation of 1-[(s)-α-phenylethyl]-azethidinone-2
495-499
Azo coupling and aminomethylation of 2,5-diphenylpyrrole and its derivatives
499-503
Kinetics of the cycloaddition of maleic anhydride to arylaminomethylene derivatives of 3-methyl-1-
phenylpyrazole-5-thione
503-507
Recyclization of 1-amino-3.5-diaryl-2.6,6-tricyanocyclohexa-1,3,-dienes to pyridine derivatives
508-512
Electrochemical reduction of bipyridinium salts
513-516
Preparation and properties of betaines of 4-pyridyl-3,4-dihydropyridine-2-thiones(1H)
517-521
Acid deuterium exchange in methoxyquinolines and their N-oxides
522-529
α-phenylisocinchomeronic and 4-azafluorenone 3-carboxylic acids
529-532
Reaction of 1-methyluracil with phenylbenzhydrazonoyl chloride
532-538
Reaction of diaroylethylenes with ortho-phenylenediamine and its derivatives
538-542
Nitroazines. 5. Use of the japp-klingemann reaction for the synthesis of nitrotriazines
543-546
Reaction of 3,4-diaminofurazan with carbonyl compounds and their metal complexes
546-549
Crown ethers bound to sulfanilamide preparations
549-551
2-Hydroxymethylamino-4-thiazolinone. Confirmation and chelate formation
551-557
Acid deuterium exchange in benzazoles
557-564
Benzazolin-2-thiones in the michael reaction. 2. Reaction of benzothiazolin- and benzoxazolin-2-
thiones with acrylonitrile, acrylamide, and methyl acrylate in the presence of basic catalysts
564-567
Heterocyclization of compounds containing diazo and cyano groups. 2. Synthesis and
recyclization of 4-substituted 5-amino-1,2,3-thiadiazoles
567-571
Divinyl sulfide. 15. Cycloaddition of divinyl sulfide and its 2-methyl derivatives to thiourea and N-
monoalkyl- and N-monoarylthioureas
572-577
Mass-spectrometric study of benzopyridosilaazepines and -azepinones
577-580
Electrochemical preparation of pyridinyl radicals, substituted by electron acceptors in the β-
position
581-582
Synthesis of 4-aryl-5-thioxo-4,5-dihydroindeno[1,2-b]pyridines
582
Reaction of O-aryl-N-di(2-chloroethyl)amidoguanidyl phosphates with acetoacetic ester
583
Pyrimidinetetrasulfonic acid
584
Addition of trichloroacetonitrile to vinyltetrazoles
585
Effect of the acid-base properties of heteroaromatic compounds on their electrophilic substitution
reactions (review)

587-608
Condensed heterocycles. 45. Synthesis and structures of imines of 2-selenolo-3-benzo [b]
furanaldehyde and 3-selenolo-2-benzo [b] furanaldehyde and their derivatives
608-612
Condensed heterocycles. 46. Crystal structure of 3-mercapto-2-benzo[b]-furylidene-(p-
methylphenyl) amine
613-616
Mass-spectrometric behavior of benzo-substituted dibenzo-18-crown-6 ethers
616-619
Catalytic properties of rhodium hydridocarbonyl trithienyl-phosphine complexes in the
homogeneous hydrogenation and isomerization of unsaturated compounds
620-624
Reactions of aromatic and heteroaromatic compounds carrying electron-acceptor substituents.
26. Acylaminomethylation of 2-acylthiophenes, 2-thiophenecarboxylic acid, and its esters
625-629
Improved method for synthesis of substituted tetraphenylporphins
629-632
Tautomerism of azine derivatives. 11.14N-NMR and17O-NMR investigation of intrachelate
tautomerism of acylmethylpyridines
633-639
Condensation of 4-azafluorene with γ-butylene glycol and glycerin
640-642
Synthesis starting from 3-methyl-2-phenyl-5-(3-methyl-2-phenyl-3,4-dehydropiperidyl-6)pyridine.
2-phenyldinicotinic and 4-azafluorenone-2-carboxylic acids
642-646
Synthesis of methyl esters of 6-dialkylamino-2-(carbethoxy)-methylthiopyrimidine-4-carboxylic
acids
647-650
Synthesis of 2-aryl- and 2-hetaryloxazoles from the oxazolines and oxazolidines
650-653
Synthesis, structure, and spectral properties of some bioxazoles
654-663
Course of bromination of thiazole and 2-methylthiazole
663-666
Synthesis of macrocyclic compounds containing thiophene and thiazole nuclei
666-669
Synthesis and structure of methyl-substituted 1,3-Dioxa-2-Silacylohexanes
670-675
Synthesis of dibenzofuran and its nitro-substituted derivatives
676
Furo[2,3-c]pyrylium — A new heteroaromatic system
677
Alkylation of furan and thiophene with tert-butanol in the presence of the strongly acid cation
exchanger amberlyst 15
678-679
New method of isolating N-substituted 3-aminomethylenethiol-4-en-2-ones
679
Synthesis of bis(o-xylylenedithio)tetrathiafulvalene
680
Reactions of copper and silver acetylides with hydrazone bromides — A new route to 1,3,5-
substituted pyrazoles
681
New synthesisof imidazo[4,5-f]quinoline derivatives
682
Reaction of 2-aminobenzothiazoles with glycidyl phenyl ether
683
Ion-radical and redox transformations of cyclic acetals (review)

685-695
Effect of the heteroatom of a benzo[b]-annelated five-membered heteroring on the structure and
properties of an aminovinyl ketone fragment included in the ring
695-699
Condensation of 3-methyl-3-buten-1-ol with some ketones
700-702
Pyrylocyanines. 22. Styrils derived from methoxy-substituted 4-methylflavylium salts
703-707
Reactivity of cyclic sulfides in reactions with quinones
707-710
Preparation of spiroaziridinefluorene, spiroindoxyl-fluorene, and Β-aminopropionic acid ester with
a 4-azafluorene fragment
710-713
Mechanism of the Fischer indole synthesis. Quantum-chemical interpretation of the
rearrangement of substituted cyclohexanone arylhydrazones to tetrahydrocarbazoles
713-722
Thermal heterocyclization of methyl aryl ketazines. 2. Reactions of the tautomeric enehydrazine
form
723-732
Research on imidazo[1,2-a]benzimidazole derivatives. 22. Synthesis of 2,3-dihydroimidazo[1,2-
a]benzimidazoles starting from 2-imino-3-(2-hydroxyethyl)benzimidazolines
732-739
Heterocyclization of compounds containing diazo and cyano groups. 3. Two pathways in the
cyclization of 2-diazo-2-cyanoacetic acid derivatives under the influence of bases
740-745
Reactions of 4-nitro-1,2,3-triazole with alkylating agents and compounds with activated multiple
bonds
745-748
Chemistry of heterocyclic N-oxides and related compounds 13. Acylamination of pyridine N-oxide
by aniline, p-anisidine, and their N-p-tosyl derivatives
749-751
Synthesis of substituted 2-pyridones and 4-aza-3-fluoridones
751-754
Condensation of N-(piperidylidene-4)arylamines with acetylenedicarboxylic esters
755-758
Synthesis and luminescence of benzo[f]quinoline derivatives with fused alicyclic rings
759-762
Quantitative determination of the electronic effects of 3- and 4-pyridazinyl groups from NMR
spectral data for isomeric aminophenyl- and phenylpyridazines
763-770
Synthesis of condensed pyrazines from N-substituted amino-o-quinones and ethylenediamine
771-774
Chemical properties of ylidene derivatives of azines. 3. Synthesis and reactions of ylidene
derivatives of halopyrimidines
774-779
Free radicals in the perimidine series. 2-Tert-butylperimidyl radicals
780-782
Fluorine-containing azoles. 4. 2-Perfluoropolyoxaalkyl-substituted perimidines
783-785
Electronic structure and mass spectra of substituted hexahydro-1,3,5-triazine-2-thiones
786-790
Condensed imidazo-1,2,4-azines. 14. Synthesis and reactivity of 3-chlorine-substituted
imidazo[1,2-b]-1,2,4-triazines
791-795
Reaction of 2-alkylaminobenzothiazoles with acrylic acid
795-799

Investigation of nitrogen- and sulfur-containing heterocycles. 44. New heterocyclic systems.
Derivatives of imidazolidino-[3,2-f]pyrido[2,3-b]-and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-
thiazines. Synthesis and structure
800-805
Synthesis of bromo-substituted 2-formylpyrroles
806-807
Recyclization of 4-cyanobenzo[c]pyrylium salts upon reaction with hydrazine
807
1,1′Azobenzimidazoles
808
Synthesis of benzopyrano[3,4-c]-and benzothiopyrano[3,4-c]-[2,1,3]selenadiazol-4-ones
809
Structures synthesis, and properties of 1,2,3-thiadiazoles (review)
811-827
Synthesis of acetylenic derivatives of 1,4-dioxane
828-829
Homolytic telomerization of vinyltrimethylsilane with 5,5-dimethyl-1,3-dioxane
830-834
Mechanism of amination of aziridines and oxiranes. 3. Quantum-chemical investigation of the
effects of specific solvation
834-839
Mechanism of amination of aziridines and oxiranes. 4. Quantum-chemical investigation of the
effect of the polar solvent
839-844
Crystal and molecular structure of 6-methyl-2,7-diphenyl-1,3-diformylindolizine
844-848
Mass-spectrometric behavior of isatin oximes
848-851
Reaction of 2,3,3-trimethyl-3H-indole salts with acrylamide. Synthesis of 1,2,3,4,10,10a-
hexahydropyrimido[1,2-a]indol-2-one derivatives
852-855
Formation of 2-imidazoline derivatives in the reaction of 1,2-hydroxyamino oximes with phenyl-
and methylglyoxal
856-860
The NMR spectra of cyclic nitrones. 3. Effect of protonation and a hydrogen bond on the chemical
shifts in the13c NMR spectra of derivatives of 3-imidazoline 3-oxide
861-868
Organolithium and organosodium compounds of n-substituted 2-alkylbenzimidazoles
868-872
Chemistry of 2-hetarylbenimidazoles. 7. Transformations of trans-1-methyl-2-[Β-(2′-furyl)vinyl]
benzimidazole
872-875
Derivatives of imidazo[4,5-e]-2,1-benzisoxazole and synthesis of substituted benzimidazoles from
them
876-879
Tetrazoles. 21. Reaction of benzonitrile with salts of hydrazoic acid
880-883
Reaction of salts of nitroaminotetrazoles with alkyl iodides
883-886
Twofold reactivity of 1,2-disubstituted dihydro-n-heteroaromatic systems. 10. Synthesis and
aromatization of ferrocene-containing hantzsch esters
886-893
Synthesis and spectral characteristics of acenaphthene derivatives of benzo[f]quinoline
894-898
Three-dimensional structures of stereoisomers of 2-phenyl-4-ethynyldecahydro-4-quinolinol
899-902

Investigation of the acid- and base-induced transformations of nitrogen heterocycles by NMR
spectroscopy. 1. Substituted pyridines and pyrimidines
903-908
Acetals of lactams and acid amides. 47. Investigation of the behavior of substituted 6-(Β-
dimethylamino) vinyl-4-pyrimidinones in acidic media. Synthesis of 3-cyano-4-anilino-5-formyl-2-
pyridone and 3-chloro-4-cyanobenzo[b] [1,6]-naphthyridine
909-914
Synthesis and catalytic oxidation of 2,5-dimethylpyrazine
915-917
3-Aryl-1,2-dihydroquinoxalines
918-922
Reaction of 7-acylmethyl-8-bromo-3-methylxanthines with formamide
923-925
Reaction of 3-nitro- and 3,5-dinitro-derivatives of 2-pyridone with hydrazine hydrate
926
Formation of pyrimido[1,2-a]benzimidazoles in reaction of 1,2-diaminobenzimidazole with
chalcones
927
Direct introduction of azoloazine residues into resorcinol
928
1,2,3-Seleniumdiazolo[4,5-d]pyrimidine-5,7(4h,6h)dione — A new condensed hetero system
929
Synthesis and properties of 1,6-dioxaspiro[4.4]nonane and its derivatives (review)
931-943
Synthesis and three-dimensional structures of 2-(2-furyl)-acrylonitriles
943-945
Conformations of isomeric 2,3,4-trisubstituted tetrahydrothiophenes
945-950
Synthesis and structure of derivatives of 7-aminobenzo[b]thiophene
951-953
13C and 15N NMR spectra of 2,3-substituted 2H-azirines
953-955
13C NMR spectra of N-substituted carbazoles. Transmission of the electronic effects of
substituents through the nitrogen atom to the carbazole ring
956-959
Nitration of tetrabenzoporphins
960-964
Electrochemical behavior of metal complexes of derivatives of dibenzo[c,j]dipyrazolo[3,4-f 3′,4′-
m][1,2,5,8,9,12]-hexaazacyclotetradecynes on a pyrographite electrode
965-970
Synthesis and structure of 1-benzoyl-2,5-dimethyl- and 1,2,5-trimethyl-4-arylpiperideins
970-976
Synthesis of stereoisomeric alkyl- and phenyl-substituted 5-cyanopiperidine-3,4-diols
976-980
Arylation, alkylation, reduction, and pyrolysis of 1h-1-methylindeno[2,1-b]pyridine
980-982
Investigation of stereoisomers of 4-alkenyl-trans-decahydroquinol-4-ols in mixtures by the method
of reaction chromato-mass spectrometry
983-985
Naphthyridines in hetarylation reactions
986-990
Synthesis and properties of derivatives of 1,4-dihydropyrimidine-5-carboxylic acid
990-994
Synthesis and mesomorphic properties of aryl 5-alkyl-(and alkoxy) pyrimidine-2-carboxylates
994-1001
Synthesis and spectral examination of the position of tautomeric equilibrium in 2-thioxo-4-
quinazolone

1001-1003
Diazabicycloalkanes with nitrogen atoms in nodal positions. 13. Reactions of benzo[b]-1,4-
diazabicyclo[2.2.2]octene with electrophiles
1004-1009
Cyclotrimerization of thiocyanic acid in organic solvents
1009-1010
Stereoisomerism in macrocyclic bis(piperidones)
1011-1016
Investigation of substituted 1,3-oxazolidines using 1H and 13C NMR spectroscopy
1017-1022
Synthesis and spectral and luminescent properties of 4-(5-aryloxazoyl-2)benzoic acids and their
derivatives
1022-1025
2-(4-Cyanophenyl)-5-aryloxazoles
1026-1027
Hetarylethylene derivatives of 2,5-diaryloxazoles and 2,5-diarloxadiazoles and their luminescence
and scintillation properties
1028-1031
Polynuclear heterocyclic compounds based on the adduct of o-cinnamoylbenzoic acid and
cyclohexanone
1031-1035
Optical and electrophysical properties of metal complexes of tetra(1,4-
dithiacyclohexeno)porphyrazine
1036-1039
Synthesis, structure, and transformations of 1-aza-3-oxa-7-thiabicyclo[3.4.0]nonan-2-one
1039-1044
Efficient method for the hydrolysis of 4-chlorotetrahydropyrans
1045
New reaction of malononitrile and arylidene- and 1-arylethylidenemalononitriles
1046-1047
1H-isobenzofurylium (phthalylium) salts (a review)
1049-1058
Mass spectrometric decomposition of Β-phenyloxiranecarboxylic esters
1058-1063
Photochemistry of unsaturated lactones. 2. Photoannelation of 2-acetyl-3,4,4-trimethyl-2-buten-4-
olide by terminal alkynes
1063-1068
The chemistry of 1,5-diketone derivatives. 2. Preparation of 2-hydroxy-1,3,5-triphenyl-1,5-
pentanedione and some heterocycle derivatives
1068-1071
2,2-Dimethyl-5-(5-r-2-furfurylidene)-1,3-dioxan-4,6-diones. 1. Synthesis, properties, and structure
1072-1075
Isomerization of 5-acyl-6-halo-1,6-diazabicyclo[3.1.0]hexanes, a case of inversion rather than 1,2-
acyl migration
1076-1079
Mass spectrometric study of ring-chain tautomers of 3-amino(hydroxy)pyrazolidines
1080-1083
Nitrosochlorination reaction of substituted imidazolin-2-ones
1084-1087
Mass-spectrometric study of the cyclization of diazo compounds. 9. 2-Diazo-2-cyanoacetamides
1087-1093
Synthesis and conversions of 2-aryl derivatives of s-triazolo[4,3-a]pyrimidine
1093-1096
Synthesis of acid-base transformations of 3-aroyl-6-methyl-2-oxopyridines
1097-1099
Synthesis and acid-base transformations of (4-styrylpyridinio)-alkanesulfonates
1099-1104

Acid hydrolysis of N-methyl derivatives of 4-phenyl-5-oxo-4,5-dehydroindeno[1,2-b]pyridine
1104-1107
1,2,5-Trimethyl-4-(p-hydroxyaryl)-δ3-tetrahydropyridines and their spatial structure
1107-1110
Synthesis of 1,5-methano-2-benzazocines from 3-hydroxy-1,3-dimethyl-6-phenyl-4-piperidone
1110-1113
Alkylation of quindoline and quindoline-11-carboxylic acid
1114-1117
Reaction of azinium cations. 5. Addition of water and methanol to 1,4-diazinium cations in the
presence of bases. equilibrium constants and PMR spectra of the mono- and diadducts
1118-1125
Heterocyclic analogs of pleiadiene. 59. Reaction of 1-acetonyl- and 1-phenacylperimidinium salts
with hydrazine and ammonium acetate
1126-1131
Reaction of vinyl ethers of the pyridine series with bromine and iodine
1132-1134
Structure of the alkaline salts of 2-phenyl- and 2-p-methoxyphenylimino-4-thiazolidinones
1134-1139
Synthesis and spectrometric investigation of the thioamides of thiazole- and benzothiazole-2-
carboxylic acids
1139-1144
Synthesis of substituted 1,3-thiazinoazoles
1145-1148
Synthesis and mass-spectrometric study of 2-amino- and 2-chloro-5-aryl-1,3,4-thiadiazoles
1148-1152
10-Alkenylphenothiazines. 2. Synthesis and mechanism of acidic hydrolysis of cis- and trans-10-
2-phenylvinyl)phenothiazines
1152-1157
Photodimerization of 2,6-diphenyl-4-(5-bromofuryl-2)-pyrylium and pyridinium perchlorates
1158
Formation of heterospirans, containing a γ-lactone ring, upon treatment of dialkylacetylcarbinols
with malonic ester
1159
Novel polyfunctional spiroheterocyclics based on acetylenic hydroxyacids
1160
Synthesis of benzothiazepines (review)
1161-1170
Reaction of furan compounds with hydrogen sulfide and aspects of its application
1170-1173
Synthesis and three-dimensional structure of 4-hydroxy-4-methyl-3-chloro-6-
alkyltetrahydropyrans
1174-1177
Alkylation of benzo- and dibenzocrown ethers by various alcohols
1178-1185
Synthesis and properties of bis(vinylenedithio)- and bis(dimethylvinylenedithio)tetrathiafulvalenes
1186-1189
5-Substituted 2-methyl- and 2-methyleneindolines
1189-1192
Heterogenous-catalytic synthesis of 2,3-dihydroselenophene and 3,4-dihydro-2H-selenopyran
1193-1195
Benzindoles. 24. Reduction of nitro-2,3-dimethyl[4,5]- and nitro-2,3-dimethyl[6,7]benzindoles
1195-1198
Synthesis of 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones
1198-1202
Mass spectra of piperidine dicarboxylic acids and their esters
1203-1207

Conformation of the piperidine ring in isomeric 1,2,5-trimethyl-4-phenyl(triorganosilyl)piperidin-4-
ols from the PMR spectra
1208-1213
The 13C NMR spectra, isomerism, and conformational analysis of substituted piperidin-4-ones
1214-1225
Dual type of reactivity op 1,2-disubstituted dihydro-N-heteroaromatic systems. 11. Aromatization
of N-sulfonyl-1,2-dihydroquinolines and isoquinolines containing an α-indolyl or pyrrolyl
substituent
1226-1228
Reaction of N-arylidene-2-naphthylamines with allylacetone
1229-1231
Synthesis of substituted 2- and 4-hydroxyaminopyrimidines
1232-1236
6-Aminopyrimidine 1-oxides. Acylation and methylation
1236-1241
Reactions of azinium cations. 6. N(1)-alkyl-1,2,4-triazinium salts. Reactions with indoles — The
first case of the double addition of nucleophiles to a triazine ring
1242-1249
Nitroazines. 6. Direct introduction of indole residues into 6-nitroazolo[1,5-a]pyrimidines
1250-1255
Polarographic examination of 5-aryl-2-(2-thienyl)-oxazoles and -1,3,4-oxadiazoles
1255-1258
Conversion of 2-amino-5-R-phenyl-1,3,4-oxadiazoles into 3-R-phenyl-5-alkoxy-1,2,4-triazoles
1258-1261
Synthesis of arylazoles and their luminescent properties
1262-1266
1,4-Dihydrobenzothieno[3,2-b]pyridine-5,5-dioxides
1267-1271
Photochemical rearrangement of 4,5-ethylenedithio-1,3-dithiol-2-thione to 4,5-ethylenedithio-1,2-
dithiol-3-thione
1272
Stereospecificity of direct 13C-1H spin-spin coupling constants of vinylpyridines
1273-1274
Photochromic fulgides of the indole series
1274
Replacement of bromine by hydrogen in bromo derivatives of tetrahydropyrimido[4,5-
b][1,4]benzthiazine under conditions of electron-impact ionization
1275-1276
1-Tellurachromylium perchlorate
1276
Phosphorylated pyridines and their benzo-homologs (review)
1277-1291
Alkylation of Β-dicarbonyl compounds by 1,2,3-trihalopropanes as a method for the preparation of
Β-substituted furans
1291-1295
Pyrylocyanines. 23. 2-Pyrylocarbocyanines with substituents in hetero residues
1295-1300
Thermal hydrothiolysis of di(2-thienyl)sulfide in the gaseous and liquid phase
1301-1306
Structure of the intermediate particles in the radiolysis of indolinespiropyran
1307-1310
Indole derivatives. 128. Synthesis and properties of 5,6- and 4,5-ethylenedioxyindoles
1311-1315
Electronic and photoelectron spectra of amino-1-methylnitropyrazoles and their quantum-
chemical interpretation
1316-1321

Reactions of heterocyclic cations with n-containing nucleophiles. 15. Reaction of 2,6-
diphenylpyrylium perchlorate with semi- and thiosemicarbazides
1322-1326
Asymmetric synthesis and absolute configuration of 1-α-phenylethyl-2,5-dimethyl-4-piperidone
isomers
1327-1333
Synthesis of 2,3-polymethylenepyridines from 3-aminoacrolein and cyclic ketones
1334-1336
N-glycosides. 7. Synthesis of 4,5′-anhydro-3-(2′,2′-O-isopropylidene-Β-D-ribofuranosyl)-4-
hydroxyhexahydropyrimidine-2-thiones
1336-1341
Diazabicycloalkanes with nitrogen atoms in nodal positions. 14. Synthesis of dibenzo[1′,2′-b,e]-
1,4-diazabicyclo[2.2.2]octadienes containing a tertiary amino group in the aromatic ring
1342-1345
α-Dimethylaminomethylene derivatives of succinimide and glutarimide in the Fischer reaction
1345-1349
Cyclizations with hydrazones of nitroglyoxalic acid. Synthesis and structure of tetrazolo[5,1-
b][1,2,4]triazines
1350-1354
Synthesis and properties of 1,4,9-triazaspiro[5,5]undecane and 3,7,11-triazaspiro[5,6]dodecane
1354-1357
Acid-base interaction of tetraazaporphin in organic solvents
1358-1362
Unusual reaction between 6H-6-oxo-5-haloanthra[1,9-cd]-isoxazoles and quinoline
1363-1366
Formation of derivatives of thiazoline by the reaction of thiourea with 2-bromo-3-aminopropionic
acid
1367-1369
Reaction of 2-thiopyrrolidones with monochloroacetic acid and its methyl ester
1370-1372
Condensed heterocyclic compounds containing a thiazole ring. 12. Derivatives of thiazolo[3,4-
b][1,2,4]triazine
1373-1376

OXO- AND THIOXO-I,3-THIAZINES (REVIEW)

G. A. Mironova, V. N. Kuklin, UDC 547.869.1(047)
E. N. Kirillova, and B. A. Ivin

Literature reports on the methods of synthesis, chemical properties, and tauto-
merism of oxo- and thioxo-l,3-thiazines have been summarized.

1,3-Thiazines, interest in which has increased steadily over the last decade, remain
relatively little-known compounds in comparison with pyrimidines and 1,3-oxazines. It has
nevertheless been established that a number of oxo- and thioxo-l,3-thiazines possess useful
properties, in particular high biological activity. The object of the present review is to
summarize the available information on the synthesis, chemical properties, and tautomerism
of 2-, 4-, and 6-oxo-l,3-thiazines, their sulfur analogs, and other derivatives.
It is preferable to divide the methods of preparation of these compounds into the four
general methods of synthesis of six-membered heterocycles, depending on the number of atoms
present in the fragments destined to form the ring [i]. Methods of synthesis which involve
modifications of compounds already containing the 1,3-tiazine ring will be considered in
the section devoted to the chemical properties of these compounds.

N C~ C N'~C"c NIC'C N/C"c N"C"c
] I I i I J [ I
Cxs/C C..S C C S C C"S C C S ''C
type A type B
(8+0) (s+x)

N/C'C N C--.C N/C C N C"C
I r l f i f I
C C- C C C S C C
~S S" r
type C type D
(4+~) (o+:0

(6 + O) CONDENSATION
Reactions of this type have been relatively little used for the synthesis of 2-, 4-,
and 6-oxo-l,3-thiazines. However, many reactions of types B-D occur via intermediates simi-
lar to those formed in type A reactions. The closure of six-membered fragments to form the
ring usually occurs by nucleophilic addition of nitrogen or sulfur to the carbonyl carbon
atom or the more reactive carbon of the protonated carbonyl group.
There have been no reports in the literature on the use of reactions of this type for
the synthesis of 2-oxo-l,3-thiazines, but there are a few examples of their use for the pre-
paration of 4- and 6-oxo-l,3-thiazines [2-5]. Condensation of the 2-thiocyanatocarbonyl
chlorides (I) in the presence of dry hydrogen chloride gives substituted 4-oxo-l,3-thiazines
(II) [2, 3]. The reaction must be carried out at O=C as a result of the high reactivity of
the carbonyl carbon. The reaction is assumed to proceed as follows [4]:

R ~. .SeN 2HCl ~i.. S>, ICI Cl- R S. ~.CI]c]" l~ - s. cl
"cii ~'~ ,cl[ ..'(:I ~- ....... |'--~,- I
c el / 2 c ~INH~ ! 9 R~/J" ./

II
1 RI=R2 II.CH:~: R I .R2=(_ r

Leningrad Institute for Pharmaceutical Chemistry, Leningrad 197022. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 3-16, January, 1986. Original article
submitted May 2, 1984.

0009-3122/86/2201-0001512.50 9 1986 Plenum Publishing Corporation 1

The condensation of the 3-thioureidobutyrate (ili) in methanolic sodium methoxide at 80~
has been used to obtain 6-oxo-l,3-thiazines [5]. The unusual nucleophilic attack on the car-
bonyl carbon by sulfur is explained by the authors [5] as being due to the formation of the
anion (IV) in an alkaline medium. In this case, the electron density at the sulfur atom must
be increased to a greater extent than that at the amino-group, while simultaneously the posi-
tive charge on the carbonyl carbon is reduced by conjugation. These factors result in the
preferential formation of the C-S bond.

0 O CH~
" r ~i I
CH3"C~CH't:--OC2H~'
I NaOCli4]_
I CH 3,
"r "
CH-I.-OC.~H~ Na+ N' "b~
,.
9 t I ---- [I /
HN..C.NH 2 N:. /~2 ,-b,,
9" - ~{'. ] NH~ 'S" '~O
II S' NH 2 J '

II[ IV

A general method for the synthesis of 2,4-dioxo-l,3-thiazines and their thio-analogs,
which permits the introduction of substituents into the 5- and 6-positions, is based on in-
tramolecular nucleophilic attack on the carbonyl group or the more reactive corresponding
enol ether by the sulfur atom in acyldithiourethanes [i, 6]. For example, acetoacetyldi-
thiourethane slowly cyclizes to2-ethylthio-4-oxo-6-methyl-l,3-thiazine on treatment with cold
concentrated sulfuric acid [6]. Reaction of the acyl chloride (V) with the S-ethyldithio-
carbamate (VI) affords the unstable acryloyldithiourethane (VII), which on cyclization gives
2-ethylthio-4-oxo-5-methyl-l,3-thiazine (VIII) [6].
O O

il + ml~cssc~H~ - - - - | li I , I
9 - [ 4'~11 ~c" [
.c Ic.~o s" "sc,,z~ ] s%.~
V VI L. " Vll / Vlll

The isomerization of 2-thio-4-oxo-6-methyl-l,3-oxazine to the more stable 2,4-dioxo-l,
3-thiazine on treatment with concentrated sulfuric acid [7] may be regarded as a reaction of
this type.

(5 + i) CONDENSATION
Type B reactions comprize the condensation of five- and one-membered fragments, in the
course of which bonds are formed between the heteroatoms and a carbon atom, or between two
carbon atoms. The five-membered fragment is frequently an acyl isothiocyanate [8, 9], an
unsaturated acid [10-13], or an acyldithiourethane, which condense readily with amines,
thiols [8], aromatic carboxylic acid derivatives [11-13], or orthoesters [i, 14]. The reac-
tion is normally carried out in aprotic nonPolar solvents in the presence of acetic anhydride
[14] or polyphosphate ester [11-13]. This type of condensation is not used for the prepara-
tion of 2-oxo-l,3-thiazines. An example of its use for the synthesis of 4-oxo-l,3-thiazines
is the reaction of 3-chloro-3-phenylpropenoyl isothiocyanate (IX) with amines to give the
substituted thioureas (X), which then cyclize to 2-alkylamino-4-oxo-l,3-thiazines (XI) [8].

/0 HNRIR 2 .~0
C H--C=CH C / . . . C H--C~--CH-C~"
. . . . . . . |fN I
6 5 CII "NCS 6 ,5 CII *'NHCSNR R ~ R1RZN / CsH5
IX X gI
R~ =H,Alk,Ar.; R2~AIk,Ar

The condensation of the 3-acylamino-2-butenoate (XII) with 2,4-bis(4-methoxyphenyl)-l,
3,2,4-dithiaphosphetane 2,4-disulfide (XIII) has been used to prepare the 2-substituted 6-
thio-4-methyl-l,3-thiazines (XIV) [I0]. In the first step, the 3-(2-thioacylamino)-2-buten-
oate (Xlla) is formed, and on boiling in xylene this cyclizes by nucleophilic addition of
the sulfur to the carbonyl carbon. Simultaneously, the oxygen atom at C(6) is replaced b y
sulfur.

S
jS\ll
P-CH~OC.H~ - - P ~ ~P--C.H..-OCI.I.-p
" " - II--S . . . . cH~C:_: c
C113~C ~:CII-COOC21I~, S 3"111 - / t~C--OC2H s
RCONH" - ................................. NX\

XII
R'\
C--SI~

Xlla
B=Clia,CH(CH s)z,c(cll~) ~ coil s

Clt 3
XIY

This type of condensation is used rather more extensively for the synthesis of 2~4-di-
oxo-l,3-thiazines and their sulfur analogs, Condensation of the acyldithiourethanes (XV),
which contain a reactive methylene group, with the orthoesters (XVI) gives the intermediate
N-B-ethoxyacryloyldithiourethanes (SVII), which cyclize in the presence of acetic anhydride
to the corresponding 1,3-thiazines (SVIII) [i, 14]. Triethyl orthoformate is the most re-
active in the reaction. It appears that the use of triethyl orthoacetate or orthopropion-
ate increases the electron density at the electrophilic site, thus hindering the formation
of the C--S bond.

o o

~ OHC~.' ~ ~ s 2 9 1~:~ 'S""sC~H5
XV! XVll . XVIiI
R1 ~CN,COCH~; R2=H,CHs,CaH~.

The acyldithiourethanes (XIX), obtained by reacting the isothiocyanate (IX) with thiols,
cyclize to 2-alkylthio-4-oxo-6-phenyl-l,3-thiazines (XX) by intramolecular nucleophilic re-
placement of halogen by sulfur [8]. Reaction of the isothiocyanate (IX) with sodium hydro-
sulfide occurs via the unstable dithiocarbamate (XXI) to give 2-thio-4-oxo-6-phenyl-l,3-
thiazine (XXII) [8]. This compound (XXII) has previously been obtained from sodium hydro-
sulfide and 3-phenylpropionyl isocyanate [9].

0 0

HC I C ' - N t !

,>" co,,;,,
lX XT~ XX

Cl ...?N+ ~ ,C~
~S Coli 8
C6H5
x ~ r

R=C2H~,C3H?,CoHsCH 2

The condensation of substituted acrylamides (XXIII) with aromatic carboxylic acids has
been the subject of several studies [11-13]. Varying the reaction conditions and the reac-
tants affords differing reaction products. When benzoic acid or its anhydride i~ used, the
principal cyclization products are 6-thioxo-l,3-oxazines (XXIV), which isomerize quantita-
tively on heating in protic solvents to give the 6-oxo-l,3-thiazines (XXV) [12. The driving
force in this reaction is the greater stability of the 1,3-thiazine ring in comparison with
the 1,3-oxazine ring [7, 12]. It is noteworthy that condensation only occurs in the presence
of polyphosphate ester.

i 0 ~ir ~CII
NC NC II
(
r h c o , ~: l ~
i " R i '
"'l-
['.. "~'I ~'-H~
PhCOC|N" .CC
[]. . "INH
. z. . " ". ( p('!H'"5"
h ( T O ) 2 0. . . . . . (I IIN .E',)II- - .] "~" tlN
tlSCS ~ ' t'h " "' II~CS" :';H CII(.i5 .~ "" (I |eh 0 "" "'S Ph
~Xll[ X.XIV ~V
R:,;CH,(;ONtl 2

(4 + 2) CONDENSATION
Type C reactions, which comprize the condensation of a four-membered unit (8-diimines,
8-iminopropionitriles, isothiocyanates, or thioacylketenes) with a two-membered unit contain-
ing a multiple bond, are quite widely used for the synthesis of oxo- and thioxo-l,3-thiazines.

s

1 ~ C .. /NHAr CS 2 ..-"
1 C ~NHAr \

~'\,, S

N' 'S

XXVIIItc ~ d

XXVI--XXVIII a Ar=p-OCH~C~H~, b, e Ar=C~H~, d Ar=p-CI-tsC~H~; a-d R~=C~H~;
a,e~d R~=C~I-t~, b R~=CH~

The condensation of 8-diimines [15] or ~-iminonitriles [16] with carbon disulfide has
been employed to obtain 2-thioxo-l,3-thiazines. In the case of the diimine (XXVI), nucleo-
philic addition of the diimine to the CS2 carbon first takes place. The subsequent course
of the reaction depends on the electronic effects of the substituents in (XXVI), Electron-
donating substituents R2 at the electrophilic center hinder the formation of the C--S bond,
and in this case the reaction products are the pyrimidines (XXVII). The absence of a sub-
stituent with a +M effect in the benzene ring attached to nitrogen results in a decrease in
the yields of pyrimidines (XXVlI), the thiazines (XXVlII) being formed in yields which are
largely independent of the type of substituent present [15].
The activating effect of the cyano-group in ~-imino-B-arylpropionitriles (XXIX) together
with basic catalysis favor the addition of sulfur to the methylene group. When the reaction
is carried out in dimethylformamide at 2~ addition of a further molecule of sulfur occurs
with the formation of 5-substituted-2,6-dioxo-4-aryl-l,3-thiazlnes (XXX) [16].

H
I
NH N.~ R .
.--~-'CH~CU
X~3X US2'~-CsHI
'ON"r-- E ' ~ S~

s
R=Ar~M~; RI=CN,CO2CH~ XXX

4-Oxo-l,3-thiazines are most frequently obtained by (4 + 2)-cycloaddition. Usually,
thioacyl isocyanates [17, 18] or isocyanates [18-20] are condensed with alkenes [17], al-
kynes [17], ketenimines [19], or phosphacumulidenes [18]. The reactions are normally carried
out in nonpolar aprotic solvents, the temperature used being dependent on the reactivity of
the reactants. The condensation of thiobenzoyl isocyanate (XEXI) with nucleophilic alkenes
and alkynes [17] has received especially close attention. The rate of this reaction is great-
er with alkynes than alkenes, and increases as the electron-donor properties of the substitu-
ents at the multiple bond of the nucleophile are increased.
O
CsHs__C_N~C= 0 NaCH(CN)C%C2H s , li 9 i ~o • N
[r - ~" C'H'--C-:IO~C--CH'C~ --~" II II

-~.~c
o " - ~R ~ . . ~-.~, o ~ . o

N N

cs. ~ "s ~ c6~ ~ "s" "c6H5 c~H~ "s" "N(C2Rs)~

The lower reactivity of the ketenimines (EXXII) in t h e i r reactions with isothiocyanates
(XXXIII) requires the use of more severe reaction conditions [9], The condensation is sen-
sitive to the electronic effects of the substituents. The yield of the 1,3-thiazinethione
(XXXIV) decreases as the electron density of the isothiocyanate (XXXIII) is increased, and
when electron-acceptor substituents are introduced into the keteneimines (XXXII).

S t~ -- . ~ 1
, II =
RIR=--~-C=C~.NR:s + ]~ 2,NC--NC8 CsHsCH
3- R42N/ ~ ' S ~ N R 3

X]ODI 13[XIII XX~V.

XXXIV a,b I~=R2=CHs, e RI=R~=C6Hs; a,b Ra=p.CH3CsH4,c RS=p.OCH3CsH4; a
R~=C~H~, b,c R4=i-CaHr

The cycloaddition of the isothiQcyanates (XXXV) to the phosphacumylidenes (XXXVI) af-
fords products with a zwitterionic structure (XXXVII) [18] in yields which are highly depend-
ent on steric factors (as the volume of R is increased, the yield of the thiazinethione
(XXXVII) decreases).

x
(Ph)3P
S
R--C--N--C~-~.g + (Ph)3--P--C=C=C-.~X
II
S S R
XXXV XXX'~ ]OtXVll
R=N(A.I.k)2; X=O,S,Nph

The four-membered unit can be thioacylketene (XXXVIII), which reacts with diisopropyl-
carbodiimide [ 2 1 ] .

o

f (Me)2HC% N ~ , - / R
Ph-- C--C..~-C=O § I-C3H? --N~-C =-N-- C3ST-i
S (Me)2HC--N S 'Pb
XXXVIII R=CN,CO2C2H~

An interesting route to 4-oxo- or 4-thioxo-l,3-thiazines is by the reaction between 3-
substituted-2-oxo- or 2-thioxo-4-tosylimino-l,3-thiazetidines (XXXIX) and diethylaminopropyne
[22, 23]. Attack on the carbonyl or thiocarbonyl carbon by the ynamine appears to result in
recyclization of the four-membered to the six-membered ring.

X
R\ ~/CH 3
R N"C'~'S + CH3--CmC--N(C2Hm)2 ~ N [~
- - \CJl / TaN
~.~J \N(C2Hs)~
NTs
R=II.C~H~; X=O,S 9

The (4 + 2)-cycloaddition reaction has rarely been used to obtain 6-oxo-l,3-thiazines.
The only example known to the authors is the condensation of N-thioaroyl-N'N'-dimethylformi-
dines (XL) with ketches [24, 25]. Phenylketene is less reactive than its unsubstituted ana-
log.

~=c..(u,)2 § R-c~c=o ---- 9 ]!
XL Ar '5 0
ll::.lt,l'rSl{~

Type C reactions have not been used for the preparation of 1,4-dioxo-l,3-thiazines.
They have, however, been used extensively in the synthesis of 4,6-dioxo-l,3-thiazines and
their sulfur analogs. The previously-mentioned isothiocyanate (XXXI) reacts with diethyl
sodiomalonate to give the straight-chain adduct (XLI), which cyclizes in the presence of c~-
pyridone to the 1,3-thiazine (XLII) [17].

,0
N,i /C02C2l[5
XXXI + NaC[4(CO~C~IIs)2 ...... ~m- C~Hb-CSNHCOCH(C02C,~H3) ~ . . . . -D- I1 ]I
CSI[~"~"'~S "~ " O H
XLI XLII

The rate of condensation with nucleophilic alkenes and alkynes increases when gem-electron-
donor substituents are present:

i
Ce~f~"' "~ S'
9

~R
T.
r
'='~
xxxx
,
CH3CmCOC~H5 ~ C6H 5 S 0 C 2H~t
110 e
R--OC2H~,SCH ~

The isothiocyanates (XXXIII) condense readily with reactive ketenes to give 5-substitu-
ted-2-alkylamino-4-thioxo-6-oxo-l,3-thiazines (XLIII) [19].
S

XXXIII + R~R2C--C-----O J~- R2
R42N ~S / ~'~0
R ! =R2=Ar;R4=Alk kqlII

One of the few examples of the condensation of a C3N fragment with the CS unit is the
reaction of 2-imino-4-oxothiazolidine l,l-dioxide (XLIV) with potassium tert-butoxide, car-
bon disulfide, and iodomethane in dimethyl-formamide solution [26].
0

~I RI SC 13
0 z "O
XMV R ~,R2::Ar XLV

(3 + 3) CONDENSATION
This reaction (type D) is that most frequently used for the preparation of the 1,3-thi-
azine ring. The most frequently-used method for the synthesis of oxo-l,3-thiazines is the
condensation of acetylenecarboxyli c acid derivatives with thioureas or dlthiocarbamic acid
derivatives, and for the preparation of 4,6-dioxo-l,3-thiazines, condensation of the appro-
priate thioamides with 'malonating' agents. Despite the extensive use of this type of syn-
thesis, there have been no reports of its use to prepare 2-oxo-l,3-thiazines or their thio-
analogs.
1,3-Thiazines with an oxo-group in the 4-position are formed by the condensation of B-
substituted acetylenecarboxylic acids (XLVI) with thiourea or its N-alkyl derivatives [27-36].

2 Jk R1
"'N"
1~
~
3
R=tl
C
II
NHR ~
I R ~=H
" -X
C-
I
R "..N + I -.i----- C + C ::S --~ S ---d~-
~C~ 3 RI/IN~/~'S X
R IN >" NR2R
XJ.NI XLVII XLVIII

RI=H, Alk,Ar; R2=H, Alk,At; R3=H, Alk; X=CO2CHs, Ar, 2-furyl
The mechanism of ring closure has unfortunately received little attention, and it is
not possible to provide an unambiguous explanation of the effects of substltuents on the
course of the reaction. The condensation is carried out in both protic and aprotic polar
solvents. It appears that initially ~-addition of the thiourea sulfur atom to the sp-hy-
bridized carbon takes place preferentially, and in several instances [35] the products of
such a reaction (XLVII) have been isolated. The NCS fragment can also be provided by 4-sub-
stituted thiosemicarbazides, which condense with acetylenedicarboxylic ester to give 2-imino-
3-amino-4-oxo-67alkoxycarbonyl-l,3-tbiazines [37]. The thiazine structure was assigned to
the product of the reaction of ethyl propiolate with thiobenzamide [38], but regrettably
these authors failed to provide any confirmation of this structure.

1,3-Thiazines with an oxo- or thioxo-group in the 6-position have been obtained by con-
densing substituted thiobenzamideswitb cyanoacetlc acid in the presence of PC1, or POCIs [39,
40]. The introduction of electron-acceptor substituents into the thioamide, and electron-
donor substituents in the a - p o s i t i o n of the c y a n o a c e t i c a c i d , reduce the y i e l d s of c y c l i z a -
tion products.
NIl 2

ArCSNH 2 + CN--CHqCOOH ~-- ~-
E At" "" "co ~ " 0
R=H.AIk

Reaction of B,B-dichlorovinyl ketones (XLIX) with thioamides or thioureas affords 6-
thioxo-l, 3-thiazines [41-43]
R' t H N .3 ~ N R3
" C .>0
I
.tt~/C.~ ,CI ~i ~ R2 I C ~ C / S R2 ~ S .
C~-CI I el
C! S

XLIX L
Rr=ph, Alk; R2=CI, H; R3=NH2; NHAlk, NAlk2, Alk. Ar
2,4-Dioxo-l,3-thiazines and their sulfur analogs are formed by condensing dithiocarbamic
acid [i, 44, 45] or its N-alkyl derivatives [44, 46] with propiolic [i, 44, 46] or y-hydroxy-
tetrolic acid [45].
The condensation of dithiocarbamic acid derivatives with propiolic acid in the presence
of PCIs had been studied previously [46]. Subsequently, acetic anhydride with traces of sul-
furic acid was used in place of PCIs [i, 44], the yields of 1,3-thiazines being considerably
increased. The reaction proceeds via the formation of the product of the nucleophilic attack
on the ~-carbon by sulfur. In several cases these compounds (LI) could be isolated [46].
O
ii. <'~~176162 .-lit-. ~3
It'CtCCOORz .+ ~'biiiCSSil ._._~ ,, NltR" ..... ! i

LI LI,
RI=~H,Cit20[I; R2=II; R3;-iI,Alk

It is preferable to use the free acetylencarboxylic acids in this reaction, since the
use of esters results in the cyclization giving low yields and requiring more severe condi-
tions [i].
(3 + 3)-Cyclocondensation is most frequently used to obtain 2-substituted 4,6-dioxo-l,3,
thiazines. These methods are based on the reaction of thioamides with a variety of 'malonat-
ing' agents, namely, malonyl chloride, malonic acid, and carbon suboxide [47-67].
In a study of the condensation of thiobenzamides (LIII) with malonyl chloride, it was
suggested that initially the sulfur atom of the thioamide (LIII) was acylated to give the
intermediate (LV), which is either converted into the 4,6-dioxothiazine (LVI), and reacts
with a second molecule of the thioamide (LIII) [47].

0

N .!L..,
.rcsN~ 2 + cH..(cocl) 2 ..... Arc(=Ns.)~eOc.2coct ....... ~
MI! LV Ar ~ S
I L~,'I

LIII
ArCSNHCOCII2COCI ------,.... ArCSNHCOCH2CONHCSA~

It has been found that the dichloride (LIV) or carbon suboxide react with S-alkyldith-
iocarbamates (LVII) or thioacetamides to give both cyclic (VLIII) and straight-chain (LIX)
products [48-50].
~-_r176
LIX . LVI[ LVII[

There have been several studies of the reaction of n~alonyi chloride (LIV) with alkane-
thiocarboxyllc acids or N-substituted thioamides to give 2-arylidene-or 2-alkyiidene-4,6-
dioxo-l,3-thiazines [51, 52].
,i~ O
hiV R~ N - ,###BOT_TEXT###quot; ~:H,~
,R ~~zGHt-'SNH~" ....... ~ El , C - : : S'~3 ;'~i Clfz
O
Rl~ H,AIk: R :=:~lt~;Ar

Disubstituted maionyl dichlorides react with NNt-disubsLituted thioureas to give 3,5,5-
substituted 2-a!ky!imino-4,6-dioxo-l,3-thiazines [53, 54].
R3 , , O

R~ =Alk; R'?,t*,~D, lk ,A r

When O-alkylthiocarbamates react with the acid chloride (LIV), in addition to 2-alkoxy-
4,6-dioxo-l,3-thiazines there is also formed 2,4,6-trioxo-i,3-thiazine, apparently as a re-
sult of the reaction of the former with the hydrogen chloride liberated [55].
.OH OH

s --~:o s --~"o
Malonic acid and its derivatives react with thiobenzamides in the presence of condens-
ing agents (PCI3) to give 5-substituted-2-aryl-4,6-dioxo-l,3-thiazines [56]. A drawback of
this method is the partial resinification of the cyclization products. This reaction takes
place in acetic anhydride with O-ethyldithiocarbamates or N-acetylthiourea [56, 57], but in
this case further acylation of the 1,3-thiazines formed takes place to give the 4-acetoxy-
compounds [57].
A highly efficient 'malonating' agent is carbon suboxide, which reacts with thioamides
to give 2-substituted-4,6-dioxo,l,3-thiazines (LX) [57-60]. The reaction may be complicated
by the addition of C30= to the thiazine (LX) with the formation of hi- (LXI) and polycyclic
derivatives [57, 61].
OH X N O OH
X-CSNH 2 + C302 )=- J
X~- %o,._ TT-T
0 0
l ~X LXI

The reaction of carbon suboxide with N-acetylthiourea has received the closest attention.
It has been found that acylation reduces the electron density at one of the thiourea nitro-
gens, facilitating NS-cycloaddition of the carbon suboxide [49, 55, 57]. The use of thiourea
or N-arylthioureas results in the formation of 2-thiobarbituric acids [58, 62, 63]. Unsym-
metrical NN'-dialkyl(or aryl)thioureas are converted to 2-dialkylamino-4,6-dioxo-l,3-thia-
zones [63, 64].

CHEMICAL PROPERTIES
The chemical properties of oxo- and thioxo-l,3-thiazines have received much less atten-
tion than the condensation reactions used in their preparation. The majority of studies have
examined alkylation, acylation, and electrophilic and nucleophilic substitution. It is worthy
to note that several reactions have been used to modify compounds already containing the 1,3-
thizaine ring. For example, alkoxy-, alkylthio-, and alkylimino-l,3-thiazines are frequently
obtained by alkylating the appropriate thiazines with diazomethane [i, 6, 28, 45, 65], dimeth-
yl sulfate [i, 6, 41], or iodomethane [29, 41]. The use of dimethyl sulfate is complicated
by the possibility of the opening of the thiazine ring in the presence of caustic alkali.
Alkylation takes place both at the ring nitrogen [i, 6, 28] and at the nueleophilic centers
of the substituents [i, 29, 41, 45, 65]. Methylation of 2-substituted 4,6-dioxo-l,3-thiazines
w i t h diazomethane in ether affords only O-methylation products, which were originally regarded
as 6-methoxy-l,3-thiazines [60]. Subsequently, however, quantum-chemical calculations and the
~3C NMR spectra of *SN-phenyl-4,6-dioxo-l,3-thiazine and its O-methylation product showed that
the latter was 2-phenyl-4-methoxy-6-oxo-l,3-thiazine [68]. Acylation has been closely examined
in the case of 2-substituted-4,6-dioxo-l,3, thiazines (LX). The use of acetic anhydride gave
the O-acetyl derivatives [69]. Another method of preparation of O-acyl derivatives is by acyl-

ating the sodium salt of the thiazlne (LX) with aromatic carbonyl and sulfonyl halides [70,
71]. In addition to O-acylation, examples are known of the N-acylation of amino-groups in
the 2-position of the aminooxothiazines (XLVIII, L) [28, 35, 41].
The 1,3-thiazinediones (LX), which comprize a heteroaromatic system in which C(s) is ac-
tivated to electrophilic attack, react with great ease withelectrophilic reagents. For in-
stance, reaction with phenyldiazonium chloride gives 2-substituted-5-phenylazo-4-hydroxy-6-
oxo-l,3-thiazines [56, 65, 72]. Reaction of (LX) with disubstituted aminomethanols affords
the Mannich bases (LXII~ [73]. Nitration, halogenation, and sulfonation of 2-aryl-4,6-diox O-
1,3-thiazines, even under mild conditions with equimolar proportions of the reactants takes
place exclusively at C(s) of the thiazine ring [72]. Nitration has been effected in nitric
acid (d 1.42) in acetic acid in the presence of acetic anhydride, and halogenation with bro-
mine in organic solvents (preferably acetic acid), lodination has been accomplished only
with iodine chloride. When sulfonation of the thiazine (LX) was carried out with sulfuric
acid of SO~ in pyridine, no product could be isolated, However, sulfonation takes place
readily with SOa in dichloroethane.

I
OH q'J~|
I
N'"":::'~:',/CH:~NR:z N
I
":- '
NO~

9 .,v,~ ~OJ' "/x .....s ""o
I ! o,,

LXH ",'-'. 1 Br

~" C~ . IX
"':'
: .................. ""
3 I
01[ ~-- .d- X S "'0
.I . . . N:::N--Ph ~,, J) so,J!
N.

l~III

It is interesting that the nitration of 6-(2-furyl)-l,3-thiazines (XLVIII) takes place
in the s-position of the furan ring [35].
Reactions with nucleophilic reagents occupy an important place in studies of the chemi-
cal properties of oxo- and thioxo-l,3-thiazines. For example, the hydrolysis of 2-alkylimino-
[i, 34, 35] or 2-alkylthio-4-oxothiazines [i, 6] is frequently employed for the preparation
of 5- and 6-substituted-2,4-dioxo-l,3-thiazines~ The reaction is usually carried out with
acid catalysis [I]. In alkaline media, cleavage of the thiazine ring often takes place [72].
One of the most interesting of the chemical properties of substituted 2,4-dioxo-13,-thiazines
is their reaction with ammonia [6, 44] and primary amines [14, 44] when the thiazines are con-
verted into the corresponding pyrimidines. The first step in this reaction appears to be
cleavage of the ring by the nucleophile, and in several cases aeyclic reaction products (LXIV)
have been isolated [14].

q) 0

N ~ ' -

II " "
EtS "- "" S "" CH NIIR S ~" ~N"'
ux.]v I
R

Acyclic products have also been obtained in the reaction of 6-substituted 2-amino-4-oxo-
1,3-thiazines or the thiazines (LX) with secondary amines [28, 74-76]. It is interesting
that in the case of the thiazines (LX) the intermediate ammonium salts (LXV) have been iso-
lated, these undergoing cleavage on heating in organic solvents,

O

ItNR, N ~ I~
i,x: ---"" ]I I" ~"J . ~(' . - ....
. . X(::SNII~:Oe~.,('ONR,
r

J
1:-%

The reaction between 4,6-dioxo-l,3-thiazines and sodium a!koxides may follow two routes,
since 2-aryl-4,6-dioxo-l,3-thiazines form stable salts with sodium ethoxide [71], whereas 2-
alkylidiene-4,6-dioxo-l,3-thiazines rearrange to the piperidones [51].

Nucleophilic replacement o~ the halogen atom in 2-chloro-4-oxo-l,3-thiazines (II) has
been examined using amines [3]. Depending on the amine taken and on the reaction conditions
either the 2-alkylaminothiazines are obtained, or acyclic compounds, but cleavage always pre-
cedes replacement [3].

o
Jl
RaRIN ~S #
L###BOT_TEXT###quot;VI I.XVII

It has been shown to be possible to convert oxo-l,3-thiazines into their thioxo-analogs
by treatment with P~S~o [24, 25, 77]. The reverse transformation has been effected with mer-
curic acetate (ii), and in the case of the 6-thioxo-l,3-thizaine (L), the 6-oxo-compound is
obtained [41].
The structures of the reduction products of oxo-l,3-thiazines are dependent on the re-
action conditions. For example, when sodium borohydride is used only the C=N bond of the
thiazine (XXV) is reduced [12], whereas the catalytic hydrogenation of methyl 3-methyl-2-
imino-40oxo-l,3-thiazine-6-carboxylate gives N-methylsuceinimide [28],
Less general chemical properties are the conversion of the carboxamide group in (XXV)
(R = CONH=) into the nitrile by treatment with trimethylsilyl polyphosphate [78] and the di-
merization of 2-alkyl-6-methyl-4-oxo-l,3-thiazines on heating with a catalytic amount of tri-
fluoroacetic acid in dimethylformamide [79].
Oxo-l,3-thiazines are potentially tautomeric. It is unfortunate that up to the present
only the ~automerism of 2-substituted-4,6-dioxo-l,3-thiazines (LX) has been studied. These
thiazines can exist in at least four tautomeric forms (LEa-d).

N.--./" 011 / 0 ' 0

ix a Lx b LX'c LXd

On the basis of the IR, PMR, and UV spectra, Beilin et al., [60, 68] have shown that
when the substituent in the 2-position of the thiazine ring is varied, the structure of the
fl-dicarbonyl fragment also changes, in the opinion of these workers owing to the "differing
contributions of the substituent to the conjugation of the thiazine ring." For instance,
crystalline 2-(p-chlorophenyl)- and 2-phenyl-4,6-dioxo-l,3-thiazine were assigned a zwitter-
ionic structure (LXd) on the basis of the similarity of the IR spectra to the spectra o f
their salts, and the absence of absorption above 1600 cm -~. In solution~ these compounds
already exist in the enol forms (LXa) of (LXc), since their IR spectra correspond to that of
4-methoxy-2-phenyl-6-oxo-l,3-thiazine. The enol form was confirmed by the PMR spectra, since
in DMSO solution they showed signals for olefinic (5-H, ~ 5.4-5.8 ppm), hydroxylic (12.0-
12.6 ppm), and phenyl (7.5-8.3 ppm) protons. The spectra showed no signals for the methylene
group with 6 = 3.5 ppm, as observed for compounds with structure (LXb) and an olefinic proton
for the anionic form with 6 = 4.7 ppm such as is present in the spectra of the salts. In or-
der to determine the relative stabilities of the tautomers (LEa) and (LXb) s the atomization
energies of these forms of 2-phenyl-4-hydroxy-6-oxo-l,3-thiazine were calculated by the PPP
method in Dewar's o, ~-parameterization. It was found that the tautomer (LXa) was the more
stable. From the IR spectra of crystalline samples and of solutions, 2-alkylthio-4,6-dioxo-
1,3-thiazines were assigned the diketonic form (LXb)o 2-Methyl- and 2-alkoxy-4,6-dioxo-l,3-
thiazines display an interesting structural feature. The IR spectra of crystalline samples
of these compounds shown characteristic C=O absorption at 1650-1628 cm -~, showing that they
exist in the enol form. However, solutions of these compounds in DMSO solution (from their
IR and PMR spectra) contain both the keto- and enol-forms [60]. It is difficult to arrive .
at any conclusions concerning the structure of 2-amino-4,6-dioxo-l,3-thiazines in the ab-
sence of adequate spectral data. In the opinion of Baranova, Dashkevich, et al., [6].
63], the PMR spectra of these compounds in DMSO indicate the presence of two tautomeric forms
(enol and diketonic).

i0

SUMMARY
This review has shown that the attention of workers has been concentrated for the most
part on the synthesis of 4-oxo-, 2,4-dioxo-, and 4,6-dioxo-l,3-thiazines. These compounds
are most commonly obtained by condensing acetylenecarboxylic acids with thioureas or dithi-
ocarbamic acids, or by reacting thioamides with malonic acid derivatives or carbon suboxide.
The chemical properties of this interesting group of heterocycles have received relatively
little attention, and it is not possible to arrive at any firm conclusions as to the effects
of variations in the ring heteroatoms on their chemical properties, and the position of these
compounds amongst their hetero-analogs. The available information does enable novel, pre-
viously inaccessible compounds to be prepared. It hardly needs to be mentioned that the 1,3-
thiazine ring is present in naturally-occurring biologically active compounds such as cephal-
osporins and antibiotics. Oxo-and thioxo-i,3,-thiazines possess properties which are valuable
from the practical point of view, such as antiinflammatory [54], analgetic [80], tranquiliz-
ing [81], antipyretic [39], diuretic [39, 70, 71], fungicidal [80], and antimicrobial [43]
activity.

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12

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MASS-SPECTROMETRIC STUDY OF THE CYCLIZATION REACTIONS OF DIAZOKETONES.
8.* I-DIAZO-3,4-EPOXY-4-ARYLBUTAN-2-ONES

A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, UDC 543.51:547.537'
T. P. Pokidova, V. G. Kartsev, and V. S. Petrosyan 284.4'235.2

An analysis of the mass spectra of l-diazo-3,4-epoxy-4-arylbutanones has shown
that the molecular ions of these compounds lose a molecule of nitrogen and that
the [M-- N2] + ions formed cyclize to form hydroxyfuran structures, whose fur-
ther fragmentation determines the whole picture of the dissociative ionization
of the compounds investigated under electron impact. The majority of the [M --
N2] + ions have the form of the cyclic intermediate formed in the first step of
the cyclization process. It cannot, however, be ruled out that a certain por-
tion of the [M -- N2] + ions are stabilized as a result of a Wolff rearrangement
and do not cyclize at all.

We previously [2] showed that under electron impact in the gaseous phase diazoketones
which contain a heteroatom or a heteroatomic grouping in their chain eliminate a nitrogen
molecule and cyclize to form heterocyclic systems owing to the practicable cooperation of the
heteroatom, rather than decompose according to a mechanism involving a Wolff rearrangement
[3, 4]. Since the action of acids on diazoketones in solutions produces similar products [5,
6], it was concluded that it would be possible to predict the direction of this reaction on
the basis of mass-spectrometric data. The results of the treatment of phthaloyldipeptide
derivatives of diazomethane with acidic reagents completely correspond to the predictions
made on the basis of the mass spectra of these compounds [2, 7].
Continuing this investigation, we studied the mass spectra of a series of arylepoxydia-
zoketones I, whose conversions in solutions were not previously investigated.

H I!

s2~ O R ~

sa-h
I a RI=H, b RI=CH3, c h RI=OCH3, d RI=NO2, e RI=F, f, g Rs=CI;
a--f R~=R3=H, g R2=}I, R~=D; h I{~=OCH:~,l~:'~=l!

The first step of the fragmentation of these compounds under electron impact, as would
be expected [I, 2], is the elimination of a nitrogen molecule. This results in the formation
of [M -- N2] + ions, whose structure makes it possible to draw a conclusion regarding the direc-
tion of the reactions of diazoketones with acidic reagents, which is the main goal of the
present work. The possible structures of the [M -- N2] + ions (see Scheme I) can be suggested
on the basis of the preceding investigations [i, 2] and the data in [3, 4].

*For report 7 see [i].

M. V. Lomonosov Moscow State University, Moscow 117234. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. i, pp. 17-22, January, 1986. Original article submitted Decem-
bet 4, 1984.

0009-3122/86/2201-0013512.50 9 1986 Plenum Publishing Corporation 13

6 5.5 2.2 0. Ketene B can also cyclize to form ion C [8].45 1.8 15.9 17. the majority of the ions of type D will have the enol form.5 0..1 3. F) results in the complete disappearance of the peak of this ion.1 10.N=] + ions allows us to conclude that they mainly have a cyclic structure (form D.3 1.2 Ic 0.. Here and in the following.7 0.2 If ~ 0.2 1. Nevertheless.5 -- Id -.4 1.6 . since additional stabilization of such a structure is caused by the formation of the aromatic furan system. Intensities of the Peaks of the Characteristic Frag- ment Ions in the Mass Spectra of Diazoketones I in the Total Ion Current . in fact. Scheme i ]+" H H H H i I .7 -.4 0.9 3.7 10. are unstable.0 0. it may be postulated that in the case of diazo compounds I.0 20. par- ticularly the ketenes.4 3.6 0.* and the presence of electron-acceptor substituents in the benzene ring (NO~. The intensity of the peaks for M + does not exceed 0.4 1.6 0.9 2. #The formation of this ion form M + in the case of compound I is confirmed by the peak of the metastable ion with an apparent mass of 21.8 lh 0.4 1. It should be noted that both intramolecular cyclization and a Wolff rearrangement can take place simul- taneously with the elimination of a molecule of nitrogen and can. initiate this pro- cess.3 1.9 18.5 3.7 1.1 4.9 2.5 0. Ion D can exist in two principal tautomeric forms: a keto and an enol form. occurs under the conditions of our experiment [3.6 1.1 0.3 7. Some of the [M -. ioni- zation of the diazo compounds.7 1.C ~ .e.0 3.0 i 6.2% and of [COCHN2] + which has a mass-to- charge ratio equal to 69# (see Table i). 7.6 le 2.4 4. the enol form is predominant in the gaseous phase [9]. 14 .6 9. I I ~_c<_pc_co CnN2 -N~ \ / Ar --C--C--C0.. like M + of the previously studied diazoketones [2].6 lg 0.4.2 : 7.4 1.1 2.2 3.0 1..1 3. TABLE i. 4].2 0.1 4..2 0.1 2.0 The ions of type A with a linear structure are unstable and are stabilized either as a result of a Wolff rearrangement (ion B) or as a result of intramolecular cyclization (inter- mediate D' and ions of type D). the numbers char- acterizing an ion determine the value of m/z.8 0.0 6.5 7.~ 0 ~C / CIt "CH "~0 II / D' o c +" Ar "/C~'o/CH2 D D The molecular ions (M+ of compounds I.5 0.7 0. 3.8 7. therefore.5-dihydrofuran.8 5. 4.2 11. rather than the products of their thermal decomposition.3 1.5 5.9 6.3 -.1 5.e.4 1.1 0.N ]+ ions de- compose prior to the migration of the hydrogen ion (the D'-D transition) and the formation of the hydroxyfuran pseudomolecular ion.2 6.0 0. 0.7 1.8 0.1 21.3 0.5 0.5 1.8 0.0 4.5 0.0 lb 0.2 0.7 1.3 15.8 5. An analysis of the fragmentation paths of the [M -. 1.~ C .1 1.5 0.1 2. i.4 0.CHN ]+ fragments with an intensity of 0.4 6.5 1.1-0. In the case of 4-isopropyl-3-hydroxy-4.9 4.6 6.6 0. the formation of [M -.CH +" Ar . see Scheme i). proves that diazo compounds I form M +.1 1. *The fraction of the ions of a particular type in the total ion current is given in percent. Corn- pond M~ [M-N~I' F~ F'2 F3 F~ Fs F~ Flo 105169 i !a -.C H : C = 0 o o 0 M+ A B A~ I IJ" 0 + ~C.1 1.5% of the total ion current.6 0.6 8.

IM_N2 _CHO]+ . In the mass spectra of pheny! epoxides the peaks of the ArCH + and ArC + ions have the maximum intensities [I0]. CH-. However. Ar-C~C~ I+" F8 F5 F6 (ArCO+) I05 "The genetic relationship of these ions was not established. peaks of ions characteristic of the decomposition of aromatic epoxy compounds should be observed in the mass spectra of diazoketones I. .. and F9 may be represented differently. Fa. 7 and 2. . confirms the cyclic structure of D for these ions. r e s p e c t i v e l y .TSa 09 ArCllO-]+ " [ M . the forma- tion of ions of type F6 as a result of the elimination of a COCH=O particle from the [M -.~ . . . Fz. On the other hand..CO "~" "~ CH~ -uco' j-'" . which has the maximum intensity in the mass spectra of the compounds investigated.. as was observed in the mass spectra of 1. an additional mass-spectroscopic finding which confirms the cyclization of the [M -. " c ~ ~ -%o Ar ..N=] "+ ion in one or two steps. is practically absent in the mass spectra of aryl epoxides [10] and arylepoxyketones [ii]. As a result of the attack of the oxygen atom of the epoxy ring at the methine group. other experimental findings attest to the fact that the majority of the [M -.2%. The main directions of the fragmentation of the [M-. Fa. First. 4].c .. therefore. . ~. the Wolff rearrangement does not result in the destruction of the epoxy ring. the lone pair of the oxygen atom can form a bond either with the carbon atom (the electrophilic center) (this results in the formation of intermediate D') or with the acidic proton of the methine group with the subsequent cleavage of a C--C bond and the forma- tion of fragment FT.+. N=] + ions is a Wolff rear- rangement [3.* attesting to the destruction of the epoxy ring in the initial steps of the fragmentation.I o. r e s p e c t i v e l y ) . 5 % .~O J --I!. if it is postulated that the first step in the transformation of the [ M .N ~ -C01+' Fs Fz o --2 _]+. the peaks of these ions have intensities below 0.5%. ~ --cHco I I +' Ar ~CII----CII ~ I ---C.3-oxazin-5-ones [12] and 4.c~ Ar ~ C H ~ C H ~ + " .Na] + ion is the formation of the fragments of type FT. . Second. which bears a positive charge and a free electron.Na] + ions of diazoketones I may be represented by the general scheme Scheme 2 A~"c~.~--. \/ 0:~ ..' 0 O *An e x c e p t i o n i s compound I e .N=] ~ ions (and possibly all of them) are stabilized as a result of intramolecular cyclization. 15 . In addition. They a r e a l s o s u f f i c i e n t l y intense in the mass spectra of un- substituted diazoketone I a ( 1 . while its appearance from intermediate D' as a result of the elimination of a COCHO par- ticle or from ion Fa (elimination of a CO molecule) is not impeded.c~ \ \ ArCtl2+ A~CH=CH --.5-dihydro-3-oxofurans [9].. The structures of ions F~. the Wolff rearrangement does not account for the formation of ion F~ (see Scheme 2). Third. In the case of diazoketones I.. the peak of the ArCHO +" ions (F~o). The proves the impossibility of its formation from linear ions A and B (see Scheme i). f o r w h i c h t h e i n t e n s i t i e s of the peaks of these fragments are 5 .. while the decomposition of intermediate D' with the formation of such an ion is very favorable. 5 and 4 .' .

Substituents in the benzene ring do not alter the principal fragmentation paths. The fragmentation of diazoketone Ig according to such a mechanism should result in the complete loss of the deuterium label in the case of the existence of ion D ex- clusively in the enol form and in its partial loss when the keto form of this ion is present.N] + ion [i0. ii]. In order to refine the fragmentation scheme.N2] + ions. Tile cyclic structure of the [M --N2] + ions is also confirmed by the formation of the F~ fragments as a result of the elimination of a molecule of formaldehyde from the keto form of ion D or an HCO" radical from ion F:. therefore. The behavior of fluorinated derivative le is anomalous.N2 -.N2] + ions are assumed to have a cyclic structure.N2] + ion does not result in the loss of the deu- terium label. As was shown in [13.0. the experimental findings presented can be explained only when the [M-.0%. and 1. respectively. In this case. Such a sharp increase in the number of ~ ions decomposing along paths not associated with the initial formation of a furan ring indisputably reduces the proportion of [M -. The partial loss of the deuterium label may also be the result of the elimination of a hydro- gen atom from ion F2. 4] may be a process which competes with the intramolecular cyclization and takes place for some of the [M-. all the mass-spectrometric findings described do not allow us to completely discount the possibility of a Wolff rearrangement. Electron-acceptor sub- stituents (compounds Id-f) make this fragmentation path competitive. and ArC + fragments (5. therefore. i. This is reflected in the increases in the relative intensities of the peaks of the F7 ions in the mass spectra of compounds Id-f (see Table i). the [M -.5 and 4. Electro1~-acceptor substituents in the aromatic ring increase the acidity of the methine group.RCO] ion is not observed at all. The Fs ions apparently form along several paths. the peak of the [M -.CH-X I i X=~r z 16 . however. 16]. The successive elimination of a hydro- gen atom and a molecule of CO from the [M -. The calculation of the intensities of the peaks in the mass spectrum of this compound showed that the deuterium label is completely retained in ion FI.1%). Cleavage of the C(2)--C(s) bond in M + results in the formation of ions F9 and 69. the peaks of the ArCH +. Therefore. The peaks of ions Fa and 69 have the maximum intensities in the mass spectrum of this compound. 1. we synthesized compound Ig with deuteration at the diazo group. which are characteristic of the fragmentation of aryl epoxides [i0]. 14]. the structure of fragment F~ can vary as a function of the mechanism for its formation and is. It is not possible to evaluate the contribution of each of these paths to the formation of ion F3. The intensity of the peak of ion F7 is alsoincreased (see Table I). not presented in the scheme. position 5 in the furan ring formed is occupied by an aryl substituent. It is known 14 that substituents in positions 2 and 5 of the furan ring (R) can result in the appearance of an alternative direction of fragmentation~ An RCO" radical is eliminated along with an HCO" radical. For example. this ion has a cyclic cyclo- propane structure. _•/•--CH--CH- S \ / 0 CO. Nevertheless. in the mass spectra of compounds Ia-c with electron-donor sub- stituents. while 30% of it is lost in F~. are also intense. The elimination of an HCO" radical is the main process in the fragmentation of furans [13.6. i4].N2] + ions eliminate the benzyl hydrogen atom. and such elimination can occur either from intermediate D' or from linear forms A and B of the [M -.. and the mass spectra of diazoketones I display peaks for both these ions (see Table i). The mass spectra of these compounds display peaks for the corresponding ion 55 with relative intensities equal to 4. The electronic properties of the substituents in the benzene ring play an important role in the competitive elimination of the HCO' and RCO" radicals.e. it should be assumed that the formation of ketene ions of type B according to a mechanism involving a Wolff rearrangement [3. In the case of diazoketones I. these fragments have similar ionization energies [15.N=] + ions in form D to the total number of ionized molecules of this compound in comparison to the other compounds of type I.

whose further fragmentation determines the entire picture of the dissociative ionization of the compounds investigated under electron impact. Sibel'dina. Sepetov.4).1). Lebedev. 189 (15. 51 (16. 78 (12. EXPERIMENTAL All the compounds investigated were synthesized at the Chernogolovka Branch of the In- stitute of Chemical Physics of the Academy of Sciences of the USSR. 41 (16. Khim. Geterotsikl. 6. Sharbatyan. In the case of fluorinated derivative le. K.0). 106 (36. LITERATURE CITED i. M. 63 (11. 139 (100). 138 (29.2).3). G.2). 69 (95. Lett.N~] + ions have the form of the cyclic intermediate formed in the first step of the cyclization process.4). and L. 78 (10.0). A. 69 (17.9).4). Meier.4).8) Ill 191 (28. T. 151 (23.1) Ig't" 160 (14. 165 (36. M. Soedin.-P. P. 28.4).. Tetrahedron. (relative intensities of ion peaks as percentages of the maximum) pound |a 131 (19.3).9). 138 (27. The behavior of epoxythiophene li is similar to that of the compounds described.5).8).7).7). 118 (33. 139 (85.5).9). 77 (21. 95 (68. in this case.2).. 120 (84. Lebedev. The mass spectra of compounds If and Ig were additionally recorded under identical conditions (the temperature was 100~ and the energy of the ionizing electrons was 50 eV) on an MKh-1303 mass spectro- meter with a similar admission system. Tetrah. It cannot. 101 (49. be ruled out that a cer- tain portion of the [M -. No. Kazaryan. the epoxy ring opens and a cyclic furan ion forms.t).6). Muller. which has a similar structure [17]. Khim.0). I0. 79 (13.0). 125 (33. 109 (76. 102 (37. 788 (1985).1). 5. 65 (51. 65 (22.3). 91 (63. 77 (54. T. 51 (19. i. Karsev. 3.N=] + ions formed undergo cyclization with the formation of hydroxy furan structures. Sipyagin. Sipyagin.2). A. Petrosyan. 111 (21.6). 69 (67. 141 (80. 89 (28.0). 4. Mass Spectra of Compounds la-i Values of m/z:'~ Co m .4). I0. Kartsev. 108 (61. A. G.9).8).8). 95 (23. A.8)..8). 138 (66.9). V. 141 (43. 154 (28. and E. 112 (68.2). Soedin. A.3). 140 (100). and V..9). Kinson and B.7) li 166 (91.2). 125 (48. 103 (16.6). 97 (I00). H. No. 17 .3).5).0).7).4) Ic 161 (24.e.8). secondary reactions with the formation of other products are possible. 14. 77 (31. A. 1075 (1969). Geterotsikl.N2] + ions are stabilized as a result of a Wolff rearrangement and do not cyclize at all.2). V. 135 (100). 105 (33.7). an analysis of the mass spectra of diazoketones I showed that the M + ions of these compounds lose a molecule of nitrogen and the [M -. 105 (70. 89 (38. too.0) Ib 145 (21.9). V.9). 77 (36.3). 137 (13.3). 55 (59. Sipyagin.0).3). Dissertation for the Degree of Candidate of Chemical Sciences.3). however. P.8). Soedin. 91 (13. Kartsev and A. 137 (39. 91 (32.0). F. G.4). M. 149 (30. 2. V. The deuterated form of compound Ig was obtained by holding diazoketone If in deuteromethanol (CD3OD) for 24 h with further evaporation of the solvent and recrystallization of the deuterated derivative f~om deuteromethanol.5) If 159 (30. 124 (55.1). 121 (33.1).. Khim.6) le 177 (40. 111 (83. Thus. 92 (19. Trost. 105 (100). 89 (43.4). Moscow (1982). 142 (30.2). 69 (57.0). Zeller. Lomonosov Moscow State Univeristy (MGU). it may be postulated that cyclic furan systems will form when the diazoketones studied are reacted with solutions of acids. 69 (30. 70 (14. 1327 (1980).0). 142 (62. tThe spectrum was obtained on an MKh-1303 mass spectrometer. I10 (26. 119 (I00). The mass spectra of diazoketones la-h were obtained on an LKB-2091 mass spectrometer (Sweden) with the use of a system for the direct admission of the sample into the ion source. Geterotsikl. and all the fragments are described well by the general scheme for the fragmentation of diazoketones I presented.9). A.9).7). 120 (15. 117 (13. 165 (45.9) Id 205 (51.5). M. The mass spectrum of this compound differs significantly from the spectrum of epoxyketone lli. 6. G. 1324 (1980). 166 (100). No. The temperature of the samples was 60-140~ and the energy of the ionizing electrons was 70eV. On the basis of the investigation carried out. 140 (87. N.6). 5831 (1972). 90 (36. 109 (100). 159 (10. 107 (33.1). TABLE 2.4). 151 (lO0).8) i *The i0 most intense peaks are given. 51 (25. The majority of the [M -. 110 (27. S. 136 (85.

F. 8.728. and 7-aminomethyl. Hoppiliard. Sarkisova. ~7A. and V. and K. G. Anteunis and M. Scharmann. A.07: L. E. and S. 2-phenyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxybenzofur- an hydrochloride (phenykoberan). M. 6-.. 6-. 2077 (1966). N. 9. Petrosyan. Lett. M. Moscow 119021. Helv. Original article submitted December 18. Geterotsikl. Lebedev. Ordzhonikidze All-Union Scientific-Research Institute for Pharmeceutical Chemistry. M. Ann. One of them. T. Sipyagin.. Stute. Reed. 283 (1969). No. 6-. has found application in the practice of medicine [i]. we have used them as a basis for obtaining various. H. 141 (1941). b R-kRI=(CH2)~. Musumara. January. Khim. S. A. Fetizon. A. T. UDC 547.~. Faraday Soc. and Yu. L. Lebedev. Alekseeva. Soedin. Translated from Khimiya Geterotsiklicheskikh Soedinenii. 41. Acta.. i0~ H. AND 7-AMINOMETHYL DERIVATIVES IN THE 4. primarily the 2-. Vandewall. J.c R=H. Petrosyan.50 9 1986 Plenum Publishing Corporation . The bromination of 2-methyl-3-carbethoxy-4-acetoxy-5-methoxybenzofuran (II) by N-bromo- succinimide in the presence of benzoyl peroxide gives 2-bromomethyl derivative III. R. Occhipinti. Lyubchanskaya. No. S. Tetrahedron.. K. A.. Dupin. 71. 17.5-DIHYDROXYBENZOFURAN SERIES A. R~=CH(CH3)z *Deceased. Aminomethyl derivatives of benzofuran are of definite interest in the area of the search for drugs. 623 (1983). and 2- dimethylaminomethyl-2-piperidinomethyl-. Mass Spectrom. 35 (1951). . 12. Kartsev. 1986. In the present work. M. Bull. G. Soc. G. S.25 The 2-. No. 22... 24. 7. R. 16. viz. K~gu. 13. Ballistreri. / -. F. 1332 (1983). Soc. SYNTHESIS OF 2-.and 4-methoxy-4-hydroxybenzofuran. 2119 (1971). 18 0009-3122/86/2201-0018512. Abe. Nakanishi. Khim. Stevenson. 522 (1968). V. Japan. 12. Acta. K. ii. derivatives. P. Chim. S.. 2223 (1966). P. 15. 19. E. Chim.and 4-methoxy-5-hydroxybenzofuran [2]. 5933 (1963). When III is re- acted with an excess of the amines. We recently synthesized derivatives of 4-hydroxy-5-methoxy. i0.1. v 0 "CH~ I II OCOCH3 OH '.5. Audier. Heyns. Chem. 1984. Disc. P. Sasaki. pp. Tetrah. Sharbatyan~ A. Geterotsikl. V. OH OCOCH3 %"~ Ao o J[ 'il '%. N. J. and V. 14. A. and H.* V. 23-27. and 2-isopropylaminomethyl-4-hydroxy-5-methoxybenzo- furan (IVa-c) are obtained by reacting the corresponding amines with III. Org. elimination of the acetyl group is observed along with the replacement of bromine by the residue of the amine. I. Audier. P. K. Sharbatyan.422. Chem.. Reed and W. ~. i0. Sipyagin. M. Kartsev. 269 (1981). Spectrochim. Soedin. (Rome).. Grinev. i. H. and 7-aminomethyl derivatives have been synthesized from derivatives of 4-hydroxy-5-methoxy. S. 2-Methyl-3-carbeth- oxy-5-methoxy-7-dimethylaminomethylbenzofuran has been Converted into the 7-cyan- omethyl derivative. M. and J. CH3 C00C2H 5 HNRR I H3 C00C2H 5 ~//" ~0 / ~ CH2Br ~//~ OA CH2NRR I III IVa-s IV a R=R'=CHa. No. D. Sheinker 543.

Here we also observe additional splitting of the signals of the C(3a). ) a n d C(5) s i g n a l s s h o u l d f a l l i n t h e w e a k e r .[Cs.5 Hz). and the aminomethylation of isomeric 2-methyl-3-carbethoxy-4-methoxy-5-hy- droxybenzofuran (VI) by bis(dimethylamino)methane and dimorpholinomethane gives 6-aminomethyl derivaties Vlla and b. aJc(~a~. and C(7) a t o m s and f o r t h e C ( a ) a n d C ( T a ) a t o m s a r e known t o be o b s e r v e d i n t h e 106-127 and 145-155 ppm r a n g e s .4 ppm (3Jcc~'~ocH~ = 4 HZ) belong to the C(3a). 37c~ 2CH .).6 162. An e v a l u a t i o n o f t h e c h e m i c a l s h i f t s o f the aromatic carbon atoms with the-use of the increments of the substituents f o r b e n z e n e [5] r e v e a l s t h a t i n t h e s p e c t r u m o f V I I I t h e C ( .' It should be noted that the spectrum ot compound VIII in CDCL3 displays additional splitting of the signals of C(. The multiplicity*.O-H = 4 Hz). VII bR+RJffi(CH2)20(CH2)2 In order to determine the positions of the substituents i n compounds Va. Vb R+RI=(CH2)~.4 113.8 119.) (2JG<~v4OH = 4 Hz). C(3 ). the signal of C(~) is a sextet (~7c. The signal of C(3a) is a singlet.7-CH~ = 4.4 I 147. the signal = of C(~) is a quartet (~fC.6-H 8 HZ).~rSOCH~ = 4. Carbon-13 Chemical Shifts of Compounds Va. Vlla RffiRIfCH3.2) I C. Vlla. and C(5) atoms. Vb. we a l s o t o o k i n t o a c c o u n t t h e d e p e n d e n c e o f t h e v a l u e s o f t h e s p i n .) is a doublet (fc~4~. 109. and 149. where at singlet at 112.9 139.4 Ilia 105.4OH = 2. C ( s ) .eH~ = 5 Hz).1 113. The s i g n a l s i n t h e X3C s p e c t r u m of u n s u b s t i t u t e d benzofuran for the C(3).5 Hz) 119.6 109. as well as of C(3a) and C(5) (3Jq~v4OH = S. C(6). ~Jq~l.~ 7CH~ =4.1 (q.f i e l d g r o u p a l o n g w i t h t h e s i g n a l s o f t h e C ( a ) a n d C(Ta) a t o m s . which participates in a chelating hydrogen bond with the oxygen atom of the carbethoxy group at C(3) [3].9 (t. The chemical shifts of the signals of most of the carbon atoms of the benzene fragment change only slightly upon the transition from Va to VIII (Table i). ppm in CDCI3 Compound C.! 140. 2Jc~2~' 2-CHa = 7..2 149. TABLE i.6 (t.6 143.9.0 138. C(. To a s s i g n t h e s i g n a l s h a v i n g s i m i - l a r c h e m i c a l s h i f t s and t h e same m u l t i p l i c i t y . =7C(~.). 3Jci.3) Ci3a) C~4) C(5) C(7) [ C(TR) Va Vlla I 16~. by the proton of the OH group. R'RNCH~0 %CH~ Br TOLCI% CH2NRR~ CH2N(CH~)2 va. C(3a).6 I 108.5 VIll 162. we c o m p a r e d t h e Z3C s p e c t r a o f compounds Va and V l I a and t h e s p e c t r a o f V I I I . C ( 5 ) . and VIII . 2J~7 7-CH~ = 6 HZ). r e s p e c t i v e l y [4].s p i n c o u p l i n g c o n s t a n t s o f t h e c a r b o n a t o m s of b e n z o f u r a n w i t h t h e p r o - tons of the substituents on t h e number o f b o n d s [ 6 ] .5) were assigned to the C(=). b VIIa. the signlet at 142.5 Hz.5 1132 190. = 2. 19 . w h i c h was p r e v i o u s l y o b t a i n e d i n [ 3 ] . the signals at 162.9 119. 112. The spectrum of compound Va is similar in many ways to the spectrum of VIII.5 I 109.6 The aminomethylation of 2-methyl-3-carbethoxy-4-hydroxy-5-methoxybenzofuran (I) by bis- (dimethylamino)methane and a mixture of formalin with piperidine gives 7-aminomethyl deriva- tives Va and b. the signal of C(~) is a doublet of triplets (~Jc~H = 158. C(7). and C(5) atoms due to the proton of the hydroxyl group. and the quartet at 139.2 (t. of these signals is consistent exclusively with placement of the aminomethyl group at C(7). V I I a and V I I b .5 HZ). the signal of C(.7 ~ 7cu~ = *The splitting of the signals in CD~OD is given.6 112. and C(7a) atoms. On t h e b a s i s o f a l l t h e c o n s i d e r a t i o n s just enumerated..7 147.6 (q.0 147. which vanishes in the spectrum recorded in CD3OD. ~[~ 0 -CH. This splitting is absent in the spectrum of VIII in CD3OD.5. C(4). respectively. b Vlll Va. C(. OH OCH~ OH .8 161.7 143.

5.. the chloromethylation of derivatives of 4-methoxy- and 5-methoxybenzofuran produces derivatives of bis(benzofuranyl)methane exclusively [7]. The structures of the compounds synthesized were confirmed by the data from ~H NMR spectra (Table 3).5 Hz) at 119. ~]~(7~. Demethylation of the methoxy group in position 4 by hydrogen chloride was ob- served during the reaction. OCII3 / OCH3 OH CH~0 ~ _ . .5 ppm.l~ = 1. {.~)~k .. A mixture of 5... C(~a). ~ i c h can be unequivocally attributed only to the presence of an aminomethyl substiuent iu position 6 in compound Vlla. in the form of a doublet (2]C(7~)... and the precipitate was filtered out. and i mg of benzoyl peroxide was boiled for i0 h.1 g (88%) of compound III. The reaction 20 .85 g (5 m m o l e ) o f derivative III in 15 ml of dry benzene was given an addition of a solu- tion of 0. " 2. 2-Bromomethyl-3-carbethoxy-4-acetoxy-5-methoxybenzofuran (III). 3.. which are observed. We also obtained 7-cyanomethylbenzofuran derivative Ve from 7-dimethylaminomethyl de- rivative Va. respectively..5. CH3 Oft z :- CII30. The characteristics and yields of the compounds obtained are presented in Tables 1-3. Compound Va reacts with methyl iodide in dioxane to form a methiodide." . the mother solution was evaporated to dryness.~o. A solution of 1. 2-Methyl-3=carbethoxy-4-acetoxy75-methoxybenzof~ran (II~. and the residue was re- crystallized from ethanol.5-dimethoxybenzo- furan (IX) and obtained 7-chloromethylated derivative Vc and bis(benzofurnanyl)methane der- ivative X. O {-:It~ "~'i~ " 0 .7.15 g (73.e R~CN According to the literature data. ~]c. and a quartet = (3/C(~). a doublet (~Jc. viz. and 0. : ' .>H:~CI . =-~ . CH 3 CH 2 " (' k%. was heated at 60~ with stirring for 2. N a C N CII2R Vd.. respectively. and the signal of C(~a) is a sextet (sJc(7=vG. i] ~ '" ~ ( H e l l o ) ' ~"~F:Y'~ . .68 g (15 nunole) of dimethylamine in i0 ml of benzene with stirring. This gave 6....5 g (I0 mmole) of methoxybenzofuran I. ll ml of car- bon tetrachloride.6%) of II.. e vd R=o%iis.H= 3 Hz) at 147.7.5.. . These reactions result in the formation of 2-methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-ethoxymethyl- benzofuran (Vd) and 2-methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-cyanomethylbenzofuran (Ve) with high yields. \ COOC21I 5 CHsO / "']~ C00C2H 5 1.. .5 Hz. We also carried out the chloromethylation of 2-methyl-3-carbethoxy-4. This gave 2.~ V e X . EXPERIMENTAL The ~H and :3C NMR spectra were obtained on Varian XL-200 and XL-100 spectrometers. The hot reaction mix- ture was filtered. A mixture of 2. The spectrum of compound VIIa differs significantly from the spectrum of Va with respect to the values of the chemical shifts (Table i) and especially with respect to the character of the multiplicity of the signals of the carbon atom of the benzene frag- ment.a 5. and dried. ..cij~ 4:5 Hz). which is converted without isolation under the action of sodium cyanide into compound Ve. The course of the reaction was monitored chromatographically on Silufol-254 plates in a 9:1 benzene'methanol system with development in UV light. The reaction mixture was diluted by I00 ml of water. The splitting of the signals of C(7) .01 ml of concentrated H2SO. and C(s).G-CH~4.45 g (19 mmole) of acetoxybenzofuran II. I0 ml of acetic anhydride.4.(~ '~ s "-.5 h. are the most characteristic from this point of view. Compound Vc reacts with nucleophilic reagents.4 g (19 mmmole) of N-bromosuccinimide.3~v~. 2-Dimethylamingmethyl-3-carbethoxy-4-hydroxy-5-methoxybenzofuran (IVa).~l= 11.. CIl :~I "CII 5 Va . in CDCI3 with TMS as an internal reference. ethanol and sodium cyanide. washed with water.~COOC2H 5 z ""~''~Y-. = s/c<~>:H = 8 Hz) at 147.

9 6.0 69.5%) of the hydrochloride of compound Va. The reaction mixture was diluted with 1 liter of water.3 5.0 6. IVa-c.92 6.8 ~.42 tq 3.0 IVa 170--173" 54.4 10.3 CisH2006 62.1 '2~.4 10. and Vllb were recrystallized from ethanol.1 11. III. and dried.5H1606 61.72 4.10d (~rUao8 m. Compounds Vlla and Vllb were obtained in a similar manner from 2-methyl-3-carbethoxy-4- hydroxy-5-methoxy-7-piperidinomethylbenzofuran (VI).5 *Compounds II.33 d.87 7.3 5.6 1.25t 1. washed with acetone.3 4.72 g (21 21 .3 CIsH24CINOs 58.0 11.5 73. % pound formula l- H [CI(Br) N c H [Cl(Br) N II 129--131 61.3 C14HIsCIOs 56. Characteristics of Compounds II.87 s 1. A solution of 2.42 q.0 25.5 4. Va. 1. 3.3 C.7 51. 7.0 IVb 181--1824 58.4 CIgHmCINO~ 59. and the precipitate formed was filtered out.6 3.5 Vb 220--221: 59. pound 2-CH2Br.5 88.6 III 96--97 48.45 t mixture was left to stand for 24 h at 20=C and then washed with water (two 50-ml portions. Ve. washed with acetone.sH2oCINO5 54oE 6.2 ~.4 6.8 6.9 5. 2-Methyl-3-carbethoxy-4-hydroxy-5-metboxv-7-piperidin0methylbenzofuran (Vb).5 -.95 s 4.0 Va 205---207 55.42 t Vc 2.7 C2~H32Oto 54. ppm.5 C. and the pH was adjusted to 3 with concentrated hydrochloric acid. 87.92 s 3.2 10.8 60.9 9. Vc and Vd were recrystallized from hexane.5 Ve 174--176 52. dried.0 g (60 mmole) of methoxybenzofuran I in 250 ml of dioxane was given an addition of 24. and Vlla were characterized in the form of the hydrochlorides.sNOs 62.3 4. Vc. and the benzene) layer was separated.3 9. The residue was dissolved in 20 ml of acetone and given an addition of concentrated hydro- chloric acid to pH 3.0 48.92 6. Proton Chemical Shifts of Compounds III. Va-e. This gave 0.7 6. and X Found. Vd. ~Decomposition.5 6..5 6. dried over magnesium sulfate. III. and Ve 6 .9 5.9 CIsH~2CINO5 55. VZIa. Vllb. % Com.sH22CINO5 55.73 4.9 6.S 3-COOC2Hs 5-OCH3.42 q 3.4 6.7 6.0 X 257--259 54.6 9.8 16.4 4.H 7-CH2OC2Hs III 4.92 6.5 9.3 4. and dried.66 s 3. 7-CH2CN.8 6. The precipi- tate formed was filtered out. The precipitate isolated was filtered.82 4.44 t Ve 2. Vb. 7-H.5 6.2 3. 7-CH2CI.5 Vc 126--128 56.84 g (51%) of the hydrochloride of IVa. Compounds IVa_c.4 6.3 CI6H2~CINO6 55.8 77.) 1. Va. and evaporated to dryness. Vb. A so- lution of 15.sH. S 6.55q .5 g (240 mmole) of bis(dimethylamino)methane and boiled for 20 h.9 6.9 6.1 '10. IVa-c.3 g (69.8 C. TABLE 2.3 5. and Vllb was characterized in the form of the base. Compounds IV and IVc were obtained in a similar manner.sH~3NO6 51. TABLE 3.79 s 1.7 49.4 10. % Calculated. 2-Methyl-3-carbethoxy-4-hydroxy-t-methoxy-7-dimethylaminomethylbenzofuran (Va). washed with water. The base obtained was dissolved in i00 ml of acetone.0 18.1 C~sHlsBrO6 48. This gave 14. mp/~ ~ Empirical Yield.8 9. X was recrystallized from ethyl acetate.94 s 4.6 5.75 g (llmmole) of compound I in 50 ml of dioxane was given an addition Of 1. in CDCI3 Com- 2-CH~. and Vlla were recrystallized from acetone.2 51.0 45.2 5.0 C.3 6.0 IVc 180--182 56.8 Vr 85--86 62.3 C. and recrystallized from acetone.40 q 3.70 4.45 Vd 2.7 10.6 4.0 Vlla Vllb 175--176~" 136--138 55.

A . F . N. Izobr. washed with water. A. No. 3. A . Reson.9 g (87. R. 2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-chloromethylbenzofuran (Vc) and Bis(2-methyl- 3-carbethoxy-4. and given an addition of a solution of 1. The reaction mixture was diluted with 200 ml of water. Sarkisova. N. No. C . N. Grinev.9 g (63%) of compound Ve. 2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-ethoxymethylbenzofuran (Vd). K.5%) of the hydrochloride of compound Vb. Vasil'eva. Soedin. The precipitate was dissolved in 20 ml of acetone. 216. dried. This gave 0. The alcohol was evaporated to dryness.48 g (5 mmole of Vc in 30 ml of dioxane was given an addition of a solution of 0. Lyubchanskaya. K. Sarkisova. 1322 (1984). A. Geterotsikl. Levy and G. Guillaumei. J.03 g (21 mmole) of sodium cyanide in 7.5 ml of water. N . Bull. The re- action solution was diluted with 200 ml of water. Soc. This gave 2. The passage of hydrogen chloride through the reaction mixture was continued for i h at 5-I0~ The pre- cipitate formed was filtered out. D . Nelson. V. Platzer. washed with acetone. Lyubchanskaya. P .5%) of compound X. Grinev. Royer. Grinev. I. and recrystallized from acetone. 22 . Vol. and dried. 8. This gave 0. 14 (1981). 5.. A . P. S. L. Progress in Nuclear Magnetic Resonance Spectroscopy. Carbon-13 Nuclear Magnetic Resonance for Organic Chemists. Chim.245 g (4 mmole) of sodium cyanide in 3 ml of water. Khim. 6. The precipitated methiodide was filtered out. A solution of 1. p. A solution of 1. This gave 0. The mixture was boiled for 3. Yu.1 g (42 mmole) of methyl iodide with stirring. This gave 4. Khim.5 h. 252 (1976). L.64 g (i0 rgnole) of dimethoxybenzofuran IX in i0 ml of dry benzene was saturated with dry hydrogen chloride and given an addition of 0. No.4 g (13 mmole) of paraformaldehyde at 5~ with stirring. 2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-cyanomethylbenzofuran (Ve).1 g (49. 4201 (1972).7 ml of formalin and boiled for 25 h. Ii.683. The residue was recrystal- lized from hexane. K. 1181 (1983). and the precipitate formed was filtered out. 37 (1976).-P. and evaporated to dryness. Stolyarchuk. Panisheva. 530. and the mixture was boiled for 14 h. washed with 30 ml of benzene. A solution of 2. and L.mmole of piperidine and 0. and the residue was recrystallized from hexane. S.6 g (21 mmole) of Va in 40 ml of dioxane was given an addition of 6. N. P . No. K. dried. Org. V. G . A solution of 6. France. Buisson. Ivanova. Hansen.. dried. and E.8 g (77%) of Ve. and the precipitate isolated was filtered out. and dried. Then the reaction mixture was diluted with water (300 ml). Wiley-lnterscience. I. Byul. USSR Patent (Inventor's Certificate) No. Soedin. Shadurskii. and recrystallized from acetone. dissolved in 75 ml of dioxane. B. and the benzene layer was separated. New York (1972). 9. and V. and dried.0 g (3 mmole) of chloromethyl derivative Vc in 30 ml of ethanol was boiled for 2 h. M. Demerseman. and the precipitate formed was filtered out. 7. Shevdov. washed with water. Geterotsikl.5%) of Vd. L. washed with dioxane. M. N . No. 4. Venevtseva. Magn.. Alekseeva.8%) of Vc. The mother solution was washed with water (five i00 ml portions).0 g (18. i0. Sheinker. LITERATURE CITED I. and J. 2. M. This gave 1. N . S.5-dimethoxybenzofuran-7-yl)methane (X). A. and the precipitated substance was filtered out. V.. Clark. A mixed sample with the product obtained according to method A does not dis- play any melting-point depression. washed with water. the pH was adjusted to 3 with concentrated hydrochloric acid.5 g (16.

4. Tyrina. A. G.trans- l-methoxy-3. Thioacetals lla-c were not detected. The openin~ of the acetal ring in compounds la-c should produce a carbonium ion (A). For this purpose we studied the reactions of trans. At the same time. If the reaction mixture is subjected to the simultaneous action of hydrogen sulfide and hydrogen chloride.trans-I-MERCAPTO-3-PHENYL-5-(4-METHOXYPHENYL)-2- THIABICYCLO[4. G.3-diaryl-3-(2-oxocyclohexyl)-l-propan- ones with hydrogen sulfide in methanol in the presence of hydrogen chloride result in the formation of either trans.50 9 1986 Plenum Publishing Corporation 23 . Sorokin. UDC 547. In this con- text it seemed to be of interest to study the reactions of bicyclic acetals la-c with hydro- gen sulfide and hydrogen chloride in a polar solvent.trans-hemithioacetals IVa and IVc. V. G. of trans. it is known that acetals are split under the action of hydrogen chloride.trans-I-METHOXY-3.trans-thioacetals lla-c in the reaction products attests to the fact that intermediate C with a configuration which is most favorable for the intramolecular interac- tion of the mercapto group with the carbonyl group clearly does not form.. 0009-3122/86/2201-0023512. Original article submitted August 2. Struchkov. if the concentration of hydrogen sulfide is small.0]dec-3-enes or 2~4-diaryl- 5.0]dec-3-enes (I).3-diaryl-3-(2-oxocyclohexyl)-l- propanones.trans-3. i.4. K.4. Since the equatorial attack of ions of such a type is sterically hindered.trans isomers of type II is also not observed. and the formation of cis.81:543. takes place. I. January.422: L. Saratov 410601. It was noted that the conversion of oxy- gen analogs of I into sulfur analogs of type II is not observed in methanol.4. 1984.5-DIARYL-2-OXABICYCLO[4.trans-l-mercapto-3. pp. According to the data in [i]. A. Translated from K h i m i y a Geterotsiklicheskikh Soedinenii.0]dec-3-enes or trans. The elimination of methanol from intermed- iate B gives carboniumion D and then either 4H-thiopyrans lllb and lllc.trans-acetals la-c in acetic acid which had been saturated to the limit with hydrogen sulfide at I0-15~ results in the forma- tion of trans. 1986.5-diaryl-thiabicyclo[4. In the latter case. N. has been described. 548. T. The intramolecular interaction of the mercapto and carbonyl groups which occupy axial and equatorial positions in hemithioacetal B is impeded by the rigidity of the acyclic chain. as was shown in [i]. Shcherbakov.0]DEC- 3-ENES INTO HEMIDITHIOACETALS AND 4H-THIOPYRANS.e.trans-l-methoxy-3. It was established that the re- action of hydrogen chloride with a suspension of trans. an interaction with one of thenucleophiles.CONVERSION OF trans. 4H-thiopyrans lllb and lllc are recovered as the reaction products. No. A mechanism for the reaction has been proposed. A.0]DEC-3-ENE S. Klimenko. STRUCTURE OF trans. Chernyshevskii Saratov State University. with methanol.trans-acetals la-c with hydrogen sul- fide in acetic acid under the conditions of acid catalysis.6-tetramethylene-4H-thiopyrans. N. the preferential axial attack of ion A should produce intermediate B.5-diaryl-2-oxabicyclo[4. the reactions of 1. 28-33.4.5-diaryl-2-oxabicyclo[4. which is structurally similar to the protonated form of 1. N.trans-hemidithioacetals IVa and IVc via gem-dithiol E. I. and V. Aleksandrov. which takes place when hydrogen sulfide is reacted with the acetals in acetic acid with the use of gaseous hydro- gen chloride as a catalyst. The absence of trans. Vlasova. T.737 Yu.0]dec-3-enes into trans. The structure and confirmations of the molecules have been deter- mined by x-ray diffraction analysis and I~C NMR. Kharchenko The conversion of trans.4.5-diaryl-2-thiabicyclo[4.

.3.7 ~3.. z = 4.R ' ~ . . a small quantity (9. The intramolecular cyclodehydration process E + IVa.~ 0 <. c = 16. . . . .SH H~> .. the dissolution of the original compounds Ib and Ic and the precipitation of 4H-thiopyrans lllb and c are observed after 30-40 min.71(1) ~ . i. ...4.7 cm -~.. ~ . The stereochemistry of the molecule with the principal bond lengths and bond ang- les is shown in Fig. " .trans- acetals of type I into hemidithioacetals of type IV. 2.' SFI E IVa..a.4-diarylbicyclo[3. The coordinates of the atoms are listed in Table i.aS ~...-_ /_.28 g/cm 3.trans-•-meth•xy-3-(4-meth•xypheny•)-5-pheny•-2-thiabicyc••[4.. b = 10.5-diphenyl-2-thiabicyclo[4. cR=C611s.1]non-2-en-9-ones of type VI. When there is a shortage of hydrogen sulfide in the mixture.trans configuration. . .. b R=CoH~OCI|3-4. ~ = 115. trans compounds IVa and c as intermediates is the limiting saturation of the reaction mix- ture at I0-15~ with hydrogen sulfide.. The crystals of compound IVc are monoclinic: a = 12.4. 2.e.. ~}~ / H H '###BOT_TEXT###quot; l " "'R B C 0CH 3 CH3OH] IIa-C + . c R~=C6H4OCHs-4 A necessary condition for the formation of gem-diothiolsof type E and then of trans. ._ R V /_. ( ~'R '"R V C VIc When the experiment is conducted in the absence of acetic anhydride. ... ion A can be subjected to the attack of another nucleophile.4. v(Cu Ka) = 24.425(1) ~. C A SH ..R~ H (~H S R D H+ lllb.#. we determined the crystal and molecular structure of l--mercapto-3-phenyl-5-(4-meth0xyphenyl)-2-thiabicyclo[4.~r. which is evolved when 4H-thiopyrans of type III are formed. V = 1915.•]dec-3-ene [2] and cis- 3. C a.c is stereospecific and results in the formation of substances with a trans. M = 368.575(1). The trans-diequatorial arrange- ment of the interacting parts in gem-dithiol E is most favorable for cyclization..' Z -H20 \S ~'R SH" ~ . This results in the formation of the products of the intramolecular cyclo- dehydration of 1.R I "~. / 0C}'I3 I 1 1It la. ...0]dec-3-ene (IVc).5-diketones of type V.tI2S/ttC!.0]decene-A ~'6 [3]../* . The geometry of dihydrothiopyran ring A is close to that found in the molecules of trans. :g r -CH~OH /" . c I H. viz.. i.2942(8). This is consistent with the results in [i].. ~:[t + . and the torsion angles are presented in Fig. The geometry of the methoxy group is close 24 .b Rl=CoHa. and the equations of t h e planar fragments in the molecule and the deviations of the atoms from them are given in TabZe 2. For the purpose of confirming the proposed mechanism for the conversion of trans. d c a l = 1. water..5%) of compound Vlc is recovered along with 4H-thiopyran lllc. When hydrogen sulfide and hydrogen chloride are sim- ultaneously reacted with acetals Ib and Ic. space group P2~/c.

The bicyclic system has trans annelation.) atoms deviate in opposite directions from the planar S(2)C(3)- C(~)C(5) fragment.443. 25 .7(3). S(. i.546(6). does not coincide with the standard value of 1. 1 Fig. S(2)C(.6(2).4 ~ . S(.6(3). respectively.8 ~ . in Cu Ka radiation with a graphite monochromator.4.) bond in the mer- capto group.4(3).5-diphenyl-2-thiabicyclo[4. has a trans. Fig. which was established on the basis of an analysis of their '3C NMR spectra* (see Experimental section).360 A. EXPERIMENTAL The unit-cell parameters and the intensities of 1772 independent reflections with I > 30 were measured on a Hilger--Watts automatic four-circle diffractometer. Fig. and I < e < 57 ~ . C(~)--C(6) = 1.817(5) [5].0 ~2).9(3) . 2 Fig. O-C(Ph) = 1. 2.)-C(.o) = 109. The structure was solved by the direct method according to the MULTAN program and-- re~ined by the least-squares method in the full-matrix anisotropic approximation. The final values of the R factors were R = 0. to that found in the structure of 4-methoxybenzoic acid [4]. which is equal to 1.)C(~)C(6)= 112.trans configuration.835(4). like hemidithioacetal IVc.)S(2) =108.o) = 105. The dihedral angles between rings C and D and the planar fragment of the heterocycle are 46.835(4) ~. S(~)C(.0]dec-3-ene (IVa). 4H-Thiopyrans IIIb and IIlc were identified on the basis of the characteristic signals of the vinyl and 4-H protons in the PMR spectra [6]. *A detailed discussion of the ~3C NMR spectra of hemidithioacetals of type IV and related he- terocyclic systems will be presented in a separate report. 0/20 scanning. Dihydrothiopyran ring A has a "half-chair" conformation. where O-C(Me) = 1. All the hy- drogen atoms were revealed by a difference synthesis and taken into account in the concluding steps of the refinement with fixed positional and thermal parameters (it was assumed that Bis o = 5. and the C-O-~ angle is equal to 116.)= 1.)C(~)C(. /X'16(6 " P117. Phenyl rings C (in position 3) and D (in position 5) are planar. The length of the S(.0514 and Rw = 0. Torsion angles in compound IVc.0641. cyclohexane ring B has a "chair" conformation. Bond lengths and bond angles in compound IVc. which was controlled by a PDP 8/1 computer.7 and 99.)C(. l-Mercapto-3. Phenyl substituent D is found in a pseudoequatorial position.)-C(. S(. the C(i) and C(.

6.32 (C(z)).5 ~ (from petroleum ether). 25. 128. and para carbon atoms were given in that order.0]-dec-3-enes (la. 127. Calculated for C==HzsOS=: C.87 (phenyl at C(s)). 8042 (3) . This gives 2. and crystallization of re- action product IVc is observed. and the hydrogen atom of the mercapto group is denoted by H(S ).92 (C(s)).66. S. 71.5 h at !0-15~ and then with a mixture of hydrogen sulfide and hydrogen Chloride for i h. The treatment of 20 mmole of trans. 71. and another 1.96.78 (C(xo)). S.06 (C(9)). The mixture is left to stand for 17 h in a refrigerator.4. Conversion of trans. 8893 (2) 2118 -383 7791 2023 (3) 1585 (4.5-diaryl-2-oxabicyclo[4.5 4 8 (2) 2234 3) 10602 (2) FI(81 2891 3689 9074 C(1) 4231 (3) 1866 13 8661 (2) |IIfll 3293 956 9267 C(s) 5319 (3) 2820 41 10409 (2) ||fT~ 1370 1435 8225 C~ 4245 (3) 3203 (41 10261 (3) |I ~7Q 1863 2401 7677 C(~ 3096 (3) 2903 (3] 9475 (2) .4%. 22.03 ppm (the CHsO group in the aryl radical at C(~)). The original acetals la-c were obtained in analogy to [7]. Tm = I07-I09~ :3C NMR spectrum (CDCIs): 57.02 (C(5)).trans-•-Mercapt•-3-pheny•-5-(4-meth•xypheny•)-2-thiabicyc••[4. Found: C.. 126.06. 130.20 (C(:)).0]dec-3-enes (Ibp c) into 2-(4-Methoxyphenyl)-4-phenyl-5.04.54 (C(4)).88. 122.q I 3187 3518 7729 Sc~ 5612 (i) 1777 tl) 9676 (1) 11(4~ 4195 3772 I0735 0 . 126. c) into trans.•]de•-3-ene (IVc) and trans. In the case of the aromatic substituents.32. 26. ortho. The *H and X3C NMR spectra were recorded on a Varian FT-80A spectrometer (80 MHz) with HMDS (for XH) and CDCI3 (for '3C) as internal references.13 (C(s)).05 g of hemidithioacetal IVc with Tm = 139.28. 6.) 4367 . H. 40. washed with water.23 (C(6)). 16. A suspension of 3.63. After 0.22 (C(9)). The course of the reactions was monitored by TLC on Silufol UV-254 plates with a 6:1 hexane-ether mixture as the eluent.Iig~ 2988 1325 6831 C(e) 2050 (3) 445 (4) 7454 (2) 3137 -253 6898 C(9) 3097 (4) 547 (41 7225 fl(lO~ 4903 8O5 7907 C(~o) 4238 (3) 695 (3) ~]flo. 113. TABLE i.98 (C(~o)).6-tetramethylene-4H-thiopyran (IIIb) and 2-Phenyl~4 - ( 26 . Coord.9 g (87%) of hemidithioacetal IVa with Tm = I07-I09~ (from a 1:3 ethanol-- acetone mixture).5 g of IVc are recovered. 129.37 (p-methoxyphenyl). 40. 158.72 (C(5)). the total yield is 94%. 49.) 56 1049 I1771 C(~2) 2210 (3) :715 (4) 10378 (2) -442 35O I0763 C(~) -596 (4) 123 (4) 11093 (3) *The numbers of the H atoms coincide with the numbers of the corresponding nonhydrogen atoms (with single and double prime signs for the second and third H atoms).334 (4) 9789 (3) H ~22~ 2911 1123 I0607 C(~o) 368 (3) !331 (4) 10369 (2) HI~3~ -1389 Illl lllll Cim) -1335 (3) 520 (4) 10667 (2) H (~B.l[~h 1308 442 6883 3167 (3) 1756 (3. the signals of the quaternary. H.76 (C(s)).6. Conversion of trans. meta.4.trans-l-Mercapto-3.ina~:es o f At:oms (• ~) S(i) 4214 (I) 3376 (1) 8061 fl) FI/. 130.0]dec-3-ene (IVa).~ 6393 (3) ]092 (3) 1126O (2) ll(12i 7490 3556 I0667 C(m) 7451 (3) ]445 (4) 11259 (3) 9200 3903 12027 8442 (4) 3648 (4) 12047 (3) llfI4~ 9114 3622 13453 Coo 8392 (4) ~491 (4) 12872 (3) /][iR~ 7298 3059 13470 C(~5) 7346 (4} H54 (4) 12881 (3) zL(f6) 5592 2685 12106 C~m) 6362!3) }945 (4) 12090 (3) H(.4.83. 47. 127. 17. and then compound IVc is filtered out.5 h has elapsed from the beginning of the passage of HCI.82 (C(s)).5-140. 27.trans acetal Ia according to the method just de- scribed gives 5.8) I075 4220 9067 C(17) 2129 t3) ~694 (3) i 9784 (2) H(191 -398 3941 9583 C(18) 1154 (3) L500 (4) i 9499 (3) H~21) 1409 796 II096 C(m) 291 (3) .9%. initial acetal Ic is dissolved. The mother solution is poured onto ice. 47. 126.7.9. 123.50 (C(7)).32.13.trans-l-Methoxy-3. 128.93 (phen- yl).4.49 ppm (phenyl at C(5)). and dried in air. 128. 22. 6.69 (C(7)).5-diphenyl-2-thiabicyclo[4.I13 8451 C(. *SC NMR spectrum (CDCI3): 57.trans-l-Methoxy-3-5-diaryl-2-oxabiqyclo[4. 142. 138. according to the data in [8]. 49. 139. 128.26.6 g (15 mmole) of acetal Ic in 40 ml of glacial acetic acid (with an addition of 2 ml of acetic anhydride) is saturated with hydrogen sulfide for 1.09 (C(4)). 55.56 (C(6)). 22. 134.

m. The precipitate is dissolved in ether and filtered.5 h the reaction mixture is poured onto ice.4.009 0. methylene protons).. A suspension of 20 mmole of acetal IB in 35 ml of glacial acetic acid with an addition of 2. and dried in a desiccator.0 95.3. and T m = I19-120~ (ethanol--ether).OOl I 0.oo6Io. ic.. 3J~.9 Hz). methylene protons). Calculated for C22H22OS: C. 4-H).001 O.450 -0.96 (IH.5 ml of acetic anhydride is satur- ated by a mixture of hydrogen sulfide and hydrogen chloride at I0-15~ After 0.20 (8H.9 planes in deg *Atoms not involved in the calculation of the equations of the corresponding planes. 4H-Thiopyran lllc is obtained in analogy to the method just described from 20 mmole of acetal Ic. c.352x + 0797y + 0. d.9 Hz).6%. 3.0. The yield is 4.81 (IH.6-tetramethTlene-4H-thiopyran (lllc). 8 2 7 y . 6.503 S(2) C(3) C[4) C(5) C(D* C(6)* I S(1)* Plane I .40 ppm (9H.009 .267 (ring A) C(7)* C(1o)* I C(H)* I C~lT)* H(s)* H(6)* I O:118x+ 0 .o.68 (3H. m. I c. H.~ = 5.s.60gg.6 121. S. 79.004 0.o.61-2. CH30)..95 (IH.6%.3.4 39. S. TABLE 2. d.. 3.*l S/'-"* ICr H(6)* . c.0 9 [ 46. 9. 4-H. 5. H.781 c.4. 9.6. aromatic protons.169x--0.0. 79.67 (3H.9659 . m. dis- solution of original acetal Ib is observed.20 ppm (9H.20(8H.5 h. H.1]non-2-en-9-one (~Ic) with Tm = 174-1757 (ethanol) is recovered from the residue which does not dissolve in ether. s.005 --0.=.012 10. methoxyphenyl)-5. 78. If the reaction is carried out in the absence of acetic anhydride. 3.0.261x + 0.c ). CH30). Tm = 174- 175~ A mixed sample with a known preparation of the compound does not show melting-point depression~ 27 .oo2I-o.6%.65-2.0.6%. S.7 99.002 --0.490z = .006 0. and the precipitate formed is filtered out.003 -0.6. d. PMR spectrum (CDCI~): 1.o. 4-H).009 i --0.5. 5. i.69-7. ls.oo6 0. 0.19 c )ic o) c. 6. aro- matic protons). The yield is 4.054 L --0.lo Plane 4(ringD) 1o..12. Found: C. S.756z= .0.768 C(ll) C(121 I C1131 C~14) C(15) C1161 C131"~ Plane 3 (ring C) --0.95 (IH.6 g (69%). and 4H-thiopyran lllb is precipitated from the etheral extract by ethanol.003 0. PMR spectrum (CDCI3): 1. Calculated for C2=H22OS: C.002-0.5%) of 2- phenyl-4-(4-methoxyphenyl)bicyclo[3.5. 0:549z = .022 1/2 1/3 1/4 2/3 2/4 3/4 Angles between 14. 6.72-7.0. H. 9.339 I 2. and Tm = 107- I08~ (ethanol--ether). c. s.018z= 2. 6. 3-H.oosI o. 79. and after 1. 9.8 g (72%).. 3. 6. 6. 3Js.6 ~ (9. Found: C. washed with water. According to [9].0.9.4 = 5. d. Equations of the Planar Fragments in the Molecule Ax + By + Cz = D* and Deviations of Atoms from Them in 0.

and in particular for the preparation of medicinal compounds.31 By quantitatively studying the sulfonation of thiophene and its homologs by com- plexes of sulfuric anhydride with ethers. Indian J. London (1965). On the other hand. O. A. Klimenko. I. Soboleva. alcohols. etc) [6. and V. S . 435 (1975). A. which is the reverse of the increase in the basicity series of a donor. Khim. 1984. L . Klimenko.8): 541. V. 1194 (1985). Ya. K. S. 2. steroids. and V. R . Klimenko. Stolbova. Zh.07(088.226..49:546. The Chemical Society. Chem. Bryan. in recent years great attention has been paid to the study of the structure and reactivity of complex compounds of S03. G. Klimenko. North-West Correspondence Polytechnical Institute. F . No. B. 6. Mehta. O. R . Shustareva.732. Aleksandrov. 5]. and B. polysaccharides. Zh. G. LITERATURE CITED I. No. 1311 (1967).. L . Klimenko. 7]. Khim. ii. S . I. 8. and V. Ya. and S. A. Evtushenko. V. 2]. Kharchenko. Ionin.. K. Zh. D'yachenko. Passet in 1979 at the XVth Scientific Session of Chemistry and Technology of Organic Compounds and Sulfur- Containing Oils in Ufa. Kharchenko. G. 34-39. 470 (1979). No. Geterotsikl. Soedin. and trialkyl phosphates it was possible to determine kinetic and thermodynamic parameters of the process. 561 (1965). No. V!asova. Tyrina. 499 (1978). T. G. Kharchenko. Soc. 12. L. Kharchenko. I. Struchkov~ and V. lonin. 1056 (1980).127:547. J . including thiophenes. V . which are widely used in fine organic synthesis [3]. 13.. Supplement 1956-1959. Khim. 9. Strukt. Tyrina. Kharchenko. K. T. 19. no quantitative data are available in the literature* on the sulfonation reaction of 5-membered heteroaromatic compounds. January. Shcherbakov. Stolbova. Leningrad 191041. I. K . and V. Special Publication No. i. 3. Despite the large amount of quantitative information of the electrophilic substitution in the heteroaromatic ring [i. pp.. N. where thiophene sulfonic acid and its homologs are intermediate pro- ducts in the synthesis of sulfamide and sulfanilamide derivatives [4. G. S. 18. Tables of Interatomic Distances and Configuration in Molecules and Ions. K. I. Chem. 1986. Khim. V . 4. V. K. T. Yu. Khim. amides. T . !. 8. besides the study of kinetics and mechanism of sulfonation of thiophene and its homologs. 28 0009-3122/86/2201-0028512. Soedin. *We have made a preliminary report on this problem in coauthorship with B. Original article submitted November 21. Org.. Geterotsikl. I. Geterotsikl. it was also of interest to study and quantitatively compare the reactivity of complex compounds of SO3 with different organic donors.. S. STUDY OF KINETICS AND MECHANISM OF SULFONATION OF THIOPHENE AND ITS DERIVATIVES BY COMPLEX COMPOUNDS OF SULFURIC ANHYDRIDE T. Sorokin. Translated from Khimiya Geterotsiklicheskikh Soedinenii. E. No. 5. Soedin. Klimenko. Kharchenko. J~ B. Desai. to propose a SE2 type reactionmechanism and also to reveal a quantitative depend- ence of the rate constant of the sulfonation reaction of thiophene on the basic- ity of the complex-forming agent: The sulfonating activity of the complexes studied increases in the series ~ amides < trialkyl phosphates < ethers. Merchant. N. V . G. 4. K. which are of interest as mild sulfona- ting reagents for the sulfonation of acidophobic compounds (heterocyclic compounds. V. T. Sutton. and V. 7. 193 (1977).50 9 1986 Plenum Publishing Corporation .. G. Druzhinina UDC 541. E . Org. Therefore. Evtushenko. B. J. V. 9. Khim. Atovmyan. S. G.

e. or there is practically no reaction (DMFA. Time-dependent change in con- centrations of reaction compounds and reaction products during sulfonation of 20 21` thiophene by a DMFA. during the transformation of the heterocycle into a monosulfonic acid according to equation: where D is a donor. we chose thiophene.S03). mole/m3 3 3o Fig. As the initial substrates. 0 I0 2o 30 c0 50 60 70 80 90 I00~. In all the experiments. i). This amount was the same and equal to the initial concentration of the complex or the corresponding thio- phene.SOs). w h i c h p r o v e s t h e absence of stable by-products in analytically determinable amounts. tetrahydrofuran (THF. 29 .S03).2-dichlor- oethane) or in the complex-forming agent medium. at a considerable excess (>60:1) of the heterocyclic compound with respect to the sulfonating agent (the SOs complex). and trialkyl phos- phates [tributyl phosphate (TBpoS03)]. dioxane (DO. and 2-bromothiophene (less active in electrophilic sub- stitution reactions). To determine the order of reaction with respect to the SOs complex. S03). the order of the reaction with respect to the substrate is also equal to i. amides [dimethylformamide (DMFA. the sulfonation reaction is carried out in an inert solvent (l. As in the sulfonation of benzene homologs by SOs and its complexes [7. rain In the present work. i. the change in the concentration of the initial sulfonation agent (the SO3 complex) and the sulfonic acid formed in the reaction was quantitatively recorded by the method of differential nonaqueous potentiometric titration of an aliquot portion by an alcoholic solution of diphenylguanidine in mixed solvent medium (acetone--isopropanol--glycer- in). during the reaction of thiophene and its derivatives with complexes of SOs with different organic donors.S03 complex (Py. In the benzene series. It was thus possible to determine the overall amount of sulfonic acid and of the unre- acted sulfonating agent for each experimental point over the whole kinetic curve. TBP. 2-methylthio- phene (more active than thiophene). The nature of the kinetic curves obtained for the sulfonation reaction of thiophene and its homologs was shown for the example of a sulfonation reaction of thiophene by the DMFA. THF. 9 C. since the sulfonation of benzene proceeds very slowly (DO-SOs. ii].SOs complex in a i.S03). As has already been shown in [7. 1-4) con- 1o .SO~ complex at different temperatures (see Fig. The UV spectra of the reaction mixture taken after the end of each experiment confirmed the formation of monosulfonic acids only. the pyridine. 9].S0s)]. Depending on the activity of the corresponding complexes and the reactivity of the het- erocyclic compound. centration of sulfonic acid. I'-4') con- centration of sulfonating agent. which shows a first order of the sulfonation reaction with respect to the SOs complex. I. 400C (3) and 50 ~ (4). 2-dichloroethane medium at 20~ 30~ (2). The experimental data thus obtained obey the kinetic equation for a pseudomonomolecular processes. we quantitatively studied the sulfonation reaction of thiophene by complexes of S03 with various organic donors: ethers [diethyl ether (E. similar studies could not be carried out. which is less active than thiophene. thiophene was sul- fonated under pseudomonomolecular reaction conditions.. 10].S03.S03)]. which are more active than the known agent [8.

The formation of the intermediate complex as the result of the reac- tion of the sulfonicacidwiththe SOs complex. as during the sulfonation by the SOs complex in an inert solvent medium.. SOs . and successfully used previously for the determination of the kinetic parameters of the sulfonation of benzene derivatives by complexes of SOs with ethers [7]. while the reaction rate obeys a kinetic equation of the second order up to complete transformation of the heterocycle into the sulfonic acid.94 *In dichloroethane (DCE). of which one should be considerably more active than the other. 13].SO 3 '(in 1. the donors in this case are the sulfonic acid formed during the reac- tion and the complex forming agent (organic base) bound into a complex with SOs at the begin- ning of the reaction.279 THF.DCE).SOs complex.SOs complex. For the reaction of each of the two sulfonating agents with one and the same substrate. there are two sections on the anomorphosis of the kinetic dependence. which is the presence of the complex forming agent probably has the structure of Het.528 70."C kmole'sec stage 1 ~ . mS/ System T.4 phene and DMFA. proposed in [12. SOs .e.29 1.S~ 50 2.2 7.551 and DMFA.e.6E Thiophene and 93. in this case the anamorphosis of the kinetic dependence has two sections.9. the anamorphosis of the kinetic dependence is in the form of a straight line. D (Het is hetero- cyclic radical). and the second by k=. each has a characteristic rate.85 4.53 4.141 DCE) Thiophene and 2-Bromothiophene DO'SO~(~n di.59 and DO" S03 (in 30 6.e.48 I0 0. which is determined by means of a differential kinetic extra- polation method. leads us to as- sume the existence of at least two sulfonating agents in the reaction mixture.106 0.6 9. I0 . In general.. To prove this supposition. a deactivation of the sulfonating complex by the sulfonic acid takes place (see scheme). i. a stage which in general ends at 40-50% conversion of the initial reagents is first observed.657 (in.689 31. D complex does not limit the rate of reaction.55 2.13 29. By using this method fn the case of the sulfonation of thiophenes it is possible to determine the values of kinetic parameters given in Table I..3 ~6. the sulfonating agent is the D. and not with SOs itself is confirmed by the fact that during the sulfonation in the complex forming agent medium.SOsH . In this case.SOs complex. the formation of the Het-SOsH .1c Z'SOs.87 1..425 2-Bcomothiphene 70 14. It is clear that the sulfonating activity of the intermediate complex is lower than that of the D.7~ 61..0.6. and from our results it could be assumed that there exists in the reaction mixture a complex of sulfonic acid with SOs. i. which also leads to the slowing down of the rate of reaction. and then monosulfonic acids are further slowly formed. and l~s Derivatives by Sulfurlc Anhydride Complexes k'lOS~ 5~.17 2..285 dioxane) DCE) ~63.sec System 7'. when the dissociation of SOs complex is suppressed. the sulfonation of thiophene was carried out with a threefold excess of D.77 3. An excess of substrate does not lead to this result.330 Thiophene and 19.tage llstage Z lhiophene and 5... it can be assumed that in this case.. 314.~C kmole. The fairly sharp change in the rate of sulfonation.9 SO 3 (im DCE) 0. the sulfonation reaction of thiophenes comprises two stages. 30 .SOs (in 37.53 1. until a final yield of 85-100% is reached (after 2-5 h).545 e~ner) 15..495 0.008 DMFA. mS/ k'lOS~5%.60 2-Methylthio- 595.01 oxane) 17.17 4. 60 5. (i. i. According to the data in [7]. or in the presence of an ap- preciable excess of the latter.576 13.285 Thiophene and 1053 .183 DCE) 5.0 . -15 1.789 0. Since slowing down of the reaction rate begins after ~50% conversion of the initial compounds.174 0..58 TBP'SO S (in 155.72 7. The first stage is characterized by a rate constant kz.

D. Thus.75) indicates the great sensitivity of this reaction to structural changes in the substrate molecule and the high polarity of the tran- sition state of the sulfonation reaction that fully corresponds to the o-complex during el- ectrophilic substitution. The values of the kinetic and thermodynamic parameters that we calculated for the sul- fonation process..SO~ > DO.2-dichloroethane. which proves a common mechanism for the benzene and thiophene series. limited by formation of a o-sulfonation complex.75o.D Complex e.. values satisfactorily correlate with Hammet's o n constants in accordance with the equation (~ = 0. the data of the material balance for the sulfonating agent at each point of the kinetic curve indicate the absence of intermediate products. lead us to conclude that the sulfonation of thiophenes by SOs complexes proceeds in accordance with a bimolecular electrophilic substitution mechanism of the SE2 type (see scheme below): Scheme of reaction mechanism + Ds% ~ . is concluded by the formation of an intermediate complex Ret*SOsH . the further formation of the sulfonic acid takes place in a similar way. We carried out a comparative study of the reactivity of the complex SO3 compounds on the example of the sulfonation of thiophene at --15~ in 1.complexSO~ ~s ~s%n so. At the second (slow) stage. 7~i__-~__ s%"'D~etc.~+// S so~.. the increase in the el- ectron denisty of the reaction center (electron-donor substituents) favors the acceleration of the sulfonation reaction.SO3 > DMFA-SO3.99): Jgkt= -2..75 fully correlates with the con- stants 0 of other electrophilic substitution reactions in the heteroaromatic ring [I. For example. as the result of the interaction of the intermediate complex with the substrate with rate con- stant k2. ~'H "~S03H'-SOs'"D .75. the log k. From the results obtained (Table i). in the case of sulfonation by DMFA.. Our data and the results of the other authors on the absence of a kinetic isotopic ef- fect in sulfonation reactions of aromatic compounds by sulfuric anhydride [Ii] or its com- plexes [7]. and also the fact that stages 1 and 2 of the reaction obey a second order kinetic equation. It should be noted that when a sample is poured into water (to stop the reaction).SO3 > THF..75-8. the SO3 complexes can be arranged into the following series according to their sulfonating activity: E. confirm our supposition on the mechanism of this theoretically interesting and practically important reaction (Table 2). According to the value of the rate constant obtained p = --8. The high value of O in absolute terms (8. 2] and of the sulfonation reaction of benzene homologs by sulfuric acid [i0]. The determined value of 0 =--8.i The first stage. but it is ~i00 times higher than in the case of 2-bromothiophene (Table I). The study of the influence of substituents at the 2-position of the heteroaromatic ring on the rate of sulfonation in the thiophene series shows that in the case of substitution into the 5-position. introduction of a methyl group in- to the 2-position of thiophene considerably increases the rate of reaction at both the first and second stages. and therefore.S03 > TBp.~ ~%'" D ~ ip~. SO3 .SO3 complex at i0 ~ in dichloroethane. 31 . the activity of thiophene at the first stage is -30 times lower than in the case of 2-methylthiophene. the intermediate complex formed in the reaction mixture immediately decomposes.. while decrease in the electron density (electron-acceptor sub- stituents) favors a decrease in the reaction rate. o o--.

Geterotsikl.72 157.1-3. Thus.89 32. Before car- rying out the experiment. A.33. the values of k and the activation energies Ea were determined by the method of least squares on an Odra-1204 compus LITERATURE CITED i.80.0%. The amounts of the complex-forming agent and the substrate required in the reaction were cal- culated from the known concentration of SO3.40 7. the lower the basicity.24 4. fitted with a thermometer. Soedin. and poured into 3-5 cm s of cold water. i. 3.64. Khim. Marino.46. reflux condenser..1 . Complex-Forming Agents and Substrates. m3/ A H ~ 5 ~ A S ~ 5 % K0.SO 3 (in DCE) which is the reverse of the relationship of the basicity series (pK~) of the complex-forming agent [14]: E < DO < TBP < THF < DMFA. 3151 (1977). 7 0 . 22.1012 (im ether) Thiophene and DO-SO3 (in 56.lgk2=.02 83. Khim.. The concentration of the solution was determined from the dif- fernece in weights or by titration of aliquots with an alcoholic solution of diphenylguanidine. Sulfuric anahydride was obtained by conventional methods [8. Vses. Ob-va. I0'c 81. each experiment was repeated not less than 3 times. and the mean value of k was found. No. N.. 2.0 1.08.94 60.62. complex-forming agents and thiophenes corresponded to handbook data.0 .8~ into a weighed flask with 1. Dzh. the higher is the sul- fonating activity of the corresponding complexes.74 8%02 3.~J6 63.e. The mixture is vigorously shaken.97 10. Nauka. and a sampler. 5.1011 Thiophene and DMFA~SO 65. 9] from 65% oleum. For the determination of k.SO3 (in 26. The rela- tive error of the determination of the concentration of the sulfonating agent and the sulfonic acid is 0.86 8. This dependence is expressed by correla- tion equations (z = 0. EXPERIMENTAL All the reagentsused in the investigation were thoroughly purified and dried.75 3%05 (in DCE) 2-Bromothiophene and 85. a given amount of S03 was distilled at Tbp (44. The temperature is maintained with an accuracy of •176 The number of samples withdrawn in the experiments is 14-17. 424. A. lgkl=O:35--1. After thermostating for 50-60 min. Method of Kinetic Investigations. 32 . Preparation of Solutions of Sulfuric Anhydride. a tube filled with P~Os.46. lOs DCE) 1. A c a l c u l a t e d amount of the substrate solution.11pK~.2-dichloroethane at a known concentra- tion is added by means of a hermetic microburette.67 5. Then. Values of Kinetic and Thermodynamic Parameters of Sulfonation of Thiophene Derivatives by Sulfuric Anhydride Complexes Stag_e_l Stage _ _ System AW ~ 5 ~ A S ~ 5 ~ K 0. The relative deviations from the mean value for k are -1-3%. an aliquot is withdrawn for analysis to determine the concentra- tion of the corresponding complex. 1 4 pK=. Budylin. lOs 76. 579 (1973). m 3 / kJ/mol4 J/mole" k~ole" ~J/molel~egree /mole" kmole"see |de~ree sec Thiophene and E~SO3 61.89 31. New Trends in Thiophene Chemistry [in Russian].46.99). the rate of sulfonation of thiophenes depends on the nucleophilicity of both the substrate and the complex-forming agent. Moscow (1976). Kost and V.10" D~A. Finally. 105 50. A calculated amount of a solution of the complex-form- ing agent in 1.71 4.2-dichloroethane. ION dioxane) Thiophene and TBP. Zh.2-dichloroethane is charged into a 150 cm 3 four-necked glass reactor with a jacket. a sam- ple (3-5 cm 3) is withdrawn from the reactor. thermostat- ed at the same temperature is added to the reactor.11 3. 109 78. p.53. a sealed stir- rer. TABLE 2. and a calculated amount of SOs in l. The char- acteristics of the solvents.

8. No.RI=-CH=CH-~CII=CH -- All-Union Scientific-Research Institute of Technology of Blood Substitutes and Hormonal Preparations. A. E. which are synthe- tically more accessible than the natural prostaglandins and have the same or comparable bio- logical activity. followed by alkylation with ethyl 7-iodoheptanoate and reduction of the keto group by sod- ium borohydride. M. Obshch. A. Dombrovskii. 5. Tray.b Ilia. 40-43. A... i0. E. G. P. Gilbert. Chemist's Guide [Russian translation]. The synthesis of compounds la. p. 541. Terent'ev and L.n H 9 lI lla. 1986. Passer. Un-ta (1974). 18. UDC 547. 1 [in Russian]. Garraway. Kadatskii. in which the side chains corres- pond to the side chains of natural prostaglandins. J. 969 (1962).07 and P. G. Buchin and A. 33. Cerfontain. b is shown by the following scheme: RI ~ ~N" ~CHO I~~ "" " ' N ' / ~ C H = C | I C O . Original article submitted December 4. for example. Gracheva. Khim. Mir. P. we were first to synthe- aize dl-2-(trans-3-hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (la) and dl-2-(trans- 3-hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (Ib). Cerfontain..C ~ I I 1 1 . L. Mel'nik. Sulfonatlon of Organic Compounds [Russian translation]. Vol. W. 896 (1961). 2]. Khim. W. derivatives of indole. Kaanderp. Hanna. i. Bosscher and H. V. Anal. Translated from Khimiya Geterotsiklicheskikh Soedinenii. This is mostly due to the fact that some of the azacyclic analogs of pro- staglandin are strong inhibitors of the thrombocyte aggregation [6]. Special attention is paid at present to the synthesis of analogs of prostaglandins in which the cyclopentane ring is replaced by a nitro- gen-containing heterocycle. 24. pp. C. E. B. 0009-3122/86/2201-0033512. Moscow (1976). 723 (1948). pyrrolidine. SYNTHESIS OF HETEROCYCLIC ANALOGS OF PROSTAGLANDINS FROM PYRROLE AND INDOLE V. V. 6543 (1968).b la. and G.741'754'295'361. E. 1984. Zh. Chem. Rec. 12. Moscow (1976). b R~ R R1/ -N / " CII=CtI-CO:CbH ~. A. Chem.50 9 1986 Plenum Publishing Corporation 33 . S. In recent years. A. Carter. 81. A. M. Kochergin Heterocyclic analogs of prostaglandin. Lipkin.~-n R1 "N ( ~C112)6~-C00C2iI~ ( ]CI|2)g-'COOC2I| 5 Iva. L. A... 13. Anal. 262. Papa. p. In search for new potential thrombocyte aggregation inhibitors. Obshch.4. Pestic. 801 (1962). January.. Khimiya. Ford. I. Chim. 9. T h i o p h e n e and Bithiophene Derivatives a s Prospective New Group of Antiseptics [in Russian]. and F. 34. 21. Terent'ev and G. studies on the preparation of prostaglandin analogs. received great impetus [i. and J. Izd-vo Sarat. 6. 416. 7. Dawson. 43 (1975). H. fi R4. 1524 (1951). Gaevoi. Moscow 109044. A. Siggia and J. Moscow (1969). ii. in: Proceedings of VIIth International Congress of Surface Active Agents. P. Kazitsyna. p. Sixma. 14. Tetrahedron. dl-2-(trans-3-hydroxyocten-lyl)-N-(6-eth- oxycarbonylhexyl)pyrrole and -indole were obtained by the condensation of 2-for- mylpyrrole and 2-formylindole with 2-oxoheptylidenetriphenylphosphorane. P. K. p. Reillej and L. Zh. Gordon and R. M. b I. and others [i. 102. 3-5]. ~. Commercially available 2-formylpyrrole (lla) and 2-formylindole (lib) served as the starting materials for the synthesis of these compounds.ll a R~RI=}I. oxazole. Sci.

The condensation of aldehydes ila.36 g (1. mp 146-147~ RfI0. Brand LI00/160. b. the extract was washed with water. b by the Wlttig condensation with 2-oxoheptylidene- triphenylphosphorane was carried out in carbon tetrachiorlde by boiling for several hours. The individual compounds dl-la and -Ib were isolated chromatographically on silica gel.5 cm. oil. b by ethyl 7-1odoheptanoate in DMFA in the presence of NaH at 70-80~ leads to 2-(trans-3-octoocten-l-yl)-N-(6-ethoxyearbonylhexyl)pyrrole (IVA) and -indole (IV5). 2-(trans-3-Oxoocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (IVb) was obtained in a sim- ilar way as compound IVa. A 0.42 g (4 mmole) portion of 2-formylpyrrole was added with stfrring to a solution of 3 g (8 mmoles) of 2-oxo. with elution by a 2:8 ethyl acetate--hexane mixture. The yield of pure ketone was 0.i g (4 mmoles) of NaH and 0. After chromato- graphic purification. extracted by ethyl acetate (4 • 50 ml). Attempts to saponify the ester group in compounds la. b by alkaline or acid hydrolysis led to resinification. The aqueous solution was extracted with ether (5 x 50 ml). for i h at 70-80~ followed by cooling. The yield of ketone Ilia was 0. and dried over Na2SO~. 1:19 (system B). dilution with water. Rf 0. EXPERIMENTAL The I R s p e c t r a w e r e r e c o r d e d on a UR-20 spectrometer. and the yellow oil obtained was dissolved in 5 ml of ethyl acetate. and the solution was deposited on a column with silica gel (d 2.41 mmole) of 2-(trans-3-oxoocten-l-yl)-N-(ethoxycarbonylhexyl)pyrrole in 7 ml of 2-propanol.64 (B). A suspension of 0. After chromatographic purification. Rf 0. the PMR spectra of a BS-27 spec- trometer (60 MHz) with reference to TMS as internal standard. i:i (sys- tem C).05 g (10. b.b are shown in Table i.51 g (94%).5 mmoles) of 2-(trans-3-oxoocten-l~yl)pyrrole in 5 ml of ab- solute DMFA was stirred for 1 h at room temperature. Thus. 2:3 (system A). a yellow oil was obtained. 0. Treatment of ketones file.78 (B). which was deposited on a column (d 2. mp 94-95~ Rf 0. A solution of 0.4 g (3. 0.6 g (2 mmole) portiona ofethylT-iodoheptanoatewasadded toe mixture of 0. The reaction mixture was boiled for 6 h. three-step synthesis of nitrogen-containing prostaglandin analogs has been proposed. Re- duction of the carbonyl group in ketones IVa. The '3C NMR spectra were re- corded on a Bruker WP-80DS spectrometer.5 mmoles) of ketone lllb.37 g of ketone lllb (88%) was obtained. A 0. Ilia. dl-2-(trans-3-Hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (la). 2-(trans-3-Oxoocten-l-yl)indole (lllb) was obtained and isolated in the same way as com- pound Ilia. The structure of the intermediate and final compounds was confirmed by IR.68 g (80%).2 g (18 mmole) portion of 2-formylindole was added to 1.63 (B). and the mixture was stirred at room temperature for 2 h. ~3C NMR and PMR spectroscopy.4- addition. 2v(trans-3-Oxooeten-l-yl)p~rrole (Ilia). A qualitative analysis of the mixtures was carried out by TLC of Siiufoi UV-254 plates in the following systems of solvents: ethyl acetate-- hexane. The solvent was evapor- ated.6 g (2 mmoles) of ethyl 7-iodoheptanoate in 5 ml of absolute DMFA was added dropwise to the reaction mixture. 2-(trans-3-Oxoocten-l-yl)-N-(6-ethoxycarb@nylhexyl)pyrrole (IVa). A 0. Some of the spectral characteristics of compounds Is. with stirring. IVa. The reaction mixture was diluted with water. A mixture of 0. and led to dl-la and lb.5 cm. acetone--chloroform.73 (A).heptylidenetriphenylphos- phorane in 25 ml of CCI~. but without the side-processes of 1.25 mmoles) of NaBH~ in 3 ml of water was added to a solution of 0. 2-(trans-3-oxoocten-l-yl)pyrrole (Ilia) and -idole (lllb) thus obtained had the required E- configuration of the double bond protons (the SSCC of olefinic protons is 16 Hz). whose ac- tivity in the thrombocyte inhibition test in a rabbit is equal to 40% of a standard (ara- chidonic acid).3 g (1. a simple.7 mmoles) of 2-oxoheptylidenetriphenylphosphorane. I 20 cm) with silica gel L40/100) with elution by a 2:8 ethyl acetate--hexane mixture.I g (4 mmoles) of NaH and 0. and acidifica- tion with i N H2S0~ to pH 5. After a chromatographic purification on a column with silica gel (d 2. 40/100 silica gel was used for column chromatography. After distillation of the solvent. enabling obtention of dl-2-(trans-3-hydroxyocten-l-yl)-N)a(6-ethoxycarbonyl- hexyl)pyrrole and dl-2-(trans-3-hydroxocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole.14 g (0. ethyl acetate--heptane.5 34 . and dried over Na2SO~.b by sodium borohydride in 70% aqueous isopro- panol at room temperature took place nonselectively. I 20 cm) LI00/160. Oil.6 g of ketone IVb (77%) was obtailed.

53 (IH).53 117. Ilia.27 M (IH) 4. 6.b I IR spectrum. d 2. 5.70.28 121. 29. 27.37 d (IH). i n CCI~ C(t) C~2) C(3) C(4~ C(5)' C(6)' C(7)"C(8)'C(22) I C(9) C(to) .28 m (4H) 0. C(H) Cil2) C(13) I IV b 14. cm.69 120. 6 .85 d . 1 = 1 6 Hz IV a 970 1600 1680 1740 7.81 42.22 d.8 d (IH).[ I 33.60.55 129.75.8 d .58 71.b.20 t (3H) IVb 970 1600 1680 1740 la 96O 1650 1740 3200--3700 7.70.35 (1H) 3.92 t 1. Spectral Characteristics of Compounds la.46 127. 26.01 ~o ~n .56 13. I 33.86 t 1.90 t 8. ppta ( j .01 (IH). 6.V .97 m (4H) 2.20s (IH).38 41.75.b. 6.32 100. 29.93 t 8.78 119.70 s (IH).d 3.88 118.03.76 I t c(14)I C(l~)I c(m)I C(17)I C{. 28.42 120.60 t (2H) 0.05 23.88 30.33 59. ppm. d 2.22t (3H) (IH) lb 96O 1620 1740 3180--3600 ZSC ~ spectrum.70. IVa. ~ Cilia Compound CH-CH N--CH2 EH3 i n sid~ trans C=C c=o coo NH OH CH~CH OH CO~--CH2--CH3 CO--CH2 chain NH COOCHz--CHa Ilia 975 16t0 1670 3290 6.97 24. TABLE i. 25.76 42. I = 1 6 Hz IIIb 960 1610 1650 3320 7.16m (4H) 2.28 t (2H) 0.65 t (2H) 0.26 134.20 59.21 119.75. HZ).71 172.25 172.55 30.49 21.a)I c(19)I c(-oo) I C(21) I C(2a) I C{24) I c(25) I 136.42 Ib 13. 6.~ PMR s p e c t r u m .42 108.59 31.88 125.

. Translated from Khimiya Geterotsiklicheskikh Soedlnenii. January. The known methods for the preparation of this compound are multistep and proceed with a low overall yield. Original article submitted December 4. 1986. A 0. Yu.. Geterotsikl.i g (20 mmole) portion of NaBH~ and 20 ml of 70% 2-pro- panoi were added to 0. 6. 2]. N. used for the protection of an exposed light-sensitive material fogging during its treatment in light [i. Academy of Sciences of the Ukrainian SSR. J. 3. which does not exceed 20% [3.. i0. 12060P (1983). A. 204 (1975). 53. Usp. 4]. 4. without purifi- cation.757. and P. LITERATURE CITED i. is hydrolyzed by boiling with an aqueous solution of sodium hydroxide. ~7 ~-~" " ~'N% I1 NOz COOt. After chromatographic purification. Khim.8 mmole) of ketone IVb. E. Ref. G.. Ambrus. Zh. G. No~ I~ pp. D. we used the method of constructing the indole ring. 689 (1984). Acta Chim. 44.. dl-2-(trans-3-Hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (Ib) was obtained and isolated in the same way as la. Barta.. Soedin. 36 0009-3122/86/2201-0036512.Cl. Usp. Suvorov. NEW SYNTHESIS OF INDOLE-7-CARBOXYLIC ACID V. 44-45. A. 5. Horvath. 0.32 g (0. V. Nazina. consisting in a re- ductive cyclization of B-(dialkylamino)-2-nitrostyrenes [6]. Sdti..I COOCH~ COOH When acid I is heated with dimethyl acetal (II) in DMFA. M. Caldwell. Levkoeva and L. 2.08 g (52%) of com- pound la was isolated.. I. Parraclough. 661 (1975).~)='N-CH(OCI%)z J. I.I~COOH . No. Avramenko. consisting in reductive cyclization of ~-(dimethylamino)-3-carbo- methoxy-2-nitrostyrene by the action of iron in acetic acid. 98. Ambrus and I. and A. In developing a new variant of the synthesis of indole-7-carboxylic acid [5]. which. V. Nikolyukin UDC 547. Fe. K. 0. The overall yield of indole-7-carboxylic acid is thus 60%. Mironov. Oil. A. Indole-7-carboxylic acid is used in the synthesis of optical filter dyes.73 (B). ~ 25 cm) L40/IO0 with elution by a 1:19 acetone--chloroform mixture. Institute of Physical Organic Chemistry and Carbon Chemistry. and N. an esterification of the car- boxyl group takes place together with the formation of an enamine grouping. Reduction of enamine III by iron in acetic acid gives methyl indole-7-carboxylate. U. Gg. Hung. Dulenko and Yu. Kochergin. Levinova. Prostaglandins.. we selected 2-nitro-m-toluic acid (I) as the starting compound. 1074 (1975).. Fonskii. Oil. Donetsk 340114. P. Patent No.78 (B). D. N. C. 2. 2094793. Khim. The latter compounds are most conveniently obtained by the condensation of substituted o-nitrotoluenes with DMFA dialkyl acetals [7]. Harris. and P. In accordance with this. Rf 0. G.cm. Rf 0. 1984. Dombrovskii. Khim. Khim. I. Yakhontov. Sci. Barta.18 g (56%) of compound Ib was obtained. + (CH. 463 (1978).50 9 1986 Plenum Publishing Corporation . S6har. free of the above drawbacks. V. G. M.07 A new preparative method for the synthesis of indole-7-carboxylic acid has been developed. I. V. N.

Borror. 3941807. 3823 (1967). 1290 cm -~ (NO2). Ref. 23. 5.25 mole) of DMFA dimethyl acetgl [9] and 50 ml of DMFA is heated in an argon atmosphere to 130-140~ for 24 h. A.5 h. The residue on the filter is washed thor- oughly with benzene. The precipitate is filtered. Yield 38. 42. M. 1670 cm -~ (C=O). 2N224P (1966). and dried.5 g (80%). 3. R. 22. No. Borror. 1699 (1979). on a water bath. washed with water. IR spectrum: 1720 (C=O). Yu. Shiwe. Nikolyukin.05 mole) of 2- nitro-m-toluic acid [8]. 8. Bet. V. 32. The com- bined organic extracts are washed with water and saturated sodium carbonate solution. 1530.. A.2%.. 195 (1984). Abdulla and R. Repke. Soc. 4124592. N 11. 9. N. Calculated: C 57. EXPERIMENTAL The IR spectra were run in mineral oil on a UR-20 spectrophotometer. 41 (1968).. IR spectrum: 3420 (N--H). The mixture is boiled for 5. 4. Tetrahedron. H 5. When the temperature in the flask reaches 50~ the bath is removed. Amer. and the unreacted iron is filtered off. 22. US Patent No. Khim. 1097619 (USSR~. and the mixture spontaneously heats up to 80~ This temperature is main- tained by a cold water bath until the end of the exothermal reaction. then cooled. and acidified with hydrochloric acid to pH 2. A. 800 ml of ethanol. Benzene is distilled off. Bloom.5 ml (0.. Zh. and the aqueous filtrate is extracted 3 times with benzene. Ozobr. A. The reaction mixture is cooled. Indole-7-carboxylic acid. 23N238P (1976). H. Chem. 35. A. Tetrahedron. and P. 9. 7. Khim. Chem. Singer and W. Kirillova. Khim. C12HI~N=O~. US Patent No. US Patent No. !0!.8. with vigorous stirring. 0 R. published in Byul. 3954799. A mixture of 75 g of B-(diethylamino)-3-carbomethoxy-2-nit- rostyrene. Ref. and V. Ref. Brinkmeyer. H 5. Clark and D. The precipitate of indole- 7-carboxylic acid is filtered. J. Bredeck. using an aspirator. Zh. A mixture of 9 g (0.6. filtered. B-(Dimethylamino)-3-carbomethoxy-2-nitrostyrene. Zh. Rebsdat. N 11. after which the flask contents are heated for another 30 min.6. 2. Ber. and dried. I. Found: C 57.3 g (74%). Yield. Chepurko. K.. Ikan and E. Dulenko.. 76 (1984). 180 g of iron powder. and water is added to the residue. R. washed with water. The red solution formed is evapor- ated under vacuum. and 80 ml of acetic acid is heated. 5700 (1955). Inventor's Certificate No. H. 37 . V. Vasil'ev.5 liters of water are added. and a solution of 35 g of sodium hy- droxidd in 310 ml of water is added to the residue. Simchen. and S. LITERATURE CITED S. Kazymov. mp 131~ (from isopropano!). and dried over sodium sulfate. M~ller. Hayffer. 13N223P (1979).4. 1635 (C=C). 423 (1909). 4. Rapaport. mp 205- 206~ (from an ethanol-water mixture). G.. Yu. 77. E. Heterocycles.2%.

3'-di(6.10b. These data conform with previous reports on the re- action of I with phenylhydrazine in the presence of CH3COOH and KBH~ [7]. B) leading to indoloacridine Va and tetrahydrocarbazole VI. tane)-l. 6] during the indolization of 2-R- substituted derivatives of cyclohexanone.3.3. 1986. acridine (Villa) [3] and acridinium salt (iXa) [4] were isolated fmom the re- action mixture. we studied the transformations taking place during the reaction of methylene-2-2'dicy- clohexanone (I) with phenylhydrazine in the presence of acids.8'759.lla-octahydroquinindoline. whose A. 1984. The quinindoline structure was confirmed by the synthesis of this compound from 2.2-Dimethyl-3-oxa-4a-(2'. The acridinium salt IXa can be considered to be a product of the reaction of I with aniline.02'7)tridecan-2-ol-13- ones in an acid medium.9.2-dimethyi-3-oxa-4a-(2'.4-tetrahydrocarbazole by the ac- tion of ammonia.6-dimethyltetrahydropyran-4-one) with phenylhydrazine in acetic acid.2. paths of the reaction of diketone I with phenylhydrazine are represented by the scheme given below (following page).together with the indolization processes (paths A.9:543.2. 46-52.3. pyridination process (path C) also takes place. D rings are analogous to the corresponding structural fragment of strychnine.3. No.2. 2] of the study of the reaction of 1. 38 0009-3122/86/2201-0038512. N.2-dimethyl-3-oxa-l.* ALICYCLIC 1.11.3.7. Tilichenko UDC 547.4.3'556.2. i.8. The data obtained show that diketone I reacts with an equimolar amount of phenylhydra- zine in acid medium with no clear-cut results . 1.1. and also the already known tetrahydro- carbazole (VI). pp.7-dioxa-sym-octahydroacridine were obtained by the reaction of methylene-3. Indoloacridine Va is formed as the result of the indolization of monohydrazone II with the participation of the ~-CH2 group of the hydrazone fragment.14-tetramethyl-2-oxa-ba. A similar splitting was observed [5. Postulations were made for the paths of formation of these compounds. 2.4 - tetrahydrocarbazole and 3.l-d. January. The appearance of tetrahydrocarbazole VI in the reaction mixture can be ex- plained as occurring by splitting of a substituent from the position 4a of the intermediate carbazolenine IV.6-tetramethyl-2.ll. C.816'835.3.5'.5-DIKETONES.3.14.10. 3.10-phenyl-sym-octahydroac- ridinium salts are formed by the action of phenyl-hydrazine on alkylidene-2. B.4-tetra- hydrocarbazole.50 ~ 1986 Plenum Publishing Corporation . Moskovkina and M. The. Vladivostok 690600. as the result of which compounds Villa and IXa are formed. followed by dehydration of compound III. 9-R-sym-octahydroacridines. and 9-R. Translated from Khimiya Geterotsiklich- eskikh Soedinenii.5-diketones with phenylhydra- zone.2.5a. As the result.2.594. 2.SYNTHESIS OF HETEROCYCLES FROM 1. *For article 2.422 8-R-7aH-5.2'-dimethyltetrahydropyran-4'-on-5'yl-methyl)-4aH-l. similarly to that described in [4].2'-dimethyl- tetrahydropyran-4'-on-5'-ylmethyl)-4aH-l.12-Octahydroindolo[3.3' 812.e]acridines.2'- dicyclohexanone or the corresponding 8-R-tricyclo(7. indoloacridine (Va). see [i].6. Original article submitted December 26. In a continuation [i.4-tetrahydrocarbazole.6. the previously unknown heterocyclic compound.10b-(methanoxyisobu.3. 3. Far East State University. The formation of acridine VIII is explainable b y t h e possible splitting of aniline from the intermediate decahydroacridine VII. V.5-DIKETONES IN REACTION WITH PHENYLHYDRAZINE T.

5-diketones [8-10].CH~O_C6H~ The structure of indoloacridine Va particularly follows from the analysis of its spec- tral characteristics.3.4.2'-dimethylpyran-4'~on-5'-ylmethyl)-4aH-l. Another variant of the synthesis of indoloacridines that we have developed is to some extent free of these drawbacks. 3. c R=CeHs. 39 .14.' 1 RffiH I CetlsNHNII2 Ill V I NIIC. indicating a conjugation of the tetrahydrocarbazole ring with the C=C bond (in the UV spectrum of tetrahydrocarbazole.6. spectra.5-diketones) proceeds in low yield and is im- peded by the necessity for the chromatographic separation of the mixture of compounds ob- tained. Thus.-dimethyl-3-oxa-l.••a-•ctahydr•quinind••ine (XV). mixed melting point) [3-5]. while in the UV spectrum there is a long-wave maximum at 312 nm. 3.14- tetramethy•-2-•xa-5a.2-dimethyl-3-oxa- 4-a-(2'. R R NHC~II5 VIII a-d VII + R o~ OH I x a-d xla-d NHC~a5 [ ClO 4 - IX'a V~ X a R = H .6-tet- ramethyl-2.3. we obtained phenylhydrazones Xla-d in good yields.5a. Vllla.2. in the mass spectrum.4-tetrahydrocarbazole (XIV). IXa) was confirmed by comparison with the corresponding standard samples (comparison of constants. During the reaction of compounds Xa-d with phenylhydrazine. It should be noted that the preparation of indoloacridine (Va) and its 8-R-substituted derivatives (obtained from other alicyclic 1. The structure of other reaction products (VI. b R=CH3. a long-wave maximum is observed at 282 nm [5]). R R R ~ ~5 . there is no absorption of the C=O and NH groups and absorp- tion bands are observed at 1660 cm -x (C=C). Heating of these compounds in concentrated acetic acid led to the formation of indoloacridines Va-d.3. as well as the known 3.2.3. In the IR spectrum. When the corresponding monophenylhydrazone XIII was treated with glacial acetic acid at room temperature. we also obtained new heterocyclic compounds: 2. after which compounds Vb-d were isolated by crystallization (Table i).3.6-dimethyltetrahydropyran-4-one) (XII) [II] considerably differed in its behavior in the reaction with phenylhydrazine in acetic acid from other alicyclic 1. d R=p.4-tetrahydrocarbazole (XVI). which are the products of an intramolecular adolization of the corres- ponding 1. and 2.••.H~ IV Vl II \.3'-Methylenedi(6.2.5- diketones.7-dioxa-sym-octahydroacridine (XVII) [ii].••b-(methan•xyis•butane)-•.2. a peak of the molecular ion is observed at m/z 263.••. It involves the use of tricyclohexanolones Xa-d as the starting materials.

as well as the signals of four aromatic protons and four methyl groups. while quinindoline XV by the addition of NH3 to the C=N bond.01 and 2. 74.i "0 ""J "~N X". a peak of the molecular ion is observed with m/z 340. The C(~) methylene group protons appear as doublets at 4.4 ppm._ 11 . C(tsa)). Compounds XV and XVI can be regarded as products of further transformations of carba- zolenine XIV under the reaction conditions.2 ppm is characteristic of a quaternary alkyl-substituted carbon atom (C(1ob))."-I~" ~o.~ NItC6H5 XV XVI Xlll O~ -~ -. We obtained confirmation for the formation of compound XV by this path by carrying out the reaction XIV with ammonia in ethanol at room temperature.::~. a peak of a molecular ion (m/z 341) and characteristic peaks of fragmentary ions with m/z 201 and 143 are present.J~" o 0 / ~ . The signal at 148. quinindoline XI was obtained in a yield of 50%.7 ppm (s) confirms the presence of the C=N fragment in the quinindoline structure.'~.=. 80.. amines. "'~":. The shift of one of these sig- nals into a weak field shows that the'carbon atom is bound to the hetero atom.11 into a singlet. Similar experiments were carried out for signals of the methylene group protons at C(t) (doublets at 3. in the absorption region of the aromatic carbon atoms (ii0- 128 ppm). J = 13.5 Hz).~"'~. having a hereto atom as one of the substitu- ents.7. The CH=--CH--CH= fragment is revealed as a four- proton multiplet at 3. o-"y"-~o o XqI i CsHsNHNH2 lo ~'~. 3-Oxatetrahydrocarbazole (XVI) was probably formed by splitting a substituent from the 4a-position of compound XIV. The three singlet signals (72. 2 "~ 0/'"7/~7/A" 0 H+ .28 and 2.69 ppmj J = 13. signals of carbon atoms belonging to four methyl groups 40 . with an absorption band of the C=O group at 1713 cm -t. .11 ppm (J = 11. signals of three iso- lated methylene groups (AB system) and the CH=-'CH--CHa fragment were revealed by the spin- decoupling and differential spectroscopy methods. According to the Fischer reaction mechanism.~ .55 ppm. In the IR spectrum of quinindoline XV. In the PMR spectrum.. The absence in the reaction mixture of indolization products with the participa- tion of the ~-CH= group clearly results from its being screened. The structure of compound XIV is confirmed by the IR spectrum. Two other signals of this ring are displayed as signlets at 130~0 and 164. and phenylhydrazine at the C=N bond [12].5 ppm) indicate the presence of a further three quaternary carbon atoms (C(3).. ammonia is liberated during the indolization of hydrazone XIII. This indicates the presence of a disubstituted phenyl ring in compound XV. . In the mass spectrum. In the spectrum. . there are four signals giving doublets under the off-resonance conditions.5 Hz).0 and 3. and a molecule of acetone from the ion with m/z 201. .10 ppm. It is known that indolenines are capable of adding ammonia..qI Tile formation of compound XIV is explainable by the occurrence of indolization of mono- phenylhydrazone XIII with the participation of a -CH group ~ with respect to the hydrazone fragment. As the result.25 ppm and one-proton multiplet at 1.0 Hz) and at C(s) (doublets at 2. there are absorption bands of NH and C=N groups at 3370 and 1660 cm-t. Irradiation of the signal at 4. followed by the closing of the six-membered ring during the reaction of the carbonyl group and the NH2 group.8. In the mass spectrum of this compound.0 ppm leads to degeneration of the signal at 3. C ( ~ ) . . The signal at 42. . The latter indicate a splitting of a y-pyranonylmethyl fragment from the molecular ion. In the t3C NMR spectrum.

24) 87.10.% H.20 I 8.0 7. 68. 3600 (OH) i 80.12 333 40 Vd 195--196 1655 (c=c) 318 (4. .40 7.15 277 C20H=3N 86. Xlb from a 1:4 ethanol-ethyl acetate mixture. +The compounds were crystallized: Xla from a 1:3 ethanol--ethyl acetate mixture.% M c.55 [ 7. R = H.80 369 25 *V.30 7.75 3.06 7.9. 3440 (NH). cm.40 263 CtgH21N 87. OH) $.86 I 8.38 4.83 CuoH28N~O"HCI 68.60 [ 8.90 404 41 Va 1660 (C=C) 312 (4.79 5. c from ethanol. 3000--3400 (NH.60 8. b R = CHs.33 8. d from methanol.11 7.% 132---133 1650 (C=N).40) 88. Vb.32 263 7(15) Vb 99--100 1~0 (C=C) 314 (3.10 277 . d R = p-CH30-C6H.75 369 C26H~zNO 84.l-d.0 8.03 Hydrochleride XII several Desks 80.30 3.11. 3330 (NH). Characteristics of Phenylhydrazones of 8-R-Tricyclo(7.77 8.30 7.60 ] 7. 3342 (NH.% N. c R = C6H5.10 339 C2sH=sN 88. OH) * 67.i %"max( log Empirical formula [ ! c. Vd from ethyl acetate.1.2.92 6. d.5 [ 7.90 5.. Xlc. ~The spectra were run in mineral oii.92t 8.85 7 .7.20 J 7. Xla.73 Z 404 C27I-I~N202 77.12-Octahydroindolo[3.0a'7)tridecan-2-ol-13-ones (Xla-d) and 8-R-7aH-5.78 7.30 5. 6.90) 86. 9 8 8.TABLE i.40 374 78 XI c 158--159 1602 (C=N).70 6.% [ H.10 J 7.3.37 63 Hydrochloride XI~ several peaks 70 153--154 ]655 (C=~N).% N.90 I 374 C25H~oN~O XId 159--160 1602 (C=N).40) 84.8.62 4. 3580 (OH) 77. 3000.98 5.5 V c 160--161 165o (c=c) 318 (4.17 CmH26N~O"HCI 68.e]acridines (Va d) UV spectrum '" Calculated Foun~ Compound~ Mp~ ~ IR spectrtun.

5 Hz).15. The ether extract is dried over MgSO4 and ether is distilled to yield 2. C12 (2H) A 2. The extract is dried over MgSO~.37 ppm (J = 12. Reaction of Methylene-2. The initial 1.4. The mixture is separated by preparative TLC in system 3. It interacts with two methylene groups. petroleum ether-ethyl acetate 5:2 (system i. mp I14-I160C is iso- lated.10. When cool. signals are observed of protons of four methyl groups (1. bp 151-153~ (5 mm). four protons of a disubstituted benzene ring. The presence of three isolated methylene groups (at the 4.16.3. the spots on the chromatograms were developed by iodine vapors].~. at 250 and 22.4-tetrahydrocarbazole (XVI) was confirmed by elemental analysis.4. and 42 . ii Hz) and a broadened doublet at 2.5863. A 5. 7. due to splitting of (CHs)2CO] and by IR spectrum (3473 cm -~. 46%. mp I15-I16~ The aqueous solution is made alkaline with potassium carbonate to pH 9. the second.3.2'dimethyl-3-oxa-l.I g. The ether extract is dried over MgSO~. the NH~CI precipi- tate is filtered. The chemical shifts are given with reference to TMS. A 20 ml portion of petroleum is added.1 ppm#.46 ppm (J = 11.74. 69. One of them at C ~ (2H) is represented by a doublet of doublets at 1. while the other at C= (2H) is in the form of a doublet of doublets at 3. mp 72-73=C (pet- roleum ether). From the zone with Rf 0.7. n D 1. The preparative TLC was carried on plates (20 > 35 cm) with nonstationary A1203 layer (grade II of activity) in a i0:i petroleum ether--ethyl acetate mixture (system 2) and in a 5-1 heptane--ethyl acetate mixture (system 3). according to the data in [5]. respectively. A mixture of 6. bp 48-500C (10 mm). mp 74~ B__~. i.2 g (30 mmoles) of diketone I and 4. and the UV spectra on Specord UV- vis in methanol.5 Hz) and a broadened doublet at 3.5~ ~ .8. 48.4~ 23~5.37 ppm.6.2. The aqueous layer is combined with wash waters (aqueous solution i). according to the data in [3]. 12. C:5 (2H) A 1.5-diketones I. 42. 30.5.88 g (7%) 2O of 7aH-5.1 g. mass spectrum [a molecular ion is observed at m/z 201 and a fragmentary ion at m/z 143.9. For the corresponding AB systems.l-d. The oil that separated is extracted by ether (3 • 25 ml). and a signal of an NH group proton (which disappears during a deutero exchange) at 4. Two fractions are c o l l e c t e d : the first. The mass spec- tra were determined on LKV 9000 mass spectrometer at 70 eV. Bruker HX-90-E for 13C.13 ppm (J = 14. 1. the solvent is distilled off to yield 6.3 Hz). which are separated by distillation 2O in vacuo. The structure of 2.2'~Dicyclohexanone (I) with Phenylhydrazine~ A__~.2 g of reaction products.03 ppm (J = 13. sym-octahydroacridine. the NMR spectra (in CDCI3) on spectrometers Bruker WH-250 for IH. XII and ketones Xa-d were obtained by methods described in [8-11.3 g (30 mmoles) of phenylhydra- zinc hydrochloride in 25 ml of dry dioxane is boiled for 6 h.3 g of a mixture of compounds in the form of a partially crystallized mass.6319.03 ppm (J = 14 Hz). The mixture heats up to 60~ and is left to stand for 24 h at room temperature.12-octahydroindolo[3. 15-positions) was revealed by double resonance.40. There is also a CH2-CH-- CH2 fragment. bp 167-1700C (i mm). EXPERIMENTAL The course of the reaction and the identification of individual compounds were control- led by the TLC method [Silufol UV-254. aniline.49 ppm).1.3]acridine (Va). The aqueous layer and the wash waters are combined. The ether solution is washed with a dilute hydrochloric acid.38 ppm.7-7. respectively.5 Hz). and evaporated to yield 3.18 g (48 mmole) portion of phenylhydrazine is added to a solution of i0 g (48 mmoles) of diketone I in i00 ml of glacial acetic acid. 6 ppm) and live metilylene groups ~23. The extract is washed with water (2 • 30 ml) and a NA~C03 solution to a neutral reaction. In the PMR spectrum of compound XV.95 ppm (J = 11.5 g of a mixture of products.5. The only nonaromatic methine proton is displayed as a multiplet at 2. The characteristics of compounds Va-d and XIa-d are listed in Table i. n D 1. and water to neutral reaction. 13].83 ppm (J = 14. and the residue is dissolved in ether. B 3.63 MHz. B 2. 4. The IR spectra were obtained on a Specord IR-75 spectrophotometer (in CHCI3). and the oil that separates is extracted by ether (3 • 30 ml). is obtained.2.5 Hz).29. 1:3 (2 • 20 ml).57. the following chemical shifts and SSCC were found: C~ (2H) A part 2. 66. From the zone with Rf 0.3 ppm) are also observed. Dioxane is evaporated.11. the NH group). B 2. 1. 0. It is then diluted by 150 ml of water. 0.58 g (7%) of tetrahydrocarbazole (VI). 1.25..6.

mp 199-200~ C. After evaporation of ether. Phenylhydrazones of 8-R-Tricyclo(7. indoloacridine Va (0.39. The aqueous layer is made alkaline with sod- ium carbonate to pH 9 to give the corresponding acridines: 9-methyl-sym-octahydroacridine (Vlllb 20%. Transformation of 3. N 4.08 g (i0 mmoles) of diketone I in l0 ml of absolute dioxane.crystals of compound Vl are filtered. Found: C 69. washed on the filter with CH3COOH (2 • 5 ml) and alco- hol. A 20 g portion of polyphos- phoric acid is added to 6.b could not be crystallized and they were obtained as hydrochlor- ides.3'-Methylenedi(6.83. mp 198-199~ (from ethanol). Ammonium perchlor- ate is added to aqueous solution 2. 0.5 g of a mixture of products. H 8. and dried to yield indoloacridines Vb-d. 1608 cm -I (vibrations of the aromatic ring). Dioxane is evaporated. 5%) and tetrahydrocarbazole VI (0.90.73%. 3.5 g (60 mmoles) of phenylhydrazine in 30 ml of ethanol are added to this solution in the course of 2 h. Acridines Vlllb. and the precipitate of N-phenyloctahydroacridinium per- chlorate IXa is filtered.1. From the extract.2 g. according to the data in [4]. Found: C 81. 3315 cm -I (NH). Additional amounts of indoloacridine Vb-d and tet- rahydrocarbazole VI (10-15%) are thus isolated. From this product. Yield l.3 g (40 mmole) portion of phenylhydrazine is added to 40 mmoles of the corresponding ketone Xa-d in 150 ml of absolute benzene.80. A 4. as described under A.68.13 g.0='7)tridecan-2-ol-13-ones (Xla-d) by the Action of CH3COOH and Polyphosphoric Acid. IR spectrum~ 1705 (C=O). Transformation of Phenylhydrazones of 8-R-Tricyclo(7.08 g (i0 mmoles) of phenylhydrazine in 6 ml of dioxane is added. with stirring. The reaction mixture is boiled in a flask fitted with a Dean-- Stark trap up to the end of separation of water (5 h). C2oH23NO. The oily products are extracted by ether. H 7. 50 ml of water are added to the residue.6 g (20 n~noles) of hydrochloride of phenylhydrazone Xla. A 2 g portion of polyphosphoric acid is added to 2.7 g. The mother liquor from the isolation of compounds Vb-d is neutralized with sodium car- bonate to pH 7.3 g (3%) of indo- loacridine Va and in addition. M 293. A.2 g (40%) of acridine Villa and 0. M 293. mp 142-143~ (from ethanol). A 16. N 7.6-dimethyltetrahydropyran-4-one)monophenylhydrazone (XIII). and the resi- due obtained in the form of a glass-like mass. The hydrazone thus dissolves and a new crystalline precipitate separates. M 358.39.6-Dimethyltetrahydropyran-4-one)monophenylhydrazone (XIII) by the Action of CH3COOH. N 7. Benzene is evaporated. to this mixture.l g (i0%). and the oil is extracted by ether. washed with ethanol (2 • 20 ml). and 9-p-methoxyphenyl-sum-octahydro- acridine (Vllld) 20%. the extract is washed with water to neu- tral reaction.3-Methylenedi(6.3 g (20%) of hydrazone XIII. From the aqueous solution. From the aqueous solution. Hydrazones Xla. which is then stirred at room temperature for 6 h.16 g (20 mmole) portion of hydrazone XIII is dissolved 43 . A 7.41. then cooled. The extract is evaporated to yield 3. and evaporated to yield 2. Acridine Vllld has been prepared by us for the first time. as described under A. 9-phenyl-sum-octahydroacridine (Vlllc) 22%. A corresponding phenylhydrazone Xlb-d (30 mmoles) is heated in CH3COOH for 2 h.2 g (3%) of tetrahydrocarbazole VI are obtained by prepara- tive TLC.82 g (15%) of indoloacridine Va and l.d. Yield.4 g (10%) of acridinium salt IXa are isolated in a similar way as described above. the precipitate is filtered.90%. IR spectrum: 1580. mp 230- 231~ (from ethanol). Calculated: C 70. from which 2. Calculated: C 81. N 4.1 g (60 mmole) portion of diketone XII is dissolved in 40 ml of ethanol with heating and 6.97.82%.2g. compounds Villa (0. 14%) are isolated.5 g of aniline are obtained. and poured into 50 ml of H20.5 g of an oily product. The oil that is obtained is extracted by ether and separated from the equeous layer (aqueous solution 2). and left to stand at room tempera- ture for 18 h. M 358.l g (30%) of tetrahydrocarbazole VI are isolated by preparative TLC. crystallized under ethanol only in the case of Xlc. H 8. I g (27%) of acridine Villa and 0. The reaction mixture is heated for another hour.1.70%. H 7. the residue is separated by preparative TLC. B_~. dried.c were identified by direct comparison with the cor- responding samples [3]. 4.3. A solution of 1. 35%) and IXa (0. and dried. The oil is extracted by ether (3 x 30 ml). The precipitate is filtered.3. The mixture is cooled. 0. 0.08 g (i0 mmoles) of 2.0217)tridecan-2-ol-13-ones (IXa-d). mp i15-i16~ From the filtrate. The aqueous solution of I is made alkaline with sodium carbonate to pH 9. The re- action mixture is heated on a boiling water bath for 2 h. 5%) were isolated. C21H3oN203.

Chim. i:!.. N 8. Soedin. Soedin. Grandberg. Org. Khim. Soedin. 80.. The compounds remaining in the mother liquor after the isolation of quinindoline XV.. and neutralized by a Na=COs solution to pH 7. 9. N. Khim. i0. S. mp 161-1620C (ethanol). A. Vysotskii. Yaguzhinskii. and M. 45 (1956). N 4..61. Obshch. H 7. V.. 3444 (1964). I. mp I18~ (from water)]. Obshch. N. 821 (1983). M. M 341].2'-dimethyltetrahydropyran-4'-on-5'-ylmethylo- 3-oxa-4~H-l.91. Obshch. 500. N 6.11. The precipitate is filtered to yield 1. Preparation of Quinindoline XV from Compound XIV by the Action of Ammonia. L. Soedin. 826 (1973).5 cm) with 300 g of silica gel 40/100 . Uch. Khim. Barbulescu. 7.25%. Moskovkina. M 341. M. p. 2. No.01%. Moskovkina. 6:1. and 30 ml of ethanol are added to the residue weighing 7 g. Teknol. Zh. I. which was identified from TLC. A gradual elution is used (systems: petroleum ether--ethyl acetate.35 g (50%) of quinin- doline XV. 96 (1961).10. Akimova. A. N. V. Geterotsikl. Tilichenko. The reaction products that separate are extracted by diethyl ~ther (4 • 50 ml). Zh. ~.3.8 g (26%) of quinindoline XV. Izd-vo Inostr. Vysotskii. Khim. Kost.27. 6. N.23. and the precipitate that separates is filtered to yield 0. Tilichenko.2. I. Kost. 376 (1971). I. ~. Ch'iu. LITERATURE CITED i. Vershinina. 34. M 201. Izv. Moscow (1954). Found: C 74. IR spectrum: 3473 cm -: (NH). in: Yearbook of Saratov University [in Russian] (1954). G. 6. 8. T.2-dimethyl-4a-(2'.6.26. H 7. I.i. 4. N 4. N.90.56 g (14%). 5. Tilichenko. N. The mixture is left to stand at room temperature for 5 h. V. Khim. No. Rev. Khim. The extract is dried over MgSO~. 3. N. H 8. Lit. M. 7.96%. N 7. 3. N. V. G. 33. and M. R. mp. Vol. 9. H 8. mp 150-160~ (petroleum ether). Zav. Khim. N. and L. and then is diluted by an equal volume of water.8 g (12%). N. C2~H2s- N=O2. V. 645 (1976). Soedin.23%. The following compounds are isolated: 3-oxatetrahydrocarbazole (XVI) [0. M. CIsHIsNO. Geterotsikl.. 976 (1970). 30. are separated by column chromatography: 5 g of the mixture separated on a column (42 • 2. Yudin and Y. Tilichenko and T. V. then evaporated to half its volume. Calculated: C 77.in JO mi of CH~CO{~H~ The reaction mixture is left to stand for 24 h. the ether is evaporated. IR spectrum and melting point of a previously iso- lated sample. M 201]. mp I19-120~ (from petroleum ether). 3..)..32. Elderfield (ed. 12. V.47.3.. ~. Vyssh. M 340. 13. 2. Moskovkina and M. Heterocyclic Compounds [Russian translation]. Khim. M 340. Berbulesku. Khim.70.3.. V. 174-176~ IR spectrum: 1660 (C=N).21%. Vysotskii and M. IR spec- trum: 1713 cm -~ (C=O). 898 (1975).. Zh.6-tetramethyl-2. N 8. N. 645 (1963)..4-tetrahydrocarbazole (XIV) [0. according to the data in [ii]. S. 3108 (1960). and M. N. H 7. A. Calculated: C 73. 3380 cm -~ (N--H). No. 3:1. 44 . Khim. T. li. No. Geter- otsikl.10%. C2~H=TNO3. Found: C 77.7-dioxa-sym-octahydroacridine (XVIII) [0. N. 0:I. No. Geterotsikl. Tilichenko. and 3. 5. Found: C 73. Tilichenko. Khim.7 g (2 mmoles) of compound XIV in I0 ml of ethanol. Kaminskii.6 g (11%). Geterotsikl. Calculated: C 74.16. Tilichenko and T. 500 ml in each case and fractions of 50 ml are collected. p. H 8. Zh. Beditse.. Tilichenko. Tilichenko. I. A 2 ml por- tion of 25% NH~OH is added to a solution of 0. 6.

Moscow 109088.~.SYNTHESIS OF DERIVATIVES OF 4-1MINO-2-AMINO-2-1MIDAZOLINE. Polyakov. R--. pp.c/C~. NEW EXAMPLE OF A MULTICOMPONENT CONDENSATION INVOLVING ISONITRILES A. Zolotoi.-*'N'-. A. No. Academy of Sciences of the USSR.-- VIIa-k vm a-k The condensation products are.-C(RZR3)--C=~N'-R4 ] -~-------a" I II If! IV NC3. O. -J -.mCN T ' J'"C / "NH E "r 1 . Institute of Chemical Physics. L. p-tolylisonitrile and benzylisoni- trile contain two molecules of bound HSCN. Imidazole derivatives VII and VIII are readily interconverted upon the corresponding change in solution pH. R 1 ~. Medvedeva. / R4 I R ~"/ \R 3 . I. i.CS_NI~R4 \ \ I + II + III + H$CN c-~ Ncs. Translated from Khimiya Geterotsiklicheskikh Soedinenii. A. f_--N 9 /! \ . we assume. 1986. that differences in the reaction mechanism be- tween them may arise only in the step involving stabilization of intermediates IV and V.. Atovmyan 789. This is supported by the elemental analysis and IR spectral data (Table i).R2 L ~CZ S~%'-N-"~N_LR~ H VI Upon using this reaction for the preparation of hydantoins VI with Rx = H and CH3j we found an unusual multicomponent condensation leading to imidazole derivatives VII and VIII.N/ -. have strong IR bands for the S-CEN group at 2030-2080 cm-* and give a positive test for the thiocyanate ion with FeC13 solution.239'233. D'yachenko. The x-ray diffraction structural data for model compounds VIIi and VIIIe are given in Fig.422'51 !sonitriles have been found to react with ketones and ammonium and methylammonium thiocyanates in methanol or ethyleneglycol at 20~ to form derivatives of 4-imino- 2-amino-2-imidazoline and 2.. 1 and in the Experimental. O. /. Since the conditions for the reaction studied are identical to those for a well-investi- gated four-component condensation. as a rule. 53-61. The site of the addition of the second HSCN molecule could not be determined but is most likely N(2) of the imidazole ring. which were more complex than previously assumed [2]. Ugi [i] has shown the possibility of preparing 2-thiohydantoin-4-imines by the conden- sation of amines I and ketones II with isonitriles III and thiocyanic acid by the scheme + RIMH2 + R2-C0-R ~ + R4-N~C + I|SCN ~ ~ R v . Their structures were established finally only by x-ray diffraction structural analysis.HSCN + VIII. UDC 547. Moscow 117334. apparently as a result of the reaction 2 VII + VII. in our opinion he explained by the following scheme: # All-Union Scientific-Research Institute for Chemical Means for the Protection of Plants. revision submitted January 22.1:543. Compounds such as VIIa and VIIe formed from acetone. B.50 9 1986 Plenum Publishing Corporation 45 . January.4-diaminoimidazolium salts. As- suming the formation of aziridinimine IX as an intermediate. 1985._ =.N H . and L. 0009-3122/86/2201-0045512. 1984. Ori- ginal article submitted August 7.1'783' A. imidazolium salts Vll. the preparation of VII and VIII may. R R2/-. I R2"C/R~ A IRZ" C ~'I~3 "'N" "CS-NH-R ~.R 3 .

C-: R R4 / NR4 .. This conclusion is in accord with the x-ray diffraction structural data... R 2 and R 3..R. These conformations for IV and V may be represented along the C--N bond as follows.3-thiazolidines are not found among the products.S I I .. of the following resonance forms of imidazolium salts VII: I ---NIl / ----" [ tl / "----" t I_ +/ N_ ~---N --N N --. I'/:-~ SCN IX R ~ .N r 1 X R'--N "/ "C~. Thus. :C. ' XI XI! +H+ +IlSCN . 46 . the key compound controlling the condensation is aziridinimine IX./C. The IR spectra of all imidazolium salts VII and imino-2-imidazolines VIII taken in KBr pellets are in full accord with the x-ray diffraction structural data.<C . although this form was not found in the usual state for thioamides [3]. : .~--R W.N L e~r I '-N" c r. . to the expectation of a tautomeric equilibrium involving at least two forms. the steric factor apparently determines the nature of the reaction such that multicomponent condensation is found upon slight repulsion between R*.L~ :~.V 9" ' " ' : ' " .5-dilmino-l. --N..C. Nc:~" ' : R' . Conformations of the reaction site close to eclipsed must precede the formation of both IX and VI from in- termediate IV or V.. might have been expected due to the possible stabili- zation of the thiol form by the nitrogen atoms of the guanidine group. c. IV V The steric hindrance which is important for realization of the conformation leading to the formation of aziridinimine IX is minimal for R* = H and CH3. Thus. | }~'...... R I R2 R ~ R2 I . " R2NI "r R~ " (: '' R ' "'~:/ rN__. >'--%_. while four-component condensation is found in the case of strong repulsion of these substituents.. The rate of consumption of X in the abovementioned reactions is apparently rather high and.. thioamide (A) and thiolimide (B).. .' _M//C .... The formation of tautomer VIIIB. as a result. i). especially for iminoimidazolines VIII.R'~ ..: . The bond lengths found indicate a definite contribution.. The delocali- zation of the ~-electron density leads to the levelling out of the lengths of the C-N double and single bonds (Fig.. J_:: ...C. An increase in the intensity of the C=N band at 1620-1660 cm-* by almost a factor of 2 in going from VII to VIII is characteristic for the IR spectra of these compounds.C.'~%..::.. T h i s increase is probably a conse- quence of the extension of the conjugation chain involving the two azomethlne groups. for example. This is related.jz r. N--R t .." -- VIIa %'II b ~Ic Special interest is found in the results of the spectral studies of solutions of these two groups of compounds (Tables 1 and 2). ~ VIII ------~" The reaction of thiazolidine X with IV or V may be presented analogously to the forma- tion of VII and VIII._. the corresponding 2..~ ~' I R*N..

j in CHCI3 show weak bands for a bound SH group at 2400-2600 cm -~. Thee these findings indicate that reaction according to the scheme ~C(S)NH_CH2C6H 5 . As in compounds such as VII. The IR spectra of solutions of salts VII in CHCI3 do not contain a band characteristic for the SH group. guanidine and amidine groups at 203.C H ~ s H s I 'HI ~II j ~CH~ The s p e c t r u m h a s a s i g n a l a t 1 4 5 .. The spectral data for iminoimidazolines VIII are rather complex in nature.~ bond and of the aromatic carbon atoms. On the basis of elemental analysis and PMR spectral data.~ ---C = N ~ . derivatives Vll in media of different polarity such as CHCI3 and DMSO are virtually in a single tautomeric form A. it contains two similar NH--CH2 group doublets in the PMR spect- rum (see Experimental) and two C=N bond signals in the ~3C NMR spectrum. the IR spectra of Vllle. c :J it~ 84 $7 CI22) C(23) % Vllle Vllj " 9 $12 ) Fig. c. In addition to the signals for the carbon atoms of the thio- amide. According to the spectral data. Some support for the equilibrium proposed above for solutions of VIII was obtained in the ~3C NMR spectrum of VIlli.2 ppm for the base. f. we studied the possibility of the synthesis of a model compound with fixed tautomeric structure B. signals for a free NH group at 3440-3490 cm -I and lack the absorption characteristic for a bound NH group. h.-Cliff -. imidazolium salt Vllj and imino-2-imidazoline Vllle. Structure of the products of the multicomponent condensation. Thus. there is a broad signal at 140. 47 . in contrast to salt VIIi. which indicates that the azomethine group nitrogen atom is also protonated in solution. which is apparently a result of the overla p of the signal for the thiolimide group S . 4 ppm a s s i g n e d t o t h e t h i o l i m i d e g r o u p . The somewhat u p f i e l d s h i f t o f t h i s s i g n a l i s due t o t h e s a l t c h a r a c t e r o f t h i s compound. To support this assignment. h-j.2 (double signal)..9 and 170. containing an NH group in either the free or bound state. We should note the absence of coupling of the NH-CH3 group protons in the PMR spectra of Vlla. the iodomethylate obtained from VIlli is a monoalkylated compound whose *SC NMR spectrum lacks a thioamide group signal. The iodomethylate thereby obtained has a structure analogous to imidazolium salts VII. i.

.co "el . I I I :> r~ I./3 I-.c~. zzzzzz~zzzz~zzz~z ~1 ~ I I~ ~ ~ .i 0 1.M I i-4 I-4 ~1 I I I I~1..1-1 ol-4 . ~1 I~1 I~1 ~~1~ i a~l I I l..M I I-4 I-4 I-4 :> '1:1 Itl .-4 Itl m 4.t u 48 ..r.co 00 r..1 0 o .I o~c~ o~o ~ o o c~ ~ o o .

26 (NH. 2S. 1. 1.96. t ) (.s ) VII r 1. The broadening of the NH signals in the PMR spectra of these compounds is also more pronounced relative to the salts. PMR Spectra of Vll and Vlll Compound Chemical shift. which complicates the de- tection of the thiolimide group. s ) [in(CD~)~CO] 1. ) VII i 1.56 (NH.02 (NH.44 (6H. s CH3). 9.!. 4.25.o): 3.69 (20H. 2 d. or-s_L ibr.48 (NH. 4. CHIN).13--2. m. 10. 9. 2 d CH2N)j 4. 7. 3.HCL s a l t . CH.48--2. 1.80. 2. 3.73 (2H.q' : R nN*" +zC N~ 1 " - H -S -C-=N The conversion of VII to 2 XIII in the case of R ~ = p-CH3C6Ha proceeds more rapidly than in the case of R 4 = CH=C6Hs. On 49 . CHIN).26 (2X3H. 7. 2. This difference is attributed to the lack of the deshielding effect of the positive charge of the quanidine fragment upon going to the free base.70 (2H. CHIN). A mass spectrometric study of Vlllh-j and Xllla showed that Villi and VIlli do not give molecular ion peaks. b r . 4. m cyclo-C6H. 7. 7.88.62.21.26 (20H..b r . 4.45. n~ cyclo-CsHs).4 (NH b~. C~H~).91 (16H.. CH=N). CHz).12.17 {10H.90 (NH. 8.9.o).17 (10H.72 (NH.33 (2}t. 9. s ) V i l l i .21 (6H.37 (2H.07.42. 80~ 1. 2 d CH. m.13. m C6H5)_. 7. 6. 7.05--1.14. br.. we propose the following scheme for this reaction: I R2 ~ ~R:N--F. CH.48. ppm VII a 1. TABLE 2. C~Hs). 4.~N). C~H~).32 (2• 2s. cyclo-C6H. b r . 7. 7. 7. 3.24 (2• 2 s.49 (d2• 9s. 2 d. br. b r . 6. cyclo-C.72 (16H. The NCHa s i g n a l s f a l l i n the . Pseudoanalogs of thiazolidinimines XIII.o). CnH~).32. 10. r~ cyclo-CsH. 2. b r . 2. CH~--N).d CH2N). m cgclo-C~H~o). CHs).4. 9.83 (NH. CH2N).28 (NH. CH~--N).77.27 (2>(2H.16 (10H. 4. s . b r .41.06 (20H.01.67 (2H. 7. br.97:7.18. 7. 9.21 (10H.92 (20H. 4. 1. salt VII is converted to thiazoli- dine XIII. CHIN). Thus. br.75 {2X2H.H. {~(CDs)?CO] 1. CH2N).61 (20H.o).o).28~ 2.68. 9. Upon brief heating at reflux in benzene or toluene.50.62 (NH.m.05 (NH. 7.d250 MHZ ) 1.24 (2• 2 s. were not found among the reaction products.13 (2• 2 . 4. ra C6H4).75. b r . but gradually decompose upon heating at reflux in water-ethanol solutions of KOH with~. d . CH_~N). 7. 1. br. 4.07. lq__.22 (2• 2 s CH~--N). CH.o).25 (6H. 7. 7. 1.44.31. d.s ) VIII 1.70 (2H. cyclo-C~H.19 (10H. 4.The NCBa :signals f a l l i n the region of the solvent siBnals4.39 (8H. s N--CH3).36 (2• 2 a N--CH3). ~ v i i J 1.4 [ R~ /~ xN--R VII ~ .12~1. cyclo-C~. 3. 10.53 (NH. cyclo-C6Hlo). 4. Till --.43--2. m. 2 s. 2. 4. m C6Hs). d. 8. 4. 10.87. C~'H~). 4. b r . s ) VIII a 0.35 (2H.17.15. m cyclo-CsH~). M.76 (2H.12.-e=. b r .40. Ar--CHz). 4. 7.14 (8H. 2s.82 (2H. 2. m.28 (10H.~N). 9. d.36 (2tt. SI][ --r { { I { R' -N-~ b.the release of H=S and formation of unidenti- fied compounds. 7. C6H~). 2inCH~N). Imidazolidines VIII are stable upon heating.s. s ) The PMR spectra of solutions of Vlllg and VIlli in DMSO-d6 show a significant downfield shift of the N--H and N-CH3 group signals in comparison with Vllg and VIIi. C~Hs). 7. whose formation is especially facilitated in the case of R ~ = p-CHsC6H4 by the conjugation of the aromatic ring electrons with the C----Nbond. b r .16.26 (2H. 3. b4~ys(2X2H.19. m-.20 (10H.~N).65 (4• 4 s. 3. 7. 8. On the whole. s j VII h A t 250 Mtlz 1. 2 s C6H~). b r .72.. 9. d CH2N).10 (6H. m. s ) VIII h ( At 250MHz ) 1.~--N). s .H. 10.26 (2• s.. b r .41 (20H.21. 9.27 (10H. 4. 6.s CoHs). 3. 3. d .~egionofLhesolventsignals4. . Ar--CHs). 8. Ar--CHs). namely. 4. b r . s .65 (20H.27 (2H.04--7. iminothiohydantoins VI. while the (M + i) peak is present in these spectra.06 (2• 2 sCHzN).6. even at 15 eV.84 (20H. one of the steps of this conversion presumably in- volves the thiolimide form. 2 s.15.

) 146 (3). The structures were determined by the direct method according to Andrianov et al. i R = + R a = (CH.) 160 (3). which apparently. g. As expected.53 g (55%) Vllf and 0.7 (9).04 (3).CCH2. Structural parameters for the hydrogen bonds: VIIi.HCl + KSCN (NH~SCN was ~sed in the case of VIlb. [4]. which was isolated upon evap- oration of the solution and lwashing of the residue with water (0. The PMR and '3C NMR spectra were taken on Bruker HX-90E (90MHz). The condensation with acetone and p-tolylisonitrile has several special features: only Villa is formed in ethyleneglycol while both VIIa and VlIla are obtained in methanol.). Vlla. and C atoms and isotropy for the hydrogen atoms to R = 0...743(5). In addition.62(4) ~ V = 1407.875(8). C(. the ion peaks are given in units of m/z.052(3) A. y = 89.oN(4). which were washed with hexane and dried. h. d-f. C(. 8 = 80.. where n = 4 and 5. c.) 1. b = 18. 0.)2.H(5) 1. By analogy. N(~). EXPERIMENTAL The IR spectra were taken on a Perkin-Elmer 457 spectrometer in KBr pellets and CHCIs and CCI~ solutions.7 g VIllf were obtained in the reaction with benzylisonit- rile in methanol.22 g/ cm ~.)~. space group P2. Molecular representations were obtained using the ELLIDS program [5]. respectively.. The hydrogen atoms were localized from the R maps. chromatograph- ically-pure product as lightly colored crystals.)N(~)H(.H~.247(3) A. The refinement was carried out by the method of least squares in the full-ma~rixapproximation according to Andrianov et al. k R 2 + R = = (CH=)s. c = 12..) 156 (3).7)N(4)H(. Ab- sorption was not taken into account..).23(2) ~ . i-k R* = CH.3 (9) 9 VII. e. In the latter case.)N(4)H(. the reaction mixture contained VIlld.46 g (53%) Vlla. 9Here and subsequently. f R 2 + R a = 2CH3. i-k.. g.77 ~a. h R* = H. [4] assuming anisotropy for the S.7 (8). d c a l c = 1.. h) in 8 ml ethyleneglycol or methanol at 20~ The reaction mixture was stirred for 6 h and left overnight to yield a single. The isoitriles were obtained according to ~gi [i]. j. and WM-250 (250 MHz) spectrometers for solutions in (CDs)2SO with TMS as the internal stand- ard. b = 11. C(.- C. Varian.) 103.. 50 . CHsNHa.22 ~3. c.)H(5)N(.O.N(. N. The x-ray diffraction structural an- alyses were carried out for monocrystals of Vllj and Vllle. z = 4.) 161 (i)~ VlIIe.C2Hs) ions (487 and 486 for VIlli and 459 and 458 for Villi) in these spectra indicates their molecular mass (515 for VIlli and 487 for Villi) in accord with the structures p~oposed for these compounds on the basis of the above results. d-f. a = 90. A sample of 0.65 g VllIa in the precipitate was filtered off and VIIa was obtained by pre- cipitation from water. The effect of structure of these similar compounds on the mass spectral intensity distribution clearly requires a sepa- rate discussion.)H(. In the preparation of VIld. N(. The reaction course and compound purities were monitored by thin-layer chromatography on Silufol UV-254 plates in 1:5 acetone--benzene and 1:2 acetone-hexane solvent systems. The mass spectra were taken on an LKB-2091 mass spectrometer at 70 eV.98(4).54 are a = 14. The mass spectrum of Vlllh. a.814 (4) ~. M = 515.88(3). c.NsS. y = 65. N(~)H(..[CH3--N-C(CH2)n-C-NHCH~C6Hb].)N(. V = 3127. 8 = 90.3 (9). N(.N(*) 2. k R ~ = C2H. the presence of peaks for the (M -.01 mole isonitrile was added dropwise with stirring to an equimolar mixture of 0. are formed as a result of M -.76 are a = 10. for Vllli and VIlli../b.)N(. angle N(~)H(. 1. g.the other hand. C(.056-0. The solvent was evaporated and the precipitate was filtered off and dried with 5 ml acetone and then hexane to yield 1. The major crystall~graphic data for Vllle.C2H4) and (M -.)N(.055.H(. deal c = 1.H4.92 (3).. Sets of 2846 reflections for VIIi and 2914 reflections for Vllle with I > 2o were measured on DAR-UM (for VIIi) and Syntex P1 (for Vllle) diffractometers.) 146. N(.8 g). d. M = 574. c = 12. space group PI.93 (4). Villi and VIlli give strong peaks for ions 272 and 286 ..) 2. Cs. the mass spectra of these compounds have ion peaks* 91 (C6HbCH2 +) while the (M + i) peaks are 3"5 times stronger at 15 eV than at 70 eV. f-j R ~ = C6HbCH2. b. 2-4-Diaminoimidazolium Derivatives Vlla.22 g/cm s.H(. a = 79..01 mole ketone. in contrast to VIlli .) 99. This precipitate was extracted with three 20 ml portions of chloro- form and the extract was dried over MgSO~. contains not only an M+ peak (487) but also a greater number of strong peaks for ions with high mass numbers. z = 2. a-e R 4 = p-CH. N(~).N(~) 2.-C(~7)N(~)H(~) 146.185(6).899(5). b.891 (3). bond lengths: N(4). The major crystallographic data for Vllj.809 (3). C32H~N6S2.

48. 37. The ratio of the E and Z isomers was 1:5. 119.3 (NCHs). 596 (1981).9 (C=S). Chekhlov.6. These compounds are insoluble in water.3.0. 66. the intensities are given in parentheses.47 (cyclo-C6H1o). 145. 17. ~ C NMR spectrum. dried over Na2SO~ and evaporated. 2 s. 31.8 (cyclo-C6H~o.8.5 (Cspiro). 13.1. 173 (7). 22. mp 87~ Found: C. d. br.2 (double signal as a result of overlap of the guanidine and amidine C=N signals). VIlli. d.4-19. 136. Andrianov. 4. 454 (10~.1. and B.0. 3.95 ppm (SCHs).8. PMR spectrum: 1. 65. 135. 232 (5). 281 (91). I . S.6. Thiazolidinimine XIIIj was obtained in 100% yield. 405 (7). CH3N).. *Here and subsequently.4. 71.4. s). 65 (6). New York (1971).7.1 (N-CH3). 157.9.4 (cyclo-C~H1o). 128.4.3. s). Ann. br.9.7. S.13 (10H. 27. 272 (i00).3. Rosendahl. NCH3). 4. Isonitrile Chemistry. cy- clo-C6HIo). 58.3 (C=N--Ar).01.M + 487 (16).9%. and DMF. An Automatic Prog- ram System for The Solution of Crystal Structures [in Russian]. 179.7. 130.4.8 (cyclo-C6H1o). N. 230 (21). 70 (7).2%. 13. 129. 138. 70. s. Rentgen-75. 121.2. 13. 98 (i0). 71. 22. Schaumann. 91 (55). Ugi. 257 (i00). 69. 37.4. IR spectrum (KBr): 1610. 181. 7. 26. 14. N. 13C NMR spectrum: 178. cyclo-C6H~o).6. S. PMR spectrum: 1.9.7. 98 (14). H. s. W. 125. Calculated for C13HITNsS: N.1 (NCH3). Calculated for C16H2~N3S: C. 232 (33). 2.29 (2H. and most organic solvents but are partially soluble in acetone. 3. 34. 107 (7). 145. 8.7. s). These compounds are soluble in acetone.3.03-7. 4. 134. 166. I. 56 (i00). 137.5 h. 11. 63. 286 (100). 92 (9).7.2. 170. IR spect- rum (KBr): 16. 2 s.6. 2. LITERATURE CITED I. V . 38. Tarnapol'skii. Thiazolidinimine XIIIe was obtained in 70% yield. Ugi. 91 (14).8 (N--CH3). 45. H. mp 185~ Found: N. N. 3361 (1971). 45. 36. 20. 4.7. 58. Kristallografiya. 273 (14). Thiazolidinimine XIIIj was crystallized from toluene upon cooling. 33.7 (hr. 36. 453 (301. benzene.62 ppm (NH.5 (Cspiro). CHCI3. iii (14). D.46-1.5. br. ethanol and chloroform. 68. Chem.9. 24. 23. 2-Amino-4-imino-2-imidazoline Derivatives (Vllla-k (Table i).9 (C6H5). CH3--Ar).2.3 (N--CH2C6H~). 14. 1695 cm -~ (br.. Ber. 6. 37.66 (1OH. 35. 178. 65 (7). 245 (8). 159 (9). F. 140. 22.2%. IR spectrum (KBr): 3415 (NH).14 (5H. Chernogolovka (1975). S.2%.015 mmole 10% aqueous NaOH was added to a solution of 0.24 (6H.7 (NC=NH). 68 (5).74 (20H. 132. 91 (98). 26.3.8.5%.1 br.2%.e. 271 (141. 11. 3160-3650 cm -~ (br.3 (C6H5). 7. Bodesheim. 354 (9). 24. 68 (9). br. Walter and E. Calculated for C32H~INsS: C. 176 (7).8.8.3-Thiazolidin-5-imines (XXXa.24 (Cspiro). 126. 92 (7).8. C6H5).2. 336 (19).5. I. 127. 38. S. m. the ion peaks with intensity greater than 5% of the strongest peak are given. N . (M + i) + 488 (13).3 (C=S). 82.0. 362 (17). S. 120.5. 51 .4. The product was obtained in 70% yield. C6H5). 5. C6H5). (NHCH2). A . IR spect- rum (KBr): 1585-1600 (C=C. 666.e. 14o4. 127. S. p. NHCH2). 1640 (C=N). Products XIIIa and XIIIe were isolated from the oil obtained after solvent removal. 4.0 (Cspiro). A sample of i0 ml 0. 136. 4. 133. 46.9%. 380 (9). 131. p. 136. 12.6. L. 129. C=N). s. dimethylsulfoxide.9.j by heating at reflux in 2% toluene solution.3%. 7.68 (2H.7. 3. 337 (56). 118 (7). S-CHs). s.33 ppm (NH. 157. br.4 (br.9. The chloroform solution of VIII was separated. 54 (1963). 11.3. ether. 9. 7.9. 127. C.01 mmole VII in chloroform and stirred for 0. 72.0 (C6H~). 381 (ii).6.8-20. ~3C NMR spectrum of VIIi: 203. 72. H. 338 (20). S.3 (SCN). Safina. (M + i) + 516 (18).215 (9).1 (N--CH2C6Hs). 4. 117 (16). 258 (19). iO4.j) were obtained from VIIa. 21. 14.15 (3H.3 (guanidine C=N).48 (2H. 3435 cm -I (NH). 116 (27). m. Academic Press. 16. mp 205~ Found: C.365 (9). 57 (7). 132 (14).3. Academy of Sciences of the USSR. 170. 34 (6). K. 127.9.7 (quanidine C=N).0 (amidine C=N).8.8. XIIIa was dis- solved in a minimum amount of acetone and separated by thin-layer chromatography using 1:3 acetone-benzene as eluent. i0. The reaction was monitored by thin-layer chromatography.5.0. M + 247 (99).4 (S--C=N). Div~son of the Institute of Chemical Physics. 128. 10. Thiazolidinimine XIIIa was obtained in 65% yield. The iodomethylate of VIIIj was obtained by treating VIIIj with a five-fold excess of CH31 for 48 h. H.4.49. 3420 cm -l (NH). 13C NMR spectrum of Vllj: 204. Sh. 126. 37. XIIIe was obtained by crystallization of the oil from hexane. 11. 117. 118. CH=N). NH).20.9. and F. 21.0 (amidine (C=N). 31. 1.1. 125 (5). C=N). 31. 32. 35. mp 155~ Found: N. 2 s. N. Calculated for C16H21N3S: N.6. Villi.22 (3H. 96 (i0). 3.4..0.29. Mass spectrum: 41 (7). Mass spectra*: Vlllh. 1640 (C=N). 145. 66.

oxime IX.NEW DERIVATIVES OF IMIDAZOLINE 3-OXIDE AND THIAZOLINE WITH 2.--i-.5-dialkyl-4-hydr0xy- phenyl)-2-butanones I and II prepared by the alkylation of 2. Heating butanones I and II with 3-amino-3-methyl-2-oximinobutane (III) and I with amino- oxime IV in the presence of p-toluenesulfonic acid leads to the corresponding 3-imidazoline 3-oxides V-VII. The structure of such compounds consists. Novosibirsk 630090. the yield of the product. 1986. Nitrosylation of 3-imidazoline 3-oxide con- taining a phenol substituent proceeds either at the imidazoline ring amino group or at the phenol fragment.50 9 1986 Plenum Publishing Corporation . I.4:781. VIII RI=CHz III. A.563. Interest in such heterocyclic compounds is related to the use of sever- al 4-thiazolines as light stabilizers for polyolefins [4]. 2]and hydantoin [3]. Novosibirsk Institute of Organic Chemistry. pp. January.6-dialkylphenols by methyl vinyl ketone in the presence of bases [9] were used as the starting materials. specifically. Translated from Khimiya Geterotsiklicheskikh Soedinenii.YI. 62-67. 52 0009-3122/86/2201-0052512.IV Y. The use of a 2. Readily available 4-(3.1: 541. Intermolecular cyclization of (2. VII. Martin UDC 547. Original article submitted October 31. Siberian Branch of the Academy of Sciences of the USSR. we synthesized new imidazoline and thiazoline derivatives contain- ing a phenol moiety. VI. VII R~=C6H5 The condensation of ketones I and II with aminooxime III proceeds rather smoothly to give high yields of 3-imidazoline 3-oxides (~80%).6-Dialkyl-4-hydroxyphenyl)-2-butanones and aminooxides were used to obtain the corresponding 3-imidazoline 3-oxides.124:678.5-fold excess of aminooxime III in the reaction with ketone II leads to a side reaction involving the formation of butanone oxime VIII in 62% yield. while benzimidazoline-2-thiones have been proposed for use as oil and rubber antioxidants [6].O -3~]~"--~:I N r --N R1 CH . ~ -CH3 ----~/ + ! ! C~-O C~N--OH [ Ill.3'789. V. Imidazoline derivatives h a v e b e e n synthesized by the acid-catalyzed condensation of ke- tones with aminooximes [7]. heat and atmospheric oxygen. P. V. 1984. a sterically-hindered phenol and heterocycle such as pi- per idine [i. was 5% in this case. IV. Compositions of 3-thiazolines and thiurams act as thermal stabilizers [5]. as a rule. In the present work. A similar conversion was observed in the condensation of ketone I with aminooxime IV. of two functional fragments.6-di-tert-butyl-4- hydroxyphenyl)-2-butanone with sulfur and ammonia gave a 3-thiazoline as two dia' stereomers. VI R2=CH~.II VIII.048 (2. and V. II..C H 3 . IX R'=t-C4Hg. 0It OII ~.6-DIALKYLPHENOL FRAGMENTS T.YII I CH~ CH 3 I. A promising area of research in the chemistry of polymer stabilizers lies in the creation of additives with a broad action range which protect the polymer from the action of light. No. F.IX I. Krysin. V. Titova. while thiazoline derivatives have been prepared by the reaction of ketones with sulfur and gaseous ammonia [8]. / R~ R2 /Ott R 2 "~ .

Due to its instability [13].'-' + NO2 X~ XlI The PMR and elemental analysis data (Tables i and 2) permit the unequivocal assignment of structure X to one of the reaction products. the presence of the 2-(3. OB 7 O . 1625 (heterocyclic nitrone ~ ) and 3610 cm-z (OH).5-~ny~)-~-ethy~]-3-imidaz~ine-3-~xide.. which have not been extensively studied.O H . ...CII~(( ~ ' ~ .o - H§ --A---~. r r w o ~.__~o i~~ HO- 53 . 11 ~J~q/2 H ~ CH2CH2-~(/(" . The formation of XI and XII may be represented by a scheme beginning with the attack of the para positive relative to the benzene ring hydroxyl group by a nitrosium cation [ii] and oxidation of intermediate XIII and quinonitrile XIV [12]..6-di-tert-butylphenol (XI)and XII. The signal for such forms XA and XB in the PMR spect- rum were assigned taking account of the anisotropic effect of the N-nitroso group on the B- methyl group protons [i0] of the imidazoline fragment and the aromatic ring protons. Xl XIII XIV 9 . Pathway B involves substitution of the nitro group by a hydroxy group and the formation of quinol XII [14.5-tetramethyl-2-[2- (~-hydr~xy-3.. XIV is rapidly converted by two independent pathways. Further proof for the structure was obtained in the Z3C NMR spectrum in CDCI3 which shows signals at 186.H~( )f)--. The reaction of V with NaNOa was carried out in order to study the effect of the phenol substituent on the nucleophilic pro- perties of 3-imidazolines.OH XA XB In addition to substitution in the imidazoline ring. the phenol fragment in nitrosylated leading to the formation of 4-nitro-2..5-di-tert-butyl-4-hydroxyphenyl)ethyl fragment in the structure of 3-imidazoline-3-oxide V sharply reduces the selectivity of the nitrosylation at the amino group due to the appearance of an additional reaction site in the phenol substitu- ent.8 ppm related to the carbonyl carbon atom and carbon atom attached to the OH group. Hence. N V" "/"Nz ~'CIl:.9 and 89.. XII was assigned the structure of 2.. N-Nitroso compounds are known to exist in solution as two stereomeric forms [7]. Pathway A involves the loss of an alkyl- eneheterocyclic substituent from the geminal unit [14]. CII~r --01] ~ "N HI / "CII~Ctf~ " \ ~ ' ~4~:=0H .5-di-tert-butylcyc~hexadien-2.. The IR spectrum of XII shows bands at 1680 and 1655 (C=O and C=C).. --0H "~" CH2-C. -"~') j . V "-. The PMR spectrum indicates cyclohexadiene and imidazoline 3-oxide fragments in XII (Table i).5. 3-1midazoline3-oxidesreadily underg o nitrosylation [7] to give sterically-hindered nitrosoamines.4.. .. Thus. 15]. \ .

melting points and elemental analysis data for V-XII and XVl in Table 4.If . ~. EXPERIMENTAL The IR spectr 9 were taken on a UR-20 spectrometer in CCI~ and KBr pellets.3 g 2-oximino-4-(3.6-di-tert-butylphenol XI '~ 54 .5-dimethyl-4-hydroxyphenyl)butane (VIII) and 2.~cH a s . 3. We have prepared 3-thiazoline XVI by heating ketone I with sulfur and gaseous ammonia for 7 h at 120~ Thiazoline XVI is a i:I mixture of diastereomers XVIA and XVIB wh:[ch may be separated by crystallization. 2. A mixture of 29 g (105 mmoles) ketone I. 3 g (1.5-di-tert-buty~-4-hydr~xypheny~)-~-ethy~]-3-imidaz~$ne 3- oxide (V).4 g (72 mmoles) aminooxime III and 20 mg p-toluenesulfonic acid under the conditions described in A gave 3.5-Trimethy•-4-pheny•-2-[2-di-tert-buty•-4-hydr•xypheny•-•-ethy•]-3-imidaz••ine 3- oxide (VII) was obtained analogously under conditions described in procedure A from 5. A mixture of O. dried over MgSO~ and evaporated to give 12 g product. A sample of 62 ml 5% hydrochloric acid (pH 2-3) and 50 ml 10% aqueous NaNO2 was added to a solution of 11.5 g (19..5 mg p-toluenesulfonic acid was maintained in an argon stream for 2 h at 80~ and for 8 h at 130~ After cooling.5 g (30 m~oles) V in 200 ml 50% aqueous ethanol and maintained for 3 h at room temperature. Nitrosylation of 3-imidazoline 3-oxide (V).076 g starting ketone II and 0. The in~ermolecular cycllza~ion of ke~ones by the action of sulfur and a~unonia with the formation of 3-thiazolines has been studied by Asinger [8].5-di-tert-butyl-4- hydroxyphenyl~butane (IX). The UV spec- tra were taken on a Specord UV-VIS spectrometer in ethanol. and XII in CDCIs and for VII in CD3OD.5-dimethyl-4-bydroxyphenvl)-l-ethvl]-3-imidazoline 3-oxide (Vl). The results of these tests will be published separately. and IX in CCI~. A. B__=Heating and subsequent treatment of a mixture of 5.5.7 g 2-oximino-4-(3.177 g (1. and 4 g 3-imidazoline 3-oxide VII.53 mmoles) aminooxime III and 1.7 mmoles) aminooxime IV and 15 mg p-toluenesulfonic acid. The PMR spectra were taken on a Varian A-56/60A spectrometer for V. 2.5-Tetramethyl-2-[2-(3. the glassy mass was separated by column chromatography of sil- ica gel with gradient elution using chloroform-ethanol to yield 0.56 mmole) ketone II. which was subjected to column chromatography on silica gel with gradient elution using chloroform- ethanol to give five fractions containing 0. alicyclic and heterocyr ketones with at least one hydrogen atom in the ~-position relative to the carhonyl group undergo this reaction.5-Tetramethy~-2-[2-(3. The *SC NMR spectra were taken in CDCI3 on Bruker HX-90 and WP-200SY at 22.:N) char- acteristic for thiazolines [16]. for VI. 0. CII-SII ] C ==0 [ CH3 O~I XY Preliminary experiments of the compounds synthesized showed that some of them have both thermal and light stabilizing action. OH 9 S . 8.'"~crI 2' . 0. washed with hexane and dried to yield 31 g V. The oil separated was ex- tracted with chloroform. X.5 g (29 mmoles) ketone II.5. The iR spectra of these compounds show a band at 1660 cm -l (O. Column chromatography gave 2.52 g (20 mmoles) ketone I.3 C NMR spectral data (Tables 2 and 3). 12 g (103 mmoles) aminooxime lll-and 0. Further proof of the product structure was obtai~led from the PMR and . The precipitate was filtered off. VII.346 g VI.2 g imidazol- ine 3-oxide VI.5 g (7%) 4-nitro-2.4. Such conversions for carbonyl derivatives of 2. 2. Various aliphat~c.63 MHz.6- dialkylphenols have not been reported.05 g p-toluenesulfonic acid was heated in an argon stream for 2 h at 80~ and 8 h at 130~ The cooled glassy mass was treated with hexane. The yields.5.4.3 g starting ketone I.

4 C (2". and 2. I [ CH3 CH~--CI-12 H&roi I OH V 1610 [CCI. 28. 129.2C 1.42 6. bcenter of triplet of doublets.8 C(2.3 s.2 (C(xs)). 278 (3.58( 1. 176. 30.6 C~s) 65.5 (C(~a)).26 VI 1655 [KBr] (C=N) 224. 34.5-di-tert-butyl-4-hydroxyphenvl)-l-ethyl]-3_imidazoline 3-oxide (X).27 1. 129. 2.) d. JAX = 4. 89. 1.54 7.4 s' 152. J = 4 Hz. 9. 135. CMultiplet center. Xmax.5. JBX = 12 Hz.05 14.4 s.0 C (3'.28c 6.84 1.7 (C(s. 68.3 (C(6)).84 3635 (OH) Xt 1625 [KBr] (C=N) 229 (4.55c 6. 167.6 Cr t.4 (C(~a. Ama~ pound ~ [ log !-C4H9 L ore 6-CH.6O) 1.I 2.9 (C(xo)).81 ppm for VIII and IX ( C H z ~ H ) .38) 1.00 1.12 3640 (OH) XVI B 1660 [CCI4] I [278 (3.57) 1.6 . ppm [solvent] trum. 89.~7)).6.1 C(6) b 46.6 C (]') s.o~ 2.6 C~z) b 31. (C=N). 55 .2 ppm (C(7)).67 2.54 VIII 1610 [KBr] (C=N) 281 (3. 26. 1.53c 1.5-tetramethyl-2-[2-(l-hydroxy-3.64 }(a) 2.I( 6.6") d.2 C(w) s. 145.5-onyl)-l-ethyl]-3-imidazoline 3-oxide (XII).4~ 2. 125.8 g 3-imi- dazoline 3-oxide V.4 C(9~ qq.9)).30) 1. 61. 89.7{~ 6.cm~l UV spee.7.77 6. 124.5-di-tert-butylcylohex- adien-2. UV spec PMR spectrum (in CDCI3).89 (b) 1.3 9 18.8 (3.1 C (4") s' 152. TABLE 2. J = 12.94. 34.00) 1.2 g 2. 142.12C 6. 3. JAB = 14.99 3650 (OH) 278 (3. bSlight predominance of the B form.56 1.05 [4. ppm Com.0.2 (4.3~ 2. 34.9 31.8 (C(x2)).4.1 s.9 (C(~.96 3650 (OH) 1.7 (C(x~)). 29. 228 (4. 27. TABLE i.6 s.34i 4.] (C=N).5 (C(2)).1 s.66c[ 5. Chemical Shifts (ppm) in the ~aC NMR Spectra of XVIA and XVIB Carbon atom XVIA XvIB Carbon atom XVIA XVIB C(2) s.57 1.2 :q.3 C(4) 168.2 g.94 1.] (C=N).3 ~1 32.42 7. (C=N).~6)). 18.32). 1.14 ~278 (3.2 d.8 32. 131.23). 17-CH2 10-CH2aI CH 8-CHa J9-CHa OH I XVIA 1660 [CHCI3] I278 (3.0 q 65.00.3". 132..2 (identified by comparison with the PMR and IR spectra of an authentic sample). 151.7 d.3 (C(. 1.39 b[2.29) 2.4 Coo s.l PMR spectruma. CMultiplet center. X3C NMR spectrum: 186.5t ~5") s.7 g 1-nitro- so-2-[2-(3. 35.65 2. Spectral Indices for XVIA and SVIB ~R spectrum.17 1655 (C=C).7 $.84 (a) XII 1625 [CC14] (C=N). JBX = 8 Hz.47b 12.30 VII 1540 [CCI.4 C(]2) q.4 t~ 46. 124. 135.41).2 s.52c 6. 3610 (OH) ai.1 2.34 4.3 C (~') s' 151.08 3640 (OH) I aMultiplet center (ABX system) for XVlA.32 1.3~ 4.3 (C({9)). for XVlB.76) ! -. JAX = 4.96) 1.20) 1.66 (b) (a) 304 (3.27 277.00 [ 2.!7 5. ~. 233 (4.5J 2. 7.04c 3.":m-I':[solvent] trum. 32.39 5.01. 125.))..08. 5.6 (C(5)). 30. TABLE 3.86 1. 284 (3.15 5. JAB = 14.51 1. 3. .28 c 6.42 2.7~ 1. 1680 (C=O). 41. 41.27) 1.14 IX 1635 [KBr] (C=N).04c 3. Spectral Indices for V-X and Xll IR spectrum.

M. G. LITERATURE CITED i. D. A mixture of i0 g (36 mmoles) ketone I and 0.67) av.. ii. Izd. and V.64 76 VII 133--13~ 77. V. and F. Volodarskii. Levin.41 30 XlI [62--t64 70. VIII.00 4. West German Patent No. L.02 9. V..80 ' 10. i0.4. The Infrared Spectra of Complex Molecules [Russian translation]. Kirillova.096. X. Moscow (1963). dark red mass crystallized upon the addition of hexane to yield 5 g 3-thiazoline XVI as diastereomers XVIA and XVIB.48 CzJ]3~N202 73.47 C3sHs~NO2S 76.23 10. Skripko. Sharma. Indices for the Compounds Synthesized Com.07 9. 32. Khim. L.19 [0. Khim. Mamatyuk. 8. Chem. 40.37 9. 17.. 24116B (1961).55 9. 2082 (1964). bRelative to the starting ketone. V.J~I3~N203 . Moscow (1976). Khim.85 7. 8.395.~lllTN()2 69. % pound formula C H N(S) c H N(S) i V 175--177 73. Popova. 24N188 (1975).67) XVI b 85--87 76.62 C17112. B. Izd. 2-4-Dimethy•-2-[2-(3.42 9. K. T. Lit.23 7. Ber. Three-fold washing with hot hexane gave 2. Abstr.64) (5. Merkur' eva. and V.69 9... Titova. J. 299 (1966). Smith. B. Ershov.5 g color- less diastereomer XVIB which turns pink upon exposure to light. A. 1402 (1956).42 9. Zh. V. 5N210 (1976). Z. V. A. N.. Khim. 4. Evaporation of the filtrate gave 2. Org.. 16.5 g of insoluble diastereomer XVIA as a colorless precipitate. 648 (1958). I.. D. V. 87 (1980).. 1. Newland.391.739. A.23 6.159. % Yield. ii.77 2.71 2. Zh. 6. Zlobina.63) (5. Byul. and E. VI.47 25 (5. US Patent No. Usp.2C)2 77. 13.54 8.75 [0.02 (. E. L.31 . R. A. Heuck. Amery. XVIA and XVIB were crystallized from hexane. Org. Bloom and G. Inostr. 23. M. Khimiya. p. A.39 C~114(. J. Name Reactions in Organic Chemistry [in Russian]. i. Shakirov. E. No.N~O2 68. 89. Org. Khim. and G. A. Krysin. V.233. 1239 (1975). F. Randell and M. P36758S (1968).162. p.5-ditert-buty•-4-hydr•xy•heny•)-•-ethy•]-5-(3. Mfiller.N.41 C2~1t3. 3. 9.}.80 2. the glas- sy. Izv.~1-t2~)NO2 74.864 g (27 mmoles) sulfur was heated for 7 h at 120~ in a stream of ammonia. I. Martin and L. TABLE 4. A. Ref. Ley and E.. Traynham. 1. Chem. 20. US Patent No.70.47 25 {5.27 6. 1.(}. % Chemical Calculated. V. Akad.03 4.57 9. 3NI9OP (1980). Vatsuro and G. M. V.. Nauk SSSR.q 8. Henry.5-di-tertbuty•-4- hydroxybenzyl)-3-thiazoline (XVI). British Patent No. Mauz. Org. Chem. 154 (1963). British Patent No. O. 15. 7. Chem. VII. I. 5. Battiste and J. 12.N~O2 70. Geterotsikl.363. Bellamy. Khim. Volod'kin.30 6. Ershov and G.47 C36Hs~=NO2S 6. After cooling. V. Ser. 388..35 9. T. 4.75 62 IX 126--128 74. Bogdanov. Zlobina. Zh. Ref. C.80 C. Khim.i06.57 10.81 7. 3.41 47 VIII ~00--201 69. Rochlitz. P. Zh. Matveeva.. K. 2. M. Abstr.48 78 VI 129--13s 70. 103 (1979). R.599. USSR Inventor's Certificate.75 C.11 6.a [34--135 76.39 9. IX. 14.3I 7.80 5 X 159--161 68. Khim. J. No..17 18 XVI. Izobr. [~) ~ Found. 56 .53 10. Crook.246.13 9. Pankova.16 C.. 331 (1984). Ershov and G.80 2. Zh. A. Ref.. Chem. and XII were crystallized from 1:2 ethyl acetate-- hexane. V. Soedin. Mishchenko..

Palishkin. UDC 541.. The acid--base characteristics of N-(2-benzimidazolyl)-O-methylcarbamate were evaluated.. 1986. the structure and properties of this compound have not been studied.42:547. 2].4 and 533. which correspond to structures I and III and excludes struc- ture II. The structure of BMC may be represented as tautomers I-III ~\ /c-oc~ 3 \ / . 68-74. In struc- ture II. The XES of BMC shows two Nls lines. M. Translated from Khimiya Geterotsiklicheskikh Soedinenii. x-ray electronic spectra (XES). we carried out a detailed study of the structure and physicochemical properties of BMC in the polycrystalline state and in various media. V. and the other two have three o-bonds and supply Pz electrons of the unshared pair to the ~-bond system. IR.5-2 eV lower than the Ols line for the oxygen atom in the bridging bond. we should expect the appearance of two Ols lines with i:i inten- sity ratio and two Nls lines with 1:2 intensity ratio. III Since monocrystals of BMC could not be grown. N-(2-Benzimidazolyl)-O-methylcarbamate (BMC) occupies a special posi- tion among these compounes [I. Of the three nitrogen atoms. The spectra of this compound were interpreted using quantum chemical calculations and experimental data. 1984. i. The Cls line at 285. Benzimidazole derivatives have a set of biological properties which permit their use as pesticides and drugs.62:543. revision submitted December 28. one of the oxygen atoms is in a C=O double bond and the other is in an OCH3 group. S.3-0. The x-ray electronic spectra were taken on a Kratos ES-100 spectrometer by pressing the compound into a copper lattice. the XES method permits the qualitative differentiation Of the valence states of atoms in molecules. January. Eo Zaitsev.2 eV and I. i).. In the present work.o n H." The Ols values in the XES of BMC hydrochloride are higher by 0. 0009-3122/86/2201-0057512. Original article submitted August 21.5 eV (Fig. Moscow 117923. pp. \ ~-. Kukalenko. and electronic spectroscopy were used to determine that N-(2-benzimidazolyl)-O-carbamate in the crystalline state and in organic sol- vents exists predominantly in the benzimidazole carbamate form. ~F. No. one is a C=N double bond.5 S.SPECTROSCOPIC STUDY OF THE STRUCTURE OF N-(2-BENZIMIDAZOLYL)-O-METHYLCARBAMATE B. Since the bond energy of the in- ternal electrons in atoms within molecules depends on the electron density of their outer shells. In the XES of tautomer II. and V. Thus~ the BMC molecule has car- bonyl and bridging oxygen atoms. Table 1 shows that the Ols bond energy of the oxygen atom within a double bond is 1. both oxygen atoms are of the same bridging type while the three nitrogen atoms are divided among two nitrogen atoms in double bonds and one atom supplying Pz electrons to the T-system. However.'i intensity ratio (Table i). The intensity of the line with higher energy is twice P. The XES of BMC shows two Ols lines with energies 531. The assignments of these values to oxygen atom types were carried out using literature data for the XES of compounds containing oxygen atoms of a determined type.0 eV obtained from the vapor of diffu- sion oil condensed on the sample was used as the standard. 1984. there should be one Ols line and two Nls lines with inverse intensity relative to the intensity of the Nls lines in tautomers I and III.o ~---o i . Lumumba International Friendship University. Thus. In accord with the valence state types for the oxygen and nitrogen atoms in the XES of tautomers I and III.785. Brysova X-ray electronic. IR and UV spec- tra as well as quantum chemical calculations were used to establish the predominant tautomer.50 9 1986 Plenum Publishing Corporation 57 . P.

Hence. Thus. 58 . TABLE i. The XES of benomil shows two Nls lines close to the Nls values in BMC (Table i) but with 1:3 intensity ratio.6 533..5 and 399. The electronic spectrum of BMC tautomer I has three absorption regions (Fig. N~C [" 0 ~ 0 -I 531.5 eV is related to the six "pyrroiic" . HCI 531..a'-dipyridine is 399.1 eV are observed in phthalocyanine for the eight nitrogen atoms with signal halfwidth d~/2 = 1.4 that of the low-energy line.. the Nls line atom of a double bond nitrogen atom is 399. Pariser--Parr--Pople quantum chemical calculations [8.5 eV was assigned to the C==N bond nitrogen atom. 2). nitrogen atoms N while the value of 399.1 eV [4].and o-energies to the total energy of BMC (Table 2). from ~n-~ to ~m (33%) and from ~n to ~m+1 (10%).7 J OCtt.5 400. S 533.. The ob- served fine structure of the long-wavelength band with difference in frequency between the components A~ = 800 cm-* is a consequence of electronic-vibrational transitions (Fig.4 398. while the electron-withdrawing fragment is the benzimidazole ring (Fig. the first absorption region is related to the complex electron- ir transition from the highest occupied molecular orbital (HOMO) ~n to the lowest unoccupied molecular orbital (LUMO) ~m (41%). 2). two Nls energies of 400. The Nls value of 400. the examination of the XES indicates that BMC in the crystalline state exists predominantly as tautomer I or Ill. the facile tauto- merle transition between these forms is possible depending on the solvent.2 eV in the XES of BMC was assigned to two NH group nitrogen atoms and the line at 398.5 eV higher [6]. the Nls bond energy in a. ~-conjugation is 1..0 532.6 Benomil (V) 531. According to the calculation.1 eV is related to two "pyridinic" nitrogen /l\ atoms (N=C) [7].7 eV and 1:3 intensity ratio.4 eV due to the induction effect of the proton.5 398.. The energy characteristics of tautomers I-III were calculated in order to determine the existence of tautomers in the gas phase. the Nls energy of 400. The similarity in the atomization energies of tautomers I and III and the en- hanced solvation coefficient in tautomer III relative to I indicate that.4 533.9 400. According to the heats of atomization of tautomers I-III.BHC. 3).1 eV and the corresponding value for a hydrogen atom in p. these compounds have similar stability with some preference for tautomer I in the gas phase due to the gain in H-bond energy in the tautomer series 1-Ill. In five-membered aromatic rings such as imidazole. eV 0Is NIs Compound . N . The Nls values in BMC.. while for the Nls values for pyridines in the solid state lie in the range from 388 to 399 eV [5]. The redistribution of H-charge in the molecule upon going from the ground state to the first excited state indicates that the electron-donor fragment in this transition is the carbamate group.HCI are higher by 0. Bond Energies of Internal Electrons Eb. The transition is polarized at an angle of --13~ relative to the long molecular axis (x-axis).7 400. OCII~.4 I "11 ~ [4] 531. the effect of the electrostatic interaction with the medium and evaluation of the con- tribution of the ~. According to XES data.9 533. Finally. 9] were carried out using a var- iable ~ [10] according to the program of Kosobutskii [ii]..2 .5 399. The electronic absorption spectra were taken on Specord UV-VIS spectrometer in ethanol and CHCI3.2 398.

C(~). According to the calculation.26 I03.77 5. eV 0. 1 Fig.78 4.24 24. Fig. 2 Fig. The existence of isobestic points indi- cates the existence of an ionized form of the molecule in solution (Fig." / C .60 3. and ~n-~ + ~'m (17%) This transition is polarized by --32~ relative to the x-axis and is local- ized predominantly in the benzimidazole system (C(I).~ M I 23. Energy Characteristics of Tautomers and lonic Forms of BMC ".3 . / 59 . L~4.30 I08. / / O.2 7 --Z0~---Z. the anionic form IIA of tautomer II is formed in alkaline solution (Table 3): H / . ~il .62 4.73 49. The third complex electronic transition appears in the experimental spectrum as a shoul- der kTabie 3) and is localized in the benzene ring (C(2) and C(3) are electron-withdrawing and C(~) and C(6) are electron-donating) and in the carbamatoimidazole fragment (the imida- zole ring is electron-donating and the carbamate group is electron-withdrawing). ~n + ~m+.38 J-:% OH IA 24.4 I \EU~..'-Bond O -Bond ne~t of ~olvation " ~nergy~.oz r :~98Eb. 0.29 I08.30 I03. eV 50 42 34 9. 2). C(a). X ray electronic spectra: a) Nls for BMC. C(5) and N(9) are electron- withdrawing while C(a). C(6) and N(7) are electron donating).0 /\ - ~imEb. (19%). TABLE 2.27 I03.10 Ill 23. The fourth transition is given in Table 3. eV tion.78 49.17 The second n-electron transition is also complex: ~n + ~m (48%).eV '?'-s!~--g3*3-g-3iEb.70 II 23. The band with two re- solved vibrational components (Av = 950 cm-*) corresponds to this transition in the observed spectrum. Compound ?~ ~ ev EO . energy ~tomiza-~oefficient.50 49.10 ~ c ~ Fig. b) Ols for BMC..44 49.92 49. i.8#.67 4. Electronic absorption spectra of BMC in ethanol (i) and of BMC in alkaline ethanolic solutions (2-4). A bathochromic shift is observed in the spectra for BMC in alkaline ethanolic solutions relative to the spectra in ethanol for all bands.i 0 z.fJCH. 2. eV b3b 5a3 531 gb. c) Nls for BMC-HCI and d) Ols for BMC-HCI. AI I 1.

The band at 3330 cm-* is assigned to vibrations of the ex- ocyclic NH bond forming strong intermolecular hydrogen bonds.~'~ "~". 3. T h e intensity of the 250/245 nm band is very re- duced.387 "~-" 18& a -..4 Nx " . 2675. 5) and in di- lute solutions of BMC in CHC13..o~ /.."':' A'/ j' .li . . and 2810 cm-* which we assigned to the stretching vibrations of the NH group bound hy a strong intramolecular bond to the carbonyl group.~.3 C]II - Fig. and b) in the first excited state. The calculated spectrum of protonated tautomer IA is in satisfactory accord with the experimental spectrum (Fig. ---I .. -IZ4 " 035 \x ~/ b " .27s . Fig.2 and pKb 5. The strong shift 60 . (. The pK a value of 11.od.o. The calculated fneutr/fanion = 0.. 2755.. C--O~ The acidity and basicity constants of BMC in 50% ethanol were determined spectrophoto- metrically using Na2B~O~..... 0'8LAI ..18) and KH~PO~ (pH 6. V2"b..~B H (~ o L. %584 43 :. which prevents its observation due to overlap with the adjacent strong band. ~%. The IR spectrum of BMC in vaseline oil at 3700-2100 cm -I shows a diffuse band with a set of maxima at 2555. This assignment is in accord with the lack of this band in the IR spectra of polycrystalline benomil (Fig./ 1.00~ ".. .. 14]."'r'~. The IR absorption spectra were taken on a Specord IR-75 spectrometer. The long-wavelength band re- tains its fine structure and undergoes hypsochromic shift by 4 nm..~o~' 4. Molecular diagrams of tautomer I: a) in the ground state. 2. The long-wavelength band is attributed to the extent of 87% to the transition ~n(HOMO) § Tm(LUMO) and the intensity (f = 0. this band is shifted hypsochromically. The bands at 1640-1655 cm-* were assigned to the C=O bonds since the vC==N band of benzimidazole is observed at 1620 cm-* while the vC-_~ band of iminoesters are observed at 1615-1575 cm-* [13.... 3 Fig. 4. 4 Fig..4 and experimental Cneutr/eanio n = 0..3. The doublet nature of the band is due to the appearance of vibrational structure in the electronic transition. The intensities of the bands at 212 and 228 nm undergo inversion and a hypsochromic shift of 4 nm.~' .238). 4).3 ratios for the long-wavelength transitions are in satisfactory accord (Table 3).~K .t@ .. According to the calculation.0 for 2-phenylbenz- imidazole [12]..Ie. %012 .. This transition is polarized along the long molecular axis. 3) BMC in CHCl~ after the passage of gaseous HCI.~ -.86) buffer solutions. '~ . Electronic absorption spectra for i) BMC in CHCI~..621) is 2..377 000 " " \ ' 6 ~" 004 /342 o.. ~%/%:..64 and pkb value of 5..60 fall withing the pK ranges for reported benzim- idazole derivatives: pK a 13. L:: x4.. The spectra of the solutions of BMC in acidic ethanol media and in CHCI3 through which gaseous HCI was introduced show that the BMC molecules are protonated as indicated by the ob- servation of isosbestic points (Fig."x..oi~ -. and 4) calculated spectrum for protonated tautomer IA.6 times greater than for the neutral form (f = 0. respectively.I0~20 (pH 9..53 for benzimidazole and pK a 12. /Z" 9@ ' ... The oxide anion is electron-donating while the henzimidazole system is electron-withdrawing. 4). .I 37 no I -. This protonation leads to a significant change in the absorption spectrum (Table 3).

083 -84 -0. TABLE 3.239 -64 0. .3 0.76 (8--11). 0.32 (7--10) 208 0.46 (7--11) y~ pH<7 283 280 14508. direction9 I vectors I' caxc.224 71 -0.397 -32 0. 0. 6 9~]t I~//11 12 245 12520.59 (7--9).42 (7--11) 212 197 23483. 12 0.57 (7--9).79 (8--11).32 (7--9) *Experimentally not distinguished since the solvent has strong absorption in this region.50 (8--9). 0. .54 (8--11).9 0.57 (7--1o).9 0. 0.57 (7--9). 0.62 (8--11).9 -0. The r e p l a c e m e n t of a hydrogen atom at the ring nitrogen a t o m by a n amide group destroys the intramo]ecular hydrogen bond with the carbamate group in isomer I and ]eads to the formation of a new bond: 61 .8 0. deg.5 0.5 0. The low-intensity band at 1712 cm -x in the IR spectrum of BMC is related to rotational isomer i': ~"" ----N O. 266 8816.621 . -o 0. (~).7 0.::C_.41 (8--10). -0.27 (7--10) y~ pH>7 304 301 18446.9 0. 7 287 14142.7 ~'.276 I0 -0. 9 H This hypothesis i s s u p p o r t e d b y ttle f i n d i n g o f a v e r y s t r o n g b a n d a t 1712 cm .9 0.0.41 (7--9) 228 227 14318.9 -0. of the vC= 0 band is a result of strong hydrogen bonding.9 26l 266 11650. -0.81 (8--9).93 (8--9) i ~(oc] 296 18203.429 -41 0.43 (8--10).8 0. 0.61 (7--9).51 (6--9).35 (7--11).x i n t h e spectrum of benomil.35 (8--1o).64 (8--9).38 (8--11) 225 231 21316. --0.238 '-13 -0./5 "N C--OCH3 25O 249 9273.339 9 -13 0.69 (8--9). 0. 0.256 -35 0.8 0. 0. Experimental and Calculated Absorption Spectra for BMC Tautomer I in Ethanol (7 <_ pH < 7) ~max.59 (8--I0). 0.69 (8--10).l y• pH----7 " 294' 278 5333.60 (8--1o).52 (7--9) 204 0.287 6O 0. 281 13360. 16].39 (7--9). -0. 0. The existence of a C=O bond in BMC in the polycrystalline state is also indicated by the sharp bands at 1276 and 1292 (doublet) and 1198 cm -x characteristic for vibrations of ester C-O--bonds [15. --0.35 (7--11) II r 9~}1 J~111 12 "~ 226 237 66504.54 (7--9).46 (7--9).308 10 0.3 0. r by a broad band in the region 210-250 nm in the ex- perimental spectrum.7 0.32 (8--10) 276 11159. 0.50 (8--10).34 (7--9) 242 0.47 (7--11) 2O8 199 12276.6 0. 277 14508. rim Intensity Transition I ~olarization[ MKV eigen Form of tautomer I exp "~]calc"'IExP 9. 253 11407.140 -19 0.

P. . Vladimir (1974). Chemical Bond and Molecular Structure. VINITI. Zaltsev. M. b. and N. ~. Theoret. i ~-~ 0 20 16 12 B 6 37 33 29 25 21. Durham. 22. K.~ . 6O & 2O i 8O ~ Fig. 6. ~. Chem. and A.. V. Clark. G. This behavior indicates that the structures of the benzimidazole ring and the carbamate group in BMC and benomil are the same. Sel'sk. Sisler. p. i. Molodkin. Khim. the latter is favored energetically..'(\N. . G. M.. The form and number of bands in the NH stretching band re- gion in the spectra of benomil in vaseline oil and in CC14 solution are the same but are shifted toward higher frequencies in solution by 20 cm -i. D. Kulakov. 49.'~C i l )cll~ i iJ: o<:lI.!O~' cIB i ~:~ . 64. ~. 5.. J. S.HCI in the crystalline state shows a strong band at 1753 cm -~. r. 62 .. J. 3. Ii. . Kosobutskii. BMC... M. Chim. 407 (1965). Kukalenko and E. The Application of X-Ray Electronic Spectroscopy in Chemistry [in Rus- sian]. Pople. Proceedings of the Sixth Conference on Molecular Spectroscopy. ii. Koord. Nefedov. V. Clark. 1860 (1978). The ~NC=O frequency of the amide group is strongly shifted toward lower values due to intramolecular hydrogen bonding and is 1635 cm-Z. 25~ No. 9. Barker and D. The carbamate and am!de group C=O bands in the spectra of dilute solutions of benomil in CCI~ are higher by 19 cm -I. A.. S.. This is in accord with the assignment of the band at 1712 cm-* to the vibration for the free carbamate group of V since the vibrational fre- quency of the free amide group does not exceed 1680 cm -I [15]. Trans. S. 24 (1970). A. 8. 2. Co~mun. V. Yu.. 4. Khoz. IR spectra in the crystalline state and in vaseline oil for BMC (a). Khim. Nikolenko. Chem.. Khlm. Teterln. No. The increase in vC==O relative to the frequency of this band in BMC is attributed to a strong inductive effect. The IR spectra of BMC. A.C"-I" I "N ('411~ . 7.'O tI. Clemons and H. B.. ~ I 9 _:~ bl . London (1977). while a six-membered ring is formed in V. LITERATURE CITED i.l "7. and benomil (c). ii. Pariser and R. Dvoichenkova. Davydov. i0. Acta. Phys. This is in accord with the XES data which indicate that the energy of the C=O group increases upon protonation of BMC. Author's Abstract of Chemical Sciences Candidate's Dissertation. N.~ . which was assigned to C=O group vibrations. T. A. "'~" ]I O'.< i _ . L. Ivanova. Vol. Neorg. Forster. . 466 (1953). . K. Faraday Soc. Zh. . V. Tolmacheva. 36 (1970). T. D.HCI (b). I. Physiol. R. 1375 (1953). 339. V. 1976. Moscow (1973). Parr. E. N. p. 32 (1971)..+IJ~ .. Nishimoto and L. Baranov. Pesticide Biochem. 21. ~o 60 s0~ ~0 20 <0 w . A. C4H~ IY "r Since an eight-membered ring is formed in isomer IV. S. A l l - Union Glass Research Institute. 3031 (1977). 5.

In order to establish the most important structural features governing the reactivity of heterocyclic compounds in oxidation. 2343 (1961). The rates of total and partial oxidation W a of the remaining compounds are similar. and F. 4-MP. Katritsky (ed.50 9 1986 Plenum Publishing Corporation 63 . Mathis. Moscow (1963). The Infrared Spectra of Complex Molecules. L. Izd. Inostr. 2-MQ. Skolmeistere. and 4-MQ give predominantly the partial oxidation products. diazines. 3. name- ly pyridines. Chem. and to obtain further information on the reaction mechanisms under comparable conditions. 13. No. pp. It is noteworthy that the sequence of reactivities of 2-. B. 2. Bellamy. J. whereas oxidation of 3-MP. 16. Academy of Sciences'of the Latvian SSR. O. Mathis. Moscow--Leningrad (1966). The Application of UV.12. B. Shimanskaya A study has been made of the reactivity of methylpyridines. 14.> 3-. and between the partial oxidation rate and the charge on the ring carbon atom adjacent to the methyl group. Moscow (1971).8:542. 3-4. and also to their reactivity in pro- totropic reactions. the total conversion rate of monomethylpyridines and the amounts of aldehydes formed on oxidation over B-VO(POs)2 decreases in the isomer sequence ~ 4. REACTIVITY OF METHYL DERIVATIVES OF NITROGENOUS HETEROCYCLES IN VAPOR-PHASE CATALYTIC OXIDATION L. V. 0009-3122/86/2201-0063512. p. 275. UDC 547.> 2. 369 (1971).3-DMP. p. Vyssh. J. 2. Izd. Soc. Under impulse conditions.7 D. R.6 Eo. Kupletskaya. L. A. January. Yansone. and methylquinolines in oxidation in the vapor phase in the presence of B-VO (P03)2. 112. and 4-MP obtained under conditions which restrict the occurrence of subsequent reactions is similar to the rate of deuteration of the methyl groups in these compounds [2].). ~. and M. In the pulsed vapor-phase oxidation of these com- pounds (Table i) in the presence of vanadyl ~-polyphosphate at 400~ the principal reaction products are the monoa~dehyde and oxides of carbon.5-DMP. These facts lead to the conclusion that the limiting step in the heterogeneous catalytic Institute of Organic Chemistry. 4-MQ also under- goes vapor phase oxidation more readily than 2-MQ both in total and partial oxidation (Table i). 1985. p. 1986. R. Original article submitted May 7. A. Under these conditions. just as when vanadium oxide catalysts are used [i]. the oxidation of representatives of three classes of nitrogen heterocycles has been studied. A. J. Shkola. 15.. Comparison of the total oxida- tion rates (Wtot) of the pyridine bases shows that introduction of methyl substituents into the pyridine ring increases the overall reaction rate. Ya. Baccar. Relationships have been found between the overall reaction rates of heterocyclic compounds and the charge on the ring nitrogen. P. and DMPZ results in extensive oxidation. 3-. with a correlation coefficient of 0. The vapor phase oxidation of methylheterocycles with atmospheric oxygen over vanadium catalysts forms the basis of the industrial production of heteryl aldehydes. methylpyrazines. 75-79. Struct. and quinolines. Izd. but there is not clear relationship between the reactivity of the pyridines and the number of methyl groups present.4-DMP. The partial oxidation rate of methylpyridines is given to a first approximation by the Hammet-type expression InWa = --3.5-DMP.5 + 4.. Mol.93. L. Barrans. IR and N'MR Spectroscopy in Organic Chemistry. Nos.. 122. R. Physical Methods in Heterocyclic Chemistry [Russian translation]. Morgan. Kazitsina and N. Riga 226006. A. P. 3. which are inter- mediates in the synthesis of biologically active compounds. Translated from Khimiya Geterotsiklicheskikh Soedinenii. for example with sodamide [3]. Golender. Khimiya. Secches. i. Leitis. A.943. K. In the quinoline series. Meksh. J. Lit.

For all the compounds examined.3 8 11 2.6 0.6 56 13 Methylpyrazine (MP) 1.e.5-Dimethylpyrazine (DS~Z) 2.TqN+O. and reactivity of the 2-CH3 group is less than that of the 4-CH3 group.4-Dimethylpyridine (2. with a correlation coefficient of 0. Similar behav- ior has been found in the oxidation of pyridine bases over vanadium oxide catalysts [5].6-Dimethylpyridine(2.7 1. which provides a good de- scription of the electron density distribution in organic molecules [8]. this sequence of reactivities of the methyl groups is maintained. according to nonempirical quantum chemical calculations [4]. F=345. the overall reaction rate increases (Fig. this relationship may be described by a trinomial equation.0 60 .4-21.and trimethylpyridines over a vanadium phosphate catalyst.9 3.5-Dimethylpyridine (2. the shift in electron density at this position is reduced.9 1. there is no +M effect (the increased basic- ity of pyridine consequent upon the introduction of a methyl group into this position is at- tributed mainly to the +I effect). In the oxidation of di.9 2 4.3-DHP) 3.2 81 6 2. 2-Methylpyridine (2-MP) 2. However.TEEs~ S=0. With methyl groups in the 3-position.> 2.2 48 7 2..2 86 9 3. 7]. for pyridine the values vary from 908.4 kJ/mole.3 8 4 5. i). in nitrogen heterocycles.0. as calculated by the MO LCAO PPDP/2 method.8 2.0 4-Methylpyridin~ (4-MP) 0.8 3. and the reactivity of 3-MP is similar to that of toluene. the rates of conversion of the CH3 group to CHO decrease in the sequence 4. 64 .8 3.0 3..and 4-MQ do not lie on this plot.and 4-MP conjugation is increased to such an extent that some authors have assumed that the formation of quinoid structures is possible [3]. For example.18. as a result of the high electronegative in- ductive effect of the heteroatom at the 2-position. and the rate of this step is de- pendent on the mobility of hydrogen in the methyl group.4.0 1. involving the nitrogen atom. to a first approximation it is desirable in assessing the effects of adsorp- tive interactions on reactivity to compare the reactivities of these compounds with their basicity.3 1.:3 . even using the same method of measurement.5-961. An experimental measure of the basic properties of molecules in the vapor base is pro- ton affinity (PA).4-DMP) .and 6. Furthermore. For compounds 1-14. which characterize steric hindrance in the reaction of the N-heterocycle with the catalyst. 2-MP should also be more stable overall then 4-MP.6-Trimethylpyridine(2.3-Dime~ylpyridine (2.6-TMP) 3. interaction with acidic sites on the catalyst surface is most likely.and 5-. where EEs ~ is the sum of the steric coefficients [9].4.> 3.3 3-Meuhylpyridine (3-MP) 3. The variations in the reactivity of monomethylpyridines in vapor phase catalytic oxida- tion are usually regarded as being due to the superimposition of r and inductive effects. the hydrogen of the methyl group thereby becoming highly mobile. However. as qN is increased. Rates and Selectlvity of Oxidation and Methylhetero- cyclic Compounds over Vanadyl Polyphosphate Con%" pond 2 seC) I v i np ridineal- Compound oxidized Idehy~es. % J Wtot ~l J I Pyridne (P).6-DMP) 4.%6 3.7-943.9 3.5-DMP) 2.5 "~7 15 2-Hethylquinoline (Z-MQ) 2.4-DMP) 4. i.5-DMP) 3.8 47 12 2-Me~lyl-5-ethylpyridine(MEP) 3. Since. However. namely the value of the negative charge on the nitrogen atom (qN). in 2.4 2.7 65 I0 3~5-~imethylpyridine (b.89: lnWcot = -2.0 0.1 80 oxidation of nitrogen heterocycles has an ionic mechanism.1 89 16 4-Methylquinoline (4-~) 8. and for 2-MP from 922. The points for 2.5 2.4-Dimethylpyridine (3.3 I O0 14 2.7 44 8 2. We therefore re- sorted to a theoretical measure of basicity. the literature data on the PA of nitrogen heterocycles is high- ly ambiguous [6. TABLE i.

S=q23.8 In V~ot 1.08 O. tile most important factor is the electron density at the ring carbon atom attached to the methyl group. and 2) the surface complex in the transition state is largely ionic in character.5+4.41.5 0.5 r=0. Fig. Taking some diazines and quino]ines as examples.5 9 1~" ~ 5 o16 1.2 0 0.7 Fig.. S=0.. L i X6 .3. the heteroatom in pyridine may be regarded as a substituent introduced into the benzene ring in place of the CH fragment. it may be that their use here indicates a similarity in the transmission of electronic effects in nucleophilic substitution and in vapor-phase catalytic oxidation at the stage of interaction with the catalyst. two conclu- sions may be drawn with respect to the mechanism of the partial oxidation of methylhetero- cycles: i) Oxidation of the CH3 group to CHO is a nucleophilic reaction. Plots of inW a against the induction contant (a) and the charge on the carbon adjacent to the methyl group (b).9 1. obtained from the inWa-o plots.1 -5 -4 -3 -2 .= -3. 2b). 1. From the values of the reaction constant s. It has in fact been found that an adequately linear in Wa--ln qC(CH)s plot is obtained for methylpyridines (Fig.7 1~13 -1.0 b 'Z 9/ IO/' 0 11 7 I(I 12"~ "3 7 12 -0. 1 Fig. The description of oxidative reactions of other methylheterocycles in a single series with methylpyridines by a Hammet-type equation has not so far been possible as a result of the absence from the literature of o-constants which take fully into account electronic in- teractions in these compounds. 65 . 2 Fig.0 I~ Wa 075 a "0" / ~'5~2"/ ~.0 .. Plot of Wto t against the charge on the nitrogen atom. As is well known.and 2. F=56.20 -0. In this case...16 -0.4-DMP. 2. The positive values of the parameter p obtained for the partial oxidation of methylpy- ridines lead to the conclusion that the reaction proceeds the more readily as the electron density at the ring carbon adjacent to the methyl group is reduced.9 tnqc(cH3) o15 X 0 -1 . These features of the mechanism of the oxidation of methylpyridines appear to hold true both for vanadyl phosphate and vanadium-molybdenum oxide systems. as in [ii].93.0+0. In the case of 2. the rate of formation of monoaldehydes in the oxidation of compounds 2-12 is satisfactorily approximated by a Hammet- type equation with o-constants describing the electron-acceptor properties of the he teroatom (Fig.0. 0.5 lnw. which is dependent on the electron-acceptor properties of the heteroatom.5 In Wa=3. 2a): In W. 1.12 -0. and in partial oxidation to the aldehydes. Correlational analysis shows that the principal features determining the overall reac- tivity of methylheterocycles in vapor-phase catalytic oxidation are the basic properties of the heteroatom. which have a considerable influence on the mechanism of the oxidation reaction. we have shown that the incorporation of methylheterocyclic compounds of different types into an overall reaction series appears to require the use of multifactorial correlational relationships which take into account the basic properties and the structural features of the compounds to be oxidized. r=0.93. i. Since these o-constants were calculated [12] from the rate of replacement of chlorine by alkoxy-groups in pyridines. the sigma constants used were the sums ON2 + on-CH 3 and (ON~ + On_CH3) . 3" /'~0 I i itrtqcccH3) I 0. 1.6Eo.

I01. V. 3. Shimanskaya. V. New York (1979). Chem. Nauk Latv. M. 195 (1972). G.5% of Reoplex 400 and 10% SE-301 on Chromosorb W-AW (40-60 mesh). and urea. 931 (1969). N. Academic Press. 1061 (1968). 36. Miller. 73. 8. Sposob. 6. H. Amer. a quantitative description of the rates of catalytic oxidative reactions using the approaches developed here has been ob- tained for pyridine derivatives only. proceedings of the 3rd All-Union Con- ference [in Russian]. Marphey. N. and the free volume of the reacLor was packed with quartz. Kon- stant. Soedin. 6184 (1979). Yu. CaCI2. Welder and J. A. A.25-0. 2.* The grain size of the catalyst and the inert packing w~th 0. Soedin. lO. M. Bowers. N. H.. Soc. The impulse vol- ume was 0. L. and Ion Physics. Tupitsyn. T.. and A. Kolodina. The reaction products were analyzed chromato- graphically on a column with a stationary phase containing 2. 4-MP. N. p. part 2. A. Ya. L. and V. A.2 ~m) in the pulsed mode. 2-MP. p. Tupitsyn. ~. Pal'm. 7. Org. Ya. 2. EXPERIMENTAL Oxidations were carried out in a microreactor (3 ~:m ~ ]. Since such information is not atpresent available to us. Novosibirsk.). Mass Spectrom. Khim. in: Gas-Phase Ion Chemistry. respectively. 6. 3308 (1951). R. Ya. ~. The preparation and properties of the catalyst have been described previously [13]. Zatsepina. Liveris and J. and 1. Shlmanskaya.5 mm. 47. Sh. Shimanskaya. M. Khim. Slavinskaya. Tupitsyn. Ii. p. Geterotsikl.6-DMP were first purified by crystallization of their complexes with Mn(CNS)2. I. 12. Ser. No. C.. and Z. T. 5. Ya. Gedrovits. 85 (1980). Soc. Riga (1976). Del Bane. J. L. Vol. F. The column temperature was 120-160~ Before use. Mir. R. in: Semiempirical Methods for the Calculation of Electronic Structures [Russian translation]. 4. *We thank our colleague at the Institute of Inorganic Chemistry of the Academy of Sciences of the Latvian SSR u Ya.. E. LITERATURE CITED i. 2. N. 9. Skolmeistere. No. 3486 (1963). Leningrad (1977). J. Reakts. Moscow (1980).. 731 (1977). 66 . N. N. V. J. F. Leitis. Franklin. Advances in Heterocyclic Chemistry [in Russian]. Akad.. Aue and M. in: The Mechanisms of Organic Reactions. V. A. the compounds were dried over KOH and redistilled over CaH2. 1664 (1982). D. and the air flow 40 ml/min. ibid. Gedrovits for the gift of catalyst samples. p. The catalyst volume was 0. 13. J. Zinatne. Klopman and R. Kane. Soc. SSSR. Gol'dberg and M. Bowers (ed. Ivens. Kirova. gatsepina. Amer.4 ~i. Brown and W. F. I. Chem. Izv. Fundamentals of the Quantitative Theory of Organic Reactions [in Russian]. A.. M. Chem. 32.5 ml. 6. and A. S. V. Leitis. Khimiya. Zatsepina and I. J.

XIII Y=N. IX. VII. The tert-butylamides of both acids are obtained in the open amide forms. Riga 226355. which is also characteristic of 2- acylbenzoyl chlorides [i].N ) together with C=O absorption for the isoindolinone at 1703-1685 cm-* (in Nujol). On passing from the crystalline state to the dioxane solution. and M. XII X=N+H CI-. CeH s Oil A VII=X ~-XIV X~-XIY [. pp. This is confirmed by the presence in their IR spectra of one. I.. 1986. VI).VI . llI. whereas in solution in dioxane they exist in the open (ketocarboxylic) forms. VIII. XII Y=CH. X. According to their IR spectra.. Petrova UDC 541. IV. XIV Y=N+HCI - Their hydrochlorides (II. and only one C=O band at -1800 cm -I. The object of this investigation was to synthesize and examine the ring-chain isomeric interconversions of N-monosubstituted 4-benzoylnicotinamides and 3-benzoylisonicotin~mides. Acylation of benzylamine with the chlorolact0nes (V) and (Vl) gave the cyclic isomeric amides (2-benzyl-3-hydroxy-3-phenyl-6-(or 5)-azaindolinones VII and IX). both acids (I. Ya. there is a char- acteristic shift in this absorption towards higher frequencies as a result of fission of the A. II. IX. and of their protonated forms. Original article submitted November 23. 1984. VII.1'298. XIV X=CH..62:547. I I =--_ so=. and their benzyl- amides also occur as the cyclic forms (azaisoindolinones). and (VI) as the free base. XIII. 0009-3122/86/2201-0067512.O=C or O--H. No. II.. V. The chlorolactone (V~ was isolated as its hydrochlor L- ide. V. Treatment of the acids ( I ) a n d (III) with thionyl chloride affords the acid chlorides. IV) also possess the open structure. It has been shown by PMR that N-tert-butyl-4-benzoylnicotinamide displays a greater tendency to undergo closure of the isoindolinone ring (KT = 0. Batse. XI X=N. although in the IR spect- rum of 3-benzoylisonicotinic acid hydrochloride (IV) there is weak absorption at 1805 cm -I.-. III) resemble 2-aroylbenzoic acids [i] in the crystalline state. VI. IV. Valter.1 4-Benzoylnicotinoyl and 3-benzoylisonicotinoyl chlorides have been found to ex- ist in cyclic forms (3-chloro-3-phenyl-6(or 5)-azaphthalides). Y COC~s Cell5 B O H C6H ~ "el A I-IV I-IV 'V. V. X.50 9 1986 Plenum Publishing Corporation 67 .. the IR spectra of which showed broad OH absorption typical of intermolecularly associated hydroxyl groups (O-- H.24 in CDsOD) than does N-tert-butyl-3- benzoylisonicotinamide (KT = 0). i. N. but in the case of heterocyclic o-carboxylic acids this phenomenon has received little atten- tion [2]. III. VI. Pel'she Polytechnic Institute... Translated f r o m Khimiya Gerero- tsiklicheskikh Soedinenii.824'826. E. VIII. which exist in the cyclic chlorolactone form (V. XI. January. E. _ _ Y ~" Y .SYNTHESIS AND RING-CHAIN ISOMERISM OF N-MONOSUBSTITUTED 4-BENZOYLNiCOTINAMIDES AND 3-BENZOYLISONICOTINAMIDES R. and A. 80-83. indicating the presence of small amounts of the lactol form (IVB). Ring-chain isomerism in 2-acylbenzoic acids has been the subject of thorough study [i].

The IR spectrum of the hydrochloride (XII) shows a strong. X). cm' The cyclic isoindolinone structure is retained in their hydro- It is known [3] that cyclization of 2-acylbenzamides is prevented by the presence of a tert-alkyl substituent on the nitrogen atom. The same capacity to exist in the cyclic form is also seen in the crystalling hydro- chlorides (XII) and (EIV). and it has now been found that acylation of tert-butylamine by the chlorolactones (V) and (VI) affords the N-tert-butylamides (XI) and (XIII). together with the pre- sence of the amide-ll band.. 1669 (C=O). amide-l. The appearance of a low-intensity band at 1698 cm-* (Fig.5-5). 68 . O-H. mp 215-219~ IR spectrum (Nujol): 2400 (broad band. 1680 (C=O). I 700 1600 1500 #. x111 ~k Fig.13 ppm. PMR spectra were obtained on a Tesla BS-487C (80 MHz) in solution in CD. form A. The ratio of intensities gives the equili- brium constant. taking the N-tert-butylamides as examples. form B). 1595. Their IR spectra. confirming that this amide exists only in the open form (XIIIA) in solution in CDsOD. 1552. within the limits of sensitivity of the PMR method.43 ppm. It has thus been shown. This. show absorption for N--H. which is characteris- tic of the ring-chain equilibrium XIA $ XIB [4].24. as suspensions in Nujol and as solutions in dioxane (c = (2. and generally speaking the spectrum at 1800-1480 and 3600-2400 cm-* is similar to that of 2-benzyl-3-hydroxy-3-phenyl-6-azaindolinone (VIII). The PMR spectrum of the amide (XI). and a single band is seen at 1670 cm-*. broad band for the isoindolinone C = C at 1707 cm-*. I) could be due to the presence of small amounts of the protonated cyclic form (EIVB). that 4-benzolnicotin- amide shows a sreater tendency to exist in cyclic forms as a result of intramolecular addi- tlon of the amide N--H to the C = O bond than does 3-benzoylisonicotinamlde. the absorption for the ketone C=O and amide-I overlap.OD at 25~ 4-Benzolnicotinic acid (I) was obtained as described in [5]. obtained in Nujol. C=O. This behavior also holds true for the hydrochlorides. 1577. over the range 1800- 1480 cm -~. In the PMR spectrum of the amide (XIII).O=C hydrogen bonds. K T = [XIB]/[XIA] = 0. 1551 cm -~. confirms the open structure of amides (XI) and (XIII) in dioxane solution. 1581. and 1. In the spectra obtained in dioxane solution. (dioxane): 1721 (COOH). and amide-ll. 1592. shows two signals for the pro- tons of the tert-butyl group (6 = 1. EXPERIMENTAL IR spectra were obtained on IKS-14A and Specord 75-IR instruments. there is only one signal for the tert-butyl group at 1. thus confirming the cyclic structure of 2-tert-butyl-3-hydroxy-3-phenyl-6-azaindolinone hydrochlor- ide (XIIB). differs little from that of the base (XIII).12. obtained in CD3OD. i. COOH).10 -2 mole). 1706 (COOH). IR spectra of crys- talline N-tert-butylamides W and their hydroch!orides.. chlorides (Vlll. The IR spectrum of the hydrochloride (XIV).

Calculated: C1 25. Calculated: C1 14. mp 238-242~ (decomposed) IR spectrum (Nujol): 3353.i g (86%) of colorless cyrstals. 1606. H 5. N 8. 1674 (C~O). IR spectrum (Nujol): 3095. Found: C 64. C! 11. 2869 br. 2584 br. (diox- ane): 1668 (C~O + amide-I). 1409 cm -I. 1578. 1722 (COOH).1%.9.0%. 2727 br.46 g (2 mmole) of the acid (I) and 1. 1799 (C=O). 1593. IR spectrum (Nujol): 2417 (br. 1531 cm -I (amide-II). 1721. 1676 (C=O). To a solution of 0.6%. 234-236~ (decomposed).4. mp I19-i20~ IR spectrum (Nujol): 3269 (N--H). C2oHITCIN202. To a solution of 0.8%. H 6... IR spectrum (Nujol): 3369 br. 2858. !R spectrum (Nujol): 3412 hr. 2690. C2oH~TCIN202.9%. 2698. N-tert-Butyl-3-benzoylisonicotinamide (XIII).9. 2955. N 8.9%. Found: C1 14. 1642 (amide-I. 1814 (C---O). mp I03-I06~ (decomposed). mp 174- 176~ IR spectrum (Nujol): 3044.9.. 1603. Mp 220-222~ (decomposed). N 8.51 g (90%) of colorless crystals of (V) were isolated.. 3098. 69 . N 9. Calculated: C1 13. After 24 h. C~TH~gCIN20=.9%. 3357 pl. After two recrystallizations from ben- zene--hexane. N 8. 1595.1. IR spectrum (Nujol): 3352 hr. 3097.0%.1. Hydrochloride CX). Calculated: C 68. A solution of 0. 1529 cm -~ (amide-II). and 0. Calculated: C 64. 2483 br. COOH).. 2352 hr. Found: C 75.4 ml (20 mmole) of thionyl chloride in 15 ml of benzene was boiled for 4 h. 1594. H 6.16 g (100%) of colorless cyrstals of the hydrochloride (VIII). 1556 (amide-II).7. mp 205-206~ IR spectrum (Nujol): 3390.7%.9%. HYdrochloride (VIII). 1540 sh. H 6..8. Found: C 71. 2902. 1720 sh. After two recrystallizations from benzene-- hexane.4.0. 1685 (C=O). 1544 (amide-II). C17HIsN202. 3100.. 1552.. 1506 cm -~. 3-Chloro-3-phenyl-6-azaphthalide Hydrochloride (V~.9%. C~3HIoCINO3. 2830 br. 3067 sh. 3030. H 6.1. C13HIoCINOs. 1646. Hydrochiorides (X). H 4. C1 i0.14 g of the isoindolinone (VII) in 2. N 7.i g of the acid (I) in 2 ml of anhydrous diox- ane was added 5 ml of ether saturated with dry hydrogen chloride. H 6~6. Hydrochloride (XII). 3080. 1536 cm -~.. 3066. N 9. C1 I0. 2508 br. 3211 (N-H). 3157 br. (XII). 1644. H 5. 1594.43%. 2954. 3051.. yield 36%. 1551 cm -~ Hydrochloride (IV) was obtained similarly to the above.9.3. 0. mp 183~ Two recrystallizations from ethanol gave 0. 1579. 2931.1. (XI). The hydrochloride (V) (2. 2968. C~3HeCINO2. N-tert-Butyl-4-benzoylnicotinamide (XI). 2845. 1609.9%. 1588.. C1 10.3~ N 90%. Hydrochloride (II).3. 2580.. 2989. mp IIO-III~ IR spectrum (Nujol): 3390 (N--H). 1590 cm -~. mp 272~ (decomposed). 1643.4%.0. 1581. 3071. Calculated: C 72. and added to a solution of 2.36 g (46%) of color- less crystals.6.. 3057 br. IR spectrum (Nujol): 3410 br. Found: C1 13. (dioxane): 1730 (COOH). and (XIV) were obtained similarly.3. 1680. Calculated: C 72. 2979.9. 2931. There was obtained 0. Calculated: C 75. Calculated: C 68. C2oH~6N202. Found: C1 13. H 5.i. 1591.1. 1634. C~THIsN202.3. mp.0. 1716 (C=O).3%: C2oHI6N202: Calculated: C 75. N 8. H 6. Found: C1 24. (dioxane): 1714 (C=~O). The mixture was kept for 12 h at 20~ then diluted with i00 ml of water.9%. 3-Chloro-3-phenyl-5-azaphthalide (VI) was obtained as in the foregoing example. Mp 224~ (decomposed). 3043.0%. iR spectrum (Nu~ol): 3393. 3066. Compounds (IX). 1595 cm -z. 2920. Found: C 69..1. Found: C 76.9%. the solution saturated with sodium chloride. N 8. 3126. C1 ii. 1596.4.0%. 1618. 3017. H 5.3. 1703 (C= O). 2457 br. (dioxane): 1711 (C=O). C1 10. !619. H 4.0%.5 mmole) was suspended in i0 ml of dioxane. N ]0. ]707 (C=O). 1563. 1594. There was obtained 0. 1632 (amide-I). 1507 cm -l. Yield 94%.1.. 1613. 1619 cm -2. and (XIII) were obtained similarly from the chlorophthalides (V) for (XI) and (VI) for (IX and XIII).5 mmole of benzylamine and 5 mmole of triethylamine in 5 ml of dioxane. 2-Benzyl-3-hydroxy-3-phenyl-5-azaindolinone (IX). and benzylamine for (IX) or tert-butylamine for (XI) and (XIII with the addition of triethylamine. 3068. H 5. 1671 (C=O). e 3-Benzoylisonicotinic acid (III) was obtained as described in [5]. N 9.. 3058. Calculated: C1 13. 3282. 1805. 1670 (C=O).0. mp 95-98~ After three- fold recrystallization from benzene--hexane. 1581. Found: C 71. 1580. 2-Benzyl-3-hydroxy~3-phenyl-6-azaindolinone (VII).5 ml of dioxane was added 15 ml of ether saturated with dry hydrogen chloride. yield 56%. (dioxane): 1671 (C=O + amide-l). H 4. 1677. 1635. Found: C 67. 1543 cm -~. 2578 br..90%. 1722.6. N 7. C~3HgCI~NO2. N 8.1..74 g (94%) of (VII) isolated. 1549 cm -I..4%. mp 171-173~ (de- composed).0. 1706 (C=O).

Chem. 1551 cm -~ (amide-II). A. A . Found: C 63.2. Liepin'sh. Geterotsikl. H 6. LITERATURE CITED i. Org. Original article submitted November 27. It has been shown [2] that tertiary enaminoamides react with aromatic amines.. T. G. V. 4. Mp 220-222~ (decomposed). Z. SSR.. C1 ii. 701 (1976). Ser. 2923. Khim. the molecu- lar peak (162).1'831:543. 2. Valter. respectively. R. The structures of the products were confirmed by their spectra and by direct synthesis. Artamonov. viz. E. Zinatne. pp.1'583. Latv.0. Zh. *For communication 45. Valter. Shneider.. C~TH~9- CINa02. 5. I. Ring-Chain Isomerism in Organic Chemistry [in Rusdian]. P..8. Baranova.i. J. together with the ele- mental analysis. Yalysheva. B . E. it was attempted to carry out this reaction with ~-cyano-B-dimethylaminocrotonamide (I) and ethyl anthranilate (II) in or- der to obtain the secondary N-arylenemonoamlde (III). 3096 (N-H). the trans- amination being best effected in acetic acid. The structure of (IV) was confirmed by compar- ison with an authentic sample synthesized by a literature method [3]. Khim. 0rdzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry. Riga (1978). N 8. Granik UDC 547.7%. 3062. 1634. see [i]. Heterocyc. in parentheses. 1595. No. 2501 br. 1698 (isoindolinone C=O). and N. the m/z values for the peaks are given (with the intensity relative to the maximum ion peak. A . The IR spectrum of the compound showed absorption at 1670 and 1700 cm -~ (CO). 119 (M -. V.. Paul and B.CONH) +. Translated from Khimiya Geterotsiklicheskikh Soedinenii. 1984. ACETALS OF LACTAMS AND ACID AMIDES. A . No. and 92.. The product obtained was the compound (IV). Calculated: C 64. E . 13. No. Chistyakov.51'422 It has been shown that the reaction of the enaminoamide a-cyano-8-dimethylamino- crotonamide with anthranilic acid and its ethyl ester unexpectedly gives quina- zoline-2. 3160 and 3250 cm -~ (NH). the mass spectrum of which contained three main peaks%.3. %Here and subsequently. Soedin. E. 2. 3.4-dione and 2-methyl-3-cyano-4-quinolone. Karlivan. 1986. R. 70 0009-3122/86/2201-0070512. These findings. Khim.5' 856. Kampare. R . H 6. IR spectrum (Nujol): 3361 (O--H). G . %. N 8. ~. Valter. Karlivan~-Izv.4-dione (IV). 84-87. For this reason. lead to the conclusion that the reaction of (I) and (II) follows an unexpec- ted route to give quinazoline-2. R . which has a functional substituent (the ethoxycarbonyl group) in the ortho-position in the benzene ring. Korytnyk.8%. and S. 13. 46. 2976. V. Nauk. and G. Moscow 119021. 244 (1981). C1 11. 805 (1977). 4. and V. Hydrochloride (XIV). B. S. 1657 sh.0. Akad.* UNUSUAL REACTIONS OF ~-CYANO-B-DIMETHYLAMINOCROTONAMIDE WITH ANTHRANILIC ACID DERIVATIVES N. Valter.50 9 1986 Plenum Publishing Corporation .. January.3'398.391. 1668 (C=O + amide-I). 514 (1980).

? il M.. A likely scheme for the formation of the latter is shown below.. Heating the enaminoamide (I) in acetic acid in the absence of ethyl anthrani- l a t e ( I I ) a f f o r d s a complex mixture... since under these con- ditions (heating in acetic acid) ~-cyano-fl-anilinocrotonamide (XI) does not cyclize to (VII).~! (Me)2N )-~<.. &. 129 (6). It is noteworthy that (V) was previously synthesized from 8-aminocrotononitrile [5]. ~ COOH COOH CN Me Me . The formation of the quinolone (VII) ap- pears to be also due to the conversion of the enaminoamide (I) into fl-dimethylaminocrotono- nitrile (IX)... On h e a t i n g i n acetic acid the enaminoamide (I) undergoes reversible c l e a v a g e o f HNCO. ..... . 184 (i00)....m e t h - y l g r o u p s a t 2 .t. CN "'" "" ~ ' N "Me ""~ "'N'" ''Me I[ H VII X[ According to this scheme.. and 3400 cm -~./. and s i g n a l s a t 6 . 1615. which then undergoes deamination to (X) and cyclization..95 ppm (NH). f o l l o w e d by c y c ! i z a - tion. from which a hydrogen atom is eliminated to give a stable fragment 119 (i00).. 6 . ~ "-'" " Me ....p y r i d o n e (V~ wa~ i s o - lated [5]. A s i m i l a r c l e a v a g e o f HNCO h a s b e e n p o s t u l a t e d p r e v i o u s l y i n t h e c a s e of N .= .2 .. r e s p e c t i v e l y . l~ 11 " <>-" .. 4 8 .)~N J-.. i" . and 92 (ii). The principal mode of mass spectral fragmentation was elimination of CO (as in unsubstituted u-pyridone) to give a fragment of mass 120 (51).a" " "[" " Me CN ~~ ' ) . J->. One of the main routes of mass spectrometric fragmentation.. which in turn decomposes in the well-known way with loss of a hydrogen atom and HCN to give the ion 128 (5). The spectrum also contains ion peaks at 130 (4).. "~ CN ~~ 1CN '~ "~ "~'i CN ''~ ~" T CN '~ v The f o r m a t i o n o f the q u i n a z o l i n e d i o n e (IV) may be r a t i o n a l i z e d as follows. I. ..c y a n o ... The IR spectrum of (V) shows absorption at 720. The structure of the quinolone (VII) was con- formed by its mass spectrum. The next step in this investigation was to attempt to carry out the transamination reaction with anthranilic acid (VI) rather than with ethyl anthranilate (II).. "~ .~.} :~ ~. from which 4 .. 1370.~.. The formation of the quinazolinedione (IV) and the pyridone (V) is shown by the scheme above...COOH) . / CONII~ (Me). j... .~..N CN "'"-/ "N '~' " " U "x'CN . / ">11" CN L ~ T CONH a (Me)2N / T "V H LX CN + Lc )1 VI ... : + HN. 1410. ...5 ...... . cooer ri/>] o hie CN "/ "NIl. .c a r b a m o y l - amidines [4]. Heating (I) and (VI) in acetic acid gave a complex mix- ture (which contained no starting materials). ~ ....COOEL ..:::_. the B-monosubstituted enamine (IX) reacts with anthranilic acid (VI). It was of interest to examine this reaction in another case. as in the case of unsubstituted 7-pyridone [7]) is elimination of carbon monoxide from M +" to give the indole ion-radical 156 (15).... in full agreement with the data reported in [5]. .. The PMR s p e c t r u m o f t h i s compound (DMF-D6) showed s i g n a l s f o r t h e 4 . :-:" 0 "N " H I). namely the reaction of the acid (VI) with 8-aminocroton~c ester (XII)..'o .. from which it was possible to isolate 2-methyl- 3-cyano-4-quinolone (VII) [6] in low yield. 2 5 and 2 .'" L t H X J / IJ ~ CN I|2NOI~. li . The quinolone (VII) was also obtained by direct synthesis from a-ethoxycarbonyl-B-anilino- crotononitrile (VIII) by the literature method [6]. / A (CH.d i m e n t y l . 71 . )1 . in which the strongest peak was for the molecular ion. 870. i~/":'-)'[ "" " . On heating these compounds in acetic acid. 1660.~.. iv NH 2 o 11 CN "~~ q Oi~ O " Oil " .. 2210. 1 2 (3-H) and 7. ..and 6 ... The mass spectrum of (V) contained a strong molecular ion peak at 148 (78). Me CONII 2 /.

H 3. filtered. VI R = H EXPERIMENTAL Mass spectra were obtained on a Varian MAT-II2 spectrometer with direct introduction of the sample into the ion source.8. CaHeN20. and washed with water and alcohol to give 0.9 g (50%) of (IV) mp 350~ (from DMF). confirming the presence of the pyran ring.3 mmole) of the enamine (I) in i0 ml of glacial acetic acid was boiled for 2. The IR spectrum of (XIV) shows absorption at 3160 (NH). evaporated.10-tetrahydropyrano [4. CtPOEt -~Nl:ia. M+" 227 (81).0.2%.4. then cooled.4-dione (IV).V. it was possible to isolate the previously-described 2-methyl-4- quinolone-3-carboxylic acid (XIII) [8] and the pyranoquinolone (XIV). 2-Methyl-3-cyano-4-quinolone (VII).95 g (30 mmole) of the ester (II) in 15 ml of glacial acetic acid was boiled for 5 h. A mixture of i g (6. 120 (35).5%.32 g of a mixture of (XIII) and XIV). filtered.3%. N.a mixture of two compounds was obtained.21-8. and probably [M -. The mother liquors were acidified with HCI to pH 3-4. and Ph at 7. 2-Methyl-4-quinolone-3-carboxylic Acid (XVIII and 3-Methyl-!.26 g (i0 mmole) of 'the ester (XII) and 4.5. CH at 6. the solid filtered off.26.74 g (20 mmole) of the acid (VI) in i0 ml of glacial acetic acid was boiled for 7 h. H 5~6. 9 "cooI-t [. Calculated: C 59. 4. N 5. and the insoluble solid filtered off and washed with water and alcohol to give 0.4.5 h.3. 6. ~COOR ~ (COOR H + I ~"" ~NH2 NH2 "!'Nt~ "~ "N- 11 CH:=C"" ~CONH z ILVI XY .3-b]quinoline-l.2%. Calculated: C 68. and washed wit b alcohol to give 0. H 3. The ionization chamber temperature was 180~ and the energy of the ionizing electrons 70 eV.7. H 4.'~ a ~ : : . CttHeN=O.2%. .8.11 g (30 mmole) Of the acid (Vl) in i0 ml of glacial acetic acid was boiled for i0 h. N 17.2.09 g (4%) of (XIII). 72 . b) are formed. A mixture of 1. Found: C 71. 92 (C6H.i g (8%) of (VII). rap 239- 243~ (from DMF)[8].4%. '-" "~NH~ / NH ~ "" / i " : " "N'" 1t ""Me "N" " ' ~ It . The solid which separated was filtered off and washed with water and alcohol to give 0. and peaks for [M .61.lO-dione (XIV). The (X!V) mole ~ cule is stable to electron impact. Found: C 64.~ t .10 ppm. b g ~ H II R = E t . N 17. 1750 (lactone CO). 25) and 77 (Ph+. Calculated: C 64. o 9 L'.02 N NaOH. the normal transamination products (XVIa.3. eva- porated. The mass spectrum of (XIII) contained a strong peak for the molecular ion at 203 (75). which was separated by treatment with caustic alk- ali.-H20 ~ .7. and washed with alcohol to give 0.5 g (3. it was found that when the enaminoamide (XV) (which does not contain a CHa group in the ~-position of the enamine) reacts with ethyl anthranilate or anthranilic acid.Me H VI Xll Xlll XIV ' To conclude this investigation. H 5. into whicl~ it is sub- sequently converted under these conditions.9.4.CO] + 199 (I00). mp 300~ (from DMF). and washed with water and alcohol to give 0.NH= +. at- tributed to the fragment H2NC6H~C~O +. Found: C 68. quinazoline-2.. A solution of 0. Using this method.9%.9. H 4.6-Dimethyl-5-cyano-2-pyridone (V). . . mp 294-2960C (from methanol) [5]. The mixture was dissolved in 0. CaH6NaO~. N 15. and 1670 cm "t (quinolone CO). and the solid which separated was filtered off. H 4. signals being present for CH3 at 2. 11).CH3] + at 188 (i00). N 18. Found: C 59.H 4. N 19. mp 360-368~ (from DMF) [6].0.~ . CIaH3NO3. IR spectra were obtained on a Perkin-Elmer 457 in vaseline oil.9%.-J" . ~. N 15.7.08 g (4%) of (XIV).53 g (I0 mmole) of the enamine (I) and 4.05 g (10%) of (V).1. The PMR spectrum in DMSO-D6 also corresponds to the proposed structure. The spectrum shows a strong molecular ion peak.' . A mixture of 1. Calculated: C 71. [M-.CH~COCH3] + 170 (59).5 mmole) of the enamine (I) and 2.

Partridge.07 D. Chem. and V. Japan. A mixture of 0.3'665. W.6 g (4. Khim. 2319 (1969). 4]. cooled. Ya.5 g (15 mmole) of the ester (II) in i0 ml of glacial acetic acid was boiled for 6 h. Geterotsikl. 1986. they were converted into the per- chlorates by ion exchange by treatment with NaCIO4. Moscow (1966). The use of this classical method for the synthesis of the salts was restricted by preparative diffi- culties. Soc.3-dione. Wiley. Granik. P. Hynam.2.2-b]pyridines have not been described.0. . Grout.24 g (19%) of (XVIa). Getero- tsiklo Soedin.3.2%. Coll. Mir.. and V. J. giving the 2-arylideneindan-l.821. 88-90. Chem.). Dubur When N-methylated 4-aryl-5-oxo-4.. 42. Kuleshova.2-b]pyridinium salts. a-Cyano-~-(o-carboxyphenyl)aminoacrylamide (XVIb). Djerassi. H 3. ~-Cyano-~-(o-ethoxycarbonylphenyl)aminoacrylamide (XVIa). Lusis. A method used by us previously [I. Academy of Sciences of the Latvian SSR. Kh. Soedin. H 3. Interpretation of the Mass Spectra of Or- ganic Compounds [Russian translation]. 538 (1984). Zandersons. these were heated with methyl toluene-p-sulfonate or dimethyl sulfate. K. Translated from Khimiya Geterotsiklicheskikh Soedinenii. 7. Granik.50 9 1986 Plenum Publishing Corporation 73 . since pyridinium perchlorates are read- ily crystallizable compounds. and D. 2518 (1962).No. mp 227-229~ (from DMF). and K. N 16. N 18. 2. Blatt (ed. E. Soedin. H 5.2.9. 6. H. Bull. 6. B. G.1. .. 1984.e. V.2-b]pyridines (II) [3.5%. K. R. The starting materials were 5-oxoindeno[l. T. cleavage of the dihydropyri- dine ring occurs. SYNTHESIS OF 5-OXOINDENO[I. January. Organic Synthesis. UDC 547. 2] for the preparation of pyridinium salts by the oxidation of N-methylated 1. 929 (1985).0.3 mmole) of the enamine (XV) and 2.5-dihydroindeno[l. Kiselev. 7. in addition to the formation of the indenopyridinium perchlorates. When the salts (III) were obtained as the monosulfates or tosylates. Granik. In the case of pyr i- dines (I). V. Khim. Found: C 60. Mutsenietse. I.. A.2-b]PYRIDINIUM SALTS A. M. 0009-3122/86/2201-0073512. The aim of this investigation was to develop methods for the synthesis of N-methyl-5-oxoin- deno[l. No. V. i. N 16.2-b]pyridines (I) or the N-methylated 5-oxo-4. Calculated: C 57. Ii. LITERATURE CITED l~ L.6 g (4. Ershov. and the solid filtered off and washed with water and alcohol to give 0. . Ershov and V. A mixture of 0. 2]. S.. 2. and G. Similar conversions of polycyclic dihydropyridines such as dihydroindeno[l. M. Amakasu. Chem. Sato. 1590 (1969). and M. Khim. mp 227-229~ (from DMF). Kaimanakova. No. We have previously converted the 1. J. Solov'eva.9.3 mmole) of the enamine (XV) and 2 g (15 mmole) of the ester (II) in i0 ml of glacial acetic acid was boiled for 6 h. p. Z.2%. i. M +" 259. S. R. Soc. Original article submitted December 3. S. J. No.5-dihydroindeno[l..4-dihydropyridines with hydrogen perox- ide in the presence of perchloric acid was complicated in the indenopyridine series by the occurrence of side reactions.1%. Found. G. resinification and the hygroscopicity of the products. New York. London (1946). Riga 226006. namely. C~HI3N30~. therefore. 1553 (1982). No. M +" 259. Calculated: C 60. H 5.2-b]pyridines are oxidized with hydrogen peroxide in the presence of perchloric acid. cooled.2-isomers by reducing pyridinium salts [i. G.4-dihydro-isomers of cyclic pyridine derivatives into the corresponding 1. N. Chapman and Hall. L. Coutts and D. Williams. in addition to salt formation. Soc. Takeda. Ohashi. 4.24 g (19%) of (XVIa). and the solid filtered off and washed with water and alco- hol to give 0. T. N 18. pp. . Budzikevich. C 57. C. A. G. Wiberley. cleavage of the dihydro- Institute of Organic Synthesis. K. 79. G. Vol. Geterotsikl.

3%.4 3. I{ I1 ! .. i.. h R=CN. N-Methyl derivatives of 5-oxo-4.3 4. which will be the subject of a further communication. %. !.1 3. + i ~. A. g .. and IR spectra on a PE 580 B.3-dione (IVd) (yields 40-60%). 10%).3 14 Illh 171--174 61. and (llc). Properties of Indenopyridinium Perchlorates (III) Found. since the salt (Ilia) was obtained in 55% yield on prolonged boiling of (lla) in alcoholic solution acidified with HCIO4 (similarly.0 6.~C6H4.1 C24H22CINO8 59. in addition to the expected 2-(p-nitrobenzylidene)indan-l. Np.5 3. It is noteworthy that the synthesis of indan-l. The 4-(p-nitrophenyl) derivative of the indenopyridine (lid) did not af- ford the corresponding salt under these conditions. a-i I. giving the oxirane (V).1 4.0 3. the reaction product being 2-(p-nitro- benzylidene)indan-l.3-dione (IVd) there was isolated 2-spiro-(2'-indan-l'.9 27 Illf 230--232 54.8 4...0 C~4tt2oCIF~NO8 55. as a result of which addition of oxygen to this bond takes place under the reaction conditions.. O s~r 0 / ~ ~O o . j .5 3. from the reaction mixture there were also isolated ti~e acid hydrolysis products of (II) (in the case of (lla). in addition to the salts (III)..2 5. and mass spectroscopy.6 35 pyridine ring took place. i R=CONHC6H~.gBrCINO7 51.i Ar=C6H~. The compounds (II) were synthesized as described in [4].2-b]pyridine (II) are fairly readily oxidized by atmospheric oxygen. <iT-" N' cl~_ i(. two amide bands are seen at 1694 and 1668 cm -I The type of anion in the salts (III) has no effect on these IR bands.3'-dione)-3-(4'-nitrophenyl)oxirane (V). 32%.9 3.0 4. In the oxidation of (lid).1 C23H19CI2NO7 56. e Ar=2-CIC6H4. the electron acceptor group in the 2-arylideneindan-l-3-dione activates the >C=CH group.9 42 Illc 188--190 51.7 4.c Ar=4-BrCeH4. b Ar=4-CH~OC6H4. (lib).9 b _ / ~ .9 2.5 3.8 4. ~ .5 3. internal standard TMS.2-Dimethyl-4-aryl-5-oxolndeno[l. V :} .6 2.4 3. )i ti N" CII~ t II I H:~%l . EXPERIMENTAL PMR spectra were obtained on a Bruker WH-90 spectrometer in DMSO-D6.2 4.f R=COOC2Hs. % :om. In the IR spectrum of (lllh). / (I O Ar II II ~Ar ~! ". The in- denopyridine (I) (i0 mmole) was heated with 2 ml of dimethyl sulfate (until a neutral reac- 74 . Preparative- ly.7 38 lllg 268--270 61..1 CmH.2 CmH I~C1N20~ 54. llI a .6 2.8 48 llli 208~210 64. a . 28% of lllb was ob- tained from lib). The properties of the indenopyridinium perchlorates are given in Tables I and 2.5-dihydroindeno[l.8 5.5 3.9 2.1 55 lllb 210--213 58.5 C~HmCIN~O~ 64. ~ Empirical Yield.3-dione derivatives of oxirane has hitherto been effected in basic media only [5]. The IR spectra of the 5-oxoindenopyridinium salts (III) show strong absorption for the 5-C0 group at 1735 cm-*.1 3.5 C2aH2oCINOz 60.2 2. d Ar=4-NO.-::7---<( )? --N% ~"/ " " N" "" clI3 " ~' : : CH-Ar i IIIa-i Cl-la cPo.. The structure of (V) was confirmed by ~H and ZaC NMR.O~ "HCI04 y] ###BOT_TEXT###quot; .2-b]pyridinium Salts (III).0 3. % .113 c.ound C H N formula Ilia 272--273 60. Synthesis of 1. . % ~Iculated. ~.6 C~:Hz~ClNO~ 61.7 6.0 3.5 3..7 5.2 3. but in the 3-COCHa derivative (lllg) the absorption at 1712 cm-* is clearly separated. IR.. as well as by direct synthesis. TABLE I.6 28 llld 237--240 54.8 5.f Ar=2-F2CHOC~H4 Clearly.:' ..5 CmHIaCINaO5 61.6 19 Ille 184--187 56..3 4.-4~ ' q. g R=COCH3. The absorption due to the CO at C(a) in the esters (Ilia-f) merges with that for the 5-CO group.2 3. 0 V II.0 4..

. TABLE 2. 4. 2-Spiro-(2'-indan-l'. IH. K.53 (ra. .16 (s. treated with ether.42--8.60 (m IH) 7.88 .2-b]pyridinium tosylate.40--8.d. V.52 (m.55 2.06 (q 2H) 8.31 (m.87--8. LITERATURE CITED i* D.32--8.52 2.78--7. 2H) -. IH) [IIb 4. N 4. 2H) 18. V. Zandersons. 8. Soedin. Saper.7 (C(2)). Lusis. the oxirane (V) was isolated from the ether solution (yield 35%). Khim. No..90 0.60 (m. 17. 192.57 (s.93 (t 3H). Follow- ing oxidation of (Ild).09 (m. Kh.3 ml of 57% perchloric acid. The reaction mixture was diluted with water. filtered. 7.128 (o. Soc.17 ~/q. 3H).79--8. 7. 2H) 7. and G. N 4. Dubur.38--8. ~ C N~IR spectrum: 63.60 (m.1. 1723 cm -I (CO).2-Dimethyl-4-aryl-5-oxoindeno[l.47 2. and the colorless solid which separated was filtered off and recrystallized from ethanol. 2. and B.84 0.54 2. PMR Spectra of 1. 2H} 8.09(m.1.84--8. 393 (1984).0 Hz] / 7. and G.07--7.9l 0. Khim.0l lq~ 3H}. IH) llli 4.8 g. Petrov. H 3. The yield of the oxirane (V) was 1. 7. 65.60 (m. 7. Found: C 64.42 (d 2H) IIIc 4. Mutsenientse.18--7.5%. and the tosylate recrystallized from chloroform-hexane.27--7. 3H).71 ~1. C. 3-H).10 (q. and the residue cooled and treated with ether. The aqueous solution was saturated with NaCIO~. IH) I!If 4. Dubur. IH) /8. mp 220-223~ yield 69%).53 2.10 7. Geterotsikl.18 ('t. Ya.49 ( s 5H): 7.68 (m. 6H) and 8.94 7.19 .3'-dione)-3-(4'-nitrophenyl)oxirane (V).89 (~ 3H).92 0. Kh.CO] + . 5H) 7. Geterotsikl. 278 (15) [M --)OH]+ .87--8.79 (s IH) 8.58(m. Z. (In the case of 1. 2-(4'-Nitrobenzylidene)- indan-l.2-di- methyl-3-cyano-4-phenyl-5-oxoindeno[l.58 (m.88 (s 3H). D.2-b]pyridinium monomethylsulfate.3 ml of 30% H202 and 1.12 (r~ 3H) 4.80 2.24--8.. Ya.80 (. No. 7H) Illg 4. 8. IH) Illh 4. 3H). 4H) [7.2-dimethyl-3-acetyl-4-phenyl-5-oxoindeno[l. B.31--7. 3H). 21]) ]8.. No.9. 75 . The compound (IVa) was identical in its physicochemical properties with the authentic indan-l. 8. mp 217-219~ IR spectrum: 1756. V. Soedin. 1225 (1982). which was recrystallized from acetic acid.71 (m.94 0.86 ( t 31f}.69--8. Mazheika. 3H).99 (t 3H): 7.03 (m.62 2. M 295. J. i0 mmole) was boiled for 4 h in 50 ml of ethanol with 2.44--8. K.1 (CO). 4. Sturgeon.09 (m. 3H).3-dione (2. I. 2H) 7.55 2. 3H) IIId 4. 5H) 7. Z.in the remaining tosylates was carried out by method A.51 2. CI6HgN05.12 !q. Dubur. Ya. 3.3-dione (IV). Zandersons. mp 250- 253~ yield 65%). 508 (1983). Lusis.67-8. 4. Lusis.10 (m. (~3z~l (s. The ethereal solution was evaporated to give the 2-arylidene~ndan- 1.7 ppm (CO).36--8.1 (C(~). A. Calculated: C 65. 9. 4. 7.2H) 7. (In the case of 1. Mutsenietse. 104 (i00). The cooled reaction mixture was treated with dry dioxane. 3. 3. .12 (d 2H).83--8.51 3. Yield 35-60%.40--8.5 g (8 mmole) of methyl toluene-p-sulfonate were heated at 130-140~ for 12 h.3m 3-. 1H) Ill e 4. 182 (18) [M -. 2134 (1949).42--8. Exchange of the anion for CIO~.38--8. and G.2. Khim. 10.19 g (65%). 9. H 3. V. iProtons at :.. 4. 5H) 7.38 (d 2H). Mass spectrum: 295 (6) [M] +'. 3H). Kh. IH) tion was obtained) for 6-8 h at 60-80~ The mixture was cooled. IH) 4. 2[t) IJh_ f=72. The N-methyl compound (II) (i0 mmole) was boiled in 80 ml of ethanol with 20 mmole of hydrogen peroxide (30% aqueous solution) and i0 mmole of perchloric acid (57% aqueous so- lution) until the red color disappeared (1-4 h).11 (m.83--8.3-dione derivative [6]. Geterotsikl.60 (m. and the colorless or pale yellow indenopyridinium perchlorate which separated was filtered off and recrystallized from propan-2-ol. and the solid separated and dissolved in the minimum amount of water.7%. The solvent was removed in vacuo.~_ c(9) Ill a 4. I. The perchlorate (III) which separated was filtered off and recrystallized.89 ( t 3H). 190. D.03 (m.57 (m. No. V. Chem. 5H) 7. Mutsenietse. 7. yields 40-65%. PMR spectrum: 5.aromatic protons. The indenopyridine (I) (3 mmole) and 1.09 (s 3I-]) 7. K.33 ppm (d.2-b] pyridinium Perchlorates (III) Compound 1-c[-I.43 (m.61 (m.~-A~ ic(6. 2-cH. Soedin. A..

No.50 9 1986 Plenum Publishing Corporation . K . 1985. 388 (1976). N. The effect of the 5-cyano group on the oxidation-reduction proces- ses accompanying nucleophilic replacement of chlorine in 6-chloro-7-azaindoles by primary and secondary amines has been considered. Ya. J. Dokl. *For communication66. B.5. Chem. i. 7-Azaindoline compounds were dehydrogenated by chloranil to N-substituted l-benzyl-4-methyl-5-cyano-6- amino-7-azaindoles. With still weaker nu- cleophiles -. ~. Leimgruber. and about 35% of the starting chloroderivative II is recovered unchanged. A . The starting material for the synthesis of compounds la-g was l-benzyl-4-methyl-5-cyano-6-chloro-7-azaindoline (II) [i]. 4] that the nucleophilic replacement of chlorine at position 6 in the 7-azaindoline system is a serious problem. O. Nauk SSSR. normal nucleophilic replacement is accompanied by redox processes.II reacts already at 110-120 ~ to form l-benzyl-4-methyl-5- cyano-6-hydrazino-7-azaindoline (IV). increased the reactivity of the chlorine. P. Only in the case of the sterically more hindered di-n-butylamine is the substitution less complete (55%) under these conditions. M. Sycheva. Yakhontov N-substituted l-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles have been synthe- sized from the respective l-benzyl-4-methyl-5-cyano-6-chloro(and 6-hydroxy)-7- azaindoles. We have shown [3. 91-96. 76 0009-312286/2201-0076512. and W. Czajkowski.. The chlorine in compound II undergoes nucleophilic substitution with most primary and secondary aliphatic and heterocyclic amines at 180-185 ~ to form N-substituted l-benzyl-4-methyl~5-cyano-6-amino- 7-azaindolines (IIIa-e) in high yield (77-87%). not only at 180-185 ~ but is recovered practically unchanged even at 250 ~ Raising the temper- ature to 280-290 ~ causes significant thermal decomposition of II.87:543.g. UDC 547. and enabled it to undergo nucleophilic substitution by various other amines at lower temperature (180-185 ~ without the occurrence of redox reactions [2]. e. 13_55. In order to broaden the study of the antiserotonin effects of isomeric azaindoles it was of interest to obtain the hitherto unknown 6-amino derivatives of l-benzyl-5-cyano-7-azaindoles (I). 4]. S. pp. Aren. 41. However with a stronger nucleophile -. and G.* SYNTHESIS OF N-SUBSTITUTED I-BENZYL-4-METHYL-5-CYANO-6-AMINO-7-AZAINDOLES T.51 and L. R. Original article submitted February 21. Tengi. Moscow 119021. An analogous effect of an ortho-cyano group was observed in our case. The presence of a cyano group ortho to chlorine in l-benzyl-6-chloro-7-cyano-5-azaindol- ine. January. Anisimova. S. The selective effect of various 6-amino derivatives of l-benzyl-7-cyano-azaindoles on central serotoninergic systems has been described in [2]..~hich is distinguished b y a higher redox potential than would be expected.compound II does not react at all. so that along with the 6-amino-7-azindolines there are formed the respective 6-amino-7~azaindoles and 7-azaindoles unsubstituted at position 6. Weigele. For these reactions in such a system. S.viz. Ordzhonokidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry. V. see [i]. Translated from Khimiya Geterotsiklicheskikh Soedinenii. 6-chloro-7- azaindolines that do not contain a r group react with amines only at temperatures of at least 250~ . hydrazine -. AZAINDOLE DERIVATIVES. because of the electron density distribution extremely severe conditions are needed. De Bernado. Org. Akad.. 67./. 1986. Under such severe conditions. J. The amounts of the latter are determined by the nucleophilicity of the amine and the redox potential of the azoindoline compound [3.aromatic amines of the aniline type -. 320 (1960). Arch. 6. Vanag.759:543.

Sci. g) RR'N = CsH 5 CH2NH. b) RR"N = piperidino. IN-. llld). 77 . 7 '. c and lllb.. l-benzy!-4-methyl-5-cyano-6-benzylamino-7-azai n_ dole (Ig).]+. NC. c. Med. show ion peaks with m/z 70 and 84 that correspond to fragments of the respective cyclic a- mines. III a) RR'N = morpholino. ."'~. I. d) RR'N = (C2H 5)2N.NC2H. [M -.Cr CH. and needs further intensive study. reducing the number of head agitations caused by administration of 300 mg/kg of 5-hydroxytryptophane.e~. but the amino- azaindole Ig was separated in 81% yield.] + (Id. [M-. show that the N-benzyl group is easier to detach in the azaindole compounds I than in the azaindoline compounds III. Moreover. e) RR'N = n .] + (Ib. llle. [M-. The yield of the 5-cyano-6-piperidino-7-azaindoline compound lllb was ]0%.. Ilia). viz. [M -- C21I. [M-. Evidently in this case the redox process is dif- ferent from that previously observed [3. [M -.C2H~] +. These data. [M-. f corresponds. lllc). manager) by Canad. this is substantially lower than the overall conversion of VI to the aminoitrile lllb via the corresponding 6-chloro derivative II. f). The spectra of Ib. a CIIZ(T6TT~ {!ti~C~II~ IV 11 1 V I. The other decomposition route of the molecular ions is the stepwise detachment of the RR'N substituent. In connection with publications on the direct replacement of the oxo group in azine sys- tems by secondary amine residues [6.C2H. The increase in peak intensity of benzyl cation observed here causes the IM/ICHzC6H 5 ratio to decrease.~ NC. lllb).CH.] +.C3H50] + (la. [M -. as a result of which the following ion peaks appear: [M-. *Carried out in the pharmacology laboratory of the All-Union Scientific-Research Institute for Pharmaceutical Chemistry (Academician M. The mass spectra of compounds la-g and llla-f showed molecular ions. Andreeva. 1t 3 Ctlj N C -.HT] + (Ic. D.CeH ~ VI III . 4].C2H~OH]+.2CJ|..i" CI N N . . The characteristic feature of the decomposition of the azaindoles la-f is a certain de- crease in the peak intensity of the molecular ions as compared with the respective substi- tuted azaindoline llla-f. 0" " N N N It ! E ~ "' I C H ~C'6H ~ (ll. Study of these N-substituted compounds la-g* showed that only compound Id shows weak central antiserotonin activity in 50 and i00 mg/kg doses (internal) in mouse tests. but of the corresponding oxidized compound.] +.C3H7] +. The corresponding 6-benzylamino-7-azaindoline lllg was also entirely absent. f.7. e. 4]. in the reaction of compound II (5-cyano-6-chloro-7-azaindoline derivative) with benzylamine not even traces of l-benzyl-4-methyl-5-cyano-7-azaindoline (V) could be detected in the reaction mixture. where along with a 6-amino-7-azaindole an azaindoline compound dehalogenated at position 6 is always obtained [3.CH=OH] +.C. In contrast to these previously described redox reactions between a 6-chloro-7- azaindoline without a cyano group and an amine. -. which are shown in Table i. Mashkovskii. For all these compounds the most characteristic decomposition is the formation of benzyl cation (m/z 91). to whom the authors express sincerest thanks). N.r Cli 3 CII~ 9 " CIt~E CIi3 NC . The 7-azaindoline compounds llla-f were de- hydrogenated to the 7-azaindoies llla-f by chloranil in boiling xylene in 78-88% yield. c in which NRR' are pyrolidine and piperidine residues. [M-. in the reaction of chloroazaindoline II with benzylamine the previously noted [5] lower redox potentials of 7-azaindoline compounds as compared with the 5-azindoline ana- logs caused the formation not of 5-cyano-6-benzylamino-7-azaindoline derivative lllg.C~Hg] + (le. [M-. 7] we studied the analogous reaction as exemplified by the reaction of l-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline (VI) with piperidine and phosphorus pentoxide. "N ~ "~'N/ ' N " "N ~ "N I I I 1~ I" I I NH 2 Cii. f) RR'N = (n-C~Hg)2N_.~ I H N ' " . ! ~-~ . to which the peak of maximum in- tensity in the spectra of Ib-f and Ilia. c) RR~N = pyrolidino.. the mass numbers of which confirmed the proposed structures.C ~ H g N H .C4H.

332 (100).36).0 C2oH=N40 72. 77 (31) Id 48--49 75. 277 (87).8l).0 8. 430 87 312 (0.6 8. 331 (18). 84 (27) Ic !04--105 76. 348 (0.3 6. 242 (I.2 7. 250 81 (hexane) 297 (0. 320 (1O0).9 2210 -. 276 (17).~ 16.08) 91 (100) If 60--61" 77.9 17. 290 (43).79) 276 (21).8). 81 265 (1. 248 (I. .5 17. 261 (14). 278 (23).7 6.6 2200 -.5 6. 376 (14).85) 91 (23).1 CmH24N4 75. 291 (17).61) 263 (14). 301 (12). benzene 247 (0.-.4 5.8 C2olqzoN40 72.10) 91 (100). 287 (72).8 17. 244 (0.7 C2oH2oN4 76.54).47).3 17.76) 291 (55). 305 (90). 318 (100).22N4 75. 91 (40) 24O (O.28).93) 91 (100) Ig 186--187 78. benzene) 205 (0. 106 (22). 303 (38).1 8. 274 (7). 240 (0..9 C~tII~2N4 76. 339 (0. %) IM/I CH~Cnl'I~ I Ilia 136--137 ~2.7 15. % i mlz C H N C H N CN NH [ [ (intensity. 291 (50).4 6.9 17.75).81).27) Ib 114--115 76. 244 (I. 162 81 (hexane.2 16.0 15. [. 31 83 (hexane) 270 (I.5 2180 -.75).5 C2oH2~N4 75. 91 (65) WPurified by chromatography.51). 277 (36).0 16.0 6.7 2200 -. 100 76 hexane 296 (0. 244 (I.6 7.9 2200 3380 350 (0. 374 (4). 91 (100) Ill" f 39 40* 76.51). 90 88 hexane 270 (1. 318 (19). ~ Found. 277 (70). 289 (16).(: 17.7 7. 347 (0.7 5.38).0 2180 -. N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-azalndolines and Azaindoles Com.4 co TABLE i. 290 (19). 335 (0.7 C~3H2oN4 78.9 7. 91 (62) IIIb 85--86 T6.4 6. 258 (0.25).1 6.5 C2oH24N4 75.O 7. 334 (0.9 2190 -.26). 263 (~ 91 (100).[c{a_ 1 ) Imax I I UV spectrum.6 C24H32N4 76.39). 275 (12). 352 (100).57).03). 91 (10o) la 118--119 72.6 C2oH. 275 (11). 275 (14).5 2190 -. 275 (42).5 2180 335O 347 (1. 330 (31).8 C~oH24N4 75 7. 273 (8).5 14.(~ 14.8 14. 354 (0.t~_. % IR soectrum. 91 (73) 248 (I.5 0. (hexane) 257 (0.80). 97 86 hexane 292 (0. 334 (100).73) 70 (25) IIId 75--76 ~5. 14 55 298 (0. 289 (59).2 16.01) 261 (20). 289 (17). 255 (0.6 2190 3380 349 (0.29). 275 (6{}). 262 (7).7 17.5 17. 19 86 (hexane) 272 (1. 316 (90).41).3 6.36).05) 91 (100). 277 (34). 303 (21).9 C24H3oN4 77. % Empirical Calculated.II).5 6. 338 (0. 84 (9) IIIc 121--122 ~5. 244 (0.20). 86 272 (I. 319 (14). 3.( Mass spectr~n pound (solvent) formula . 346 (0. 275 (17). 318 (25).2 17.9 2190 -.0 17.0 16. 334 (23).9 2180 -. 353 (0.7 17.28).6 6.8 7. 333 (41). 277 (8).58 (0.77) Ilia 145--146 ~'5.74).0 2210 -.05). 303 (11).4 17. 25 88 (hexane) 262 (I. 259 (0.7 15.74).[ Inn l o g e Yield.07) 91 (100) ie 98--99 75. 3Ol (23).6 17.0 7.9 17.4 5. 137 78 (hexane): 266 (I.8 C2oH=N4 75.2 17. 332(100).0 7. 289 (17). 262 (13). 32O (97).

with TMS internal standard. s. The residue was recrystallized from hexane. The cooled reaction mixture was treated with 50 ml of water and 20 ml of 50% aqueous potassium hydroxide and extracted with chloroform. ether. l-Benzyl-4-methyl-5-cyano-6-(di-n-butylamino)-7-azaindoline (lllf) is synthesized as described in the preceding test. Total yield of II.33 (s. There was obtained 1. 2H. A mixture of 0.21 g (1.5 mmole) of phosphorus pentoxide. H 6.1 g (53%) of aza- indoline lllf. 91 [PhCH2] + (i00).6 mmole) of azaindoline II and 15 ml of amine was heated in a 55 ml steel autoclave for i0 h at 180-185 ~ The reaction product was treated with i00 ml of water and 30 ml of 50% aqueous potassium hydroxide and extracted with chloroform. The material was soluble in DMFA and hot alcohols. 263 [M--NH2] + (9).3.5 h. 3-CH2)~ 3. Rf values of the two materials were identical in chloroform (0.1%. 202 [M-. Mass spectrum: 279 [M] +" (I00).3 g (44%) of IV. After removal of chloroform and excess di-n-butylamine the residue was ground with hexane. h 50 cm) with i00 g of 40/100 ~ silica gel. NH2-NH. The residue was recrystal- lized from hexane or a 3:1 hexane--benzene mixture. l-Benzyl-4-methyl-5-cyano-6-hydrazino-7-azaindoline (IV). The benzene solution was evaporated and the residue was recrystallized from 3:1 hexane--benzene.68 (br.71 g (81%) of azalndole Ig. then with 1. 0. 4-CH3)~ 2. insoluble in water.23 ppm (s.. mp 256-257 ~ (from methanol). The energy of the ionizing electrons was 70 eV. 7. the temperature of the ionizing chamber was 180 ~ PMR spectra were obtained on a JNM-4H-IO0 instrument. There was obtained 1.86 (t. A mixture of 6. The residue was recrystallized from i:i hex- ane--benzene. which did not depress the melting point of an authentic sample obtained by the method described above. The chloroform ~xtract was dried with magnesium sulfate and evaporated in vacuum. Calculated: C 68.6. The chloroform extract was dried with magnesium sulfate and evaporated in vaduum.4 g (1.05 g (10%) of lllb.06 g of chlorozazindol- ine !I.Ph] + (45). UV spectra. N 24. and excess amine was removed by addition of toluene and vacuum evaporation. H 6. EXPERIMENTAL Mass spectra were obtained on a Varian MAT-II2 instrument with direct introduction of sample into the source.1.25-7. CH2- C~Hs).66) and benzene (0. The reaction product was treated with 50 ml of water and 20 ml of 50% potassium hydroxide solution. There was obtained 0. then with 500 ml of i:i hexane--benzene which eluted 0. 11. The hexane filtrate was evaporated and the residue was placed on a column (d 30 mm. and 2 ml of piperidine was held for i0 h at 170-180 ~ in a steel autoclave. 2H.06 g (35. acetone. A mixture of 1.5 liters of 7:3 hexane--benzene which eluted 2. dried with magnesium sulfate.3%). i-Benzy!-4-methyl-5-cyano-6-benzylamino-7-azaindole (Ig). PMR spectrum in DMSO D~: 2. and has an identical IR spectrum. 1. General Synthesis of N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-azaindolines (Ilia-e). Found: C 68. 79 . 4.13). IR spectra. 2-CH2).44 (t.35 (m. A mixture of 3 g (10.8. Colorless crystals. NH2NH).5 mmole of azaindoline IIIa-f and an equal weight of chlora- nil in 50 ml of xylene was boiled for 1. and the residue of chloroazaindoline II was filtered off.5 mmole) of hydroxyazaindoline VI. The residue was treated with 40 ml of boiling benzene. The material did not depress the melting point of an authentic sample. The chloroform extract was dried with magnesium sulfate and evaporated in vacuum. The reaction mixture was stirred at 110-112 ~ for i h and cooled to room temperature. 4. N 25. General Method for Synthesizing N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-aza- indoles (ia-e). 5H. The column was washed with 200 ml of 9:1 hexane--benzene. The properties of compounds la-g and llla-f are shown in Table I. l-Benzyl-4-methyl-5-cyano-6-piperidino-7-azaindoline (lllb). 3H. 2H. After cooling the xylene solution was washed successively with 150 ml of 10% sodium hydroxide solution and three 150 ml portions of wa- ter. and evaporated in vacuum. and the residue thereof was filtered off to give 0.7%: C~H27Ns. on a Carl Zeiss (Jena) Specord M-40 spectrophotometer in chloroform. The precipitate was filtered off and washed with 40 ml of benzene. 2H. and extracted with chloroform. on a Perkin-Elmer 457 spectrometer in mineral oil. IH. excess benzylamine was removed by addition of toluene and evaporation in vacuum.53 (s. To a solution of 3 g (Ii mmole) of II in 45 ml of butanol at 110-112 ~ was added four i.I ml portions of hydrazine hy- drate over i h.22 g (55%) of starting VI. CH2C~Hs).7 g (6 mmo!e) of compound II and 9 ml of benzylamine was stirred for i0 h at 180-185 ~ in a flask with a reflux condenser.

Nitration of 1. I. I. Vainsh- rein. I.5-e]PYRIDIN-2-ONES Yu. A.783'821:542. N. Nuak SSSR. Khim. SYNTHESIS AND SOME REACTIONS OF 4-NITRO DERIVATIVES OF IMIDAZO[4. N. A. 1984. M.. Akad. Krasnokutskaya. 6. 20 cm high) with 90 g of 40/100 ~ silica gel. No. D. Soedin. Soedin. I.03 and 8. I.. Soedin. Sycheva and L. Yakhontov. Polezhaeva.5-c]pyridin-2-ones have been studied. No. Original article submitted December i0.5-c]pyridin-2-one (Va). 4. Academy of Sciences of the Ukrainian SSR. 6.5-c]- pyridin-2-one (VI) the pyridine ring protons do not show spin-spin coupling. Izv. Akalaev. and 1. 80 0009-3122/86/2201-0080512. III) are inert to nitrating mixtures.5-c]pyridine and its N-methyl derivatives do not undergo nitration. and S.1:543. I. 2. I. I. and L.5-c]pyridin-2-one (IVa) with nitrating mixture proceeds at about i00 ~ to form the mononitro derivative in almost quantitative yield. N. D. Mashkovskii. V.5-c]pyridine (I) and its i. Yakhontov.25 Imidazo[4. M. Gunar. The residue after evaporation of xylene was placed on a column (30 mm diameter. and A. 40 (1980).-farm. Set. Yutilov and I. Geterotsikl. No. Arutinyan. Svertilova UDC 547. I.3-dihydro-2H-imidazo[4. Palant. and Yu. Krasnokutskaya. 2. Donetsk 340114. N. the spin--spin coupling constants (SSCC) of which. the PMR spectrum of the product in CF3COOH solution (Table i) has two doublets of aromatic protons (8. D. and L. A.. but the 2-oxo derivatives of these compounds are easily nitrated when heated. Yakhontov. Khim. 953 (1970). These compounds do not change when treated with nitric acid or potassium nitrate in concentrated sulfuric acid and high-strength oleum at temperatures up to 200 ~ The same result was obtained after heating the dinitrate of base I with gaseous sulfur trioxide at I00 ~ For this reason it was of interest to carry out the nitration of 2-oxo derivatives of compounds I-III. D. No. No. A. N. 1986.958. Khim. Yakhon- toy. V. Vainshtein. 192. E. V. M. However. N. N. Translated from Khimiya Geterotsiklicheskikh Soedinenii. 84 (1985).. unambiguously demonstrate their vicinal location.6 g of If was eluted. Palant. Geterotsikl. 789 (1971).and 3-methyl substituted deriv- atives (II. 119 (1970). Zav'yalov. N. Zav'yalov. 3. The column was washed with 100 ml of hexane and 300 ml of 9:1 hexane-benzene. L. Izv. Azimov. L. Akalaev. No. A. No. Institute of Physical Organic Chemistry and Coal Chemistry. I.63 ppm). work in this direction is of considerable importance in devel- oping the chemistry of this heterocycle.422. E. January. Geter- otsikl. M. Nauk SSSR. Khim. N. Gunar. Arutinyan. 773 (1973).. E. LITERATURE CITED l. Nauk SSSR. N. V. l-Benzyl-4-me~hyl-5-cyano-6-(di-n-butylamino)-7-azaindole (If) was synthesized as de- scribed in the preceding experiment. T. For example. and S. M. Some properties of the resulting 4-nitroimidazo[4. 5. Ser. 97-102. 7. Krasnokutskaya.3-dihydro-2H-imidazo[4.5-c]pyridine molecule has not been previously studied. We have shown that imidazo[4. pp. Bychikhina. at 6. Gracheva. this is possible only in 4-nitro- 1.50 9 1986 Plenum Publishing Corporation . especially because with the analogous sub- stituted imidazo[4. 5. The introduction of a nitro group into the imidazo[4. Yakhontov.5-b]pyridines the strong activating effect of the oxo group appears in this reaction [i]. Khim. I. Akad.5 Hz. Yu. Zh. 445 (1968). 4. 6. P. In the spectrum of 7-nitroimidazo[4. Akad. A. Khim.. N. Dokl.

IG7=7.3i--CHz) . .@. O--CH2--) .38 s. lv~ = 6. 21t. Of tile two free a-positions in the pyridine ring of IVa-c. 4. 8./67=6. IH) 3.3 Nr 3. 8.4 DMPA .l)--CI-1a) .. e.97 3s Is. only C(.78 (d.0 DMSO . N(I)--CHa) ./4G~ 0 VII a CFaCOOH -.09 d.74 d.. IH) . Com. I H) J67 =.68 (d.87 (s. 1H) 7.02 (d.47 (d 1H) 7.03 (d.77 is.9 Nr 3.43 s. but it does not promote the entrance of the nitro group at the other unoccupied e-position of the pyridine ring. IH) 7.31 (d. 3H. C--CI-{a) VIII e CFaCOOH -. 1.5 J DMSO .4 3. IH) 7. 3H).85 ~s 3H. 1~=5. 7.C--CHa) VIII d CFaCOOH -. 81 . 3H. 3H. 3H. 1H) 7.31--CHa) .. IH) 3.87 3. The PMR spectra of Vb. where the N(3)-methyl group shields the reaction center. 7.03 (d.98td. 3. . JGr= 6.65 S~ 31-t. 8. O--CH2--) .13--1.. N~I)--CtI3) 9 DMSO -D. It is important to note that aside from the substances mentioned. 1H)4.98 (d.67 I% 21-I. stops the reaction at position 4 completely.76 ( q. .63 (d. N~--Clta).t5 (d. the reaction goes at 125-130 ~ to give 4-nitro-l. 3H.77 s. 7. N(3)--CI-Ia) w [5] CFaCOOH 9. 8. Further increase in the shielding effect of the N(3) substituent. the 1-methyl derivative of base Iva also nitrates (iVb) [2]. 1}1) . O--CH3) VIII e CFaCOOH -.IN) 7.)--CH3) Id.63 (t.04 (d..01 (d.01 it. N(3)--CHa) . l N(3)--CH3).D r -. IH) Ja. Joy=5. 4. 7. 1H) 7.34 (d. N~3~--CH3) J67=5. 7. 1H) S. 311.8 N. 1. no nitro derivatives of other structure could be detected in the nitration products of bases IVa-c. 2H. 3I-1.87 (d./67=6.7. lil) 3.5-c]- pyridin-2-one (IVe).4 N./67-.40 ( .0 N.0 Vb CFaCOOH -. All this indicates that the reaction under consideration is highly selective.73 ~d. ltI) 7.=5..60 r 3H. 8. J~v = 7. PMR Spectra of N e w l y Synthesized Compounds .3~----CH~) .6 3.95 .2 ve CFaCOOH -. 8.~--CHa).3H.49 ~S.63 (d. 6 .20 (d. lit) 3. 3H. 31-1.94 (d. 8. 1}t) 3.3 -. IH) 8./~ = 6.IH) !6.3-dihydro- 2H-imidazo[4. C--CIt~--C) . But the introduction of a nitro group into 3-methylimidazopyridin-2-one (IVc) requires more severe conditions. I H) 3. lit) . N. viz. N(./67= 7. O. 7.70 {t 3II. 167=6. c resemble that of Va. C--CHa) Analogously to the formation of Vb.D6 -. 3H.63 ( d . IH) 7.31 (d. 2.89 ~.60 (s. (d.19 (d.40 (ra. Chmeical shift. 4H.0 VII c CFaCOOH -.2 Vd CFaCOOH -. N.. 31-1.66 ts.63 ~.8 3.5.-CH~--).. IH) 7.65 {s. 1. 3H. ppm SSCC./87=6. 8. Even in the case of IVc. 1. 2H. IH) 3./67=5. IH) I67=5./67 = 6.0 No )--s . 3I-t. 1H) 7.33 (s.02 (s.76 (d.56 3. pound So ivent Hz C(? ) N. IH) 7. Ill) ~.9 VII d CFaCOOH -.9 VII b CF3COOH -. N~)--CHz) (d. .06 (m.6 N(a~--CHa). 1H) . IH) 9. at C(6). 8.31 (d.08 (d.D -.86 d.00 ts. 3H. 3H. the 4-nitro derivative forms. 4. 3H. 4. and are distinguished from it by the N-methyl signals (Table i)..38 (d.g.and O-alky! C(4) C(6) groups va CF6COOH -.80 s .) undergoes attack by a nitrating agent.82 s. in 3-ethylimidazo[4. 3H. N~I)--CH3) VIII b CFaCOOH -. 2.42 ~ 3H.17 it. TABLE i../67=6.5-c]pyridin-2-one (Vc) in good yield.2 Nm--CHa). C---CH_~--CH2--C) . 8. I<~ = 6. 1H)3. ltI) 7.

When such solutions are treated with dimethyl sulfate at room temperature. i.0 5.9 37. R " 1. dR=nCaHT.HIsNaO~ 59. 2.8 3.i. TABLE 2. b.3-dihydro-2H-imidazo[4. Vc from nitromethane. I Cas ] C H ! Va . Moreover when Va-d are reduced by hydrazine hydrate no catalyst is needed and the amine yields approach quantitative [3]. Vb from water or ethanol.9 VIIc 242--24~. We therefore assign this compound the structure of 4-nitro-l. I!I ) [7]' A.1 2.36 g (3 mmole) of compound I. F.N ..2 4. h e R=H.9 85 *Compounds Vlla.86) and 0. The two latter re- agents give especially good results. The properties of the resulting 4-hydroxy.7 6.1 Cal'lsN~Os 46.96 (~) Vc 274~275 [ 43.3-dimethyl-l.2 4. a compound forms with mp 224-225 ~ in high yield that is insoluble in alkali but soluble in alcohol.8 6.0 :37. N .1 g of U=SO4 (d 1.5 80 VllIb 144-~145 55. 51. The contents of the tube were poured on ice and neutralized with po- 82 . internal standard..1 23. Vlld from eth- anol.0 27. Vllb was reprecipitated from weak acid solution by ammonia.and 4-alkoxy-l.5-c]pyridin-2-one.1 6.8 Cyt'i~N40 51. Such a conversion is easily carried out by heating Vd with water or the appropriate alcohol in the presence of alkali.0 CI2H=rN~O~ 61.6 g (9. b R=CHa.3 95 Vllld 75--76 59.9 77 [B) Vd 225 46. Villa from water or nitromethane. Reaction of Nitrating Mixture with Imidazo[4.~O2 53.8 2.78 and 3.3 3..2 Clot-I~sNsO~ 58.8 99.9 Vllle 78--79 58.3 99. The properties of V.3 7. V..8 19. . Since they are weak acids. they dissolve readily in aqueous alkali to give yellow solutions. similar to what occurs with 2. e RI=C2Hb.1 C~H~N4Os 43.d R'=CHo. I 28.3101 43.. besides the coublets of the aromatic protons at positions 6 and 7 and the N-methyl singlets.96 ppm in CF3COOH).. a-e v a-d vlla-d VIII a-fi~ IV.R . the signals of the O-alkyl hydrogens also appear (Table I). and hydroiodic acid.8 5. 1.2 33. Vd.1 28.9 5. This material is also obtained with bases Vb.9 5. ___N ~ iv.c recrystallized from water.and 3- Methyl Derivatives (II.8 21. EXPERIMENTAL PMR standards were obtained on Tesla BS-467 (60 MHz) and Varian XL-IO0/15 (I00 MHz) in- struments.9 28.1 Csl.-dimethyl- 1. Vlllb-e from hexane.. and VIII are shown in Table 2.yfi~. e R=n..9 5. 4-Nitro-l.5-c]pyridine (I) [6] and Its i.0 4. c are methylated with diazomethane in nitromethane medium. VIII aR=H. VII. 2. l 9fi Vlr" 240 53. In the PMR spectra of bases VIIIb-e.8 18.7 C71{eN4OII 43.3 29.5-c]pyridin-2-one (Vd).2 18.99 (B) Vb 309--.9 (B) vIIb 360 50.~" \.N302 55..2 7.9 5.9 90(A). can replace the nitro group by a hydroxy or alkoxy group.3 17.50) was heated in a sealed glass tube at 170-180 ~ for 5 h.and 4-nitropyridines [4].2 C~I'IBN~O 48..7 CrHaN40 51.0.4 92 (A).3 33. e R=C2H6.7 21. CtI= .lO0 J 39.21 3.7 C91'1. its PMR spectrum contains methyl signals (3. Vd.0 6. however.4 20.C4H9 All the nitro compounds V are easily converted to the respective amines Vlla-d by such reducing agents as iron. sodium sulfide.9 C. VII a. The nitro compounds Va-c (Table 2) are high melting and insoluble in many solvents.7 31.5-c]pyridin-2-ones .3-dihy- dro-2H-imidazo[4. 4-Substituted Imldazo[4.3.2 3LJ 9~ (A).9 26.6 5.9 34.3 3.98{ ) Vlla 309--31( 47.3 20.0 C~li~NoO~ 40. I 4. g b R'=H.0 94 VIIle 50--51 61.5-c]pyridin-2-ones (VII) are shown in Table 2.5 mmole) of HNO~ (d 1.9 34.82 ( ) Villa 310--311 53. d R=CHa. TMS.5 31. r ' -.iN40 53.9 9:3{A). hydrazine. A mixture of 0.3 C~I-19N. e .6 3.2 23. Va from DMPA.9 5.3-dimethylimidazo[4.8 31.1 99.

1.33 ml of HNO3 (d 1. A mixture of 2. To a solution of 2. the solution was evaporated to dryness.38 g (20 mmole) of base I and 2. There was isolated 0. The aqueous alcohol solution was evaporated to dryness.3-dihYdro-2H-imidazo[4.5-112. 79. washed with water and dried. and recrystallized from dioxane to give 0.tassium hydroxide to pR 6-7. the residue was washed twice with hot alcohol.5-c]pyridin-2-one (Vd).9.50) was heated in a sealed tube at 200 ~ for 4 h.2 g. and the extract was evaporated. B_z.. A mixture of 2. poured on ice.5 ml of water was added ]. 4-Nitro-l.0 g (14.5 h the reaction mixture was heated for 2 h in a boiling water bath.0.27 g (2 m/Role) of base If.5 mmole) of compound Va and 0.5-c]pyridin-2-one (Va). Into the inner tube of a straight Liebig condenser held horizontal was placed 1 g (4 mmole) of imidazo[4.and 4-nitro-3-methvl-l. To a solution of 60.6%.6 ml (6. or unpurified unreacted I give a yellow color. washed with cold water. 88% of the starting compound was separated. C6HbN3. The ability of 7-nitroimidazo[4.5 h at room temper- ature.50) and 52 ml of concentrated H2SO~ dropwise at 4-5 ~ . and finally w~th ammonia to pH 5. Calculated: C 29.170~ In all the experiments the isolated base samples did not depress the mp in a mixture with an authentic sample of I.30g (25%)of I. The precipitate was filtered off.6%.3 g (85%) of the starting compound.5~ Nitration of 3-methylimidazopyridine III was attempted under similar conditions. and gaseous sulfur trioxide was introduced while water vapor at i00 ~ was passed through the jacket.5 g (i0 mmole) of I dinitrate and 6 g of 60% oleum. To a mix- ture of 1.3. or give reason to speak of the presence of nitro compounds. mp 111.3 ml (13. mp 167-168 ~ B_~. Recrystalliza- tion from dioxane gave an additional 0.44 g (94%) of compound I. After the mixture was heated. and the mixture was heated for 3 h at 100 ~ . 4-Nitro-l-methyl. The mixture was cooled.8 g (67%) of imidazopyridine I. mp 167-168 ~ The mother-salt solution was evaporated almost to dryness and washed with boiling alcohol (3 • 20 ml). After 10-15 m2n a precipitate formed.4 g (90%) of the dinitrate of I (prisms). The precipitate was filtered off.8 mmole) of potassium nitrate in 8 ml of concentrated H2SO~ with cooling in ice.80 ml of H~SO~ (d 1. and dried. mp 169. The cooled mixture was poured on 1 kg of ice and neutralized with dry ammonium carbonate. mp 101-101.3.2 ml of HNOs (d 1. There was ob- tained 4. After being held at room temperature for 0. mp 168-169 ~ (according to [6]. and the residue was recrystallized from 2 N HNO.0 g (5. The solid residue was washed with alcohol (3 • 5 ml).35) was evaporated on a boiling water bath. Yield.-dihydro-2H-imidazopyr2dines (Vb and Vc) were obtained similarly. mp 165-167 ~ C_:. and recyrs- tallized from dioxane. N 28. at such a rate that the temperature of the reaction mixture did not exceed 30-32 ~ .22 g (81%) of starting compound II. A mixture of 0. The precipitate was filtered off and dried.3-dihydro-2H-imidazo[4.-dimethyl-l. mp 220-221 ~ (with decomposition). A. The colorless precipitate was filtered off.5-c]pyridine (IX) [8] and similar nitro compounds to give an intense yellow color in alkaline medium was used for the qualitative detection of small amounts of nitration products of compound I. The mixture was stirred another 0.8 mmole) of base IVa [5] in 8 ml of concentrated H2SO~ was a-dded 1. mp 101-102 ~ (from ben- zene) (according to [7]. N 28. mp 111-112 ~ (according to [7]. mother liquors. 1 ml of 8% KOH solution and 0.2 mmole) of dimethyl sulfate were added. Found: C 29. D.0 g (440 mmole) of base IVa in 220 ml of concentrated H=SO~ was added a mixture of 52 ml of HNO3 (d 1. In no test did alkalization of reaction mixture. and the solution was neutralized to pH 6 and evaporated to dryness. The oil that separated crystallized when cooled. After cooling the contents of the tube were poured on ice and neutralized to pH 6 with sodium carbonate solution. H 3.8 g (14. 2.4 mmole) of d:[methyl sulfate dropwise with vigorous stirring. There was obtained 0.2HN03. but in [5] compound IV was nitrated at 125-130 ~ . and 0. and 83 .86).3.5-c]pyridinium dinitrate.6 g. Reerys- tallization from i:i benzene-hexane gave 0. Yield. and neutralized with aqueous ammonia. dried.50 g (14. The precipitate was filtered off. A. After 2 h heating the tube contents were dissolved in 5 ml of water. H 2. After cooling the mixture was poured on ice and made strongly alkaline with 40% sodium hydroxide solution. prepared at 2-5 ~ was heated in a sealed tube at 100 ~ for 2 h. and the residue was recrystallized from dioxane. dried.5~ 4-Nitro-3.3 mmole) of potassium hydroxide in 13.4.

The bright yellow precipitate was filtered off. 0._. To a suspension of 0. This amine did not depress the melting point of samples obtained by methods A and B. A solution of 0. 20 ml of 45% hydroiodicacid.5 ml of nitromethane was poured 1.3-dimethyl-l.80 g of Va and i0 ml (200 mmole) of hydrazine hydrate was heated at the boiling point for 2 h. After cooling the solution was neutralized with concentrated HCI and evaporated to dryness.5 h.0 mmole) of NaOH in 30 ml of water was added 0. and the filtrate was evaporated to 1/3 its starting volume and alkalized with aqueous ammonia to pH 8. Yield.75 g (91%).95 g (i0 mmole) of Vb and 15 ml (300 ml) of hydrazine hydrate. D.57c]pyridin-2-one (VIIIa)~ A mixture of 2. 1.40 ml of dimethyl sulfate were added and the mixture was left overnight.16 g (4. The precipitate was filtered off. Yield.50 g (2.8 mole) of Vd.0 g (18 mmole) of pulverized carbonyl iron was added in portions with vigorous stirring.25 g (60%). The phosphorus was filtered off. 1. and 5 drops of concentrated HCI was heated to boiling. washed with water.5-c]pyridin-2-one (VIIIB) was obtained hy method C from 1.20 g (i mmole) of nitro compound Vc in 1 ml of nitromethane was methylated with 1. Yield. 1.54 g. 1 ml of 8% NaOH was added and the mixture was stirred another 3 h. 0. 0. The precipitate was filtered off.65 mmole) of compound Vb in a solution of 0. Then another 1 ml of 8% KOH was added. Yield. and the mixture was left overnight. 4-Amino-l.8 m_mole) of compound Va in a mixture of 4 ml of alcohol. 4-Amino-l-methyl-l.5-c]pyridin-2-one (Vile) was obtained by boiling a mixture of 1. Yield.40 ml (4 mmole) of dimethyl sulfate dropwise with stirring.the mixture was kept for i h. washed with water. C~ A mixture of 1. and 1. The precipi- tate was filtered off and washed with hot water (3 x 2 ml). Et To a solution of 0. and dried. The precipitate was filtered off. 4-Amino-l. A suspension of 0.32 g (1.3-dihydro-2H-imidazo[4. Yield. 0. 1.95 g (i0 mmole) of Vc and 20 ml of hydrazine hydrate. washed with 5% NaOH.3-dihydro-2H-imidazp[4. and dried. 1. and dried. The precipitate was filtered off. i0 ml of hydroiodic acid (d 1. and the mixture was boiled for 6 h. A.16 g (76%). B. and 0.9 mmole) of dimethyl sulfate dropwise with stirring. Yield. 0.65 ml (6. washed with a minimal amount of cold water. Yield. Into a suspension of 0.!7 g (50~)..2 ml of 6% NaOH solution was added 0. Yield. Yield.50 g. a solution of 0. and 1.i g (10 mmole) of Vd and 70 ml of 5% NaOH solution was heated at the boiling point for 4 h.0 g (32 mmole) of red phosphorus was boiled for 4 h.20 g (i mmole) of compound Vb in 1.5-c pyridin-2-one (Vlld). 0. After holding for i h at room temperature. A mixture of 1. 0. Yield. After the ether was distilled off the residue was recrystallized from alcohol.0 g (32 mmole) of red phosphorus was boiled for 4 h.40 g (2 mmole) of compound Vc in 4.71 g. 4-Hydroxy-l. The solution was evaporated to dryness and the residue was re- crystallized from water. After holding for 0. 4-Amino-3-methyl-l.2 g of sodium hydroxide in 2 ml of water. A. A mixture of 1.3 ml of 4% ether solution of diazomethane as described in method C.64 g. Yield. The mat- erial did not depress the melting points of the methylation products obtained by the methods described above. washed with water. 84 . The reaction product was extracted with chloroform (3 x 5 ml).7). and dried. B~. 1.64 g.3-dihydro-2HTimidazo[4. The reaction product was extracted from the residue by methanol (3 • 8 ml) and the solvent was evaporated.58 g.0 g (5.41 g.3-dihydro-2H-imidazo[4.0 g (4. B. 2 ml of water. C__~. and the fil- trate was evaporated to 1/3 its original volume and alkalized with 20% NaOH solution.08 g (i0 mmole) of Vd and 15 ml of hydra- zinc hydrate.3-dihydro-2H-imidazo 4. The phosphorus was filtered off.3-dimethyl-l.2 ml of a 4% ether solution of diazomethane and the mixture was held for 1 day at 10-15 ~ . 1.18 g (84%).5-c]pyridin-2-0ne (VIIa).5 mmole) of Va. It was ob- tained similarly to amine VIIa by method C from 2. and the filtrate was evaporated to half its volume and alkalized with 20% NaOH solution. and dried. Yield.04 g.

only in individual cases [5] has glycosylation of a 6-sub- stituted adenine with a carbohydrate fragment been used. The purpose of the present work was to synthesize potential cytokinines in the 6-sub- stituted adenine glucuronide series.0:1. January. No. Geterotsikl. Bystrova and Yu. USSR Inventor's Certificate 717.. M. G. 350 (1973). 4-Alkoxy-l. Original article submitted April 29. LITERATURE CITED i. 6-benzylamino. R. Miroshnichenko. Stetsenko. Byull. The structure of the glucuronides was demonstrated by the UV. 138 (1973). London (1961). Saito. Izo- bret. Khim.8 N6-substituted adeninyl-9-~-D-glucofuranuronosides have been obtained by the conden- sation of trimethylsilylated 6-aminopurines with 1. To the solution obtained by heating 0. USSR Inventor's Certificate 521. Khim. Soedin. Mizuno. p. Yutilov. Pa~gle.I mole of Vd. 5. Byull..277. I. The TLC data bear witness that other nucleosidic products are formed in the reaction (not more than Institute of Organic Synthesis.(IIb). "Meristemnye Kul'tury" Agricultural Plant. S . No. Lidak 577.O mole of the appropriate alcohol was added 0. Ignatenko. 26.3:631. Soedin. No. R . A. Part 2. Svertilova.. 6-morpholino.(IId). Khim. Svertilova.. and 6-furfurylaminopurine (IIf) with 1. A. 2. M. 8]. Geterotsikl. Klingsbert (ed. Yu. and I. which is more re- active than SnCI~ which we used previously [6. 3. When the reaction was carried out at 80 ~ for 12 h (II:III:TMS-TF 1.2. UDC 547. A.2-dichloroethane in the presence of the condensing agent trimethylsilyltrifluoromethanesulfonic acid (TMS-TF). pp. G.2 moles). V. SYNTHESIS OF N~-SUBSTITUTED ADENINYL-9-~-D-GLUCOFURANURONOSIDES Yu. M.3-1actone (III) [7] in 1.. Riga 226006. Itoh.5-tri-O-acetyl-B-D-glucofur- ano-6. G. 1277 (1976). Yu. Svertilova and Yu.15 mole of NaOH ~o~KOH)~ini.. No. in: Pyridine and Its Derivatives. 479. No.1:1. Svertilova. M . For the synthesis of nucleosidic derivatives of kinetine (6-furfurylaminopurine) and other 6-substituted adenines. Yutilov. i. Ryabokon'. T. Khim. Geterotsikl. and A. New York. M. 7. Izobret.7'483: I. 2. 7. the principal product was the Ng-~-D-glucofuranoside of N~-substituted purines (IVa-f). 6. Ikehara. Zhola. H . 121 (1980). due to the instability of the glycoside bond and the lactone ring under the reaction conditions.50 9 1986 Plenum Publishing Corporation 85 . Translated from Khimiya Getero- tsiklicheskikh Soedinenii. Yutilov. Mizzoni. 1985. 1986. A. I . and K. Chem. 80 (1976). 28.3-dimethyl-l. mainly the amination of 6-chloro. i.and 6-methylmercaptopurine nucleosides has been used [1-4].3-1actone. J. Academy of Sciences of the Latvian SSR.. M.055. and the mixture was boiled for 2-4 h. Ogre 228300. 9. Ukr.(IIe). 6-cyclohexylamino- (IIc).5-c]pyridin-2-ones (Vlllb-e). Attempts to use l-(6-chloro. 4. 103-106.113. 1837 (1963). 8. O.2.@-2. Eilazyan. Yu. Soedin. Maurin'sh. We therefore synthesized the compounds by condensation of the tri- methylsilyl derivatives of 6-methylamino. A. Zh. Y. No. 6-butylamino. A. 0009-3122/86/2201-0085512. IR 9 and PMR spectra. Yutilov and I. Ya. The sodium (or po- tassium) nitrate precipitate was filtered off. M.857.or 6-methylmercaptopurin- yl-9)-~-D-glucofuranosides that we had previously synthesized [6] to obtain these compounds were unsuccessful. 378 (1969). A . R . N . 39. Yutilov and I. excess alcohol was distilled from the filtrate the reaction product was extracted with hot chloroform (50-60 ml) and the solvent was evapo- rated. Yu.). Org.5- tri-O-acetyl-~-D-glucofurano-6. 4. E. and M. No.3-dihydro-2H-imidazo[4.(IIa).

Ph).0 8. The structure and configuration of the synthesized nucleosides were established on the basis of spectral data. 2. 7. OAc).8 0. m (3H CI.33 6.75 3. (~.. ii. 2. Changing the proportions of reagents or raising the reaction temperature to boiling did not increase the yield of nucleosides IVa-f.34 6.11 dd . o . I'-"1" P"I2 I IVa 8. The glucuronide of 6-dimethylaminopurine could not be synthesized by this method.. OAc). 2CH.).78 3.7~ 3..). t (IH. TABLE I. i R = morphlino . 0. otoo. ! 6. 4.95 (101 I. This enables us to confirm that during the glycosylation of the purine bases the 86 . 6.06..22..15 i (311.75 3.. 2. 3CH).0 8.26. CH).).O 3.. f R = furfurylamino - The PMR spectral data (Table i) confirm the 8-anomeric configuration and the presence of a hexafuranose ring in these compounds [14].'i" .4 5... 5CH.1t..28 d 5.12.-OAc).414. m (2H.47. The spin-spin coupling constant (SSCC) values of the carbohydrate protons of IVa-f (at least 6 Hz) are typical of furanose deriva- tives..!2. CH. 12] of the related heterocyclic bases..20 131i.s 3. t (3H..10.97. 5.91 2. 0. ra (Ill. . m (2H. 1.s 4.tlil) i IVe 8.70 (4H.07. P"Ac 0 II sJi(cH=) = Za. m (2H. lILt IVb 8.20. Analytically pure samples of IVa-f were obtained by column chromatography of the reaction products on silica gel.. and in the 1800-1805 (7-1actone C=O) and 1750-1760 cm-* (acetate C=~) regions.4 4.11 dd 5.24. .13.21..0 .2. lilt) IVO 8.~8.f nL- OA~ IVa-f l-llI a R = N H C H a ..12 5. 1. ca~'mlc...09. . 2...31 6. m (IH. 5. 4.. s (3H..26 d 5. OAt). 3. 3.5.m (lit. I0] and the Ng-ribofuranosides [2-5.84 ]2.s 4. Ill{) IVd 8. OAt).1.6 5. 2.8]5.18 I (3H. CI4!!).20. m (4]-t. 5. 13].32 6. 2CH2) IVf 8.11 d 5.13rid ' 0. unreacted lactone III and 6-am- inopurines la-f are left in the reaction mixture.I:~).84..L. 6.67.. The properties of the UV absorption spectra of the 6-aminopurine nucleosides IVa-f are identical with those of the Ng-alkyl derivatives [9.. . and are significantly different from those of the N7 derivatives [5.4 8.86 2..8 8.. m (Ill.s 3.09.. OAt). 4.co.9 d 5.17 i (3I'|.. 6. Furthermore.2)..0 8.8 o.321(5.--!"\o..8 5.0012.s (311..06. !6. CH. J 2CI12). s(3li.m (4[{.:~pound~ i V a ~ .6 0.. Appar- ently they are isomers of nucleosides IVa-f.8~] 2.23. 4. NH) 5-10% of the total).t..74. o.13 5. OAt).10.. Parameters of PMR S p e c t : r a o f Co. 2...48.~. 6 26--6 38 (3H. The IR spectra of IVa-f contain absorption bands at 1595-1615 (purine C=N).27 dd 'i5.11 d 5.Xc). because the silyl derivative of 6-dimethylaminopurine does not react with lactone III even at the boiling point of the solvent. 7.37-..17--1. 6..73..s 3. a ( l i i . OAc).16 5. s (3t[.29dd e. m (5H.0 l.8 836! (3H.37 6.7. b r R = HNC~H's. these could not be separated in pure form for identification. s (3H.22 (3{I..13 dd 5.O 3. OAc n R N~'r------N .'.17 5. OAc). EI I~). c R = H N C e H x l i d R = HNCH2CeHs.l. OAc).28.75. I L58.

The fractions con- taining IVb were combined and evaporated.f as stimulators of sprout formation in the growth of cuttings from meristem.2%. The residue was dissolved in a minimal amount of chloro- form. The silylated purines lla-f were used without further purification.f by the tissue culture method in synthetic culture media. and eluted succes- siveiy with 500 ml of chloroform and 300 ml each of 99:1 (by volume). The solution was evaporated in vacuum.48 g (6. kinetin was added to the medium.6-4. Cytokinine properties were studied for IVd. 16] from 6-chloropurine or 6-methylmercaptopurine.[~]D~U 89. C. Silylation of 6-aminopurines la-f was carried out by boiling the purine in hexamethyl- enedisilazane (20 ml per g of purine) (for Ib-d). The chromatograms were developed by spraying with a i:i mixture of 0.3 ~ (c 0.2 ~ (c 0. The fractions containing IVa were combined and evaporated to dryness in vacuum. DMFA). In this case 6-benzylaminopurine (BAP) was added to the culture medium to stimulate sprout formation. and 97:3 chloro- form-ethanol. 6-Aminopurines la-f were synthesized by the procedures of [15. To compare the action of glucuronides IVd and f.56. IR spectra in mineral oil on a Perkin--Elmer spectrometer. Cal- culated: C 52. IVd and IVf act approximately at the level of kinetine. with addition of 2 ml of trimethylchloro- silane (for le.5 • 60 cm) with LI00/250 silica gel (Czech- oslovak SSR).2-dichloroethane was added 1.6-1acton (IVb) was obtained condensation of 9-trimethyl-silyi-6-butylaminopurine (lib) with lactone III.4. [a]D =~ 69. H 4.38 ml. Elution was carried out with chloroform. N 17. Material was eluted with 500 ml of hexane.1%. After cooling to 20 ~ the solution was poured into a vigorously stirred suspension of sodium bicarbonate in 300 ml of chloroform and 50 ml of acetonitrile. It was determined that the activities of IVd and IVf are lower than that of BAP.1 mmole) of lactone III and 1. H 5. The SSCC value J. UV spectrum: %max 265 nm (log 4.2% naphthoresocinol in ethanol and dilute (I:i0) phosphoric acid followed by heating at 110-115 ~ for 15 min.9%. Calculated: C 49. until all lactone IVa had come off the column. transferred to a column of i00 cm 3 of silica gel with chloroform.42. N 17. The tests were carried out on the growth of Dianthus from meristem in a modified culture medium.2. Rf 0. The mixture was stirred for i h. UV spectrum: Amax 267 nm (log c 4.6. N 16.71 g (1.furanose form is not converted to pyranose. the mixture was evaporated to dryness and transferred with hexane to a column of I00 cm 3 of silica gel. After solvent was evaporated the residue was dissolved in 20 ml of chloroform.. 7. Specific rotation w a s determined on a Perkin--Elmer 241 spectropolarimeter. The tests show that at concentra- tions of 0. Found: C 49. i0 cm 3 of silica gel was added. l-(6-Methylaminopurinyl-9)-2.6.32 mmole) of TMS-TF and the mixture was heated in an oil bath for 12 h at 80 ~ . The fractions containing IVb were evaporated to give a frothy residue.gH23Ns07.24). The yield of analytically pure IVa was 0. and the combined fil- trates were evaporated in vacuum. then by linear gradient elution with 500 ml each of hexane and ethyl acetate. The yellow oily residue was dissolved in the min- imal volume of chloroform and repeatedly chromatographed on a column of i00 cm s silica gel with chloroform.3.250 ml/g.DMFA).6-1actone (~ya). PMR spectra in DMSO-D6 on a Bruker WH-90 in- strument. The course of the reaction and the identity of the reaction products were monitored by TLC on Silufol-254plates in a 9:1 chloroform-methanol system. Column chromatography was carried out on a LKB (Switzerland) column (2.35 g (15%). mp 204-205. 87 .71 mmole) of 9-trimethylsilyl-6-methylaminopurine (lla) in i00 ml of 1. 98:2. CI~HITNsOT.54.~. similarly to IVa. Found: C 52. To a solution of 1. Rf 0. H 4. l-(6-Butylaminopurinyl-9)-2.4. with HMDS internal standard.0 Hz is evidence for the 8-anomeric configuration of the lactones IVa-f. = 3. H 5.6.6%.21).125 and 0. for the growth of plants from m eristem. N 16. Yield. Another experiment was carried out to study lactones IVd. and the solution was again evapor- ated.5-di-O-acetyl-8-D-~glucofuranurono_3. f) or 2 ml of pyridine (for la) until complete dissolution.5-di-O-acetyl-B-D-glucofuranurono-3. 20-30 ml of p-xylene was added.1. EXPERIMENTAL UV spectra were recorded in methanol on a Spectromom-204 spectrophotometer.84 g (6. the precipitate was filtered off and washed with 2 • i00 ml of chloroform. 17%.53.

Brown. J. Kvasyuk. J. Khim. Soc. Chem.5-di-O-acetyl-8-D-glucofuranurono-6.40. K.27).56.53. E. H 5.NsOT. H. Robins. 411 (1952). A.1. Soc. and H.6. H 4. J. N 15.54. Amer. Chem. Found: C 52. Davies. H 4.5. 513 (1976). A. R. H 4.1 ~ (c 0.5. Kissman. Soc. 1880 (1965). 16. Yield 23%. 13. Chem.6%.NsOs.. Zidermane. 5238 (1957). L. [aiD 77. Chem. D. mp 175-177~ Rf 0. 21. No. 55. A. N 15..7. Found: C 50. R. C22H2.. UV spectrum: Ima x 266 nm (log e 4. J. Bull. M. 88 . 1532 (1981).54. Geterotsikl. Studia Biophys. [a]D 2~ 85. Soc. J. 30. 12. M. Soc.56.5. Biesele. 5695 (1956). J. W. C=IH25N~OT. N.30). Liepin'sh.2%. Found: C 56. Mikhailopulo. UV spectrum: imax 266 nm (log e 4. Khim. and isolated similarly to IVb. H 4.. Robins and H. J. A. N 15.8 ~ (c 0. Org. l-(6-Benzylaminopurinyl-9)-2. oV 4. 39%.0.3-1actone (IVd) was synthe- sized from 9-trimethylsilyl-6-benzylaminopurine (IId) and lactone III and isolated similarly to IVa. Uno. K. M. A.9. No. 15. 490 (1957).5-di-O-acetyl-B-D-zlucofuranurono-6. M. DMFA).. E. 18 (1955).4%. Moore. H. J. A. C2oH. Soc.8.28). Calcu- lated: C 52.gNsO. Ikehara and H. Pa~gle. Soedln. I. N 15.. 79. H. Amer. and B. R.. A. Burgi. DMFA). A. 79. 9. Pa~gle. Coll. Yield. Elion. 5. A. G. Found: C 54. Mikhailopulo. Weiss. N 15. Baker. A. Pidacks. Zemllcka and F. Yield.3-1actone (IVf)was syn- thesized similarly to IVa from 9-trimethylsilyl-6-furfurylaminopurine (llf) and lactone I!I. 8. E.5~di-O-acetyl-8-D-glucofuranurono-6. Chem. Maurin'sh. Shaeffer. Montgomery and C. Prasad and R. Sor 74. Chem. Yu. Daly and B.7.. Ii. l-(6-Cyclohexylaminopuri~yl-9)-2. Maurin~. i0. 80. 29 (1976).5-di-O-acetyl-8-D-glucofuranurono-6. A. A. E. B. G. J. H 4. Chem. LITERATURE CITED i. Yield 26%. J. 2. Blackburn and A. Kissman and M. J. J. A. ii. Hampton. J. Lidaks. DMFA). M. C. 4347 (1960). Amer.3-1actone (!Vc) was synthesized similarly to IVa from 9-trimethylsilyl-6-cyclohexylaminopurine (IIc) and lactone 2o IIl. B. Hitchings. UV spectrum: Imax 267 nm (log e 4. 7. Lin. 177 (1956). Chem. J. H 5. 6401 (1957).3-1actone (IVe) was synthe- sized and isolated similarly to IVa from 9-trimethylsilyl-6-morpholinopurine (lie) and lac- tone III.26). J.4. J. J. R.0 ~ (c 0.6%.7.. Temple.8%. Kulinkovich. Zidermane. and G. J.. Sorm.. N. and I. ii. ~. UV spectrum: imax 277 nm (log e 4. Chem. M. Chem. Calculated: C 51. Calculated: C 56.3%. J. [a]D 2~ 70. Johnson.. 77. Akhrem. and I. 221 (1965).. Calculated: C 54. N 15. Amer. 6. DMFA). Org.54. mp 11-113~ Rf 0.0%. J. 3. V.. H. mp 175-176~ Rf 0.0%.2 ~ (c 0. Johnson. Christensen. Timoshchuk. 79. 700 (1958).56. Mp 99-101~ Rf 0. H 4. E. 41%.4. Thomas. 78. A. K. J. ~. and was isolated similarly to glucuronide IVb. and G. l_(6_Morpholinopurinyl_9)_2. Amer. Lidak. Amer. 21. 147 (1984). E. CliH2. A. and M. A. Nucleosides and Nucleotides. A. W. 1053 (1956).5. Chem. Pharm. 14. Amer. Bioorg. Soc.. Kilevitsa. l-(6-Furfurylaminopurinyl-9)-2.2. 13. B. [a]D 2~ 83. N 14. N 15. Yu. J.7. J.

VIIa CAr +~ /z / Oil .. O.50 9 1986 Plenum Publishing Corporation 89 . ~Vla C. In the present work. (~H2)~Ar Ar--(CIIT)C~N C?'HsOtt"" NH'Itr . I. Lunin.-.. .. .* SYNTHESIS OF 2. 2. 1 VI]I a ..6-Trisubstituted symm-triazines containing sterically-hindered phenol frag- ments were synthesized by the cyclotrimerization of ethyl iminoesters. lllc.4. 4.C C(ClI~ s -C(('H. we synthesized 2. F.IVa. Original article submitted November 20. F.~)a la. ~ v.4. I.. Hc~ A~ . Karakhanov. 1984.+.. The introduction of sterically-hindered phenol groups into symm-triazines permits the preparation of antioxidants and thermal and light stabilizers for polymer materials and lub- ricating oils [2-4].H~) Ar Vll--Vllle. and O. UDC 547.. --. Malova 2.6-di-tert-butylphenol fragments (VII) and (VIII). b . we studiedthe use of this method for the preparative synthesis of 2. I. January.422 A.4. the reaction was carried out in an excess of ethanol at I0-15~ with subsequent maintenance of the reaction mixture for four days [I0]..~.. In our previous work [5].oco:o " I [ 1-xt~-e mw..5-di- tert-butylaniline. A.SYNTHESIS AND PROPERTIES OF symm-TRIAZINE DERIVATIVES. In the case of 4-hydroxy-3. *For communication 3. we demonstrated the feasibility of preparing such sym~-triazine derivatives by the reaction of chloro-symm-triazines with 4-hydroxy-3.-.. Laawad Yakhya. .C +~ .491.07:543. Derivatives of symm-triazine may be obtained by the cyclotrimerization of the iminoes- ters of carboxylic esters in the presence of their hydrochloride salts [6. and IVa-c were formed in good yield upon carrying out the reaction at 0-5"C using equimolar amounts of the corresponding nitrile and ethanol with subsequent maintenance of the reaction mixture for 10-12 h at 20~ Iminoester salts III and IV are rather stable compounds and may be stored for prolonged periods avoiding moisture. 9].-~c. Gubkin Moscow Petroleum Chemistry and Gas Industry Institute. M. No.~" ':~.~m42 .. 1986.C)lllo.4. Kelarev... in which shielded phenol fragments are attached to the heterocyclic ring by means of C--C or C--S bonds.'-^ ~ " ~':~'.INH H N:~:'I~ . Ha C. i.c " ~. In a continuation of this investigation.6-TRIS~BSTITUTED symm-TRIAZINES CONTAINING STERICALLY-HINDERED PHENOL FRAGMENTS V.6-trisubstituted summ-triazines containing 2.6-trisubsti- tuted symm-triazines.vt. 7] or other acid agents [8. pp.). i "'N ff.5-di-tert-butylbenzonitrile (la).4. Translated from . R. see [i]... 107-113. Cc-+-oc. 0009-3122/86/2201-0089512.~+ .c.VIIIa CAI'==+ S --O11 . Iminoesters V and VI required for the preparation of this type of heterocyclic compounds were synthesized by the ordinary scheme from the corresponding nitriles I and II. The iminoester hydrochlorides lllb. V. Khimiya Geterosiklicheskikh Soedinenii.6- Trimercapto-symm-triazine derivatives containing shielded phenol residues may be formed by the cyclotrimerization of the corresponding thiocyanates in acidic medium.~ The hydrochtoride salts of ethyl iminoesters III and IV were prepared by the Pinner re- action by passing dry HCI into a mixture of the corresponding nitrile I or II and absolute ethanol in a suitable solvent.

2 4. Vc.0 I CITI'I~TNO.7 l~.3 CmI-I3tNO2S. C.67 66.7 5. . . . .3 67 (260 [2H) ]V~ [54--155. .~I'12~NO~ 74.9 9.5 0. The C=N+--H stretching vib- rations in the spectra of salts III and IV are found at 3155-3100 cm -~. .4..5-di-tert-butylphenyl)-symm-triazines (Vlla) was isolated in only 12% yield after carrying out the reaction under the above conditions (90=C. This difference in the behavior of iminoester Va is realted to the reduced reactivity of the iminoester group as a consequence of its conjugation with the hydroxy group [i0]. which is characteris- tic for NH vibrations in imine salts [12]. .3 8.(~1 1. individual compounds could not be isolated. increasing the reaction time to I00 h and increasing the temperature to 120- 125*C.25 74. CITH27NO2S 66. In ad- dition.8 5.. 89 172--174 {16. .0O.S. 60. 75 IVb 233--235 -.2 ii0. The cyclotrimerization of iminoesters Vb. the steric hindrance due to the tert-butyl groups in the vicinity of the reaction site undoubtedly play a definite role.1 4.1 0.--136 -.. CI91"13INO:~ 74.0 I -. Thus.2 . .7 9..0 4. L : . .0 8. . 90 .8 74 Vb 80. . 1IC1 65.0 8.6 9.9 4. 24 h) and the start- ing iminoester Va was also isolated.5 86 Vlc Macro -~ "6" 0..2 4.. ~: .ol'hlNO2" I ICI 86.6 9. HCI 50. 92 lllc 116--118 .1 ~.2 8. 91 IVc 134. and Vlc were purified by chro- matography on alumina columns with elution by i0:i benzene--metha- nol.6 9.9 76 V|b I05--I06.0 0..2 4.3 0.5 .6 4. Dexter et al.5 O.5 9.51 57.5.62 57.jNO2 9I ICI 55.. ..6 i3. Vc and Vla-c was carried out at 90-95~ for 20-25 h in the presence of iminoester hydrochlorides III and IV (3-5 mass % relative to iminoesters V and Vl). 88 IVa 16.9 5. [13] have reported the preparation of symm-triazine Vlla by the direct alkylation of 2..91 ~. TABLE i. . heavy tar forumtion was noted using this method in the case of iminoesters Vb and Via and thus..31 -.--8 I 0. Salts llla-c and IVa-c melted with decomposition. HCI 61. ii].6.2 4. The IR spectra of iminoester salts III and IV show strong bands at 1670-1655 cm-* char- acteristic for C=N + stretching vibrations [i0.2 1 . Vllc.7 0. V~ and 'l'iies Hydrochlortde Salts Iii and IV ~ . Vlb. . 11C1 59.5 1 CI71127NO. .3 3.. .5-di-tert-butylbenzamide and nitrile In. The yields of symm-triazines Vllb. .6-trisubstituted symm-triazines VII and VIII. 92 9 2 i4.30 74. . . This band in the IR spectra of imino- ester bases V and VI appear at lower frequencies (1635-1615 cm-').'2 0.It~TNO2 73. all our attempts to reproduce this procedure were unsuccessful and only tar formation was noted.4 93 Vc Macro 0.42 73. . CI..9 9.3 :[.1 8.0 8.. tThin-layer chromatography on alumina with heptane eluent. ~ ~ Found. ..5 t. However. .-166 -.8 -... .4l - *III and IV were purified by reprecipitation from glacial acetic acid in dry ether. 2.2 1113) (iml I~. . the yield of symm-triazine Vlla could not be markedly increased. ~ r C Che~aical Yield. 65. We should note that the major reaction products upon carrying out the cyclotrimerization of Va at 145-150~ for 15 h are 4-hydroxy-3.5-di-tert-butylbenzoic acid (Va) are smoothly converted to the corresponding 2.0 -. T h e NH group vibrations in the IR spectra of im- inoesters V and VI are seen as medium-intensity bands at 3370-3340 cm -~.4864 Ethyl iminoester bases V and VI were obtained by treatment of suspensions of the imino- ester salts in ether or methylene chloride at 0-5 ~ by 10% aqueous KOH or saturated aqueous K2COa.5 0.5 -.. .2 i4.3 68 Via 133--135 0. hydrochloride salts lllb and IVa were converted to the corresponding iminoesters by treatment with triethylamine in dry ether.4 :J.9 9. with the exception of ethyl iminoester 4-hydroxy-3.2 I CLaI-I~oNO2S.4.(] 8. C.7 CIgH~.6 -.58.7 4.86.~]-I~oNO2S ~6.1 8. A study of the cyclotrimerization of ethyl iminoesters V and VI showed that these com- pounds. SnD 2~ 1.~.9 4.0 4.8 1 -.l 4.8 9. . The cyclotrimerization of iminoester Va proceeded with much more difficulty.4 4.0 9.3 4~0J10. ~ .. Vb. Despite varying the reaction conditions by using other acid catalysts. l C. However. 60. % Corn- pound IIla 258~260 . V and Via were purified by recrystallization from aqueous ethanol..8 8.NO2S 57.3 -. Characteristic of Ethyl Im~noesters V.di-tert-butylphenol with cyanogen chloride (3:1 mole ratio) in the presence of AICI3 in tetrachloroethylene.. .9 8. and Vllla-c were 80-88% (Table 2). .2 IlO. 6-tris(4-hydroxy-3.

C(CII3} 5 IIa.6-triarylthio-symm-tria- zincs may be obtained by the cyclotrimerization of alkyl.. The bands at 885-880 and 825-820 cm -~ are characteristic for the 4-substituted benzene ring while tile two bands at 1265-1210 cm-* are characteristic for the Ar--OH bonds [19].12-5.0 10. TABLE 2.5 15.14-7. -.0 78.8 9.5-di-tert-butylphenylthiocyanate (lla) and 4-hydroxy-3. in CCI.6- trimercapto-symm-triazine containing shielded phenol residues.9 ]5. l c(ciI:) 3 In the present work.8 9.4 8. 69(B ) *The recrystallization solvents were aqueous DMF (Vlla and Vllb).46 178. s(cn~)A.2 88(.3 5.. Upon heating in DMF in the presence of catalytic amounts of HaSO4.VIHa i.3 81(A}.? Ar VIIla.75 ppm.4 8.3 ~.6-di-tert-butylphenol and formaldehyde.2 C48H~N303S3 1~9.4 813 510 11. We attempted to use this method for the synthesis of derivatives of 2.6 VIII 211--212 (I. I The IR spectra of symm-triazines VII.5 80(A) VIII c 57--59 0.50lB9.9 CsII-175N303S3 170.9 C511-ITsNaO3 178.7 5.4. The condensation of 4-mercapto-2. .7 84 (A) VII 209--210 0.and 2. . while X was obtained by the reaction of 2. . 16-18].'~" formula potmd tive ree- C H N s d H N S t.IX Ar(C|I2) S N "~(C][. VIII and X). and i:i toluene--hexane (X). 45(B).3 '..9 11.6-trimercapto- sym-triazine with 2.X .5 B.0 CasH63N30~ ~..6-di-tert-butylphenol with cyanogen chloride gave Villa. ~ Ry.4 15.5-di-tert-butylbenzylthiocyanate (IX) were converted in good yield to the corresponding symm-triazines Villa and X.L':.4 5.3 -. VIII and X show signals for the hydroxyl group protons as singlets at 5. IIu. aqueous ethanol (VIII b and Vlllc).X .4. The signals for the tert-butyl group protons are seen as singlets at 1.2 I 1.0 5.22 ppm.6 C4sFI69N30~ 9. .X Ar .82 139.11 .3 C4sI-I6aN303S3 58. [14] have reported that 2.4. 4-hydroxy-3.6 5. f"(" ")")/-Oil .7 C481-1~9N303S3 [59.A) ~. VIII and X have a narrow band at 3650-3635 cm- corresponding to the stretching vibrations of the nonassociated OH group in the hindred phenols [15]. The spectra of these compounds show bands of different intensity characteris- tic for the stretching and deformation bands of the symm-triazine ring (Table 3) [7.0 B. li ~ N/ 7 "N lIa. . The PMR spectra were taken on a Tesla BS-487C spectrometer at 80 MHz using the 6 scale with HMDS as the internal stand- 91 .1 12. 67 (B) VllI b 102--104 0.0 86(A) X 195--196 ( 197---198 [261) 0.8 i~.5 0 92 78.VHIa. B) cyclotrimerization of thiocyanates. Martin et al. C) convergent synthesis. % Yield.and arylthiocyanates in the pres- ence of acids.4. which is characteristic for sterically-hindered phenols [20].4 ~z-.. The PMR spectra of s3~m-triazines VII. The aromatic ring protons give rise to singlets with intensity 2H at 7. glacial acetic acid (Vllc). i~. % Calculated.1 VII-VIII and X Found. SA) Cyclotrimerization of iminoesters.1 86 4-8 I1.0 11.66 170.6-trimercapto-symm-triazine derivatives Villa and X were also obtained by convergent synthesis. IX. 2.30 ppm. EXPERIMENTAL The IR spectra were taken on a UR-20 spectrometer as a suspension in vaseline oil (III and IV).4.5 0:54 78.hod ) VII !' 310--3tl. (V and VI) or in KBr pellets (VII.4. %=~'/ Chemical (prepara- ~OIR..6-Trisubstituted symm-Triazines 77 919. *In 20:1 benzene-methanol.-:O.62-1.6-trialkyl.5 37(B.0 8. Characteristics of 2.4 4. ethanol (Villa). 15 (A) VII 161--162.42 [38.

18 (heptane).42 (6H. Calculated for CaoH2sNOS: C 73. 1. s.protons) VIII. protons) VIII. CH2').95 (20:1 benzene--ethanol).5. a r o m . 4.protons) *The PMR spectra of Vllb. S 9.46--4.4. H CH2).0.~H 7. 7. Spectral Data for 2. arom. s. C[la) .18 (3tl. %~) In-plane ring deformation vibrations. s lert-C4Ho).0 g (246 mmoles) 2.18 (6H.1 g (55 mmoles) KOH in 45 ml absolute ethanol was added dropwise in an inert gas stream to a stirred solution of 12.8 g (279 mmoles) freshly prepared acrylonltrile was added dropwise with stirring in an inert gas stream over l0 mln to a mixture of 51.28 (6H. a terl-C4H~). N 4.62 (54H.68 (12}t.5_di_tert_butylphenyl)propionitrile (It).6-di-tert-butylphenol were removed at reduced pressure. The residue was crystallized from hexane to give 19.. VIII and X IRspectrum.7 g (13%) nitrile Ic.8.22 (3H. Vllc and X were taken in DMSO-D6.~. A sample of 15 ml 15% aqueous HCl was added to the residue and the organic layer was extrated with two 150 ml por- tions of benzene.5-62~ Rf 0. and evaporated to dryness. ~_(4_Hydr0xy_3. ~) out-of plane ring deformation vibrations. 7. ard. while the spectra of Vlllb and Vlllc were taken in deuterometh- anol. 4. VII 1. dried over CuSO. 7.14 (3H. A sample of 14.74 (12H.protons) 1. SRing "breathing" bands.75 g (50 mmoles) chloroacetoni- trile was added dropwise in an inert gas stream at 5~ The mixture was stirred for 3 h at 65-70~ cooled to 10~ poured into 200 ml cold water. 5.58--4. N 4. OH). s. arom. A solution of 3. 92 .12 (3tJ. mp i13-114~ [24]... The reaction mixture was stirred for 8 h at 60-65~ and then DMSO and unreacted 2.4. 4.6-di-tert-butylphenol [25] in 35 ml absolute ethanol at 5-10~ The reaction mixture was stirred for 30 min at 5~ and then 7. and acidified by dilute HCI to pH 6. TABLE 3. tert-C4Hg). ppm G--H vibrations % 6~ 8a~ %'0-II (CHa.6. H lert-C41Ig). ferl-C4|tg). s. The reaction was monitored and the purity of the compounds obtained was checked by thin- layter chromatography of Brockman grade II alumina with iodine vapor development or on Silufol UV-254 plates with development in UV light.6_di-tert-but71phenol (llb~.6-Trisubstituted summ-Triazines VII. 7.). V-rl .9 g (50 mmoles) 4-mercapto-2.66 (54H. 5. 5. 5.5-di-tert-butylphenyl- acetonitrile (IV [22] as well as 4-hydroxy-3. c. The organic layer was extracted with three 50 ml portions of ether.s. rap 60. The benzene solution was washed with 150 ml waterj dried over CuSO. 4. s .20 (3H. The extract was washed with water. VIII t. The oil was crystallized from 20:1 hexane--benzene to give 6. H 7.8%.0%.5-di-tert-butylphenylthiocyanate (lla) [23] were obtained according to published procedures.74 (54H.5-di-tert-butylbenzonitrile (la) [21] and 4-hydroxy-3. s. s CH.75 (541t.72 (541t.25 (5!t. a OH). Found: C 73. cm"I 'Vs' ~"a s triazine ring Vc-o PMR spectrum. S 10. mp 110-112~ Rf 0.14 (6H. and evaporated to dryness. 7. 4-Hydroxy-3.1. m CH2--CH2). m CI-12--CH.56 (6H. 5. s OH). s.~). atom. atom. f- VII. OH). 4_Cyanomethylthio_2. 3.0 g (120 mmoles) KOH in 150 ml dry DMSO.18 (6H. s.protons ) VII ~ i. OH).57 g (51%) nitrile lib.22 (6H.3.6-di-tert-butylphenol and 6.

dried over CuSO~.3. S 11. H 7.5~ Rf 0.18 ppm (IH.6-Trisubstituted symm-T~iazines (Vlla-c.5~ The ethereal layer was separated. The reaction mixture was maintained for 1 h in vacuum created by a water pump on a steam bath.66 (18H. A mixture of 30 mmoles ethyl iminoester Va-c or Vla'c and 3 mmoles of the corresponding iminoester hydrochloride was heat- ed at 90-95~ for 20-25 h with protection from atmospheric moisture. dried over CuSO~ and evaporated to dryness.5-di-tert-butylbenzoic Acid (IIIa). N 4. IVa-c was filter- ed off and dried in vacuum over KOH (Table i). PMR spectrum of iminoester Vc (in CCI~): 1. Found: C 74. 4. Villa-c). IVb or IVc in 300 m! ether or methylene chloride at 0.27 g (i0 mmoles) hydrochloride IIIb in 120 ml dry ether at 0~ and stirred for 1 h at O~ T h e precipitate was filtered off. Calculated for C~6H=3NOS: C 69. Ethyl Iminoester of 4-Hydroxy-3. t CH3).20 (IH.2. The dark oil isolated was extracted with I00 ml ether. s.5-di-tert-butylbenzyl chloride in 50~ml ethanol was added dropwise to a stirred suspension of 19.1. t.3. and evaporated in vacuum. The extract was washed with 50 ml water. The organic layer was extracted with three 75 ml portions of ether. mp 97-990C.4%.5%. H 7.5-di-tert-butylphenylacetic Acid (Vb).6-Tris(4-hydroxy-3. s. 8. The PMR spectrum of Via in deuterometh- ano!: 1. OH). NH). Ethyl iminoester Via was obtained analogously. Hydrochloride Salt of the Ethyl Iminoester of 4-Hydroxy-3. The residue was crystallized from heptane to yield 10. The solvent was removed at a water pump and the residue was subjected to chromatography on a 3. s. OH). q. CH2CH=). The residue was either crystallized from aqueous ethanol (Va) or subjected to chromatography on a 3.4 g (200 mmoles) potassium thiocyanate in i00 ml ethanol. mp 42-43. The reaction mixture was cooled to 20~ and poured into !00 ml cold water. The extract was washed with i00 ml water. The reaction mix- ture was heated at reflux with stirring for 2 h and then. The extract was washed with water. NH). m.12 (2H. Rf 0. Three drops of concentrated aque- ous KOH was added to a stirred solution of Ii. B~ Five drops of concentrated sulfuric acid was heated to a solution of 4. A sample of 35 ml 10% aqueous KOH was added dropwise to a stirred suspension of 25 mmole ethyl iminoester hydrochloride IIa.2 g (54%) thiocyanate IX. 1. IIIc. 5. The residue was treated with dry ether. S ]1. OCH2).5-di-tert-butylphenylthio)-symm-triazine (VIIIa). 4-(B-Cyanoethyl)thio-2.24 (2H.4. tert-C~Hg). cooled to 20~ poured into 200 ml cold water and neutralized with dilute hydrochloric acid to pH 7. A sample of 150 ml cold water was added to the residue. CH~).6 g (12 mmoles) Ia in 40 ml absolute ethanol and 20 ml dry ether.12 g (12 mmoles) triethylamine in i0 ml ether was added dropwise to a stirred suspension of 3. tert-C~Hg).48-4.4. q.0 g (46 mmoles> 4-mercapto-2.22 (3H.6-di-tert-butylphenol(I~Ic).24 (heptane).4.5-di-tert-butylbenzylthiocyanate (IX). 5.0. N 5. H 8. A solution of 34.5 • 50 cm alumina column with i0:i benzene-- methanol as the eluent.72 (4H.2 (18H.34 (2H.12 ppm (IH. The solvent was removed at a water pump. The organic layers was extracted with three 50-ml portions of ether. IIIc. 2. s. s. A sample of 1. s. dried over CaCI2 and evaporated to dryness. Hydrochloride Salts of Ethyl Iminoesters IIIb~ IIIc~ IVa-c.52 (20:1 benzene-methanol).6-di-tert-butyl - phenol in 60 ml dioxane and then. Calculated for C=~H25NOS: C 74. The residue was sub- jected to chromatography on a 3.2. A stream of dry HCI was passed for 2 h at I0-15~ through a stirred mixture of 4.7%. The precipitate was filtered and dried in vacuum over KOH. Ic. Ethyl Iminoesters of Acids Va.5 • 75 ml alumina column with I0:I benzene-methanol as eluent (Table i). 80-85 ml solvent was distilled off. 2. 18. 4-Hydroxy-3.3. N 4.0 g (15 mmoles) thiocyan- ate IIa in 15 ml dry DMF and heated at reflux for 8 h. The reaction mixture was maintained for 72 h at 20~ and evaporated to dryness at reduced pressure.0. S 93%. s. 4. aromatic protons).3 g (135 mmoles) 4-hydroxy-3.3 g (138 mmoles) acrylonitrile was added dropwise at 20- 25~ The reaction mixture was stirred at 70~ for 5 h.65 (IH. S 9. OCH2). N 4.3. 7. Found: C 69.3.9 g (70%) nitrile llc.5 • 80 ml alumina column with 30:1 benzene-methanol as the eluent (Table 2). The residue was crystallized from aqueous ethanol with activated charcoal to yield 20. 7.34 (3H. Vc. 93 . VIb and Vlc.52 (2H.1. washed with 120 ml water and dried over CuSO~. s. aromatic protons).9. 4. H 8. A stream of dry HCI was passed for 1 h through a stirred mixture of i0 mmole nitrile Ib. IIa-c and 12 mmole ab- solute ethanol in 30 ml dry ether at 0~ The reaction mixture was maintained for 4-5 h at 200C and cooled to --15~ The hydrochloride precipitate of IIIb. 8. 7.

12.. S. N. Pliev. Khimiya. 4. Izd. Nauk SSSR. Shvekhgei- mer. E. Soedin. 5. US Patent No. and G. V. Shvekhgeimer. No. 81. Hotelling. A. V. 46. 1557 (1985). US Patent No. Goncharenko. washed with 150 ml water and then with 100 ml 2:1 ethanol--acetone to yield 23. Chem. B. Khim. Sterically-Hindered Phenols [in Rus- sian]. 47. and V..197. G. The organic layer was extracted with three 50 ml portions of ether and dried over CuSO~. 6. B. 21. Khim. E. 2401 (1983). 32.. Kelarev. Mir. 9. 12NI82P (1976). A. 16. 1333 (1957). H. E. 594. Org. 13. 1076 (1977). Soedin. 1678 (1984). IR Spectra and the Structure of Organic Compounds [Russian translation]. F. Bauer. Kelarev and G. Avram and G. N. Neuwort. Cohen. Geterotsikl. I. and A. Abstr.862.. Obshch. Org. 4. 7.4. Yakubovich. Infrared Spectroscopy. im.. F. 31.453. 105575 (1974). and J. West German Patent No. F. Malova. Zaitseva. Shvekhgeimer. 17. A. Moscow (1965). 12. Pankratov. L. Muller. L. No.25 paraformaldehyde in 30 ml glacial acetic acid. p. Previc. 527.939. 2. I.1 g (69. J. A.8 (130 mmoles) 2. Anorg. Org. V. 124 (1970). 408 (1974). V. 3409 (1962).2 g (67%) symm-triazine VIIIa. Koshelev. Ushakova. 24. Boitsov. The solvent was distilled off and the residue was crystallized from ethanol to yield 5... Chem. and M.. F. 3. P. Izv. N. Schaefter and P. A. A. Zh. Mikaya. and A. 24. Khim. B. 88. Physical Methods in Heterocyclic Chemistry [Russian translation]. Mendeleeva. M. and M. US Patent No. V.84 g (i0 mmoles) cyanogen chloride in 25 ml acetone. S. mp 210-2]I~ (from ethanol). J. and then 13 ml 20% hydro- chloric acid was added. M. I. J. 23. 53. 94 .. VUZov..4. Akad.-G. Ukr. Ammar Dibi.. Moscow (1972). 22N243P (1975). 22. V. An ethanolic solution of potassium mercaptide obtained from 8. Allenstein. K.. Knell. 3. Lunin. Braz. Kornienko. Khim. Zh. 645. V. O. Khim. 645 (1980). p. A~mar Dibi. 582 (1982). Geterotsikl.). 38. P. Khim. 20. 15. Org. Chem. Hattescu. Khim. Scheffler. I0. 2778 (1961). 2. The reaction mixture was heated at reflux for 3 h. G. The reaction mixture was stirred for 6 h at 45~ The precipitate was filtered off. Khim. Kelarev.14 g (40 mmoles) 2. Zh. 14. Lunin. P. Teknol. I. and S. N. Chem. Windgassen. J. Khim.-G. T. Gaspari.6-di-tert-butylphenol in 80 ml glacial acetic acid was added with stirring to a suspension of 7. Usp. Vishnyakova. T. A. V. Ser. No. Bazov. I. Chem. R. Brunetti. L. Ershov and I. M. 37. Katritzky (ed. P. The filtrate was poured into 100 ml water. Ref. A. Khim.155.14 g (30 mmoles) 4- mercRpto-2. Zh. Kelarev. E. R. V. 19.5-di-tert-butylbenzylthio)-s. I.68 g (30 mmoles) KOH in 30 ml absolute ethanol was added dropwise to a solution of 1. US Patent No. Chem.. Zh. D. ii. 62782 (1972). Volod'kin. Wiley-lnterscience (1970). Z. V. I. 77. Ann. W. ii.038. E. Nikiforov. 20. B. 1129 (1971). A. B~ This compound was obtained by analogy to symm-triazine Villa from thiocyanate IX in 37% yield. C. Stegmann. 2. V. Grilles. L. 19. 22. 5.942. Ref. V. Soedin.905. P. G. Zh. Chem.8 g (45%) symm-triazlne Villa. 3. Ostroverkhov. Belostotskaya. 26. H. Abstr. 8.6-di-tert-butylphenol and 1. and A. Martin. C__~. Vishnyakova. 3. V. Shvekhgeimer. D. Izd. Finkel'shtein and E.. Lunin. Spektroskopii. Petrova. 1496 (1962). 27. Ershov. G. M. Rodzum. I.5%) symm-triazine X. Obshch. M.. I. Usp. Khim. Prikl. E. i Khim. 26. Abstr.. 25. A.6-trimercapto-symm- triazine and 7. A. No.. 81. Glebova and T. Mir. p. p. Grace. Khim. 2. Ya. lzd. 18. 52833 (1978). Vses.The residue was subjected to chromatography on a 3. and K. 376 (1965). Moscow (1966). mp 195-196~ C__z A solution of 27.006. and A. mp 194-195~ LITERATURE CITED i. Izv. A. Khim.5 • 50 ml alumina column with 10:1 ben- zene-methanol as eluent to yield 1. 79 (1961). Geterotsikl. A. cooled to IO~ and the KCI formed was filter- ed off. Golubeva. Dexter.vmm-triazine(X ) . A.. Khim. J.. and V.. 1598 (1959). 13. R. Nakanishi. Weidhein. Klemehuk. F. 1814 (1978). Lunin. V.6-Tris(4THydroxy-3. V. I. M. Manor. Kelarev.

and xantho- tricine and their structural analogs [4-6] having antiviral activity [7]. [8] have shown that 3-azido derivitives of benzotriazine cyclize in solution mainly to give the angular tetrazolo[5. S. On the other hand.2. by a n a l o g y t o t h e s t u d i e s o f Messmer [8] and B o g a t s k i i [9] f o r t h e c y c l i c f o r m .2. 0009-3122/86/2201-0095512. 5-methylpyrimido[4. Sidorov. the lack of reliable data on th~ nature of the ring fusion of the tetrazole ring in 1.2. The present study is a continuation of our previous work [1-3] on the physicochemical properties of pyrimido-as-triazine antibiotics including rheumacine. Original article submitted November 20. E. o 0"" N ~ ' N "N 0 "N "N >:N 0 N N N-=N=rN I I I I i CHI CIII N :n-~:N CH 3 la I b IC I n o u r p r e v i o u s w o r k .4]triazine-6. Klyuev. we studied the molecular and crystal structure of this com- pound by x-ray diffraction structural analysis and established that the tetrazole ring is fused with the as-triazine ring at the C(~)--N(4) bond (structure la) and not at the C(~)--N(8) bond (structure Ib.2. Fig.-b]benzo-as-triazine is observed in highly polar aprotic solutions. Yu. Translated from Khimiya Geterotsikliche- skikh Soedinenii. Esipov The structure of the tetrazole. Moscow 113105. In the present work. G.2. a uracil ring (A).4]triazine-6.2.5-b ]pyrimido [5. O. No. Aleksandrov.8-dione. In addition.5-e][l.26:547. 4-triazine [i0]. UDC 539.4]tri- a zine-5. 5-p-chlorophenyltetrazolo[l. no data were given on the state of the azido--tetrazole equilibrium for this iso- mer pair or for the PMR and UV spectra of the azido derivative. Nishigaki et al.8-dione (la or Ib) in the crystalline state and elucidated the differences between the cyclic form (la or Ib) and its isomer (Ic) in the aizde form relate to dissociative ionization upon electron impact.4-triazine exists in crystals as the linear analog.4-3][l.2. Dione la consists of three planar condensed heterocyclic rings. Sverdlovsk 620002.8-DIONE AND ITS AZIDE IN DIFFERENT PHASE STATES N. The effect of bases on this equili- brium was discovered.4-e ]-a s-triazine- 2.2. Azev.8-dione was established by x-ray structural analysis. fervenuline.r a y d i f - fraction structural a n a l y s i s h a s shown t h a t t h e t e t r a z o l e isomer of 3-azido-5-p-chlorophenyl- 1.5-e][l.4-triazines requires a special study in each specific case. 3-dimethyl te trazolo [4. A. pp.2.4]TRIAZINE-6. 1984.l-c]benzo-as-tri- azine and only a small amount of linear tetrazolo[l.5-b]-l. as-triazine ring (B) and tetrazole ring (C. Recently. i. The tautomeric equilibrium with its azide isomer in solution was examined. we a d o p t e d t h e a n g u l a r s t r u c t u r e (Ib) for both the crystalline and g a s e o u s s t a t e s of this molecule. January.STRUCTURE AND SOME PROPERTIES OF TETRAZOLE 5-METHYLPYRIMIDO[4. Thus.5-e]- [I. A.4-dione but they did not present melting point or elemental analysis data for this compound. In order to determine the nature of the condensation of the tetrazole system in pyrimido- [4. M.4]triazine-6. py- rimido[4. x . Thus.859. i). 114-120.5-e][l. G. Table I).8-dimethylpyrimido[5.5. namely. T h e r e i s no common o p i n i o n p r e s e n t l y i n t h e l i t e r a t u r e concerning the na- ture of the cyclization of the 3-azido group in 1. we established the nature of the ring fusion in the tetrazole. and S. Messmer et al.1 E.2'866o796. Kirov Urals Polytechnical Institute.4-triazine derivatives.7-dione cycl izes to linear i. The structural results were compared for isomers la-c (taking account of possible tautomerism) for different aggregate states.50 9 1986 Plenum Publishing Corporation 95 . 1986. Analytical criteria were proposed which permit identifica- tion of the tetrazole and the azlde forms in the gas phase. and has a All-Union Scientific-Research Institute of Antibiotics. [Ii] studied the UV spectra of model azolopyrimidopyridazines and found that 3-azido-6.

Messmer et al.91(5) ~.0L'3~ 9 .070 N(4) N(5) N(6) N(7) C(4) N(8) 0. i) indicates the electron delocalization usual for such conjugated nitrogen-containing heterocycles: All the formal single C--N and N-N bonds are shortened while the double bonds are extended relative to the standard values: C-N.4160 2. */s + z) and O(a).o.)-O(~) [1.90~ --0.071 0. B/C = 1.~. C~N. N=-N. The some- what greater C(z)-O(a) bond length [1.186(8) ~] is a con- sequence of the participation of O(a) in hydrogen bonding.021--0.004 C(s) O*(i) 0"(2) C*(m 0.x.010 0..0077 . 1.+ . i . i. 1.009 N(4) N(5~ Nt6) N(z) C(~) 0.4126 2. 1.035 0.5 ~ with rings A and C.+ TABLE I.000-0.038-0.. 2.219(7) ~] relative to C(.007-0..l-e]-as-triazine.170 0. 96 .011 0. */a + z) [N--H0.O. Crystalline azide and tetrazole isomers are sometimes capable of interconversion.010 0. respectively. Fig.91C -0.005-0.x.3'-diazido-5.002 --0.0324 -0.4839 -0.--. i -. <[N--H.3-3]tetrazole[5.043 0. Planes A.+-?:+.) N(~) C(2) C~3. co ~ ' . The plane of the central ring B forms dihedral angles of 1.5'-bis-as-triazine [14]. highly compressed boat conformation.29 ~ [12].. Equilibrium between these isomers is es- tablished in dimethylsulfoxide solution.3-3]-as-triazine spontaneously converts to solid pyrido[2.020 *Atoms not included in the calculation of the corresponding plane. A unique case of the conversion of the tetrazole isomer of naphthothiazole upon heating to the aizde isomer and the reverse process upon cooling were noted by Postovskii et al.010 0..001 --0.0228 -0.016 0. 1.91(5).8.021-0. A Plane Atoms A N(u C(.001 0..y.109 -0. [13] noted that solid 3-azidopyrido[2.N. N~a) 0..007 0. The bond length distribution in Ia (Fig.8 and 1.O(a) (*/= -.~%3.908 -0.007 0.020 C(s) O*(1) 0*(2) C*(8) -0.013 Nu) C(..y..0000.:.474| N--N.008 0. A/C = 3.047 -0.O. Irreversible conversion to the tetrazole isomer occurs upon heating crystals of 3..4193 2.4161 2.) N~2) Ct2) C~3) 0.. axes parallel to the c-axis. 1. .001--0.0092 -0.5 ~ . H. The reverse process of the conversion of solid tetrazole derivatives of quinazoline to azide derivatives has also been noted [15]. Thus. and C form the dihedral angles: A/B = 1.000-0.451. Bond lengths and angles in la~ :.907 0. 168(2)~ which leads to the formation of spirals of la molecules about 2.2103 0.25.006-0. %~ 7~.2.0017 -0.H--N a (I/a -. _ + -+ .006 0.0.2999 -0.. B.O.819(7). Each molecule of la in the crystal participates in the formation of two intermolecular hydrogen bonds: N(a)--H. Coefficients of the Plane Equations Az + By + Cz -- D = 0 of Several Planar F~agments of la and Deviation of the Atoms from These Planes.028 0. ~ :L ~ BO } ..014 -0. [16].

N d +" (~.N2] + was discussed in our previous work [3])..0167 5o5(~64) ..a . The appearance of these ions is probably not dictated by ion-- molecule reactions (1-10 -7 tort vacuum) although some workers have made such conclusions [20]. .. 2.3) [ q h .0388 192..0351 --~-320 (121.. there are no isomerizational processes for azide Ic and tetrazole Ia under the conditions of direct inlet to the ion source (150-170~ injector temperature) as indicated by the different values of the IE a n d P E of the [M-. .. 80 60 192 M+" 4O 2O 0 40 60 80 100 120 140 160 180 200 220 Fig.1) 81. . .. . -+392 (94. /3max 9+o 100 93 la M§ 41 8O 6O 40 ]3 67 81 94 ] [ 192 l 2O 121 164 1 100(0) .0449 220..+ 3 7 3 (121..) 192. . TABLE 2.. ~. .5-e][l..0462 C..I ICNp !)1. ... The ion composition was found by high-resolution mass spectrometry (Table 2).. Mass spectra of isomers Ia and Ic.0326 504 (t21) . .0455 C611sN402 166. V)] M§ 220.0491 506 (192) ..2.0174 94.. we must study the possible interconversion of these compounds in the gas phase.0143 C4H2N~O 94. . .0538 C6fI6N602 194. . The DTA curves for each compound differ and there are no peaks for ther- mal isomerization effects which should be observed in temperature ranges excluding change in the sample mass (TG and DTG curves). .l .0292 CslIaN30 121. #Calculated mass of the daughter ion (m/z)..0326 [--~387 (92.. it is more realistic to assume the addition of a hydrogen atom to the nitrene *The lack of interconversions upon heating crystals of I and Ic was indicated in a thermo- gravimetric study... .. 2).0351 C~I14N402 164.lll .. . Precedents exist for such isomerization [17.0364 161...0399 CstI4N~O~ 192.0457 [ ( M .4) leD2-I!NCO] +" (OOa) 121.N2] + ions upon photoionization [3]~ This finding indicates definite differences in the nature of the fragmentation of isomers Ia and Ic and requires detailed examination of their mass spectra (Fig. The fragmentation sequence of the molecular (M+) and major fragment ions for Ia and Ic was established relative to the mass spectra of the metastable ions obtained in the secondary fieldless space on a "reverse geometry" spectrometer (DADI/MIKES technique [19]).N21+" I{l}.0333 C4H~N3 93. .0290 121.1) [ { P a .9) *Parent peak (m/z)..0395 506 (220)* +441 (191. In our opinion.7) [(d}..-N2) +21tl ~" 166.0308 CaI't3Na 81..0552 [ M .0340 93. I.) 164.8-dione and Their Met- astable Ion Mass Spectra Measured Ion Calculated Mass spectra of metastable ions [de- Ions composition flecting voltage of the electrostatic la 1C sector (E0 and El. 18].H4NsO2 220.0270 ---+248 (94.CO] ~" 93. .I .1) [qba .. 3 o.-i . prior to examining the analytical aspects of the mass spectrometric fragmentation of isomers Ia and Ic.. Figure 2 indicates that the major difference in the nature of the fragmentation of azide Ic relative to tetrazole isomer la lies in the detection of ions with m/a 194 and 166 (the difference in the ratio of the intensities of the peaks of ions M+/[M -.N~) +2HI +" 194. However. Hence. . Elemental Composition of Ions Indicated by the High-Resolution Mass Spectra of Tetrazole (Ia) and Azide (Ic) of Pyrimido[4. 97 .4]triazine-6. +433 (164...

.4 (2: 2.i .~ 5391 (6' 7804 (5)] 7290(8) i 4.7 (2) 3. |C4H2N20]+" 220 0 N N N +' ~ 94 l "" / CIt3 ~ /-HCN / t _N2..N=) + 2H] +.2 (2)1 0. The appearance of the other fragment ions is related to the decomposition of the ~ ion. (3) 3.l{3) 3.0 (3~.0 (2) o. 4.1.9 (2) 3J (2 0.9 (3) N(7 4951 (if.0 (31 6. 3.6 (3) '2.5 (2) 3.[ (2j 0. The formation of amines was observed in the thermolysis of tetrazoles [17].1 (21 4.0 (2)I-0.6 (3) 3.1 (3) 0.4 (2 0.3 (2) -0.2 (2)I o.1 (2}1-o. and %3.. The #s ion and ions with m/z 94 and 93 (Table 2) arise as the result of one-.8 (4) 0.I} 2924 (5 8139 (4)1 448 (6'.4 (31 0.8 (2 0.4 (2)]-0. +2B=~klb*c~)] .2 (2)'.3 (3) 3.o (3) 3.37 and 3.00 ppm disappears). 0. Information on the azide--tetrazole equilibrium in solution was obtained by PMR spectro- scopy.3 (2)] 0. i H Ctt3 @~ 93 @2 These results indicate that la and Ic in the gas phase have structures analogous to those in the crystalline state (Ic is apparently associated in pairs). The addition of hydrogen to the nitrene in this specific case is apparently accomplished by migration of hydrogen atoms upon the thermal decomposition of the dimeric or trimeric aggregate of Ic existing in the gas phase.37 ppm increases and that of signal at 3.7 (3) 3.o (2) 02 (2) N(4) 4558 (5 7010 (5)I 4995 {6] 3.4 (2) N{~ 2534 (5 6309 (4~1 -454 (71 3. ~ -N2'-HNCO'-HCN M + (la.5 (2) 3.0 (3) 0._ItNco :+'" "" L ~ --.2 (2) I-<3 I2) C(~ 2404 (61 7417 (5)1 -847 (8) 3.I < +.3 {3'.1 (21 0.4 (2)1-o..2 (2)1 0.2 (2) C~4 4447 (71 8131 (5)I 4730 (8) i. This hypothesis is supported by the increase of the peak intensities of the ions with m/z 192 and 194 over time and the lack of me(as(able transition from M + for the ion with m/z (Table 2). 8605 (4)I 6190 (41 5.3 (2) 0.0 (3) 3.3 (2! 1.3 (3) C~5 3495 (6} 7810 (4)1 2054 {8) 3.8 (3) 5. 6. Upon the addition of a few drops of CF3COaH.00 ppm.7 (2) 3.2 (2) N(5 5177 (61 6811 (5)I 6599(7) i 4. the [M -.8 (2) O{2~ 2980 (5 4871 (311 1365 (ff 6. TABLE 3 .7 (3) N..8 (3) 4. Thus..5 (3: 0.2 (31 o.2 (2) C~6 2794 (8) 9316 (5}1 78 (9) 5.. Atomic Coordinates (xl0 ~. which proves the identity in structure and energy parameters (release of the same kinetic energy) for ions ~.3 (3) 3. the PMR spectrum of la in DMSO-d6 has two singlets with ~ 3.0 (2'.3 (2) I o.5 (31 03 (2)1-0.5 (3'. Atom B. xl0 ~ for H) and Their Anisotropic Temperature Factors T = exp[-i/4(B**h~a*~+.7 (3) o.2 (2) N.0 (2)i-0. 4.8 (2) 3.7 (31 0.Na] + (~i) arises both due to dissociative ionization and thermolysis leading finally to ionization of the nitrene and its amine addition product [(M-. B=~ B~= I Oql) 1902 (5 7724 (3ti-2219 (6 5.6 (21 2.2 (2) 3.57 ppm decreases (the signal at 14. The possible existence of such aggregates was noted previously for derivatives of tetrazole [22] and pyrazole [23].3 (21 0.6 (3 o.7 (31 03 (3) I o8(21 ' .9 (3) 3. The metastable ion mass spectra obtained for isomers la and Ic coin- cide fully..3 {3} 3.8 (31 0.0 (2 2.0 8 (3) N~8 391l (51 8533 (4~1 3225 (7} 4.4 (3) -0. or two. The following decomposition scheme illustrates the formation of the major ions: o -N2 ~HN ~ 2 ~ .o (2) C~3 3898 (6) 5637 (4)1 2405 (8) 3.4 (3)j 0. 21] formed exclusively from the azide form upon the loss of an N2 molecule as a re- sult of thermolysis.and three-step reactions. the in- tensity of the signal at 3.3 (2) -0.2 (2) 0.9 (2 o. [17.6 (3L-0.1 (21 0.5 (2) N~s) 4137 (5 6237 (4)1 3856 (6: 3.3 (3)]-0.3 (3) HN<~ 241 (5) 586 14~I-142 (7) $ H(~2) 227 (5) 971 (4)1 107 (7) H{~) 223 (5) 948 (5)1 -107 (7) 377 (5) 962 (4)1 --5 (7) $ ~Value of B. in azide Ic. The downfield signal apparently is related to the NH group 98 .2 (2: 3. ~=..3. Thus.9 (4) 2. 18.2 (2 0.4 (2' 3.57 ppm a n d a broad signal with 6 14.6 (3) 3.IO ----~ j ~i.o (2) 3oo8 (71 5850 (5}1 I079(8) 3.

I.2. E. 6. Bogatskii. Bondar'. at 35~ we find 65% la and 35% Ic. Goodman. Azev. Verreshchagina. while the interconversion of the intensities of the signals at 3. EXPERIMENTAL The electron impact mass spectra were taken on a Varian MAT-311A mass spectrometer under standard conditions with 70 eV ionization energy and 1. 44. V. Khim. A. G. 16. L. I. M. Esipov. Yu. A. Ya. 7. A. J. E. N. and L. *Only the positional parameters were refined for the hydrogen atoms found in the difference map with fixed Bis O = 5. I. A. The x-ray diffraction structural analysis was carried out on a Syntex P1 four-circle dif- fractometer using ~CuKa radiation.7-dimethylpyrimido- [4. N. and A.. E. No.01 V error in the measurement of the peaks on a digital voltmeter.-farm. PFC standard and 0. Goleneva. I. Arzneimit. 41. A significant shift in the Ic § la equilibrium toward tetrazole la (A = 15%) is also observed in aqeuous solution upon the addition of an equimolar amount of sodium azide. and N. J. and V. Khim.254(3). 1823 (1979). Tamas. Saburova.0 mA cathode emission current. A. N. Carlin.. Danilina. The azide--tetrazole equilibrium is established most slowly in dimethylsulfoxide solution (4-5 h). S. 573 (1984). Yu. the equilibrium is shifted toward the azide. V. The PMR spectra were taken on a Perkin--Elmer R-12B spectrometer at 60 MHz with TMS as the internal standard using the 6 scale.288(2). there is a shift in the tautomeric equilibrium toward the azide. at 35~ we find 91% la and 9% Ic. 0rg.57 ppm upon acidification reflects the conversion Of the tetrazole isomer to the azide isomer. N.. N.056.5-e][l. R. Soe- din. S. 547 (1983). Forsch. Thus. Messmer. Soedin. Zyakun. Postovskii. and Yu. 4. Moscow (1981).. c = 7. 8. A. The structure was solved by the direct method and refined by the method of least squares in the anisotropic full-matrix approximation* to R = 0. Goleneva. Zh. F. Azev. C.8-dione. M. Chem. Since only signals for la and Ic are seen in the PMR spectrum. The accelerating voltage was 3 kV and the injector temperature was 150-170~ The high-resolution mass spectra and the mass spectra of the metastable ions were measured on the same instrument. 1122 (1966). S. 2860 (1976). 9. The M/AM resolution was 15.-farm. Geterotsikl. The atomic coordinates and temperature factors are given in Table 3. Pid~mskii. Adanin. L. I. Upon increasing the temperature of the solution of la.. Khim. PMR spectroscopy may be used to observe the formation of azide form Ic from an auth- entic sample of linear tetrazole la. A. Azev. Andronati.. Geterotsikl.456(2) ~. I. 4. graphite monochromator. 1270 (1979).000. In aqueous solution. Goleneva.. Klyuev. M. N. Rw = 0. The unit cell parameters of ~rthorhombic crystals of la are a = 9. Pid4mskii. while at 140~ we find 67% la and 33% Ic. F. G. M. 0rg. Org. 99 . A. Paudler. No. 2. 13. Chernyshev. I. 5. Kuech]er. 50 (1981).0 A=. and W.. Khim. Nessmelyi. L.2~. Makarov. L~ Atwood. W. J. 16. Minina. 39 (1980). L. 18. Khim. Klyuev. Kuechler. Zh. M. and A. Hajos. A. in: Ab- stracts of the All-Union Symposium on Magnetic Resonance in Biology and Medicine [in Rus- sian]. 14. J. 15. 9. It is interesting that in the case of 3-azido-5. Ya. Esipov. i0. V. A. Zh. Postovskii. A.2. Azev. at 35~ we find 32% la and 68% Ic. Yu. M. The tetrazole isomer predominantes in pyridine. Pid~mskii. p. Ya. z = 4. The thermal analysis was carried out on an MOM derivatograph under the conditions de- scribed in our previous work [18]. Aleksand- rova. 8/2e scanning (2 ~ ~ 2e < 120~ A total of 614 reflections with F 2 > 2o were recorded. W. and A. Hunter. Z.049.4]triazine-6. Heinisch. Chem. Postovskii. ]773 (1977).. Zhilina. we may conclude that angular tetrazole Ib does not exist in solution. space group P2. Zh. ~ = 12. E.37 and 3. N. F. LITERATURE CITED i.72 g/cm 3. Verreshchagin. A. and A. At 100~ we find 77% la and 23% Ic. V. At 60~ we find 89% la and 11% Ic.proton in the uracil fragment. Adanin. 3. E.-farm. Khim. the fraction of the tetrazole isomer [4] in pyridine is 15% less than for the monomethyl derivative la. d c a l c = 1. and G. E. A. Kazakova. A.

Chem. Sirotkina. Academy of Sciences of the USSR. Tomsk Institute of Petro- leum Chemistry. A. V. N. D.. 433 (1969).50 9 1986 Plenum Publishing Corporation . A. 2218 (1977). 33. N. and K. J. 16. D. Flammang. Nishigaki. G. Obshch. 10-ALKENYLPHENOTHIAZINES. Dokl. p.4: V. Postovskii. I.952. i. Ya. 12. pp. E. F. Khim. Polzunov Altai Polytechnical Institute. Org.TRANS-ISOMERIZATION OF 10-PROPENYLPHENOTHIAZINES V. A. Ichiba. Forkey and W. A. A. R. Maque. I. UDC 547. Anfinogenov.634 A study was carried out on the isomerization of lO-allylphenothiazine (I)in DMSO by the action of t-BuOK. E. and L. The effect of the t-BuOK concentration. we studied the isomerization of 10-allyl- phenothiazine (I) in DMSO by the action of t-BuOK. Novosihirsk (1982). Hajos. 575 (1973).. J. Un- der conditions of kinetic control. I. Zh. Fraser and G. Khim. Org. Org. 20. 85. Benko. Postovskii and I. Senga. Org. 1422 (1984). January. Benko. Filimonov. 19. 13. A. and V. P. E. G. The isomerization proceeds stereo- specifically at room temperature by the action of t-BuOK at an elevated temper- ature by the action of KOH and NaOH to give cis-10-propenylphenothiazine (II). Grandberg.. M. Mmquestiau. Barnaul 656099. Khmel'nitskii. Of the N-akenylphenothiazines. i. 17. and I. 15. Kost and I. C. S.. N. Kirov Tomsk Polytechnical Institute. There has only been mention of 10-propenylphenothiazine obtained by the multistep procedure in the proof of the structure of the product of the alkylation of phenothiazine by l-chloro- 2-dimethylaminopropane [4]. Ya. Klyuev. A. Lobanova. M. Goncharova. Heterocycl. No. Chem. Rusinov. N. and L. 179. temperature and reaction time on the isomeric composition of the 10-propenylphenothiazines formed was studied. i0. N.. and V. Wentrup. c. R. I. In order to obtain lO-propenylphenothiazine. 1628 (1983). 16. Carpenter. Yu. Siberian Division. Zyrayanov. only N-vinylphenothiazine has been studied in considerable detail [1-3]. Lipatova. i n : Abstracts of the All-Union Conference on Aromatic Nucleophilic Substitution [in Russian]. New York (1966). R. A. p. Postovskii. Soedin. I00 0009-3122/86/2201-0100512. KOH and NaOH. Napilkova.and trans-10-propenyl- phenothiazine with 44-45% trans isomer III. SYNTHESIS AND CIS. Klyuev. ~. 115 (1981). Translated from Khimiya Geterotsikliches- kikh Soedinenii. 23. 21. V. 22.ii. Tyurenkova. The base-catalyzed isomerization of N-allylamines is commonly employed in preparative or- ganic chemistry to obtain N-allylamines [5] but this reaction has not been studied for thia- zlnes. 48. 26. which Isomerizes under the re- action conditions to give an equilibrium mixture of cis. while the homologs of this compodnd have not been described in the literature. Zh. 2334 (1963). Messmer. I!I (1968). Akad. 121-124. Ya. 19. 1986. Special Publi- cation No. Tomsk 634004. 4969 (1970).. 1984. M. A. E. I gives II. Geterotsikl. Tetradedron. KOH and NaOH. Original article submitted November 21. I. London (1965). P. L. A. I. D. 347. Yu.. 6. No. Wentrup. Chem. Konchits. O. Tables of Interatomic Distances and Configuration in Molecules and lons. The isomerization temperature has virtually no effect on the II/III isomer ratio. 14. 34. 18. K. Azev and N. Nauk SSSR. Advances in Heterocyclic Chemistry. V. N. J. Org. R. I. Mass Spectrom. 4118 (1969). A. 18. Istratov. 13. Shurukhin. Ogorodnikov 541. Mass Spectrom.869. Vol. Tomsk 634055 and S. Gradnberg. Khim.. and R.2:542.

15 mole/liter and the reaction is complete in this case in 15 min. the reaction rate reaches a maximum at a catalyst con- centration of 0. PMR spectroscopy at room temperature indicates that the reaction proceeds with high steric specificity to form exclusively cis isomer II. ~ Time. The time for total conversion is 4320. s \ i.. The trans isomer III appears in the reaction mixture at 70~ and its content after 5 h reaches 39%.oo = 0. . pure cis isomer Ii gives a mixture of cis and trans isomers II and III with approximately the same composition..049. The effect of temperature and reaction time on the ratio of isomers II and III was eval- ulated relative to the integral intensities of the methyl group signals in the PMR spectra (Table I). Hence. A further increase in the reaction temperature to 150~ increases the con- tent of III to 44-46%. . this is apparently related to the greater thermodynamic stability of cis- isomer II relative to the trans isomer III. temperature has virtually no effect on the equili- brium constant (K) which was found to be 0. The high thermodynamic stability of cis isomer II relative to trans isomer III distin- guishes lO-propenylphenothiazine from previously studied 9-propenylcarbazoles.C ~ C l t a I 11 1II The isomerization both by the action of t-BuOK and KOH or NaOH gives the complete con- version of phenothiazine I to a mixture of isomers II and III.. % 5O 300 l oo/o 7O I0 84/16 60 69/3 l 180 62/38 300 61/39 10 77/23 120 59/41 300 56/44 100 10 71/29 180 56/44 300 57/43 150 10 60/40 180 54/46 300 54/46 *Here and subsequently.82 • 0. /. In the presence of t-BuOK. ll" "H 11 ( ...717 N solution in t-BuOH.62 • 0. other products were not de- tected. within experimental error. for which the cis isomer is less stable than the trans isomer due to steric interaction of the methyl group and the planar carbazole ring [7] Our results indicate that the steric interaction i01 . Under analogous conditions. ally]phenothiazine forms II which isomerizes under the reaction conditions to an equilibrium mixture of the cis and trans isomers.15 mole/liter t-BuOK. in which the isomeric purity of the cis-isomers is not greater than 90%. The II ~ III equilibrium is reached 3-5 h after the onset of the iso- merization and. 0. Dependence of the Composition of the Isomer Mixture of Propenylpheno- thiazines II/III on Time and Temperature Upon the Isomerizationofl([l]o = Tempera:' II/III ture. i~ ~ '~ . under kinetically con- trolled conditions. . TABLE i.03 (AG.083. . isomer min ratio. This finding distinguishes this reac- tion in the phenothiazine series from the isomerization of dialylallyamines [6] and 9-allyl- carbazoles [7]. As shall be shown below.. 0. We note that thin-layer chromatography indicates the absence of starting compound I in the reaction solution. z~ "~" ~ " "N " I i s ~ ! II Cl~2Ci'Ia CH a C~-C~ . . U.Ii kJ/mole). II and III. The ef- fect of the amount of catalyst on the time required for total conversion of phenothiazine I at room temperature as determined by thin-layer chromatography is given below. and 0. 75(65) and 15 min for 0. .

~.6.16. the isomerization of phenothiazine I in the presence of KOH and NaOH proceeds stereospecifically both at room temperature and at IO0~ Although the catalytic activity of KOH and NaOH is much less than that of t-BuOK (Table 2).m ].002 KOH (8.mole Catalyst(mole) Temperature. in contrast to t-BuOK. The PMR spectra were taken on a BS-487C spectrometer in CCI~. some twisting of the phenothiazine system in II about the C--N bond leads to a significant suppression of p--. The high thermodynamic stability of cis isomer II relative to the trans isomer of 10- propenylphenothiazine permits us to categorize 10-propenylphenothiazlnes as "anomalous" olefins. %The IR spectrum of II is completely identical to the spectrum of the mixture of II and III. 0.1. TABLE 3.5-7.063 t-BuOK (1.0 -.9.013 NaOH (1.68.6. %Reaction time corresponding to complete conversion of I.d i [ 7.9 10-4) 50 I0 0. l0 -4) I00 270 0. Unfortunately.l0 -2) 60 30 68 0. cm Compound I' '" II III [ H~ 6.251 KOH (2. It is quite obvious that the ster- ic interaction in the extra configuration between the cis-methylgroup and the hydrogen atom at C(. CHa = 1. thus.d Chemical shifts.0l t-BuOK (4. conjugation [7. We should note that. we are not able to give an unequivocal explanation for this inter- esting finding.29. ii].002 KOH (8."I 5. This decrease in the steric strain in II is likely a consequence. J Ha. we should recall that the participation of the nitrogen unshared electron pair in the extra configuration to the total z-electron conjugation is re- duced [I0] and. m 1.10 -~) 25 3600 0. firstly.9. Time.d 6. TABLE 2.5. CHs = 7.6. these hydroxides are conveniently used for the preparation of cis-10-propenylphenothiazine II to their availability and ease in handling. Hz 5. d I 13.5 ~z" %The signals of the phenothiazine protons form a multiplet at 6. the SSCC are: J HB. Conditions for the Preparation of cis-10-P~openyl- phenothiazine II l*.1 ppm.0 I 1657 I i I 945 .10 -~) 25 15 89 0.55. j. The structures of 10-propenylphenothiazines II and III were demonstrated using IR and PMR spectroscopy. of the methyl group and the phenothiazine system in cis-i0-propenylphenothiazine is absent or very weak compared to cis-9-propenylcarbazole. In the study of the effect of the reaction conditions for 102 .t Yield ~ min % of II. The spectral parameters are given in Table 3. ppm t. EXPERIMENTAL The IR spectra were taken neat on a IKS-29 spectrometer. whose cls isomers are more stable than their trans isomers despite steric strain [12-15]. This reaction is efficiently catalyzed by KOH and NaOH in DMSO. Secondly. Spectral Characteristics of 10-Propenylphenothiazines PMR spectrum (CCl~)* IR spectrum ~. [ -- eFor compounds II and III.10 -2) 60 60 64 *5 ml DMSO per g I.0. of the non- planar structure of the phenothiazine system [8] and the quasiaxial orientation of the sub- stituent at the nitrogen atom (extra configuration [9]).) of the nonplanar heterocyclic fragment in isomer II is less pronounced than in planar cis-9-propenylcarbazole.

Bjorkquist. Sirotkina. Rodionov and V. LITERATURE CITED I. A. 23. Gorbachev. 832. the spectra were taken in benzene. Shostakovskii. Bailerge. 34. L. 4. A. V. N. V. 38. Magn. Univ. Chem. N. D. Fi!imonov. D. 15. Anfinogenov. Vacuum distillation and crystallization from ethanol give 13. Kurov. 25A. J. L..the isomerization of I on the ratio of isomers II and III. Skvortsova.. R. A. The precipitated oil was extracted with benzene. 178 (1984). V. Found: C 75. Scapini. 1917 (1969). V. D. Khim. M. Soedin. Geterotsikl. N 6. Obshch. E.0. and G. H 5.Propenylphenothiazine (II). H 5. A sample of 5 g (21 mmoles) I and 7 ml 0. Godishnik Sof. 28.2. Samples of powdered KOH and NaOH were used. 225.2%. G. Isomer III could not be isolated from the mixture. cis-10. Soedin. Vysokomol. Naumova. Geterotsikl. 114 (1974). 3. PMR spectroscopy indicated that the solution contained cis isomer II.69 N t-BuOK in t-BuOH in 25 ml dry DMSO was m a i n - tained at 100~ for 1 h. 5 (1976). Khim. Charpentier. G... Acta Chem. Bjorkquist. G. Prahl. Huet. Tetrahedron.51 N t-BuOK in t-BuOH was added to a solution of 15 g (63 mmoles) 10-allylphenothiazine I in 75 ml dry DMSO and the mixture was maintained at room temperature for 15 min. S 13. 18. G. 16. and G.. and S. 3. D. The reaction was monitored using thin-layer chromatography on Silufol plates with 6:1 hexane-ether as the eluent. I. A sample of 31 ml 0. 2. 437 (1976). Zh. Mondelli. Skvortsov. A. Skvortsova. Liukas. F. Ber. I. Comptes Rendus. Tetrah. Khim. No. 103 . and S. G. Fronsa. 340 (1980). 6. M. 2473 (1978). D.. Chem. 54. 8. 95. and M. The reaction in the presence of KOH and NaOH was carried out by analogy to the above procedure under the conditions indicated in Table 2. D. S 13. Pal'chuk. Calculated for C:sHI3NS: C 75. Gorshkov. Kamenov. 13. and G. I. N.3. P. 9. Tasinen and P. Kurov. and S. 5. and E. Filimonov. 4. Sauer and H. J. PMR spectroscopy indicated that the mixture of isomers II and III was 54:46. G. Lett. I. G. Reson. Ju!ia. G. Khim.9 g (78%) of a yellow oil. 12. Simov. Epiotis. E. Geterotsikl. 12. Svyatkina. Org. K. 102. L. Schouteeten. i0. P.4 g (89%) cis-lO-pr0penylphenothiazine as white needles with mp 34-35~ bp 182-184~ (4 hPa)... Kamenov. M.. McDowell. J.. 382 (1972). 497 (1973).4.. H. S. ii.. Soedin. F. The benzene layer was washed with water and dried over potassium carbonate. Stoyanov. 14. 7558 (1973). and G. 1094 (1982). Soc. Larin. D.4%. Filimonov. G. T. Turchaninov. V. Vacuum distillation at 191-193~ (5-7 hPa) gave 3. Am. Gorbachev. No. 3433 (1974).4. After the complete conversion of I. 247 (1965/66). Sarkanen. T h e isolation of the products was carried out by analogy to the pre- vious procedure. 1892 (1983). Acta Crystogr. Phenothiazine I was prepared according to the method of Simov and Kamenov [16]. Khim. 7. 60. 1640 (1982). Zh. N 5. Mixture of cis-10-propenylphenothiazine (II) and trans-lO-Propenylphenothiazine: (III). 8. G. E. No. Khim.. 306 (1947). No. the solution was poured into water. Simov and L. Soedin..9. Scand. Zh. Org.

137 Decarboxylation of monocyclic a-carboxy-substltuted pyrylium [i]. IR spectrum: 3500. yield 46%. ~/-<~ ~COOH 9 -[. 3. IR spectrum: 3500.812+546. N" CH~O .25. Suslov Rostov-on-Don State University. OCH. 3. CII O" "):" " "~'~'OH 9 OCH3 OCll 3 _ Ilia ~ b ~ Ketols llla. A.50 9 1986 Plenum Publishing Corporation .72 (s. 1725. 0CH3). 30CH3).55 (s.31 and 3. pyridinium salts [2]. 7. For all the compounds studied. b takes place as the result of opening the heterocyclic ring in adduct II. an attack by the anion formed on the benzophenone carbonyl group carbon atom. It is probable that the formation of ketols Ilia. and sub- sequent hydrolysis of the enamine. 1715.30 (s. LETTERS TO THE EDITOR NEW TYPE OF RECYCLIZATION OF 2-BENZOPYRYLIUM SALTS V.95 (d. .50 (d. 30CHs). iH). 7.5 h. January. yield 68%. l- aryl-3-carboxy-2-benzopyrylium salts la. . 1986. 6. b. Original article submitted July iO. 1590.20 ppm (s.f :ooo. mp 290-291~ yield 23%.70 (s. V. 3. previously unknown salts la.70. JAB = 5 Hz. 7. 1240 cm-*. pyridine and its bezologs [3] proceeds with the retention of the heterocyclic structure. mp 97-98~ (from benzene). PMR spectrum (CDCIs): 3.62 (s. 125-126.4-dimeth- oxyphenylpyruvic acid with veratraldehyde or anisaldehyde in polyphosphoric acid. PMR spectrum (CF3COOH): 3. 6H).82 (s.. Brovchenko and E.s OCII3 la.. The initial. 1 /11 tl i:" 0(:]]3 ocll. 3.b II a R=OClI~. b convert into ketols llla.. CH2).52-7.80 (s. 6. 2s.b were isolated after column chromatography on aluminum oxide (eluent--chlor- oform).). IH). IH).. 1235 cm-*. the elemental analysis corresponds to the calculated val- ues. 3. CRy). Salt la. 104 0009-3122/86/2201-0104512. We found that when heated with a twofold excess of morpholine in benzene for 2.): 3. 2H). 5H). M + 344.bR=I! H C 1I. 1755. decarboxylatlon of the intermediate enamine. IR spectrum (CHCI.20 ppm (m.80 (s. lllO cm-*.): 3545. in a similar way as described in [4].sO -~ /~. pp. mp 296~ (from acetic acid). yield 20%.. 1600.42 ppm (m. OCHa).92 (s. Ketol IIIb. quart.42-7. .36 (Ch. 3. IH). OCH~). Scientific-Research Institute of Physical and Organic Chemistry of the M. 6. 1985. G. 1600. CH30 ' //~. No~ i. OCK3).b were obtained by the reaction of 3. Translated from Khimiya Geterotsikich- eskikh Soedinenii. Salt lb. 1600. PMR spectrum (CDCI. Rostov-on-Don 344090. IR spectrum (CHCI3): 35. 1095 cm-*. 8. mp 150-152~ (from benzene). Kuznstsov UDC 547. 1755. Ketol IIIa.

January. Katritzky. Yu. 252660. Nauk SSSR. K . 1364 (1977). P. was also isolated from the reaction mixture. Dokl.. L. In fact. 0009-3122/86/2201-0105512. 4. 498 (1982). and the following mechanism can be suggested for this reaction: ~ 5 clo4. The latter was isolated in individual state. It could be expected that a similar reaction will proceed also with carbon monoxide. Tetrahedron Lett. R. The above described reaction is a new reaction in the series of pyrylium salts. 92. unsubstituted at the 4-position.. 347 (1968). 46 (1959). Moscow (1971). Krivun. J. a small amount of blue dye is formed. previously described in [3] (6% after heating for 6 h and passing CO). Translated from Khimiya Geterotsiklicheskikh Soedinenii.262:547. Awartani.~ zo. No. Gavrilyuk UDC 546. 2. I c'-o -CO 2 ! ~ t ~ §~ o o J | -HCIO 4 1 I 2clo~. Org. A . c~.. " Institute!of Organic Chemistry of the Ukrainian $SR.50 9 1986 Plenum Publishing Corporation 105 . R. V. and G. Pakett. LITERATURE CITED i. 236. %H5["c.~o. whose mechanism is still unknown. M. a complex redox process. Dorofeenko. contaminated by unidentified impurities. 3. and R. Principles of Modern Chemistry of Heterocyclic Compounds [Russian translation]. Akad. N. V. 459 (1982). N. Chem. or for example malonodinitrile in the presence of triethylamine [2]. Andreichikov. such as triphenylphosphine [i]. p. 1305 (1957). 2. 40. i. 23. Chim. Chem.814 It is known that pyrylium and benzopyrylium salts. it was found that when CO is passed for a long time into a hot solution of flavylium perchlorate I in glacial acetic acid. react with nucleophilic reagents. 47. Mir. Acta. R . 3. p. Nauk SSSR. Kiev. Bet. J . Helv. Kr~nke and K.. REACTION OF FLAVYLIUMPERCHLORATE WITH CARBON MONOXIDE I. 1985. Akad. and was identified as flavylomonomethinecyanine II. Kholodova.. although such examples were not reported in the literature. Tobel. T h e initial salt I. However. Original article sub- mitted April 15. F.! Cell~ Cell s _1 C6H5 C6H5 H LITERATURE CITED io S. C. Dickore. Patel. Stamos. Dokl. Wizinger and H. 126. 260. it can possibly be stated that at the first stage a nucleophilic addition of CO takes place at the 4-position of salt I. 182. 1986.

I'-Me2N). Ordzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry. iH. IH. ii.814:547. 1505 (1976). (from IV). 6. I.): 1. mp 89-92~ and VII {yield 45% (from V. K. a-CH3). 7'<. p. together with 51% of VI).6.H -.824 and V. Mass spectrum. 2-CH).96 (s. E. V.4-dimethyl)cyclohexylidene-l-propene (V).63 ppm (d. 3. G. 4'. 6H. Poliektov. Under the same comditions. Granik.25 (two s. No.CH3] ~245}. 3H.50 9 1986 Plenum Publishing Corporation . J = 14.7.03 (s. J = 14.7-dimethyl-5. Grigor'ev. S. Granik It is known that amide acetals react with primary enamines to form enamidines [i]. N. mp 183~ (from ethyl acetate).UNUSUAL REACTION OF N.N-dimethylacetamide diethyl acetal (I) with 2-aminomethylene-5. V. 4H. B. 3.l-bisdimethylamino-3-(2. Marchenko.3~DIONE. 6H.4'-CH3). No. m/z: M +" 305. 1. T.92 ppm (d. Jan- uary. H. PMR spectrum (CDCI. 7. 7. Khim. mp 88-900C (from hep- tane). K. Information on the possible mechanism of this unexpected reaction and additional examples will be submitted later on. B.46 (d. 3-C~).7 Hz. 2. The following compounds were synthesized: IV {yield 38%. Chistyakov.3-dione (II) [2].5'-CH2).8-tetrahydro- carbostyril (VII). and R. according to the data in [3]. 106 0009-3122/86/2201-0106512. SYNTHESIS OF COUMARIN AND CARBOSTYRIL DERIVATIVES A. Moscow 119021. u-Me2N in each case).5-DIMETHYLCYCLOHEXANE-I. A. mp 163~ (from ethyl acetate). G.VI {yield 96. I-Me2N). 1986. Translated from Khimiya Geterotsiklicheskikh Soedinenii. Compounds IV and V were separated by fractional crystallization from ethyl acetate. IH. Mass spectrum. not the enam- idinodiketone II is formed. [M -. LITERATURE CITED i. m/z: M +" 264. Soedin..5-dimethylcyclohexane-l.8-tetrahydrocoumarin (IV) was obtained. 4'. 7. When the diene-diamine IV was boiled in a 10% aqueous HCI.6- dioxo-4. Shanazarov. mp 276~ C!I 3 _ CH3~CH 3 + ~ 2' I 0E~ + CH3" "C}I~ CH s" "CH 1 II ~ iV Y A IHCI A IICI 0 N..09 (s.7-dimethyl-5. 2.CH3] + 290. Original article submitted August 20. J = 14.~:_n<~Ctl3 ..16 (s. M. [M-. i. 3'.32 (s. 7.08 and 3. 4H. UDC 547.86 (d.35 (s. or a mixture of compounds IV and V give a mixture of courmarin VI and 5-oxo-7.5'-CH2). 5-oxo-7.6. 127. F.6-dioxo-4.4-dimethyl)- cyclohexylidene-l-propene (IV) and l-dimethylamino-l-(a-dimethylamino)ethylideneamino-3-(2. 3H. amidine V. Glushkov.NMe2 %'I 0 0. 3-CH). we found that in the reaction of N. 4'-CH. but a mixture of l. unexpectedly. J = 14. 3'.4 Hz. 6H.N-DIMETHYLACETAMIDE DIETHYL ACETAL WITH 2-AMINOMETHYLENE-5.v "N" "0 H UI The results of the elemental analysis of compounds IV and V for C. Sochneva. mp 276~ (from ethyl acetate) according to the data in [4]. V. 1985. O. 3.Me2N] + 220}. 3:7 (PMR spectrum) is obtained in an over- all yield of 90%. //0 CH~ + CH CH 3 v "0 0 CH 3. 2CH). Geterotsikl. V {yield 9%. G.05 (s. PMR spectrum (CDCIs): 1. [M--NMe2] + 261 and [M--NMe2 -.). 12H. Vlasova.4 Hz. In contrast to this. and N correspond to the calculated data.7 Hz. IH.

1. 7.-NItR IB IA la-c. s. Ib. P.90. la. as assumed in [3.772.8 (C==N). )~ N ' II R ! I I N C S N I I N~II N ' . 1986.. and not the linear structure A.25 (1H.3-3. Chem. 3-CH3). 8.. H.~N HIe T IlO" ~N HA S ~ ::C.93 (3H.09 (3H.73 (3H.07 (AB system.. lib R = C6Hs. CSNH2). t.6 (q. NCH3). d.50 9 1986 Plenum Publishing Corporation 107 .N I I R I lIB -" R NNHCSNHR I .. 2. H 7. Yu. 2NH). lla R I = CH3. 3. CH3CH2N). 47. 3. UDC 547. lla R = CH3.45 ppm (IH. Calculated: C 44. 3. ~3C NMR spectrum (DMSO-D6): 51.6 Hz.2. JAB ~ = 18 Hz. 2H. T. m. Kirov Military Medical Academy.91 (AB system. 2H.5 and 14. 5-CHs). 3-CH3).5 (q.8 ppm (s. 4-C). Brutane. Chem. d. J = 19 Hz.0-145. A. s.61 and 2. JH--CH = i Hz. 5-CH3). s. J = 7 Hz.61. s.9. OH). p. C==N). S. 2H. 151. 15. CH2).15 (AB system.. 2.d. R~ HNC. 3-CHs). 5- CH3). 6. Sellstedt. 23.9 (q. s. and M. R. 5-C). J. j2 = 0. CH2). PMR spectrum (DMSO-D6): 4. 1. s. 141 (1971).. 154. s.6 Hz. We found that compounds I have actually a cyclic pyrazoline structure B.72 (3H.7 (t.65.. Sol. Nuak Latv. H 7.. 2NH). 2H. Roegig. Zelenin. JAB I = 18 Hz. m. PMR spectrum (Py-Ds): 1. N 22. 8. but the corresponding 5- hydroxypyrazolines B.85 (2H. N--CH3).2'497..0.8 Hz. 3. 95.. OH).3 ppm (2H. 2C==S). Compound Ic [3]. j2 = 0. 5 Hz. b. Tomchin. J= = i Hz. 1337 (1972).35 ppm (2H. Sch~del. j2 = 0.79 and 3.4 (s. and S.. 2C2Hs). Manger.58 (3H. m 2NHC2Hs). t.1 (t. Shul'tsa. 8.1 ppm (Carom' 8 sig- nals) . D.AND 5-THIOSEMICARBAZIDO-2-PYRAZOLINES K. J = 0. 9.. CH2). 2NHCH3).45. Mp 95-97~ PMR spectrum (CDCI3)" 1.1'422:04 O. . Translated ~rom Khimiya Geter- otsiklicheskikh Soedinenii. Ya. 4.94 (3H. and M.4%. Valter. 4]. but their structure has not yet been studied. Derivative Ib [3]. 7. V.80 (IH. M. 13C NMR spectrum (DMSO-D6): 14.84 (AB system. Org. Foundi C 44. 1. 2.6 (s. January. t.15 (6H.~NHN f" = I S ~-~-C .8 Hz.3%. 37. m Harom) . 9. 2H. s. PMR spectrum (CDCI3): 1. Leningrad 194175. 1985. t. 84. 5-CH3). 7. Derivative lla was obtained by condensation of acetylacetone with N3-methylthiosemicar - bazide in aqueous acetic acid. 2-CH3).65 ppm (2H.53 and 3.17 (2H. 7. 128. PMR spectrum (CDCIs): 1. SSR.92 (AB system. Ic R I = C2Hs. CTH~3N~OS. 8. 3-CH3). 174.75 (3H. CH2). B. JAB x = 18 Hz. 0009-3122/86/2201-0107512. CH3CH2N). A.6 Hz. 5Hz. i. 1. s. 3.. 37. Compound la [3].2 (10H. m. Strakhov..0 and 181. S.^ R R NNIIC. CSNH2). 6. d.. J = 4 Hz. V. CH2). N 22. s. J = 0.58 and 2. 6.00 (3H. 5-CH3).91 (3H.96. No. s. Ber. NH). 2C=Hs). 7.7.8 (4H. lib R I = H. It .16 and 3.3-diketones with thiosemicarbazide and its N3-substi - tuted homologs in a 1:2 ratio have an antitumorigenic activity.5-8. J. Original article submitted June 25.91 (2H. 7. Izv. 1.30 (IH. NHB). N-- CH3). 2. These compounds I were as- sumed to be bisthiosemicarbazones A [1-3].30 (IH. A. NHa). We shall add that also the condensation products of these reagents in a ratio of i:i (II) are not monohydrazones A. No.6 Hz. iO. I-THIOCARBAMOYL-5-OXY. JAB 2 = 18 Hz. Akad. Compound llb [4].87 (3H. NH=).4 (C==S). 6. 2294 (1960). s. 175. s. J = 0.4 (4-CH2). 2. 6.20 (2H. t.4 (5-C.. N. Malov Products of the condensation of 1.01 (3H. 124.

and A.. Barry. J. Our data agree with those known on the structure of malonodialdehyde bisthiosemicarba- zone [5]. LITERATURE CITED i. H. Chem. L. Losse.. Buttkus and R. C. J. Irish Acad. Twomey. which in their activity sre not inferior to bisthiosemicarbazones of 1. and D. 3. Proc. Bet. 91. 21 G. 108 . C. Hessler. M. Berth. O'Callaghan. 5.and 1. Chem. 3895 (1971).2. C.. Soc. J. Twomey.. 65B. Suprunchuk. A. B. The pyrazoline structure of the above described compounds is interesting in con- nection with the search for antitumorigenic preparations. Bose. 40..4-dioxo compounds [i]. No. 2400 (1967). Org. O'Callaghan and D. No. T. N. 150 (1958). 1053 (1962). Canad. 309 (1967). 4. Chem. Bayley. 36. 6. and C. 22. V. H. W. Gingras. Chem. Conalty. N. Roy.

oxazoles. 1984. Original article submitted January 4. CH O ~ . February. and triazoles) containing indole fragments. A. this method has not yet found extensive use for the synthesis of indolylazoles since azole carbonyl derivatives and arylhydrazines containing azole residues have generally been difficult to prepare. However. The condensation of N(. we preferred to organize the subjects not according to the indolylazole types but rather according to the means of their preparation from specific classes of compounds. oxadiazoles. Shvekhgeimer UDC 547. Moscow 117296.7 A systematic review is given for advances in the synthesis of various azoles (im- idazoles. 1984.METHODS FOR THE SYNTHESIS OF AZOLES CONTAINING INDOLE SUBSTITUENTS (REVIEW) V. No.5-pyrazolinedione [4] or with <l-(2-oxopropyl)-2-methyl-4-nitroimidazoles [5-7] was used to prepare another type of indomethacin analogs containing heterocyclic fragments at C(3) of the indole ring. we have limited ourselves to noncondensed indolylazoles. in which the residues of the two heterocycles are joined either directly to each other or by carbon chains.. Translated from Khimiya Geterotsiklicheskikh Soedinenii. In compiling this review of the literature data. [l-(4-chlorobenzoyl)- 2-methyl-5-methoxyindolyl-3-acetic acid] [2.)-hetaryl-4-methoxyphenylhydrazines with levulinic acidwas carried out in order to synthesize structural analogs of the drug indomethacin. . In our opinion. anti-inflammatory and high fe- ver-reducing activity. I.2-diphenyl-4-(3- oxobutyl)-3. benzthiazolyl-2 The indomethacin analogs I synthesized display analgesic. I. 3]. pyrazoles. M. PREPARATION OF INDOLYLAZOLES BY THE FISCHER--ARBUZOV REACTION The Fischer--Arbuzov reaction is the most general and common method for the synthesis of indole derivatives. this approach to the systematization of the vast literature data gives a clearer concept of the synthetic possibilities of the speci- fic methods. Kelarev and G. CHz-COOH ! Hei Het = 2-chlorothiazolyl-4-carbonyl. thiazoles. . An enormous amount of experimental data has now accumulated in the literature on the syn- thesis and application of heterocyclic compounds containing indole substituents. which may be useful in selecting approaches for further studies on the prepara- tion of new indolylazoles. In the present review. 147-172. i.)-(4-methoxyphenyl)hydrazines with 1. However.50 9 1986 Plenum Publishing Corporation 109 . Gubkin Moscow Institute of Petroleum Chemistry and Gas Industry. 2. The condensation of N(.751:547.)-aroyl-N(. only a few indolylazoles were very briefly considered among other bisheterocyclic compounds in a single review [I].77:324. 1986. A significant number of biologically active compounds have been found among these bisheterocyclic compounds. pp. 0009-3122/86/2202-0109512. revision submitted August 3.

R z = H.. alkyl. How- ever.. VI VII R = H. R 1 = H. alkyl. i0] synthesized indolybenzlmidazoles IV.2-diphenyl-3. COOH. alkyl. which display strong an- tiviral activity [ill.. 3-benzoxazol-2-ones with phenylhydrazine in polyphos- phoric acid [12]. These indole derivatives ii0 .Ar I! n = i.(2-oxobutyl)-l. A patent has been issued for the preparation of 5-(indolyl-3-methyl)hydantoin (Ill) en- tailing Fischer--Arbuzov cyclizatlon of the phenylhydrazone of ~-(5-hydantoyl)propionaldehyde upon heating in hydrochloric acid [8]. CHs A patent was i s s u e d i n 1981 f o r the synthesis of 2-(5-R-3-R~-isoxazol-4-yl)indoles (R = H.(2-oxopropyl). i 2-Alkyl-3-(2-benzoxazolon-3-yl)indoles (V) were obtained in 65-70% yield upon heating 3. High pesticide activity was n o t e d for these compounds.. 5-CH3. CaHs. the yield of these indolylazoles did not exceed 25-40%. ---NH 0 ~ . n = 0. Ph. [9. IV CH3/ ~ N ~ ~ / J H R = H. 0 ~ . aryl). COOC2Hs..N/~--O II H III Tatevosyan et al. 5-Ci.or 5-acetylthiazoles were converted by the Fischer-Arbuzov reaction to indolythiazoles VI or VII.. CH3.5-pyrazolidinedione-4-yl.. The phenylhydrazones of 4.or 3. Nll C6Hs_NII-N:CH-(CIL~)2 --. Her = 1. R l = H. ~. .or 2-(4-oxopentyl)benzimidazoles with phen- ylhydrazine in the presence of sulfuric acid. n = 0. 6-SO2NH2 2-(l-Methyl-2-R-imidazol-5-yl)indoles (R = H. Her = 4-nitro-2-methy!-l-imidazolyl Compounds containing high analgesic activity were found among indolylazoles If. o R H V R = CHs. respectively [15]. by heating 2-(3-oxobutyZ). CO-At CHj CO. which were obtained in high yield by the cyclization of 4- aeetyl-5-R-3-RZ-isoxazole phenylhydrazone in polyphosphoric acid. SC2H5) [13] and 2-(3-methylisothiazol-4- yl)indole [14] were prepared by the cyclocondensation of l-methyl-2-R-5-acetylimidazoles and 3-methyl-4-acetylisothiazole with phenylhydrazines in the presence of zinc chloride.

. CHs. (. Iii ..' i-.H. i ! 'N i ("OR I~. CHs. which is a cyclic analog of tetraminoethylene. proceeds at C(s) with the formation of 3-(1. N" It.OR Xlll XII R = CHs.3-diacetyl-2-(indol-3-yl)-4-imidazoline (X) in- stead of the expected N-acetylindole. R x -.3-diphenyl-2-imidazolidinylidene). PREPARATION OF INDOLYLAZOLES BY THE ALKYLATION OR ACYLATION OF INDOLE AND ITS DERIVATIVES l-(Imidazolinyl-2-methyl)indoles (VIII) are formed upon the alkylation of 2-arylindoles by 2-chloromethylimidazoline in the presence of sodium hydride [17. Ph Bergman [21] in an attempt to acylate indole with N-acetylimidazole in acetic anhydride isolated the indole hetarylation product. 20] found that the alkylation of indole and 2-substituted indoles by bis(l. aromatic.Ar ~/~N H Ar H ! N-- N--. 18]. 1./'~. COR + RCOCI . CHs.are key compounds in the preparation of biologically active tryptamine analogs containing isoxazole fragments..J VIII H R = H. .3-dfacylbenzimidazolin-2-yl)indoles (XII). which is an important intermediate in the synthe- sis of tryptophan [26].3-diacetylimidazolinium cation generated from N-ace- tylimidazole. ~ sH5 COCH 3 9 N-. R* = H. -NaCl ~. which resulted only in N-acyl-o-aminophenols and tris(indol-3-yl)- methane [25]. Ph.3-diacylimida- zolin-2-yl). CHs The formation of salts Xll as intermediates was confirmed by the preparation of XIII un- der analogous conditions using N-acylimidazoles instead of imldazole. C1.'" " N i. ~.or 3-(l. thienyl-2. D detailed study was carried out on the hetarylation of indoles not substituted at C(s) by N-acylimidazolinium or N-acylhenzimidazolinium salts (XII) in situ. The benzoxazole fragment could not be introduced into the indole ring by the reaction of indole with benzoxazole in the presence of acylating reagents in an inert solvent or by using benzoxazole salts. [22-24] reported that the reaction of indoles with imidazole or benzimidazole in the presence of the acid chlorides or aliphatic.. 2. CI I . The reaction of indole with 4-ethoxymethylene-2-phenyl-5-oxazoline in acid medium gave 4-(indol-3-ylmethyl)-2-phenyl-5-oxazolone.N/~-. ~'Ol: . 4-CHs0CaHa Hocker and Merten [19. CHa. Ar = Ph) 4-ClC6H4. Also. or heterocyclic acids gave 3-(l. heating indole with thiazole in acetic anhydride gave l-acetyl-2-(l- acetylindol-3-yl)-4-thiazo!ine (Xl) [21]. Sheinkman et al. H ix_ x kl R = H. R ~ = H. This author considered that (X) is formed by electro- philic attack at C(s) in indole by the 1.3-diphenylimidazolidin-2-yl) indoles (IX).

o.. 4-CHa0CeH4.i ii Ii'~'i. ' " 1r " "R " 1 S... P~ . CONH= 4-(Indol-3-ylmethylene)-5-oxazolones (XIX). .+~ % N XIV R = H.. C6HsCH2 3-Formylindole does not undergo this reaction..o+ +"~"i"'. R ~ = Ph.N'-di(4-ethoxy- carbonylphenyl)ethylenediamine...N'-dlarylethylenediamines with subsequent hydro- lysis of the N-acetyl derivatives formed [31].m.. "N" Ar I 11 ] COCII3 ~. 2.:'+ .4-(NO2)=C6Ha. indolylimidazolidines could not be prepared from N. 4-CHsC6H~ The reaction of 3-formylindole hydrazones with 2. (:(>r X'... 4-BrC6H~. CHaO. 4-BrC6H~. thiazolyl-4. "~.N'-di(4-nitrophenyl)... Ar Ar < . + A . + i COCH 3 XVI1 oi! R = H. For example.. The introduction of electron-donor groups in the benzene ring of the amines leads to increased yields of indolylimidazolidines XV. C2H~...' Ar = Ph.. Ph. N Nh2 ..3-Disubstituted 2-(indol-3-yl)imidazolidlnes (XV) were synthesized by the cyclocon- densation of l-acetyl-3-formyllndole with N. electron-withdrawing substituents hinder the cyclocondensation. i[... NOa 3.m " ~i 'I . and other biologically active indoles are readily formed 112 . Heating Schiff bases XVI with acetic anhydride gives both acylation and cyclization to form l-acetyl-2-(l-acetylindol-3-yl)oxazolidines (XVII) [33]. 0--.or N.5-disubstituted tetrazoles XVIII [34]. R z = H.. _ + + ++ XWI h + + + + . apparently due to insufficient electro- philicity of the carbonyl group carbon atom..+~ I + '~% N" "r ~" ~:" N' ( I t J R NO 2 R NO2 X"~'III R = H. CHs. which are important intermediates in the synthesis of tryptamine. . (CHa)aNCHa. II + l +~ ii-+ -i[ + [+~ ~.~ ArlIN CI[ z N Ar '. which is a stronger nucleophile. On the other hand. which are intermediates in the preparation of anti-in- flammatory agents [27-30]. R a = H. C6HsCH2.. tryptophan. L~.~j .". PREPARATION OF INDOLYLAZOLE$ FROM INDOLE C~BONYL DERIVATIVES 1. Heating a mixture of indole or i~s derivatives not substituted at C(z) with 2-chioro- ethyl Iso~hiocyanate in 1.4-dinitrophenyl azide proceeds anomal- ously with the formation of 2.2-dlmethoxyethane in the presence of sodium hydride at reflux gave l-(Aa-thiazolin-2-yl)indoles (XZV). 3-Formylindole reacts readily with 2-mercaptoethylamine. 111 N ~ f~ .. to give 2-(indol-3-yl)thiazolidine in high yield [32]..

5-Diaryl-2-(indol-3-yl)imidazoles were isolated in 60-67% yields as a result of the cyclocondensation of 3-formylindole or its N-methyl derivative with aromatic a-diketones [40. -CO--NPh--NR*--. CN.5-dicarboxylic acid (XXII). H H ~X R = H.from 3-formylindole and N-acyl derivatives of glycine in the presence of potassium acetate in acetic anhydride [35-38]. 41].I~ 02NCH2COOR ~02 "-~ --'. pyrazol- ine. X = O. R x.Ind--CtI-CH--COOB I _lIND2 CONII2 CH(NO2)COOR ROOC H2NOC/k~N/0 O X~ XXII R = CHs. --NH--CO--S--. 113 . isoxazoline. pyrazoline and thiazolidine containing the --CHaCO--group i ~ t h e ring [49-53]. These dyes have been proposed for use in photographic films [42-46].8-unsatumated ketone XXV [54]. NHa The Knoevenagel reaction of 3-acetylindole with 5-formyl-3-phenylisoxazoline gave the corresponding ~. aryl. here and subsequently. -H20 I N0 2 Ind C00R NH~_. S. ClO~- Dyes obtained by the condensation of l-methyl-2-phenyl-3-formylindole with 3-substituted derivatives of 5-pyrazolone and 5-isoxazolone have been used for the same purposes [47. Y = CH. R 2 = H. Ts-. R x ffi CHs. Ph The reaction of 3-formylindole with nitroacetate esters in the presence of sodium ace- tate gives esters of the N-oxides of 4-(indol-3-yl)-3.. N. --C(CHs) = N-O-.= I-.Y X . 1"-'*d--CliO + 02NCH2C00R ~ Ind--CH(OH)CH(NO2)COOR ~ Ind --CH:C--COOR -~---m.. IndolylmethyldenazolesXXIV which display strong anti-inflammatory action are formed by the condensation of 3-formylindoles with derivatives of imidazolidine. The extremely reactive nitroalkene X X w a s proposed as an intermediate.. 48]. The treatment of N-oxides XXI by aqueous ammonia gives the diams of 4-(indol-3-yl)isoxazole-3.. Ind = 3-indolyl 4. R.Ind ~-~:--':. 7 B" ~3 " R B- XXIII R. aryl~ R s = CHs. --CRs = N--NRa-. . alkyl.- . R a.5-dicarboxyisoxazolines (XXI) [39]. which rapidly reacts with the starting nitroesters.. R ~ = H. COOCaHs. B . (X h I I R R X = --NH--CO-RNH--. CeHsCHa. O. R s = H. R*. cyanine dyes XXIII were synthesized from substituted 3-formylin- doles and the corresponding 2-alkylbenzazole salts. Se. Indole aldehydes may undergo condensation with some azoles containing active methylene or methyl groups. Thus.

XD~XIII R = H. The phenylhydrazone of N-substituted aldehyde XXVI (R = Ac) undergoes more rapid cyclization un- der the same conditions to give pyrazoline derivative XXVII (R = Ac. monoamine oxidase inhibitors [58]. These authors consider that nucleophilic addition at the -CH=CH . R = H) upon heating at reflux in acetic acid is slowly cyclized to l-phenyl-5-(indol-3-yl)pyrazoline (XXVII. Ind Ind ~ CO-CH=CIt-A~ + N~lt4'tI~O ..-X XX~I R=H.] ~N. Ar Indolypyrazolines EXXI have valuable properties and are central nervous system depres- sants [57]. a-epoxyketones. 61]. R: = Ph). 114 . R ~ = Ph).i~l ~Ar H H XX.8-Unsaturated aldehydes and ketones. In6--CO-CH~ + OHC--.~_. which are the products of the Knoevenagel reaction of 3-formylindole and methyl aryl ketones. /CHInCH-CO-At ~ ~ . pyrazoline XXVIII (R = H. These compounds also have strong luminescence both in the solid state and in solution [561. The introduction of an acetylgroup at N(z) in the indole system reduces the electron-donor effect of the indole group and increases the reactivity of aldehyde XXVl (R = Ac) relative to nucleophilic reagents. !~ ~N~7s Ar I R X. and anti-inflammatory agents [59].8-diketoesters of the indole series are convenient starting compounds for the synthesis of various indolyl- pyrazoles.double bond is diffi- cult in ~-(indol-3-yl)acrolein due to the strong electron-donor effect of the indolyl group..~XII . Heating 8-(l-acetylindol-3-yl)acroleln (XXVI. ] I n COClI~ COCH a ~VI X~X The reaction of l-(indol-3-yl)-3-aryl-3-propenones (XXX). R = Ar with hydrazine hydrate or phenyl- hydrazine in acetic acid at reflux gave 1-substltuted 5-(l-acetylindol-3-yl)pyrazolines (XXVII).. However... carrying out the re- action in acetic acid leads to the formation of 1-acetyl derivatives of p y r a z o l i n e s XXX!II (R = Ac) which are completely stable compounds [61].. and a. ~. ..C0-CH=: C l l ~ 0 1 N XXV a. with arylhydrazines lead to the formation of 1. . Indolylpyrazolines XXXIII which contain indolyl fragments at C(s) of the pyrazoline ring were synthesized by heating l-(indol. The phenylhydrazone of 8-(indol-3-yl)acrolein (XXV."HaO . //-~. 8-diketones. anticonvulsants.3-yl)-3-aryl-l-propenones (XXXII) with a large excess of hydrazine hydrate [60.) of the pyrazoline ring (R = H) a r e rather unstable compounds which decompose upon purification. which upon treatment with ethanolic alkali are converted to l-substituted 5-(indol- 3-yl)pyrazolines (XXVIII) [55]...3-disubstituted 5-(indol-3-yl)pyrazolines (XXXI) [56-59]. upon de- acylation.. . Suvorov et al. [55] have proposed the following method for the synthesis of l-phenyl-5- (indol-3-yl)pyrazole (XXIX). Ac Pyrazolines XXXIII w h i c h a r e n o t s u b s t i t u t e d at N(.. ~ I~d. R: = Ph) and.

69]. .. the heating Df ketones XXXWIth hydroxylamine gave 3-aryl-5-(indol-3-yl)isoxazollnes (XXXIV) [62]..lerivatives from l-(in- dol-3-yl)-3-phenyl-l-propenone (XXXII).. 64] or 3-(indol-3-yl)-4-arylpyrazoles (XXXVI. 63. while pyrazoles XXXVI are obtained in eth- er in the presence of BF3"0(CIHs). while l-phenyl-3-(indol-3-yl)-4-arylpyrazoles (XXXVl.. 67]..'.-~ " " ~2~/A~. Unsaturated indole ketones may also be used to prepare indolylisoxazollnes. ~ "'N" I} ' I N7114" 1f:~0 .At . leads to the formation of either 3-(in- dol-3-yl)-4-hydroxy-5-arylpyrazolines (XXXV) [54. 64]. these pyrazoles have high anti- inflammatory activity [68. which were converted to l-R-5-(indol-3-yl)pyrazoles (XLIII) upon subsequent hydrolysis to the acid and decarboxylation. Ph The ethyl ester of 4-(indol-3-yl)-2. depending on the reaction conditions. which. R = H) [60].. For exam- ple. .CO A r I N Ind ]C<XVlll hid N" ~D~LE XL R=H.:--~..~g~..% .At .. 115 . hid C 0 Ctl . while the action of hydrazine hydrate or phenylhydrazine gave 3-aryl-5- (indol-3-yl)pyrazoles (XL) [64.{ CO CIi CII A r . Considerable interest is found in the reaction of indole ~-epoxyketones with hydrazine hydrate.4-butanedionoic acid (XLI) reacts with hydrazine hydrate or phenylhydrazine in acetic acid to form the ethyl esters of l-R-5-(indol-3-yl)py- razole-3-carboxylic acids (XLII). [rid ~I" had 01f . Pyrazolines XXXV are obtained upon carrying out the cyclocondensation in alcohol using catalytic amounts of acetic acid. R = Ph) were ob- tained in e:her in the presence of BF3 etherate [60]~ The reaction of ~-diketones XEXVIII with hydroxylamlne gave 3-aryliS-(indol-3-yl)isoxa- zolines (XXXIX) [66].At Ind Piozzi and Fuganti [60] studied the reaction of vinyl 3-indolyl ketone with hydroxylam- ine to give 3-~indol-3-yl)isoxazoline and noted the inability to synthesize analogous isox- azoline derivatives from l-(indol-3-yl)-3-phenyl-l-propenone (XXXll).x x:kx v I H f" Ar i coil b "%'<>{!'i l R = H i Ph Carrying out this reaction in acetic acid gives l-phenyl-3-(indol-3-yl)-5-arylpyrazoles (XEXVII) [63.

while heating with a stoichiometric amount of formamide and phos- phorus pentasulfide gives 4-(indol-3-yl)thiazole [72]. -" . For example. CHs Indolylthiazoles XLV-XLVIII have a broad range of pharmaceutical activity and are cen- tralnervous system depressants. 72].~. '~ N "~ ~ "~<. while this reaction with thiourea or N-substituted thioureas gives 2-amino-4-(indol-3-yl)thiazoles (XLVI) or their N-substituted derivatives [14. . )I h ~" . C(=NH)NHz Significant interest is found in the condensation of 3-chloroacetylindoles with the func- tional derivatives of several azoles in the synthesis of indolylazoles. . H H It ~NI! XLVIII R = H. Thus. 74].. and antibacterial agents as well as substances used for lowering arterial pressure [14.~' R ELl[ XLIII Ind CO' f)H. CHs. Heating this hydrochloride with an equivalent amount of isothiocyanates gives 1-substituted 5-(indol-3-yl)-2-imidazolethiones (L) in 30-50% yield.N.~'~t coo('Jl:~ ~0 [t)d ' XLIV R=H. The reaction of this hydrochloride with molten potassium thiocyanate gives a 16% yield of 5- (indol-3-yl)-2-imidazolethione (XLIX).'N'" ~'R ~'S"-"'R 1 . .!I] ~ : . N lnd i I ~. . . the re- action of ~-chloroketones with 2-imidazolidinethione gives 5.. An interesting transformation occurs in the reaction of ester XLIV with hydrazine hydrate in ethanol at reflux which gives the hydrazide of 5-(indol-3-yl)pyrazole-3-carboxylic acid. The cyclocondensation of 3-chlbroacetylindoles with acid thioamides gives 2-substituted 4-(indol-3-yl)thiazoles (XLV) [14. pyridyl-3! R 2 = H." " N ~ R \s N~m2 II II H XLV XLVl R = H. 73].. 73]. The desulfurization of 2-imidazolethiones XLIX and L by nancy nickel in ethanol leads to the corresponding indolylimidazoles LI and LII which display tuberculostatic activity [71. 72. .. the reaction of 3-chloroacetyllndole with acetamide proceeds with heavy tar formation and 2-methyl-4-(indol-3-yl)imldazole was isolated from the reaction mixture in only a 4% yield.~(IO9 COOC. CHs. NH2.....6-dihydro-3-(2-R-indol-3-yl)- thiazolo[3. 74].. Indole a-haloketones have been used in the synthesis of indolylimidazoles and indolyl- thiazoles. LI. 116 .. heating 3-chloroacetylindole with a large excess of formamide gives 4(5)- (indol-3-yl)imidazole [71]. aryl.2-a]imidazoles (XLVlI) while this reaction with 2-amino-Aa-thiazoline gives 2- imino-3-[l-oxo-l-(2-R-indol-3-yl)ethyl]thiazolidines (XLVIII) [14]. Suvorov et al.+.<. 3-Aminoacetylindole hydrochloride was used in the synthesis of indolylimidazoles [71.COOC. ~ COCH. R ~ = CHs. .CI "'~'/ ". Ph Treatment of 8-diketoester XLI with hydroxylamine in the presence of pyridine gives a high yield of the ethyl ester of 5-(indol-3-yl)isoxazole-3-carboxylic acid (XLIV) [70]. analgesics. For example. [71] noted the inabil- ity to extend this method for the preparation of indolylimidazoles from the amides of other acids.

(CHs)2NCO. CHsO.~ CII COOII NH2~. The condensation of derivatives of indol-3-ylacetic acids with o-phenylenediamine leading to the corresponding 2-(indol-3-ylmethyl)benzimidazoles (IV) [9] has been described in [9].2- diphenyl-3. CHsO There has been a report of the use of l-acetylindoxyl (LV) as the starting agent for the preparation of some indolylazoles.t R LIV R ffiCHs.5-pyrazolidinedione gives a quantitative yield of I. ": L. R a = H.0CH~. R s ffiH.5-pyrazolidinedione (LVI) [81]. I r7 L N ~S N li It lnd--I. -" "N 1~'~ "P'" ".NHT.. For example. I~1 ~.POCIa "-~ it I H C0CH3 LIII In 1981. C~H9 117 .(1-acetylindol-3- yl)-3.. R x ffiH. CHs. 4. ~ .II The antibiotic pimprinine was isolated from several natural products and identified in 1960 as 2-methyl-5-(indol-3-yl)oxazole (LIII) [75].. NO2. 11 ~ . . 4. Houwing et al. lnd Ind KSCN NH II J =. PREPARATION OF INDOLYLAZOLES FROM INDOLE CARBOXYLIC ACIDS AND THEIR FUNCTIONAL DERIVATIVES Indole acids themselves have rarely been used for the preparation of indolylazoles until recently. the condensation of indoxyl LV with 1. 9 1-Ac. 80] reported the preparation of pimprinine analogs (LIV) by the condensation of substituted 3-formylindoles with ~-tosylisocyanide or with dimethoxy- N-tosylmethylimine. The structure of pimprinine was confirmed by its synthesis from 3-aminoacetylindole hydrobromide [76-78].0 O~ C6H 5 I 0>" ~'C6115 ! COCI[~ CCCH3 LV Lvl Heating carboethoxyisopropylidene hydrazone with l-acetylindoxyl in polyphosphoric acid at 90~ gives intramolecular cyclizationwith the formation of 3-methyl-l-(l-acetylindol-3- yl)-5-pyrazolinone [82].aO + CsHsN CH3 D" C 2. CHO R~ It "N + Ts CH N ::C ~ ~ k .~. these analogs display antihistiminic activity [80]. ~ IIN CH~ IV R = H.~ H " ~ ' / ' " ~z'"ctt~i} NI. o~ -N C e H s . " l. [79. R2 .:. " ' k . 2-diphenyl-4. IICI XIJX LI lnd Ind R RNCS Ni N It L I.

Thus..N'-diphenylethylenediamine leads to 1... the nitriles of indole acids have been studied most ex- tensively. The hydrogenation of 3-indoly!acetonitriles or their N-acetyl derivatives over Raney nickel in the presence of N.. heating these nitriles with anhy- drous ethylenediamine in the presence of sulfur compounds gives 2-(indol-3-ylmethyl)-A=-imi - dazoles (LX).. Ind-(CH2)n-C00lI + NII2C(ClI20H)-~ . and serotonin antimetabolites [90].~-cN Co%HN-~. 87]. l-cyanomethyl-3-alkylindoles and ethylenediamine give 3-alkyl-l-(imidazol- inyl-2-methyl~indoles (LXI)..il~ ~_t / " C6HsHN-CH 2 Ni '~" . 118 . Ac Great interest has been found in the reaction of 3-indolylacetonitriles with ethylene- diamine which gives indolylimidazoline s [88-94]. C1. the yields of indolylbenzim- idazoles did not exceed 30%. Of all the functional derivatives of indolecarboxylic acids used as starting materials in the preparation of indolylazoles. 94]. phosphorus pentasulflde. ellipticine. which stimulates brain activity and was prepared by the reaction of the methyl ester of 2-(indol-3-yl)propionic acid with lithium methyl isocyanide at --50~ [83]. [84] used the condensation of ethyl (indol-3-ylmethyl)malonate with hy- drazobenzene in ethanol in the presence of sodium ethylate to obtain 1.3-diphenyl-2-(indol-3-yl- methyl)imidazolidines (LIX) [86. Analogously.. However. aluminum sulfide [88] and p-toluenesulfonic acid have been used as catalysts for this reaction [89.5-dione.. Hydrogen sulfide. The reaction was carried out by heating the corresponding acids with a large excess of o-phenylenediamine in 4 N hydrochloric acid at reflux. .V- N----~-CH20H C}I20H Lu n=l-4 5-[a-(Indol-3-yl)ethyl]oxazole (LVIII) is an important intermediate in the synthesis of the alkaloid. The reaction of ~-(indol-3-yl)alkanoie acids with tris(hydroxymethyl)methylamine gave 4-di(hydroxymethyl)-2-~-[(indol-3-yl)alkyl]-A'-oxazolines (LVII) [64].o I LIX R=H. vasoconstrictors [91]. CHsO Indolylimidazolines LX which may be formally considered as tryptamine derivatives have various biological activities and are antidepressants. F.4-dlonewhich has tuberculostatic activity [85].2-dlphenyl-4-(indol- 3-ylmethyl)pyrazolidine-3. S-[~-Carbomethoxy-B-(indol-3-yl)ethyl]thiuroniumhydrobromide obtained from the methyl ester of ~-bromo-8-(indol-3-yl)proplonic acid and thiourea is cycllzed upon heating in water to give 5-(indol-3-ylmethyl)thiazolidine-2. Br. carbon disulfide. Ind-C[{(CII3)-COOCIl ~ + LiCII=N=C ~ Ind-'CH(CII'~).J c' . H~ F" it. which display strong vasoconstrictor activity [93]. ~ Ind-(CII2). repellants [92]. H H LX R : H. "O 1 LVIII Suvorov et al. ~sH5 ~\ c.

. 4-chloro-5-methoxyindol-B-yl.zNtICO0~2 H 5 "CO 7 CIt2NIt 2 I LK'r 12/'.~ii IXIV R = H... a series of indomethacine analogs LXIV has been prepared containing a tetrazole residue instead of the carboxyl group. LXVI gives 8-(tetrazol-5-yl)tryptamine (LXVlI) which displays antidepressant and hypotensive activities [i01].[I." 2 1{ COOC . CI{. CII2COOC.4-t riazole. The synthesis of these compounds is carried out by the prolonged heating of 3-indolylacetic ac- ids with sodium azide and aluminum chloride [96] or ammonium chloride [97] in DMF or THF.' e . This compound also has antiserotonin and antihistimine activities [98. R = R* = H) [97]. CH30. I L x~WII Ind* = 4-chloroindol-3-yl.5-bis(indol- 3-ylme thyl) -i.. . R* ffi H.":<. ~ ]I i! l) 1. Upon alkaline hydrolysis and decarboxylation. The reaction of ethyl ester of 3-cyano-3-(indol-3-yl)propionic acid with sodium azide and ammonium chloride gives the ester of 3-(tetrazol-5-yl)-3-(indol-3-yl)propionic a c i d (LXV). which yielded 4-amino-3."~ N ~ .V[H . Indol-3-ylacetonitrile has been used in the Knoevenagel reaction with several hetero- cyclic aldehydes to give trisubstituted ethylenes LXX [104]. 9 t:~ m.l n ( ] ' 9 t:H .' h)d I CH [I i. Br. CHs Of all the compounds synthesized.>:. In the search for effective anti-inflammatory agents.:" . 2. N -N N . t~.X 2nd ~ = 6-chioroindol-B-yl Taborsky [103] obtained an unusual result upon the prolonged heating of indol-3-ylace- tonitrile with anhydrous hydrazine (in 2:1 mole ratio)..l '. ':/ ! ~"~" N N ! It 1II H LXll The cyclocondensation of indol-3-ylacetonitrile with B-mercaptoethylamine gives good yield of 2-(indol-3-ylmethyl)-Al-thiazoline (LXII). i00].. ~ h~d ! CH [i . INI l i " N ] N .. 119 . N N N ~ N -N indl -C}I-CN - N.li > L:...T i: cN NtI~ r t ). which combines significant bacteriosta- tic activity with low toxicity [95]. 6- chloro-5-me thoxyindo l-3-yl N-Acetyl-~-cyano-8-carboethoxy-6-chlorotryptamine reacts with sodium azide in the pre- sence of AICIs to give the corresponding tetrazole LXVIII. Cl. These tetrazoles (LXIII) were subsequently acylated at the nitrogen a t o m of the indole frag- ment in the presence of sodium hydride [97-100]. greatest activity was found for 5-(l-p-chlorobenzoyl- indol-3-ylmethyl) tetrazole (LIV.. NHAa NIIAe i N N N .d' e. ~/ " N/ COCJ14CI i). i H JP" N .. which upon alkaline hydrolysis is converted to ~-(tetrazol-5-yl)-6-chlorotryptamine (LXIX) [102].2H5 (. which upon hydrazinolysis and subsequent Curtius rearrangement in the presence of ethanol is converted to the corresponding urethane LXVI.N~ .C2Hso 11 CH2COOC~II 5 }I i I{ I "N H .~ COOCIH~ :i 1[ NI.. ]L hi . N N~'I~ .

.....C" " "oc~% l~... Indol-3- ylacetonitrile and B-(indol-3-yl)propionitrile and aromatic nltrlle N-oxldes...2-bifunctional compounds yields a large number of var- 120 . We should also note that 2-(indol-3- yZalkyl)-AZ-imidazolines (LXXZZ. Thus. s-C4Hg~ indol-3-ylmethyl In our previous work [112-116].. . 3-cyanoindole. we have shown that the cyclocondensation of carboxylic acid iminoester hydrochlorides with 1. 2~ Ar = Ph... from the ethyl iminoester of 3-indolylacid and a-amino acids according to the scheme: Ind --CHI-C ~NH ~ + tI2N-CHR-COOH .. generated ~n s~r from the corresponding arylhydroxamic acid chlorides.....C[{R'(CH2). . A~ i . ii0]... l[Id ~-(CH~)n'~CN N 0~ .... i-CsH~. CHs0... i-C4Hg.4-oxadiazoles (LXXI).C|I* llot Bet = s 1-benzylimidazolin-2-yZ. These authors [105-107] have noted that the yields of adducts LXEI synthesized by the thermal condensation of nitriles with arylhydroxemic acid chlorldes are signlficantly higher than in the reaction with nitrile N-oxldes.... Clls....... Oxadiazoles LXXI were also obtained upon heating of these nltriles and arylhydroxamic acid chlorides in an inert solvent for >48 h.2.... "r:<~. However~ only limited information is available on the use of indole acid iminoester hydrochlorides for these purposes....... CIIR_(CII2)n_... R z = R 2 = H..4. .=(~llO ~ h~d {!~...... The condensation of indolylalkanoic acid imlnoester hydrochlorides with ethylenediamine has been described [108-110]. [111] have synthesized 5-imidazolones (LXXIIs which are unstable under ordinary conditions. gave 3-aryl-5-[(Indol-3-yl)alkyl]- 1........ {~N lnd*~ClI~*CN + [Iot.. n = 0. Fel'dman e t a l . n = l) displays strong sympatholytic activity [108]. ...... ..... 3-CHsC6H~ Dyankova et el. n = l) have recently been found to possess pronounced ra- dioprotective activity [5. 4-ClCsHd.. This reaction proceeds rapidly under mild conditions and gives a high yield of 2-substituted A2-imidazolines (LXXII). ~ Ind ~-CIt2--c~NIt'HC1 0H~ N~ ~F ~0 ~NIICHRC00C2H5 ~_C2Hs0H ~ Ind --CH2~ ~ ' 12~III R = H. R'.I'"....... 3-CHsOC~H~. [106..~/~" I Zl " -NIIdCt It L~XII R = H. CI. . R 2 = H. Carboxylic acid iminoester hydrochlorides may be used as convenient starting materials in the synthesis of various azoles. Ph. 4-meth- ylthiazol-2-yt A convenient method f o r the p r e p a r a t i o n of indolyZoxadiazoles e n t a i l s ~he s cycloaddition of indole nitriles with nitrile N-oxldes [105]... 107] have found that the best yleld of adducts LXXI is achieved upon carrying out this reaction in the presence of boron trifluoride etherate.. 4-OaNC6Hd...... . ~ /~ Ind --CIIz-C~ NH ~2H50H OC2H5 -C2}Is0|I NHCftRC00H HCI .. ... i. i 2-[B-(lndol-3-yl)phenethyl]-A2-1midazoline hydrochloride (LXXs163 R = Ph.... which enhances the dipolarophilic activity of the nitrile group due to complexation.}1 . . R x = II..... -HCI n = 0.S)'~"...

4-OiNC~H4.3. Hydrazides of substituted 2-indolylacetic acids upon treatment with cyanogen bromide in an inert solvent give 2-amino-l.5-disubstituted 1. i. 4-CIC~H4.4-oxadiazoles (LXXXI) containing indole fragments at C(.3. NR. and acid amidoximes lead to the corresponding 2-substituted A=- imidazolines (LXXIV.y l . CHIC1. X--J ] Ind--(CH2).2. C1 5-(Indol-2-yl)-l.) [123].m e t h y l i n d o l . O.5-disubsti- tuted ].f . benzimldazoles (LXXV. X = CI. 1. N ~ Ind1---c~S + R-C0-CH2X NH2 -H20 -I~ IndI S LXXVII Ind I = l . CHIC1.4-oxadiazoles (LXXI). 4-CHsOC6H~.( C H 2 ) dX. Robba [119] and Ainsworth [121] have noted that heating N-acyl derivatives LXXVll with phosphorus pentasul- fide gives low yields of 2. benzoxazoles (LXXV. R z = H.3i4-oxadiazoles (LXXIX) [119.4-thiadiazoles.l" "~o~ --Ri LXXIV "NH2 lad --(CH2)~--Cz~'0C2115 NH'HCI-~[ 2 ~NOH R'-C~I~i2_ N ~/R"o N--]~ ~ -:~ :~ o~ n = O.__. R = H./"CH3 ~. X = 0).3. R = R z = H) was also synthesized by the reaction of 2-indolecarboxylic acid hydrozide with ethyl orthoformate [119.4-triazoles containing indole fragments.4-oxadiazoles (LXXVI). 2-thien- ylmethyl. X = NR).3.3.i n d o l . X = NH. Rt R~ H H LXXVII! R = H. o-aminophenol. C6HsCHI. CHIC1. 2-thienyl. hydrazides. Heating N-acyl derivatives of 2-indolecarboxylic acid hydrazides (LXXVIII) with POCI3 gave 2-substituted 5-(indol-2-yl)-l.4-oxadiazoles (LXXX) [122]. CHICH=CN.3 .5-disubstituted 1. Br Indole acid hydrazides have found as yet only limited use for the preparation of 1. indol-3-ylmethyl. R = CH3. Ph.2 .] | ~HXCH2CH2NH2 R1CONHNH2 N---N . 118]. 120]. the reactions of 3-indolecarboxylic and 3-indolylacetic a c i d ethyl hy- drochlorides with N-monosubstituted ethylenediamines. X = NH).4- oxadiazoles. A2-oxazolines (LXXIV. Thus. 121]. r------. 5-nitro-2-furyl The use of indole acid thioamides for the preparation of indolylazoles has been indi- cated only in a report of the cyclocondensation of l-methyl-2-indolcarboxylic and 3-indole- carboxylic acid thioamides with halomethyl ketones to give 2-indolyl-4-substituted thiazoles (LXXVII) [117. /CH 3 .4-oxadiazole (LXXIX.3.4-thiadiazoles. R' = H. 5-nitro-2- furyl. CH3. Ph. o-phenylenediamine. and 3. CHCI2. 2. indol-3-yl. Ji. and 1. CH3. monoethanolamine.ious azoles.2. R R ~'~ . I n d ' .y l . 121 . Ph. Ph. N---N LXXX Treatment of benzylidene derivatives of substituted 3-indolecarboxylic acid hydrazides with bromine in the presence of sodium acetate in acetic acid or iron chloride in ethanol gives a 38-40% yield of 2-phenyl-l. X = O).3. R= = CHs.

i]/''''0''~- C~H$ %-'""~'N. l-(2-methylindol-3-ylacetyl)-4-R-thiosemi- carbazides (LXXXV) cyclize to give high yields of 4-R-3-(2-methylindol-3-ylmethyl)-l.4- triazoline-5-thiones (XC).--N l.. R R' R = H. /CONHN=CHCeH" "'///'"I]. .2. Heating LXXXVll with orthophosphoric acid gives 40-45%yields of N-substituted 2-amino-l.4- thiadiazoles (LXEXIX).XXXlX "~ --~" Ind :~'~CONHNHCSNHR Ind2 / ~ O ~ N H R LXXXV]I NaOH N--NH Ind2 N S R XC [nd 2 = 5-hydroxy-2-methylbenzo[g]indol-3-ylD R ffi C H s . cH~ I .. + KI | I.XXX. benzthiazol-2-yl Upon heating at reflux in alkaline solution. N--NH CH~ -r L~N~CH 3 ~ LXXXV H LXXXVl R = CHs..4-oxadiazoles (LXXXVIII). / . Ind --(CH2)n-'C~NHOK+CI-(CH2)3-Br Na2CO~ CI CO" Ind ~-( 12)n. C6HsCO.4-oxazole-5-thione LXXXIII. which display antimicrobic activity. 4-CIC~H.. Ph Indolylisoxazolidines XCl are formed in 50-60% yield upon the treatment of potassium salts of indol-3-ylalkylhydroxamic acids by 1-chloro-3-bromopropane in the presence of base [1261.. 122 ... [123] also showed that the reaction of 5-hydroxy-2-methylbenz[g]indole- 3-carboxylic acid (LXXXII) with carbon disulfide and base in ethanol gives the corresponding 1.. CHs Hiremath et al.3.. HNHet I N--NH N--N/CH2 ~S H ~ ~N~ ~CH3 CH2-~-~O~ N ~'~CH~ T.. H~PO4 ~ N--N Ind 2 /~['S ~/~NHk N. [125] in 1981 reported the synthesis of various types of indolylazoles using thiosemicarbazides LXXXVII. N R~O' 7 .. . Hiremath et al. The oxidative cyclization of LXXXVII by iodine in an al- kaline solution of potassium iodide gives N-substituted 2-amino-l.II IXXXIII Her ffi 4-phenylthiazol-2-yl.3 XCI The reaction of methyl thioesters of substituted indole-3-dithiocarboxylic acids with aminoacetaldehyde diethylacetal has been used to prepare 3-(5-ethoxy-A2-thiazolin-2-yl)in - doles (XCII) [127]./ ~0" n=l.4- triazoline-5-thiones (LXXXVI) which are cardiac activity stimulators [124]. which upon the action of formaldehyde and 2-aminothiazoles is converted to Mannich bases LXXXIV.... 4-ethyl-S-methylthiazol-2-yl.. Ph.3.2. while heating of this compoundwith aqueous alkali gives 4-R-I..3.... R I = H. CH2 : CH-CH~.....

Ph Tominada et al. Harris [129] has proposed using indol-3-yltrimethylthioformamidinium perchlorate (XCVI) obtained from indole and chlorotrimethylthioformamidinium chloride as the key compound for the synthesis of indolylazoles. +" - J -. J3C2H 5 ~ ~ C~scH3 + 'H2NCHaCH(CCzHs)2 _.-N "~ . in using this method.%~~. .. 136] have synthesized 4-(l-acetylindol-3-ylmethyl)-2. .5-oxasolid- inedione which displays strong anti-inflammatory activity and is a central nervous system stimulant by the action of phosgene on l-acetyltryptophan. H .. respectively. the starting sulfur-containing compounds are not readily prepared due to dis- advantages of the latter two synthetic methods.// i . H XC. 132]...=H~NCII?CH>XH ~ N H 2 XCVI ~x-J X=O... Thus.I Salt XCVI has high reactivity in reactions with bifunctional nucleophilic reagents and thus various hetarylindoles may be prepared using this ~ompound [130]. R* = H.5C. N--N N-q Ind S NH2 I n d -. CH. we encounter great difficulties due to the extremely hy- groscopicity and instability of the starting chlorotrimethylthioformamidinium chloride and perchlorate.~. . . which require special care in their use.. 123 . .+ \ ? .... .S . The use of phenyl isocyanate instead of ammonium thiocyanate gives 3-phenyl-5-(indol-3-ylmethyl)-2-thio-4-imidazolone [133~ 134]. . CH. "r "~'" 3 ~>'~" "" " N'" " Cli~ I CH3 XCV However. Indole amino acids and hydroxyacids and their derivatives have also been used for the synthesis of several types of indolylazoles.. /C-----N 0 /.Ind However. Oki and Nagasaka [135. "</ "iN" "CH~ /--. 2-Methyl-4-(indol-3-ylmethylen)-5-oxazolone (XlX) was synthesized by the Bergman method involving treatment of N-chloroacetyltryptophan by acetic anhydride in pyridine [37]. [128] have described the preparation of indole derivatives of A~-imida - zolines XCIV or Aa-oxazolines XCV from the iodomethylate of 1._ R XCII R = H. tryptophan and ammonium thiocyanate in acetic anhydride gave l-acetyl-5-(indol-3- ylmethyl)-2-thio-4-imidazolone [131.2-dimethyl-3-indolcarboxylic acid thiomorphilide (XCIII) and ethylenediamine or ethanolamine. < ~S~.

.XCVll R = CHs.. which is an inhibitor of tyrosine and hlstldlne decarboxylases [139]... I (H2N)2C=S Ind --C 0 I NIl 2 /CH~ [ CH~ C _ _ -.~ * H"I" II H XCVIII XCIX In addition to indolemycin XCVIII itself...4-oxazolidinediones CI.C00C2]IS "~011 + CH .-.. The condensation of these esters with urea leads to a mixture of diastereomeric 5-[a-(indol-3-yl)ethyl]....~ + . N Ind CLT~Cli C. L~ CN CH. in turn. while this reaction with methyl isocyanate leads to diastereomeric 3-methyl-5-[u-(indol-3-yl)ethyl]-A2-oxazolidine-2. Considerable interest is found in the method of Oikawa et el. [137.N'-dimethylguanidine......--.OOCIi.N'-dimethylguanidine gives some amount of isoindolemycin XCIX as a result of the ready stereoisomerization of indole- mycin under alkaline conditions [141].. 2-methyl-5-(indol-3-yl)oxazole (LIII) which entails the oxidation of the methyl ester of N-acyltryptophan by dichlorodicyanoben- zoquinone in anhydrous TRF to give a high yield of 2-substltuted 4-carbomethoxy-5-(indol-3- yl)oxazoles (XCVIZ).. 138] for the pre- paration of analogs of the pyrlmidine antibiotic. 0 CI. [142-144] have shown that.. may be obtained by the hydroly- sis of 2-amino-A2-4-oxazolinones C [145]. NHCOR CI "~ "'CN Ind " "0 "R o . Ph.2- dimethyloxazolidine. The cyclocondensation of the esters of racemic indolemycinic acids with guanidine or urea and several other compounds was studied in order to prepare indolemycin analogs and de- termine their biological activity [145]. Rao [140] isolated the antibiotic indolemycln from natural substances and iden- tified it as 2-methylamino-5-[a-(indol-3-yl)ethyl]-4-oxazollnone. N-methylthiourea may be used as the second component of the reaction for the preparation of indolemycin. ~ N "' CH~ (CH3NH)'C=NH. II. . ..A2-oxa - zolidine-2.~-j.... [141]. The reaction of indolymycinic acid esters with guanidine or thiourea gives a mixture of racemic 2-amino-5-[a-(indol-3-yl)ethyl]-A2-oxazolin-4-ones (C) [145]. Preobrazhenskaya et al. which is converted upon hydrolysis to the corresponding 5-oxasolidinone.H4 The reaction of tryptophan amide with acetone gave 4-(indol-3-ylmethyl)-5-imino-2.4-diones (CI). this antibiotic was prepared as a mixture of two isomers XCVIZI and XCIX by the scheme of Shach et al.. H H _NHCH~ CH~HN -~ ...-~-CO0 CzH ~ .. 4-CHs0C..4...N CH~NCO lnd --CIt-CH(OH)~OOC2H5 Ind --C I 0 CH3 CH~ CII Ind -.r.. in addition to N.~OOC. which are also formed upon the methylation of 2. which...diones (CII)....... In 1963. the condensation of the ethyl ester of a-hy- droxy-B-(indol-3-yl)butyric acid (a-indolemycinic acid) with N.CH 0--O I CH~ CI 124 . In 1960.

O C61L o~ N td~lt~ Ind. As noted above.+ -. R 2 = H. N R O--S02CH 3 Ind --C S NIl Ind .. SYNTHESIS OF INDOLYLAZOLES FROM INDOLE AMINES The N-alkylation of azoles of indole Mannich bases. 3-(N. the action of indole Mannich bases on azoles does not yield transamination products. heterocyclic substrates are alkylated only in apro- tic media such as upon heating in xylene at reflux [150. . R2' = (CH2)5 .) and their derivatives obtained upon acylation of the indole ring at the nitrogen atom are effective antiviral compounds [148].C S NHR' cm ) R R I ely CV R. CtH~CH2.nd-CH2. 5-pyrazolidinedione gives exclusively the dialkylation product CVII. ~ O NH _ _~_ N 0. R 3 ffiCH3. CH3 Diastereomeric 2-methyl-5-[a-(indol-3-yl)ethyl]-~-thiazolin-4-ones (CV. The condensation of CIII with thiourea or its derivatives gives a mixture of 2-imino-3-R-5-(indol-3-ylalkyl)-4- thiazolinone (CIV) and 2-amino-5-(indol-3-ylalkyl)-A2-thiazolin-4-one (CV) [146-148]. namely. R =R~ = R 2 = H). 5. The dialkylation reac- tion is facilitated by an increase in temperature to 160~ and the use of polar aprotic sol- vents. thromboses.N-dimethylaminomethyl)indole (gramine). alkoxy. 3-(N-piperidinomethyl)indole [149-151] and substituted gramines [152-154] has been used rather commonly for the preparation of indolylazoles. The methyl esters of racemic a-hydroxy-8-(indol-3-yl)propionic acids serve as starting materials for the preparation of thiazoline analogs of indolemycin. l-(indol-3-ylmethyl)benzimidazole (CVI.2-diphenyl-3. With the exception of benzimidazole. the condensation of ethyl 3-indolylmethylmalonate with hydrazobenzene leads to 1. Upon the action of meth- anesulfonyl chloride. Greatest interest among indolylazoles CVI is found for substituted l-(indol-3-ylmethyl)- imidazoles which may be used as drugs in cardiac disease.. Ind --CH-CH-COOC2H 5 + H2 NCSNHR~ .5-pyra- zolidinedione by the methylsulfomethylate of gramine in DMF [157]. 151]. O~__N/Ce~5 Ind CH2"-NICH3) 3 "~" a~ . this compound was obtained in higher yield by treating the sodium salt of 1.CH2N(CII3) 2 4 << I .. NH2. alkyl. alkenyl.5-pyrazolidinedione [84]. pyrazol-l-yl. On the other hand. R = R* = CH.2-diphenyl-3. and diabetes-related vascular problems [153-156]. acyl. / ] O" Cell 5 0<" XC6115 CYI! 125 . Her = imida- zol-l-yl. Subsequently. alkyl. CF. benztriazol-l-yl It is noteworthy that in addition to the direct alkylation product in the alkylation of indole by l-(N-piperidinomethyl)benzimidazole. HO. -CH~OSO3Na CH3OSO s O~ ~CeH s [ Vampilova [157] also indicated that the reaction of gramine itself with 1. R CVl R. R* = H... R* = H. these esters are converted to O-mesylates CIII. benzimidazol-l-yl. 3-(N-piperidinomethyl)indole is formed as the result of a transamination reaction and benzimidazole is also obtained [149].2-diphenyl-4-(indol-3-ylmethyl)-3..

y l ) . The alkylation of these derivatives at C(.. ' ] / R R R CXII CXIII R = CHs. Ar = Ph.N-PO] " ~ 2 "~I. COCHs. Despite extensive studies in this area.. These dipolarophiles were used in the 1. 4-ClC6H~| H e t = 3 .. The synthesis of 2-amino-4-(indol-3-ylmethyl)-Aa-thiazoline (CVlll) from a-chloromeChyl- tryptamine hydrochloride and thiourea was carried out in a search for radioprotectlve indole derivatives [158]. These authors also noted that the presence of electron-with- drawin~ substituents in the indole ring (5-N02 or I-COCH3) enhances the reaction rate and the presence of a methoxy group reduces the reaction rate.hl d CXl R = NO2.-C~N-*Ot D. Ar ~ .A 2 . Ph../CsH 5 C2H500C ~ ...2-dimethylindole) and oxyfemedol (5-hydroxy-3-ethoxycar- bonyl-l-phenyl-2-methylindole) [106. dimecar- bine (5-hydroxy-3-ethoxycarbonyl-l.. The cyclocondensation of esters of u-nitro-~-(indol-3-yl)acrylic acid or 2-nitro-1- phenyl-3-(indol-3-yi)-2-propen-l-one with sodium azide gives 4-substituted 5-(indol-3-yl)- 1. / R I Ind'-CH=CRR I + [Ar. 159]. .. CN.a r y l - a~-isoxazolin-5-yl The adducts synthesized in this reaction CXIII inhibit chollnesterase activity and act as central nervous system stimulators and hypotensive agents. one of the most general methods for the synthesis of various heterocyclic systems is the 1.[ ' ~ R N~ 0/'~-.5 . THE PREPARATION OF INDOLYLAZOLES FROM OTHER INDOLE DERIVATIVES Presently. the information of the participation of indole derivatives in these reactions has been lim- ited. R I = H. ~ [Ar-C~. Ar ffi Ph. The use of indole acid nltriles as dipolarophiles in 1. 126 .i s o x a z o l i n e s (CXI) in 17-53% yield..3-triazoles (CXIV) [160]..3-dipolar cycloaddltion reaction. N ' ~ "~ll~ NH~' HCI CVlII 6.) yielded the corresponding allyl derivatives CXII.3-dipolar cycloaddition with nitrile N-oxides has already been discussed above [i05-i07]..( i n d o l ./Celts Ind-"CO~ 0 I d' r CX Dyankova [106] has d e s c r i b e d the c y c l o c o n d e n s a t i o n of s e v e r a l s u b s t i t u t e d i n d o l e a l k e n e s with aromatic n i t r i t e N-oxides to give 4 . CH2~II:CH2 CIt2~Het H0 I COOC2H5 HO ~" C0VC2H ~ HO. namely.a r y l . . Piozzi and Fuganti [60] have synthesized the corresponding indolylisoxazolines ClX and CX in the reaction of vinyl 3-indolyl ketone or the ethyl ester of 8-(indol-3-yl)acrylic acid with benzonitrile N-oxide. COOCaHs.... 4-02NC~H4..2.\s~___ [ ~ cOO%H~ " ~" . .3 ... 4-O~NCsH~ A series of indolylisoxazolineswith interesting pharmacological properties was obtained upon the introduction of the isoxazoline fragment into known indole drugs. ~1.3- dipolar cycloaddition with aromatic nitrile N-oxides.s u b s t i t u t e d 3 ..

R ~ = H. These r e a c t i o n s give good y i e l d s of 3 . CHsO. R* = H.R . i = CsHT. 4-02NC6H. The r e a c t i o n of 2 .i s o x a z o l i n e s CXVI.( 1 . 127 .p h e n a c y l - 5 . C2Hs.a r y l .3 . Ar f I n d --CH-CHzNO 2 + R--CH:CH 2 %HsNCo md.4-(CHsO)2C~Hs. "i----- CXV R = CHs.R . among which com- pounds have been found w i t h a n t i b a c t e r i a l and a n t i f u n g a l a c t i v i t y . 4-pyridyl. H e a t i n g CXXI or CXXII with a l k a l i in w a t e r . 161. r e s p e c t i v e l y [164.y l ) p y r a z o l e s (LX). C00CHs N-(Indol-3-yl)alkylthiazolines (CXVII) displaying antiactinic activity were synthesized by the reaction of 2-[ (indol-3-yl)alkylamino]ethanethiols with Rongalite (formaldehyde sod- ium sulfoxylate) [163].y l ) i s o x a z o l e s (XXXIX) or 1 .( 1 . I ] ind-. Ph. 3.p h e n a c y l .5 . 162]. NO2 The 1. These adducts display pronounced anti-inflammatory activity comparable to that of indometh- acin.5 .A 2 .d i a r y l . C2HsO.y l ) p y r i l i u m p e r c h l o r a t e (CXVIII) with hydroxylamine or p h e n y l h y d r a z i n e gave monooxime CXIX or monophenylhydrazone CXX.N ~ / ~ S CX~I n=2-5 Zhungietu e t a l .3 ./~'-R c X~.5 .p ~d--(CH2)" .i n d o l . These N-oxides are r e a d i l y formed i n the d e h y d r a t i o n of the c o r - r e s p o n d i n g p r i m a r y n i t r o ~ompounds u s i n g p h e n y l i s o c y a n a t e i n the p r e s e n c e of t r i e t h y l a m i n e . 6 .d i p o l a r c y c l o a d d i t i o n i n v o l v i n g i n d o l e n i t r i l e N-oxides [106. ROC~ I i t CXIV R = CHs0. [164-167] used i n d o l y l p y r i l i u m s a l t s f o r the s y n t h e s i s of i n d o l a z o l e s .3-dipolar cycloaddition reaction of indole aldimines with aromatic nitrile N-ox- ides was used to synthesize 4-alkyl-3-aryl-5-(indol-3-yl)-A2-oxadiazolines (CXV) [106].4 .A 2 .R - i n d o l . CN.a r y l .-I Ar = Ph.( 1 .(CH2 ) _NHCH2CH2SH + HOCH2SO3Na ---.i n d o l .i n d o l .( 1 .R .3 .~ t h - anol a t r e f l u x gave 3 .p y r a z o l i n e s (CXXII). 4-C1C6H4 S i g n i f i c a n t i n t e r e s t i s found i n the 1 . r~ Ind-CH~-R § [Ar-C~.( 1 .i s o x a z o l i n e s (CXXI) or 5 .p h e n y l ..N-~OJ ---~.3 . 4-CHsC6H.y l ) . CHs| R 3 = H.. 165]. COCHs. which upon h e a t i n g in a c e - t i c a c i d c y c l i z e to give 5 . R = Ph.3 . 5 . 3 ..R .3 .y l ) .i n d o l . Ar = Ph.d i s u b s t i t u t e d A 2 . F--~-- . n-CsHT.C H ~ I ar (CaHs)~N N'-O.11.

. The treatment of CXXVI with hydrazine hydrate in ethanol gave 3(5)-(indol-3-yl)pyrazole (XXIX)._J/ In~ ~ = l-methylindolyl-3 Stupnikova et al.. CH3 It -CH~N=CHN_"2 11 .N OH . -ArCOCll~ / . In conclusion.. -ArCOCH~ /~'N" IIL ~" CsH5 ma Csl[ I ~ Ar ~'-"0 C~ Ar CXXI! Ind ~ = l-methylindol-3-yl. l-methyl-4-(3-1ndolinylidene)-l.4-thiadiazole (CXXVIII) [173]._J~_NHNH 2 CeH~ j. whose structures were established by chemical and spectral methods._.4-di- hydropyrlmidlne (CXXVl). we note that two new indolylazoles were recently isolated from natural substances. 4-CH~CIH.... Ar .._~x~ 0+ _ CX~X CXX! ClO~ Ar Ar ' ' .... One of these compounds was identified as 2-imino-l. while the other was identified as 3-dimethylamino-5-(indol-3-ylcarbonyl)-l. whose formation apparently proceeds by the following scheme [170]. 2.. H CXXV CXXVI This anhydrobase holds considerable interest as an intermediate in the synthesis of var- ious heterocyclic indole derivatives including indolylazoles [168-171].. ._/ H XXlX The reaction of CXXVI with hydroxylamine in acetonitrile gives a low yield of 3-(indol- 3-yl)isoxazole [171]. .CsH 5 Ind ~ + ~ InclI ---(' 0 ~ ~'N/~" -CsH~OH I CIO 4 - / /OH CXXIV CXXIII ~. 128 . ~ / ~ N .....3-dimethyl-5-(indol-3-ylmethylene)-4-pyrazolidinone (CXXVlI) [172]. Heating hydrazlne hydrate with 4-(l-methylindol-3-yl)flavinlum perchlorate gave 3-phen- yl-5-(l-methylindol-3-yl)pyrazole (CXXIV) as the flnal product [166].N XXXIX Ax Ar Indl. CsH 9 ~CeH5 . Ar = Ph._~ / .. ..l NHCsH~ Ar Ar /~ . . NHNH2 NHNH 2 ~ _. l-benzylindol-3-yl. [168-170] have recently established that treatment of the iodomethyl- ate of 4-(indol-3-yl)pyrimidine (CXXV) under mild conditions with ethanolic KOH gives a quan- titative yield of the completely stable anhydrobase.

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etc. Nuzhnaya. ii. Guyot. Akad. Chervinskii. Stupnikova.. 169. Yu. A. Ya. 6. we note only that expressions for the reactivity indices of such re- actions. wfiich were obtained on the basis of the coupled variant of perturbation theory for a transition density matrix in the PPP method [9]. 15.* PHOTOISOMERIZATION OF FIVE-MEMBERED HETEROCYCLES Yu. S. 9. V.. Klyuev. Klyuev. 173-180. A. No. Baranov. J.. M.168. 5]). as well as on the alternative method of correlation diagrams (see [3. No. 212 (1982). more easily subjected to quantum-chemical treatment. N. 170. and R. Nuzhnaya. Soedin. A method for describing photochemical reactions of the X type in Dougherty's terminology [3]. No. 6-8]. Institute of Physical Organic Chemistry and Carbon Chemistry. V. Murphy. T.. T. one of whose main steps is photoelectrocyclic contraction or ring formation. Dokl.. therefore. Backef. Baranov. Heitz. Kazlanskas. Getero- tsikl. pp. B. Nauk UkrSSR. B. Khim. Durgeat. for example.141:539. V. Donetsk 3 4 0 1 1 4 . (1) Then from the expression for the change in the n-electronic energy of the ground state in first-order perturbation theory with respect to ASik 6Eih ~ = 2 P ~hA~ik (2) it follows that in the ground state the bond orders between the not directly bonded atoms Pik can serve as the reactivity indices in intramolecular recyclization and cyclization re- actions. S. Brassy. Khlm. 51 (1980). V. Stupnikova. T. Nauk UkrSSR. QUANTUM-CHEMICAL TREATMENT OF RECYCLIZATION REACTIONS. Original article submitted July 31. and B.50 9 1986 Plenum Publishing Corporation 133 . and S. N. Tetrahedron Lett. 2. the reactiv- ity is determined mainly by the changes in the electronic structure of the molecule upon ex- citation and is. R. 61 (1977). [4. Academy of Sciences of the Ukrainian SSR. Sivyakova UDC 541. R. and the perturbation matrix is rep- resented by the following matrix elements: (H~)~= ( ~ 6 ~ + 6 ~ h ~ ) ~ . Tetrahedron Lett. N. we developed in [2]. In such reactions the energy of the light is utilized only for bringing the reactant into an excited state and is not converted into the thermal energy needed for overcoming the activation barrier.. Vysotskii and L. T. 0009-3122/86/2202-0133512. 1566 (1980). B. T. Without dwelling in detail on the problem of using the index approach for the description of the reactivity of molecules in electronically excite~ states (see. Soedin. 173. February. V. Ser. Geterotslkl. Wells. and S. 53 (1982). No. M. 1986. A. G. I. etc. and L. P. Lopatinskaya. In this case. Zaritovskaya. 172.72'77'78 The pho~oisomerization of a number of five-membered heterocycles has been con- sidered in the framework of the coupled variant of perturbation theory for a one-electron transition density matrix in the n-electronic approximation of the MO--LCAO-SCF method. Here the perturbation may be characterized as intramolecular coupling (see [3]). Set. J.196:547. Stupnikova and Kh. N. spent on light-induced electron transfer. C. V. were presented in [2]. Klyuev. 1984.) in the case of electrocyclic reactions. 1457 (1980). Translated from Khimiya Geterotsiklicheskikh Soedinenii. No. Stupnikova. No. Akad. Quinn. Dokl. *For report 8 see [i]. Nuzhnaya. V. 8. 2. No. M. 171 9 T. T. N.

. Several quantities whichare directly or indirectly related to them were used in [13-15]. O ( D ) ] _. .i:>--. and its conversion into the vibrational energy of the ground state.88) 6Ei: = 2. . ii].. "o'( ". i. The arguments in sup- port of the use of AP*ik are based on the correspondence between these quantitites (see [ii]) and the location of the excitation energy in a molecule. (3) and for triplet transitions calculated in the Tamm-Dankov approximation. "i. which are generally calculated according to the HUckel method. In the cases in which this strengthening (increase in the coefficients Kik) is so great that the sum of the indices Pik and Kik becomes positive (see [2]).Yr = 2K~. the change in the ~-elec- tronic excitation energy in first-order perturbation theory with respect to ABik may be writ- ten for the slnglet states in the form [9] (Eq. from the data in Table 1 (see also [2]) it follows that the photorecycli- zation of the furan molecule in the S.~h. .. and in states $2 and T. etc. In the present work we examined the relationship between the indices Kik and the occur- rence of the photoisomerization of several five-membered heterocycles in the PPP approxima- tion. The bond orders in elec- tronically excited states. Table 1 presents the indices for the four lowest singlet and triplet states of fur- an. which reflects the change in the electronic structure in the ground state under the action of perturbation (i). pyrrole. in a given excited state) as reactivity in- dices is less substantiated and gives a poorer description than do AP*ik (see~ for example. The latter were used for the treatment of photochemical. ..:-. Ila II b II C II d . . The use of the sum of the free valences of the positions at which cyclizatlon occurs. in a similar manner we obtain 6E~.~m. di-~-methane.YY~. it should involve the formation of intermediate IIa followed by its isomerization to IIb. . 17]). . particularly. . or localization energies ~of course. "o~ I III i ~ + CO ..J= Tr {2ItmYD2+2G (r~h) YD2+ [O. From the data presented it follows that the transition of a molecule to the excited states is generally accompanied by weakening of the bonds between the directly bonded atoms and strengthening of some of the bonds between the not chemically bonded atoms. . and supermatrix G describes the interelectronic interaction. which is the first step in its further conversions. D]_.: x ' 2 ..TA. photoelectro- cyclic contraction of the heterocycle. . (4) where D is the unperturbed transition density matrix corresponding to the excited state un- der consideration. When a molecule undergoes a transition to an excited state. Scheme 1 L 2 s '>: '. "%o~ ' ' . Yik is the matrix of bond--bond mutual polarizabilities... should occur at positions i and k. served as photoelectrocyclization indices in [12. its redistribution during a reaction. Mulliken populations~ including transition pop- ulations.. 15. and T2 states should take place with the formation of acylcyclopropene intermediate Ill.. rearrangements [10. and thiophene. 13]. O (D) ] _ Y r~h} = 2 K~:A. " . / "o[ "O] o I 134 . . For example. Tr {Hm YD 2+ O (Yik) Y D~+ [ D. + [G ( D r ) . [16. In [2] it was shown in the example of the photochemical ring-contraction reaction of furan that the main contribution to the indices Kik is made by the changes in the long-range bond orders AP*ik upon excitation of the molecule.

were discovered [23]. This circumstance should result in the photolytic cleavage of these bonds with the evolution of acetylene as the reaction product.4 T. the direct participation of the atoms of functional groups.4SI < [P=i4J and IK=. in fact. 18-22]. as follows from Table l. 19.. and. In this case. f. however.v -sit fr i "2 st" \ sli 3. As follows from the data in Table i. / 9 "-3 4 .4TI > IP=. 24]. 135 .. i. Sensitization by mercury [Hg(SPz)] gives a steady yield of CO and C3H4. especially in the T= state. cyclopropene was not discovered either upon the direct irradiation (Sz state) or upon the sensitization (Tz) of thiophene vapor [28]. the intermediate formation of a Weinberg zwitterionic tri- cyclic intermediate [27]. that the presence of strong electron-donor or acceptor substituents in a molecule can cause changes in the relationship between the Pik and the Kik and. A radical mechanism with subsequent recombination of the radicals has likewise not been ruled out [26].e. recyclization should involve the intermediate formation of a structure of type VI along path d in Scheme 2. in contrast to the case of furan. in the case of the S= and Ti states. 22]. as a consequence. isomerization should not occur owing to the fact that IK=. the photoisomerization of pyrrole in the second singlet and first triplet states should be similar to that of furan (path b). acetylene. In the second triplet state iK=. An analysis of the values of Kik for the pyrrole molecule (Table i) reveals that in the Sx state.4 S < K=. however. the photoisomerization of the thiophene mole- cule (IV) in the T= state should involve the formation of 1--3 and 2--4 (or i--4 and 3--5) bonds (paths a and b in Scheme 2). 22. the corresponding photoisomerization [19. be stressed. A structure of type V implies the active participation of the d orbitals of the sulfur atom [18. in contrast to the case of furan. 4 Ya ~'b vc (%) "s~ S2(TI) * VI . I x\C. According to the data from the calculation.. for example. The occurrence of a reaction along path a. The latter find- ing is consistent with the fact that K=. in the isomerization process is possible. when unsubstituted pyrrole was irradiated in the gaseous phase (Sz). We note that.J 1 \~ // [. A similar picture is also observed in the SI state.. 2. the 2--3 (4--5) bonds are weaker than the 1--2 (i--5) bonds (see Table i).~I. There are still no experimental data on the photoisomerization of furan in the $3 and Tz states (path b). Finally. of the nitro group [25]. without consideration of the d orbitals the positive long-range orders of the I--3 (i--4) bonds do not appear. has been thor- oughly studied [6.Sl < IP=. in particular. In fact. It should.sI.~_ 2 . Scheme 2 2 3 4 5 5 @ 3 I 5 _. which is large in comparison to the direct irradiation of furan. decomposition products.

117 0.375 0.II0 Pyrazole So --0.344 0.227 0.4 h'2 .024 0.344 -0.446 -0.105 .047 -0.045 0.i70 0.061 0. the value of Pik + Kik in the S.3 K.158 0.750 -0. this implies the pos- sibility of the occurrence of a reaction both along the ring-openinE-contraction--formation 136 .). It is seen that the isoxazole molecule (VII) should readily isomerize to oxazole.514 0.035 *The corresponding Pik are given for the So ground state.131 $2 -0.091 0.223 -0.051 St 0.0.314 0.358 0.078 0.284 0. 0.055 0.489 .3t0 $2 .070 0.0.0.732 Ti -0.0.065 zole St 0.223 -0.153 0.180 0.243 9 0.60.3 K3. Nevertheless.t31 0.150 T2 0.686 0. 0.021 -0.018 -0.831 0.094 0.390 " 0.201 T~ 0.356 0.460 0.4 K2.544 0.0.497 0.125 0.0.088 0.128 0.238 --0.209 -0.347 T.0.030 T~ 0.102 Isothia.189 0.291 -0.713 0.102 0.0.456 $2 --0.058 0.131 S.176 0.094 --0. 0.401 0. in the case of the $I and T2 states.035 0.431 0.070 0.068 0.144 -.535 0.763 0. 4.26 I 0.036 0.~ Furan So 0.122 0.442 0.241 .0..011 0.107 0.001 .666 0.370 0. Reactivity Indices in Photoisomerization Reactions of Azoles Compound State A'*I.740 0.0.282 --0.254 $2 -.0.092 *The corresponding Pik are given for the ground state So.0.361 0.040 St 0.087 0.107 0.0. IIO S~ 9 0.128 .079 0.052 0.196 .032 0.604 --0.0. 22.208 0.205 .627 0.146 0.0.559 0.165 0.018 0.184 0.726 -0.108 S.036 0.052 0.386 0. .070 0.241 .0.4 A'L. When the weakness of the i--2 bond is taken into account.136 -0.280 TL 0.189 0.101 -0.076 0.208 0.064 T2 0.292 0. So -0.092 0.5% 0.201 .052 0.205 0.155 -0.080 T2 0.352 --0.478 -.184 -0.864 Tt -0.356 -O.167 .274 --0.4O0 --0.064 0.367 Imidazole So -0.007 0. Reactivity Indices in Photoisomerization Reactions of Five-Membered lieterocycles Compound State K*I. TABLE i.372 Thiazole So -0.195 0.747 T~ -0.424 S.275 -0. 0.204 -0.465 0.205 0.086 0.037 Tz 0. 0.230 0.175 -0.2 K2.326 0.070 -0.400 St -0.348 $2 .758 .715 0.001 0.096 0.16I Pyrrole So 0.501 0.9 0.005 0.459 S.07 l 0.190 -0. There are still no experimental data on the reactions of thiophene derivatives in these states.0.054 0.354 -0.111 0. 0.056 $2 0.175 Isodazole So -0.025 T2 0.188 -0.050 T2 0.003 0.179 --0.282 --0.348 -.762 .355 Tt 0.0.101 0. .039 0.635 0.0.075 Thiophene So 0. 0.028 0.742 .196 0. lOI -0.305 0. Table 2 presents the indices Kik and Pik for photoisomerization reactions of azoles.058 0.~ Ks~ Oxazole So -0.071 0. TABLE 2.240 -D.180 0.332 0.736 7'2 -0.474 -0.082 0.043 0.315 0.0.849 T.350 -0. Scheme 2 is confirmed by all the data available in the literature (see monographs [19.386 -0.270 0.672 0.312 .201 -0.059 0.175 -0.256 Tt 0.064 0.262 $2 -0.090 0.763 -0.207 --0.187 -0.500 0.500 0.541 . 0.409 -O.033 0.378 --0.008 0.211 0.257 0.067 0.127 0.112 0.4 /(2.365 -0.028 . -O.014 St 0.0.058 .252 0.024 0.079 0.302 0.493 0.212 0.075 -. state being greater than 0 for both the 2--4 bond and for the 2--5 and 1--3 bonds.757 T2 0.3 A'2. 29] etc.

The influence of the functional groups on lthe direction of the photoisomerization of ox- azole is more pronounced than in the case of isoxazole. 137 . although this mechanism differs somewhat from that adopted in [22]. photoisomerization through azirine intermediate VIII (Scheme 4. We stress that. bonding be- tween positions 2 and 5 (the formation of intermediate Xlll) should not occur in this reac- tion. 30. although there is already another isomerization path with cyclization at positions 3 and 5. . 22. 30] and the literature cited therein. electrocyclization at positions 1 and 3 (intermediate XV). although the value of P2~ + Ka~ in the S. 29. b 'IX C md a I $1{$2'T1) . incidentally. . Since the values of Pik + Kik for the S.. Oi OT O1 ! i. in contrast to the case of the $2 and T. as is seen from Scheme 5.path and along the path of intramolecular cyclization with isomerization (with the intermed- iate formation of IX and X) or isomerization with the formation of a zwitterionic tricyclic intermediate. it gives the same products. The isomerization of isoxazole (VII) to oxazole (XI) is reversible. From the calculation in [22] it follows that the introduction of phenyl and/or methyl groups into positions 2 and/or 5 of the oxazole ring results in in- itial electrocyclization at positions 2-5 (intermediate XIII). 0 :_ J IXa LX. For the experimental data on this reaction see [19._N 2 -.~ . 5 ). rather than at 2 and 4 (intermediate XVI). Scheme 3). but also the reaction conditions. % "F--:r~" . states.. as follows from the calculation. it is curious that not only substituents.]. . and T2 states. state is fairly high. 29. the introduction of suhstituents should not alter the predominant direction of the reaction. Path b should also be predominant in the T2 state... 22. In the second triplet state the re- action can follow path b in Scheme 4 with the intermediate formation of XII. As is seen from Table 2. does not re- sult in isomerization to oxazole. the main reaction path should in- volve the intermediate formation of azirine VIII (path b. . which. while the reaction should proceed predominantly by means of bonding be- tween positions 2 and 4 in the T2 state. state. O o'1 ~ s~(r2) N'% ''~ -". is predomin- ant in the S. path a) being preferable for the oxazole mole- cule in the S.. have a significant influence. Experimental data confirming the conclusions drawn are found in monographs and re- views [19. However. according to the data from the calculation. " o~ VII VIII "1 '~ ('r:t) Xa i --~o x~b ~/---~ xc xd 4/___N2 4 N Z / 2 o~ o %( The photoisomerization of pyrazole XIV is distinguished from the isomerization of isox- azole by the fact that in this case. Scheme 3 %_. state of molecule VII are significantly greater than zero. particularly the solvent. in agreement with the data from the experiment and the nonempirical calculations with consideration of the configuration interaction in [31]. etc... according to the data in Table 2.

.. m. N ...).. 1-4... ~ . .. # %.... 5 4 F %__!.. With respect to the reverse isomerlzation of imidazole to pyrazole..~3 M Ht ~I X]V X~ blS~(rD '" ~' '~N"1 4" N2 3 2 It L s ...... The possible photorecyclization paths of the S. . . the predominance of a particular tran- sition state is greatly dependent on the nature of the substituents and the reaction condi- tions. "" ~ If o~ ~ . As we have already stated above. at the present time 95% of all the isomerization products of iso- thiazole and thiazole in the lowest singlet state (see [19. it follows from the calculated data that it should be completely analogous to the isomerization of oxazole.j L N2 -<>3 N~ 4 __N? 4 5 1t 1t It As was noted in [22]. The photoisomerlzatlon paths of pyrazole in the S= and T.. and 2-4 positions of thiazole and isothia- zole in the lowest singlet state (see Table 2).. 138 . 22....N3 4 'o'i 7 . 32.. 29. s2(r.. 33]) can be explained either by a tricyclic zwitterionic mechanism or by an intramolecular cyclization-isomerization mechanism.... this is manifested by the presence of large positive values of Kik S for the 1--3.. Scheme 4 3 2 3 01 xx .~ Scheme 5 3 ---~?/N r=(s~) ~ N2 5 ab- It 5 ~ 5 C~. .OI 9... b vm i c. -... states are not presented in the scheme. since there are no experimental data on these reactions.. state of isothiazole (XVlI) under the assumption of a bicyclic transition complex are pre- sented in Scheme 6. In the framework of the scheme developed here.. ... . e. ._N 3 2 .

i0. K. Seger. Abronin. van Driel. New York (1975). XNTL. p. Z. 3432 (1971). Henning. 1529 (1975). New York (1980). Khim.. Wiley. Strukt. Minor. Beekhuis. 20. Khimiya. G. 8. B. Chem.. Thai. P.. Chem. 19. A. J. A. El-Basil and R. France. Ztschr. 164 (1980). M.. 26. J. M. No. Vysotskii and L. 4131 (1978). Comm. Khim. S. A. Academic Press. J. Dewar and R. R. 15.~ s for the S. L.-A. J.. Naukova Dumka. Plenum Press. Chem. Plenum Press. Applied Quantum Chemistry [in Russian]. 20. Phys. Zaklady Kvantove Chemie (Principles of Quantum Chemistry). Zagradnik and R. J. Mestechkin. Hilal. 45. Geterotsikl. Zh. 17. de Mayo (ed. Dougherty. O. Chem. O. Wiley. 3501 (1967). Chim. Vysotskii. J. 22.-G. No. Interscience. 24. LITERATURE CITED i. 51. and M. 5. R. Zhidomirov. Japan. Chem. 32. M~hlstadt. 18. J. 329 (1967). in: Chemical Reactivity and Reaction Paths. 24. Bagatur'yants. Zimmerman and T. ~ 3 -N 2 ~'~/:' s~(T2) sl XWI[ bi ..). E. in: Rearrangements in Ground and Excited States. 27. ii. A. E. Moscow (1979). Comm. 8. Soc. Cowan and R. 22. Faraday II. Chem. Lablache-Combier. Soedin.. 7. Comm. 74. E. Drisko. S. Chem. Chem. 1277 (1982). Prague (1976). Soc. Org. 25. V. New York-- London (1976). 679 (197~). Soc. Roland-Gosselin.. and M. Sagitullin. C. N. 4876 (1980). The PMO Theory of Organic Chemistry. and G. B. Yu. 3.N~(T2 ) 4 --N ? According to the calculated data. Am. Marshtupa. in the $2 and T. Vol. and B. D. Am. New York (1974). Elements of Organic Photochemistry. G. i00. G. Barltrop and J. Photoreactions of this type were studied in [34]. U.. 36. Density Matrix Method in Molecular Theory [in Russian]. P. A. Chem. M. Sauer. and S. E. 2. Polak. Buchardt (ed. Chem. V.. Zimmerman and R. N. Coyle. and C. 139 . in: Photochemistry of Heterocyclic Compounds. 1729 (1976). 1576 (1970). and I. New York--London-Sidney (1976). Hiraoka. No. p. Ladhoff. H. Pasteris. 7. P. 2. 7650 (1973). Padwa. Khim. H. Usp. Hiraoka. 89. 93 (1969). 6. J. Muszkat. 1610 (1971). Weltin. H. Lablache-Combier and M. 12. Chem. 21. H. Kellogg. H. P.. Chem.. J. E. 16.. S. R. Yu. state is also an indication of the possibility of the elimination of an HCN fragment with the formation of a potentially antiaromatic C=H2S system.. 93. and H. Ried. J. states this reaction should involve bonding between positions 2 and 5. F. Michl. R. D. E.. 16. M. Kiev (1977). 13. No. Dardelog. 21. Soc. Am. Sivyakova. Welter. J. H. Hunt and S. H. R. 9. Zemskii. C. 95. 9.. Excited States in Organic Chemistry. 23. Scholz. 4. London (1975). Chem. Poquet. Wu.). 1209 (1980). Am. 370 (1976).). A. Bull. Kalafat. Hiraoka.. T. Soc. Klopman (ed. B. Stupnikova. A. Wynberg. 574 (1970). 123. 14. Remy. Chaillet. M. Bull. We note that the existence of large positive values of K. 3. 2749 (1978). 501. No. Scheme 6 . M. Soc. I. Soc. 1306 (1970). A. Tetrahedron. Sharafi-Ozeri. Tetrahedron. A. C. 9. Dietz. T. Chap. E. 38. No.

4. Comm. 1148 (1970).. 33. 99. XWll R = S~-C. f S R O C ~NH R ~* . a new method has been developed for the prepara- tion of nitriles in furan series from the corresponding furfural derivatives. A. revlsion submitted April 16. as well as impossibility of their use for the preparation of individual compounds. Nishimoto. N-aminotriazoles. M.Hs. Depending on conditions. X R = 4-OC6H~CHs. Reid. Soc..28. February. Van der Plas. Ohashi. 34. J. XVIII R = 3-S~-C. IV R = --C -~ CC~Hb...H~CHs Krasnodar Poiytechnical Institute. A. Kul'nevich UDC 547. phosphoric.. hydrochloric and other mineral acids.2 Based on the Schmidt reaction. Chem. with which it was possible to avoid resinification of furancarboxaldehydes. Chem. limited number of suitable methods. H. i05. C. Chem. 140 0009-3122/86/2202-0140512. SYNTHESIS OF 5-SUBSTITUTED CYANOFURANS AND THEIR REACTION WITH HYDRAZINE P. 32.SO2C6Hs. H. 1985. XIII R = SCHzCOOC2Hb. Krasnodar 350700. Instead of sulfuric. London-- New York (1973). and K. 6. III R = C6Hs. A. 1984. XXVll R = H. while the time of the reaction was shortened. Am. difficulties related to the regeneration of the reagents. No. XXVl. Matsushita. pp. When anhydrous magnesium perchlorate was introduced. XXIX R = Br. 386 (1970). 1986. J. Chem.4- SC~Ha(NOa)z. V. XXIV. XIX R = thio - furo-5-yl. Wiebe and J. VII. Chem. No. ii.72:543. Marda. for example. Adv. XX R -.. XXI R = 4-SO2C. T. i. Lanreni. Jio. Krantz and J. XXV. Comm. 4842 (1977). XIV R = 2. S. The known methods for the preparation of cyanofurans from furancarboxaldehydes [1-6] have several disadvantages: multiplicity of stages. we used 72% perchloric acid. and also Lewis acids [7].25+547. Translated from Khimiya G e t e r o - tsiklicheskikhSoedinenii. XXVll R = CHs. Academic Press. XII R = SCHs.1' 722. Soc. XI R = OC6H4CI.. ~R ~NHNH2 H H XXII. and thus the yield of products I-XXI increased to 76-96%. J. XXIII R = NO2. 31. VI R = I. i (1970). 1753 (1983). Pavlov and V.882'722. Original article submitted July 13. 2965 (1969).792. II. Canad.. IX R = 4-C6H~NO~. H. because of scarcity of starting mater- ials. the reaction of 5-substituted cyanofurans with hydra- zinc leads to amidrazones.5-dihydrotetrazines. 8. 30. 29. Heicklen. For this purpose we used the Schmidt reaction [7]. XV R = 5-thio-2-cyanofuran. A. Heterocycl. VIII R = CH2CI. Kojima and M.H4Br. it was possible to re- duce the amount of perchloric acid to catalytic quantities. Am.422. or 1. Chem. Yonezawa. but the yield of the nitrile did not exceed 50%. T. 47.X ~ I. Tanaka. 5-nitro-2-cyanofuran [5]. 181-186. M. No. and T.. Ring Transformations of Heterocycles. Vol. XXII.2+547. G. 2.50 9 1986 Plenum Publishing Corporation . XVl R = 5-thio-2-oxo- furan. ~/ ~-.XXIII ~"VII .2. considered to be unsuitable for the preparation of nitriles of the furan series.

Ohashi.. VII. XXII. XVl R = 5-thio-2-oxo- furan. VI R = I. T.H4Br. Wiebe and J. London-- New York (1973).2.SO2C6Hs. Lanreni. SYNTHESIS OF 5-SUBSTITUTED CYANOFURANS AND THEIR REACTION WITH HYDRAZINE P. limited number of suitable methods.422. as well as impossibility of their use for the preparation of individual compounds. H.H~CHs Krasnodar Poiytechnical Institute. Chem. Adv. No. difficulties related to the regeneration of the reagents. Van der Plas. Krasnodar 350700. VIII R = CH2CI. and K. XIX R = thio - furo-5-yl. Tanaka. XV R = 5-thio-2-cyanofuran. When anhydrous magnesium perchlorate was introduced.. Pavlov and V. T. Kul'nevich UDC 547. 34. 4842 (1977). considered to be unsuitable for the preparation of nitriles of the furan series. 181-186. Chem. Instead of sulfuric. and T. XXIX R = Br.Hs. A.882'722.. III R = C6Hs.2+547. G. XIV R = 2. J.. A. 30. we used 72% perchloric acid. XXVll R = H. Heicklen. X R = 4-OC6H~CHs. Translated from Khimiya G e t e r o - tsiklicheskikhSoedinenii. and thus the yield of products I-XXI increased to 76-96%. Canad. Matsushita. 386 (1970). 1984. and also Lewis acids [7]. Chem. IX R = 4-C6H~NO~. C. H. phosphoric. i (1970). Yonezawa.50 9 1986 Plenum Publishing Corporation . it was possible to re- duce the amount of perchloric acid to catalytic quantities.72:543. 6. XI R = OC6H4CI. while the time of the reaction was shortened. f S R O C ~NH R ~* . H. 99. February. XXVl. i05. Original article submitted July 13. Chem. S. 1148 (1970). Jio. ii. XXIV.25+547. Marda. revlsion submitted April 16. Chem. 8. J. 1985.. Nishimoto.1' 722. No. Soc. XXV.. A. XVIII R = 3-S~-C.792. Ring Transformations of Heterocycles. IV R = --C -~ CC~Hb.4- SC~Ha(NOa)z. but the yield of the nitrile did not exceed 50%. XX R -. The known methods for the preparation of cyanofurans from furancarboxaldehydes [1-6] have several disadvantages: multiplicity of stages. Comm. because of scarcity of starting mater- ials. pp. 32.5-dihydrotetrazines. V. 1986. A. Soc. 5-nitro-2-cyanofuran [5]. Kojima and M. ~/ ~-.. XXI R = 4-SO2C. II.. XIII R = SCHzCOOC2Hb. 2. Chem. XXVll R = CHs.. Krantz and J. Comm. Reid. 2965 (1969). 140 0009-3122/86/2202-0140512.2 Based on the Schmidt reaction. Am. 33. 31. Am. Academic Press. 47. the reaction of 5-substituted cyanofurans with hydra- zinc leads to amidrazones. Vol. M. for example. For this purpose we used the Schmidt reaction [7]. a new method has been developed for the prepara- tion of nitriles in furan series from the corresponding furfural derivatives. XXIII R = NO2. 29. Heterocycl. XWll R = S~-C. or 1. N-aminotriazoles. with which it was possible to avoid resinification of furancarboxaldehydes. 1753 (1983).4. M. hydrochloric and other mineral acids.X ~ I. Depending on conditions. ~R ~NHNH2 H H XXII.XXIII ~"VII .28. J. No. i. XII R = SCHs.

washed once more with water. VIII. EXPERIMENTAL The IR spectra were run on a UR-20 spectrophotometer in mineral oil. and two deformational vibration bands at 1665-1645 and 1610 cm-*. In the IR spectra of the compounds synthesized. V. and S02 at 1340.5-di(2-furyl)-l. The IR spectra of dehydrotetrazines XXVII-XXIX are char- acterized by the presence of one single stretching vibration band of the secondary amino group in the 3320-3330 cm-* region. XXI correspond to those described in [1-6]. II. the signals of the NH and NH2 group protons are recorded as a broadened singlet. and for XXV and XXVIII in CDCI3. VII.4. The spectra of the remaining compounds were recorded in DMSO-D6. 5-Substituted-2-cyanofurans (I-XXI). IX.2.and 5-nitrocyanofurans with an alcoholic solution of hydrazine leads to the corresponding amidra- zones.2-dihydro-l.i mole of furancarboxaldehyde and 0. 141 . the characteristic absorption bands of the stretching vibrations of the CN group are present in the region of 2244-2205 (I-XXI). but instead of perchloric acid. the benzene layer is separated.01 mole) of 72% perchloric acid]. Compound XVI is recrystal- lized from CCI~ and VII from a mixture of chloroform and cyclohexane. 3. and their characteristics are given in Table i. but when HCIO4 was used in the form of diox- anium perchlorate. Benzene is removed under reduced pressure. to unstable products. and the residue is distilled in vacuo or recrystallized from alcohol. 5- Nitro-2-cyanofuran. VIII. but there is no information on the reaction of furan nitriles. a previously prepared dioxaniumperchlorate is used [5 ml of 1. and that 2-cyanofuran and 5-methyl-2-cyanofUran. VII. while the corresponding 4-amino-3. which could not be isolated. At the end of the evolution of nit- rogen.ii mmole of a ben- zene solution of hydrazoic acid.01 mole) of 72% perchloric acid is added dropwise. XI) absorbs at 1260. X-XIX were synthesized for the first time.4-triazole (XXIV) is isolated un- changed. 1230.5-di(5- R-2-furyl)-l.2. In the IR spectra of triazoles XXIV-XXVI there are two stretching vibration absorption bands at 3350-3325 and 3150 cm-* of the primary amino group. XI in (CD3)2CO.7 g (0. but their yields are 10-15% higher. and tetrazines has been discussed fairly comprehensively in [8-10]. aminotriazoles.2. while the stability of the desired end products depends on the nature of the substituent at the 5-position of the furan ring (Table 2). The PMR spectra were recorded on a Tesla BS-467 spectrometer (60 MHz) for compounds I.6-di(2-furyl)-l.03 mole) portion of anhydrous magnesium perchlorate is added to a mixture of 0. XII-XXI in CCI~. the use of perchloric acid as the catalyst led to the resinification of the reaction mixture. which resinifies under the above conditions. X. The reaction of 5-bromo. C=O at 1780-1680 cm -I (XIII-XIX) the COC grouping (X. with stirring. Compounds IV.6-di(5-R-2-furyl)-l. Our studies showed that the direction of the reaction depends on the conditions under which it is being carried out. V. using HMDS as internal standard. at 35~ The rate of addition is controlled by the current of lib- erated nitrogen. When 3. In the preparation of compounds X and XI. In boiling alcohol in the presence of sulfur. but not violent.4. Heating of 5-R-2-cyanofurans with an excess of hydrazine hydrate gave 4-amino-3.4 ml (0. and 1130 cm -I (XX. and then 1. The benzene solution of hydrazoic acid was in all cases prepared by the method described in [7]. The reaction of different nitriles with hydrazine with the formation of amidrazones. A 6.4.4 ml (0.4-triazoles (XXIV-XXVI) in a high yield.2-dihydro-l. The purity of the compounds synthesized was checked by chromatography of Silufol in a 3:20 ethanol--toluene system. 3.5-tetrazine (XXX) is formed in 81% yield. is an exception. using t-BuOHas internal standard.2. Compounds X and XI are prepared in a similar way.5-tetrazines (XXVII-XXIX) are formed. XX.4-dioxane and 1. the mixture is treated with water.6-di(2-furyl)-l. The characteristics of the previously known compounds I-III. In the PMR spectra of compounds XXIV-XXIX. and one deformational vibration band at 1740-1770 cm -I.5-tetrazine (XXVII) is heated in pyridine in the presence of copper sulfate. IX.2. and dried over sodium sulfate. 1150. XXI). which should be rapid. they could be obtained in a yield of 69-76%. for III-VI. and the yield of 5-nitro-2-cyanofuran even increased from 50 to 92%. which disappears during deuteration.

C H 2S) XIV 7.7. H) Amidrazones XXlI.5 ml (0.02 it. H).0 .7.05 m H'H" = I 0 . CH3). then cooled.38 ~. H'). 7. 30 ml (0.~CHa-.47 m.32 s II 7. H =2.~H~ S02 XXI 7.60 (m) XlX .85 (m) an r i n g tern pro- H. H").51 (s. 8-H 4-H " R J R:' . Cyanofurans I-XXI Com.75 1.0 3. XXIII.40 ~. oMPc[Bp]j PMR spectrum. 7.01 mole of cyanofuran V. 7. u = 5.85 (d. CH~O) -I: J CH. A 0.i mole of 5-R-2-cyanofuran. (XXIII). H") j. H') XVII 7.97 (d. 1{5') XX ...55 (q .. I -- ! 'H'"N = 1.40 It. I% 7..33 m % V: Vl! VII: 4.. i 9.8 mole) of hydrazine hydrate is boiled for 3 h in a nitrogen cur- rent. 30 ml of ethanol. 2. A mixture of 0. and the residue is recrystallized from CCl~ (XXiI) and CHCl..03 '. 7.4.00 6.o i~m pro. 6. A mixture of 0.0 I H~'H~'= 0. d.. m ring 7.82 d ).60 O ) XV XVI H wt H f -.6 mole) of hydrazine hydrate 142 .48 s 8...27 (d... H4') .08 (. 4-Amino-3~5-di(5-K-2-furyl)-l.t R4 Ja4 7.4-triazole (XXlV-XXVI). H~'). 3-6-Di(5-R-2-furyl)-l)2-dihydro-l)2.q.44 (d..2. =8.75 -j- 7.58 (d.75 O It m J.5-tetrazines (XXVII-XXIX).. 0 7. washed with water and recrystallized from CHCI3.H.10 (dd.51 ( q. 4.. 7..i mole of 5-R- 2-cyanofuran and 40 ml (0. I.68 (m) XVIII 6. CH~). H'"). ppm SSCC) Hz pound" (Ira) .67 (dd .8 I 2. The mixture is stirred. and left to stand overnight..--.01 mole) portion of hydrazine hydrate is added to a mixture of 0. VII in 10 ml of alcohol." H~'H4' : 37 HJHs' = 2.0 XII 2.H. the crystals are filtered. XI 6. TABLE i.45 (s) XIII 1.50 6. The alcohol is distilled off under reduced pressure.55 (q.

8 -. 80 72. 76 77. C.0 6.9 14.8 -.8 C.3 16.4 !0.5 C.4 6. C. XXIX from toluene.~ 4.3 6.0 23.8 15.5 1.2.(.3 6.3 -.7 15.C 6.l 8.6 2.tH6N20~ i2.7 4.8 2.0 -.54 g (81%).5 %3 5.8 78 45.4 16.4 6.8 ~5.5 1.7 15.4 10.8 9.9: .6 C.0 CsHsNOS 51.4 20.3 ~.9 3.3 96 52.~ 5.4 91 25. The yield of compound XXX is 1. and recrys- tallized from CHCIa.0 8.7 2fi 6.0 2.2 8.7 98 59. CsH~N~O~ 13.6-Di(2-furyl)-l.0) 54.7 2.8 [2. % formula S H N (2al) H N (Hal) 34.8 2.5-tetrazine (XXX).oH4N202S.2HgNO2 72. % Found. After heating for 1 more hour.HzNO r8.HTNOsS 58.8 -)5.4 16.oHsNO3S 54.6 6.4 4.4 89 62. 143 .3 -.4 14.5 1..( 2. 3.)7.1 14.9 4.01 mole) of CuS04 and i0 ml of pyridine is heated with stir- ring for 5 h at 50~ It is then cooled and filtered.5 7.8 I.7 13. Calculated.7 13. 69 50.0 f. Compounds XXVII. XXVIII are recrystallized from chloroform.2 3.7) CsH=INO . The filtrate is poured into I00 ml of ice water.5 10.7 12.5 %3 15.8 92 52. 82 70.4) CItH. After 2 h.0 Cj~H6NOaS 59. CsHsNO Z7. the mixture is treated as described above.6 3.0 79 53.5 g (0.5) CsH~BrNO 34.3 -.1.7 85 43.0 2.CINO2 60.01 mole) of 1.4 4.5 10.3 -.2 4.8 CgH~NO3S 53.CINO ~0. the crystals are filtered with suction.2 2.7 3.0 13.8 14.4 i7.0 90 46.HsN3OsS 45.7 1.4 1.4 2.0 -.0 23.7 9.9 93 55. 55.dihy- drotetrazine XXVlI.8 2.9 6.4 %9 6.8 3.3 1.4 14.3HzNO ~0.1 13.2.0 5. A mixture of 1.9 C.4 16.5 10..4 5.0 13. C. 92 50.3 -.4.0 2.7 14.9 15.5 78 27.0 5.1 2.7 6.3 CI~HsBrNO~S 46.7 2.0 CsH3NO M.~HTNO2S 62.2 3.8 1.4 CgHsNO.4 76 51.6 7. 84 ~0.4 6.8 13.9 C.4 10.S 52.2) C6H.3 -.2 4. % Empirical Yield. 2.8 94 34. 6.2 8.3 14.6 [0.4 4. washed with cold alcohol.6 90 58.7 :3.3 6. -.92 g (0. crystals begin to sep- arate.3 i7.3 1.5 C.1 98 and 2 g of sulfur is boiled in a nitrogen current. 26.7 1.5 7.

4 25.8 2.6o ~d) 6. s) 32O0 XXIV 240 3350 1645 5.91 (.5) (29.05 .1 29.3 2.3 13.0 29.55 (d) . Hz Empirica] Calculated.04 (d) .3 3. 4.5 2.95 (@ 5.1) (39. 54.66 (d) 5.5 25.0 -. s) 2.5 CsH6BrNaO 29.2 29.3 3. Characteristics of C o m p o u n d s Synthess IR spectrum.0 49.~d) 5. 4. .5 90 3150 1610 XXVI 244: 3325 1665.5 87 XXIX 1255 3325 1760 7.5 5.4 5..~. % pound |'14 fgrmula VNH 6N~I / NH R Hs .26 (CHzC) 6.3 25.03 (a) .4 2.5 5.0 50.2 20. Dr. 5.03 (d) 0.70 . 4.2N402 54.9 .s) 6.39 (br.8 -.0 4.5 8 5 CsHeBrN~O..6) XXVII 208 3330 1770 7 8 3 ~br. 35.5 5.0 29.) 6.5 50.) -.0 4.1 20.7 83 (29.3 3.0 -.0 -.6 92 3300 (39.2 29.0 4.0 .i-d $- TABLE 2.4i 2. 35.66 (d) 6.00 (d~ 6.3) (29.66 (d) -.54 (d) 0.8 20.2 20.2 88 XXVIII 189' 3320 1740 7. s ) 5.9 4.7 3.4 CIoH.5 2.4 12. ..]8 (d) 0.11 (dl . 7.5 81 *With decomposition.9 20. 3. $) 6.2) 3200 XXIII '160 ~ 3555 1600 4. 5. 3. .s~ 2. ]2.7 3. 54.5 CIoHt2N40~ 54..~ ! Yield.80 (d) 6.9 89 3325 3. 4.50 .hr. cm-~ H~R spectrum Found SSCC. 35.5 2.55 ldd ) 6.5 2f 20. s ) .50 ~dd ) 6. s) 5. % Com.10 ( b r .0 CsHsN40~ 50.5 2.83 ( b r .4 CsH~N402 50.9 3.6) XXX 195 1600 6. 29.33 (d.08 (d) 7.7 3180 1620 (29.5 25.1 29.2 87 XXV 242 3325 t665.41 (1~r~) 6.35 (CH~C) 6.5 3. .05 ( b r .88 ( d d ) 6.9 CsH6N403 35.5 32. 35.2 CsHsN402 50.4 32.6 CsH~BrN40 35.4 C N (Hal) C H N (Hal) XXII 108 3500 1600 4.57 ( b r .

G. D. Ioglbhukta. Buzykin.. formic. CHLORINATION OF 1. LITERATURE CITED i. V.3-dioxolan-4-one (III).729. p..0 ~:~'" C I C H 2 \.. Ollis (eds. and E. J. . P. Likhterov and V. Nitrogen-Containing Heterocycles. determination of the composition of the reaction mixture was not achieved. General Organic Chemistry. Corp. J..). 6. and hydrochloric acids. but was unstable on hydroly- sis. Andove and A. L. P. 5.3-dioxolan-4-one'(II) underwent chlorination. Shridhar. Jmhofer. 1986. ~. evidently. Synthesis. O O. [Russian translations]. Khimiya. 5-Methyl. 2. New York (1953).. The present work is devoted to the reaction of 1.0 '~ i c ~/r tlJ:%b O. 1 9 No. 386 (1980)..(I) and 5-chloromethyl-l. 301 (1958). and P.). 5. Moscow (1974). 3.SSR. and B.. Krogh. No. pp. Dokl.. /O & II Ill It was established (GLC) that the compound synthesized was a mixture of cis and trans isomers. Zil'berman. 6. G. Yu.B..3-dioxolan-4-ones with chlorine and aims to establish the effect of the substituent at the 5-position of the ring on the direction of chlorination. This. Lit. promotes a selective replacement of hydrogen at the 2-position. Original article submitted November 13. Kitaev. D.H--20~" C IC H ~ C H C O O H + HCO011 + HCl -l Oil Translated from Khimiya Geterotsiklicheskikh Soedinenii.3-dioxolan-4-ones in the pre- sence of benzoyl peroxide is determined by the nature of the substituent at the 5-position of the ring. Chim. Reinhold Publ. 9. February. Nauk Arm. . Chem. Gopalreddy. Re- placement of hydrogen by chlorine proceeds only at an increased temperature (80-I00~ and in the presence of free-radical initiators. Khimiya. Sosnovsky. A. Wolf. having a --I effect. In this case a chloromethyl group. while a methyl group mainly causes replacement of hydrogen at the 5-position. 162. I. it showed thermal stability and was readily distilled. 0009-3122/86/2202-0145512. In the case of dioxolanone I on chlorination to an increase in weight equal to the replacement of one atom %f hydrogen by chlorine.7:542. (1951). Peters. p. The Furans. R. 167 (1983). 4. ~tlis UDC 547. 722 (1979). Izd-vo Inostr. C I C H 2 . A Grigoryan. G. R. Hydrazones [in Russian].944 It is shown that the direction of chlorination of 1. Moscow (1985). Moscow (1972). 291. 237. and S. 8. Indian. can be accounted for by the influence of the substituent with a --I effect. p. P. 447. i0. Reactions of Nitriles [in Russian]. Mndzhoyan. which to a large extent lowers the reactivity of the C--H bond at the 5-position of the ring to attack by an electrophilic chlorine radical. III . G.. . 41. A. Kovac. 187-189. 1692 (1976). 429. Y.3-DIOXOLAN-4-ONES V... Vol. Akad. 2. In the second case chlorination proceeds selectively and leads to 2-chloro-5-chloromethyl-l. N. P.50 9 1986 Plenum Publishing corporation 145 . A. 8. J. Among the products of hydrolysis were identified 3-chloro-2-hydroxypropionic. No. 1984. revision submitted February 26. Barton and W. Dunlop and F. G. Afrikyan. p. V. D. Nauka. Sect. in: Organic Reactions [Russian translation]. E. M. 1985. Simms (ed. Gaset. 7. S. N. Coll.

4680...32 hPa).trans-dioxolanone III. and at --5~ over the course of 0.0 C1 VI VII The properties of the unsaturated compounds obtained were dependent on the nature of the substituents at the 2.5.2-Chloro-5-chloromethyl-3-dioxolan-4-one (III). We established that in the presence of triethylamine as a base.. replace hydrogen at the 5-position... mp 40~ (5. IR spectrum: 1830 cm-* (C=O). andhydrochloric acids. colorless liquid with an odor similar to that of acid chlorides! it could be distilled under vacuum and hydrolyzed with the formation of pyruvic. d42~ 1. formic and hydrochloric acids. C1 26.H. formic. d~ 2~ 1. with flame ioniza- tion detector.4%. 1680 cm -I (C=C). C! ~ 0 C H ~ O . dropping funnel.3-dioxolan-4-one (VII).. Found: C 28. Cl 26.119 mole) triethylamine in 40 ml ether.. ..3. Their composition and structure were confirmed from the data of el- emental analysis and IR spectroscopy. ~ 5 ~ _ .0 0 ~. The triethylamine salt was filtered off. were obtained in high yield. thermometer.4579. the solvent was removed. 4= 9 CH2..CIO. thermometer. and free-radical polymerization inhib- itors (p-methoxyphenol and phenothiazine). crystalline substance.: "~--~S ~ O.0. CICt'2.2. The reaction proceeded smooth- ly at 0-5~ The 5-chloro-5-chloromethyl-lj3-dioxolan-4-one (V) obtained was a substance of low thermal stability. and reflux condenser with calcium chloride tube were inserted 136.. H 2.. C~H~CI2Os. Dioxolanone I was obtained according to a standard method [1]. and after the suspension was dissolved vacuum evaporation was carried out at 50~ The residue was 3- chloro-2-hydroxypropionic acid. H 2. nD 2~ 1. Calculated: C 27.. according to [3]: rap 78-79~ A test mixture with a known sample melted without depression.~ . and this was heated to 90-95~ Chlorine dried with sulfuric acid was passed through until there was a gain in weight of 35 g and the mixture was distilled under vacuum. MW 135.7%.'~--'-'~ O~.5. For proof of this hypothesis we chlorinated 5-methylene-l. Found: C 35. respectively. being at the same time both lactones and ~-chlorethers.~/O 0~/~O IV V The dioxolanones III and V synthesized are isomers. IR spectrum: 1831 cm-* (C=O). MW 134. Chromatographic analysis was carried out on a Tsvet series chromatograph. and 3% neopentyl glycol succinate on cellite 545 as adsorbent.3-dioxolan-4-one (VI).0%. in both cases splitting off of hydrogen chloride occurred and 2- chloro-5-methylene-l. and reflux condenser with calcium chloride tube were in- serted 20 g (0. Calculated: C 35. %)benzoyl peroxide. . . H 2.~. C4H.3.. The first was a mobile..2-~. H 2. 2-Chloro-5-methylene-l. and the residue was distilled under vacuum._Cl---. Into a reaction vessel fitted with stir- rer.33 hPa). 12.4724. forming a thermally unstable compound. The product was easily hydrolyzed by water. Hydrolysis of dioxolanone III was carried out on a boiling water bath.. MW 169.001 wt.3-dioxolan-4-one (VI) and 5-chloromethylene-l. and it was not possible for us to isolate it by vacuum distillation.. 146 .5.5 g (77%) was ob- tained. Stirring was contin- ued for a further 2 h at the temperature indicated. mp 77-78=C (from an ether-chloroform mixture)..5 g (i mole)dioxolanone II [2] and 0.. It is well known that such compounds display exceptionally high reactiv- ity in reactions with various nucleophilic reagents. MW 171. Cl 42. EXPERIMENTAL 1R spectra were recorded on a UR-20 instrument using a thin film between KBr plates.O :~ CIHC ~ ~O . . undergoing quantitative conversion to pyruvic acid (determined by polarography). "l . i0 g (7%) initial product was ob- tained as well as 120 g (75% based on initial reactant) cis. C1 41.~ .and 5-positlons.7.3. chlorine would. nD 2~ 1.5 h was added dropwise a solution of 12 g (0. mp 57-58~ (1. Into a reaction vessel fitted with bubbler.. 50 ml ether.0.3-dioxolan-4-one (IV).0014 g (0.118 mole) dioxolanone III. It could be supposed that in the case of dioxolanone I.4740.4%.~ .. The second was a stable. on the contrary.

A. A. At 20-250C a solution of 17. 1817. Bashkir State University. LITERATURE CITED i. Gataullin.5-dihydrofuran [3]. Acta Chem.7-dichloro-2-methyl-3-oxabicyclo[4. The reactionof dihalocarbenes with alkenes usually yields the corresponding adduct via addition to the double bond (including 5. 145 (1949).6-dihydro-2H-pyran with dichlorocarbene there are formed products of addition to the double bond a~d insertion at the C--H bond giving cis. R. Etlis.313. Calculated: C 35. In a subsequent synthesis it was used without purification. 215 (1984). M .5. 6. and M. Chem.7:3. 2. 190-191. Khramushina. E. and 16. Original article submitted October 8. 609. The mixture was maintained for 5 h. V. February. 20 ml carbon tetrachloride.~. T. Ufa 450074. The solvent was removed.107 mole) chlorine was passed in. Etlis.(III) and trans. 180. 5-Chloromethylene-l. Found: C 35. P. and then with water. S.0~ (from an ether--n-hexane mixture in the presence of grade A activated carbon). thermometer. No. G. 6. G. Byull. UDC 547. Arzhakov. V .422:541.7-dichloro-2-methyl-3-oxabicyclo[4.542.1. USSR Inventor's CertificateNo. C1 26.3.and 6-membered cyclic vinyl ethers [i. and the filtrate was washed successively with 5% solutions of hydrochloric acid and sodium carbonate. No. 3. and 9.811. V. bubbler. S. Izobret. Chuprov. and free-radical polymerization inhibitors.3-dioxolan-4-one (V).634 Upon treatment of 2-methyl-5. and S.~ 17. We have found that three compounds are formed from 2-methyl-5. Salomaa and S. MW 138. Bear and H.5%.955: R. i~ i ~' ~ i I! i i c.6-dihydro-2H-pyran (I) in 37% overall yield: cis. C~HaCIO3. Into a reaction vessel with stirrer.5.i mole) of compound IV [4]. No. 1680 cm -2 (C=C). Petrushina.1. drop- ping funnel. 103 (1963). I . V. Byull.50 9 1986 Plenum Publishing Corporation 147 . Completion of reaction was determined chromatographically according to the disappearance of initial dioxolanone IV.5 g (0.6-dihydro-2H-pyran. I'~: CH~:l~ I:H~ t'H~ [ I!I. Safarov 543. 2]). which on heating decomposed with the formation of tarry products.2. Biol. 2.3. thermometer. K. 1984. 215 (1984).0]heptane and 2- dichloromethyl-2-methyl-5. revision submitted May 16. 1985. pp. and calcium chloride tube were inserted i0 g (0.105 mole) tri- ethylamine and 20 ml benzene.3-dioxolan-4-one (VII). Translated from Khimiya Geterotsiklicheskikh Soedinenii.1 g (0. Likhterov. and D.. 1805 cm-* (C=O). F.0]- heptane and 2-dichloromethyl-5. and the mixture was maintained with stirring at room temperature for 4 h.(IV) 7. 4. 5-Chloro-5-chloromethyl-3. C1 26. Izobret. and calcium chloride tube were inserted 10. Likhterov. H 2.5 g (71%) was obtained.i mole) dioxolanone V in 30 ml benzene was further added. REACTION OF 2-METHYL-5.6-dihydro-2H-pyran (V) in the ratio 1. The solvent was removed under vacuum. Balandina.9. 606.3 g (95%) crude dioxolanone V was obtained. the same course of reaction having earlier been observed in the case of 2.and trans-7. Fischer..6-DIHYDRO-2H-PYRAN WITH DICHLOROCARBENE U. MW 134.0:5.290.6 g (0. Laiho.4%. R. R . At--5~ 7. Ibatullin. L. IR spectrum. USSR Inventor's Cer- tificate No.7. mp 7. i :'~. 0009-3122/86/2202-0147512..IV V It can be proposed that the C--H insertion product appearing together with the adducts III and IV is due to the allyl structure of I. Into a reaction vessel with stirrer. 1986. J. Scand. H 2. then triethylamine hy- drochloride salt was filtered off.52-73.

53 (5. H 5..2).5).A.). The molecular ion is absent but there are fragments at M--CH= (m/z 165 and 167) and for CHCI= (m/z 83 and 85). M.52 ppm). 1~3 (. p. 201. The most intensive peak is seen for M-CHC1. 3. 71 (10.2). 138 (19. SE-30) with temperature programming from 50 to 180~ (5~ at 68-70 eV and a scan velocity of 1 spectrum/second.2. 123 (16. 2021 11964). 77 (6. 97 (6. ]01 (34. 136 (9.3).2).5010.0). 87 (18. LITERATURE CITED i. 43 ([00.2-0. 138 (5. and G.5. A. Khim. 3. 2.i .3).H. 65 16. that another allyl isomer (4-methyl-5. 65 (31. 4. lC}3 (5.8). I. J. Getero- tsikl Soedin. Anderson and C.4.5). The'lll/V mixture contains 35% of oleflne (ozonolysls) pointing to the dihydropyran V. 20. TABLE i. Found: C 46. . Ind.6).O]heptane (IV) EXPERIMENTAL GCMS analysis was carried out on a Finnegan-4021 instrument with glass capillary column (30 m x 0.6-dlhydro-2H-pyran* L . In connection with the difficulty of separating III-V the stereochemlstrles are not es- tablished.4) *Ion peaks greater than 5% given. i It. as is known for norbornene [5]..8)..5). Chemistry of Carbenes [Russian translation].6). ]65 (5.oCI=O.16.7).1). Soc. Chem. 125 (I0. 43 157. in our case we can propose that the predominant product is trans-7. 79 (14. 51 (15. Anderson and D.6-dlhydro-2H-pyran (VI)) gives only the corresponding adduct in ~70% yield under the same conditions. H 5. Compounds III and IV are extremely unstable towards electron impact (molecular ion In- tensity 0.81 ppm) and the di- chloromethyl group (5.0). (m/z 97) (see Table 1). J.2%. The reaction was carried out using the method [4] of generating diehlorocarbene from CHCIs under phase transfer catalyticconditions to give an isomer mixture in 37% yield with mp 97~ nD 2~ 1.C.5).4). 1'36 131. 4[ 12[.8). Mir.C. No. It is known. Moscow. 122 (24.2%.7).0). Calculated: C 46.[). 4085 11960).9). r HI 7 Compound m/z value (~ of maximum ion) Ill 180 (0. Tetrahedron. 2. Amer.9). Kazaryan.9). 87 (30.. Schweizer and W. 89 (10. E.7). On the whole their mass spectra are very similar. 145 (6. 82. N.5).oCI=O.5). C1 39.0) IV 180 (0. lOl (21.0). 79 (5. 125 (30. 77 (15. I n all proba- bility the different behavior of dihydropyrans I and VI is due to the high lability of the 2H in pyran I as well as the lower reactivity of the di-substituted double bond when com- pared with the trisubstituted one in pyran VI.9) V 167 (3. .3%) and they break down by several routes. PMR spectra were recorded in a Tesla BS-467C (80 MHz) instrument in CC14. 167 11981). Gevorkyan. 53 (8.3). However.O).0). E. 124 (t6.6).1.6). 103 (10. Khizantsyan. J.9).5). 97 (lOO. A. |. Parham. 98 (6. 5l (9. Hence.6.25 mm. .8)~ 124 (17.6). 77 (7. 5.0).0). dichlorocarbene adds to six-membered olefines with a preferred formation of the trans isomer. When the system potassium tert-butylate/chloroform was used the yield of products fell to 2%.2.4). C. 43 (100.4).0). 575 11963). Lindsay. 79 (6. 89 (5. Panosyan. Mass Spectra of the Products of Reaction of Di- chlorocarbene with 2-Methyl-5. No. Double bond analysis was performed o n a n ADS-4M. 65 (20.E. J. 115 (6. 41 (19. Reese. 122 (265).7-dichloro-2-methyl-3-oxablcyclo[4.53 (6.0). 4[ (30. Kirmse. V. 148 . B. P. however. C1 39. The elemental composition of the mixture of IIl and IV agrees well with the empirical formula CTH. The spectrum of dihydropyran V is significantly simpler and markedly dif- ferent from Ill and IV.3).. Chem. 11966). In the PMR spectrum there are signals charaeterlstlc of the tetrahydro- pyran ring together with signals for the protons of the double bond 15.

CHEMISTRY OF ISOFLAVONE HETEROANALOGS. while stretching vibrations of the carhonyl in the molecules are shifted to the 1664-1687 cm-* region *For article i0. antiphalloidine [9]. The structure of silibin has been established and confirmed by synthesis [4-7]. hydrocarplne [3]). which in contrast to the initial chalcones.4'-ethylenedioxyflavanoid structure. epoxides V are formed in good yields. A.have been synthe- sized from these compounds. Dif- ferent types of analogs of natural flavonolignan -.4 Benzodioxane analogs of chalcones and their epoxides have been prepared. Hydrocarpine.25:615. 1985. In the reaction of chalcones IV with hydrogen peroxide in an alkaline medium. There are intense absorption bands in the 1636-1656 cm-* region in the IR spectra of these compounds. Turov. Kiev 252017. V. Translated from Khimiya Geterotsiklicheskikh Soedinenii. Khilya.814. Koshut Debrecen University. Natural sillblnhas a 3-hydroxy-3'.272. 8].* BENZODIOXANE ANALOGS OF CHALCONE. AND ISOFLAVONE V. we decided to synthesize structurally more simple benzodioxane analogs of isoflavones (VI) and flavones (VII) and to study their chemical and biological prop- erties. which are readily soluble in organic solvents (Table i). 0009-3122/86/2202-0149512. ii. Kornilov. M.50 9 1986 Plenum Publishing Corporation 149 . obtained by an alkaline condensation of the corresponding o- hydroxyacetophenones with 6-formyl-l. Litkei. February.4-yl)chromone and has a similar structure. in which the chromone or chromanone nucleus is bound to 2. Thus. Shevchenko Kiev State University.422. A complex flavanoid (sibilin [2]) and its related compounds (for example. T.4-benzodioxane by a known method [12].4-benzodioxane have been isolated from different types of plant material. 192-198. which has been isolated later [3].4-ethyl- enedioxychalcones III and IV. A. pp. Original article submitted January 14. Debrecen N-4010. The benzodioxane analogs of chalcones III and IV are fairly high-melting crystalline sub- stances with a yellow or orange color. D.3-disubstituted 1.. Hungarian People's Republic. corresponding to the stretching vibrations of the chalcone carbonyl group.07: A. G. Since compounds of this type and those with other degrees of oxidation have not yet been prepared. silihln has hepato-protectlve [2. are colorless crys- talline substances.silibin -.5'841. FLAVONE. /o. Patonai 543. 1986. and T. The key materials for the synthesis of these 6ompounds were substituted 3. No. see [i]. is a derivative of 2-(6-benzodioxan-l. Aitmambetov. The PMR spectra of the new compounds and the re- sults of the preliminary biological testings are reported and discussed. L.~H ~O~/CH20H Of} 0 OH 0 Silibin Hydrocarpine The increased interest in this group of compounds is due to their biological activity. P. antiperoxide [i0] activi- ties and inhibits prostaglandin synthetase [ii]. 2. UDC 547.

0-8.yH.7HIoC1204 95 *Compounds Via. l ] !R spec- 3ore.5 C.8 43 Vii 205.3 C.Br04 69'7 I ~.40~ 3! VII f 239.H. The stretching vibrations of the carbonyl group in their molecules are present in the 1637-1650 cm-: region.3 41 V Ih 209----21(I 1640 6.52-7. i from alcohol.~ ~trum~ Foun.-169 1644 Ci. h. The benzodioxane ring oxygen atoms do not participate in the complexation with LSR. To confirm the structure and 9 the configuration of cha!coneslll.rH.rHnFO4 68 1630 VII i 207---208 1639 CmHI604 64 v!I j 194----. the highest LIS are characteristic for the methylene proton signals of the benzyl group. % Empirical Calculated.'d. con- siderable paramagnetic lanthanide-induced shifts (LIS) of the NMR signals are observed. Vllf.e 192 :. the signals of aromatic protons of these com- pounds form an unresolved multiplet in the 7.3 ppm.4-14.. the signal of the hydroxyl proton is observed in the weakest field (13.~Cl04 Vile 213.54 ppm.~. Ioo ~. as follows from the absence of noticeable 150 .3 37 VI g 171-172 1638 II. europium-III tris-l. The aromatic and olefinic protons give an unresolved multiplet in the 7-8 ppm region (see Table 3). In the spectra of chalcones Ilia-l...l.]..57 ppm.8 ] II. as well as the above indicated methods. The type of the functional groups located in the vicinity has only slight influence on the position of this signal. g. j-i from ethyl acetate. there is a somewhat detached signal of a proton aligned with the carbonyl group (see Table 3). 227 1641. VId and Vlla from an alcohol-octane mixture. flavones VII and isoflavones VI we used the PMR method in the presence of a lanthanlde shifting reagent (LSR)... Attempts to simplify the spectrum by means of LSR. 19(I 1638 C18H1404 73.0 I 61 Vlj 19(~. d-i are also difficult to interpret.C=O. which are clearly due to the decomposition of the LSR by the action of strongly acidic phenol proton of products IIIa-l.193 1634 C. Vlld from aqueous alcohol.2 ppm). g.197 1634 C.---.195 C.3 C.185 1646 C. Vlf.H..7H. From the shift values it fol- lows that the coordination of LSR is brought about at two centers: at the ether oxygen atom of the O-benzyl and at the carbonyl group (cf.21)6 1639 C. IV.204 vld 189. I 1.:H.8 C. ~ Yield 7. signals of the olefinic protons and the signal of the aromatic proton located at the o-position with respect to the carbonyl group (see Table 3). j. and Vile were crystallized from an ethyl acetate-petroleum ether mixture. " Formula . The signals of the aromatic protons of the benzodioxane ring form a multiplet with a center at 7.--197 1637 ClsHl405 57 VIk 189--19'0 1639 CmI-11404 45 VIIa 184-.CIO4 64. i.7 CtTHHFO4 6.eHNO5 28 VII k 195--196 C. Thus.3. because of strong signal broadenings in the presence of LSR.3-heptafluoro-7..5 C.2.2. but they can be simplified by the action of [Eu(fod). and VIlc. When this LSR is added. In all the compounds.240 1633 22. while the methylene group signals give a singlet at 4.=O4 52 VIIb 205---206 1646 10i8 C.H*~O4 55 vI[e 170---171 1643 C*. [15-17])..217 9-O.rH.7-dlmehtyloctane-4.sHi4Os 6a \qf 168 169 1638 C. 6. Physicochemical Constants of BenzodloxaneAna!ogs of Isoflavones and Flavones Via.CIO4 50 1633 V [ l h 213214 1634. epoxides V. d-ks Va.6-dlonate [Eu(fOd)s] were unsuccessful.5 I 42 V.rHhCD4 [ 6! Vlkl 168-.--214 165O I 1. The physical constants. The spectra of the benzyl derivatives IVa.1.1 ClTH~tBrO4 43 VII g 22&.604 74. The chemical shift (CS) for this proton is 8-8.o~d [cm. 1 C l'l Ital C H llal VI a [96-. spectral and analytical characteristics of compounds VI.3 ppm region.TH. In several cases. k.eH1404 64 VII 1 216-. VII are listed in Table 2.52-4. TABLE 2.l. isoflavones Vl are preferentially high-melting colorlesscrystalline substances.rap.

C~6H2404 78.C C~sHlaO5 69.8 5.9 -.1 11. pound trum.0 B..4 5. i. j R s = OCH3 As the result of the rearrangement [13] of opoxides V under the influence of boron tri- fluoride etherate. 6..~ CjzH.8 -. IVa-h. g.6 6.3 5.9 5.1 11.2 97 Illd 127--12~ 1637 72.6 $. IVk from aqueous alcohol.2 5.~H. ~ RI CH2C6H5 ~'-~/~. rap.d-k l'Vll a. c-k R* = H.6 -.7 8.2 25 IIIC 152--15~ 1642 64.8 C~H..3C104 64.r CI7H].t vi. c R = = CI.5 8. g. d. d. 77.6 5.4 -.0 5. b and Vf.l 96 IlI g 135--13~ 1638 64.~ 11. i-k from alcohol. llld. I 80 IIIj 80--81 69.~ 4.6 $.7 5.4 -. b. and Va. C=~H=~O~ 74.3 -. j-i R 2 = H. h from acetic acid. lllj from hexane.9 C~4H~9CIO~ 70.6 5. C~H2405 ~5.4 -.7 C~HIoFOs 4. C~sH~O~ ~1. e.2 C~HmCI~O~ 20. lllc. j.~ 4.3 i 1.2 ! ol o l.1 96 IVi 98--99 I 1649 77. C~H~Os 74.3 lv~. b.~'C IR spec-' Found ~ Fapirical !Yield.4 C~4HtgCIOs ~8. a. C18HlaO4 72.5 -.9 5.4 96 IV4 I10--111: 1659 78.6 5. II R=CH2CsH ~ o Ira.0 C~H~O. h R 3 = F. Va.3 -. d-k Calculated.2 85 1Va 111--112 1658 76.7 4.3 84 V k 120--121 1667 r4.1 -.3 5. TABLE i.4 C17HI3BrO4 ~.. C~sH~Os 74.7 95 IVh 118--119 1643 4. C.1 57 IIIf 140--141 1638 22.6 95 IVj 85--86 1648 74.6 C.0 59 IIlb 172--1~ 1636 64. 0 ' 0 ~ra-I ina-I R2 OR + H/C .~H=~O~ 77. g 119--121~ 1645 70.7 8. a-e R s = H.1 94 ya 120--121 1677 ?'4.1 5.4 65 y h 142--143 1678 4. d-l. 1 R* = CI.5 8. i.1 II.1 58 IIIK 138--!3~ 72.8 5.7 82 IV i 125--126 C~H.0 87 V J: 129--130 1665 ~2.8 4.3 4.3 5. ~ O/ I R=H.4 5. g.3 72 y f 142--143 1682 C~.7 5. e.6' 5.5 94 lVf 124--125 91648 18.2 6O lllh 173--174 1643 6. % Co~l.0 C~H~oBrO4 17.CIO4 64.7 8.8 ~. I " formula ~0 C = O ~ c m .5 4.4 -. e R 2 OCH3. C. e. I 90 IILI 187--188 20.3 78 /lli 145--14~ 1640 73.5 4. benzodioxane analogs of isoflavones VI were obtained in good yields. k.d-k II o va.7 ~. c H Hal C [ H Hal Illa 126--12.5 5.O4 72.5 -.~ 11.4 C~TH~FO.~CI~O~ 16.7 1-6. 1 R 3 = CI.~FO~ 5.7 83 IVe 113--115 1644 74.5 5.5 5. C~H2oOs 74.3CIO~ 64.5 4. i. Their isomers VII are formed from chalcones III by oxidative cyclization with selenium diox- ide in amyl alcohol [14].5 81 Vie 101--I02 1665 ?'1. IVa. CISHI~O~ 69.7 5.5 75 *Compounds Ilia. f R ~ = Br.5 4.gH. In contrast to the colored initial chalcones. i R 2 = CH3. flavones VII and 151 . C~H~O~ q ..( .9 5. 134--135 1669 r5.oO~ 77. Physicochemical Constants of Benzodioxane Analogs of Chalcones and Epoxides lllaUl.3 5.{ -.8 $.ICH~ "~.9 C~sH~2Os T1.5 79 IVk 113--114 1645 77.9 5.9 5.4 5. 1638 72A 5.1 79 V g 147--149 1687 ~8. CIsHI~O4 72.~ CITH.2 82 143--144 1672 ?'4. k R 3 = CH3. h were crystallized from an al- cohol-ethyl acetate mixture. Ct7Ht. IV1 from ethyl acetate.8 I 96 IV.~O~ 73.d-1 RI I I{202/0}{- R2 ~ 0 RI CH2C6H5 E3 C ~ CH~--~C 0 Vla.5 5. f-h.HI~BrOs 17.3 -.ll R~ ~ ~ x ~ .4 8() rile 140--141 1639 69.7 t.

46 Vh 4. the values of the specific LIS are given in brackets. the most characterlstleslgnals are the peaks of methine protons of the oxirane ring in the form of doublets with a small SSCC (1-1. At a 0. indicates a trans structure of all the chalcones obtained. multlplet.2) IVg 4. It is seen that the maximal shifts are observed for sig- nals of the epoxide ring protons. i) IVj 4.H S s II x / 0 0 9 I ...2-0.33 fill 4. One of the peaks is located at 4.. %CS of 2-OCHsC6Hs group protons. d-k and Their Epoxides Va. 5-.32 IIlk 4.33 (o.70. is capable of undergoing complexation with LSR. .3) IVe 4. Z-OR. c-l.L.38 IIli 4.!) va 4. The LIS values found are shown in Table 3.48 (o. The SSCC [spin-spln coupling con~ant] for these protons. PMR Spectra* of Benzodioxane Analogs of Chalcones Ilia. ~" 3-H 4-R 2 5-R ~ 6-H d).49 Vg 4.48 (0.52 lo. doublets of the two olefinic protons can beobserved separately in the PMR spectra of products IVa.51 (o2) lVk 4.3) IVi 4.51 IIlf 9 IIIg 4. or --C'CH. as also the epoxide oxygen atom.54 IIIh : 4. whereby one of the signals i$ shifted more strongly than the other. LIS for the methylene proton signals of the benzodioxane ring.1 ppm. At one side of the oxirane ring there is a carbonyl group~ which. o. .54 (o..5 Hz). d-k influence the disposition of these signals in the spectrum very slightly (see Table 3).45 vj 4. d-l.. equal to 15 Hz. TABLE 3. d-k..o) IXa 4. absence of a letter.53 Ille 4. We therefore ascribed the signal for which a higher value of LIS is observed.54 u)j 4.46 Ve 4A5 Vf 4.37 *Units of measurement: 6. Ira. ppm.3 molar ratio be- tween LSR and the substrata.45 (0.25 Vi 4.8...54 llld 4. In the PMR spectra of epoxides Va. %CS of 8-H proton.. We assigned the signals of oxirane protons on the basis of study of the interaction of LSR with compound Vl.32 IVa 4..r Vd 4..50 (0. and the other at 4. to the methine proton located in the 152 .. Changes in the na- ture of the substituents in the molecules of the epoxides Va. 7-.55-4. y. [ ' . d-k I [ Protons of t h e ~ diOxaale pax-t .. Ilia 4.0) I~h 4. I-OCH~CH:O~. I .52 IIlc 4. CH--.2) Iu 4.45 (o. S~ or --C--C~=CH .0-4.47 Vk 4.

8--7.01 4.49.46 '.7 6. . 3.88.8 7.7 7.00 4.4 6. d '. s 7.94.3--7.46.4 ppm.79' 7.60.8--7. The signals of the methylene groups of the benzodiox- ane ring appear in the form of a singlet at 4.I 5.36 VII i S (6.85 4.29.4 6.791 ~02 a -.46 7.I.4 ppm region.25 vl d f 7. d 7. 0 7.37 VII ~'!'.36 VII e 6.2 4.4 4. (6. the PMR spectra of the same compounds were measured in DMSO-D6.65] ~.7--7.4 4.7 '. dd 7.3--7. s 7.46.4 6.7-7.92 7. 7.38. 6.3--7. d 3.4 ~.92. PMR Spectra* of Benzodioxane Analogs of Isoflav- ones Vla.7 7. d !. vicinity of the carbonyl group.98 4.92. s 2. and R a practically does not influence its CS.87 S:O0: d_ 2.0--7.00 4. the signal of the 8-H proton of the benzodioxane ring is characteristic.33 VII (6.2--7. In the PMR spectra of isoflavones Vlaj d-k. As in the case of 3-(6-benzodioxan-l.2 4.30 VI s 8.2-8.. s . s 7.9--7.36 3.9--7.2---7.0--7.9 ppm.42.46.6 6. ~The PMR spectrum was measured in CFaCOOH. The na- ture of substituents R ~.53 '.32.3--7.35 ppm.3---7.49.7 6. dd : 7. s ~.6 7.2 4.4--7.9 -.3 6.3 4.95 4.29 Via'I" 7.>.7 6. d-k.4-yl)chromones.>.53 5.32 VI g 8. It is located at 6.26. d 7.53 7.93.30. d-k in most cases form a multiplet in the 6.40 '. d 6. : 8.3-4.2--7. s 7.T--7. in unmarked cases.9 '.4 6.66) '.6 '.4--7.2 4.71' dd 7.4--7.8 7.20 4.4-8. dd 7.58 3.2--7.4 2.7--7.4 2.d .40 7.29.97 4. .83.7---7.591 7. s 6.74) ~. s 7. 7.7 7.35 VII ~'l" (6.3--7. d-k and Flavones Vlla.9 7.94 4.97 4. d -.34 VII j (6.75.2--7.. d 7.3--7.7--7.77. dd 7.93 4. 6.97.84. The results of biological tests showed that the compounds with flavone structure obtained exhibited a weakly pronounced hepato-protective action.88 d 7.7 7.93 d 7. absorbs in the weakest field (8. d~ 7.7 2. s 6.0 ppm and does not coincide with the multiplet of the remaining protons.7--7 o. I 4.2--7.3--7.64) '.36 VII d 6.38.4--7.3--7.7 7. -OC~Ca20. while compounds with an isoflavone 153 .94.>.8--7.7 . d 7.7--7.47 7.36 i.96.48.2--7.3--7.22 vL k f 7. s ~.32 VI' ].63) r.7--7.7--7. s 7.28.95.3--7.32 7 83 d 2. d 7.15.35 VII (6. in DMSO).40.74.34 7.4--7. 7.7---7. s 6.03.33 VII k (6. from which signals corresponding to in- dividual protons cannot be isolated.9--7. 7.8 7.5 ppm in a stronger field than when the spectra are run in a DMSO solution (see Table 4).27 VI e 8.0--7. d !.95.30.2 4. d 6.4--7. s 6.6 7. the CS of the 2-H proton is located 0.7 6. (6.80 7.36 VI1 (6. s 7.37.2 4. r. s 6.40 7.42 ~.7 7.51. The signals of the remaining aromatic protons of compounds Via.6 7. d '.5-6.47 3.9 6.77) '.8oi 7.83 ~.4 4.31 VI k 8.49.90. d-k are similar to the CS of the corresponding signals of chalcones IVa. besides the signals of the chromone ring protons 3-H and 5-H located at 6.49 6.83.99 4.6 6.14.4--7.9 and 7.66) ~.93 4.2-4.31 w ~q" 7.8 7.40. s 7. %The spectra of the compounds were measured in CDCIa.33.2--7.7--7. S 7.4 6.32 fi.79.47 6.30 VI . It is possible that this effect is caused by the stabilization of the bipolar form of the chrom- one ring due to solvation by DMSO. c-i Compound[ Chromonerlng protons 8enzodioxane ring protons I s.3 4. located in the vicinity of the heterocyclic oxygen atom.1 6.5 6. respectively.95 B. s ~. s 7.83) r.2--7.7 7.09.25 7.77.40 6.7--7.39 7. dd 7.89.7--7.51. s 2. d '.53 *Absence of a letter) multiplet.37 Vll et (6. s 6.36 Vlr ~-t (6. TABLE 4.7 7.3--7.1 ppm). 7-H 187.34 VI 8.3--7. d 6. dd 6.61'.3--7.37 VII a% (6.98 4. s 7. s 7.87' 05 d d 7. the 2-H proton. and as a result.7 6.75' 7.82) 1.2 3.42.1 4. In the spectra of flavones Vlla-l.95 4. The signal of the 5-H proton aligned with the carbonyl oxygen atom is present in a somewhat stronger field (7.97: d 7.31 VII (7.33.2 4.33 VII i (6.5 '. s .13.7 7.9-7.58 r.3--7. d 3. d 7.2--7.31 ~.7--7.s 6. R 2. s 7.54. S 4 VIa 8.98 4.94 4.8--7.46 6.2--7.63.66) ~. The CS of signals of other protons of epoxides Va.91 3. s 7.7 6.4 ppm. s '.4 2.33.3--7. s 6. s 7.50 B.47.31 VId 8.33 (6.75. by a greater pramagnetic influence of the heterocyclic oxygen atom on the position of the 2-H proton signal.7-5.91.04. dd 7.91 4. the signal of the methylene protons of the benzodioxane fragment is located at 4. It is of interest that when the spectra are run in deuterochloroform.09.33 VII (6.9--7.82 7.7--7.30 VII a 6. 7.04.36 VII ed-I.7--7.

J. No. Siliprandi. Turov.. 403 (1972). V. 3'. G. Schulz. A 20 mmole portion of 6-formyl-l. Tetrahedron Lett. 13. the precipitate that separates is filtered and crystallized. 174 (1983). Lucchetti. S. 16. L. The precipitate is suspended in water and the mixture is acidified with acetic acid to a neutral reaction. 71. 17. A. Yu. Bindoli. R. Soc. A.. Vogel and W..4-yl)propenones (Ilia-l) and l-(2-Benzyloxyphen- . No. Panasenko. Kolotusha. Khim. 392 (1975). 25. Dokl. 8. Litkei. J. l%(2-Hydroxyphenyl)-3-(6-benzodioxan-l.. 1202 (1981). No. F. Metallic seleniumis filtered off and amyl alcohol is evap- orated under an aspirator. 12. 790 (1975). G. Soc. A.. V. I. P.4-yl)-2. 3. J.65 g (60 mmole) portion of a finely divided selenium dioxide is added to a solution of 20 mmoles of IIa-1 in a minimal amount of a fresh- ly distilled amyl alcohol. Grishko.structure have an appreciable hypolipidemic activity. L. 6. Nauk UkrSSR. The reaction mixture is held at room temperature for 20-40 h. 3. 9.. Seshadri. Bogn~r. Pelter and R. 3'. Dinya. H. Perkin Trans. 14. Ital. L. Khilya.. 365 (1976). R. the reaction mixture is diluted with water. Cavallini. Sci. Golubushina. 5. Hansel. G. The precipi- tate is crystallized from a suitable solvent. B. L. Khilya. R.. V.. A 30 ml portion of 30% hydrogen peroxide and 30 ml of 2 N sodium hydroxide are added to a solution of 6 mmoles of compound IVa.4-yl)propenones (IVa~ d-l). Chem. A. 133 (1978). Commun.7 ml of a 50% solution of sodium hydroxide are added to a solution of 20 mmoles of the corresponding 2-hydroxy-l) or 2-benzyloxyacetophenone (II) in alcohol. Gy. A. ii. H. Trost. 3.-Forsch. J... and the mixture is boiled for 18-50 h. The PMR spectra were measured on a ZKR-60 spectrometer in CDCI~ with reference to TMS (internal standard). 195 (1972). Ukr.. 49. Hung. 83 (1971). 36. Pelter. K. No. 2911 (1968). Rangenathan and T. V. M. V. A. A. 108. Akad.. P. Zh. i0. ii. Pelter. Acta Chim. Chem. M. Turov. Turov~ and V. M. Khim. J. Hansel. Sei. L. Tetrahedron Lett. Chem. Rimpler. Litkei.4'-Ethylenedioxyisoflavones (Vla. Chem. Arzneim. Chem. d-k in a minimal amount of a 15:4 acetone-methanol mixture. Soedin. Af- ter complete decoloration of the solution (12 h). Hansel. R. N. N.4'-Ethylenedioxyflavones (VIIa-l). Spasenov. Schulz. l-(2-Benzyloxyphenyl)-3-(6-benzodioxan-l.S.5 h (the end of the reaction is determined from the TLC data). and the mixture is boiled for 1-3. No. Merlini. Geterotsikl. E. Acad. and H. Geterotsikl. with the course of the re- action being controlled by TLC. 4. 1550 (1979).6 ml portion of boron trifluoride ether- ate is added to a solution of 3 mmoles of compound Va. Zanarotti. 2. Khilya. A. Soc.yl)-3-(6-benzodioxan-l. 7. R. Koch. No. Med. Res. Pelter. and A. The residue is recrystallized several times from a suitable sol- vent. Khim. Gorbulenko. V. Hansel. and R. Pelter and R. I. Ber. i0. 25. and V. P. No. Hung. Kovtun. EXPERIMENTAL The purity of the compounds was checked by TLC on Silufol UV-254 plates in a 9:1 benz- ene-ethanol mixture. Fiebrich and H. Experientia. 9. Hansel. Grishko. A 6. N. 866 (1935). and V. Rai. 3481 (1973). V.. 15. Bogn~r and Gy. G. and Z. 44i7 (1969). Pharmacol. Gazz.. P. M. The solution is washed with water and benzene is evaporated under an aspirator. d-k). Kornilov. d-k). l. No. Cormn.. and G. A. G. LITERATURE CITED i. Khilya. Cavallini and G. 67. and crystallized from a suitable solvent. 35. and N.4-benz- odioxane and 4. Tetrahedron Lett. P. The IR spectra were run on a UR-20 spectrophotometer in potassium brom- ide tablets. G. Marchenko. Mahal. Acta Chim. d-k in 50 ml of absolute benzene. 154 . A 0. 135. 775 (1980). Ser. Soedin.. Venkataraman.. and in their pharmacological effect are not inferior to the antlatherosclerotic preparation cetamlphen. 51. A.and K. R. 43 (1979). The product is filtered.3-epoxypropan-l-ones (Va. Rochefort. Potrusaeva. Acad. 1542 (1985).

by the action of a strong mineral or organic acid. 199-205. and sulfones were made by *SC NMR spectroscopy.and 1. undergo disproportiona- tion to give 5. 1984. 4.5--143.dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-propan- one with hydrogen sulfide and acids gives an intramolecular rearrangement pro- duct. Tyrina. N.1 (28) 1:8 I (40) 70% HCI04 Ctt3COOH V (180--181) (17.4-ortho-(14.4-DIMETHOXYPHENYL)- 3-(2-OXOCYCLOHEXYL)-I-PROPANONE WITH HYDROGEN SULFIDE AND ACIDS: 2a-PHENYL-2.m in the mixtUreb (mmoles) I (30) CF3COOH III (166~-168) 7. Chernyshevskii Saratov State University.ml) (amount.4-ortho-(14.15-DIMETHOXYBENEO)-cls-I-THIADECALIN S.50 9 1986 Plenum Publishing Corporation 155 . Vl. Conditions and Products of the Reactions of 1. The configurational and conformational assignments for the sulfides.] .81:543.5--143.6-polymethylenethiopyrilium salts and 2-thiabicycloalkenes or 2-thiabicycloalkanes [2-4].4-dimethoxyphenyl)-cis-l-thiadecalin. K. 5]. Saratow410601.8 (52) aproducts IV. which then.3-diaryl-3-(2-oxocyclohexyl)-l-propanones are converted by the action of hydrogen s u l f i d e i n acid media initially to the corresponding 5. namely .6-polymethylene-4H-thiopyrans [i].4. pp. T.6-tetramethylene-4H-thiopyran. Sorokin.6 (44) 3:1 VIII (191--193) 5.g IV/V or Vl~V starting acid solvent (rap. 0009-3122/86/2202-0155512. namely.5-diketones.3 (29) 5:l (III). 1986. their sulfox- ides. N. Original article sub- mitred December i0. eTrifluoroacetate III was con- verted to perchlorate VII. Translated from Khimiya Geterotsiklicheskikh Soedinenii.5- Diketone I with Hydrogen Sulfide and Acids r .15-dimethoxybenzo)-cis-l-thiadecalin in addition to the usual products of disproportionation of intermediate 2-phenyl-4-(3.4rdi- methoxyphenyl)-5. Klimenko.4) (75) VI (145---146) I 59 (40) 1:1 VII (183--184) 9. No. 2u-phenyl-2. ~ sulfide ratios compound (amount.4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-l- propanone (I) at room temperature with hydrogen sulfide and trifluoroacetic acid. G. G. bThe sulfide ratio in the:mixture was determined relative to the '3C NMR spec- tra of the crude mixtures. 2.0 (50) (30) 1V 042. l-Aryl. In contrast to other "seven-membered" 1. February. We have studied the reaction of l-phenyl-3-(3. UDC 547.5 (30) V (180--181) 1. diketone I forms the tetracyclic intramolecular re- arrangement product. Reaction conditions Reactionproducts Yield.1 (49) I (30) BF3 (30) CH3COOH V (180--181) (7o) V1 (145--146) : 4.8 (45) 1I (12) CFaCOOH tV (142. and Vll were identified by mixing melting points with authentic samples [2.422 N.15-dimethoxybenzo)-cis-l-thiadecalin (V) along with the usual reaction products.AN UNUSUAL PRODUCT OF THE REACTION OF I-PHENYL-3-(3.4-ortho-(14.6-tetramethylenethio- pyrilium salts and 2a-phenyl-4u-(3. Kharchenko The reaction of l-phenyl-3-(3. thiopyriliumtrifluoroacetate III and cis-l-thiade- TABLE i. 2a-phenyl-2.5) v (180--181) !3. and V. 5.. I. VII (183--184)' 12.

6- tetramethylene-4H-thiopyran molecule leads to reestablishment of the C(2)=C(3) double bond.>---OMe "~/ " s / '"Ph tI (o0 XIII In our previous work [6]. if+ ~.. while the substituent in the y-position is pseudoaxial and. . VIII Y = BF~...VII. The sterically less hindered double bond (C(~)=C(s)) is initially protonated in the dis- proportionation of condensed 4H-thiopyrans with acids [3]. The experimental conditions and reaction products are given in Table i. thus."Ph Ph Ph I ] II VI CsHs(OMe)2 CsHs(OMe)2 . Thus. X I I X = S02 The formation of trifluoroacetate III and sulfide IV with cis..6-polymethylene-4H-thiopyrans is in boat form. The loss of a hydride ion from a second 5. In both cases..calin IV. " \ . CsH3(OMe) 2 V + I + VII(VIII) (BF~) ~" / " ~ S . respec- tively. IV. we have established that the heterocycle in 2.X IV...IX. Carbonium ion a which is generat- ed in this step may be a hydride ion acceptor. In our case./OMe Ph y- Ill. The dimethoxyphenyl group itself is extremely active relative to electrophilic attack.I".cis configuration is in accord with the usual concepts concerning the cyclization of 1. All these compounds are given in Table 2. which facilitates attack on C(a) upon formation of the carbonium ion. ~ "~. close to C(2)...4-disubstituted 5.5-dlketone lwith hydrogen sulfide and 70% perchlo- tic acid or boron trifluoride etherate. .VIII IV V Me0.. .XI~ III Y = CF~COO. tetracyclic product V was found in addition to the cor- responding perchlorate or tetrafluoroborate VII and VIII and 2-thiabicyclo[4~ VI.. Electrophilic substitution in the aromatic ring apparently leads to intermediate XIII and then to product V due to the re- duction of second double bond upon disproportionation.. VII Y = C104. 156 .~ /0Me 15 ~4 . .~. The configurational and conformationa! assign- ments for IV-VI and IX-XII were carried out by laC NMR spectroscopy (Table 3). XI X = SO. V X = S.~\ . Sulfides V and VI were oxidized by hydrogen peroxide to sulfoxides IX and X and sulfones XI and XII. thereby facilitating its reaction with the carbonium site.cis. this ordinary process is accompanied by the reaction of the electrophilic site in carbonium ion a with the dimethoxyphenyl group at C(~).XI.~3 r 10 f . IX. we shall not treat these ques- tions in the present work.'X 6 V.. The dimethoxyphenyl group in V is bound both to C(2) and C(4) of the heterocycle. X. This led us also to study the reactions of 1. GMe ~O~ /'.5-diketones and 4H-thiopy- tans [i] and the mechanism for the disproportionation with acids [3] including the steric specificity of hydride transfer in these systems [5]. ~(.

These data indicate an intramolecular re- action of a dimethoxyphenyl group with one of the u-carbon atoms of the heterocycle.3.4.4 5.4 C2aH2oO4S 69..4-dimethoxyphenyl)- cis-l-thiadecalin (IV) were carried out in our previous work [5]. 63. 1500 (C=C arom. 1495 (C=C arom. 1500 (C=C atom. lO45 ( s . 1130 (S--O). The aliphatic part of the spectrum of V shows a singlet at 57. ~ IR spectrum.3 .8-bis(tetramethylene)-6-thiabicyclo[3.6 C23H28OaS 72.4 8. i IX 172--173 1600. 69.1 5. 1600. 1070 (C--O--C). *Assuming that the transfer of the hydride ion from the donor molecule to the acceptor mole- cule occurs in a ~imolecular complex.9 C26H~31::304S 63.15-dimethoxybenzo)-cis-lrthiadecalin .4-ortho-(14.2 6. 1065 (C--O--C) XI 156--158 1600.3 7.4-benzo-5.64 instead of doublets at 48. The formation of thiadecalin V in the reactions considered in the present work is the first example of an intramolecular rearrangement during a disproportionation reaction. and trifluoroacetic acid to give 3. cm" i formula % 81 c H S C H S III 166--168 [680--1660 (COO-). which are iso- mers of sulfide V.om~ 72.0 8.4-ortho-(14. The configurational and conformational assignments for 2~-phenyl-4u-(3.8 22 1265. 1070 (C--O--C) VIII 191--193 1600.70 and 119. 1540.o ..5-diketone I with hydrogen sulfide and perchloric acid or boron trifluoride etherate supports our mechanism for the formation of V.* The formation of t~iabicyclo[4. 1270. TABLE 2. 1600. 1040 (BF4-) 1265. The reaction products did not contain 2a-phenyl-2.6 87 1300. The structure of tetracyclic sulfide V indicates that the reduction of the'angular dou- ble bond as a result of protonation at C(~o) and transfer of a hydride ion from 5. Table 1 also gives the results of the disproportionation of thiopyran II in trifluoro- acetic acid.i !75.6-tetra- methylene-4H-thiopyran II to the carbonium site at C(9) proceeds by cis addition although the approach of the hydride ion donor from the side of the condensed aromatic ring is ster- ically hindered.70 ppm while the aromatic part shows a singlet at 134.7 C23H2802S 75.5-diketone I with H2S/CF3C02~.8 7.2 71 1045 (S--O) X 221--222.9-7.3 6. Characteristics of Compounds Obtained Found. 1525. 1495 (C=C).2 8. &] rap. % Calculated Chemical Yield.1]-7-nonene as a result of intramolecular electrophilic reaction of the benzyl group with the carbocation site with re- duction of the double bond and formation of disproportionation products [7].2 7.5 C23H28OaS 71. 1500 (C=C ~. perchloric acid. 1o2o ( o . 71. 1075 (C--O--C) I V 180--181 1605.33 ppm in IV.0 50--52 1585. The *SC--{H} and double het- eronuclear resonance spectra permitted examination of the change in the multiplicity of two signals in the rearrangement product V relative to thiadecaline IV. 1270. There have been reports of the intramolecular rearrangement of 9-benzyl-symm-octahydro- thioxanthenes upon the action of hydrogen chloride. 157 . 8. 73 125o.4 .. Salts III and VIII were reprecipitated from chloroform by the addition of ether. The higher yield of sulfide V in this experiment indicates that the dimethoxyphenyl group apparently also reacts with carbon- ium ions directly preceding the formation of 5.6 7.o ) *The recrystallization solvents were i:I ethanol-acetone for sulfide V and sulfone X and 2:1:0. 1495 (C=C).9 8.5 !6. 61.3 C23H23BF402S 61.6-tetramethylene-4H-thiopyran II from the bi- cyclic semithioacetal. The relative yield of tetracyclic sulfide V in this case is significantly lower than in the reaction of 1.6 .0]-A1'6-decene VI in addition to the intramolecular con- densation product V in the reactions of 1.c ) . We should note the finding that intermediate XIII is reduced in this reaction while the angular double bond is retained in dihydro product VI.5 hexane--ether--acetone for sulfoxides IX and XI.1 45 126% 1o3o (c--o--c).4 [7.15-dimethoxybenzo)-trans- l-thiadecalin or 28-phenyl-2.

93 127.60 136.331107.481147. (146)* (139)~. *Tentative signal assignment.41 21.241107.821150.27t 63.20 148.83.80 140.92p 23.20 i31.08 51.71 27.14 127.81 55.~ C(3) C(3) C(5) C(6) C(7) C(8) C(9) CHo) OCHa pound c(~) II ortho meta para C(12) C(I~) C(n) c.78.64 134.76 55.741110.20 57. ppm 2-Ph 2.71 127.13 128.76 C(I) C(6) C(5) c(.d 46.10 126.12 128. 130.321148.33' 27.59 XI 68.60 (130.51 137. V.94 22.11 [ 25.97 128.) IV 48.79 (13o) (133)* (138)* 55.72 44. .30 110.28 129.84 128.76 148.08.20 i 30.53II 10.601149.70 33.70 46. d 45.25 118.791107.06.141111.86 128.23 126.91 107.85.23 20.12 60.60 22.54t 61. 55.12 /25.66.20 21.d 44.oo TABLE 3.) It(.98 46.4-At or 4-Ar Com.50 43.64 104.22 127. d. u 55. "aC NMR Spectra of IV.93 30.79 134.52:t I 19.67 *The XJc_ H coupling constants are given in parentheses. 66.71 126. 142.37 107.93 128.26 19.50 19.709 28.86 [ 25.50 48.29 110.68. 129r63 130.60 148.69 136.s 35.62 128.02 46.71 148.95 55.d 23.33 110.07.38 128.94 55.29 127.86 148.~7 127.60 46.63.94 128.95 147. X 75.77 128.93 136.4) Ic~5) [c(~6) V 57. c.05 134.88 119.22 46.45 148.74 135.65 . d 55.50d 24.28 (135}? (138) ~ (137)~ IX 70.58 XII 67.54.) Ic(.93 20.39 119.10 55.61. 136.24 [ 27.39 31.67 21. and IX-XII.20 55.78.43 s 35.84 148.70:s 39.16 [ 23.46 49.

~s) --5.95 -8. The C(e) signals in both series IV + XI + XII and V IX + X are more shielded than the C(s) signals. C(7).16 C([o) +3. Reaction of l-Phenyl-3-(3. Difference in the Chemical Shifts of the y-Carbon Atoms in Sulfoxides IX and XI and Sulfones X and XII Rela- tive to the Corresponding Sulfides V and IV. The presence of an upfield signal at 22. TABLE 4. The '3C NMR spec- tra of the sulfoxides and sulfones of 2-aryl. while the C(s) signal in V is shifted downfield by 5. and X were taken with gated decoupling with retention of the *Jc-H values. analysis of the theoretical Chemical shifts of the alicyclic carbon atoms for conformations A and B or 2~-phenyl-cis-l-thiadecalin~[5] and the chemical shifts of C(5). IX.96 g (30 mmoles) di- ketone I was added in portions over 1 h and saturation with hydrogen sulfide was continued for an additional 3 h. The reaction mixture was maintained for three days until the inter- mediate 4H-thiopyran had completely disappeared and then repeatedly extracted with a total of 350 ml hexane. mp 180-181~ (from 1:2 etha- nol--acetone) in 22% yield. ppm Iv v Atom SO 802 SO SO~ -. The data of various workers [5.3. A sample of 30 ml absolute trifluoroacetic acid was saturated with hydrogen sulfide for 1 h at 20-25~ A sample of 10. The use of the SO and SOs group y-effects in IX-XII permitted the identification of the signals for C(s). XII tak- ing account of the characteristic effects of the sulfinyl and sulfonyl groups in going from sulfides to the corresponding sulfoxides and sulfones. The extract was washed with water and dried over MgS04. IX. The characteristics of the compounds synthesized for the first time are given in Tables 2 and 3.48 --3.12 t. we have assumed that the intramolecular cyclization proceeds at C(=).53 The complete interpretation of the '3C NMR spectrum of sulfide V became possible due to analysis of two series of sulfide-sulfoxide--sulfone spectra for V. 8. EXPERIMENTAL The IR spectra were taken on a UR-20 spectrometer ~n vaseline oil and hexachlorobuta- diene.7 ppm. The orientation of the sulfinyl groups in IX and XI is equatorial. The *H and '3C NMR spectra were taken on a Varian FT-80A fourier-transform spectrom- eter using HMDS (for *H) and CDCI3 solvent (for *SC) as internal standards. Hence. and C(.43 -11. 9] were taken to calculate the chemical shifts of some alicyclic and aryl group carbon atoms with subsequent comparison of the experimental and theoretical parameters. The 13C NMR spectra were taken with broad-field suppression of the spin-spin coupling of the '3C and *H nuclei with incomplete proton decoupling. X and IV. The signals for C(o) and C(zo) in sulfides IV and V (Table 3) do not differ significant- ly.48 -. C(o).o). perhaps as a consequence of anisotropy of the condensed dimethoxyphenyl group and the presence of this atom in a five- membered ring. In addition.4-diaryl-cis-l-thiadecalins will be con- sidered in a subsequent communication.52 +0.2.84 + 1. C(6). Partial evapora- tion of the hexane in vacuum gave crystallization of sulfide V.20 ppm indicates cis ring fusion according to the accepted criterion for condensed cyclohexanes [ii]. and C(e) in IV and V indicates that the cis-l-thiadecalin system is in conforma- tion A in both IV and V (Table 5). which are in good accord with the data for thiadecaline derivatives [i0].61 + 1. Sulfides IV and V or V and VI were separated by preparative column chromatography on alumina with hexane as the eluent.4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-propanone (I) with ~ydrogen Sulfide and Trifluoroacetic Acid.74 -4. The reaction course and product purity were monitored by thin-layer chromatography on Silufol UV-254 plates with 6:1 hexane--ether as the eluent. XI. Complete evaporation of the hexane from the residue gave a i:I 159 . Table 4 gives the y-effects of the SO and SO= groups in IX-XII.and 2. The spectra for V.52 -2.

Removal of the solvent and chromatography permitted the separation of V and Vl in 12 and 33% yield.4-dimethoxyphenyl)-cis-l-thiadecalin 1-Oxide (XI). V. and V. Berezhnaya. Aleksandrov. 180 (1980). mixture of sulfides IV and V in 6% yield. I. N.70 aData for the theoretical spectra of 2e-phenyl-cis-l-thiadeca- fin from our previous work [5] are given for comparison. G. 3. Kh.22 19.60 V cis-A exp.61 . 7. I.5-Diketone I with HTdrogen Sulfide and Boron Trifluoride Etherate. J. iO. Stolbova~ T. 45.l-dioxide (Xil) and 2a-phenyl- 2. 16. Zh. Geterotsikl. cis-A calc. Khim. S. N. K.15-dimethoxybenzo)-cis-l-thiadecalin 1-oxide (IX) was obtained according to the procedure described above. Kharchenko. V. mp 166-168~ (from chloroform-ether). 24. and V. Kuz'mina. S. M. i0..10 26.. Khlm. K. TABLE 5. and V.70 28. Reaction of 1. V. K. 2e-Phenyl-2. Rooney and S. 21. N. The reaction mixture was maintained at room tempera- ture for 72 h and diluted with 350 ml ether. 8.28 27. A sam- ple of 70 ml glacial acetic acid was saturated with hydrogen sulfide for i h at 20~ and then 30 mmoles 1. I. No. Sergeev. Soedin. 199 (1976). 1942 (1974). Khim. C. Khim. A. Freidlina. N. 2417 (1975). G. 4. N. N. I. V. Shcherbakov. 9.. Berezhnaya.. Evtushenko. Akad. Klimenko. Evans. Org. K. Stolbova. 15.50 19. ii. M. A. S. R. 2. J. T. E. mp 166-167=C (from ethanol). Ya. P. 2u-Phenyl-4u-(3. ii. G. Zh. Tyrina. Kharchenko. I. G. Klimenko. and E. Krapivin and L. Ya. Trifluoroacetate II crystallized upon dilution of the acid mother liquor of the reaction mixture by ether. Vierhapper. V. 178 (1980).60 22. S.20 31. T.5-diketone I was added in smallportlons along with the dropwise addition of 30 ml boron trifluoride etherate over 1. G. 34. Khim. i0. The mixture was left for 24 h at room temperature and then poured onto chopped ice. F. and V. Zh. G. Izv.4-ortho-(14.. Khim. 24. Zh.6 g (1. G. Evtushenko. Org. Comparison of Theoretical a and Experimental Chemical Shifts of Alicyclic Carbon Atoms in IV and V. Tetrafluoroborate VIII was filtered off. Sulfone XII was obtained in 90% yield. 5. The mother liquor was washed with water and dried over MgS04. Eliel and F. Chukovskaya.. Perchlorate VII and a mixture of sulfides V and VI were obtained. mp 191-193~ (from chloroform-ether) in 45% yield. Kharchenko. Kharchenko.34 IV cis-A exp. Klimenk0. The experimental conditions and results a r e g i v e n in Table i. M. S. I. Reson. Org. M. Chem. Leshcheva.. A mixed probe of this sample with an authentic sample gave an undepressed melting point. 1470 (1979). I. Kharchenk0. Org. W..4-ortho-(14. Klimenko. Struchkov. and V. R. LITERATURE CITED i.69 2(I. B. T. 2e-Phenyl-4e-(3.l-dioxide (X) were obtained from the corresponding sulfides by oxidation with excess hydrogen peroxide as described in our previ- ous work [12]. and V. respectively. ppm Configuratio~ Compound and confir. T. Sorokin.15-dimethoxybenzo)-cis-l-thiadecalin l. Magn. S. No. T. The reaction was carried out as in our previous work [2]. 6. Org. K. K.65 mmole 30% hydro- gen peroxide was added dropwise. Geterotsikl. Org. Yu. Ser. Sulfoxide XI was filtered off. Khim. R. G. Smirnova.88 31. ll. 2. A. A. Stolbova. Kharchenko. A. 898 (1984). 2425 (1974). 452 (1982). 1338 (1981).. lonin. No. and V. Soedin. G. Nauk SSSR. Dostovalova..20 30. Kharchenko. Khim.63 mmole) sulfide IV was dissolved in 21 ml glacial acetic acid and l. i0. Chem. Perepelitchenko.4-dimethoxyphenyl)-cis-l-thiadecaline l. N.. S.5 h. 41. Klimenko. Reaction of l~5-Diketone I wit~ Hydrogen Sulfide and Perchloric Acid. Geterotsikl. No. 160 .Nature of [nation the data G{5) C~7) C(B) 2~ -phenyl-cis. Stolbova. Org. 133 (1981).86 l-thiadecalina cis-B talc.40 26. 7. A sample of 0. Klimenko. Soedin. 28.

2. 10. REACTIONS OF AZIRIDINYL ALKYL SULFIDES WITH CARBOXYLIC ACIDS AND ACYL CHLORIDE DERIVATIVES R. V. S. T. Academy of Sciences of the Latvian SSR. see [i].717'279. We have found that reaction of azirine I with mercaptoacetic and mercaptopropionicacids occurs at the carboxyl group to generate the corresponding u-(mercaptoacylamino)isobutyrophenones II and III: Ce. Berezhnaya. namely.e. S.Ill I II n = i.. Klimenko. such as. Zh. 0009-3122/86/2202-0161512. react with carboxylic acids to give B-ketoamides and substituted ethanethiol derivatives. Stolbova.104 Treatment of 2H-azirines with mercaptosubstituted acids and their derivatives leads to B-ketoamides and 2-aziridinyl alkyl sulfides. 440 (1975). In cases where protonation of azirine ring and subsequent nucleophilic addition of a carboxylate anion are impossible. V. respectively) with those of unsubstituted car- boxylic acids. 1984. No. and the cor- respondin~ aziridinyl alkyl sulfides are formed. Electrophilic addition of carboxylic acids to the C=N bond of 2H-azirines gives the cor- responding B-ketoamides as a result of ~somerization and 1. CH 5 + [[S(CII2)COOH . M.. K. respectively. for instance. which are known to react with 2H-azirines to give the corresponding B-ketoam- ides.Hs-~. 2-Aziri- dinyl alkyl sulfides. themercapto group of the carboxylic acid is the only reactive site.50 9 1986 Plenum Publishing Corporation 161 . S. C~IIsCOC(CkI5)2NHC0(CII2)sSH N If." -CH 3 ~'~. At the same time.2-dimethyl- 3-phenylazirine (I) reacts with B-substituted ethanethiols to give a new type of functional aziridine derivative. Institute of Organic Synthesis. depending on the reac- tion conditions. 0rg. G.. It was of interest to us to study the reactions of azirine (I) with mercaptosubstituted acids. 1986.47. El'kinson and A. REACTIONS OF AZIRINES WITH SULFUR NUCLEOPHILES. Acylation of 2-aziridinyl alkyl sul- fides with acyl halides generates a variety of products. Riga 226006.12. aziridinyl alkyl sulfides [3].. N. Original article submitted November 30. 10. treatment of azirine I with the ethyl ester of mercaptoacetic acid for the sod- ium salts of N-acetylcysteine or cysteine yields the aziridinyl alkyl sulfides IV-VI as the only reaction products (Table i): *For communication 3.68. Smirnova.~'-. February.* TREATMENT OF 2H-AZIRINE WITH MERCAPTOSUBSTITUTED ACIDS. nucleophilic addition of the mercapto group to the C=N bond of azirine I occurs. ii. i. 4.. N. 206-211. in analogy with the results reported in [3].. For instance. during esterification or salt for- mation.. Kharchenko.40 and 4. bifunctional reagents which should be capable of entering into both nucleophilic and electrophilic addition reactions to ~ bond of azirine (I). 2. Eremeev UDC 547. and V. and as a result. pp. either products derived from cleavage and isomerization of the aziridinyl ring or (l-acylaziridinyl-2) alkyl sulfides are obtained. III n = 2 The formation of products II and III from the reactions of azirine I with mercaptosub- stutited acids should be anticipated based on a comparison of the ionization constants of these acids (pKa 3. Khim. in turn. Translated from Khimiya Geterotsiklicheskikh Soedinenii.32..2-cleavage of the aziridine ring in the initially formed 2-acyloxyaziridine derivatives [2].

5 6. 3350 69. 3200.1 51 XV 46---48 1640. 3300 63. 3330 65.8 4.0 ii.5 4.4 45 XX! 183--185 825.sH. t650.2 5. XV-XVII. HC[ 49.4 t03 C u.6 37 XIX 37--39 1050. 3280 63.1 72 (2.6 6.6 C~gH~tNO2S 69.4HvjNO2S 63.4 7. and XXI Com. 1640.2 5.3 8. 1260.sH. 3250.5 9.8 C. cm. 3300 49.3 12.3 11.3 C.5 9.lqO2S' 63.9) (21.7 9.9NO2S 65.5 10. 1560.3 9. 1540. I 7. 1690. 3300 54.7 57 VI 120--121 1600.6 5. % Calculated. % fl N I S(Cl) 1t N S (Cl ) IV [68~9 1080. 1650.5 5.3 12.2 6.3 5. 1250.1 61 XVI 119--120 1650.1) .6 8.6 hPa)] V 178--180 1410. 1430.2 5.5 8. 2It0.1 Molecular formula Yield.8 8.4H2ICIN2OS. I 5.9 9.3 7.4 7.5 11. 1730.gNaN~OsS 54. 980. 3260.9 5..1 5.4 4.H~ NOaS 62.3 C.9 6.CY~ tJ TABLE 1. % pound IR spectrum.3 9. 1650.7 9.4 6.7 11.6 6.0 6. 1720 62.2 5.1 11.7 6. Found.aHjzNaN202S 54.4 C. 2210.9 C.1 4.9 C.4H .lfides IV-VI. XIX. Physical Chemical Properties of Su. 3350 54.9 10.5 64 (2o.4 9.8 58 XVII 15---18 900.

3-dimethyl-2-phenylaziridine (IX) [5] with carboxylic acids gave the same 8-keto- amides as prepared above.~II IX Vll R = OH. ~/CH3 S~'~/'CHs /S" ~ . R* = CeH=C-C. % Molecular C. 1690. 1685. namely.C6HsCOC(CH3)2NHCOR1 ~C2HsoHR1COOHC2H5~~ / ~CH~ H X-~II HN 3I.7 6.59 1540.7 6.. 1620.a l c . 1660.3210. It is known that acylation of aziridines with acyl halides to give N-acylaziridines oc- curs only in the case of acceptor acids [7]. We have therefore studied the re- activity of these sulfides in reactions involving both retention and cleavage of the aziri- dine ring.5 4. "-CH~ . 1680.1 5. the presence of both aziridinyl and sulfide functional groups. t r e a t m e n t of 2- ethoxy-3. which are characteristic of aziridines. Treatment of the aziridinyl alkyl sulfides VII TABLE 2. that heteroly- tic cleavage of the aziridlne ring occurs upon treatment with organic acids to give the cor- responding 2-acyloxyethylamines [4]. 2-Alkoxyaziridines react in a similar manner to aziridinyl alkyl sulfides with carboxylic acids. would seem to imply a wide spectrum of chemical reactivity.44 1530.415.2 78 3250 XI 218--220 0.9 6.416. X l R* = C 6 H ~ C H = CH. treatment of sulfides VII and VIII with carboxylic acids led to the formation of the corresponding 8-ketoamides X-XIII and a substituted ethanethiol derivative (Tables 2 and 3). For instance.5. It is known.6. a better leaving group than an alkoxy group.8 56 3280 ! XII 118--120 0. however.71 1535. for example.3315 XIII 158--160 0. VI The azirldinyl alkyl sulfides were of considerable research interest.8 4. and the compounds X-XIII were identical with respect to all physi- cal chemical and spectral characteristics with these compounds. the sulfide group is. It should be noted. 1620. VIII R = N ( C H s ) a . | IIRCII/CI[(NI1COCtI3.75 1530. of course. our experiments concerning the reactions of 2-hydroxyethyl.~ Ha HN CH2 HN ~H2 HN COOC2H5 CII(NHCOCII3)COONa CII(NfI2)COONa IV ~.)COONa -\'.S'~/// CH. 3310 163 .9 CI9HIgNO2 77. % pound " rap. 1620.2 6... One observation supporting this assumption is the fact that reaction of aziridine IX with carboxylic acids requires harsher conditions than the analogous reactions of aziridinyl alkyl sulfides.41 53 3290... X R* = C 6 H 5 . Physicochemical Properties of 8-Ketoamides X-Xlll Com.IN X 153--155 0.915.. 78.and 2-dimethylaminoethylaziridinyl sulfides VII and VIII [3] with either sat- urated or unsaturated carboxylic acids unexpectedly revealed some unusual product structures. Instead of generating the expected 2-acyloxyethylamines.3.4 5. .= CH We cannot exclude the possibility that these reactions occur via intermediate 2-acyloxy- ethylamines.8 78 2210. 76.3 i4. that the reactions of aziridine IX with carboxylic acids require both longer reaction times (6 h) and higher reaction temperatures (80=C) than the analogous reactions of sulfides VII and VIII (3 h. 1655. 1680. 3080. 50 ~ RCH2CH2~q~CH3 R~C00H C6Hb~CH3 C6H5' N/ CH3 ":RCH2CHzS~. 71. However.7 CioHlTNO2 78. encompassing the chem- istry of the aziridine ring as well as that of sulfides. 1635.i formula 0) ther C H[N el.6 4. . . 77. 1655.. CSII5 CII3 C6II%>~.. / Found.4 CIzHITNO2 76. inasmuch as their structural characteristics. I %19/'~-} .6 6.816. XIII R x = CHa.3 CI~HIsNO2 71. oC | R! IR spectrum. since the rearrangement of 2-acyloxyethylamines to 2-hydroxyethylamides is known [6].. cm.

4 (H.. hydrogen chloride.56 7. ~ / . co.. which leads to in- tramolecular rearrangement of sulfide VII to the 1. which gave the hydrochloride salt of 2... In contrast. Apparently. _~CH3 %.6).. (C~Its)~N C{CH3)2NH2'HCI RCH2CH2S ' CH RI C00CH2CH2S CH . induces heterolytic cleavage of the aziridine ring. tMultiplet consisting of all of the aromatic ring proton signals.51 (CH=CH. however... 7.. which was isolated in the form of its hydrochloride salt XX [i0]. the hydroxy group of the sulfide also underwent acylation..78 6.76 6.~[-Io).XIV XIX " RICOCII R=NH2.r (=CH2.4..3-oxathiolane.71 7...58 (Hr~and 1..and[.3-oxathiolane ring system. C6['15/ ~ C INI 3 R=0H.~ I c..+ C(IR X'V-... 6. namely.X~'I! XVIII 9 R1COC1 =611. 7.R=OH . _ .4. we have demonstrated this reaction using sulfide XV. and ElY [3] with acyl halides in the presence of triethylamine readily gave the corresponding N-acylaziridinyl alkyl sulfides XV-XVII (Tables 1 and4): RCH2CII~S . C6HsCO~NIICOR I 1 + IISCII2CH2R ! SCI]2CII2R CH3 XXI Vll R = OH.. that.andHv) 1.58 (H~)..02 7. PHR Spectral Parameters of 8-Ketoamides X-Xll (CDCIs) Com. 7.72 7.42 (H..58 (C6H~)t H~) XIII 7.11--. 5. 6.{~)* Hp) XI 7. Hz) X 7. depending on the nature of the substituent in the B-position to the sulfide group.93 (Ho).+-)~"c% . 5. as well as by hydrolysis to give the known compounds [ii] ~-(acetylamino)isobutyrophenone and 2-aminoethanethioi hydrochloride.1.. 14.4 (C6H~). "" c H ~ \ / ~CH C=H= ~~ SI .4.. When 1 mole of the aziridinyl alkyl sulfide VII was treated with 2 moles of acylating agent in the presence of base. 16) XII 7.el .. In the absence of base the N-acylaziridines generated in these reactions undergo further conversions involving ring opening and formation of B-halosubstituted N-acylethylamines [9].58 (CH.1 I--7.. and the corresponding (l-acylaziridinyl-2-)-2-acylhydroxyethyl sulfide XIX was obtained.. 2-oxazolines [8] is characteristic of N-acylaziridines..6) J *Multiplet. an~ 1. 7..91 (Ho)..11--7. (C2Hs)3N " 6 5 \ N/ 3 H COR 1 X~ VII. X I V R = NH2~ R* = CHs.33 (H.Rt (J. Our experiments have shown. C6H5.91 (Ho)..25~'d6. the struc- ture of the latter was verified by spectroscopic analysis. a variety of products can be obtained from the reactions of the aziridinyl alkyl sulfides VII and XlVwith acyl halides in the absence of base. HCI CH3 CaHsC(Cl )C(CH3 )2NItCOR 1 H2_O_.. ppm pound C0H~ C1% NH H. treatment of sulfide VII with acetyl chloride in the absence of base gave an almost quantitative yield of a substituted 1. as has been demonstrated previously [I0].(~:.67 5. which is generated in the begin- ning of the reaction.89 .7... CH2 = CH The rearrangement of N-acylaziridines in the presence of acid to give ring-enlarged pro- ducts..CH3 RCII2CIt2S.4-trimethyl-5-phenyl-5- (2-hydroxyethylthio)-2-oxazoline XVlII.. TABLE 3...33 (H. 6...andH~) 1. For in- stance...11--7. workup of the hydrochloride salt of 2-aminoethyl aziridinyl sulfide XIV with acetyl chloride under analogous reaction conditions generates the sulfide XXI... 7. including both the aromatic ring proton signals and the NH group signal. 6... ~.9 . 164 .

H 6.~ndH p) 1. CH3). PMR spectrum (CDCI3): 7.3. 1645.73 . Yield 3.76 and 3. Calculated: C 62. A solution of 2. 3300 cm-* (Nil).3-dimethyl-2-phenylaziridinyl-2-thio)propanoate (V). 3. corresponding to all of the protons of the aro- matic ring.7.3-Dimethyl-2-phenylaziridinyl-2-thio)acetate (IV).2H. Hm.8 g (72%). mp 183-185~ Rf 0. m.21 (2H. N 5. S 12. m. t.29 0.0.34 (SH.5 g (20 mmole) of ethyl mercaptoacetate in i0 ml of ethanol. and H p ). mp I18-120~C.39 (3H.62 (Ho). S--CHa. 2-CH=) . s. CH3).58" 3. 4. s.44 2. C6H5). H 6.89 (2H. CH.26-2. 2.69 ppm (3H and 3H. This was prepared in an analogous manner. S 12. 2500-2680 (SH).94 (2H. 7.56 (Hm andHp )* XVII OH CH2=CI-I 7. NH). 7. 7.53 ppm (3H and 3H. 0. A solution of 2. 2-(3-Mercaptopropionylamino)-2-methyl-l-phenyl-l-propanone (III). CH3). m. COR 8.56 (Hr~ 0.7. 1650.17and 6. IR spectrum (nujol): 1545.44) XIX CH3COO CHa (H~ and H~) 0. and Hp) 1. Hz) XV OH CH3 7.51] 5.22 (5H.92 (Ho).18 2.13 7. 7.8. Hm.1. m.7. 8.0. d. s. 1. Found: C 60.77 *Multiple.48 18. and Hp).2. 0. This compound was also prepared analogously to the manner described for compound (IV) and was purified by recrystallization from a 1:3 chloroform--hexane mixture.71 and 2.18 (Silufol UV-254. This was prepared in a similar manner and was purified by washing twice with 20 ml of acetone. 165 . S 13. 3330 cm-* (NH)~ PMR spectrum (DMSO-D6): 8. ether). PMR spectrum (DMSO-D6): 8. bp 68-69~ (2. PMR spectrum (D20): 7.57 (IH. The resi- due was recrystallized from 1:3 chloroform--hexane.46 (3H. 2530-2600 (SH).89 (2H. m. Sodium 2-Amino-3-(3.64 . The mixture was stirred 15 h at 70~ and the acetone was evaporated.56 2. 3158 (3H.9. PMR SpectralParameters o f Sulfides XV-XVII.29--7.03 (3H. IR spectrum (nujol): 1550. 7..59 ppm (3H and 3H. N 5. CH3). CH3CO). CH2). t.46 (3H.51 3. 3-CH2 and SH) .29 (3H.87 and 1.5%.6 hPa) PMR spectrum (CDCXs): 7. 1. TABLE 4. Ethyl (3.78 and 2. H m and Hp). 2.78 (CH. The physicochemical properties of compounds IV-Vl are recorded in Table i.77 (IH. Ho).92 (2H. XIX (r RCH2CII~S'~_ CH3 N I .1). s. N'H)..46 ppm (6H. 2. 7.21 (2H. 6.89 and 1. s.44. Calculatedt C 60. 7. J = 5 Hz. S--CH= and NH).35 (=CH2.3. CH).62 (3H. and the residue was distilled.6. 1. m. 4. 2-(Mercaptoacetylamino)-2-methyl-l-phenylpropanone (II).3-dimethyl-2-phenylaziridinyl-2-thio)propanoate (VI). C6Hs). The reaction mixture was stirred 12 h at 50~ the alcohol was evaporated. m.03 1." R' pound C6H5 CH~ CH2--S CH2--R Ha HRt (I. CH2). CH3). NH2 and NH). m.. 0. 3. m. C.06 4.29-.7%. 1690 (amide bands. m. Found: C 61.99 (Ho). CI3HtTN02S.88 2. Ho). 8.83 and 1. 7. CH3).56 XVI OH CsHs 7. 2. 1685 (amide I and II b a n d s . N 5. J = 5 Hz. S 13. EXPERIMENTAL IR spectra were recorded on a Perkin-Elmer 580B spectrophotometer using thin films.9 g (20 mmole) of azirine I in I0 ml of ethanol was treated dropwise with a solution of 2.and Hp)* 1. 7.49 2.4. Sodium 2-Acetylamino-3-(3. 3. ppm tom.5%. O-CH2). s. sNO2S. C--O). s. Yield 2 g (47%).1. Melting points of the compounds prepared in this paper were determined on a Boeth- ius microheating apparatus. PMR spectra were obtained on a Bruker WH-90 spectrometer using 5% solutions and TMS as internal standard. s.33 (IH. H 6. q.56 (H.44 3.46 ppm (6H. Ho). s. s. 7. N 5. H 6. 7. 2.71 (6H. 3.66 g (18 mmole) of mercapto- acetic acid. CzO).33 (Ho).4%.90 (2H.49 (Ho). 7.61 g (18 mmole) of azirine I [5] in 20 ml of acetone was treated dropwise with 1.62 and 2.02 (H.9.40 2.

s. E. Mishnev.7 g (3 mmole) of sulfide VII or VIII [3] in 30 ml of acetone was treated dropwise with a solution of 0. New York (1969). Khim. F. 3. Eremeev.27 g (3. Chem.39 (SH. 0. Ya. CH3). The mixture was stirred 3 h at 50~ and the acetone was evaporated. l-(Acetyl-3. Yukawa and S.3-dimethyl-2-phenyla~iridinyl-2) 2-Acetoxyethyl Sulfide (XIX). A. 4692 (1975).37 g (3 mmole) of benzoic acid in i0 ml of acetone. Cal- culated: C 55. El'kinson. 2202 (1959). Chem.29 (2H.75 g (3. 736 (1984). Geterotsikl. 7. The filtrate was concentrated and the residue was recrystallized from 1:3 ether-petroleum ether. Mishnev. t. Khim. Kimura. and V. C~Hs). R. This compound was prepared similarly to compound XV. V.76 g (84. N--CH2). A. A solution of 0.. Am. El'kinson. No. Fetter. S. F.973 (Japan). 210 (1950).3 mmole) of acetyl chloride in i0 ml of dry tetrahydrofuran.53 g (60. and S.64ppm (3Hand3H. H.4.6. El'kinson. 2.03 (3H. CH3CO). 1. S.. Found: C 55. Patent No.4%). t. 1633 (1985). m. S 10. NH + and OK). 12. The residue was recrystallized from 1:3 acetone-- ether. CI~HIgNO2S "HCI.4. m. No. E m and Hp). Tables 2 and 3)• A solution of 0. Geterotsikl.96 (2H. 81. Eremeev and R. Chem. Eremeev. 33. NHs+).24 g (3 mmole) of acetyl chloride in l0 ml of ethanol. The residue was recrystallized from 1:3 ethanol--ether. Geterotsikl. J. 3300 cm-* (OK). V. r ii. V. N 4.62 g (77. Parcell. S.. 7.34 g (3. H. m.78 and 1. S-CH~ and 2-CH3). H 6. See Tables 1 and 4. A. Hydrochloride Salt of (l-Chloro-2-acetylamino-2-methyl-l-phenylpropyl) 2-Aminoethyl Sul- fide (XXI.08 (2H. Eremeev. R.6%.3 mmole) of triethylamine in 20 ml of dry tetrahydrofuran was treated dropwise with a solution of 0. NH).46 (5H.94 (3H. Table i). J. Belyakov. Ya. and E. No~ 5.Ii ml of concentrated hydrochloric acid in 5 ml of ethanol.. Yield 0. Yield 0.. mp 183-185~ P~[R spectrum (DMSO-D6): 9. 53 (1985). S.5%). 18i0 (imine salt band).(hydroxyethyl) Sulfide (XV. G. Ind.. 166 . S.5. Soc. Am. 4. Ho). I. (l-Acetyl-3. Bleidelis.43 g (64%). M.76 ppm (6H. The mixture was stirred i0 h at 20~ the alcohol was evaporated. 3. J. and I. Yield 0.77 (IH. Nicholson. The mixture was stirred 3 h at 20~ and the solvent was evaporated. E. Hassner. Ya. Tsukamoto. Cheng-fan.53 g (3 mmoles) of sulfide XV in i0 ml of acetone was treated dropwise with a solu- tion of 0. 3. s. El'kinson. O. 5. V. mp 153-155~ Compounds XI-XIII were prepared in a similar manner (Tables 2 and 3). Brown and A. br s. Khim. Chem. Bestian. Burke. LITERATURE CITED i. 1032 (1963). 83.3-dimethyl-2-phenylaziridinyl-2)2. M. 2016 (i961). A. F. br s. br s. Ham. mp 46-48~ Sulfides XVI and XVII were obtained analogously (the latter was purified by recrystalliza- tion from hexane). 6.7. 2. Khim. 623 (1985). ~.52 g (2 mmole) of sulfide XIV [3] in 20 ml of ethanol was treated dropwise with a solution of 0. The mixture was stirred 3 h at 20~ and the triethyl- ammonium chloride precipitate was removed by filtration. Semenikhina. No.3 mmole) of sulfide VII and 0.. Tables i and 4)~ A solution of 0. Ann.4-CH3).55 (3H. mp i18-120~ IR spectrum (nujol): 1660 (C=~-~).6. Heine.. Academic Press. s.56 (2H= t. H 6.9%). R. 8. Yield 0.. Soedin. 97 . 9. S--CH2). Dermer and G. Bieidelis. Soc. 58. A. Ethyleneimine and Other Aziridines. 3.33 (2E. 2-Benzoylamino-2-methyl'l-phenyl-l-propanone (X. Soedin. S 10. PMR spectrum (DMSO-D~): 8. N 4. m. V. 6. H. 4. C. C. O-CH2). 4. 7. 2. and the residue was recrysta!- lized from 1:3 alcohol--ether. 7. i0. J. Geterotsikl.3. R. Soedin.8%. Am. and ~. Chem. 2420 (ammonium band). S. W. A. 1396 (1963). Absto.4-Trimethyl-5-phenyl-5-(2-hydroxyethylthlo)-2-oxazoline Hydroch!oride (XVIII) o A so- lution of 0. Soc. Liepin'sh. Soedin. A. 566. 2. Ya. 8.

It can be assumed that both cyano groups are co- ordinated to the cobalt atom and are situated symmetrically relative to the plane of the por- phyrine molecule. Madakyan.NEW DERIVATIVES OF meso-(TETRA-4-PYRIDYL)PORPHINE AND THEIR REACTIONS V. the antiphase oscillation. Stepanyan. Kurtikyan. 212-216. 1985.422 Some reactions of Co-meso(tetra-4-pyridyl)porphine were carried out. aromatic. No. revision submitted April 8. S. Translated from Khimiya Geterotsikliche- skikh Soedinenii. N. also obtained directly from CoTPyP in solution by reaction with cyclohexylamine hydrobromide in cyclohexylamine [i]. aromatic. which with pyridine gave a quantitative yield of the cyanopyridine complex 7. February. the dicyano complex 5 was converted to the monocyano derivative 6. Attempts to synthesize the imidazole and benzimidazole cyano-derivatives of CoTPyP were not successful. and a cyan- opyridine complex was isolated. T.e. Ordyan 543. All the compounds synthesized (8-10) were readily soluble in water at any pH. 2. and M. Treatment of CoBrTPyP 3 or the complex 4 with excess KCN in methanol gave the complex 5. UDC 547. in neither case was the complex isolated. Aliphatic. This structure consists of two normal oscillations: inphase and antiphase. Aliphatic. 1986.2. The reaction of meso-(tetra-4-pyridyl)porphine (TPyP) i [3] with excess ethylene chloro- hydrin gave the tetrachloride of meso-(tetra-4-N-hydroxyethylpyridyl)porphine (THEtPyP) (8) in quantitative yield. R.979. K. Kazaryan. The central cobalt atom was introduced by treating THEtPyP in aqueous medium with a tenfold excess of cobalt chloride followed by concentrated hydrochloric acid. the course of the reaction was monitored spectrophotometrically. Erevan State Medical Institute. pp. Mo A. In the infrared spectra of compounds 5-7.07: A.50 9 1986 Plenum Publishing Corporation 167 . 0009-3122/86/2202-0167512. Erevan 375025. These oscillations include the valency oscillations of the cyano group.733. a structural analog of vitamin B. The two cyano groups of complex 5 give rise to only one absorption band (at 2170 cm -I) indicating that they are equivalent. and heterocyclic amines were used as ligands on the central cobalt atom. Original article submitted January 23. is IR-aetive. B. The purpose of the present work is to synthesize some cyanamine cobalt complexes of meso- (tetra-4-pyridyl)porphine (TPyP). i. By refluxing in glacial acetic acid. followed by chromatography on AI20~ (Brockmann activity grade II). Khachatryan. the cyano group absorbs in the region 2100- 2200 cm -I. The reaction of a chlorofozmrnnethanol solution of CoTPyP (2) with 48% hydrobromic acid gave meso-(tetra-4-pyridyl)porphinobromocobalt (III) (3) CoBrTPyP. 1985. New water-soluble complexesbased on Co-meso- (tetra-4-N-hydroxyethylpyridyl)porphine were obtained. in which cobalt is present as an anion. and to prepare water- soluble analogs of some previously described unsymmetric cobalt complexes [I]. The effect of the structure and functional substituents of the porphyrine molecule on its biological activity can be examined by studying a large number of different synthetic por- phyrines. and heterocyclic amines were examined as ligands. The reaction of an aqueous solution of the complex 9 with excess of the corresponding amine yielded the amino derivatives 10a-d. S. Treatment of the latter with cyclohexylamine gave the complex4. Such a structure is unique since only one of the oscillation.

... | ' f " :'=" N..C~. d + .~.ion absorbs at 2080 cm -~ . in going from complex 3 to 5 there is a shift of the pyridine ring absorption band from 1640 to 1595 cm-*.. '-<..I ~C._ 2 . in all cases these bands are at lower frequencies than in the free amines. b) cyclohexylamine.. and in several cases bands in the spectrum of the complex are stronger and (or) half as wide as the corresponding bands in complex 9.N . the frequencies of the additional bands are similar to the vibration frequencies of the coordinated ligands (see Table i).N..N N.~ ne / i II / / / / l . How- ever.. N / I "N f ~'N: . This pro- vides evidence for ligand-coordination. while the free C=_N.\ : . N/Cq. 168 .N Br- / 3 / 4 // CN /~ N" I "N CN . stretching vibrations of the C-N group absorb at 2148 cm -~. O CN 5 8 Note.. It should be noted.~< c : C ] " +/'t:'-::'x / NI'| N .NI ... An appreciable change in the frequency indicates that the cyano- group is located in the inner sphere as in the complex 6. a~ n-butylamine. " "":'= C.~:~ .. are small peaks in the same region as the broad OH stretching absorption band with maximum at 3400 cm -~ . ~i .. however.. Analogous shifts in the absorption for the transition from a pyridine salt to a free base have been re- ported in the literature [4]. Thus..CH= ..NIC ---. N" COfI.. --. ' 8 ' t N "~'~ %. . /o. In compound 6.N N. and not in a structure with separated charges. which indicate axial coordination.. since it is known [6] that the coordination of amines is accompanied by a decrease in the frequency of the stretching vibrations of the N(NH2) groups. . // . so that in compound 5 the pyridine groups occur as free bases. This is particularly the case for bands due to the stretching vibrations of the NH(NH~) group.. N. t ieaA~.. " { k + C1 N..-#' \ ~:.. d) pyridine Infrared spectral data and elemental analysis..~zOH " 9 '~ " "~" " ':':. This is to be expected.. The infrared spectra of compounds 10a-d contain more absorption bands than that of the complex 9./' -" CltzCH20H ~. ap- pear as shoulders on porphyrin absorption bands.~.. c) piperidine.t ... Bands corresponding to these vibrations. N-. N UOCU. 1 ..[. as was proposed in [5] for etioporph- r ine (cobalt) cyanide.J . CfI2CH201i . since the porphyrines which we studied contain hydroxyethyl groups...... where the cyano group is covalently bonded.. the vibrations of which partially overlap the region of absorption of the coordinated amines..iN~ . that axial coordination in the test compounds shows up less sharply in the infrared than in previously obtained com- plexes of CoTPyP with a numher of amines [i]..'~.. /. IINI "[.r .. show that the conversion of the complex 3 to the complex 5 is accompanied by the dehydrobromlnation of the peripheral pyridine groups.. Thus. some of the bands given in Table i. .

57.0 I 11..0 15..5) 1452 s h 8(dH~ ) . 530.2).3 92 591 sh. nm Found.l 91 amine 587 sh.~ 6Ol (4) i *For complex 9 the corresponding bands were at 435. O~ %0 .9 4. 552 (10. 436 (114).3 15. 1078 VtCN~.4 16. 745. Coln. 557 s h v~.2 15.4 93 585 sh (4.4 5. 2750.8 ] 11. 32'.9) 2868 v.0 11. 56. 548 (10. 546.-To.7 1 4.7 15.CoN.5 5.9 11..3). 2800.) ' 3200 Y (N H. 705. (3.8 16.) I I 16b Cyclohexyl. 9 15.4) 1465 6(CH~ ' all:. ' 2968 V. % Yield.8 4. 555 V~--L). and at 412..4 Cs3H. 3200 VtNIt) 10d Pyridine 57.3 5.).~CoN.7 ql. IR s p e c t r u m .8 11.9 11. 1440. 1385 5(Ci• ). 1375.~1.a 56. [~cc. TABLE i.0 16.S(CH:0 .~(CHA.1 11. 1385 8(CH~) .3 C~H4904CI~CoN9 57. Empirical pound Amine (~ -zo-~ F. 1088 V~CN~. and 560 nm for Co(II)TPyP.6 4.8). 3300 %'"~(NHz) 16c Piperidine 439 (91. % Calculated.~(CH:.4 C~2H5504CI~.~ccH~) . 548 (10. 56. and 584 nm. 898. 2945 V. (4.1). Aminoderivatives of meso-(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) Tetrachloride lOa-d UV spectrum. 2950 ~'.~O4CI.X . 1598 vtcc~.3 93 440 (116). cm. 562 (10. 575 V~ZI-L).j 56.1 % I I C It CI I formula II CI 10a Butylamine 436 (115).~(NH: ).1 Cs4HszO4CIsCoN9 57. TWave numbers for bands not present in the spectrum of complex 9 are given.2 4.4).30 I V. 696 pt~:u).

Apparently. To a solution of 0. In free pyri- dine.2 g (95%) of the salt. Found: C 44. shifted by 6 cm-*.28 mmoles) of CoTPyP (2) was added 500 ml of methanol.H24- CON. Br 37. 5:3). which may also involve the dative component of the metal-ligand bond.4%. Ultraviolet spectral data (see Table i) also show the greatest bathochromic shift in the spectrum of the complex 10d. B. evapor- ated to dryness. C~2EadCoKN. Found: C 65. H 2. For the pyridine ligand. increased coordination of Co(Ill) with an aromatic system. and after 3 h the mixture was chrommtographed on an A1203 column and evaporated to dryness. To 4.4. N 18.6%. H 3.. A solution of 0. How- ever. meso-(Tetra-4-pyridyl)porphinocyanopyridlnocobalt (III) (7).o. H 3. there is no N-H bond and this criterium cannot be used.0%. The complex 6 (0.5 h and 400 ml of chloroform added. Calculated: C 65. the reaction mixture was passed through an A120s column (chloroform-methanol 5:3). N 10. two new bands at 696 and 1598 cm-* in the spectrum can reasonably be attributed to a displacement of the ~*~b(CH).36 mmole) of the complex 4 in 300 ml of methanol was added 1.28 mmole) of compound 3 in 200 ml of methanol was added 1.0.12 (AI~O3. the3e absorptions occur at 702 and 1580 cm-*. Recrys- tallization from dry ether gave 0. 500 ml of chloroform.5 g (23 mmoles) of KCN..2. The reaction mixture was heated at 40~ with periodic stirring for 20 mln and then allowed to stand overnight. H 2. After standing overnight.2| H 3.07 mmole) was dissolved in 20 ml of pyrldine by heating at 70~ for i0 min. Rf 0. which. chloroform-methanol.1. A. Calculated: C 70.17 mmole) of the complex 5 in 50 ml of glacial acetic acid was refluxed for 0. N 18. To a solution of 0. The solution was 170 . the mixture was chromatographed on an A1203 col- umn and then evaporated to dryness. CdoH~sBrsCoN. The frequencies of the porphyrine ring vibrations change little on axial coordination. Chromatography was carried out on AlaO. Calculated: C 44.12 (AlaO~. chloroform-methanol.5 ml of 48% hydrobromic acid. (Brockman activity grade If).05 g. Found: C 70.3 g (0. The greatest shift is observed for the complex with pyridlne. Calculated: C 65. or distilled water. N 18. Rf 0. Potassium Salt of meso-(Tetra-4-pyridyl)porphinodic[anobromocobalt (III) (5). 5:3). When cool. T h e residue was recrystallized from dry ether to give 0. and the residue recrystallized from chloroform and ether.2. the residue was recrystalllzed from dry ether to give 0.3%.2. and also hypsochromic shifts [9] have been reported for absorption bands as a result of axial coordina- tion. meso-(Tetra-4-pyridyl)porphinocyanocobalt (III) (6). Rf 0. therefore. enabling the infra- red spectra of the cleaved particles to be taken. 5:3). After evapor- ation of the eluate.6. Examples of such bathochromic [8]. disturbs the electron system of the macrorlng more strongly. Tetrahydrobromide of meso-(Tetra-4-pyridyl)porphinobromocobalt (llI) (3).8. Found: C 65. N 17. In all cases they were found to be starting amines.3 g (0.8.o.7 g (99%) of compound 3. Ultraviolet spectra over the range 350-800 nm were obtained on a Specord UV-vis using anhydrous chloroform ~n a 4:1 mixture of chloroform and methanol. samples were prepared as KBr pellets or as suspensions in mineral oil. N 10.25 g (6.6: Br 37. H 3. The mixture was vigorously stirred at room temperature for 4 h. The ultraviolet spectra of the compounds show a small bathochromic shift compared with the complex 9 because of additional coordination. did not undergo any chemical change during the course of the reaction.5%. these disturbances are small.13 g (48%) of 5.1. The strongest bands from the macroring are at 800 and i000 cm-x.4%. H 2. similar displacements have previously been reported for pyridlne complexes [4]. Attempts were made to cleave the axial ligand from the complex at elevated temperatures (70-80~ and reduced pressure (10-4 tort).85 (Al~Os.15 g (0.9. N 18.5. N 18. A further 600 ml of chloroform was added. H 3.5 h. although ~udging from the small frequency shift. Cd.5. ~ea(CC). 0.0%. and 8(CCH) vibrations on coordination. C~H2~CoKN. and dried for 1 h in a vacuum desiccator at 40 ~ The violet crystals were carefully washed with dry ether and dried in air to give 6. and are out-of-plane and in- plane deformation vibrations of the pyrrole CH bonds [7].3%.6.i g (83%) of com- pound 6.8. The eliminated llgands were directly precipitated onto a KBr substrate cooled with liquid nitrogen inside a vacuum cryostat. EXPERIMENTAL Infrared spectra in the range 400-3600 cm -l were taken on a UR-20.1. The reaction mixture was heated at 40~ for 0. chloroform-methanol.5 g (23 mmoles) of KCN. 5. and 12.

K. T. washed with 9 acetone.9. Chem.2. N 11. 2. 884 (1977). N. Infrared Spectra of Inorganic and Coordination Compounds [Russian transla- tion].9%. Soedin. 8. H 4. Soc. Minsk (1968). Pharm. 171 . Aminoderivatives of meso-(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) T e t r a - chlori~e (10a-d. The crystalline material was filtered off and washed with the corresponding amine and absolute ether. D . J. and N.o. 95. Nauka i Tekhnika. and B.. M..3. Sharp. N 10. Chem.0. Calculated: C 61. H 4. Nakomoto. Found: C 61. CI 17.. 4. After the addition of 12 ml of concentrated HCI. I.5. D. 3. Inorg. Enikolopyan. 97.O~ Calculated: C 55. S.9. Chem. S. C1 15.3. T .9. W. Table i).24 moles) of ethylenechlorhydrin was refluxed +for 2 h (course of the reaction monitored by chromatography). S.5 mmoles) of compound 8 in 500 ml of distilled water was added 8 g (61 mmoles) of COC12 in i0 ml of distilled water. Chem. recrystallized from ether.5. 18.5 g (99%). 493 (1962). Yamanouchi. LITERATURE CITED i.. To a solution of 8 g (8. Soc. S.. Inorg. 5. Sugata. Geterotsikl. N . C~eH~4CIsCoN.. Kazaryan. the dry residue recrystallized from absolute ether and then further recrystallized from a mixture of water and the corresponding amine (i:i0).H~CI4N. R. Rf 0. Found: C 55. H 4.8%. 6466 (1975). F. Khachatryan.5 g (97%) of the complex 9. E .1. B . J.04. Sevchenko. H 4. T. M. and D. 8:1) +Found: . 2979 (1960). Scaife. 9.C 70. 1786 (1973). Johnson and J.chromatographed on an Al2Os column and eluted with a chloroform-methanol-pyridlne (10:l:3)+mix- ture. 397. S .7. A. and Y. No.4.8. Gill.9 chloroform-methanol. Amer. K. C1 17.055 g (99%) of the complex 7. J. and K. Calculated: C 70. R. and recrystallized from a mixture of water and ethanol (i:i0) to give 8. Solov'ev. Kay. 79 (1961). Moscow (1966). J. A. Spectroscopy of Chlorophyll and Re- lated Compounds [in Russian]. 7. N 17. CI 14. Madakyan. Stynes. P . 7.0%. the reaction mixture was evaporated to dryness ~n vaouo. C46H29CoN. C~. The solution was refluxed for 2 h with simultaneous distillation of+water until the volume was reduced to i00 ml (course of reaction was monitored spectrophotometrically). W . Gurinovich. A. 82 (1984). N 18. H.. Tetrachloride of meso(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) (9). Stynes. ~. Chem. Nuttal. Bengelsdiyk and R. Drago. S. The crystalline material was washed with chloroform and recrystallized from a mixture of water and propanol (i:i0)to give 1. The reaction mixture was evaporated to dryness ~n Vucuo and the dry residue recrystallizedfrom ether. R. J . 25. The eluate was evaporated to dryness and the residue recrystallized from dry ether to + give 0. A mixture of 1 g (16 mmoles) of the TPyP i in I00 g (1. N 11. C. Mir. B. A . Tetrachloride of meso-(Tetra-4-N-hydroxyethylpyridyl)porphine (8). Amer. V . H 3. Kurt~kyan. G . p. N.9%. After I0 minutes the reaction mixture was evaporated to dryness. Khim. N 10.8. No. N . 6. Chem.i mmole of compound 9 in i0 ml of distilled water was added 0. Nucl.75 (Alz 0 s. Matsushima. Fleischer.7. H. Bull. To a solution of 0. H 3.8%. James. Ordyan.7. Soc.4 mmole of the corresponding amine. V .9%.

which have both a pyrrole ring and an alicyclic ketone fragment [8.oi 'X L.5.5.2-diaryl-4-oxo-4.. II " ' "N"'R z i <~ N " R2 L_ R .. S. No....6.. ] R~ . Translated from Khimiya Geterotsiklichesklkh Soedinenii."" N.422 and N.. P.nutes and gave 62-88% of the tetracyanoethyl-substituted indoles lla-f.R~ . pp. Beirut.754.. 217-221. UDC 547. Dagher. ~.. while tetracyanoethane reacts with carbonyl compounds to form furan derivatives [7]. Lebanon. R" 2 r '1 i "'~'f.. Terent'ev. Pyrroles and indoles react readily with tetracyanoethylene (TCE) with electrophilic at- tack by the latter at position 3 of the pyrrole ring [1-3].d~ f~ g g:R* = R s = H..04'339.6. Lomonosov Moscow State University. In a continuation of work on the reactions of the 1. 2. the molecular ion (M+) of compounds lla-f* could not always be recorded. M. 9].. When heated to I00-150~ they decomposed.tl "J II . so that satisfactory elemental analysis data could not be obtained.. ".2:543.0172512.7-tetrahydroin- doles.7-tetrahydroindole with tetracyanoethylene occurred at the 5 position of the tetrahydroindole ring.. the reaction was complete in two to four mi. Feb- ruary.. and only the use of field desorption (FD) enabled their molecular weight to be established. ti6H~ lla. and 3-methy[-4- oxo-4. Moscow 117234..7-TETRAHYDROINDOLES K. i It" CI|~COOH i.6.5.7-tetrahydroindoles. which quickly darkened in air (Table I). R 2 = C. .. it is known that TCE.CN O NC ~N NC / "CN ! . f "" g i CsHsN21I 3.. A Fischer rearrangement of the phenylhydrazones of these 4-oxotetrahydroindoles gave pyrrolo[2. Primary decay of the M + ion of com- mA peak corresponding to [M--HCN]+ is observed in the region of greatest m/z values.2-diaryl-4-oxo-4.. IICI. B. . LebaneseUniversity. 1986. ]]10:t.. we have studied the reaction of the indoles la-f with TCE. as white or light-colored crystals. 1985. 172 0009-3122/86/2202....TETRACYANOETHYLATION AND FISCHER REARRANGEMENT OF SOME 4-OXO-4.. II NC. V. Even on ionization by electron bombardment in the mass spectrometer. il . Kulikov The reaction of the 1. can react with alicyclic ketones by the Michael reaction to give u- tetracyanoethyl derivatives [5].H5 It was found that by mild heating (40-60=C) in ethyl acetate solution.6.50 9 1986 Plenum Publishing Corporation ..CN~ 'R~ O I" "'" " N "'R 2 I ~zN ~ /f ~ ~ R3 . ii .5. like acrylonitrile [4]. However.3-c]carbazoles. i[ i ""//'"N" " R2 ! . Original article submitted February 15.

centered at 3.32).6. This conclusion is supported by the fact that the 3-methyl-4-oxo-4.71-6. 277 (23). 402 (38).7-tetrahydroindole If also reacts with TCE to give the tetracyanoethyl derivative of llf. in both PMR spectra there was a sharp single-proton doublet of doublets from the 5-Ha proton. 363 (53). R" = H. 301 (50).38) 128 (100).7 ppm in the upfield region. 121 (100). This type of decay indicates the presence of a tetracyanoethyl residue at position 5 of the heterocyclic nucleus (ring system). In the UV spectra of compounds lla-f were observed two short-wave bands at 250 and 280 nm.23). 467 (28). 402 # (5)~ 375 (9). characteristic of aryl pyrroles [I. but also at 173 . FD . or with the loss of a molecule of TCE or tetracyanoethane by a McLafferty rearrangement. *eFD: 493 (i00). whereas when TCE is mixed with the previously reported 6. 365 (60).50) 131 (18). 6.44). 88 282 (4.30 ppm. TABLE 1. 149 (84). It was found that the presence of methyl groups at position 6 of the 4-oxo-4. Consequently. These data confirm that the tet- racyanoethyl residue in these compounds in on the 5-C atom and in the equatorial position. 301 (100). 91 (25) lic 3-C ['IaC. possibly because of steric hindrance. two 2-proton doub- lets from the para-substituted l-phenyl residue at 7. partly superimposed on this. 168 (10).~]-I4 250 (4.3 ppm and.~ I ~ "l tvam. 402 (100). 440 (4.35). Conclusive proof of the position of the tetracyanoethyl group was obtained from an analy- sis of the NMR spectra of compounds lid and e. 245 (40).60). ]03 (100) *lla-e R 2 = C6H5. cm'~l Mass spectrum. 64 278 (4.02) lib 2-CHzC6Ii4 245 (4. 129 (14).19).38). 364 (100). 62 286 (4. 105 (50). which is probably due to the partially ionized particle formed by strong hydrogen bonding between the acidic proton of the terminal dicyanomethyl group and the earbonyl oxygen atom.4t). 365 (33). 429 (78). 135 (19). 489 (59). 244 (60).9 ppm and a multiplet from one proton (6-Ha). {05 (80) IIf 202 (4. 91 (100) lie 4-BrC~I-[4 248 (4.45) 149 (73).T e t r a c y a n o ethyl-4-oxo-4.5. the C=O group stretching vibrations absorb at lower frequencies (1640-1645 cm-*) than those of the ketones la-f (1660-1650 cm-*) [i0]. 400 (50).22). tThe M + peak and the I0 most intense peaks are given. if5 (20).j [. %) u LIa C8H5 248 (4. 468 (4. 439 (21). not only at position 5. 474 (4. 145 (12). III (20).7-2.5. 429 (25).6-dimethyl substituted derivative of these ketones [i0].60). 230 (44). 364 (100). and one long-wave band at 468-475 nm. 244 (42). 400 (21). I07 (30). 85 234 (4. llf R 2 = H. and only starting compounds are isolated from the reaction mixtures. 466 (25). 472 (4. 250 (15). In addition to a multiplet from the five pro- tons of the 2-C6H~ group at 7. 230 (37). 388 82 278 (4. 149 (]8). 460'~(27). ii].7-tetra- hydroindole ring had a significant effect on reactivity. 244 (26).6. Ion peaks for 79Br are given in italics. 109 (15). Properties of 5 . 165 (67). 150 (10). 415 (23).# m/z (relative intensity.44) 245 (55).7-tetra- hydroindoles lla-f u tmethanol~-] IR spec-.52) 273 (37). 62 250 (4. since the coupling constants are 5 (axial-equatorial) and 15 Hz (axial-axial). ~FD: 430 [M + i] + (15). 389 (32).2-7. 404 (10).60). 119 (87). 299 (16). 403 (16). 149 (20). 475 (4. 402 (i00). (1oo) 474 (4.30). 375 (20). Furthermore. 375 (85). there was a singlet from the 3-H proton at 6. 115 (37) lid 4-CH3C~H4 217 (4.72 ppm. ]05 (13). pounds lla-f occurs primarily by the successive elimination of two molecules of HCN. a three proton multiplet from the two pro- tons of the methyl group (C(I))and one equatorial proton on the C(6) atom at 2. 429 M + (19). the reaction does not take place. R 3 = CH3.5.1-7.

28).. I78 (12). and in the IR spectra of compounds !llf and g..oo.3-c]carbazoles)..38) 3420 I(17). and the use of excess phenylhydrazone. 295 (4. 228 $h 3115 . 174 .08) Ili f 240--242 202 (4.37). . H 5...41). . d.6.205 21 (4. and a band at 1420 cm -~ which we attributed to the azo group. .40). 91 (I00). compounds Ic. which are typical for aryl. Calculated: C 85. ]IN ' N -l'..7-tetrahydroindoles can serve as suitable starting compounds for the preparative single-stage synthesis of a number of pyrrolo[2. III (33). which are readily oxidized by atmospheric oxygen to the aromatic compounds lllc. . ~c.3-c]carbazoles. . I05 (4.HI + ions.19). 218 (36).and methylindoles [ii]. 248 (4. instead of the usual Fischer rearrangement. [3). and g.0%. f.12). CH~ C611s [ ~ ' h call5 C6H5 ~ '-j IV ('6H5 Thus.-c113. 219 (82). 191 (27). .q (~0).. 256 (4. . 186 (12).28).~72 (iO0). 328 151 (7). 432 (4. 29O 149 (33).1. there are strong peaks corresponding to M + and [M -. The formation of the enazo compound IV. 164 (10). gave.33). 17. N 4-N --~~. 2-diphenyl-4-oxo-4..19). 351 sh 49 (9).6. is also apparently due to steric factors. g. . the carbonyl group. 228 sh 3420 . f. 253 (6) 179 (6) ]78 295 (4.7-tetrahydroindoles were not successful. this material absorbed at 402 nm. . in the UV. ~Found: C 84. TABLE 2. However.72 (I00)..33).5. normal hydrazones (confirmed by the Fischer rearrangement to give the corresponding 1. 253 (4. and in the IR. ~-. . 356 31 (4.2-dihydropyrrolo[2.6-dimethyl-substituted 4-oxo-4.6-dimethyl-l. a mixture of phenylhydrazlne hydrochloride and 6.~20 (100). However. 328 (4. p ~m I t .36). 281 (23). which have no substituent at position 6. and [M-CHs--C6H~N~--H]+. iso- lated in yields of 21-55%(Table 2). (4. 152 (9) Illg * 285--287 202 (4. [M-CH~--C~HsN2] +. 256 (4. of a yellow crystalline material.7- tetrahydroindole (Ig) gave an 88% yield (based on reacting ketone).. On prolonged heating in glacial acetic acid. . d.07). further decay of this ion corresponds well with an enazo structure for IV (see reaction scheme).77(3) (3. 371 (iT). in the IR spectra.06) IIld 220-~223 210 (4. 9.. and g . . there is an N--H stretching band at 3420-3415 cm -x. LTB(37). In the mass spectrum of this compound was observed an M + peak with m/z 403. 9-54 34 (4. H 5. apparently. 140 02) (8). 255 (4.9.~177 200 (4. 229 3460 282 (lO0).. 371 ([2). 357 (5). 290 (4. 165 (9). 440 (3.26) *The M + p e a k and the l0 most intense peaks are given. 141 (20).22).~o >. 3420 1(9). In the mass spectra of the pyrrolocarbazoles III. 229 3505 . there was a strong con- jugated C=C stretching band. caused by the geminal methyl groups at the 6 position.. 254 (i?). I09 (30).0%.45).5. 253 (9). . Their UV spectra were very similar to one another.28). 190 (16). .. d. C2oH~N2. #For the reacting ketone l.40). Thus. 4-oxo-4. 356 (i7).L'". . O i.22).. when heated with phenylhydrazine hydrochloride. . f.o 111r I75~. ' --Lc)~. 179(II). an additional band at 3460-3505 cm -x. (20).5. and leads to the formation of [M-CH~] +. 254 55 (4.. the reaction mixture always contains the start- ing ketones. 186 (rT).27). 350 gh (2o) (8... 105 (5).6. our at- tempts to carry out an analogous Fischer rearrangement starting from 6. Proper=ies of the Pyrrolocarbazoles lllc.28). or an increased reaction time does not in- crease the yield of the final heterocyclic compounds III. 280 (13). i i! I ~v. .

p. 81. I:I). K. Academic Press. 175 . I. Nasakin. Am. G. 7. The resulting solution was concentrated to 3-4 ml and the precipitate of II filtered off. E. I.7-dihydroindole (IV) was obtained analogously from 1 0 0 m g ( O . 12. N. Reactions and Methods of Studying Organic Compounds [in Russian]. 8~. IR spectra on a UR-20 (in mineral oil). 2nd Edn. R. Geterotsikl Soedin. and bands with Rf 0. R. No. 388 (20). Soc. B. poured onto 40 g of ice. 296 (4. and the precipitated material separated and washed with water followed 9 by 5% sodium hydroxide solution. Y. Chem. 5. based on the ketone) of the azo compound IV. B. R. Shirota. Bull Chem. Moscow-Leningrad (1952). W. Characteristics of compounds lla-f and lllc. f. Geterotsikl. Soc. 180 (5). Soedin. Kusabayashi. Kh. the bands with Rf 0. 6010 (1959). Heterocycl. 1462 (1984). Khim. Lange. d.8-0. Sil'vestrova. g are given in Tables 1 and 2. 3. Byull. A. PMR spectra on a Varlan XL-100 (in deuterochloroform). Preparative chromatographic separation of the compounds was carried out on Silufol UV-254 plates in ethyl acetate-hexane. and H. Terent'ev (Terentiev). 283 (18).45-0. UV spectrum.04). using TMS as a standard. Bundel. Nikolaev.. A.3 m~mole of ketone I and 0. %max (log e): 250 (3. LITERATURE CITED 1. 3 2 ~ m o l e ) of ketone lh and 46 g (0. Dagher andP. Khim. E. 291 (1984). 105 (38). A solution of 0. 989 (1983). Hanna. Bands with Rf 0. V. Noland. No. W. EXPERIMENTAL UV spectra were obtained on a Varian Cary (in methanol).2-diphenyl-4-phenylazo-6. 77 (i00). 645 (1982). Yu. G. W. Khim. A. No. C. 1620 cm-* (~C=~). N. Dagher. p. Kukhtin.9 yielded 56mg (88%. voltage of emitter 6 kV. Yu. J. Mass spectra were run on a Varian MAT-f12 at an ionization energy of 70 eV with direct introduction of the compound into the ion source. Ezaki. compounds were visualized in UV light. E. The latter was recrystallized from a mixture of ether and hexane (i:i). 6. and the mixture stirred and heated on a water bath (40-45~ for 2-4 min. Kost. Heterocycl. F.97). and S. Terent'ev. Bulai.. m/z (%): 403 (33) M +. 402 nm (4. Sunberg. S.. the produce was dried and chromatographed. Izobr. 149 (ll). 1605 (1982).5. f. E. Terent'ev (Terentiev). 20.03). and R. and V. Geterotsikl. Petrov. 12. 5-Tetracyanoethyl-4-oxo-4. Khmel'nitskii. V.. 4.32 n~nole) of phenylhydrazine hydrochloride by re- fluxing for i0 h. O. V. 165 (8). Kost. the pyrrolocarb@zole III. and B. Pyrrolo[2.. Z. 38 (1980). Alekseev.9. G. and R. Little. The Chemistry of Indoles. with mp 230-232 ~ (from a mixture of ether and hex~ne. Kuryla.7 mmoles of the ketone I and 90 mg (0. J. P. B. Krespan. 3. Japan. V. I...3 mmole of phenylhydrazine hydrochloride in 4 ml of glacial acetic acid was refluxed for 8 h. J. Mass spectrum. Chemc_. O. New York (1970).5 yielded the starting ketone. g). 3:7. GNTI Chemical Literature. 402 (8). V. A. 9. Yu.. Chem. 91 (70). S. Terent'ev. I. P.3-c]carbazoles (lllc. Nasakin. G. 2. 2783 (1958). 47. 759607. No.7 mmole> of TCE in 15 ml of dry ethyl acetate was added 1 drop of concentrated HCI. Maximov. 4 5 8 3 6 (1972). Dagher and P. 298 (6). R. B. Middleton.. Field desorptlon mass spectra were obtained on a Varlan MAT-212. Maxlmov. Heckert. Hanna. B. Soc. A. and C. E. J. IR spectrum (CCI~): 1420 (~N==N).7-tetrahydroindoles (lla-f). 19. Bundel. P. Mikawa. Shmorgunov. 488. 6. G. K.6. A. Am. 38. Soedin. J. USSR Inventor's Cert. 8. i0. il. d.6-Dimethyl-l. Terent'ev and A. After again washing with water. K. Chem. To a solution of 0. Alekseev. E.

the position and intensity of the long-wave band do not change significantly (experimental section). unlike the 1.~._.~o~.'. In the IR spectrum of compound lla. e R l = CHs. 222-226.b. E. Ilia.. Vb. Translated from Khimiya Geterosiklicheskikh Soedinenii. O" O -.. tb... N|] "" N . which do not show the characteristic long-wave UV absorption bands present in the spectrum of A.Ceil 5 c.. IVa. February. 9 .-~.. UDC 547.~ j _A. M. and PMR spectroscopy. X --~. CHEMISTRY OF THE PYRAZOLIDINES. No. which form the enolates II... I +.7-.. The structures of these compounds were confirmed by UV... Leningrad197022. both the C=O absorption band at 1670 cm-* and *For communication 25 see [I]. From this it can be concluded that these compounds. Institute of Bio- chemistry and Physiology of Microorganisms. there is no signal in this region.IIs 0 ' Cell.2'775'778'542. R x = C2H~. 0:~.. Ve R ~ = C2H5. Leningrad Institute of Pharmaceutical Chemistry.. but as Nil-acids.5-dioxopy- razolidines (la-c).5-dioxopyrazolidines with alkyl halides in the presence of sodium alkoxide gave l-phenyl-2-alkyl-4-benzyliden.2-5... Ilia-c. For compounds B. " . . M.R 1 2 I ' ' ~--- / . Aronzon. and by mass- spectrometry.5-dioxopyrazolidines react with sodium alkoxides to give sodium salts of the 4-(a-alkoxybenzyl) compounds B.~X----N. the benzyl proton signal9 is shifted upfield to 5. b. . and A.. however. as a result of bonding with the alkoxy-anion.i~ RI O. d X ffiOCHs. c iv a ma-d Ia-Va X = H.Na+ I a-c lla 0~ Call 5 0. Adanin. since there are two possible reaction products -. obtained by the reaction of la with sodium methoxide and isolated by a precipitation with absolute ether.2-disubstituted analogs (A)." ". e R s = CHs In the UV spectra of compounds la-c in alkaline ethanol. .N/Cells 0%.4 ppm [2].. 176 0009-3122/86/2202-0176512. Moldarev.. Pushchino-on-Oka.and l- phenyl-2.50 ~ 1986 Plenum Publishing Corporation .the product of the reac- tion with alkoxide. it was shown [ 2 ] that 4-benzyliden-l. 2. Illc.. \___y Ob. 142292. react with sodium alkoxide not as Lewis acids. -' N. ~.. . L. e X = NO~. confirming that the exocyclic double bond has been retained (Table i).5-DIOXOPYRAZOLIDINES B. A~-cH-\ I 0 "C6H5 O'" C~...C~:I{ s.. ~-?"-~".. ~..4-dialkyl-4-(a-alkoxybenzyl)-3. ~-~. and the alkylation product.2-diphenyl-3. Va....722. 26. Previously. The enolates B react with methyl iodide to give 4-methyl derivatives C.~ A B C It was of interest to perform this reaction with the 4-benzyliden-l-phenyl-3. in the PMR spectrum of compound la in CDsONa. pp. lllb. 1986..j t ORO.953 V.4-dioxopyrazolines.. Va.. b. IR. O~ N C~IIs ~. M. Ic.. IVa. OR~/"-~'~L./ . Original article submitted February 26. 0 ~ Cell 5 0 " " '\k_"iY. Zyakun The reaction of 4-benzyliden-l-phenyl-3. 1985. b R ~ = CHs. Academy of Sciences of the USSR. Va.* ALKYLATION OF 4-BENZYLIDEN-1-PHENYL-3.Na + R ~ va.

42--7.82 (m 21t}. 3.4-tetrasubstituted derivatives 177 .85 {s 3H) 4. The alkylation of compounds la-c occurs in a step-wise manner.C ~ I I 4 . !7.63 (d. From these data we can definitely conclude that no O-alkylation products are present. The dual character of the products of the reaction of la-c with sod- ium alkoxide.32--8. [3.2tI.08--7.(lllb) derivatives from methyl iodide in the pre- sence of sodium methoxide. where the long-wave maxima of llla-d disappear on going from an acidic to an alkaline medium.28 (ra. The reaction with excess sodium alkoxide and alkyl halides was carried out with compound la. and also the products of further alkylation of the latter.and E-isomers.18 (s 3H) 1. R' C~ (IH) I R2 R~ r~ la 7.23 ( s 3H) Va 6. 8. !7.18 (s.3H) *Spectrum of I was taken in DMSO. and by the formation of complete alkylation products Va and b from 4- benzyliden.21 (s.65--7. In the UV spectra of compounds V.16 (s 3H) 1. is shifted from 7.02--8.38 (m 10H) 2.42 (m.72 ( q2H).48 (m. and also compounds with electron-acceptor (Ib) and electron-donor (Ic) substituents.94--7. 8H). 5Hi 16.78 (m 8H)..62 (m. III-V in CDCI3.3H) 5.65--7. 5H) 7. and also by the splitting of the signal from the single benzylidene proton (Table i). 7. 2.s.15 ( ~ 2H).94 (s) lllc 7. and of the 4-methyl-4-(a-ethoxy-p-nitrobenzyl).(Ilia) and 4-p-nitrobenzyliden. Because of the asymmetry of the molecule.76 {q.83 {s. bands at 1785 and 1718 cm -I (C=O) or 1618 cm -l (C=C). 2H}. 81-1). the signal from the benzylidene proton. and no band at 1630-1618 cm -~.20--7.3 (m.65 ~. In the PMR spectrum of the intermediate IVa. 7. In the PMR spectra.55 (s) 3. 2H.42 (m.4-tetrasubstituted dioxopyrazolidines. 21-t) 1.32 (m.33 (s.(Ve) derivative from methyl iodide and sodium ethoxide.25 (s 3H) 8.65 (q. PMR Spectra of the Starting Compounds and Their Alkylation Products 0 N--C~Hs -.13 @) 3. as shown in the reaction scheme.05 .22--7. 3H) 4.25--7.07 (s 3H) 7. were obtained (Table 2).68 (In.92 (s) 3.87 (~ 3H) IVa 6. 21t) 2. Evidence for the structure proposed for III comes from infrared spectra. compounds I and III are obtained as mixtures of Z. 3H} 8.3--7.52-8. and con- tain two strong bands at 1750-1740 cm -I and 1710-1700 cm -I.~'II).11. 5[-I) 6.82 (s) I l l t 7.3H).01 (Ill. and also sig- nals from protons of the N-alkyl groups are observed (Table i).93 {~' It 7.58 ~n.81 (s). 7.4.4. which is bonded to the methoxy anion. and also from ultraviolet spectra. the N-alkylation products llla-d.2.I 8. 5H) 18.68 (m 2H). 7.2.11--7.65 (m. TABLE i. (without a substituent at position 4).3H) Vt 7.X .2tt) 7. in the IR spectrum. The IR spectra of the products of complete alkylation of V are similar to the spectra of 1. in agreement with the proposed structure.15--7.. in this it differs from compound B.58 (m. this also is characteristic for 1. which are present in III.65 (s) 3. and the previously reported [2] course of the alkylation of compound A indicates that alkylation of compounds la-c with alkyl halides in the presence of excess sodium alkoxide can occur at either the N or O atom. 7. 2H) It 7.81 Is . disappear.01--7.80 (~} . J=8Hz}.27 ~s. 3. 1.18 (s. 3.15--8. 3H) 7. 2H) vd 7.--7. 17. No O-alkylation products could be detected.81 (s 31t) Ilia 7. At the same time. 3H) 4. and are replaced by a strong enolate band at 1565 era-x [2].15--8. Under the conditions employed.71 (d 2 1 1 .95(s) 11=9 Hz).83--7.42--8.2H) 3. 3. 18.79 (s}.82 to 5.90(s) (8..98--8. which are in the fixed dioxo form [3].91(s) 18.13 ppm. 8. the C=C band at 1625 cm -x are retained. This is confirmed by the presence of two spots with very similar Rf values on thin-layer chromatograms of compounds la and b and Ilia and b.81 (-~2n} 7.9--7.21 (d. 3tt) 7.17 (m 2tt).45 ~a .45--8.52 ( m . 7.5H) 7. V. signals from the benzylidene proton. an absorption maximum occurs at 232-240 nm and is independent of the pH of the medium. this was confirmed by the formation of compound IVa from the N-methyl derivative Ilia and sodium methoxide.93 {s} J = 4 Hz) .

Vb.1 16. 1:7. 1595.661.5.-.01).2 lO.4 I00.3%.38). The presence of two asymmetric carbon atoms in the product of complete alkylation V leads to the formation of a mixture of isomers. 379 (4. ethanol 178 . Ib. 235 (4.0 I 1630.4%.9. and --CH groups.0]C n'l lr. lllb m/z 175.3 C191{19N305 II. Pound: C 62. the formation of the M -. 3:4.0 Va 113--114/t3 11750'5901710 (sj..41C.2 1588. In the mass spectra of the monomethyl derivatives (Ilia-c) (Table 3). 1685 235 (4.24) IIII~ 164--1651 ~5.8. For compounds la-c. 1595. 1:3. and V was obtained from their mass spectra. b.40). H 5.~N. 374 9. which in compounds la-c migrates to C(4) with the formation of the X-C6H~--CH=CH-C--O+ ion.15) 11.15) lllC 148-. Pound: C 61.l 40. Ilia m/z 130. lllc. the decay of the molecular ion under electron bom- bardment is independent of the nature of the substituent in the para-position. nm (los ~).95). H 6.6 CmH2oN~O3 8. H 5. ~ _~ ~pectrum. benzene-chloroform. and splitting of the C--N and C-C bonds in the heterocyclic ring to form the X--C6H~-CH=CH-C-O + ion. Calculated: C 62.4 47. 260 (4. Calculated: C 70. IR spectrum. for Va. Alkyla~ion Products m i rap. which then decays further with loss of the para-substituent.N~O5 II.2 C'2(. i:i (after dry- ing the chromatogram and repeatedly chromatographing in the same solvent system. H 5.5%. H 6.7.CH3 fragment and the unchanged values of the ketene fragments (la. ethan~-i max. ethyl acetate-heptane. and involves the rearrangement of the molecular ion and the ejection of a CaHO2 (similar to the fragmenta- tion of the benzylidene derivative of 1.since the molecule does not contain a labile hydrogen atom (Nil).149121 1620.~O4 13. 1515 (4. 1565 8. EXPERIMENTAL IR spectra were obtained on UR-20 and Specord IR-75 spectrometers (mineral oil). Pound: C 70. 1592. 252 (4. UV spec- tra were taken on SF-16 and SF-26 spectrometers using the following solvents: ethanol.7 50.7 15. [3].C 36. Thus.7 C17III4N~O. 240 (3 88) 11.H2.sHjTN203Na 8. ethanol If~ Ilia (S.0 19.04) 8. 1700. 1:2.5-dioxopyrazolidine [4]).0 CjgII2oN20~ 8.4 *For compounds Ilia and b. Additional confirmation of the structures of compounds I.. 244 9.JljsN2Or~ 9.3%.2-diphenyl-3.2. H 5.5 C. 1510 247 (4. Vb was isolated initially as a mixture of sub- stances with a wide melting-point range (132-142~ Thin-layer chromatography gave two very close spots. chloroform--pet- roleum ether. TABLE 2.0 (4.4.2 152--153165116181718568(@. each spot gave two spots with the same Rf). 330 (4. llld m/z 160) in- dicate that the CH3(C2Hb) group was joined to the nitrogen atom and did not affect the exo- cyclic double bond. 1730.2%.601 llId 142-'143l'1515851718' 1682.46) IVa 1650. ethyl acetate--heptane. The PMR spectra of compounds V contains signals from the alkyl group protons and signals from the single proton at the ~-carbon of the benzylidene residue. 1620. 235 (4. ~ Lirical =" t (from .0 Ve 176--178t !9 1740. 5:1. 324 13. 1693 (~.0 i Vb 182~183 t !7 11748'5951710 ($. the PMR spectrum of this mixture had split signals from the N--CHs. Vb and c were chromatographically uniform also in the systems: ethyl acetate--hexane. and e. O-CHa. After purification until chromatographically 9 the PMR spectrum of Vb (mp 182-183 ~ contained no split signals. (3. ethyl acetate--hexane. ol4 (4.2%. Calculated: C 61. and Ic. 1595 237 (4.1718'1682 ~ . for lllc and d. III. Ve. Additional evidence is the absence of an acyl ion from the spectra of llla-d -. The low intensity of the molecular ion peak of the final alkylation product V and the + formation of the X-C6H4-CH=OR fragment is consistent with the absence of conjugation between the heterocyclic ring and the benzyl group as a result of the addition of the alkoxy group at C=C. %Va.46~.35) sh 9.

8.33). 78 (6). 320 (4.39). l-Phenyl-2-alkyl-4-benzyliden-3. 89 (6). 307 (48). 77 ('59).1% KOH in ethanol (concentration (I-4). 179 . kma x (log E): acidic ethanol. 252 (4. IR spectrum: 1705. M +) Va 77 (14/. C17H~4N203. 1675 (s).5 (12). 324 (4.1). 196 (26). Absolute ether (50 ml) was added to 0. 130 (48). CI~HIaN~O2. 180 (loo).+) lb 75 (10). UV spectrum. 96)* pound la 51 (181. 102 (6). 22. 129 [9).5 (22). 130 (61. 133 (61. 134 (8). IR spectrum: 1713. 78 (7). 2q4 (100. and 0.57 (61.10).15). 83 (20).51. diluted twice with water.5).5-dioxop~razolidine(lla). 226 (301. 117 (11). 78 (61. 201 (9). 1592 cm -l. 122 (101. finely divided cyrstals of IVa in quantitative yield. mp 249-250 ~ (from aqueous DMFA). alkaline ethanol. 372 (4. 77 (41). 105 (8). 145 (13). 325 (4. 195 (28). 239 (7).5). mp 278=280 ~ with decomposition (from butanol). TABLE 3. internal standard HMDS. 77 (3. 105 (181. 264 (1(10. M+) Ilia 51(171. 117 (22). 91 (51. %max (log c): acidic ethanol. 91 (. Com- pound Ilia (0.53 (61. M~) *Peaks with intensities greater than 4% are given.5-dioxopyrazolidines (la-c) were obtained in 50-56% yield by re- fluxing ethanolic solutions of equimolar amounts of l-phenyl-3. 232 (3. 161 (8). Acidifying the aqueous solution gave llla-d (Table 2). The mixture was left at 20 ~ .2%. 1658 (s). 107 (7). 135 (. 102 (32). mp 282-284 ~ with decompositon (from dioxane). 332 (100. 145 (21). 105 (6). IR spectrum: 1670. UV spectrum. 369 (5. 1590. i ~mole) was dissolved in a freshly prepared solution of 0. 278 (100.14). . 103 (16). 209 (18). Ib. IR spectrum: 1710. 94 (5). m/z (relative intensity. mp 246~ Sodium Salt of l-Phenyl-4-benzyliden-3.95). 263 (71.264 g (i mmole) of compound la dissolved in a freshly-prepared solution of 0.51. temperature of vaporization of sample 20-250 ~ ionization energy 70 eV. 308 (15). UV spectrum.5%. Cx6N~xNsO~.5). 121 (6). Found: N 9.28 g. III. Preparative chromatography for the isolation of V was conducted using alumina activity II in a thin layer (4 ram) on plates measuring 20 x 20 cm. Calculated: N 10.5-dioxopyrazolidine (III). brought to pH 9 with 5% sodium hydroxide solution. 1572 cm -l. Liter- ature data [5]. la. 204 (6). 121 (1001.046 g (2 mmoles) of sodium in i0 ml of absolute methanol. temperature of source 250 ~ . 1620 (s). 249 (4. 160 (. 241 (14). 77 (371. 161 (34). Calculated: N 13. 240 (161. 105 (12). alkaline ethanol. M ~) Itld 51 (81. 162 (61.7%. 102 (421. 117 (6). 348 (4. 1592 cm -~. 4-Benzyliden-l-phenyl-3. 294 (191. 107 (71. 1615.5%.5-dioxopyrazolidine and the corresponding aldehyde for 2-3 h with subsequent recrystallization of the precipitated mater- ial. M. 250 (4. 132 (71. 246 (4. 160 ('55). Mass Spectra of Compounds I. 129 (8). 121 (51. 130 (51). The product (0. 173 (5). containing 0. 158 (7).':$ (61. 83 (14). 134 (51. Found: N 13. 132 (81. 131 (7). 77 (791.511. Addition of ether gave white.6% of Vb as a coloress crystalline substance. alkaline ethanol. 77 (78). 1625. 383 (4. 89 (5). 166 (1001. 91 (6). 129 (6). 10'5 (6). 167 (9). 323 (100. M+) Vb 77 (10t. 120 (15).201 (71. mp 280 ~ . 117 (15). 1675 (s).5~. Ic. 63 (10). 308 (100. 1. 83 (21). 119 (6-). 121 (16). 63 (6). 22. Calculated: N 9. Compound lllb.26 g) was isolated as a red material. PMR spectra were recorded on Varian T-60 and Tesla BS-487 C instruments. Methyl (ethyl) iodide (300 mmoles) was added to a solution of 50 mmoles of compound la-c dissolved in a freshly prepared solution of i0 mmoles of sodium in 50-100 ml of methanol.39). 1595. 118 (.046 g (2 m- moles of sodium in i0 ml of absolute methanol.. 106 (91.6%.30). Sodium Salt of l-Phenyl-2-methyl-4-(a-methoxybenzyl)-3~5-dioxopyrazolidine (IVa). 13l (44!. 161 (1.33).54). 83 (11). 147 (7). 106 (6). Chromatography was carried out on Silufol UV-254 plates. 309 (100. 1'52 (75). 270 (4.35% HCI. 227 (51. 270 (4. 319 (4. 134 (161.37). 145 (15). 78 (6). 91 (5).05). 83 (1. before evaporation gave 11. 181 (11). M +) Ic 51 (12~. 105 (20). 2~ (181. Mass spectra were recorded on a LKB-2091 mass spectrometer with direct introduction of the sample into the ion source. 91 (61. the solution evaporated to half-volume. 1565 (s) cm -~. solvent chloroform. 279 (7). 187 (7). 175 (22). and V Com. 101 (161. 101 (131. N[+) Ille 51 (6). 160 (49). M+) Vc 77 (lq). M +) llib 51 (1. 176 (171. and exhaustively extracted with ether. 77 (22). 254 (13). 263 (B). 1683. 1663 (s). 76 (10).51.i0 -5 mole/liter). %max (log g): acidic ethanol. 17'5 (241. 312 (4.6%. 78 (6). Literature data [6]. Found: N 10. 63(5). 105 (24). 279 (5). 187 (6).

B. B. 227-232. No. A.5-c]pyridin-2-one (Ib) and its 3-methyl congener (la). 39. to a f f o r d a p a l e . an additional 22% of chromatographically homogeneous Vb was isolated.L. Clenuuenson reduction of the acetonyl bromide Illb gives. 254 (1979). Pure Vb was also isolated during the synthesis of IIlb (see above).. Th. Further recrystalllzation from ethanol gave chromatographically homogeneous Va and b. the starting materials Ilia and b were recovered.5-c]imidazo[l. Kira. E. Two of these new compounds which are of widespread interest are 4-amino-1- methylimidazo[4. Donetsk. coupled with the similarities in the UV spectra of the quaternary salts llla-d (Table i).. 2. Yutilov and K. No. 2. Geterotsikl. Asher.. o b t a i n e d during the s y n t h e s i s of compounds I l i a and b were d r i e d with sodium s u l f a t e . Archly. Soedin. 2. No. REACTION OF 4-AMINOIMADAZO[4.24 mole) was added to a solution of 40 mmoles of compound Ilia or b in a freshly prepared solution of 80 mmoles of sodium in 80 ml of absolute methanol (for Ve. Institute of Physical Organic Chemistry and Petroleum Chemistry.3-dlmethylimldazo[4. B. from which after thin-layer chromatographic purification of alumin was obtained a colorless oil <Ilia) or crystals (lllb). 1018 (1897). Soedln. The facile nitration of imidazo[4. 180 0009-3122/86/2202-0180512. either 5-acylmethyi salts of the starting amine or 2-substituted imidazo[4.5-c]pyridin-2-ones with a- bromomethylketones have been studied. l-Phenyl-2'4-dlmethyl-4-(~-alkox~benzyl)-3. Sammour. f i l t e r e d . 170 ml of absolute ethanol). 4. B. Org. 224 (1974). Aronzon.50 9 1986 Plenum Publishing Corporation . E. Khlm. Citterlo. In the present paper we report our results of the study of the reactions of la and b with u-bromomethylketones (lib-h) and a-bromoacetaldehyde (lie).5-c]pyridin-2-one in the 4-position has opened up many new possibilities for the preparation of a wide variety of Substituted derivatives of this compound [1-3]. 10. Bet.7'284'233:543. A. The latter compounds are also easily obtained by treatment of the 5-acylmethyl salts with alkali. The addition of the allphatlc a-bromomethylketones lla-d to amine la occurs upon reflux in alcoholic solution over 1-2 h and gives salts llla-d in hlghyleld (Table i). and M. 6. 2. which has~een previously prepared form amlne la with n-propyl iodide [4]. 606 (1975). Depending on the nature of the reagents and the reaction conditions. The mixture was left at 20 ~ for 96-120 h and worked up as in the preparation of Ilia-d. Mustafa. Moldarev and M. No. Methyl iodide (0.783'822. M. containing (TLC) two spots with very similar Rf values.L. Origlnal article submitted December 10. Aronzon. 820 (1981). Khabarov UDC 547. Khim. after acidification of the reaction mixture with hydrogen iodideD the iodide salt of 4-amlno-5-n-propyl-l. E. On acidifying the aqueous solutions.5-dloxopyrazolidine (V).. During the preparation of Vb. 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii.. M. Geterotsikl.S-c]PYRIDIN-2-ONES WITH a'BROMOMETHYLKETONES Yu. Selva. Moldarev and M. 6. 1986. Moldarev and M. 516 (1965). leads us to believe that reaction of amine la with the a-bromomethylketones lla-d generates the 5-acylmethyl salts llla-d..L. Academy of Sciences of the Ukrainian SSR. 298. This observation. No. after extraction. compound V was isolated from the ether extract as described in A. A. Aronzon.2-a]pyridin-8-ones can be obtained. February. Geterotsikl. pp. Soedln.422 The reactions of 4-amino derivatives of imidazo[4. Khlm. and e v a p o r a t e d to d r y n e s s . Pharm. A. LITERATURE CITED i. 5. 3.y e l l o w o i l ( I l i a ) or p r e c i p i - t a t e (lllb). Mass Spectrom. The combined e t h e r e x t r a c t s .5-c]pyrld- inlum-2-one (V). A. Merlinl. and L. 1984. Previous work has es- tablished that the base la can be readily alkylated at the nitrogen atom of the pyridine ring upon treatment with alkyl halides [4].

""~" N" 0 n . and g. whereas half of the starting amine was con- verted to the hydrobromide salt.. d R* = 3.5-c]imidazo[l..83 ppm in the case of an alkyl substituent in posi- tion 2. " R~ / N \ -~-.. VII a R = CHa~ b R = H. without any intermediates.~-( -%. g R = C6Hs.5-c]imidazo[l. the spin--spin coupling constant is 2. In an analogous manner salt IVb could be converted to the hydrochloride of VIIb.II. /CII3 . CIl 3 I ____N/ 0 NII2 CII3 R/ o.C.4-.. Methyl- ation of compound VIIIa with dimethyl sulfate in basic solution gave compound IVb..17 ppm in the case of an aryl substituent in the 2-position. or u-bromopro- pionaldehyde.4-(CHsO) 2C.2-a]pyridines IVa-h and VIIIa-e were con- firmed on the basis of their spectral data.. namely.2-a]pyridines [5]. h R = p - NO2C6H4 Treatment of the acylmethyl salts llla-d with basic solutions releases the free bases IVa-d. f R = B-naphthyl.2-a]pyridines IVg and h were isolated directly. an independent synthesis of a model compound... VIIla-e. d R = 2'-Ad. r + C~. and at 8.3-H) at 7..2 Hz) which is characteris- tic of 2. III.' NH2 R H0 Z t:' ~ "Vllla-e VI a. however.3-unsubstituted imidazo[l.5-c]imldazo- [l.. e R = R 2 = CH3. which are characteristic of the pre- cursor salts Via and b (3260-3275 and 3370-3400 cm-*). The spec- trum of compound Ira contains two doublets due to the vicinal protons of the imidazole ring (2. It was not possible. p-methoxyphenacyl bromide. The structures of the imidazo[4. which can be converted to the tricyclic structural derivatives IVe and f upon treatment with base.2-a]pyridine (VIIa)... a R* = CHa.'~'~ o " ~+ o .. The latter compounds are easily ob- tained in high yields via reaction of amines Ia and b with ethylene chlorohydrin. from the reactions of the amines Ia and b with equivalent amounts of the u-bromomethylketones IIb.5-c]imidazo[l.Hs. In these cases the 2-arylimidazo[4.~. b R = CHa..-'% o ~ N. eR* =H Aromatic a-bromomethylketones lle and f also react with amine la to generate salts llle and f. The PMR spectra of compounds IVb-h and VIIIa-d (Table 3) contain signals due to the 3-H aromatic proton at 7.66-7. to isolate acylmethyl salts from the reaction of amine Ia with the bromoketones IIIg and h. --)N ~n . c R = C(CHa)a. can be isolated directly..H~... VII a-d R = R 2 = H. The IR spectra of compounds VIIa and b do not contain absorption bands due to OH and NH2 groups. Compound IVa was shown to be identical to the dehydrogenation product of 8-oxo-7)9- dimethyl-2)3-dihydroimidazo[4.~. e. namely imidazo- 181 .b VI..''~. The IR spectra of the acylmethyl salts IIIa-f (Table i) contain two carbonyl group stretching bands (1700-1715 and 1715-1730 cm-*)) as well as N--H stretching bands (3270-3400 cm-~). c R* = p-CHaOC. Their IR spectra are similar to that of iodide V.83 and 8.00 ppm./ iva-h ~ . b R' = Ph. If the reactions are carried out in refluxing DMF) the hy- drobromide salts of imidazo[4.2-a]pyridines.-. These data imply that both the bases IVa-h as well as the hydrobromide salts VIIIa-e contain tricyclic aromatic structures. whereas the spectra of the free bases IVa-h (Table 2) contain only one carbonyl group stretching frequency due to the C=O of the imidazole ring at 1690-1720 cm-*. In order to verify the structures of the cyclization products arising from amines Ia and b with u-bromomethylketones. e R = 3'4'-(CHaO)2C6Ha. "~/ aN/ O f'! I +" I t NIl2 CH 3 NH 2 CH3 R"C*~ llla-f If.b VIIa... + II | I . which was obtained via re- action of chloride Via with thionyl chloride in refluxing DMF...08-8. IV a R = H..

3-dime thyXimida zo [ 4 .0 1.71). 1700 229 (4.74). 5 .mlf ~ pourtr alcohol) I era-i (ig c) C H Br H Br Ilia 263--264 1730.3 C1o[-1rzBrN402 39. 1700 229 (4.3 18.8 18. 1700 | 49. Acylme t h y l S a l t s of 4-Amino-l. H. 253 (3. Holecular formula Yield.2 6.4 17.4 4.95) IIIb 281--283 1720.0 C. ~ ] IR spec.38). 272 (3.1 C2.3 i_o.3 (3. 291 54.HIsBrN402 41.2 . 1700 225 (4.4 17.7 66 (3.3.c ] p y r i d i n . 9_.8 25..73). 1705 54.0 17. Found.4 C.9 12.4 12.09) IIIe 243--24.8 17. 252 (3.90). I715 229 (4. Com.4 15.1 5.95) III d 267--270 1725.3 C.0 25.1 1715. 254 (3.1 5.4 12.92 47.9 4.8 91 (3.aH~BrN40~ 49. 293 39.3 18.6 5.4 ~ ! 8.7 21. 290 4"2. VC--0 I.t~H~IBrN40~ 47. % " (from { t=rum.I1~TBrN402 55.7 C~oHI~BrN402.72).8 5. % Calculated.9 15.7 ~6.6 59 .9 ~5 0.36).4 5.9 4.3 18.9 6.4 4.o n e rap.74).GO TABLE i.8 46 Illf 285--287 1725.86) Itl c 280---28t 1"720.4 5.8 ! 8._.9 22.9 13.~ Spectrl.9 4.O 53.

8 28 VlIlb 350 ]1660.3 5.91 (3H.73 3.H3].51Hz . 44.oHmN40 9 HBr 42.64 (3H) 7.5 4. 1730 48.5-c]imidazo[l. 1690 59 315 1 21}.7 68 IVd 285--287 !660.r 61. ppm pound I 5.10.7 66 IVb 229--230 1660. 4.83.0 C:rtII{~N4Os9}tBr 50.5 16.3 53 Vllld 342--343 1660.97 IVd 7.00--4.9'5. 3-(p-nitrophenyl)imidazo[4.07 [6H..oN~O 59.O. 16. 8. 5(6)-H andC~oHr] IVg 8. +J = 7..~N40 9HBr 44.4 C=oHI~N40"Ha0 69.0 27.4 16. 5(6)-H.05 [9H. 7. 4.1 5. 1720 59 814. 1700 59. 1705.63.815. 183 . was car- ried out.N402-IIBr.10 69. 1700 55.1 21.4 ClsHI~N.73 [4}I.2 13. s. m.05 IVc 7.1 20.80 3.70.40 1.85 [5H.7 74 IVe 238--240 1660.3 16.66 3. 1700 ~98. 3.2119. % [ .23--7. 4. m.15 3. [4.Hd Vl]ld 8.05 [6fl.1:5.5 C.~ 59.815.85 ppm.2 16.82 [8H. 3.70. 6. 8.37.45.57.8 46 VIII.4 14. 4.9 C~oI-t2~N40 71.0 54.9 4.4 5.05 (6H.. 3-Han~H4] VIII a 7.63 7.0 21. 768 (2 d. i.47. C~.two OC}Ia) Vlll 7. does not contain a methylene group signal at 5.115. The PMR spectrum of the resulting material.9 32 X 271--273 50.08 3.40 1.60 I 7. 8.42.sN40 55.07 3.31 I8/ (2~HI.62.42. 3.55 8.87 8. 2dh 1=2.5-c]imidazo[l.41 2.t0 3.e.2-a]pyridines IVe-h and Vlllb-d.714.8 CIsHI.73.70 3.07~8. 4.m. 1690.~ 53. 3.70.8 16.5-c]iidazo[l. H~O 48.N--CH8] 1Vf 8.80 8.2 42 VIIIe 302--304~1670.67 2.50 7.00 3.78. CH2) IVe 8.55.67 [6H.10 3.7 35 *Compound IVa was crystallized out of water.m. [4H.~O9HBr 52. and compounds IVh and VIII out of DMF.1 58 IVh 350 11670. Imidazo [4.5-c ] imidazo [I. 5(6)-11 and C~Hs] IVh 7. 3.47 ppm.46.I 4. 8. Chemical shift.1 I-'l-.5 Hz. I=8.17.27--7.6 27'3 C.4 3.O 1fi.2 Hz) IVb 7.60 8. m 5(6)-H and C6Ha] ra. 173( 52.2 3.sN~. 3. 16~p 71.17 3.2 16.02--8.4 18.4 4. which serves as further evidence of the structures of the imidazo[4. m .o 218--219 -. e 4.~ ('. TABLE 2.5 (6) -HandCdt4 *J = 7.2-a]pyridine X. 8. 8.9 73 IVc 224--225 1669. 1730 50. 7. 8. 1700.4~4 7 .014.7 83 Villa 258---250J1660.48 3.78.4 4.40--7.50--7.. 8. 7. 8. 7.50.414:4114.6 25.7.212!.9 C.5116/1 C lstt . % Molecular ICalc. pound ethanol)I VC=O.2 71 IVg 258--260 1670.42.13 (12H.g (:1. TABLE 3 .48. but does contain a signal for the 2-H proton at 8.~}IlaNsOa 59. 7.6-11" 2-R I[ 3-R N--CHa IVa 7.2-a]pyridines Corn.97 (2H.. m 5(6)-Handc.2-a]pyridine X.55 7. 8. a mixture of the amine salt of la and p-nitrophenylbenzyl bromide was refluxed with an excess of a formic acid-amyl formate mixture. cm C H N C H.14.75. N IVa 222--224 1670.68 (3H. which is present in the spectrum of salt IX.0 Hz.70 3.oH. 1700 422414.5-c]imidazo[l.312t.75.60.55. CH).2 [4.11laNsO. C6H5] \ IIlC 7.92 (CHaO). 7.10 ..03 CHa) X 7.33 [ 7.43 2. PMR specra of Imidazo[4.9 19.z 21.02 ar . 5(6)-H.50 (9H) 7. 1700 5f.4H.0 C~GFII4N. Found. 8. with a p-nitrophenyl substituent in the 3-position.1 21.317.6 78 IVf 238--240 [1670.90 8.73 3. A mixture of base X and its 2-isomer IVh exhibits a temper- ature depression for a mixed melting point sample.67 VIII b 8.95 2. (CH80)2.58.7 25.717. it confirms the 2-position of the substituent groups..'3 C. 2-a ]pyridines Com- ~o: C ]IR spect_r~.

0. C**H. 2-Arylsubstituted 8-Oxo-7. 259 (3.61). .. mp 262-263~ This material does not ex- hibit a temperaturedepression in a mixed melting point determination with a sample from A. The precipitate was removed by filtration.. the mixture was refluxed 12 h.0 ml of 36% HCI..80 g (1. . washed with ice water.L B~-r.20 g (7.9. 9 N "' ~ ' ' 0 '.. h).i g of HgCla.5-C]pyridinium-2-one Chloride (Via).32 mmoles) of amine Ib and 2.... Evap- oration of the alcohol solvent and basificatlon of the residue yielded 0.. 1. bCIN~O2.. 2-Substituted 8-Oxo-7.2-a]pyridines (IVg. 302 nm (3. the aqueous layer was decanted. A solution of 0. to the residue was added 2 ml of a 40% aqueous NaOH solution . . Imax (log s): 232 (4.00 mmole of amine la and 1. A.9. 4-Amino-5-n-propyl-l.74).5-c]imidazo[l.7.COOA.. ~ .22 g (40%). 1 36..1%.. After cooling to room temperature the precipitate was removed by filtration. . COOH i . followed by acetone.5 ml of concentrated HI.0 ml of water. and 0.20 ml. A mixture of 1. dissolved in 1.76)..:. 0.5 h.2-a]pyridine [6]. A mixture of 1. . Calculated: C 37.70). The properties of compounds III. N 16.7%. CI 13. CI 13...50 g (1.. UV spec- trum.0%. The PMR spectrum of the azo compound XI does not con- tain a signal due to the proton in the 3-position. L. and the residue was washed with hot isopropyl alcohol.3 =amole) ethylene chloro- hydrin was heated at 160-170~ for i h.51 mmole) of recovered amine la.09 g (0..05 ml of 36% HCI and 1."~'~ .70 mmoles) of ethylene chlorohydrin in 184 . N 16.5 ml of water was shaken. 4-Amino-5-(B-hydroxyethyl)-l-methylimidazo[4.7. A solu- tion of 1. and PMR spec- tra were obtained on a Tesla BS-467C (60 MHz) spectrometer using solutions in trifluoroacetic acid versus TMS as internal standard.9.5 ml of 36% HCI was added. N''cn~ il I 1 ('II I 9 N ~woot. and dried. h). UV spectra were taken on a Spectromom-204 spectrophoto- meter for water solutions.9-dimethylimidazo[4. CH~ "T" IX CH NO 2 X X! In analogy with the behavior described previously for imidazo[l. .5-c]pyridin-2-one s (Ilia-f).4.I. washed with acetone. mp 228-229~ (from ethanol).9-dimethylimidazo[4.10-1.18 g (i.03 m m o l e ) o f n-propyl iodide. UV spectrum.40 (35.5-c]imidazo[l. and 2.0 g of zinc powder.3..5-c]pyridinium-2-one Iodide (V). and the precipitate was filtered. A mixture of 0.38 g (96%).JJ . and 3 ml of DMF was refluxed for i h.01 mmole) of amine la.5. EXPERIMENTAL IR spectra were recorded on a UR-20 spectrophotometer using vaseline mulls. and X are summarized in Tables i and 2.. and then dried. Found: C 37... Calculated: C 46..9-trimethylimidazo[4.3-dimethy!imidazo[4.35 g (0.18 g (51%).56 m mole) of amine la in 1.. mp 262-264~ (from ethanol).57 mmole of ~-bromomethylketone llg and h in 4 ml of ethanol was refluxed 1 h. The precipitate was filtered. 260 (3. Themixture was evaporated to dryness and washed with ether (3 x 8 ml). and then every 4 h 0.. Found: C 46. N. and final- ly crystallized from ethanol. . N 21..i iiN . 1 36.5-c]pyridinium-2-one Chloride (Vlb).6.2- a]pyridine-3-azo-4'-benzoic acid (XI).71N40. Acylmethyl Salts of 4-Amino-l.2-a]pyridine derivatives Vllle and X also do not undergo nitrogen coupling reactions.. washed with water..5. 2. the 3- substituted imidazo [4.92). % N N ~t ~.. . Yield 0. H 5.15 mmole of ~-bromomethylketone lla-f in 6 ml of ethanol was refluxed 2 h and then cooled. and 0.. VIII. IV.6.3-dimethylimidazo[4. Yield 1. A mixture (or suspension) of i0 mmole of acylmethyl salt llla-f in 5 ml of water was treated with 3 ml of a 45% aqueous NaOH solution and heated on a boiling water bath for 0.. the solvent was removed under aspirator vacuum.oH.1.2-a]pyridines (IVg. H 6.. H 4.. evaporated to dryness again. 4-Amino-5-(B-hYdroxyethyl)-l.99 g (5.12 mmole of amine la and 0. and the residue was crystallized out of ethanol. .8.62).3-dimethylimidazo[4.5-c]imidazo[l.. 22. N 21. although the 2-methyl derivative IVb reacts with the diazonium salt derived from p-aminobenzoic acid to give 8-oxo-2. Xma x (log E): 235 (4. A sol- ution of 1.. .50 ml.5-c]imidazo[l..59 mmole) of salt lllb was added. 304 nm (3.. Excess ethylene chlorohydrin was evaporated under as- pirator vacuum.7% C. B. Yield 0.. and dried. and dried. H 5.

mp 296- 297~ (from methanol). N 23.5 ml of amyl formate was heated at 170-!75~ for 2 h.8%.5. This Was prepared from amine la and ~-bromopropionaldehyde in a manner analogous to the procedure used above for compounds Vllla-d.2N40"HCI.2-a]pyridines (Villa- d). This compound was prepared from chloride Vlb in a manner analogous to that for hydrochloride Vlla.42 g (83%).2. H 5. H 5.2. cooled. The solution was concentrated to */~ volume. Js6 = 7 0 Hz.5 h.30 g (5. %max (log E): 238 (4.5 ml of 99% formic acid.08 ml (0.02 g (77%). Calculated: C 45. H 5.HCI).5 Hz. Found: N 21. UV spectrum. 4-Amino-5-(p-nitrobenzyl)-l.6-H).90 ppm (2 • IH.32 mmole) of potassium permanganate in 50 ml of acetone was refluxed for 1 hl The residue was removed by filtration and washed with acetone. H 5. and the combined acetone solutions were evaporated and the residue crystallized from water. Yield 1.2N~O.5. Calculated: C 44.1.73 g (3.38 (2 x 2H.5-c]imidazo[l. A suspension of 0. N 22.0 mmole) of chloride Via and 0. and dried.85 mmole) of dimethyl sulfate in 2 ml of 8. CH2CH2). 2d.07 g (60%).oH. 7. 5.83 (2 x 2H. Yield 0. 315 nm (3. two N--CH3).7 ml of DMF was refluxed for 1. Br 20.1! N 22. Yield 0. The substance is identical in all respects to a smple of IVb.3-dimethylimidazo[4.2-a]pyridine (Vile). washed with water. Yield 93%. washed with ether. 264 (3.bH.03.I0 g (65%).3H20.5 h. and dried.1%. 8.7-dimethylimidazo[4.12).9%.9-dlmethyl-2. and then an additional 0. CgH. 4. CI 14.0.5 Hz.57). 3. sCIN~02.1.4 mmole) of amine la and 0.35 g (0.9-trimethylimidazo[4. 234 (4.33 ml (3.85 (2H.6-H). the solvent was removed under vacuum and the residue was neu- tralized with aqueous ammonia.9-dimethylimidazo[4.36 mmoles) of KOH in 4.2ra]pyridine Hydrochloride (VIIb. and the precipitate was filtered.7. mp 215-217~ (from ethanol).20 g (67%). lmax (log ~). e. s. 5. 8.73 (2s. A solution of 0.0 mmole) of thionyl chloride in 8 ml of DMF was refluxed for 0.4! CI 14.2-a]pyridine (Vlla). 2t.3.50 mmoles) of dimethyl sulfate and the mixture was maintained for 0.HCI.5-c]imidazo[l.15 mmole of one of the ~-bromo- methylketones lib. N 2 1 .00 mmole) of amine Ib and 1.6-H). 4.0 Hz. The sample did not exhibit a melting point depression upon mixing with a sample of IVa. Methylation of 8-Oxo-2.87 (2 x 2H.6BrNb03.9-dimethyl-2. 8-Oxo-7.5-c]imidazo[l. 7. N 23.25.8 ml of water was treated with 2 ml of a 45% aqueous NaOH solution.5 ml of water was treated with 0. J23 = 8. UV spectrum.7.29 g (5. 8-Oxo-7-methyl-2~3-dihydroimidazo[4.97 (2s.4.2-a]pTridine.7-N 22. and dried. A mixture of 0. The solution was concentrated under vacuum to one-fourth of the ori- ginal volume.60 g (3. H 4. CH2CH2). J56 = 7. After cooling the precipitate was removed by filtration. N 17. 2d. the resulting precipitate of base was removed by fil- tration. 2d. 2.97 mmole) of base Vlla and 0. CIoH. washed with cold water.36).3-dihydroimidazo[4. Found: C 45. C.5.5%.2-a]pyridine (Vlla). Found: C 49.5-c]imidazo[1.0 Hz. 5.7%. C1 14.i0 g (35~).07 (2 • IH. A mixture of 0. J2'3 = J 5'6 = 8. A mixture of 1.9%. washed with water.3%.9%.7. 7.71 mmole) of hydrobromiae Villa in a solution of 0.25.35). 304 nm (4. and filtered to remove the hydrochloride Vlla.3. 6'-H).2! H 5.5 Hz. 8-Oxo-3(p -nitrophenyl)-7. two N-CH3). mp 222-224~ (from water). 1 % . Found: C 44.9.60. The mixture was cooled and the precipitate was filtered.10-1. Yield 1. cooled. 3.68.89 mmole) of bromide IX. mp 296-298~ (from ethanol). Calculated: C 49. C.5 h. Yield i. the mixture was then allowed to stand overnight. Found: C 41.60 (3H. 185 . 7. Yield 0.50.21 g (1.5-c]imidazo[l.5-c]pyridinium-2-one Bromide (IX). 7. C1 14. Hydrobromides of 2-Substituted 8-Oxo-7-methylimidazo[4. Yield 0. Dehydrogenation of 8-Oxo-7.20 g (0.2H~O.23. Br 20. PMR spectrum: 3. and crystallized from DMF.92 ppm (2 • Hz. N--CH2). C1 15.5-c]imidazo[l.3% KOH solution was added. Hydrobromide of 8-Oxo-3. N--CHs). 2t. or g or p-methoxyphenacyl bromide in i0 ml of DMF was refluxed for 1.i0 g (91%).18 g (i. 2' 3' 5'. Calculated: C 44.02. N 17. H 5.82). PMR spectrum: 3. A mixture of 0. J2~ = 8. and dried. = 7. PMR spectrum: 3. H 4. and dried.2-a]pyridine (X). CgH.16 mmole) of hydrochloride Vlla in 0.9.3. washed with alcohol and ether.7. mp 229-231~ (from alcohol).4.5-c]imidazo[l.4. A mixture of 0. mp 283-284~ (from DMF). 7. oN~O. 5.2. CH2CH2). s. C1 14. 4. The precipi- tate was removed by filtration.5.4 mmole) of p-nitrobenzyl bromide in i0 ml of methanol was refluxed for 2 h. mp 262-264~ (from DMF). washed with acetone.50 ml (7.51 g (1.3-dihydroimidazo[4. and 2. 4.5 h.8%. Calculated: N 21.28 g (1. IR spectrum (CHCI~): 1700 cm-* (C=O).

1984. when protonated by weak or strong acids.04 mmoles) of p-amlno- benzoic acid. Khim. I. 97 (1986). 1295 (1966). J.4.. have a marked effect on the orientation of nucleo philic substitution reactions. N 23. A. No. Svertilova. Svertilova. N. giving betalne hydra- zones and azolo[4.15 g (2..5 g ice and 0. Academy of Sciences of the Ukrain- ian SSR. H 4. Found: C 58. Kochkanyan. Yu. Svertilova and Yu.3'775'556. washed with water and acetone. 26. Donetsk~ 340114. and (11) by decarbonylation of the original betalne. ClaH~6N6Os. No. We have not examined the reaction of betaines with nitrogeneous bases containing a primary I n s t i t u t e of Physical Chemistry and Carbon Chemistry. 3. 6. O. Paudler and H.1~. J. Soedin. Yutilov and I. dis- plays special features as a result of the presence of charged centers.17 mmoles) NaNOa. M..2-a]p~ridine-3-azo-4'-benzotc Acld (Xl).5-e]imidazo[1. revision submitted March 19. Svertilova.50 0 1986 Plenum Publishing Corporation . Azole betainealdehydes (I) may be regarded as systems with a masked electrophilic func- tion resulting from theparticipation of the formyl group in delocalization of the negative charge. and when the betaines themselves react with annuonia or hydrogen sulfide trlcyclic systems are obtained. and 2 ml of water. Calculated: C 59. azolldlne'2. respective- ly. Izobr. H 4. including nucleotides. This feature of betaines can. K l y u e v 543. 1979. No. Compound (1) is formed by the intramolecular migration of the oxygen in the 4-position of the azole.00 m- moles) of compound IVb was added. K. Yutilov and I. 1986.4- dione-5-aldehyde azomethlnes (1) or 4-aryllmlnoazolidin-2-ones (If).277| Byull.28 g (2. 233-238. The orientation of nuc!eophilic substitution in betaines. Original article submitted December 12. A. 8-Oxo-2. Soedin. respectively. Yu.W.43 g (2. L. Chem. 4. Blewltt.g-trtmethylSmid'azo[4. L. A. The PMRmass spectra of the products are discussed.5 ml 36Z HCl and an alcohollc solution of 0. Yield 0. Paudler and H. M. Chem. VINITI.. No. as a result of the selective sol- vation of the solvent at the catlonoid or anionold moieties. We have previously reported that mineral acid salts of betaines react with tertiary nitrogeneous bases [1] and triaryl- phosphines [2] ~rlth replacement of one cation by another to give new betaine salts. mp 348-350~ (from DMF).8. 186 0009-3122/86/2202-0186512. Khabarov D and I. February.7. M. No. W. After 15 min the resulting bright red precipitate was fil- tered.8. 2. LITERATURE CITED 1.0X. USSR Inventor's Cert. December 10.50 g (69Z).. 138 (1973). N 23. and it has received little attention. depending on the reaction medium. 30. 1985.821. Zaritovsklij UDC 547. Translated from Khimiya Geterotsiklicheskikh Soedinenii. Yutilov.5-b]benzodiazepines. 1. Blewitt. M. A. Studies in this area could lead to an understanding of the processes oc- curring in point mutations resulting from replacement of a pair of heterocyclic bases in nu- cleotldes. Khim. 2. The solution was then poured onto a mixture of 2. and N. A solution of 0. M. 80 (1976).W. Org. Yutilov. The orientation in the reaction of dicentric nucleophiles (hydrazines and o-phen- ylenediamine) is independent of the extent of protonatlon. 31.3. Org. 4081 (1965).422 Azole betaings containing viclnal formyl and pyridinium groups react with aro- matic amines to glve. 4182-79. Yu. EFFECTS OF ACIDS ON ORIENTATIONINTHE REACTION OF 5-FORMYL-4-(I-PYRIDINO)AZOLE 2-OXIDES WITH AROMATIC AMINES E.A. Geterotsikl. 0.12 g NaICOa in 5 ml of water was treated with 0. 1.9'551: A. and dried. 5~ W. B. Geterotsikl. No. A. Kruglova. pp. 521.

. Let us consider the PMR spectrum of (IIe) (R = p-NOi) as an example.mi . a.55 ppm is characteristic of the amino group. and is well described by the following scheme: _ -.. and IR spectra of the products.I R Ph r- III ~X R \.6 pro- tons of the p-nitrophenyl substituent give rise to two doublets at 7.4-dione-5-aldehyde azomethines ( I I ) . (co~. N 0 k~7 t aHN. hydrated with one molecule of/water. The broad singlet at low field with 6 11. The molecular masses of the compounds (II) (R=H. Ph It 7 6 0 SP 0 ['h ~. J = i0 Hz. Bearing in mind the alternative pos- sibility of the formation of the isomeric 4-aryliminoazolidin-2-ones (III) by direct substi- tution of the cation in the 4-position of the azole ring or of azolo[4. The IR spectra of (II) show absorption for two carbonyl groups and the associated amino- group which. The mode of fragmentation of the molecular ion (M+) under electron impact was fully in accordance with the proposed structures for the azomethines (II).. /i--2~ J~ %"~ + ..65 ppm). In the reaction of the betaines (I) with o-aminobenzenesulfonic (orthanilic) acid in ace- tic acid. unambiguously establishes their structure as azolidine-2. When the reaction of the betaines (I) with orthanilic acid was carried out in alcohol or aqueous alcohol. and the reaction medium on t h e orientation of the substitution.85 ppm.. a product was obtained which did not contain a sulfo group. + I /o " "t. I i: a-d n a-d Ph IV The betaines (I) react With anils in acetic acid when the molar ratio of reactants is i:i to give azolidine-2.17 ppm. PMR. Protons I-H and 2-H form another system of signals appearing as two doublets with ~ 7.4-dione- 5-aldehyde azomethines. The integral plot gives the ratios of these signals as 1:5:2:2:1:1..13 and 9. elimination of the sulfo group occurs to give compounds which are identical with the products of the condensation of the betaines with aniline.. with J = 12 Hz. The spectra of (Ia-d) (Table i) show superposition of the signal for the I-H proton and the signals for the protons of the substituted ring on the resonance for the N-unsubstituted benzene ring protons to give complex multiplets. we examined the mass.) I I ~'"V a \c::J L 1--~ C I x2 ?xeII d ###BOT_TEXT###quot;-J/' I + i /'. The protons of the N- phenyl substituent are poorly resolved (multiplet at 6 7. in conjunction with the results given above. s .7 and 4. as shown by the absence of depres- sion in the mixed melting point. and the influence of the structure. confirming the correctness of the assignment of the signals and of the structure as the azome- thine (If). and had empirical 187 .2o . the amine.45-7.amino group. The 3. p-NOi. R < Xk.4-dione-5-aldehyde azomethines.~~ .35 and 8..5-c]quinolines (IV). and p-I) found by mass spectrometry were in agreement with the calculated values for each of the azolidine-2.2::J The PI~ s p e c t r a a l s o f u l l y confirmed the s t r u c t u r e s o f ( I I ) (Table 1 ) . e C~NIi ' ff"C7 " k-~ u g ..R] + I I n' "~::. m-CH.. "+h _~.

s 9. ~i~I .88. . ~. . .7. m 1C 4-CH~ 11.55.S .d 6.. s (1=12) 9. .--7.85 (J=12) 7. s ( 1 = 12) 9.6--7.05.65.09.62. PMR Spectral Data (in DMS0-D6) for Imidazolids Azomethines (IIa-e) i .O0 O0 TABLE i.13. . m I'D 4-[ 11.45--7. ...68. ..32fl 6.6 . .d (J=lo) } I 18A .6--8. Shi~t~. .55. d (i= ~o) . ~\. .13. m le 4-NO.06.25. m.64.~ 11. .o6. . . s 6. ..) ' .1r l~h II 7.'(J. .p~. T.d 2. s 9. s 6.. . .36. s (I= 12) 9.88-.8.".H C611s I-II 3 1-1 J I~-I1 5-1] ~-t[ I la H 11. m Id 2-COOH 11.06.. . " ComPound } 8-{1 2. d (1=12) I 7.. .d ( I = t 2 ) 10.35.

For example. L . when there is no interaction between the betaine and the aromatic amine.. due in our opinion to the assistance of the betaine in the trans- fer of a proton from the amino group of orthanilic acid to the carbon atom directly bonded to the sulfonyl group.5-b]-l. . the orientation of the re- action changes the orientation of the nucleophilic substitution. attack of the amine on the carbonyl group enhances this interaction and the nucleo- philic replacement of pyridine by the oxygen atom. II . such as we have reported previously [7]. (III) are obtained. This is also supported by the fact that the color which develops in the reaction is not due to the intermediate formation of 4-pyridino-5- formylazole-2-oxide azomethines. IR. The stability to hydrolysis of the internuclear bond between the pyridine and imidazole rings. is a intramolecular process.10 ppm. We therefore conclude that in alcoholic or aqueous alcoholic solution there is a change in the orientation of the reaction of the betaines (I) with amines... t' X Ph -0 ' "0 " vI l VII ! f'. and an amino group.bH. PMR. | li ~:/ q' "'i'---N" -C~II~ 0 " N'! "~ Cz HrcO _ Ph II Ph VL. On this basis. [J N I i t ' H . X=N -Ph ~/~"N "" l' S.! *Fission of a C--C bond is typical of betaines or ylid systems in alcoholic and aprotic media.~N30.71 and 10. ~. which from their integral intensltles (i0~2. i. . ) 2 .0 CI IH'~ . and for N--H and C-~ at 3280 and 1630 cm-*. ..". which was synthesized directly by the route shown below. and by direct synthesis. in accordance with literature reports [6]. in the reaction of the betaines (I) with a. A similar situation occurs in the reactions of betaines with o-phenylenediamine in acetic acid to give iH. leading to the formation of b-(N-methyl-N-phenylaminomethylidene)azoli- dine-2. but has not been observed in acetic acid [3-5]. either in acetic acid or in alcoholic solution. a methylene. The above conclusions are supported by the observation that the reaction of betaines with dicentric nucleophiles such as hydrazine and o-phenylenediamine. lead to different products. when the bet- aines (I) react with a threefold excess of aniline in acetic acid. and two singlets at 4.formula C. Its PMR spectrum showed a multiplet at 6.1) could be due to the res- onance of the protons of two phenyl groups. When an excess of the aromatic amine is used. [ } iN l" 0 N Z "~\ -'" ! X=S N "~1 " '. .~. which showed absorption for one carbonyl group at 1680 cm-*. lead to the conclusion that replacement of pyridine by the oxygen atom when the reaction is carried out in acetic acid. together with the high rate of formation of the azomethines (II).e. For example. respectively... . The structures of (V-VII) were confirmed by their elemental analyses. N H N N R N t~ti.~ l-IN . as is the case with triphenylphosphine [2]. the reaction involving fission of a C--C bond* and cleavage of the formyl group with simultaneous nucleophilic re- placementof the pyridine by the arylimino group to give l-phenyl-4-phenyliminoimidazolldln-2- one (III). :"-'" ~ b. since a similar effect is seen in the reaction of the betaines with N-methylaniline.4-dione (V). which is unaffected by heating the betaines in water or aqueous acetic or mineral ac- ids.10H-2-oxazolo[4. the two nucleophilic centers of which compete with the oxygen atom in the formation of CTC with the pyridinium cation in the transition state..5-benzdiazepines (VII).31 ppm. 189 ..~" ! ! c~t. no nucleophilic substitution by oxygen is observed. This was con- flrraed by their IR spectra. instead of the azomethines (lI). Elimination of the sulfo group under these relatively mild conditions is.}t z .14-7.u-methylphenylhydrazine.. This is quite feasible when it is recalled that the oxygen atom of the formyl group in the betaines is ori- ented with respect to the pyridinium cation as a result of electrostatic interaction to give an intramolecular charge-transfer complex (CTC). the 5- formyl-4-(l-pyridino)azole-2-oxide hydrazones (VI) are formed exclusively. . and mass spectra.

8. ionizing electron energy 70 eV..8.6. the 4-arylimlnoazo-2-azolld- ones (Ill)..el x. the first step is attack of the amine on the aldehyde group of the betaine. N 10.8. by using competitive solvation of the base by the pyridinium cation it is possible to achieve the result obtained in the re- action of betaines with dicentric nucleophiles.N..1%.'' -:... Consequently. H 4.O=.~ ..6HI21Ns02. and this is found experimentally. and the reaction is carried out in acetic acid.6.. ~x " t~ . instead of the azomethines (If). Found: C 69..6. ~ ~ L [ I'! ti " I{C N "t. ~ . . Returning to the examination of the reaction of betaines with anilines in acetic acid. H 2. as observed in the formation of four-membered rings in enamines X~ N' "2h . N 10.. C'l~O 'I Ph I 1I I Ph Viii This mechanism is supported by the fact that addition of a mineral acid (HCI or H2S04) or monochloroacegic acid (which are capable of protonating the betaine) to the reaction mixture results in the formation of (IIl) rather than the azomethlnes (If). H 2.fll5 0~z'lq . N 15. in which transformation of carbon C(5) of the azole ring from the sp ~.4%.. in vaseline oil. The mix- ture was then cooled. Ct.... mp 304-305~ (from nitroben- zene). C. mp 242~ (from toluene). since they crys- tallize from acetic acid as the bases..e. A mixture of i0 mmoles of the betaine (la-d) and i0 mmoles of the aromatic amine was boiled in acetic acid for 20-30 min. This makes the intramolecular replacement of pyrldine by the oxygen atom less energetically favorable. X=N-'Ph ~ "" " :/' .. It m a y be assumed on the basis of these considerations that when an excess of aromatic amine is used.. and the yellow crystalline powder which separated was filtered off. Found: C 47. : % . Found: C 63. H 5. I . the following explanation of the reaction mechanism is proposed.~ r.O .... internal standard HMDS.5%...1. H 4. H 4.2. 1 31. The betaines (I) in acetic acid are weakly protonated. thus facilitating the Intramolecular replacement of pyridlne by the oxygen of the formyl group.. yield 76%.TH.3%.to the sp'-hybridized state is rendered difficult.. the reaction merely amounting to solvation of the acid at the anionic moiety of the betaine as a result of the formation of hydrogen bonds.4-dione-5-aldehyde Azomethines (II). yield 74%.3. the relatively stable N-protonated form is produced. (llb) IR = p-I). sNsOz.. UV spectra were obtained on an SF-4 instrument. N~. C.4._.:~ . Calculated: C 47. Calculated: C 68.9| H 5.. i. --Nit. . with the acetic acid facilitating the transfer of a proton from the ammonium group in the transition state on carbon C(s) of the azole ring.. and mass spectra on a VarianMAT-311 spectrometer. / L C'tl~ 0 / / ~ " . The reaction then proceeds by a concerted mechanism.'-NH . "O I "O/ I %'11 VI "~'~"-.1~ N 14.V i/H -~ 'N"~]. I ...3%.3N30~... .8. operating frequency I00 MHz.0%. Found: C 68. [(l.' i . . (llc). The samples were introduced di- rectly into the ion source of the mass spectrometer at a temperature of 100-150~ PMR spec- tra were obtained on a Varlan XL-100..6. 190 ... yield 71%.7- H.2| N 13. at a temperature of 30~ solvent deuterodimethyl sulfoxide.. O ""N"'''I[ va I I u l i I t Ph ~'h j Ph - EXPERIMENTAL IR spectra were recorded on a UR-20 instrument. ~'-----t~.' li ii I Ii [-.0.. Calculated: C 69. N 14. mp 265~ (from dioxane).2%: C.'C . in methanol.[m'~. Calculated: C 63.9~ 1 31. mp 257~ (from DMF)..H. This should result in reorientation of the course of the reacgion to give. H~ 'N " i N:t. # " . and assists the elimination of formanilide: + tl !l . in the presence of mineral acids. N 15...C. yield 63%.o. Azolidine'2..4%.... (lla) (R = H).5| H 4. N 13. (lid). ~-.N .

Found: C 62. N 17.73 g (i0 mmoles) of orthanillc acid was added. CsHsN). and I.2.65 g.65 g. and 1. CH=N).2 g (80%) of product. Melting point of a sample mixed with (Ilia) 295-296~ (sub. 105 (44). 5 m- moles) was dissolved in a i:i mixture of methanol and water. 158 (18).5). Khim. A. Dmitruk. Melting point of sample mixed with (Ilia). 70 (12). Kochkanyan. S 10.1. N 14. Found: C 69. N. mp 257~ (from DMF).08 g (i0 mmoles) of o-phenylenediamine in methanol with the addition of a catalytic amount of hydrochloric acid was boiled for 20-30 min. H 5. t. 350 (4. The solid which separated was filtered off andlwashed with ethanol to give 6. 56 (8). 272 (1983). N 20. 65 (21). l-Phenyl-4-phenyliminoimidazolidin-2-one (Ilia). CsHsN). 4). yield 1. Found: C 69. C16HI~N~OS. C15H~sN30. 2. Baranov. 3260 cm -~ (N--H). C. A mixture of 2.i ml (I0 m moles) of N-methyl- aniline added.9.9%. N 18. and 0. 155 (1985). 9. Equimolar amounts of 4-thiohydantoin and aniline hydrochloride were boiled in methanol for 15-20 min.2%. 91 (9). 8. 60 (26). 107 (69). 310 (M+. 64 (i0). line solid which separated was filtered off and washed with methanol to give 2.9 g (40 mmoles) of l-phenyl-4-chloro-5-formylimidazolin-2-one (VIII) and 0.5).2%. Found: C 59. 250 (34). Mass spectrum. 7.. l-Phenyl-5-(N-methyl.0. i0 mmoles) was dissolved in acetic acid. and cooled to give a bright yellow solid. mp 295-296~ (sub. 67 (9). No. 55.5-benzodiazepine (VII). The deep blue crystal.30 ppm (2H.). 3.48 g (60 mmoles) of o-phenylenediamine was boiled in 30 ml of ethanol for 20 min. 191 . A. 251 (7). 3280 cm -I (N--H). A mixture of 2. N 20. Kochkanyan. mp 281~ (from dioxane).2.8. R. A. IR spectrum: 1680 (C=O). m/z (peaks ~ 3% of maximum): 50 (22). mp 283~ (DMF). 93 (14).2. 80 (50). iH. 500 nm (3.. CI~HI2N40. S 10. 52 (32). The be- taine (2.1. m. Reaction of Betaine (la) with Orthanilic Acid. Khim. I0 mmoles) was dissolved in i0 ml of acetic acid. The azomethine (la) (1. H 3. Calculated: C 69.3%. Korzenevskaya. 104 (18). 1720 (C=O).75 (IH. and S. A mixture of 8.2 g (90%) of product. Garkusha-Bozhko. mp 295-296~ (sub. 79 (i00). 63 (ii).4%. IR spectrum: 1630 (C=N). S. H 5. Getero- tsikl. N 17. R. 2. 134 (5). 3.1. %max (log ~): 260 (4. l-Phenyl-5-formyl-4-(l-pyridino)imidazole 2-oxide (la) (2..7. 2__-Formyl-4-(l-pyridino)thiazole 2-Oxide u~u-Methylphenylhydrazone (VI). UV spectrum (in methanol).2%. + + + d. 177 (12). The mixture was boiled for 50 min. 106 (99).4.61 g (58%) of product.77 g (61%). Baranov. Melting point of a sample mixed with azomethine (lla). O. Soedin. 340~ LITERATURE CITED i. CsHsN). H 3. H 4..7. The solid which separated on cooling was filtered off and washed with methanol to give 79% of product. 372 (1976)..86 g (5 mmoles) of orthan- ilic acid added.3%.08 g (67%) of product. Calculated: C 61. N. and S. 144 (41). mp 295-296~ (sub. O. 133 (16). N 14. and N. P. CH3). N 16.. The betaine (la) (2. Zh. H 4. H 5. 295-296~ (sub.3. Calculated: C 71. S.(lle). V. 205 (12). 77 (i0). mp 230~ (DMF).5.3%. 51 (41). No. Soedin. Geterotsikl. The mixture was boiled for 40-50 min.3. DMF).5-b]-l. N 18. C~HI=N404.4. H 5. DMF). S. s. Kochkanyan. The mixture was boiled for 20-25 min.7.7%. mp 340~ (DMF).3%. mp 340~ (DMF). CITHIsN30=.6.7. DMF). R.a- methylphenylhydrazine in i0 ml of acetic acid was heated for 5-10 min at 60~ The dark red needles which separated were filtered off to give 2. and the solid which separated was filtered off and washed with methanol to give 0.8. O.06 g (i0 mmoles) of 5-formyl-4-(l-pyridino)thiazole 2-oxide and 1. T. B. Cal- culated: C 59. C~Hs).9. t. 257~ .69 g (55%) of product. PMR spectrum (DMSO-D6): 3. B.65 g. V. N 16. and boiled with a threefold excess of aniline for 5-10 mino The fine- ly crystalline white solid which separated was filtered off and washed with methanol to give 2. i08 (8).27 (SH. 78 (55). H 3. Found: C 71. 8. 1720 (C=O). Obshch. I0 mmoles) was dis- solved in acetic acid. Melting point of a sample mixed with material obtained as in method A. H 3. Shvaika. Lukanyuk. 204 (48).22 g (i0 mmoles) of u. 7.40 (2H. and the bright yellow solid which separated on cooling was isolated to give 1. Calculated: C 69.45 (IH.or N-phenylaminomethylidene)imidazolidine-2~4-dione (V). 92 (16). Khim. 159 (17). O.65 g (i0 n~noles) of the betaine (I) and 1. G.).10H-2-Oxoimidazo[4.7 g (61%) of product.1)..35 (3H.32 g.3. Spitsyn. N. s. yield 75%.

255 (1978).5. Geterotsikl. 100.5. UDC 547. (5--8) 0.. (3--4) 7.78. SeuCel.. the chemical shifts for the methylene protons are assigned as the center of the corresponding multiplets.8 2. 4.4. Golovtsov 543. 3.49. adducts are formed with two and three molecules of ADCE and are separated using column chromatography. and S. (5--7) 1.. PMR Spectral Parameters for II.2-a]- benzimidazole and tetrahydropyrido[l..90 7. N. IV-Vl Chemical shifts.- *For IV-Vl.422'25 Previously unknown polynuclear c o n d e n s e d systemswith bridgehead nitrogen atoms have been obtained by treating acetylenedicarboxyllc ester with pyrido[l.2. Khim.2-a]benzimidazole) with acetylenedicarboxylic ester (ADCE). P.0213.2-a]BENZIMIDAZOLE WITH ACETYLENEDICARBOXYLIC ESTER N. I. A. 2. (6 8) 1.69 3.5. February. S. %Benzene ring protons IH-4H.82 IV 7. No.45 .37. REACTION OF PYRIDO[I. 372.10 6.. 1624 (1969). Thus their reaction with ADCE can be the same as benzimidazole [2] but with the formation of more com- plex heterocycles. Prostakov. Original article submitted October 29. The first of these is red.2-a]benzimidazole (I) [i] allowing us to expand studies of its properties.237. Kochk~nyan.2-a]BENZZMZDAZOLE AND TETRAHYDROPYRZDO[I. V. MonaCsh. P.53 . M. 3. (5--6) 6.0. Zaritovskii. 117923.2-a]benzimidazole (1) with ADCE in benzene takes place quanti- tatively at 20*C. The reaction of pyrido[1.53 1. B. Soedin. P. (P~--3) 7. Khlmiya. 3. Both of these compounds can be regarded as 1. Chem. Varlamov. With the aim of obtaining new poly- nuclear condensed heterocycllc compounds with bridging nitrogen atoms we have turned to re- actions of pyridobenzimidazole (I) (and the derived tetrahydropyrido[l. The Sulfonation of Organic Compounds [Russian translation]. No. N. pp. Translated from Khimiya Get- erotsiklicheskikh Soedinenii.85 1.56 7. 6. 1986.69.o n = 5 3.11 2. 1985. A.65. 3.09 . V. A. and E. Krapivko. Wittman. revision submitted March 26.80 --. 3.]0 7. H. 7. ! 3. Chem. 192 0009-3122/86/2202-0192512. ppm C]I~O J. E.26.4' 5.73. R.50 9 1986 Plenum Publishing Corporation . Mos- cow (1969). (1-2) 7. Gilbert.2-a]benzimidazole. Moscow. 239-241.542. Zs Monatsh. 1 {2--4) 1. 31.5. 3.O. (7--8) 8. 5.4. Zolotarev. 1OH. N. P. W~tCman. Lumumba People's Friendship University. p .% ~ .5.953: A.02 8. and E.07 2. 1619 (1969). 1984.0 V 6.90 3.21 7. crystalline material TABLE i.9.492 (I--4) 0.41 9.836. ~. (1-3) 1.03 6. 2.03 7.65 7. Shendrik.9 3. In addition. Hz I I-H I1 6. 3.7. IIH. Ziegler.67 201il. Klyusv. Beutel.71. (6--7) 7.69 i 7.8. nitrogen ring protons 5H-8H.2-disubstituted benzimidazoles. Baranov.50 7.3. and N. I.69j7. 3.12 8. We have developed a convenient m e t h o d for the synthesis of pyrido[l.28 4. H.2.08 7.02 VI 6.488. 4.

The PMR spectrum of II shows two four-spin systems for the protons of t h e dihydropyridine and the benzene fragments in the molecule with characteristic parameters. .. UV spectra were obtained on a Specord UV-VlS using ethanol solvent and IR spectra as KBr tablets.7.l'-b]benzimidazole (II). The basic product of the reaction (an analog of II) is the red. ll-te tra (carbome thoxy) pyrido [1. Assignment of all of the PMR signals can be made for II by means of double resonance and by comparison with the parameters for the starting pyridobenzimidazole I [i] (Table l).whose color is apparently due to the poly-conjugated molecular system.2-a: 2'.. The studied reaction occurs in two stages. i0.47 and 5. '. respectively.10.9.~/' ..6.. The 13C NMR spectra of V and VI clearly show signals for the methylene carbon atoms of the reduced heterocycles (corresponding to four and three carbons... obtained by reaction of benzimidazoles with ADCE have been described in [2].2-a] azepino [2 '. respectively. Direct reaction of isolated II with ADCE gives III in 90% yield. The small vicinal spin--spin coupling for these protons ( s j = 5 Hz) is apparently due to the trans orientation of the carbomethoxy groups.11.! '-b ]benzimidazoline (VI). Detailed NMR parameters for III will be reported after x-ray inve s riga t ion..N ~>~--COOCH m . respectively) as well as the tertiary carbons C.6 MHz for carbons. ll-hexahydro-8. In significantly smaller yield there is also obtained the yellow crystalline 5. .. Adduct II is initially formed and this re- acts with a third molecule of ADCE to give III. ii. " s z-- 4 5a/ 9 "Y " l---N ) ' ' ! . > / .. COOt II 5 CII300C 1~ F g " COOCtI 3 I COOCH3 IV V COOCI{3 VI The molecule VI contains the fragment 9. The large increments for the chemical shifts of protons 1 and 3 to high field (1..10-dihydro-azepino[l. The structure of this material was shown by PMR spectroscopy to be 9. Mass spectra were run on a Varian MAT-44.. 2 .7.. Com- pounds of this type..6...a ] b e n z i m i d a z o l e (IV) with ADCE. respectively (Table i). 193 .. The second adduct (IIl).42 ppm.26 and 0.5 ppm. crystalline 5. i0.5a. the highest shift being observed for IH associated with the change in hybridization of the neighboring nitrogen atom. is a yellow crystal- line material with PMR and ~3C NMR data in conflict with one another and not permitting an un- equivocal structural assignment.o and C~.o) andC(t.. A particular characteristic of the PMR spectrum of adduct VI is the presence of an iso- lated system of two methine protons with 6 = 5. The IH and 4H sig- nals in V and VI are found at significantly higher field than those in IV..). The signals for the methylene protons of the piperidine related rings in V and VI occur as complex multiplets.12-tetra(carbomethoxy)bis-pyrido[l. 12-tetra (carbomethoxy) bispyrido [i.. 6 /(2 7 cooc.2-a]benzimidazole..8-tetrahydro-9. l'-b] benzimidazoline (V). "~" N~ "'v CII3OOC/ ~ / ~ C O O C H 3 C00CIt 3 I II The a d d u c t s a r e a l s o p r o d u c e d from t h e r e a c t i o n o f t e t r a h y d r o p y r i d o [ 1 . EXPERIMENTAL PMR and '3C NMR spectra (internal standard TMS) were measured on Bruker superconducting magnet instruments (WM-250 and WM-400) at 250 and 400 MHz for protons and 63 and 100.I " N" bw" IL 2 % .91 ppm for C(. It should also be mentioned that in the adducts V and VI the four spin system for the benzene ring protons has degenerate charac- ter on account of the virtual coincidence of IH with 4H and of 2H with 3H.. when compared with I [2]) are due to the change in hybridization of the imidazole nitrogen atom from sp 2 in I to sp 3 in II. formed in significantly larger quantities. 2-a: 2 '. Chromatography em- ployed silica gel L 100/160 columns and applied layer Silufol grade UV 254 material. The presence of the quaternary carbon a t o m (C)aa in !I) is shown by a XSC NMR signal at 6 79..10.

Acheson. M + 456. Abbot. LITERATURE CITED i. 12%) with mp 196-198~ (ether) and Rf = 0.4.12-Tetra(carbomethoxy)bispyrido[l. A. 3:1).a z e ~ i n ~ [ 2 ~ .7. C2.6.t e t r a ( c a r ~ m e t h ~ x y ) ~ y r i d ~ [ ~ 2 .4. P.N20. *'C NMR spectrum (DMSO-D.62 g. Subsequently adduct !l (0. I. 5~6~7~8-Tetrahydr~-9~l~. Rf 0. 6 . Prostakov. 103. M 594. 91%) with mp 150~ A mixed melting poins with the sample described above was not depressed.98 g. JCb.86 g. H-5 = 189 Hz. Mills. Foxton. Khim. Found: C 58. ll0.1%. Anisimov. 465 nm (3.22 mmole) and ADCE (0. N 4. 29. IR spec- trum: 1750.l2-tetra(~arb~meth~xy)bis~yrid~[~2-a:2~-b]benzimidaz~ine (V) and 5 ~ 5 a . 320 (4. H 5. H 4. Rf 0. and K.3 (C(.5.30).3. ili. 130.8%. Lav- ani-Edogiaverie. N 6. Cal- culated: C 60. N 6. 1384 (1983). A.5 (C(sa~). N.4.5 (C(da)). 2.20). Am. Found: C 61.5.78(ether). 7 mmoles) in benzene (20 ml) was allowed to stand at 20~ for 5 h. mp 171-172~ (from ethyl acetate). a mixture of ether and hexane (2:1) removed III (0.80). 21.3%. iSCNMRspectrum(CDCls): 16.36 (ether).8 (C(. 9. H 4. N .05).2%. 194 . V.3 (identical solvent system). 460 nm (4.)). 145.80). P. 43%) was obtained as red crystals with mp 176.2-a:2'.i g. 430 (3. 0. No. N 5.4 rauoles) and ADCE (! g.9%.1%: M 456. 44%) as yellow crystals with mp 151~ (with decompositon. M 452. Calculated: C 60. M + 456.24 mmole) in benzene (ii ml) was held for 2 h at 20~ The residue was chromatographed to give III (0.4 (3 80). C. Found: C 60.7 (C(.H2aN=O. Soc. .97). R .7. i0.5 g) in benzene (25 ml) was stirred for 4 h at 20~ T h e reaction product was column chromatographed (30 • 1 cm col- umn) using a mixture of ether and hexane (I:i) as eluent.4 g. Calculated: C 58.a ~ . 260 (3. from ether).): 79.10.5 ppm (C(s)). 1720 cm -I (CO) J UV spectrum lma x (log e): 210 (4.1.3 (C(. Varlamov.)). M .9 (C(s)). N 6.7%. C=3H2oN=O. H 5. 33%) was eluted using ethyl acetate as red crystals. 570 (sh) nm (3. P.62). V. 307 "3. 882 (1967). 83. 5 mmoles) and ADCE (1. A solution of I V (0. Soedin.3.03 g.5..5.35 g. I. Following this was obtained the yellow crystalline VI (0. M. Fomichev.80).H~. Shendrik. 275 (4. M + 594. Krapivko. 4..l'-b]benzimidazoline (If).40). Initially.0 (C(4)).3. C2. W. A solution of I (0. S .)). A. Adduct V (0. 7 ~ l ~ l . 0. H 4.27 (mixture of ethyl acetate/alcohol.~ ] - benzimidazoline (VI).12 g.11. Calcu- lated: C 61. After evaporation of benzene the residue was chromatographed (30 • 1 cm column). Chem.5-178~ (ether) and Rf = 0. N 4.1 (C(ea)). Found: C 60. N 6. and A. B. H 5.1%. J. M 456. No. M + 452.8 ~ 9 ~ .. 43.9.H e x a h y d r ~ . 2. H 4. UV spectrum lma x (log e): 219 (4. 2. C23H=aN~O. N 6. S.00). H 5.. A solution of adduct II (0. Geterotsikl.)).3.28 g.

and l-alkyl-2-methyl-4-alkyldecahydro-4-quinolols was determined using the ratio of the mass spectral intensities for the characteristic ions [12-15]. V. V. Tables 1 and 2 give the peak intensities of the major ions in the total ion current scale. ii]. 1984. T. 1986. 2-methyl.. R 2 = CECH We attempted to investigate the effect of the replacement of the methyl group at C(2) by a furyl or phenyl group and of alteration in the molecular structure on the efficiences of different fragmentation pathways. Zhilkibaev.X V.Vl ~::'0 R IX+VII ~0 VIII III. O. Agashkin. Zamkova.2-dimethyldecahydroquinolols [4].IX. Lyuts. No.. The dependence of the probability for the formation of characteristic ions on the molecular ge- ometry in the stereoisomer series was demonstrated. 1985. 480100.51:547. Trans- lated from Khimiya Geterotsiklicheskikh Soedinenii. V. V. l-alkyl-2- methyldecahydro-4-quinolol [6]. 3]. The mass spectra of I-XII were studied for the first time.. while Table 3 gives the elemen- tal composition of several characteristic ions determined by high-resolution mass spectrometry.and 1. revision submitted April 16. The effect of molecular geom- etry on decomposition has also been examined [2-9. Esenalieva A study was carried out on the major pathways for the decomposition of stereo- isomers of 2-furyl. E. February. The elemental composition of the char- acteristic ions was determined by high-resolution mass spectrometry. III.and 2-phenyldecahydro-4-quinolinone and their tertiary al- cohol derivatives upon electron impact. UDC 543. Praliev.. R2 = OH. pp. 8]. The in- troduction of a heavy substituent at C(2) leads to marked changes in the direc- tions of the major fragmentation pathways of decahydroquinoline. IX R* = C~CH. X-XII R* = OH. The major fragmentation pathways of the molecular ions of these compounds are depicted in the Institute of Chemical Sciences. O. and decahydro-4-quinolol N-oxides [i0].and 1. Academy ofSciences of the Kazakh SSR. Z. 2.2-dimethyldecahydroquinoline [2. 2-methyl-4-chloro- decahydroquinoline [6]. 0009-3122/86/2202-0195512. IV.50 9 1986 Plenum Publishing Corporation 195 .derivatives I-XII: n \x '~. D. The configuration at C(~) and C(4) in the trans stereoisomers of 2-methyl. \ \ I.X] XII I-V R = a-Fu.831 K. VI-XII R = Ph. The major fragmentation pathways upon electron impact have been determined for de- cahydroquinoline [i]. Alma-Ata.IV. the stereoisomers of 2-methyl. We h a v e s t u d i e d the mass spectra of the following stereoisomers of 2-furyl. and M.MASS SPECTROMETRIC STUDY OF THE STEREOISOMERS OF 2-FURYL- AND 2-PHENYLDECAHYDRO-4-QUINOLINONE AND THEIR TERTIARY ALCOHOLS A. and 2-phen- yldecahydro-4-quinolinones and the tertiary alcohol. stereoisomers of tertiary alcohols [7. Mass spectrometry has found common use in the study of decahydroquinoline and its deriv- atives. their benzoic esters [5]. Orig- inal article submitted December 27. 242-247.

and for ketones with an equatorial substituent at C(=) relative to an axial substituent.8 1.9 245 7. Ion r is formed upon bond breakage in the piperidine ring.3 2.43] + in the mass spectra of the ketones is a composite peak and is attributed to two ion types..I 17. R~ R2 9 "~ It ~z H H O1 ~ -C2H5"-~ RI R2 R1 ~ I~21 r NIl H 9 [I .0 6. Ion r in the mass spectra of the alcohols makes a smaller contribution relative to ion ts.3 55 1. = C I I _ ~ I ' . TABLE i.2 228 ' 2.8 0. ".5 0.9 2.5 1.3 1. Such fragmentation is not characteristic for decahydroquinolines not sub- stituted at C(4) [2] whose mass spectra do not display a peak for the analogous i0 n [M -.8 41 2.5 9..4 1.I % 148 1..5 ] 1.7 109 3.2 1. 010 g It ~+ 9s .6 1.3 109 1.3 2.5 67 1.0 O1 218 1.6 1. The low stability of E + in the case of alcohols V and XI may be related to a through-space in- teraction of the axial substituents at C(=) and C(~). Since the decomposition of the furyl and phenyl derivatives of decahydroquinoline is similar. r and r (see Table 3).1 54 0.2 55 1.8 41 2.7 scheme.3 3. while the total contribution of ions r and r to the total ion current for the alcohols is 196 .3 {I}. I I~O]) 227 0.8 2.0 81 2. The fraction for M + in the total ion current is an index of its stability.7 1.2 2. Mass Spectra of l-V (peak intensities in % of Z a g ) Ions m/z I m/z III IV v M+ 219 13.5 65 1.6 3.0 1.2 7.8 0.2 3.2 1.4 2. =" I12N::CHR .q 94 6.2 1.0 202 2.0 0.1 81 2...C=H~] +.0 1.3 1.2 L3 53 1.0 1. CH.7 216 1.4 " 1.OH]'+ 202 1.7 3.5 [ M .~ RI R2 "\ " ~ Og CII2R .7 (1.9 % 176 10. This fraction is high- er for ketones relative to the corresponding alcohols. namely.4 3. The strong ion peak [M -. Ion r is characteristic for the decomposition of previously studied derivatives of decahydroquinoline [1-9] and is formed upon the fragmentation of the hydrocarbon ring..8 58 1.1 O4 176 176 2.0 0.2 1.9 54 1.9 [M.7 2.7 1.1 2.6 I 0.4 t t.9 (:l} it 67 1. for the trans ketone isomers VI and VII relative to the cis isomers (VIII).3 {I}8 c~6 13.7 0.9 2.3 2.6 2.8 65 1.2 39 2. " ~ )~.9 94 2.4 190 : 1.3 244 1..1 1.. The stability of the molecular ion in the case of the alcohols is higher for the cis isomer relative to the trans isomer and for the trans isomers with an equatorial substltuent at C(=) relative to the epimar with an axial hydroxy group.2 I. The molecular ion peak (M+) is one of the strongest in the mass spectra of I-XII.4 39 1.1 1..8 2. ~. it was represented in a single scheme and the substituent at C(=) was given as R.4 96 21.4 1.

4 39 i 1.6 104 1. 197 .9 O~ 52 1.3 0.). The peak for this ion in the case of the trans alcohol isomers is higher for equatorial orienta- tion of the hydroxyl group. The high intensity of the peak of this ion in the mass spectra of the 2-furyl and 2- phenyl derivatives relative to their methyl derivatives may be understood assuming that these ions have two possible sites for charge localization. The intensity of the peak of this ion is higher in the case of the cis isomers (compare the spectra data for VIII relative to VI and VII) and.2 178 1. Vl).2-dimethyldecahydroquinolines [2] and their tertiary alcohols [7] is low.8 8. while the maximum peak in the mass spectrum of 1-math- yl-2.9 3.7 1.8 91 3.~ 1. the intensity of the r ion peak for the ketones is inversely dependent on the molecular geometry relative to the Cs ions. The probability of the for- mation of analogous ions With m/z 58 in the mass spectra of 1. This may be understood considering that both these peaks contain the substituent R and are formed upon competitive decomposition with bond breakage at C(a).2 2.4 1.4 0.1 1.c O. I and for VII vs.l 1. Rex > Req.~ 1.8 1.c 53 1.1 5.a 1.0 4.5 1.tl 67 1.~.8 2.5 0.2 1.0 2.1 2.8 8.1 212 3.0 2.9 1.7 28 1. VI-VIII).1 2.7 1.5 1.9 0.2 254 L0 ~. while the nitrogen atom is the only charge localization site in the ion with m/z 58 for derivatives of 1.3 1.H20]+ 237 ). The intensity of the Cs ion peak depends on the molecular geometry.7 0.9 04 86 186 .0 1.1 77 1.4 2.1 ~bm 91 1.2-dimethyldecahydroquin- oline [2.0 O7 19 1.6 1.6 13. A clear dependences of the contribution of ion Cs to the total ion current on molecular geometry is found in the mass spectra of the alcohols:i cis > trans.2 11. 7]. The prob- ability of the formation of this ion is higher for trans isomers relative to cis isomarsl the axial orientation of the furyl or phenyl group facilitates the formation of this ion.9 eP9 04 3.7 79 1.9 less than for the ketones.8 O5 58 1.9 1.9 2.2 3.7 67 1.7 77 2.0 0.0 106 0.8 1. The contribution of ion r also depends on the molecular geometry and is greater for the trans isomers and for axial orientation of the hydroxyl group.8 1.4 238 L5 3. 41 1.t 0.c.4 7.1 1.0 1.4 1.1 O. do not contain a nitrogen atom and are formed upon breakage of the C(2)--N and C(s)-C(~) bonds.4 O~ 86 2.6 81 2. Decomposition with the loss of the methyl group at C(2) is characteristic for the frag- mentation of 2-methyldecahydroquinoline and its derivatives [2-8]. is high- er for axial orientation of the substituent at C(2) (compare the data for II vs. Ions ~9.~ 39 0.0 119 0.9 1.2 1.0 8.3 1.7 1.7 9.7 4..6 O~ 06 1.9 2.8 55 1.e.7 [ M .9 1.4 1.6-diphenylpiperidine corresponds to the ion m/z 120 formed upon analogous decompositions [16].0 9. and VI-VIII.7 2.I 1.8 O2 O0 1.3 1.4 41 2.2 1. The peaks of such ions 9 (~6) are seen in the mass spectra of phenyl derivatives VI-XII. OHax > OHeq. These ions are formed as a result of breakage of the C(2)-C(s) and C(9)--N bonds with rearrangement of the hydrogen atom to the nitrogen atom and include the substituent R .8 1.3 54 I 1.2 1.5 1. TABLE 2.2 1.2 11.8 1. II.7 79 2.0 1. The probability for the for- mation of these ions does not show a clear dependence on the molecular geometry in the stereo- isomer series.7 4. in the case of the trans isomers. II.Ions ralz VI VII VIII m/z IX X XI XII M+ 29 .6 9.3 [M-OH]+ 12 1.8 1.3 2.7 5.6 1. Ion r corresponds to the major peak in the mass spectra of alcohols III-V and IX-XII and is one of the strongest peaks in the mass spectra of ketones I.0 255 L4 ~. whose appearance probability is much higher in the ketones (I. Other ions which include the substituent R (r and r make an independent contribu- tion to the total ion current and there is no clear dependence for the intensities oflthese ion peaks on molecular geometry.) .0 0.9 1. Mass Spectra of Vl-Xll (peak intensities in % o f Zs.5 1. i.9 0.5 3.7 0.6 1.6 1.

Elemental Composition of the Characteristic Ions of I. 23].s C.iNO C iol-[ion O.~Hr : C4H. The peak for this ion is strongest in the mass spectra of ketones I and II and is not diagnostlc for stereoisomer determination.OH] + ion is found in the spectra of all the compounds studied.1NO : CjsH.~N 10:l ~02 CI. while [M -. The ionization voltage was 70 V and the acceleration voltage was 2.i N O t6 Cs['I~NO 10~ f4 CaH~O I(14 C. these ions are formed upon the decomposition of the furan ring.CH0] + ions also contri- bute to this signal in the mass spectra of furyl derivatives I-V (see Table 3). Thus.~NO 212 Ct~I'II. Ion r is apparently formed upon loss of a hydrogen atom as a result of the breakage of the ~-bond relative to the nitrogen atom..~ 3:211 81 CJI~ : C51t. HIoNO~ ~:1 C]aiij~N : C j i ) ~ N O 2:1 103 C~Hr'NO C:J 1. TABLE 3. 20(: C~al I)4NO 176 C. EXPERIMENTAL The syntheses of I-V were described in our previous work [17-19] and their structures were demonstrated in our earlier communications [20.29] + peak in the mass spectra of phenyl derivatives VI-XII corresponds to one #2 ion formed upon fragmentation of the hydrocarbon ring.5 kV.iI-ll4NO Cu. t mass I 190 CI..dt8 C~H~ :CglrN :C~H~O 9i CTI'Ir 67 C.~HI~NO CnHI2NO~ I : 1 i \. The syntheses and structures of Vl- XII were described in our earlier work [22. This find- ing may be related to stabilization of the enol form of ketones I.~ 3:4 91 C. Ion #7 contains the nitrogen atom and is obtained upon breakage of the piperidine ring. The temperature of the ionization chamber was 100=C. In the case of the alcohols. II 54 43 C4i'1~ : CaH4N Ca)'b : C~HsN : C~I-i:~O 2:1 1:2: 81 C~H0 : C~HsO 1:1[i :10 55 C4Hr : Caf'laO 2:g 41 CaI'l~ : CatIaN 10:1 CaH5 : C2HaN ~:111 238 CIrH~N V CI~t'{I.i-b CI iIti.~O 4:1 6~ CsH~ C4t-I~ :CaHO I:1 41 Ca)is : C2HaN 0:I Let us examine some other ions which give weak peaks. II.~O 5:1 I03 ! Cg'irNO 55 C4H7 : CaItaO 2:3 t. 198 . at least in M +.~H~NO 106 C~H. V. Vl and IX by High-Resolution Mass Spectrometry I Ion Elemental compositioniRatio . The high-resolution mass spectra were taken on the same spectrometer with M/(AM) = i0.. 21]. The introduction of substituents at C(2) capable of participating in charge delocalization leads to the formation of ions due to spec- ific fragmentationin addition to the fragmentation ions characteristic for 2-methyldecahydro- quinoline and its derivatives. The [M -. II. and VI-VIII.09 C~Hr--NO 178 CIIHI6NO . The peak for the [M--H~O] + ion in the mass spectra of the ketones is an order of magnitude less than for the alcohols.di8 : CTI'I(IN 4:1 II t?0 CI2t'II~NO CIdlI~--NO.6 94 C~I':16NO : CsHIoN Cg-I~O o:.000.. The peak for the [M -.~t'i~6NO :CI~HI:NO. The mass spectra were obtained on an MKh-1320 mass spectrometer with direct sample inlet into the ion source. This ion is characteristic for the mass spectra of alcohols but it is not clear why the peaks for this ion have comparable intensity in the spectra of the ketones and alcohols. 1:10tl 186 CI.~I'IICN .~N ~4 C~H~N : C~H~O 1:5 104 C. we find that the [M--OH] + ion peak is higher for the trans isomers with axial orientation of the hydroxyl group. we have established the characteristic pathways for the decomposition of 2-phenyl- and 2-furyldecahydro-4~quinolinones and their tertiary alcohol derivatives upon electron im- pact and studied the effect of ring fusion and the orientation of the substituents at C(2) and C(4) on the fragmentation of these compounds.

Kurilenko. Geter- otsikl. No. V. V. Khim. 147 (1970). Matamarov. I. A. Bakaev. Byul. I. Nauk Kaz- SSR. A.. Zaikin. D. I. Praliev. A. Nauk KazSSR. V. B. Geterotsikl. Geterotsikl. Vul'fson. A. Litvinenko. Izv. Ukhova. 7. T. A.. Ukhova. I. A. L. No. No. 9. Litvinenko. Khim.. V. S. A. and G. 2. Krasnomolova. Klepikova.. Zh. E. N. F. M. Artyukhin. K. V.. and G. No. Zhilkibaev. Izobr. Artyukhin. Vul'fson. 65 (1981). iO. No. Sokolov. Matamarov. A.112.. Esenalieva. Artyukhin. D. Agashkin. G. Akhrem. 2. E.. 53 (1971). Izv. A. I. V. 12.. Bakaev. 1443 (1978). i0. K. T. No. and G. Ser. Nauk KazSSR. D. Praliev. and D. D. V. Fiz. K. I. No.. F. Matamarov. D. O. 39 (1969). G. K. i. C. Akhrem. 58. and D. A. and D. Sokolov. A. O. Esenalieva. I. Vul'fson. 2164 (1968). Krasnomolova. A. 74 (1970). N. M.. S. Akad. Nauk SSSR. Akad. 18. P. V. 1524 (1976). 20. Akad. A. D. Agashkin. V. Litvinenko. and S. S. K. D. K. L. A. O. V. Akad. i. E. L. D. Akad. Sokolov. Sokolov. and O. Ukhova. O. 81 (1984). Zaikin. 485. D. Uskova. G. Agashkin. Esenalieva. S. 21. A. V. Manatauov. Lyuts. V. 15. 962 (1975). Ser. Izv. 9. Kh{-m-. Rozhnov. G. A. Agashkin. Nauk KazSSR. A. Zaikin. USSR Inventor's Certificate No. Khim. Khim. N. V. 4. Lyuts. and L. and D. Ser. 30 (1976). i.. E. D. Lyuts. 16. S. Akhrem. S. V. Sokolov. I. E. 173 (1977). Zaretskii. Khim. Vul'fson (Wulfson). V. 5. G. Sheinker. Nauk KazSSR. Praliev. G. B. D. 3. 23. Org. Org. No. V. O. Z. Akad. I. G. Set. Izv. G. V. S.. O. Ser. V. I. Akad.. F. No. Soedin. Ukhova. Khim. 2597 (1984). I. D. N. Lyuts. Ser. Praliev. D. Mass Spectrom. V. O. Ermakov and Yu. L. Khim.-farm.. M. N. Izv. Nauk SSSR. 19. I. Khludneva. 12. Vul'fson. V. T. Izv. V. Artyukhin. Akad. Lyuts. N. A. Litvinenko. 5. No. L. 2. Praliev. V. E. M. and D. and G. Litvinenko. V. Oldfield. Omarov. 57 (1985). and N. Khim. N. S. Ser. A.. L. 4. Ser. K. B. and G. Khim. 1257 (1969). Vul'fson (Wulfson). 17. No. II. Izv. No. V. I. Uskova.. Org. A. Nauk SSSR. 80 (1971). 7. Vul'fson. T. V. V. Ukhova. S. Mass Spectrom. Ser. L. N. Agashkin. Izv. and N. ii. V. A. V. Mar- chenko. Maclean. A~ Akhrem. V. Artyukhin. Ukhova. S. Marchenko. Nauk KazSSR. and D. 4. Agashkin. Izv. and N. 13. A. Zh. 7. 74 (1974). Khim. V. Yu. N. Zaikin. Sokolov~ and G. Zh. D. 58.. B. N. S. Akad. Ser. Zhilkibaev. Litvinenko. Agashkin. Khim. and N. No. Nauk KazSSR. No. T. O. 199 . Akad.. I. Khim. I. A. D. 209 (1972). Khludneva. S. K. Zaretskii. Praliev. No. Ser. Fhim. D. Sydykov. A. Izv. Sokolov. V. Izv. Nauk KazSSR. A. 240 (1984).. S. Khim. M. V. Khim. Sokolov. Sydykov. G. Praliev. LITERATURE CITED i. 64 (1975). Agashkin. Nauk KazSSR. I. Zaikin. A. P. Khlienko. Fiz. Akhrem. 48 (1968). K. Z. Khim.. V. Lyuts. D. Sokolov. V. V. i. Zaikin. 35. Nauk KazSSR. Soedin. A. O. 14. V. 8. Bakaev. K. K. Zaikin and N. P. and B. No. 22. Kukso. Akhrem. Bakaev. 34 (1969). E. 6. V. Soedin. Sokolov. Khim. F. Khim. and Zh. 2. Mass Spectrom. Tarakov. V. 61 (1984). A. S. V. D. I. Akad. Set.. Sokolov. Akad.. Akad. ~. N. Z. Lyuts. ~. No. I. Ser. Smetanin. T. Rozhnov. Praliev. i. Izv. Sokolov. Izv. Sokolov..

In the spectrum of iosmer lllb.836:543. Zaitsev for taking part in the discussion of the IR and electronic absorption spectra of the compounds.m. The long- wave absorption bands in the electronic spectra of these compounds were in- terpreted on the basis of the experimental and calculated data (the PPP method). i. vanillaldehyde.422 Hanna Bu Habib. Theoretically eight geometric isomers of the arylidenehydrazonoazafluorenes (four each with the s-cisoid and s-transoi4 configurations) are possible. however. only the last isomers can exist. A- zlnes III-Xll were obtained by the condensation of 3-methyl-2-azafluorenone hydrazone (I) and also 4-azafluorenone hydrazone (II) [i] with benzaldehyde. Translated from Khimiya Getero- tsiklicheskikh Soedinenii. I I . 248-253.* The bands at 1618. IV have different colors and different types of crystals| IIla~ IVa form yellow velvety flakes. Kirillova. 117923. In practice. in addition to the same absorption bands. Original article submitted December 26. VII1 Ar=C6IIg. February. two of them with the Z configuration of the arylldeneaza- methine fragment in relation t o the nitrogen-containing ring and two with the E configuration.ARYLIDENEHYDRAZON0-2(4)-AZAFLUORENES N. and L. IX Ar=p-CHaO~H4. IVb form shiny orange crystals. Murugova Previously unknown unsymmetrical azines with arylidene and azafluorenylidene fragments were obtained. VI. E. S. XI Ar=(p-OH)(m-CH~O)C6H3. which is usually assigned to the stretching vibrations of highly perturbed C=N bonds of the azine fragment [2]. 2 a z a . Prostakov. The individual geometric isomers were isolated by fractional crystallization of the azine III [(Ilia) mp 158-159~ (!llb) mp i07-108~ and the azine IV [(IVa) mp 134-136~ (IVb) mp 138-140~ The individual isomers of the azines III. 1580. anisaldehyde. M. P.Ill. L. and lllb. but it was not possible to separate them by column chromatography. By TLC it was established that two geometric isomers of the azines lll-V were present in the obtained samples. which can be explained by the coexistence of the conformers *The authors express their gratitude to Doctor of Chemical Sciences B. 1984. Lumumba People's FriendshipUniversity. UDC 547. there is a band of medium intensity at 1638 cm -I.(CIi~O)~C~tI3 In the IR spectra of isomers Ilia. 200 0009-3122/86/2202-0200512. pp. VIII----XII R=H.. salicylalde- hyde. VII. XII At= "J. 1986. In connection with the fact that azines containing the azafluorene fragment are unknown we undertook the synthesis of a series of unsymmetrical arylidenehydrazonoazafluorenes. No. Some of the geometric isomers of 3-methyl-9-benzyl- idene(4-methoxybenzylldene)hydrazono-2-azafluorenes were isolated. In the IR spectra of compounds IV-XII (Table i) there is also an absorption band in the region of 1633-1638 cm'*. 4-aza. IV.e. 2. b in tablets with potassium bromide a difference is observed in the region corresponding to the stretching vibrations of the C=C and C=N bonds (Table i). A feature of the IR spectrum of the azine (V) is the presence of absorption bands in the regions of 2600 and at -3100 cm-*. and veratraldehyde. on the basis of which it can be supposed that all these azines have the same structure as the isomer IIIb. X Ar=o-HOC6H4. N . A.50 9 1986 Plenum Publishing Corporation . and 1500 cm-x in the spectrum of the isomer Ilia be- long to the skeletal vibrations of the azafluorene fragment.-N}[ 2 N -N~:(1IAr IJI II! Ell I. Moscow. V. III--VIt R=CHa.

1550m ."~ 1180 v s 1580sh. 201 ._. 1575 m.i590s 130"~'% 1275 v s XI 121t. 1552 m.1520vs 1280 vs i140 s . l14fl v s 1520 vs 1030 vs *Ilia. tl F§ ~ l ~ .. 1590s.e. 15716 1550m .C31: 3450m~ 636 s 1615vs. and O. 1520'~ 1500 w V o-HOC~H4 3400 m o . 1553m. ISg0~h.. 1255vs. 1240 s 1170 m . i. The introduction of the arylidenehydrazone group. 1165m 3120 m[ 1547m. 1570s 2570 s b . 1638 s ! 1610m . 2600 mb.-. 1633 s 1610vs. 1260~s. 15t3 vs 112~ .1273 vs. which indi- cates that the z-~ conjugation. 1260 v s o 1]O--C~H4 2740 s.15~Os.1575m . Vlll-Xll R = H.m-(Ctt30).15Q0s. IV-Vll R = CHa. (p-HO) (mLCt-130)--. T h e two-center Coulombic intetrals Y~v were calculated by means of the Matago--Nishimoto formula [6].15~0 m. A [ w i t h a strong intramolecular hydrogen bond (the band at 2600 cm-*)] and B (the bands at -3100 cm-*). 1575s 1558m. 1555. 1506 w 3070 sb.s. 1500w p. 1555m . 15S8 s 1268 v s 1230 v$ VI 116~ . During the quantum-mechanical calculations we used the modified program in [3-5] with al- lowance for the configurational interaction of 25 singly excited states.6o8 s 1612vs. in which the long-wave maximum of the azafluor- ene fragment undergoes of bathochromic shift to -320 nm (AI . 2: : x . 1310 vs.20 nm) on account of the auxo- chromic effect of the =%N--NH= group. 1170v s 1570 vs. This becomes clear during comparisonwith the spectra of the in- itial compounds..i 2420 sb i VII [pan-(CHaO)2--C~Ha 1638 m 1613vs. L/ Y. leads to an even larger shift of the long-wave absorption band to 360 nm. . increases in the investigated systems.638 s 1617Ns 15~2 m. and with self-consistency in a linear relation- ship to the bond orders PBv using the standard parameters for C. the hydrazones I and II.X\ .o-<. lllb C~H5 1565'r 1500 w IV p-CH~OC~I-I4 . t4s m 638 s 1612v~. 1550m 2620 sb (p-HO) (m-CH~O)--C61-t~ 3100usb 1636 s I61~s. how- ever.:..1525vs 3070 s b .C~}13 1633 s" 160~s v 15GOs..~ l150s 2710 s. 1585s.(CH~O)--C~H4 1639 s I 1615vs. ~::' H R=uN. l A B For a more detailed investigation of the electronic structure of the azines III-XII we used their electronic absorption spectra and quantum-chemical calculations. which is only possible in the flat conformers. IR Spectra of the Azines of Azafluorenes lll-Xll Absorption bands. b. 1565 m. TABLE i.. N. cm"I (in tablets with KBr) Com- pound* Ar C=C C--O C = N o -H Skeletal Ilia C~H5 1618vs 1588 m. 103t s VIII C6}Is. The experimental data for azines lll-Xll(Table 2) indicate that the electronic absorp- tion spectra are not a simple superimposition of two unconnected azafluorene (r and aryli- denehydrazone (r systems. with variation in the resonance integrals 8~v and bond lengths rpv..1560m 1523vs XII o. 1265 v s 1176 ~ts 1X 1600sh.

see Table i) 9~%ethanohrhx.6D).t.39) 390* (4.]340 (4.(4.21) 270 233 (449) (4.4~) 298 312 (4. It was assumed that sp 2 hybridization is realized for the nitrogen atoms while the in- teraction between the unshared electron pairs in the hybrid orbitals in the trans position to each other can be disregarded.445 207 (4.50) 212" 234* I 253 (4.5 [). and 360 nm are mainly observed in the electronic absorption spectra of azines III and VIII.44) (4. TABLE 2. The ~ bonds are formed by overlap of the PZ atomic orbitals of the nitrogen and carbon atoms.56) 375 (4.59) (4.525237 (4. 345* (4.46) 412" (4.37).54).805 217 (4.58) 241 (4.615.27) 247 (4. Our calculated lma x values both for the first two electronic transitions and for the oth- ers agree well with the experimental data.34).52). 330 (4.53) 1310(4.45) 410' (4.25).29).34) 217 (4. One of the possible reasons for the small quite 202 ..38) 1313(4.54) ~ 367 (4.27) 227 (4.38) 345 {~.64) ]294 (3. 280 (4. dur- ing the interpretation of the spectra and the electronic structure of these compounds we started from the calculated data for one arbitrarily chosen isomer. (4.38) 225 (4.52) 237 (4.~x acid nm ([ge) 0 A B J C J . 212 (4.365 228 (4. 304 (4.61) 233 (4.57) VIII 207 (4. The first transition.43) 212 (4.3 ~) IX 213 (4.48) 1242 (4..30) 340 (4. 315 (4. Electronic Absorption Spectra of the Unsymmetrical A- zincs of 3-Methyl-2-azafluorene Ill-VII and 4-Azafluorene VIII- Xll (azafluorene =N-N=CH--Ar.61).251 424* (4. ] 235sh 273 (4.53) 267 (4.55) (4. From comparison of the experimental and calculated data and also analysis of the configuration interaction matrix (CIM) it is possible to conclude that the long-wave ab- sorption bands in the spectra of arylidenehydrazono-2(4)-azafluorenes III and VIII are formed by the two so § s * ~ * and so + s S ~ * electronic transitions.55). 387 (4.h (4. can also be considered a single- electron transition with the major contribution from the Sm-. Experimentally.67) 317 (4.66).10) (4'52 223 (4.20) 403* (4.55) 388 sh i215 (.045 390 (. is due to the extent of 98% to the transi- tion of an electron from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO).40) 357 303 (4.|65 384 (4.50) 305 (4.29). 364 (3.29) IV 213 (5. transition.435 2t2 (4.52) 220 (4.47) (4. 217 (4.53).34). This transition is polarized along the x axis and" has an intensity and order of magnitude lower than the so + s * ~ . The calculations were made for the theoretically most probable four Z and E isomers with the s-transoid configuration in relation to the N--N bond in azines III and VIII not containing substituents in the arylidene fragment and. polarized along the y axis (the long axis of the molecule).54)]2938h 330 (4.60) 267 (4.37) 242 (4.17) 248 (4. The second transition.355 VII 216 (4.35).[293 (4.19) 230(4.] 295 (4.