161 REVIEWS Hexamethylenetetramine, A Versatile Reagent in Organic Synthe: Nikola BLAZEVIC*, D. KOLBAH Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Yugoslavia Branka BELIN, Vitomir SUNJIC, Franjo KAJFEZ Department of Biomedical and Biochemical Research, Compagnia di Ricerca Chimica (CRC), 1-33048 San Giovanni al Natisone (UD), Italy Hexamethylenetetamine eadily obtainable from ammonia and formaldehyde isa rather stable reagent with an adamantane-tike structure. In aeiic media the reagent can be cleaved 10 give C—Nesubunits oF ammonia + formaldehyde, These fragmenta tion produets can then undergo synthetically useful reactions ‘with appropriate substrates, The present article gives a summary ‘ofthe formation of hexaminium salts and their use forthe introdue- tion of amino and formyl groups. There follows a discussion ofthe use of hexamethylenetetamine or the synthesis of some Wwiaza- and fetraaza systems and for ring-losure reactions 10 form five. sic, ar seven-memabered ring ssstems 1 ntoduetion 2. Hesaminiam Salis 21, Salts with Acids Quaternary Salts of Hexamethylenetetramine Introduction of Amino Groups via Hexaminium Sal 4 Introdvetion of Form! Groups via Hexaminium Salts 1. Introduction Hexamethylenetetramine** (1; CyHizNai M.W. 140.19; mp. 285-295°, sublimation), is formed in nearly quantitative yield from the condensation of ammonia and formaldehyde"? atte eo 6 H,CO + 4 Ny = oath AS t Large scale preparations and properties of hexameth- ylenetetramine have been reviewed*, The compound is soluble in water, chloroform, ethanol, and some other organic solvents. In neutral, aqueous solution 1 remains stable even at elevated temperatures; ther- mal decomposition becomes significant only at 270°, + Author to whom correspondence should be addressed ** Other names used are hexamine, hexamethyleneamine, form amin, aminoform, urotcoping_1.35,)4etraazaadamantane, 1.35.74etranzatieylo[3 34.12” ecane, methanamine, 0039-7881 /79/0332-0161 $03.00 5. Formation of Triaza-and Tetraaza-Heterocylic Derivatives Ring Closure Reactions using Hexamethylenetetramine (61, Formation of Five-Membered Rings 2. Formation of Sit-Membered Rings 6.3. Formation of Seven-Membered Rings 1. Cancasions Hevamethylentetramin, ein stabiles Reagens mit Adamantan- Struktur, wird in saurem Medium unter Bildung von Bruchsticken mit -N-Bindungen sowie Ammoniak und Formaldehyd gspel ten, Diese Bruchsticke kénnen synthetsch wertvolle Reaktionen emgehen. Der orlegende Artike! pibteine Zusammenfassung Uber slic Bildung von Hexaminium-Salzen und deren Verwendung zit infdhrung von Amino- und Form-Geuppen, Weiterhin wind ler die Verwendung von Hexamethylenteteamin zur Spathese cinigerTriaza- und TetraazacRingsysteme sowie fr Ringschla- Reaktionen unter Bildung von 5.,6> und T-ledrigen Ring-Sjte ‘men bericht. Hexamethylenetetramine has symmetrical adaman- tune-like structure and is rather stable although dihe- tero-substituted methylene groups are known to be highly reactive. The chemical and steric equivalence of the four nitrogen atoms has been demonstrated by various physico-chemical methods®*. On protonation of one nitrogen atom, the hexameth- -ylenetetramine molecule looses its symmetry and var- ious acid-catalysed fragmentation processes may thus ecur, Depending on the conditions, two, three, or more carbon-nitrogen subunits can be formed, or the reagent can serve as a source of formaldehyde and ammonia, Thus. the reagent can be used in the synthesis of alicyclic or heterocyclic structures or itcan be employed to introduce functional groups into suitable molecules. ", Meisner, British Patent 7224 (1988); C. 4. $0, $019 19561, F. Messner, F. Schweidessen, U.S, Patent 2762800 (1956): A, 80, 15602 (1956) > F Meissner, ESchweidessen, U, A. Patent 2762799 (1956); 4.51, 2848 1957) © 1979 Georg Thieme Publishers162 ‘Nikola Bltevi, D. Kolbah, Branks Blin, Vitomit Suni, Franjo Kafe? Furthermore, hexamethylenetetramine forms com- plex salts with metal ions and organic and inor- ganic acids and molecular complexes with alkyl or aryl halides, phenols, and naphthols. These com- plexes can undergo decomposition under various conditions to give amines, aldehydes, or hetero- cyclic products. 2. Hexaminium Salts 2A. Salts with Acids Interactions of hexamethylenetetramine (1) with dilute organic and inorganic acids have been investi- ‘gated’. Less than four molecules of acid form donor- acceptor bonds with 1 even in the presence of a large excess of acid. The number of acid molecules bound to 1 decreases with increasing acidity of the acid (with formic, acetic, and chloroacetic acid 3 molecules of acid are bonded to 1, with nitric acid 2, and with hydrochloric acid 1. With hydrofluoric acid, complexes containing !-4 molecules of HF per molecule of 1 are formed®; the structures of these salts have been determined by X-ray diffraction ana lysis On heating at 20° hexamethylenetetramine (1) and sulphuric acid form (wo salts, 2 (I): HzS0.-6H:0 and (1)-H,SO.-8 H20 which are stable up to 180" With salicylic acid 1 forms a 1:1 molecular complex!®, These complex salts as well as those of 1 with urea have found applications in human and veterinary therapy!" Hexamethylenetetramine (1) forms hydrogen-bonded 1:1 complexes with {.3-dihydroxybenzene (88 " Yield) and {.3-dihydroxy-S-methylbenzene (80% yield) and a 1:2 complex with 1,3-dihydroxy-2, dimethylbenzene (73 "« yield)!?, ‘The formation of iron(II) complexes in p-xylene with various ligands has been investigated; of the nitrogen-containing ligands such as urea, 1.6-di- aminohexane, hexamethylenetetramine (1) and phos- phorus-oxygen ligands such as triethyl phosphate, 1 was found to be one of the most powerful complex- ing agents'* + Ullmans Eneyhlopidie der tecnischen Chemie, 3. Band: Urban & Schwarzenberg, Minchen: Berlin, 1953, p. 168 > AF, Andersen, Acta Crystallogr 10,107 (1957, © LN. Becka, D. W. J. Cruickshank, deta Crstallogr. 1082 1960, > DI. Belkin, LV. Belkina, M. J. Rozkin, Zk, Ory. Khim, 1,655 (1970, "ACA, Ennan, O. M, Brazowskaya, ALN. Chotobates, Zh CObhck. Kh, 48,706 (1975) © A Ennan,O. M.Brazovskaya, VA. Laps, LP. Berezina Zh. Obs. Khim. 46, 16 (1976) "© ‘AcAkbacr, Zh, Prikl. Khim. 48, 1638 (1979, 1 TE, Morgov, Farmukologha, Bd. Kolos, Moskva. 1969, p. 3a 22. Quaternary Salts of Hexamethylenetetramine Alkyl halides react with hexamethylenetetramine in chloroform to give the quaternary salts 2!°. The starting materials are soluble whereas the products crystallise out, further purification of 2 is usually (Os fe (3 In by 1 ts a-Halogenated tertiary amines react with 1 to give the quaternary salts 3a—e which undergo hydrolysis in aqueous solution to generate formaldehyde'*. The stability of the salts 3ae in air increases in the order 3a<3b<3e and all are sensitive to heat N Hk Xe vary cnycun NJLEN + XecHy on Se Stach , 2 13 Hexamethylenetetramine (1) can be used as a catalyst in the preparation of urea from ammonia and carbon dioxide"*, The reagent serves to increase both the yield of urea and the degree of utilisation of ammonia, ©.6:6: 1 molar mixture of ammoniajcarbon dioxi: de/hexamethylenetetramine gives rise to an 80% yield (based on ammonia) of urea. ‘ NH Nia + cop ts om SNHe 4. Introduction of Formyl Groups via Hexaminium Salts As shown in Scheme A, aldehydes can be obtained from the reaction of hexaminium salts 2 derived from alkyl and aralkyl (mostly aryimethyl) halides. This process, known as the Sommelet reaction’”** was reviewed in 1954", The Sommelet reaction pro- ceeds in three steps: (1) formation of the hexaminium salt 2, (2) hydrolysis of 2 at pH 7 to give an amine 14, and (3) reaction of this amine with excess 1 to sive the aldehyde 15 (Scheme ©) SY. Besace, A. Marszak-Fleury, L Marseak, Bull. Soe: Chim Fr. 4 1468 (1971, Ref. #,p. 204 and coferenees cited therein. 3 WLI. Roth, A. Brandau, Arch. Pharm. 292, 761 (1959) HJ. Roth, Arch, Pharm. 292, 76 (1959), 88 E Reimann, Justus Licigs Ann. Chem. 1978 (1-8) 1252 364. Surbaey, V1. Kucheryavyi, L. M, Kozenko, Zh, Prikl Khim 42, 2528 (196) 8M Sommelet, CR dead. Sei Paris 87, 52 (1913) 2M, Sommeet, Bull. Soc. Chim. Fr 13, 1085 (1913. 3° S.1, Angyal, B.C. Rassack, Nature 161, 723 (1988), “© SJ. Angyal, D.R. Penman, G. P. Warwick, J. Chem. Soc 1983, 17 “" BUR, Snyder, , Swaminathan, H. J. Sims, J. Am. Chem Soc. 14, 110 (1952)‘ a Hod cccnee > Lf decnne x0 as La ET 1 finer + vec 4 HOR + NH + HAACHS 15 Scheme C Studies have suggested that the Sommelet reaction involves an oxidation-reduction process as shown in the last reaction in Scheme C2. Essentially, the amine 14 is oxidised by methylimine (a sub-unit of hexamethylenetetramine) to the aldehyde and ammonia, Later*®, it was suggested that the reaction includes a hydride transfer step. Table 3 Selected Examples ofthe Sommeet Aldehyde Synthesis wc X Soest Yill Re Ud te ee " on ees fe eunoke Te oe te pices fo _ yw 2-Formylnaphihalene To a solution of technical grade 2-methylnaphthalene (71.02. (0.5m) in tetrachloromethane (450g, analytical grade) in a {1 twornecked Mask fited with a mechanical stirrer and a reflux ‘condenser N-bromosuccinimide 890g, 05 mol) is added and the resultant mixture is heated with stitving under relox for 16h, The pevpitatedsuccinimige isiltered of and the solvent removed from the trate under reduced pressure, The resultant brown «il is disolved in pure chloroform (300ml) and this solution ‘is rapidly added toa stirred solution of preformed hexamethylene tetramine 40g. 05mol) ia pure chloroform (150ml) in a 21 three-necked flak fited with an_addition funnel, reflux con- denser, and a mechanical stirrer. The addition rate is regulated to maintain a vigorous refiuy, subsequenty the mixture is heated under reflux for 15h, cooled, and filtered. The powde-lke solid hich separates almost immediately on commencing the addition is fitered, washed with cold petroleum ether (2 100ml, bin 40-0"), and dried to give the hesaminun bromide; yield: 146.5 (9%) mp. 174-176, “This producti heated in $0 % acetic acid 780m under reflux for 2h, then concentrated hydrochloric acid (10m) is added and reusing i continued for Smin, The mixture is cooled, Hexamethylentetramine, A Versatile Reagent in Organic Synthesis 165 extracted with ether, the solvent removed from the exteat, and the residue exjstallsed from the minimum amount of w-exane to give white crystlline 2ormytnaphthatene: yield: 488-5078 (77-80% based on hexamiaium bromide, 64 based on 2-methy saphthalene; mp. 8559.5 A generally accepted mechanism for the Sommelet reaction was proposed later**° and i illustrated by the example*” in Scheme D. a (Cl Serene BrCl indi 1 16 outs gots 7, er (fe “ey |_Ponr ew ye a A gi cos HS -transter, in “yy one tet 7 Bre 8 Gt ats os | t ie) corcingey Hota? Moa” oer aT & ae a c 7 18 Scheme D The hexaminium salt A, derived from halide 16 and 1, undergoes hydride transfer to form the carbenium salt B which reacts with the mucleophitic hydroxy ion present to yield C which, in turn, undergoes cleavage to give the aldehyde 18 and the amine 17. Under similar conditions, secondary halides, or the amines formed as intermediates, undergo Sommelet- type reactions yielding ketones. Thus, x-ethylphenyl- amine on reaction with formaldehyde, followed by hhexamine, gives acetophenone, Following. this “HM, Doukas, J. Chem. Educ 3h 21 (1954) © R Durand-Dran, M. Lecoeg, R. Quelet, C. R, Act Paris 280, 27271960) 4. Schnekenburger, R. Kaufmann, Arch. Pharm, 304, a7. © B.Le Henafl C, R. Ae. Sei. Paris 283, 706 (1961) “ P.Le Henall, dvr. Chim. 7, 367 (1962), *7 4, Schnekenburger, R. Kaufmann, Arch, Pharm, 304, 25 «97, Sei166 route benzophenone, fluorenone, and. some unsat- urated alicyclic ketones were prepared". Usually the yields were low and this type of Sommelet reaction was not studied extensively. Using hexamine as a reagent, itis possible to intro- duce a formyl group into various aromatic or hetero- aromatic compounds. These reactions cannot be regarded as purely Sommelet reactions, although the conditions applied are very similar. One type, termed the Duff reaction**, allows the preparation of ortho- hydroxy aromatic aldehydes. The procedure consists, intreatment of phenols with hexamine in glyceroboric acid (HBO; in dry glycerol) or glacial acetic acid. The reaction*® seems to involve an aminomethylation, forming the secondary amine, which undergoes the Sommelet reaction to yield an aldehyde as shown in Scheme E for p-methyiphenol (19), for further exam- ples see Table 4, 4 "Ey ; “=a oH ‘OH Ho’ 9 20 4 HBC, Cy SOCIO" 2 ee oe remy Scheme E 22 23 A modification of this reaction uses trifluoroacetic, acid as solvent and a variety of aromatic compounds 24, including simple hydrocarbons, can thus be con- verted into aldehydes 25%. (Care ce It 1 24 25 Reaction conditions are milder and yields are higher than in the Duff procedure**-**:**. A high para-regio- selectivity is observed when the formylation is con- ducted under these conditions. Some recent examples are summarised in Table 5. Dui, J. Chem, Soc. 1941, $47, Daf, V.J. Furness, J. Chem, Soe 1981, 1512, Dol. J. Chem. Soe. 1948, 276 Ligget, H. Dich, Proc. fows Acad. Sei $2, 191 (1945) 41 100947, igeuner, K. Jelinek, Motatsh, Chem. 9, 297 (1959, rt, W. Krause, Arch. Pharm. 298, 148 (1965) Nikola Blatevit, D, Kolbah, Branka Belin, Vitomit Suni, Franjo Kailed Table 4 Selcted Examples of the Dull Reaction Substrate Solent Aldehyde Yield Referens won mc ow a 60 © eo OS 7 4 wo0y okt ies wo oO g sao sa vide a09 oe Siew! v0 soe cpm woe "8 wo Yo one one, eX) worcmar vo-L oo 7 cone one, ove, vonertt Droo sos co” “ow cits oH Table & Formylation of Arenes 24 with Hexamethylenetetramine (a) in Trifuoroacetie Acid" Yield we Ratoof Produ uw VTFA 2S. {%} come on 1% we oan 0 Q te 2 W weoX) oan wc0-)-cH0 ™ we aa tH & ve aMatch 1979 Table (continued) rene Ratioof Product, Yield u 1TFA va an » 2s 0 1m 0 6, “0 nt Ho -cHo %6 we ne The first step is probably the formation of methyl- imine or methylenimine derivatives, which are precur- sors of the aldehydes. Imines were isolated in some instances, eg, when the reaction products from toluene were subjected to rapid hydrolytic work-up. In this case the para- and ortho-toluimines were obtained predominantly. Whether such products are formed by rearrangement of the methylenimine Ar— CH;—N=CH,, or arise through exchange reactions involving methylamine, is not yet clarified. Other kinds of intermediates could be isolated under non- hydrolytic conditions at room temperature. Thus, a mixture of 2,6-xylenol, hexamine (1), and triluoro- acetic acid kept below 30° for 3h gave a complex mixture of products, from which the dibenzylam- ‘monjum salt 26 (41%) and the hexaminium salt 27 (15%) were isolated. Hy Hy e Ho: CHy~Nly—chy ‘OH CF,COo® ‘Cy 26 rT Hs 2 aaa crscoo? 27 Intermediate formation of salt 26 clearly shows that this process is related to the Sommelet®' and Delé- pine’? reactions. Some heterocycles, such as indoles*” and azaindoles**, can be readily formylated with hexamine (see Table 6), W. E, Smith, J Org. Chem, 37,3972 1972), LN. Ferguson, Chom, Rep. 38, 230 (1946) C. BH. Allon, G. W. Leubner, Organic Syntheses, Coll Vol 1V, 1963, p. 866 A. Chatterjee, K. M. Biswas, J. Org, Chem, 38, 4002 (1973) AJ Verbisar, J. Med. Chem. 15, 199 (1972, T. Urbanski, Chemistry and Technology of Explosives 3, 87 i967, L Stefaniak, T. Urbanski, M. Witanowski, H.Januszewsk, Rocz. Chom. 43,1687 (1969), “ J-McKenna, J. M. MeKenna, B.A. Wesby, J. Chem. Sac 1970, 867. Hxamethylentetramine, A Versatile Reagent in Organic Synthesis 167 Table 6 Formylation of Indoles and 7-Azaindole (U-Pyr rolo(23+b]pyridine in Acetic Acid Subsirae Produet——“Yed(%) Reference ~ cho on sos - wo Oem Op % ” A solution of 7-aaindole 236. 0.20 mmol) and hexumine 420g. ‘030mmol) is heated under reflux with siting for 6h in 337s acetic acid (250m, The resultant solution is diluted with water {$00 mi), and the product allowed to exystallise overnight. Rees: tulliation of the crude product from water gives long white oles: yield: 14.9 g (S076); mp. 216-2188, 5. Formation of Triaza- and Tetraaza-Heterocyelic Derivatives Using various agents, it is possible to decompose hhexamine into diverse mono- or bicyclic derivatives which are sometimes stable enough to be isolated and studied"®-°°", The reagents used are various bases, acids, as well as several phosphorus or sulfur containing agents The condensation product of benzylamine and hex- amine, 28, polymerizes when heated for an extended period", Depending on both temperature and time, different mixtures of produets result, eg. on increasing the heating time from 75 to 150min the average molecular weight of the condensation pro- ducts decreases from 314 to 218 and the yield from 99.2 10 98.5 %°2 gC ye Fi 130° 6 Cats CHa 28 In the mixture of products resulting from the conden- sation of 1 and benzylamine, 29 was identified and converted into the open-chain isomeric products 30 and 31 according to Scheme F* He "ELV. Zakhatoy, A. Baezin O, P, Murashova, ES, vanov, IN. Podobaey, N,V. Lardash, Zh, Prikl. Kinon, 47, 2381 11974) © G, Olkoks, Geterocikliteskle Soedinenia & Polimeri na jh osnove, Mir, Moskva, 1970, p. 136. “+ O.P. Murashova, LI Viin,V.R. Rozenberg, G. V. Motsare, V. 5. Kolbasov, Vu. A. Safin, R. V. Dzhagatspanyan, Zh rik. Khim. 48,1803 (1975)Nikola Bla2evg,D. Kolbah, Brunka Belin, Vitomir Suni, Franjo Kajler [> YeoN-cHe-n—ciis Gti cobs Gt Gt GH i N : 3.CéHs-CHy-N=cH 2, fan) | Cots CoH Cats Catto "Scot catg 30 28 29 Scheme F Other authors" proposed a different scheme for the same process (Scheme F°) ie-cs A 8 opts-cHy-nitp > 2 on ste, | Ces —CHy CH Cols 29 | Cot. SN-CHEN-CHy- cobs + CQH5-CH»-N=CHe + CoHs—CHy-N=CH—Cels ‘Scheme F’ tee 32 28 33 The first sep yielded 75 % of compound 29 on heating — = the reactants for 0.Sh at 190°, or for 2h at 1707. ‘The unseparated mixture of products obtained when the above reaction is carried out at 180-200° is usually designated BA-6, This mixture was shown to protect metals against corrosion under acidic con- ditions®**, By treating hexamine with phosphorus pentachloride in a 1:3 molar ratio, Fluck and Meiser"* prepared ttis{chloromethy!Jamine (34) in almost quantitative yield. They assumed that compound 38 might have been formed as a second product. ; (r bn cat 0°, +3 PCy SBE, NicHpmciys + NICH2WPCIahs 35 Daigle et al.®*°*-* prepared a monophosphorus analog of hexamine, 36 (40% yield) from hexamine and tris{hydroxymethy!phosphine or tetrakis[hyd- roxymethyl]phosphonium chloride. Oxidation of 36 with hydrogen peroxide at room temperature gave phosphoadamantane-7-oxide (37). Po. renon 8 CO hon non ENT oy Pictt-omn, c® Le 1 36 © GL Nemehanimova, K. E, Peredeskiy, Zh. Prikl. Khim, 4, 1879 1974. Compound 37 was quaternised by refluxing with iodomethane in methanol/ethanol, to give the azonium oxide 38a, Compound 36 on refluxing with iodomethane in acetone gave the simple azonium ‘compound 38b. Addition of sulphur to 36 gave com- pound 38¢, which, after refluxing with iodomethane, gave 384, 1,3$-Triaza-7hosphandamantane (361: A solution of tetrakis(hydroxymeyT}phosphonium chloride (234.0147 mob, previously made neutral by the addition of $0". aqusous sodiom hydroxide (63.85 g 0.8 mall smined with 37° ‘aqueous formaldehyde (400g, Small Hexamine (140g. T mol) i fidded and the resultant solution is Het at room temperature ‘overnight, After partial (80%) evaporation of water, followed by filtration. and washing with cold ethanol (200ml) the product M6 is obtain yield: 1063 8 (727 Daigle et al.” prepared a sulphur and phosphorus- containing derivative of hexamine, 2thia-1,3,S-triaza- T-phosphaadamantane-2.2-dioxide (39) from tris- [hydroxymethyl phosphine, sulphamide, and hex- amine in excess formaldehyde (Scheme G) and con- verted it to 40 and 41 as before, . Fluck, P, Miser, Angem. Chem. 83, 721 (1971): Angew ‘Chem Int id. Engl 10,653 (1971); Chom, Ber. 106,69 (1973) © Dod Daigle, A. B Pepperman Je. S.L. Vall, J. Heteroeych (Chem, 4, 407 (1978), ** Dal Daigle A.B. Pepperman Je, U.S. Patent 391189 1973) 04, BL, 120788 (1978) © D.J. Daigle, A. B, Pepperman Jr, J. Hereraeyel. Chem. 12, 579 (975), J. Daighs, A.B. Pepperman Jr, G. Bondreaux.J. Hetewe vel Chem. AF, 1O8S (1974. 78 WE: Bachmann, N.C. Beno, J. Am Chem. Soe. 13,2777 (snMarch 1979 Degradative nitrosation of hexamine in aqueous solu tion was carried out by simultaneous addition of hydrochloric or acetic acid”"-”? and a solution of Hexamethylenetetramine, A Versatile Reagent in Organic Synthesis 169 o o og . 40 ‘i 60 { "| + PICHs-Olily + HeN-SOp-NHy “> fl | om lw os aa J 39 fe (le Scheme G nN ong sodium nitrite, The main factor determining the nature of the products is the pH of the solution. 41 Thus, in hydrochloric acid at pH 1 the trinitroso compound 42 (50 % yield: mp. 104.5-106°) is formed exclusively, at pH 2a mixture of 42 and 43 (mop. 196 200°) is obtained, between pH 3 and 6 only 43 (72.76% yield: mp. 2035-207) is formed”! Variation of the molar ratio of hexamine:hydro- chloric acid:sodium nitrite results in formation of pure42(1:6:1-3),a mixture(m.p, 155-204°)of 42 and 43 (1:3:3), or pure 43 (1:6:6)"! he q Cf NS, one, . 44 (7) swormeonnmano) MON bna/ : or ° Ory v ‘, ‘O ae no, Nor toa 45 46 * H, Kezikalla, H. Pohlemann, T. Toepel. German Pate 1004618 (1957): C. 4. $3. 1807S (1959, 28 Belgium Patent 613501 (1962): C. 4. $8, 1618 1969, WE. Bachmans, W. J. Horton, EL. Jenner, N, W, Mac Naughton, LB. Scott, J. A. Chem, Soc. 78 2769 (1951), W. E. Bachmann, EL. Jenner, J. Am. Chem Sov. 78,2773 ssh. 1. Stefaniak, T. Urbanski, M. Witanowski, A. R. Farminer G.A. Webb, Tetrahedron 3, 3775 (1974), When acetic acid was employed, however, the only product obtained over a wide range of conditions was the dinitroso compound 437, jtrsotrimethykne- pydro-1 3.57-tetrazocine (43); examine (7 0.0S mo) is disolved ince water (200m), after which a solution of sodium nitrite (15g, 0.22mol) in water (SOmN ond 6 normal hydeoshloce acid are added simultaneously, Hyd tchloric acid added at the rate necessary 10 maintain the sized pl, The mixture i kept at O° for pH 2, 30min; pH 1 4Smin; pH 3, @min: pH 4, 5 days. The products are then collected by filtration; yekd at pit 1: $0" of 42: mp. 1045106": at pH: 2% of 43; mp. 207, Hexamine reacts with nitric acid in the presence of acetic acid and ammonium nitrate to give highly explosive cyclotrimethylene-trinitramine (44), also called RDX, in 82% yield”*"5. The reaction was studied in detail: two main types of cleavage of ex- amine were observed and products 44-47 were identified. Or NO> NO ais gs 47a 9 NO2 NOx yor i + HyC-C-0-cHy-N~cHy NCH, -N=CH,-N=CH,~O-C~CHy 47> The study of this reaction suggested that one type of cleavage might produce compounds containing three amino nitrogen atoms, such as RDX 44 and the linear trinitramine (1,7-diacetoxy-2.4.6-trinitro- 2.4.6-triazaheptane 47a). Another type of cleavage might lead to compounds with four amino nitrogen atoms such as DTP 45, HMX 46, and the linear170 [Nikola Blatevie, D, Kolbah, Branks Beli, Vitomir Suni, Franjo Kajler tetranitramine _(1,9-diacetony-24.68-tetranitro- 2,468-tetraazanonane 476), The first type of cleavage is favoured at high concen- trations of nitric acid and acetic anhydride in the reaction mixture. The second type of cleavage occurs, at lower acidity. These results are similar to those obtained in the reaction of hexamine with nitrous acid in aqueous solution. Under highly acidic condi- tions, trinitrosotrimethylenetriamine (42) is the main product, whereas, at lower acidities 43 is formed”? Stefaniak and coworkers” the 1,35,7-tetraazabieyclo- 46 and 48 for structural studies. also prepared some of {-nonane derivatives Keer no? a8 ‘The reaction of hexamine with acetic anhydride has, been studied recently by several authors”*78~*! and can be formulated as in Scheme H. ¢o-n A set Ya Le 9 a co-r th + R-cOH0 LK gone : (50 NN, Scheme H R-CO" ‘cO-R The yields of 49 never exceeded 45%. Siele et al.” reported a simple procedure for the preparation of 50a (Table 7) in >90% yield. This procedure was “Table 7 Products of Acylation of Hexamine (1) Prod RAcylating Temp Ret vet ant erature 49a CHy (CHCORO/NGOH TD 492 CH; (CH\COMOINHOAG 5.1" 179 492 CH; Ketone/NaOAc 15.20" » $b He) HUCO,OMNaDAC 0-10" » $e Calls" (CallCO om 2» BE CHS Or ee) Be Calls se noe Sa CH 90.100" 78 0b GH 90 100° *% Me mCAHy (eCaH-COLO 99-100" % . B Hodge J. Org. Chom, 37, 320 1972) > M. Warman, VI. Sile, EE. Gilbert, J. Heterocye. Chem 10,97 (1973). % V-I.Siek, M. Warman, EE, Gilbert, J. Hetoroeye. Ch 237 1974 and references cited therein, © ¥. Ogata, A. Kawasaki, The Charity ofthe Carbons! Grown, Vol, 2, I, Zabicky, Ed, Interscience, New York 1970, p 31 also applied for the preparation of the analogues 9b- Using acetic anhydride, water, and hexamine, at 5 10°, 49a is obtained in 65-73% yield (based on hexamine). The yield of 49a rises to 80%, when the reaction is conducted in the presence of an inor- ganic base, in an amount equivalent to the acetic acid formed. The effectiveness of water in promoting the formation of 49 presumably results from the equilibrium shift shown in Scheme I®°. Compound Slis probably the species undergoing acylation when water is present , - ne NS Re {RCO}, Oe we SS A " do-r 1 fi 5 Scheme I It was found that ketene could be substituted for acetic anhydride in the preparation of 49a; y as high as 65% were obtained. ‘Acetic anhydride 3068, 0.3 mol) is added dropwise over 60min with stirring and cooling at $10" to a slurry prepared from hexamine (14g, 0.1 mo), ammonium acetate (6,2. 008 ol), and ‘water (7m. The solution finally resulting from this procedure is sired at 10° for 30min and evaporated to dryness 10 give crude 49a; yield: 252g. Reerystalisation fom acetone gives pure 9a; veld: 21.2 (100°): mp. 197. Yoshida ct al! have studied the selective ring opening of 1,7-bis{sulphonamido tetraazabicyclo- (33,1Jnonanes 52 using the electrophilic species NO® and NO3. In these experiments the authors obtained 1,3,5,7-tetraazacyclooctanes as products. ‘The starting compounds, namely the various bis[sul- phonamido|tetraazabicyclo[3.3.1 Jnonanes, were obtained by reacting hexamine with arenesulphonyl chlorides (Scheme J}, g A ‘Scheme J Table & Sulphonamide Derivatives of 1.35,7-Teraazabicyelo [331 Joonanes** at Yield (%] 4HLC—CHa 46 Calls 5% OCH 8 eC, 8 SOWN—CH utMarch 1979 Treatment of compounds 52a and S2e with 70% nitric acid and acetic anhydride at —10° gave consi- derable amounts of resinous products; compound 53 was the major product, with the admixture of ‘a small amount of 55. §0.-Ar ON AN Aco Wn one W a Ar N ‘81-802 NOp $0,-A yn S0,—Ar 53 Shae $00-ar $02-ar ON AN N a Oi 1) ono, 1 Ano; Y S0;~ar 55a-e STa-e Liquid dinitrogen tetroxide, on reaction with com- pounds S2a-e, gave the tetrazocine derivatives ‘S4a-ein 45 10 85% yields. The same reagent in combi- nation with sulphuric acid on reaction with S2a-e led to the formation of triazacyclohexanes $5a~€ and tetrazocine derivatives 56a-e. Compounds 562- € could be easily transformed to dinitro derivatives STa-e with excess 99% nitric acid, The tetrazocine derivatives, $4 and 56, may be sub- jected to the following transformations to 57, which show the interrelationships among the three groups of products (Scheme K), GOr-mr tuning wey 9 ak M250. Onna \ Kno } jor S02-ar Ory 54 4 eo SA v0 fps ed $0)—-Ar ; 56 se nos, ON Symon Soprar Scheme K 87 According to Scheme L, the tetrazocine derivatives 56 were cleaved by acetic anhydride/acetic acid, to give compound $8; similar treatment of $4 gave 59 in 59% yield. 5H. Yoshida, 10,299 (1973 © B, Resler, Monatsh. Chem. 98, 1512 (1967) Sen, B.S. Thyagarajan, J. Heterseycl, Chem Hexamethylenetetramine, A Versatile Reagent in Orgunie Synthesis 1m sora ONS AcOH ies ft OAc ay) ste, gop v0 ct One ' Sor-ar 56 58 sores sora rh é CNW sconitero owen’ 08e er ae cea eo S07 54 59 Scheme L Compound 57, apparently, did not react with acetic anhydride and acetic acid. These results show that the cleavage of compounds $4 and $6 occurs at the carbon-nitrogen bonds adjacent to the N—NO fune- tion, but not at those adjacent to N~NO:, which ‘confirms the great stability of the O2N—N—CH. NNO: grouping 6, Ring Closure Reactions using Hexamethylenetetra- mine examine can be used in making different ring sys- tems containing five, six, or seven ring members. Thus imidazolo, isoindolo, quinazoline, quinoline, and benzodiazepine derivatives were obtained by hexamine-induced ring closure. Generally, the pre- ccursors for such compounds should have two reactive functionalities. which may react with hexamine in ‘one of more steps, yielding various heterocyclic com- pounds, Usual starting compounds are o-quinone, halo ketones, or amino ketones. During these reac- tions hexamine decomposes, giving fragments of dif- ferent size, down to a —CH=N— group. 61. Formation of Five-Membered Rings Several chloro, bromo: and —_nitro-1H- phenanthro[9,10-dJimidazoles 61a-f were synthe- sised from phenanthroquinones 60, ammonium ace- tate, and hexamine (Scheme M)? 111-Phenanthro{9.10-dimidazoles 612-f; General Procedure: To a stirred solution of phenantheoguinone (2mmol) in boiling lacial acetic acid (25m), ammonium acetate (38g. 49mm) Js added, followed by hexamine (03928, 28mmol) dissolved in glacial acetic acid (Smal). The resultant solution is heated for 1 huthesolventevaporaed in vacuo, and the erude product tise from ligroin or glacial actic acid; yids: 61-80 Product are obtained by rerystalisation from methanol Starting from 2-chloroacetamido-S-chlorobenzo- phenone, the hexaminium salt 63a was synthesised®?, which decomposed in alcoholic solution giving bis-17 ‘Nikola Blarevit, D. Kolbah Brana Belin, Vitomic Suni, Franjo Kayfer 4-one derivatives 64 and 65 Rt R' Re Re “ hs Re 600-1 iat Scheme M HP k aM, mn, ohh CIS 9 SK No? cr or Jem Cots Cots 62 63a Q 0 Nant C2MOH, NNN ON, cr 7 ry Cots Cas 64 Cots ‘Scheme N 65 The unstable compounds 64 and 65 yielded 1.4-ben- zodiazepine when boiled in alcohol®®. To prove that the intermediates immediately preceding the closure of the seven-membered ring do indeed possess struc tures 64 and 65, authentic samples of these com- pounds were synthesised by another procedure“ from 2-glycinamido-5-chlorobenzophenone (66) and compared with the original products er Dauth and Becker*® developed a method for the preparation of 1,3-dihydroisoindole (69) via a hex- aminium salt 68. Oc COQ)» VEN 67 x= oe 68 WeucsHHon, OO« 69 62, Formation of Six-Membered Rings Syntheses of six-membered nitrogen heterocycles by incorporation of one or two nitrogen atoms from hhexamine, are scarcely mentioned in the litera- ture***. Thus, 2-substituted benzyl bromides 70 form stable quaternary compounds 71** with hex- amine in acetonitrile. Inchloroform solution contain- ing small amounts of water or ethanol, however, decomposition takes place, yielding the aldehyde 72 When compound 70 contained a carbonyl group in 2-position of the side chain, the main products formed were isoquinolines 73, accompanied by minor amounts of aldehydes 72 (Scheme O). pean CHC» H/C HsOH, R wy cones OY OLE % | 72a. T3a-c 1 00 Oo Scheme O b © Recently the formation of several quinazolines fol- lowing the same reaction pattern was described®”. 2-Amino-Ssubstituted benzophenones —74a-€ reacted with hexamine, in the presence of ethyl bro- moacetate to give quinazoline derivatives 7Sa-c and 6a, b according to Scheme P. SN, Blazevie, V. Sunjé, 1 Crvelin, D. Koltah F. Kajfet J. Heterocye. Chem. 9. 831 1972 % Syiss Patent 465621; C. A, 7, 61.382g (1969) "5 €!Dauth, H. G. O. Becker, J. Prakt. Chem. 312, 440 (1970) "HL Mahe, B, Gusowski, Chom Ber. 106, 2485 (1973) © N. Blaevig, M. Oklobdaia,V. Suni, F. Kaji, D. Kolbab, Acta Pharm, Jost 28, 223 (1975.March 179 NH syer—cHy=COOCHs/R-OH, ra Cos, Tha-e 8 i le Sy eA + LU Cos Ces T5a-c 76a,b x x Xx + NO) eNO, CHOC aa Gt No: Ghats |b hy fae Rot Scheme P It was found that benzophenones with electron- accepting substituents (74a, X = NO.) gave a mixture of dihydroquinazoline derivatives 75a-c. In contrast, benzophenones with electron-donating substituents (X=Cl, CHa, 74b-e) gave only quinazolines 76a, b. When benzophenone-imine derivatives 77a-e were reacted with hexamine in boiling ethanol, similar eyclisations occurred, which led to heterocycles with three condensed rings, i.e. 9-chloro-10b-phenyl- tetrahydrooxazolo[2,3-d]quinazolines 78a— NHR! HQ RE _WfeahsoH, reve ev nA Cos TTa-e 8 BOR ® a H H H « » cits Hn H 1 © CH cH oH 7 a CH.CHLOH H u s& e cH Hq 9-Chloro-10b-phenyl-23,56-ctrahydrooxazola[2,3d}qulaazolines mee ‘Compound 7 (347 mmol) and hexamine (140 mmol) ae dissolved in 96%scthanol (80m!) and heated under ceflux for 48h. Thereafter the ethanol is completly evaporated in vacuo. The dry residue is dissolved in water (200ml) and the solution extracted with Hexamethylenetetramine, A Versatile Reagent in Organic Synthesis 173 ‘benzene (150m!) The aqueous layer is rextracted with another portion of Benzene (150m), and the second extract added 10 thelist The combined extracts ae washed with water (3 100m), dried with sodium sulphate, freed from solvent by evaporation, and the residue is crystallised from a suitable solvent. ‘The product from 2-naphthol (79) and hexamine, described by Galimberti and Erba®®, was incorrectly formulated as bis{2-naphthyloxymethy!]amine (81). Burke et al.®? described this product as an o-substi- tuted derivative of 2-naphthol, 82. Later, Mahrle et al.*® defined the same product as a Mannich base 80, ie. a compound with one additional ring of the dihydro-1,3-oxazine type. cote 818 (63. Formation of Seven-Membered Rings Hexamine was widely used for cyclisation of 1 4-ben- ‘odiazepines, compounds belonging to one of the ‘most important group of agents with central nervous activity®®, No mention was found in the literature of the use of hexamine in formation of other 7-mem- bered nitrogen heterocycles. The broad spectrum of medical applications of 1,4- benzodiazepines triggered the development of a var- iety of methods for the synthesis of these com- pounds’'-%, The crucial step in various syntheses of I -benzodiazepineis the introduction of the future Ned nitrogen atom, linked to closure of the seven- SP. Galimbert, C. Erba, Gazz. Chim, Hal 77, 378 (1947) W. J. Burke, M. J. Kolbezen, R. J. Reynolds, G. A. Short, J. Am, Chem, Soe. 78, 805 (1956) ©. Randall, W. Schallek, L. H. Sternbach, R. Y. Ning in M. Gorton, Ed. Medicinal Chemistry 4)III Psychopharmaco- logical Agents, Academie Press, 1974, p, 175-281, © LOH Sternbach, E, Reeder, J. Ong. Chem. 26, 111 (1961). LH, Sternbach, R. J. Fryer, W. Metlescs, E. Reeder. G, Sach, G. Saucy, A. Stempel, J. Org. Chem. 27, 3788 (1962, G.N. Walker, J. Org. Chem. 27,1929 196). S.C. Bell, T. & Sulkowski, C” Gochman, S, J, Childress, J. Org. Chom 2, $62 (1962) “GA. Archer, L. H. Stembach, Chom, Ree. 68, 747 (1968),174, Nikola Blazevit, D. Kolb ‘membered diazepine ring. The reagent most {re- ‘quently used in this step is ammonia, but syntheses Using ammonia often result in low yields and impure products. The inal step in the synthesis of 1 4-benzodiazepines is very similar to one of the procedures used in the syntheses of an a-amino acid in which hexamine was reported to be a suitable reagent”®, It was, there- fore, assumed that hexamine might also serve well in the synthesis of 1,4-benzodiazepin-2-ones®™ °°” 83 and 1,4-benzodiazepines?*-°? 86 and 87. The method, as finally adopted for the benzodiazepinone synthesis, proceeded in two steps: the first step was the formation of a hexaminium salt (see Scheme 'N), which, in the second step, underwent aleoholysis, to give the desired 1,4-benzodiazepine-2-one deriva- tive, The study of the reaction pathway shows, that ring closure of 1 4-benzodiazepines using hexamine ismechanistically different from that using ammonia. Large rate differences were observed in the solvolysis, of hexaminium salts, depending on the substituent on the amino group in the starting 2-aminobenzo- phenones. N-Unsubstituted 2-aminobenzophenones undergo decomposition giving products of the imida- zolidin-4-one type (see Scheme N). The imidazoli- dinone ring, then, recyclised into 1,4-benzodiazepin- 2one, as shown in Scheme Q. Nit Hct a cr er N Cats Cats 65 830 Scheme Q On the other hand, N-1 substituted compounds'* gave high yields of 1 4-benzodiazepin-2-ones in very pure form (Scheme R). No intermediate or side product formation was. observed in these instances. Only when the amount of alcohol used in solvolysis was insufficient, was it possible to identify compound 84 as a side product. This compound was described earlier'°"-"°" as being by-product in the cyclisation of 2-haloacetamido-5- chlorobenzophenone into 1.4-benzodiazepin-2-one using ammonia, In addition, a base-catalysed recycli- sation of N-4-acetyl-4-benzodiazepin-2-one into the ‘N-acetyl derivative of 84 has also been described"? We suggest that the base-catalysed conversion of 63 into 83 produces an intermediate with a positively charged nitrogen atom, as indicated in Scheme R. Branka Belin, Vitomir Suni, Franjo Kae? cy a er a Cots 83b ‘Scheme R or [evson Hs “Fc gt f * 6 ‘wy a Gt no cr NH Cots 84March 1979 Heating hexamine with 83 under the same conditions as used with 63 gave no 8&4, which excludes the recyclisation 83-+84. Various fragments formed by hhexamine decomposition might be imagined as base catalysts, acting via ammonia or methylenimine, but an intramolecular C-3 deprotonation of 63b by secondary amino groups from partially decomposed hhexamine residues is also a possible pathway. It seems, that differences in conformation between the isomeric structures A and B resulting in H-bond formation are of prime importance. R Hey We Np cr ct cr ao Cas Cats A 2 Space-flling models suggest that conformation B cannot be achieved when R=CHs, but is possible when R=H. Table 9 presents the yields in 14-benzo- diazepine-2-ones, diversely substituted, to illustrate the efficiency of the “hexamine-method” for 1,4-ben- zodiazepine-2-ring closures. 2 ge f we ol, + 62 83 Table 9. 14-Benzodiazepin-tone Ring Closures with Hexamine Staning x Prod- Yield Ref. compound wt [%] oa cl Ba 70-80 96 Ba 70-8096 8b 80 94,97 Bb 5.9096 Be 10-80 96, 96 7-Chloro-L-methyLS-phenyt-2,3dihydro- H-1,4-bemzodiazepine-2- one (83) A mixture of 2(2-chloro-N-methyt-acctamido)Schlorobenzo- phenone (10g, 3.1 mmol}, and hexamine (10g, 70 mol) in abso- lute ethanol (15 mi) is heated under refiux for 10h, The resultant solution is evaporated to dryness under reduced pressure, the residue is dissolved in water (10m), and the solution shaken with benzene (10m), The benzene layer is separated and the aqueous layer extracted with two additonal 10-ml portions of ‘benzene, The benzene layers are combined, washed, and dried with sodium sulphate. After evaporation to dryness in vacuo, the residue i dissolved in ther. Chilling induces crystallisation, and the erystals are collected and washed with ether: yield: 0798 mp. 128-130", 26 N, Bladevit, F. Kafed, J. Heteocyel. Chom, 7, 1173 (1970) ARON. Shenoy, P. R. Shankaran, S. B. Rao, Indian J. Pharm, 34, 48 (1972) Heramethylenetetrumine, A Versatile Reagent in Organic Synthesis 475 Treatment of the 2-(N-p-haloalkyl)-amino-5-chloro- benzophenone 85 with hexamine in ethanol resulted in ring closure to give a mixture of 2-deoxy-1,4-benz0- diazepines 86 and 87°%°?, Rt Rt ; { j at Lee yo] RRS * | ee es " te Le alt cr NR oy N CoHs Cots 26 ar Scheme S We assume that f-patticipation of the vinylogous- amide-nitrogen took place during ammonolysis of the 24-haloethyl) derivatives 85. However, an inter- mediate formation of aziridinium derivatives cannot be conveniently demonstrated when 2.3-unsubsti- tuted benzodiazepines are the expected products of reaction, since the same product would be formed by both direct ring closure, or p-participation of the N-2 atom. In the preparation of chiral derivatives (N.B, when one of the substituents on the f-C-atom in 85, R? or R°-4H, this atom is chiral), however, different structural and stereoisomers should arise, according to the mechanism shown in Scheme S. ‘The starting compounds, products, yields, and regio- selectivities in these reactions are given in Table 10. ‘Table 10, 4-Benzodiazepine Ring Closure with Hexamine Starting X RY RFR? Prods YieldRegio- Ref, ‘compound uct [%) select « Bro Cl; MH 6a sb oc oH HOH ab Be Br CH; «DOD ae 705/58 99. Sd Br CH; -HOCHs ad 7257/43 99. * Ratio of 2- vs. 3substituted 14-benzodiazepines, Individual values have been obtained by GILG 3 °N. Blazevie,F. Kaifet, J. Heteroeyel. Chem. 8 845 (1971). * M. Mili, V. Suni P. Mildner, F. Kajfet, Croat. Chem. ‘Acta 48,125 (1976) "°° RL Fryer, B. Proust, LH. Stembach, J. Chem. Soe. 1964, 308. 11 RL Fryer, LH. Sternbach, J. Org. Chem. 30, 524 (1965) "7M. Ogata, H. Matsumoto, Chom Ind. (London) 1976, 1067176 Nikola Blatevi, D. Kolbah, Branka Belin, Vitomie Suni, Pranjo Kaifer (Ogata and Matsumoto!”? developed another method for the synthesis of 1-benzodiazepin-2-ones by ring. expansion with hexamine. Starting from suitably sub- stituted derivatives of isatin 88, they obtained substi- tuted benzodiazepines 89 fo=cH-cl ° 4 tyros ia oor 88 89 Interestingly, reeyclisation after isatin ring opening ‘with hexamine gives rise to derivatives of the seven membered 14-benzodiazepine, while ammonia, in a similar reaction, causes recyelisation to six-mem- bered quinazolines 9. go-cHy-ci oy “nebo NSH el K aoe a 6 bons 88 90 Finally, hexamine can be used to oxidise a preformed tetrahydro seven-membered ring, as in the syn- thesis! !° of 2.3-dihydro-1 4-benzodiazepines. 92 starting from 1,2334-tetrahydro derivatives 91 on oH . WacoH, 2) OO) mee CoHs CoH, 7. Conclusions This article shows that hexamine can be used in many different ways in organic synthesis. As a rea- gent, hexamine decomposes under the influence of various agents, into fragments that can react further to give compounds of the tetraaza- and triaza-type. Another group of reactions encompasses the well known Delépine reaction for the synthesis of amines, and the equally well-known Sommelet and Duff reac- tions for the synthesis of aldehydes. In the Delépine reaction hexamine contributes one of its nitrogens to build the amine function, and in the Dul reaction it contributes the ~CH= function, We may assume, that hexamine reacts as an amine in one instance, and as an aldehyde in another. However, in the Sommelet reaction hexamine behaves as an oxidising agent which oxidises the CHCl group into a CHO group Recently, hexamine was used in syntheses of fi six-.and seven-membered heterocycles. In these cycli- sation processes, hexamine supplies one or two nitrogen atoms, or a ~CH=N- function, to the newly formed heterocycles. These reactions are very complex, and their mechanisms can be only guessed. The starting compounds should have two functionali- ties between which the hexamine fragments are built to form a heterocycle. Only a few references dealing with different molecular complexes of hexamine have been included. Such complexes find application as explosives, anticorro- sive agents, and drugs. Received: April 28,1978 9K Ishizumi, K, Mori Y. Komeno.J. KatsubeH. Yamamoto, Janamese Patent 773069; CA. BT, 182287 1977 toe Cr Thizumi, ¥. Komeno, K. Mori, 1. Katsube, Japanese Pasent 7765287: C, A. 87, 172889 (1977Errata and Addenda 1979 M. Content, D. Savoia, C. Trombini, A. Umani-Ronchi, Symes 1979 (1), 30-32, “The structure for compound 3c (p 31, Table 1) shouldbe: cH tac A008 ‘A. Mignot, H. Mostowitz, M. Miocque, Synthesis 1979 (1). 52-8 ‘The correct name for Teiramisle® should be 6-phenyl.2, tetrahydroimidazolo2,-bjhiazole, |A.N. Pudovk, IN. Konovalova, Symhess 1979 (2), 81-96; ‘The frst sentence of the experimental procedure on p. % should read as fllows: Dialky! phosphite or phosphorothioate (0.01 mol) is added to the azo compound (001 mo) in ether (10 ml. In Table 13 (p. 96) the enties R? for compounds 63b and 63e should be 4H,C--C\H, and 4-0,N—CuM, respectively. Abstract $422, Synthesis 1979 (2), 160, “The formula scheme forthe conversion 3-4 should be: 0 coow re 3 4 IN. Blaevig, D. Kolbah, B. Belin, V. Sunjt,F. Kajfe, Spmhess 1919 (3, 161-176: (Compounds TBa-e (p. 173) should be named S-chloro-1Ob-pheny|2.3,56tetahydro-1ODI onazole.2-ch quinazolines. K. Herrmann, G. Simchen, Shes 1979 (3), 204-208 ‘The lines 10 to 17 ofthe text (p. 20) should read as follows: sche Acryleyanide zuginglich'**, Aiphaische Carbonsdure-halo fenide hingegen seten sich mit Tetrecthylammoniumeyaaid 20 Acjloxymalodinitilen (,dimere Aeryleyanide") um, wofir auch ic hohe Cyanidionen-Konzentation verantwortich is. Die Reaktion aliphatscher Siurechloride 2) mit Cyanotrimethysilan ("sollte deshalb eine geeignete Synthesenmethode Fur 2-Ox0- alkannitril (aliphatische Acryleyanide, 3) durstllen,Bisher konn- te allerdings nur 1. Cagliot, F. Gasparini, D. Misti, G, Palmieri, Syahess 1979 (@), 207-208, ‘The italic sub-headings inthe Table p. 208) should be From toni- doyérazones, From Nomethyl-Nctarylhydracones, and From 2-- ntrophenthydrazones. 1035 Abstracts 5494, Syms 1979 (5), 39% The formula scheme for the conversion 1-+3 should be as fol: ieee OP erie Ay poe, + Rison Merreste tt 1 2 3 . Skatsch 1 Koblmeyer, E. Bretmier, Synthesis 1979 (6. 49 48%; ‘The name for compound 10a should be: 3-Methyls 6,18tetrahydroisoxazoo[S 4-b)chinclin. 4. Golitsi, A. Joncayk, M. Makosea, Shes 1979 (6), 461-463 “The formula scheme for the conversion tb-=4 (p, 462) should be as follows: (ean crscoe C1 Ay mimaoitvecte CeHs—CH,-S0,-N LL? te Cots=cely-802-K > rece S02-N 4 Abstract $520, Sythe 1979 (6), 473 The formula scheme should be as follows: i CHCOOC HH / HO NaOH ration RE JE ES sere tnoimonin, e Le : oe Abstract $821, Syhesis 1979 (6) 479; ‘The formula Scheme for the conversion 12 should be as fol lows: coer Shan, wacoon + WZ? EE. Teco ociienss oP] ee 1 2 E. Negishi, D. E. Van Horn, A. ©. King, N, Okukado, Synthesis 1979 (7, 501-02: For clarity the following formula scheme should be added: ceo zr + AucHy, SAREE 4 Abstract 5440, Synthesis 1979 (3), 238; cea ‘he mua shone te oveion {4 sold be a ios a Cm) LR re | wa Se see Bate | RY h a 2 1 2 . os : = Seong 10 | seem neon mero . : i . Ventureo, R.D’Aloisi, Synthesis 1979 (4, 283-287; Eniries 3 and 4 ofthe Mas: spectrum column of Table 1 (p. 284) should be 284 (CD and 318 (CD, rexpectively 4.8, Davidson, Syst 1979 (5; 359-361 Compounds 6p. 360) should be named: BediaylS-ov0-34-dihydeo-tH-1.2.tiazoles ‘A. Mekillp, D. W. Young, Synthesis 1979 (7, 481-500, The heading for Table 24 (p. 496) should be: Table 24, Oxidation of Alcohols to Aldehydes and Ketones using Potassiam Permangansie/Molecular Seves"™