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MAIN SYNTHETICAL METHODS FOR THE PREPARATION OF HETARENES

1. Ring Synthesis Strategy
1.1. Hydrolytic disconnection 1.2. Redox disconnection 1.3. The mains precursors
1.3.1. Precursors as nucleophiles 1.3.2. Precursors as electrophiles 1.3.3. Precursors as both electrophiles and nucleophiles

2. Substituent modification 3. Nomenclature: I.U.P.A.C., general rules

1. Alan R. Katritzky, A. F. Pozharskii Handbook of Heterocyclic Chemistry 2nd Edition, Pergamon 2000 2. Alan R. Katritzky Short Course in Heterocyclic Chemistry for Ph. D. Students, University of Florida 1996/1997 3. David T. Davis Chimie des Hétérocycles Aromatiques De Boeck Université 1997, Oxford University Press 1992 4. René Milcent Chimie Organique Hétérocyclique EDP Sciences 2003, www.edpsciences.org 5. Jonathan Clayden, Nick Greeves, Stuart Warren, Peter Wothers Organic Chemistry, De Boeck Diffusion s.a., 2003, Oxford University Press 2001, www.deboeck.com

References:

Modifications (improvements, additions, corrections, up to dates etc.) are subjected to no notice.

Six memebered Ring c) More Hetero atoms N pyridine N quinoline N acridine Ii it is easier to synthesise a second ring onto a first one than to synhtesise a monocyclic compound.Mircea Darabantu. I N T R O D-1 MAIN SYNTHETICAL METHODS FOR THE PREPARATION OF HETARENES D e f i n i t i o n : the term h e t a r e n e s designes all heterocyclic compounds possessing aromatic character according to Hückel rule. Mono cyclic b) Five vs. MASTER DIA. . Ring Synthesis Strategy : the following three factors increase the importance of the ring synthesis a) Fused Ring vs. X pyrrole X=NH thiophene X=S furane X=O X indole benzothiophene benzofurane X carbazole dibenzothiophene dibenzofurane The more heteroatoms one has in the ring. N N pyrimidine N N quinazoline N N N N pteridine N N N H purine N N H imidazole N N H benzimidazole N Substitution reactions tend to be easier on the whole when one has fewer heteroatoms in the ring. the more methods of synthesis they are. Synthesis Ring Synthesis Combination of the Two Substituent Modification 1.

Bergmann.Mircea Darabantu. I N T R O D-2 Baldwin’s Rules for 3 to 7 Membered Ring Closure J. 734 Z: sp3 Exo . 1976.X X Y Z - X Y Z - Endo-Dig: From 3 to 7 membered rings FAVOURED i) ii) iii) iv) all the above rules have empirical support only. Lázár. Eur. Rev. 2003. the basic support of the above rules is stereochemical (bond lenghts and bond angles). Org. Chem. Chem. 309-353 L. E. a lot of cases (before and after 1976 are in substantial accord with these rules). disfavoured does not mean impossible but more difficult to realise. 1953. J. Chem.Dig Z X Y Z Endo-Tet: From 5 to 6 membered rings FAVOURED - Endo-Trig: From 3 to 5 membered rings DISFAVOURED Endo-Trig: From 6 to 7 membered rings FAVOURED .Tet Y X Z Y Z: sp Exo . Baldwin J. Soc.Tet X Y Y: sp2 Endo .Dig X Y Z YZ: sp2 Exo . Fülöp. (Z=Y) CH=O OH HO Exo-Trig 6 OH OH (X) CH2OH D-glucose (Y) HO (Z) HO Endo-Trig Ring Closure 5 Membered ring OH O (X) OH Ar Y (X)HO N Z ! (Z) O NH (X) (Y) Ar CH2OH Pyranose chain ring tautomerism D. 53.Trig X Z Y- X Z X Z Exo-Tet: From 3 to 7 membered rings Y FAVOURED Exo-Trig: From 3 to 7 membered rings FAVOURED Exo-Dig: From 3 to 4 membered rings X Z DISFAVOURED Exo-Dig: From 5 to 7 membered rings FAVOURED - Y: sp3 Endo . Commun.Trig Z Y Y: sp X Y Z Endo . F. MASTER DIA.. Chem. E. 3025-3042 .

pair (donor) 5-exo-trig cyclisation (Intramolecular SN2) FAVOURED Stereoelectronically σ∗ X ( )k lone Y . 6 . 2 3 4 5 1 Br 2 - . pair (donor) X empty (acceptor) π∗ empty (acceptor) n-exo-tet cyclisation k=0-4 FAVOURED Stereoelectronically n-exo-trig cyclisation k=0–4 FAVOURED Stereoelectronically exo-dig cyclisations are favoured for five to seven membered rings .. I N T R O D-2a Examples : exo-cyclisations according to stereoelectronic requirements in the transition state .Mircea Darabantu. MASTER DIA. 6 + Brsix membered 3 4 5 1 .. 4 5 five membered 6-exo-tet cyclisation (Intramolecular SN2) FAVOURED Stereoelectronically 2 3 6-exo-trig cyclisation (Intramolecular RA) FAVOURED Stereoelectronically 3 4 5 5-exo-dig cyclisation (Intramolecular RA) FAVOURED Stereoelectronically 1 H2N Br N H aziridine (three membered) H 2 1O O OH O O five membered (tetrahydrofuran-2-one) 3-exo-tet cyclisation (Intramolecular SN2) FAVOURED Stereoelectronically G e n e r a l i s a t i o n: ( )k lone Y . 2 3 six membered 1 ..

.. lone pair (donor) O π∗ empty (acceptor) apropriate orientation .4-addition) π∗ empty Too far...and 7-endo-tet cyclisation are favoured all 3 – 7-endo-dig cyclisations are favoured almost all 3 – 7-endo-tet cyclisations are less favoured Plausible but… O 3 2 1NH 4 5 O O H OEt HN OEt N .. MASTER DIA... 2 4 5 O 3 O H Appropriate orientation π∗ empty (acceptor) inapropriate orientation O Base OH Ar 2 1O - O 3 4 5 i) 5-endo-dig cyclisation FAVOURED + ii) H Ar O O _ O .. O OEt 5-endo-trig cyclisation DISFAVOURED (Intramolecular 1. (acceptor) Inappropriate orientation This is the real: 3 2 1NH 4 5 . H lone pair (donor) OEt π∗ empty . 2 EtO O HN 5-exo-trig cyclisation FAVOURED O A 6-endo-trig cyclisation: favoured.Mircea Darabantu. I N T R O D-2b Examples: endo-cyclisations according to stereoelectronic requirements in the transition state NOTE: only 6. occuring in 89 % yield O MeOOC Base O O trans stereochemistry with respect to cyclanone ring A 5-endo-dig cyclisation: favoured MeO2C O MeO2C MeO2C O π ∗ 1 O 6 . 2 (acceptor) lone pair H (donor) H N .

H2C (EWG) EWG precursors R1 O + H2N-R3 precursors good o p t i o n !! Target Compound bad OR3 NH2 o p t i o n !! R2 Example 3: R N heterocyclic compound seen as a cyclic imine R N heterocyclic compound seen as a cyclic amine R NH OH R O NH2 precursor: good option !! R H2N . CN. Example 2: hydrolytic disconnection EWG O + (EWG) EWG: Electro(no) Withdrawing Group CO.g. etc..NH3 O ? bad option .1.Mircea Darabantu. R1 N R3 R2 R2 R1 NH + HO-R3 R2 precursors R1 e. I N T R O D-3 1.. COOR. MASTER DIA.hydrolytic disconnections of the double bonds are very useful since most of the ring closures to afford heterocyclic systems are simple condensation H+ / -H2O i) Nucleophilic addition ii) Elimination O + H2N-R3 R2 R1 R1 R2 Imine Schiff base N R3 + H2O c o n d e n s a t io n Example 1: originates from. Hydrolytic disconnection .

5-dimethylpyrrole seen as acid double enamine center -H+ enol 5 CH3 NH H acid -H+ center enamine H3C O N H CH3 H3C O O NH3 CH3 Example 6: the importance of the formal charges Rings containing Nitrogen H +1 -3 +1 +1 H -1 +1 +1 -2 +1 H R H -2 R N H +1 +1 +2 -2 +1 R OH +1 -3 2 x (+1) NH2 O -3 NH2 2 x (+1) Rings containing Sulphur H +1 -2 +1 H -1 +1 +1 -2 +1 H R H +1 the best precursor +1 -2 R S +1 +2 +1 -2 +1 H +1 H R OH +1 -2 SH O SH -2 Rings containing Oxygen H +1 -2 +1 H -1 +1 +1 -2 +1 H R H -2 best X electrophile +1 R Y best nucleophile R O +1 +2 +1 -2 R OH +1 -2 OH O OH -2 +1 . MASTER DIA.Mircea Darabantu. I N T R O D-4 Example 4: Imine or enamine ? It doesn’t matter… H sp2 R sp3 N H (masked) enamine H R OH NH2 H sp2 R sp3 N H (masked) enamine H H R H H R O NH2 N imine Example 5: Retrosynthesis of pyrroles seen as hydrolytic disconnection: basic basic center +H+ +H+ center 4 3 H3C H3C 2 CH3 N1 O H H 2.

for reason of availability.4-diketone currently nonavailable commercial product difficult to obtain is the above disconnection useful for a chemist ? Why ? a) Because it provides rapidly the type of precursors b) Because it provides rapidly the most convenient precursors. c) Because it infers that if. All cyclisations (or cyclocondensations) involve classic tautomerism: keto-enolic.g. Redox disconnection -this methodology provides information about the general strategy to be used to access the target compound: is there any redox step ? Example 1: . imino-enamine. reduction) by the redox disconnection. I N T R O D-5 To be kept in mind: 1. O ☺ .2.Mircea Darabantu. If a hydrolytic disconnection appears suitable.6-heptanedione Z-1. in the synthesis of the target molecule a redox step must be accomplished: e. oxidation. a redox step is revealed (e. During cyclocondensation (or retrosynthetic hydrolytic disconnection) no global redox process. 1. 3. involving the whole molecule occurs. the best pair nucleophile-electrophile sould be considered 2.a six membered hetarene redox disconnection +2 +1 -2 it looks like "inorganic" precursors H3C N CH3 H3C +2 +1 CH3 N3- H3C -2 O OH +1 -3 NH 3 3x(+1) 7 CH3 ??? 1 2[H] H3C H3C 2 3 4 5 6 CH3 O CH3 O O 2.g. MASTER DIA. etc.a five membered hetarene: it looks like "organic" i) cut (remove) the bonds between the organic and inorganic parts ii) add the formal charges +1 -3 N -1 H add two functional groups at both ends of the "cation" +1 to "neutralise" charges O O N H HO ] -1 +1 -3 -1 NH3 +1 3x(+1) [OH it sounds like ammonia Obs: the structure of the target compound (bond connection and aromaticity) is automatically issued by preserving the formal charges of each of the involved (hetero)atoms: no redox step in the synthesis Example 2: .

Mircea Darabantu.anticipated oxidation step H 4 3 + [O] 5 CH3 -H2O H3C 6 N 2 CH3 1 -H+ 2. The main precursors 1. S. O) in the target compound Example 1: b r i n g i n g one heteroatom in the target compound: NH3 H2S H2 O 4 5 3 2 4 5 3 2 4 5 3 2 N1 H S 1 O 1 Example 2: b r i n g i n g two heteroatoms in the target compound: H2N-NH2 hydrazine HO-NH2 hydroxylamine 4 5 3 4 5 3 N1 H pyrazole N2 O1 N2 isoxazole amidines NH2 HN R HN guanidine NH2 NH2 Example 3: b r i n g i n g three atoms in the target compound: thiourea thioamides urea NH2 S NH2 S NH2 R O NH2 NH2 4 5 1 N3 S 2 NH2 4 5 1 N3 S 2 R 6 4 5 4 5 6 HN 1 N3 2 4 5 6 N3 2 2-substituted thiazoles O 2 N3 2-pyrimidone N1 R N1 NH2 2-substituted pyrimidines . I N T R O D-6 The direct synthesis: + NH3 -H2O H3C OO CH3 H3C O CH3 H3C NH O CH3 NH2 H -H2O H3C N OH H CH3 H3C N H -H:.6-dimethylpyridine 1. MASTER DIA.3. Precursors as Nucleophiles: this is the traditional route to bring heteroatoms (N.3.1.

Precursors as Electrophiles: Example 1: b r i n g i n g one atom: δO δ+ R LG LG: leaving group as LG:e.4-disubstituted thiazoles Example 3: b r i n g i n g three atoms: δO Oδ δ+ δ+ R R O R HX O R NH2 4 R 5 1X 3 R N2 1.6-dione . four and five atoms in the target compound: benzoderivatives NH2 NH2 NH2 NH2 5 6 7 8 4 3 7 6 8 N1 N 4 5 2 3 6 7 8 4 3 N 1 2 N2 1 5 Quinoline 1. Example 2: b r i n g i n g two atoms: δδO O δ+ δ+ δ+ δ+ R OR δδLG LG Quinoxaline Isoquinoline NH2 O R 4 5 6 3a N3 2 R NH2 Cl N1 H 2-substituted benzimidazoles 7 7a R1 Cl O :NH2 :S R2 R1 4 5 1S N3 2 R2 2. I N T R O D-7 Example 4: b r i n g i n g three.5-disubstituted X = NH pyrazoles X = O isoxazoles O O δ+ RO δ- Oδ O OR O OR HN NH2 R' 5 δ+ OR 4 N3 malonic esters O 6 N 1 2 R' H 2-substituted-pyrimidin-4.3-dicarbonylic compounds 3.Mircea Darabantu.3. Cl as Cl-.2.g. R'O as R'OH etc. MASTER DIA.

3.Mircea Darabantu. I N T R O D-8 δO δ+ R δ+ acrylic derivatives O R 6 R 5 4 3 2 NH2 7 8 N 1 4-substituted-quinoline Example 4: b r i n g i n g four atoms: R δ+ δ+ R R δ+ O O δ+ 4 3 R R O O δ.5-trisubstituted-oxazoles O δ+ O LG LG as E+ as Nu:- O LG H O OH HO δ- O 5 4 3 2 8 OR 6 7 OR O δ- HO LG δ+ OR O 1 LG: OR.4.4-diketones 5 X 2 1 R H2X (X = NH.3. Cl as ClR2 NH2 R3 O LG O R1 R3 5 1 R2 4 N3 1 O 2 R 2. see Example 1 as E+ R3 δ+ R2 δO NH2 as Nu:- an α-aminoketone . MASTER DIA.g. Precursors as both Electrophiles and Nucleophiles: Example 1: b r i n g i n g two atoms: δas Nu:O δ+ R LG as E+ LG: leaving group as LG:e. Halo 3-substituted-coumarines Example 2: b r i n g i n g three atoms. S) Note: electrophilic fragments usually do not bring heteroatoms in the target compound 1.δ1.

form (oxazoline) . The target compound: O R1 4 3N 5 O1 2 R 1 = R2 = H / / R2 Retrosynthetic analysis: O R1 4 3N 5 O O1 2 O O R1 NH2 R2 OH O R2 OH hydrolytic disconnection R1 N-3-C-2 and C-2-O-1 N R2 O R1 NH2 OH Cl O R2 R1 HN O OH C R2 O poor ability as Leaving Group weak nucleophile in this environmen O R1 HN O OH R2 better LG than HO C=O more electrophilic Solution of the problem: weak electrophile good LG R2 O R1 HN OH Cl C R2 O R2 Δ excess H O R1 N O O C R2 O Nucleophile O R2 -H+ O _ O R1 N R2 O O Note: obsolete cyclisation of α-aminoacids as double protected N-. COO. MASTER DIA. I N T R O D-8a Example 3: acid chlorides as good electrophiles to generate good nucleophiles.Mircea Darabantu.

e.Mn+ π X E Mn: LiI. triaza. other things being equal. e. 4 5 N 3 2 4 5 N1 2 N3 N1 CH3 CH3 1-methyl-1. Note: the final a is however elided before a vowel e. thia-aza-ole → thiazole.g.Mircea Darabantu. MgII etc 3. If different.g.3-diazole 3-methyl-1.g. oxa-thia-ane → oxathiane. etc. in decreasing order of citation (nomenclature as a): O oxa > S thia > Se selena > N aza > P phospha > As arsa > Si sila > B bora etc. numbering of the positions starts at an oxygen. Nomenclature: IUPAC general rules important trivial names are given at the beginning of each chapter: e. numbering starts at a substituted rather than at a multiply bonded nitrogen atom. Substituent modification the below three main types of substituent modification are of general interest i) nucleophilic displacement: π X ii) electrophilic displacement: H LG + Nu:- π X + LG:Nu E + E+ π X π X + H+ iii) electrophilic displacement via metallation: π X H + R-Mn . the prefixes should be combined according to the above order: e.RH π X Mn + E+ . I N T R O D-9 2. oxa-diaza-ole → oxadiazole. MASTER DIA. azaole → azole - two or more identical heteroatoms are indicated by dioxa.3-diazole 1-methylimidazole 3-methylimidazole MAXIMUM UNSATURATION is defined as THE MAXIMUM POSSIBLE NON CUMULATIVE DOUBLE BONDS BY CONSIDERING: O. pyridine instead of azabenzene the type of heteroatom present in the ring is indicated by the below prefixes.g.g. sulphur or nitrogen (in decreasing order of preference) and continues in such way that the heteroatoms are assigned the lowest possible numbers.two valencies S – two valencies N – three valencies .

5dihydropyrimidine - NH 2 3 O1 5 2 N H perhydro-1. -etidină azetidine 1.3oxazole Δ -thiazoline 4 5 6 2 Rom. -ole 4 5 N3 2 4 5 N3 O1 2 Eng. -olidină 1. -olidine 4 5 NH O1 2 3 Rom. -iridină Eng. -onine 4 3 - 7 8 9 1 Rom. -ocină N 1 6 5 8 azocine 9 Eng. -ine N3 2 N3 2 Rom. MASTER DIA. -etidine 3 2 3 O1 N2 H N1 H aziridine 3 4 1 2 oxaziridine 3 4 O2 NH NH 1 Rom. 3 -irine N N1 1 H Rom.2-oxazetine 4H-1. -etă azete Rom.4-oxazepine 4 3 6 7 2 8 Eng. -olină - 4 5 N3 S1 2 Eng. I N T R O D-10 The Hantzsch-Widman Nomenclature for Heterocyclic Compounds Rings w i t h Nitrogen Ring Maximum Unsaturation Size 3 3 2 2 Eng. 1-azirine 2-azirine -irină 3 2 Eng. -ol N1 H 1.3-diazine 1.2-oxazetine 5 Eng. -oline Rom. -ină N 1 N 1 Nomenclature is made by using the prefix perhydro (total hydrogenated) which precedes the name of the corresponding non saturated structure 4 5 6 1 1. -ocine - - Rom.3-diazine pyrimidine 5 6 7 7 Eng. -epine Rom.3-oxazolidine 6 Eng. 4 -ete 4 N 1 One Double Bond - Saturated Eng.Mircea Darabantu. -iridine Rom.3diazole imidazole 4 5 6 1. onină N 2 H 1H-azonine .2-oxazetidine 2H-1. -etine 3 4 2 3 4 1 2 N1 2 NH 2 Eng. -etină 1-azetine 2-azetine 3 4 NH O1 3 4 N O1 Rom. -epină N4 3 - 4.

-olan Eng. 2 2 3 -irene O S 1 1 One Double Bond - Saturated Eng. -olene 4 5 2 - Rom.Mircea Darabantu.2-oxathietane 5 1O 2 4 4 3 5 3 Rom. -ocin 5 6 7 8 4 Rom. -ol O1 oxole furane 5 6 S1 thiole thiophene 4 3 2 Rom. irenă Eng. -epin 5 6 7 4 3 6 7 5 O3 2 Eng. -etă Eng. -irane 3 2 3 2 O 1 S oxirane thiirane 1 4 Rom. -ete Rom. -ină S1 H thiin Rom. -onin 7 8 9 Rom. onină O 1 2 Rom. -etene Rom. -olane O3 5 Δ -oxolene Δ -thiolene Rom.2-oxathiete 3 2 5 4 3 2 S2 O1 Eng. -ane S1 2 1.3-dioxepin 5 3 6 7 8 6 5 4 3 4 3 thiepane-3-one 4 3 6 7 8 8 Eng. epină O 1 2 O 1 Rom. -in Rom. -etan 4 3 3 2 4 3 4 O1 2 S O1 oxetane 1. -etenă Eng. MASTER DIA. -ole 4 5 oxirene 3 2 4 thiirene 3 O1 4 oxete 1.3-dioxolane thiolane 5 6 1O 2 4 6 Eng. -etane Rom. -ocan S1 2 thiocane Eng. -epane O 2 Rom.3-dioxane 5 6 7 4 3 7 Eng. -onan O 1 2 oxonin oxonane . ocină O 2 1 S1 2 Rom. -olen - O1 2 5 3 S1 2 Eng. -ocane S1 5 oxepin 1. -onane 6 7 8 9 5 4 3 4H-oxocin 2H-thiocin 9 Eng. -an 4 O3 1. I N T R O D-11 The Hantzsch-Widman Nomenclature for Heterocyclic Compounds Rings w i t h o u t Nitrogen Ring Maximum Unsaturation Size 3 3 Eng. -iran Eng. -epan Eng.

unsaturation possible is 2 double bonds: suffix i n e → order of citation: S > N.2.6H-1. etc. unsaturation possible is 1 double bond: suffix i n e → order of citation: S.3-dihydro-4H-thiin 5.A.6H-1. the position of the double bond can be indicated by the symbol Δa.5-thiadiazine → max. the position of the hydrogen atoms can be indicated by the prefixes dihydro if convenient suffix is not available in partially saturated compounds.U.2.5-thiadiazine → max.6-dihydro-2H-thiin with suffix according to IUPAC: in no suffix available according to IUPAC Note: the number of the indicated hydrogen is the lowest possible Example 3: 4 5S 6 3 NH S 2 1 4 2H.5.5-dithiazine → max. if the double bonds can be arranged in more than one way. in partially saturated compounds.6H 5S 6 3 N S 2 1 Example 4: 4 5 3 N 1 4 6 N S 2 3 6H-1. N → supplementary hydrogen at C-6: 6H 4H-1. 2H. S > N → supplementary hydrogen at N-2 and C-6: 2H.5-dithiazine → max. unsaturation possible is 2 double bonds: suffix i n e → order of citation: S > N. N → supplementary hydrogen at C-4: 4H 5 N 1 6 N S 2 . S > N → supplementary hydrogen at C-4 and C-6: 4H. unsaturation possible is 1 double bond: suffix i n e → order of citation: S.4-dihydro-2H-thiin 2.2.2.6-tetrahydro-2H-thiin S1 H 1H-thiin S1 S1 S1 S1 2H-thiin 4H-thiin 3. I N T R O D-12 - - indicated hydrogen: H in compounds possessing maximum unsaturation.Mircea Darabantu.P.6H 4H. MASTER DIA.b which indicates that the double bond is between the atoms numbered “a” and “b” Example 1: 4 5 3 2 5 4 3 2 5 4 3 2 N1 H 1H-pyrrole Example 2: 4 5 6 3 5 6 2 4 3 2 5 6 4 3 N1 3H-pyrrole N1 2H-pyrrole 4 5 6 3 5 6 2 2 4 3 5 6 2 4 3 2 S 1 thiane (I.4.) 3. their positions are defined by indicating the nitrogen or carbon atoms which are not multiply bonded and consequently carry an “extra” hydrogen atom: 1H.C.