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 References: 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 Modifications (improvements, additions, corrections, up to dates etc.) are subjected to no notice. Mircea Darabantu, MASTER DIA. 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. S y n t h e s i s Ring Combination of Substituent Synthesis the Two Modification 1. Ring Synthesis Strategy : the following three factors increase the importance of the ring synthesis a) Fused Ring vs. Mono cyclic b) Five vs. Six memebered Ring c) More Hetero atoms N N N ) pyridine quinoline acridine Ii it is easier to synthesise a second ring onto a first one than to synhtesise a monocyclic compound. X X X pyrrole X=NH indole carbazole thiophene X=S benzothiophene dibenzothiophene furane X=O benzofurane dibenzofurane )) The more heteroatoms one has in the ring, the more N N N N methods of synthesis they are. N N N N pyrimidine quinazoline pteridine ))) N N N N Substitution reactions tend to be easier on the whole N N N N H H H when one has fewer imidazole benzimidazole purine heteroatoms in the ring. Mircea Darabantu, MASTER DIA. I N T R O D-2 Baldwin’s Rules for 3 to 7 Membered Ring Closure J. E. Baldwin J. Chem. Soc., Chem. Commun. 1976, 734 - Z: sp3 Exo - Tet Exo-Tet: From 3 to 7 membered rings X Z X Z Y Y & FAVOURED - Z: sp2 Exo - Trig Exo-Trig: From 3 to 7 membered rings X Z X Z - & FAVOURED Y Y Exo-Dig: From 3 to 4 membered rings - Z: sp Exo - Dig DISFAVOURED X Z X Z & - Exo-Dig: From 5 to 7 membered rings Y Y & FAVOURED Y: sp3 Endo - Tet - X Z X Z Endo-Tet: From 5 to 6 membered rings Y Y & FAVOURED Endo-Trig: From 3 to 5 membered rings Y: sp2 Endo - Trig - - X Z X Z & DISFAVOURED Y Y Endo-Trig: From 6 to 7 membered rings &FAVOURED Y: sp Endo - Dig - - X Z X Z Endo-Dig: From 3 to 7 membered rings Y Y & FAVOURED i) all the above rules have empirical support only. ii) disfavoured does not mean impossible but more difficult to realise. iii) the basic support of the above rules is stereochemical (bond lenghts and bond angles). iv) a lot of cases (before and after 1976 are in substantial accord with these rules). (Y) Endo-Trig (Z=Y) HO Ring Closure CH=O (Z) 5 Membered ring! OH OH (Z) Exo-Trig 6 HO HO O (X) (X)HO N ONH OH OH Z (X) (Y) OH (X) Ar Y Ar CH2OH CH2OH D-glucose Pyranose chain ring tautomerism D. E. Bergmann, Chem. Rev. 1953, 53, 309-353 L. Lázár, F. Fülöp, Eur. J. Org. Chem. 2003, 3025-3042 Mircea Darabantu, MASTER DIA. I N T R O D-2a Examples : exo-cyclisations according to stereoelectronic requirements in the transition state . 2 2 1 Br 1 . 3 3 2 1 + Br- 4 .. 4 . 3 . - 6 6 5 5 4 5 five membered six membered six membered 6-exo-tet cyclisation 6-exo-trig cyclisation 5-exo-dig cyclisation (Intramolecular SN ) (Intramolecular RA) (Intramolecular RA) 2 F A V O U R E D F A V O U R E D F A V O U R E D Stereoelectronically Stereoelectronicall y Stereoelectronically 3 4 2 2 1 3 Br H N 1 5 2 N O O H HOOH O aziridine five membered (three membered) (tetrahydrofuran-2-one) 3-exo-tet cyclisation 5-exo-trig cyclisation (Intramolecular SN2) (Intramolecular SN2) F A V O U R E D F A V O U R E D Stereoelectronically Stereoelectronically G e n e r a l i s a t i o n: ( ) ( )k k Y YX.. lone .. lone σ∗ X pair pair empty (donor) π∗ (donor) (acceptor) empty (acceptor) n-exo-tet cyclisation n-exo-trig cyclisation k = 0 - 4 k = 0 – 4 F A V O U R E D F A V O U R E D Stereoelectronically Stereoelectronically exo-dig cyclisations are favoured for five to seven membered rings Mircea Darabantu, MASTER DIA. I N T R O D-2b Examples: endo-cyclisations according to stereoelectronic requirements in the transition state NOTE: only 6- 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 lone O O OEt pair 3 H H H (donor) 4 N 2 OEt ∗ empty .. OEt N .. π O 1 (acceptor) OEt NH2 HN .. 5 H lone 5-endo-trig cyclisation pair π∗ empty DISFAVOURED (donor) (acceptor) (Intramolecular 1,4-addition) Inappropriate Too far... orientation This is the real: 3 4 2 5-exo-trig cyclisation 1 5 FAVOURED NH.. 2 HN EtO O O A 6-endo-trig cyclisation: favoured, occuring in 89 % yield O - MeO2C MeO C O MeO C O O 2 MeOOC 2 π∗ 1 Base .. 2 6 O O 3 5 O 4 H O Appropriate orientation trans stereochemistry with respect to cyclanone ring A 5-endo-dig cyclisation: favoured π∗ empty (acceptor) inapropriate orientation i) 5-endo-dig cyclisation FAVOURED O O O O ii) H+ Base 2 4 3 5 _ - O .. 1OAr O ∗ OH Ar lone π empty (acceptor) pair apropriate orientation (donor) Mircea Darabantu, MASTER DIA. I N T R O D-3 1.1. Hydrolytic disconnection - 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 R1 ii) Elimination R1 3 3 O + H2N-R NR+ H2O c o n d e n s a t io n R2 R2 Imine Schiff base Example 1: originates from... R1 R1 3 NR O + H2N-R3 g o o d o p t i o n !! R2 2 R p r e c u r s o r s Target Compound R1 NH + HO-R3 b a d o p t i o n !! R2 p r e c u r s o r s R1 OR3 e.g. R2 NH2 Example 2: hydrolytic disconnection EWG EWG O + H2C p r e c u r s o r s (EWG) (EWG) EWG: Electro(no) Withdrawing Group CO, COOR, CN, etc. Example 3: R R precursor: good option !! N O NH2 heterocyclic compound seen as a cyclic imine - NH3 R R R ? bad option O N NH OH H2N heterocyclic compound seen as a cyclic amine Mircea Darabantu, MASTER DIA. I N T R O D-4 Example 4: Imine or enamine ? It doesn’t matter… H H sp2 sp3 RN R OH NH H 2 H (masked) H enamine R O H H NH2 sp2 sp3 H RN NR H (masked) imine enamine Example 5: Retrosynthesis of pyrroles seen as hydrolytic disconnection: basic basic + center +H+ +H center 4 3 H3C 5 2 CH3 H3C CH3 H3CCH3 H3CCH3 N1 H O NH H ON OO H H 2,5-dimethylpyrrole NH3 acid seen as acid double enamine -H+ center center -H+ enamine enol Example 6: the importance of the formal charges Rings containing Nitrogen +1 +1 +1 H H H -1 H -2 +1 -3 +1 +1 +2 +1 +1 RN R OH NH R O 2 x (+1) -2 2 NH2 H +1 -3 -2 -3 +1 2 x (+1) Rings containing Sulphur +1 the best precursor +1 +1 H H H -1 H H -2 +1 -2 +1 +1 +2 +1 H +1 +1 +1 RS R OH SH R O -2 SH +1 -2 -2 -2 & Rings containing Oxygen R +1 X Y +1 +1 H best % H H -1 H -2 electrophile best +1 -2 +1 +1 +2 +1 nucleophile +1 +1 +1 RO R OH OH R O OH -2 +1 -2 -2 -2 Mircea Darabantu, MASTER DIA. I N T R O D-5 To be kept in mind: 1. If a hydrolytic disconnection appears suitable, the best pair nucleophile-electrophile sould be considered 2. All cyclisations (or cyclocondensations) involve classic tautomerism: keto-enolic, imino-enamine, etc. 3. During cyclocondensation (or retrosynthetic hydrolytic disconnection) no global redox process, involving the whole molecule occurs. 1.2. 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: - a five membered hetarene: it looks like "organic" O O i) cut (remove) the bonds add two functional between the organic groups at both ends and inorganic parts of the "cation" N ii) add the formal charges +1 +1 to "neutralise" charges -1 -1 H HO [] OH N -3 +1 +1 H-1 -3 3x(+1) NH3 p r e c u r s o r s it looks like it sounds like "inorganic" 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: - a six membered hetarene redox disconnection +2 +1 +2 H3C NCH3 H3C +1 CH3 H3C -2 CH3 -2O OH N3- +1 -3 NH3 3x(+1) ? ? ? 1 3 5 7 h H3CCH3 2[H] 2 4 6 OO H C CH 3 O O 3 2,6-heptanedione Z-1,4-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.