The Hantzsch pyridine synthesis 12b ‘As with the Paal-Knorr pyrrole synthesis, making pyridines from 1,5 diketones depends on the availabilty (accessibility) of the starting material. An alternative muliti-component approach, the Hantzsch synthesis, enables pyridines to be made from two B-keto esters (cf. the Knorr pyrrole route). The extra carbon atom comes in the form of the carbonyl carbon of an aldehyde. The Hantzsch synthesis important cardiovascular drugs R are based on this structure a co. wa i Et0.C. Et 107 2! pHes &t0z6. CO2Et [01 EtO,C. Ny COzEt — TU > H3C oO Hs, H3C N’ H. NH H3C’ N ‘CH3 3! I3 dihydropyridine (NHg) imine formation Outline of key steps of synthesis ae R MG R, H Et0,¢. 1, HSC HC 7 HsMechanism of the Hantzsch synthesis 13a The exact sequence of events in a heterocyclic synthesis may vary depending on the conditions. In most cases a sensible guess can be made using knowledge of the chemistry of individual steps The aldol step - (see Bifunctional notes) = =~ KR = = ~ The conjugate addition step - (see Bifunctional notes) R R R oor ce sane —_een HC ‘0 io) ‘CH; HC 0 6 ‘CH H3C 0 0 ‘CH3 6 The cyclisation step - (see these notes - slide 12a) R R EtO,C. CO,Et EtO.C. CO,Et If there was a way to make the NH, enone and enolate separately then a | | unsymmetrical dihydropyridines HCN 7 CH wo Sy 1, Could be made (cf. Knorr pyrrole synthesis).Unsymmetrical pyridines from the Hantzsch synthesis 13b Making the enone component is relatively straightforward (see slide 13a), but in place of the enolate a (semi)stable enamine is used. The enamine is simply the tautomer of the imine derived from ammonia and in this way unsymmetrical dihydropyridines can be made. o RF i Pe fA tautomerisation NH3 R? oe <_— cf. slide 3b enone 5ANy \ 07 SR! o RO ° RQ pe fo} RO R* R? R! H Re R? | I — \ RAR RS Ro N~ ~R 5. 4 R an” ® Nite oo Hy ee “(person H° II transfer 9 RF O on RO o RF O Re ( R? eer R* R2 <—— <— No} RS. R57 N~ Rt Re~ SN~ Rt N~ Rt H H 22 HHantzsch pyridine synthesis: examples CO,CH3 EtO,C. CH oe a pH8S + eee Hyc~ So H,N~ ~CHs Ph 9° Et0,c_ 7 + pH8.s aes H3C" 0 HN’ H3C’ 9° 9 pH8.s 2x + J + NH; ——~—-_, H3C~ ~H ‘0 Ph O° 7 ie pH 8.5 + anne eeenereere ‘0 H.N~ ~Ph 14a