Synthesis of 1,4-Dihydropyridines by Cyclocondensation Reactions

Abstract

This review surveys the l a t e s t developments pertaining t o the preparation of 1.4-dihydropyridines using Hantzsch synthesis and other cyclocondensation reactions.The chemistry o f dihydropyridines (DHP) up t o the year 1980 had been reviewed i n several surveys of literature1-3.Among the different isomers, 1.4-DHP merits special attention, the i n t e r e s t i n these compounds increasing progressively.Investigations along these l i n e s include the synthesis of model compounds NAD(P)H-analogues o f 1.4-dihydronicotinamideand t h e i r involvement i n hydrogen transfer reactions.Recently, several review papers have appeared on the subject4-' including the transfer o f hydrogen and other groups by c h i r a l DHP~".Another b i g issue i s the application of 1.4-DHP i n medicine and industry.These compounds are c h i e f l y obtained by using various modifications o f Hantzsch synthesis.Most extensively studied are the calcium antagonists, whose synthesis1' and properties11-13 have been treated i n a number o f reviews.Several papers describe investigations of individual drugs14-l6 such as vasodilators and antihypertensive remediesnifedipine, nitrendipine.Calcium transport agonists have been also found among ~, ~-D H P ' ~-~' .1.4-MP possess antioxidant 21-26 ( d i l u d i n i s r o u t i n e l y usedZ7), h e p a t o p r o t e ~t i v e ~~-~~.a n t i t ~m o u r ' ~-' ~, antimutagenic'" geroprotec-tive3', antiatheros~lerotic~~'~~, b r o n ~h o d i l a t i n ~~~, a n t i d i a b e t i ~~" ~~, h e r b i c i d a ~~l -~~, photosen-~i t i z i n g ~~-~~ a c t i v i t i e s .1.4-DHP can be applied t o promote drug transfer across the blood-brain 47-49 b a r r i e r .The present review paper surveys l i t e r a t u r e data on the synthesis of 1.4-dihydropyridines by way of cyclocondensation published i n the years 1981-1985.Beyond the scope of t h i s paper remain the 1, 4-DHP systems w i t h an exocyclic double bond (pyridones, p ~r i d i n e t h i o n e s , pyridonimines) 1. Hantzsch Svnthesis and Related Cyclocondensations Various modifications o f Hantzsch-type cyclocondensation reactions have been widely applied t o prepare mono-and p o l y c y c l i c 1,4-DHP, the p r i n c i p a l pathways being outlined i n scheme 1.As the same o r s t r u c t u r a l l y r e l a t e d 1.4-DHP can be frequently obtained v i a d i f f e r e n t synthetic pathways, they w i l l be discussed on the basis of t h e i r structures and not the synthetic methods used f o r t h e i r preparation.Scheme 1. l.l.Monocyc1 i c 1,44ihydropyridines 1.1.1.Substituents a t P o s i t i o n 1 The v a s t m a j o r i t y of 1.4-DHP prepared by Hantzsch synthesis are 1-unsubstituted.Several I-subs t i t u t e d a,@-unsubstituted 1,4-DHP 1 have been synthesized by method E. Malonodialdehyde i s used as a B-dicarbonyl component i n method A t o form 1.4-DHP 252-56.A modification of method A i n v o l v i n g the use of amine c h l o r i d e i n p y r i d i n e affords 1-alkyl-1.4-DHP3.Aromatic amines g i v e 1-aryl-2,6-dimethyl-l,4-~4iP 4a60 (method A) and 1-aryl-2.6-unsubstituted1, 61 4-DHP 2 (method F ) .The c y c l i z a t i o n of 1,s-diketones w i t h hydroxylamine allows t o o b t a i n l-hydr-