Synthesis and reactions of heterocyclic methyl 2‐propenoates and 2,3‐epoxypropanoates with nucleophiles

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Abstract
Reaction of 2‐(3‐,4‐)pyridinecarboxaldehydes5with carbomethoxymethylene triphenylphosphorane afforded predominantlyE‐methyl‐3‐(pyridinyl)‐2‐propenoates7.Oxidation of7a‐cwithm‐chloroperbenzoic acid gave methylE‐3‐(1‐oxidopyridinyl)‐2‐propenoates8a‐cin high yield. The Darzen's reaction of5a‐cwith methyl bromoacetate yielded a mixture of stereoisomerscis‐9a‐cand methyltrans‐3‐(pyridinyl)‐2,3‐epoxy‐propanoates10a‐cin a ratio of 2:1. Oxidation ofcis‐9a‐candtrans‐10a‐cafforded the correspondingcis‐11a‐cand methyltrans‐3‐(1‐oxidopyridinyl)‐2,3‐epoxypropanoates12a‐cin good yield. The reaction of11aand12awith cyclic amines as piperidine gave the respectivethreo‐13and methylerythro‐2‐(1‐piperidino)‐3‐hydroxy‐3‐(1‐oxido‐2‐pyridino)propanoate14.The sodium borohydride reduction of theN‐alkoxylcarbonyl pyridinium salts of9cand10cafforded the correspondingN‐alkoxycarbonyl‐1,2‐dihydropyridyl derivatives15and16.A number of selected compounds (7a‐c,9a‐c,10a,10c,11a‐cand12a,12c) were found to be inactive in the P388 Lymphocytic screen. Compounds9‐12did not react with the model nucleophile ethanethiol in phosphate buffer at 37°.