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

Reaction of 2‐(3‐,4‐)pyridinecarboxaldehydes 5 with carbomethoxymethylene triphenylphosphorane afforded predominantly E ‐methyl‐3‐(pyridinyl)‐2‐propenoates 7. Oxidation of 7a‐c with m ‐chloroperbenzoic acid gave methyl E ‐3‐(1‐oxidopyridinyl)‐2‐propenoates 8a‐c in high yield. The Darzen's reaction of 5a‐c with methyl bromoacetate yielded a mixture of stereoisomers cis ‐ 9a‐c and methyl trans ‐3‐(pyridinyl)‐2,3‐epoxy‐propanoates 10a‐c in a ratio of 2:1. Oxidation of cis ‐ 9a‐c and trans ‐ 10a‐c afforded the corresponding cis ‐ 11a‐c and methyl trans ‐3‐(1‐oxidopyridinyl)‐2,3‐epoxypropanoates 12a‐c in good yield. The reaction of 11a and 12a with cyclic amines as piperidine gave the respective threo ‐ 13 and methyl erythro ‐2‐(1‐piperidino)‐3‐hydroxy‐3‐(1‐oxido‐2‐pyridino)propanoate 14. The sodium borohydride reduction of the N ‐alkoxylcarbonyl pyridinium salts of 9c and 10c afforded the corresponding N ‐alkoxycarbonyl‐1,2‐dihydropyridyl derivatives 15 and 16. A number of selected compounds ( 7a‐c , 9a‐c , 10a , 10c , 11a‐c and 12a , 12c ) were found to be inactive in the P388 Lymphocytic screen. Compounds 9‐12 did not react with the model nucleophile ethanethiol in phosphate buffer at 37°.