Reductive alkylation of pyridinium salts. Part 1. Synthesis of di-, tetra- and hexa-hydropyridine esters

Abstract

Reaction of 1-methyl-, 1-benzyl- and 1-benzoyl-4-ethoxycarbonylpyridinium salts 1 with zinc and benzyl bromide produce regioselectively the 4,4-disubstituted 1,4-dihydropyridines 3 (R = CH₃, PhCH₂, PhCO); only the latter is stable but all are reduced catalytically to piperidines 2 (R = CH₃, PhCH₂, PhCO). 1-Benzoyl-4-ethoxycarbonylpyridinium chloride with zinc and benzoyl chloride or ethyl bromoacetate gives respectively 4-benzoyl- 18 or 4-ethoxycarbonylmethyl-1-benzoyl-4-ethoxycarbonyl-1,4-dihydropyridine 17, but 1-methyl-4-ethoxycarbonylpyridinium iodide 1 (R = CH₃, X = I) with benzoyl chloride gives 3-benzoyl-4-ethoxycarbonyl-1-methyl-1,2-dihydropyridine 21. The action of zinc and benzyl bromide on 1-methyl- and 1-benzyl-3-ethoxycarbonylpyridinium salts 5 gives, after catalytic hydrogenation, mixtures of 2- and 4-benzyl-5-ethoxycarbonyl-1,2,3,4-tetrahydropyridines 6 and 7 (R = CH₃ or PhCH₂) but similar treatment of 1-benzoyl-3-ethoxycarbonylpyridinium chloride 5 (R = PhCO, X = Cl) yields selectively the stable 4-benzyl-3-ethoxycarbonyl-1,4-dihydropyridine 9. Treatment of 1-methyl- or 1-benzoyl-3-ethoxycarbonylpyridinium salts 5 with zinc and benzoyl chloride gives a mixture of products. 1-Methyl-2-ethoxycarbonylpyridinium iodide 11 (R = CH₃, X = I) reacts with zinc and benzyl bromide giving, after catalytic hydrogenation, 2-, 4- and 6-benzyl-2-ethoxycarbonyl-1-methylpiperidines 12, 13 and 14 (R = CH₃) in the ratio 2:7:1, but 1-benzyl-2-ethoxycarbonylpyridinium bromide 11 (R = PhCH₂, X = Br) gives only 1,4-dibenzyl-2-ethoxycarbonylpiperidine 13 (R = PhCH₂).