The Hantzsch 1,4-Dihydropyridine Synthesis as a Route to Bridged Pyridine and Dihydropyridine Crown Ethers

Article abstract of DOI:10.1021/jo01302a020

Mono-, di-, tri-, and tetraethylene glycols were transesterified with ethyl acetoacetate to give the bis(acetoacetate esters) 1a-d.On treatment of 1c,d with formaldehyde and excess (NH4)2CO3 in H2O a crude mixture of 1,4-dihydropyridines was obtained from which, after dehydrogenation to the pyridine form, the 3,5-bridged 2,6-dimethylpyridines 2c,d were isolated along with dimers 7c,d.Similar reaction of 1a gave only dimer 7a.The bridged pyridine 2d was methylated to give pyridinium salt 3d, which was reduced with Na2S2O4 to give 1,4-dihydropyridine 4d.Stable sodium salts of 4d and 6d were isolated.Bridged pyridines 10a-c substituted with, respectively, methyl, phenyl, and 2-furyl at the γ position of the pyridine ring have also been prepared, using 1d, (NH4)2CO3, and acetaldehyde, benzaldehyde, and 2-furfuraldehyde and Hantzsch condensation followed by dehydrogenation and chromatographic separation.Protection of the 1,3-dicarbonyl system of ethyl 4-bromo-3-oxobutanoate as its Na chelate followed by nucleophilic substitution with the bisalkoxides from tetra-, penta-, and hexaethylene glycols gave 4-substituted bis(acetoacetate esters) 16a-c.These on Hantzsch condensation yielded in low yield 2,6-bridged Hantzsch 1,4-dihydropyridines (17a-c).Treatment of 17a,b with alkali metal hydrides gave insoluble materials thought to be the internally solvated alkali metal salts of the (vinylogous) amide nitrogen of the 1,4-dihydropyridine.