Synthesis of 3-Halo- and 3-Formyl-4-alkylpyridines

Abstract

In the presence of a catalytic amount of cuprous iodide, the addition of Grignard reagents t o the 1-phenoxycarbonyl salts of 3halopyridines gives 4-alkyl-3-halo-l-phenoxycarbonyl-l,4-dihydropyridines.The crude dihydropyridines were aromatized with 2-chloranil to give 4-alkyl-3-halopyridines.Several 4-alkylnicotinaldehydes were synthesized in a similar manner from the cyclic acetal (1.3-dioxolane) of 3-pyridinecarboxaldehyde.After aromatization with sulfur, the crude acetals were hydrolyzed vith oxalic acid to give the desired pyridinecarboxaldehydes.We recently described a convenient method for the synthesis of I-acyl-4-alkyl(ary1)-1.4- dihydropyridines via the regioselective addition of Grignard reagents to 1-acylpyridiniun salts in the presence of a catalytic amount of cuprous iodide.ls2The 1-acyldihydropyridines can be aromatized with hot sulfur or chloranil to provide substituted pyridines in moderate to good yield.W e have been studying the scope of this pyridine synthesis with regard t o what substituents can be present on the pyridine ring during the Grignard reaction.The 1acylpyridinium salts are so reactive toward Grignard reagents that addition to the pyridine ring will occur in the presence of other reactive functional groups, such as ester^.^.^Thus, 4-substituted methyl nicotinates can be prepared from methyl nicotinate using this two-step p r o c e d ~r e .~ Halopyridines have been reported to undergo metal-halogen exchange vith aryl Grignard reagent^;^ however, we have shown that aryl Grignard reagents add readily to the 1phenoxycarbonyl salt of 3-bromopyridine t o give 4-and 6-aryl-3-bromopyridines after aromatization of the intermediate dihydropyridine~.~He have studied the copper-catalyzed Grignard reaction with the I-phenoxycarbonyl salts of 3chloro-and 3-brornopyridine (1).Nearly exclusive 1.4-addition results to give 4-alkyl-3-halo-I-phenoxycarbonyl-1,4-dihydropyridines 2. The crude dihydropyridines were aromatized with 2-chlorani16 in toluene-acetic acid to give 4-alkyl-3-halopyridines 3 in moderate to good yield.The results are given in Table 1.o-chloranil ___* 2 X = C 1 , Br 3 X = CI, Br R = alkyl, aryl R = alkyl, aryl Table I.Synthesis of 4-Alkyl-3-halopyridines 3 --.----.