Regioselective α-Lithiation of Unsymmetrical 1-(tert-Butoxycarbonyl)-1,4-dihydropyridines

Article abstract of DOI:10.1021/jo00254a003

The α-lithiation-methylation of unsymmetrical C-3-substituted 1-(tert-butoxycarbonyl)-1,4-dihydropyridines was studies.The yield and regioselectivity, C-2 vs C-6, of the metalation was dependent upon the C-3 substituent, the metalation base, and the reaction conditions.When the C-3 substituent was a methyl or methoxy group, and mesityllithium was the base, C-6 lithiation-methylation occurred predominately.With a strongly ortho-directing C-3 substituent , i.e., Cl, Br, OCONEt2, metalation with phenyllithium occurred mainly at C-2.An α-amino alkoxide function at C-3 acted only as a blocking group, forcing lithiation to occur mainly at C-6.Two new trisubstituted pyridines, 3-<(N,N-diethylcarbamyl)oxy>-2,4-dimethylpyridine and 2,4-dimethyl-3-pyridinecarboxaldehyde, were prepared by aromatization of regioselectively alkylated 1,4-dihydropyridine intermadiates with o-chloranil or sulfur in refluxing decalin, demonstrating a new approach to pyridine substitution.