Ambident heterocyclic reactivity: Alkylation of 2-substituted-4-methylbenzimidazoles

Article abstract of DOI:10.1016/S0040-4020(01)80708-0

The regioselectivities were determined for alkylations of 4-methyl-, 2,4-dimethyl-, 2-amino-4-methyl-, 2-chloro-4-methyl-, 2-ethoxy-4-methyl-benzimidazole, and 4-methylbenzimidazolone (as anions in dimethylformamide) with a variety of primary alkylating agents. These N1/N3 regioselectivities are correlated with the second order rate constants for benzylation (benzyl chloride/dimethylformamide/30°) of these heterocyclic anions under comparable conditions. Altering the alkylating agent, R'CH₂Cl, causes movement along the loose-tight axis of S(N)2 transition state structures and produces substantial changes in regioselectivity. Variations along the early-late S(N)2 axis, caused by altering the 2-substituent in the 2-R-4-methylbenzimidazole anions, are much less effective in inducing changes in alkylation regioselectivity. The combined results are consistent with dominant 'steric approach control' for the alkylations, where the magnitude of the steric effect is critically dependent on the length of the developing N---C bond in the variable geometry S(N)2 alkylation transition states involved. Unequal steric effect of 2-substituents on N1 and N3 alkylations and their variation with alkylating agent are explained by invoking the geometry of roughly conical 'approach corridors' to the nitrogen alkylation sites. Temperature effects on these regioselectivities are small for most systems.