Ambident heterocyclic reactivity: Intramolecular alkylations of 2,4-disubstituted benzimidazoles

Abstract

Abstract Alkali induced intramolecular cyclizations of 2-(3-chloropropyl)- and 2-(4-chlorobutyl)-4-substituted benzimidazoles bearing 4-nitro-, 4-amino-, and 4-methyl groups show enhanced N 3 N 1 regioselectivity compared to the corresponding intermolecular alkylations with 1-chlorobutane. The observed N1:N3 cyclization ratios vary from 94:6 to 10:90, with the largest preference for reaction at the ‘congested’ N3-site occurring in the 5-membered ring formation. In contrast, related base induced reactions of (2-benzimidazoly)methyl chloroacetate and 3-(2-benzimidazoly)propyl chloroacetate give excellent yields of macrocyclic dimeric systems. These results are interpreted as involving interplay between electrostatic field, through-bond electronic, and steric approach control factors within variable geometry SN2 transition state structures. Calculations (AM1 and molecular mechanics) on these systems and conformational analysis of the expected transition states for the intramolecular cyclizations do not support any appreciable use of out-of-plane approach trajectories for these heterocyclic N-alkylation reactions.