Regioselective N-alkylation of imidazo[4,5- b]pyridine-4-oxide derivatives: an experimental and DFT study

Abstract

Regioselectivities were determined for N-alkylations of imidazo[4,5- b]pyridine-4-oxide and 2-methyl-imidazo[4,5- b]pyridine-4-oxide with benzyl bromide or benzyl iodide at RT using K 2CO 3 in DMF as a base. Experimental attempts have shown that N-1/ N-3 ratios slightly varied according to the substitution on C-2 position. This was confirmed by DFT calculations in solvent phase. This computational study has shown first that this N -benzylation reaction passed through a S N2 mechanism. Moreover, regioselectivity of N-benzylation has appeared essentially governed by ‘steric approach control’. It explained that opposite N-1/ N-3 ratios were obtained with imidazo[4,5- b]pyridine-4-oxide and its 2-methyl-substituted analog. Finally, regioselectivities slightly varied with the nature of benzyl halide.