Mechanism of the reaction of 2-haloketones with 2-aminopyridine

Abstract

Time-dependent 1H NMR spectra of DMSO-d 6 solutions of p-substituted phenacyl bromides and 2-aminopyridine indicate that the formation of imidazo[1,2- a]pyridines occurs via two relatively long-lived intermediates, C and D, which are in equilibrium with each other. The assigned structures are in accord with chemical shifts, pK a estimates, and substituent effects (-OMeCH 3, -H, and -NO 2) on both the equilibrium constant ( C⇌ D) and rates of reaction. The slowest step in the reaction with phenacyl bromide is conversion of the intermediate D to product E. With phenacyl chloride no intermediates are observed and initial formation of C determines the overall rate. Even through the intermediate D is already protonated, its conversion to E is subject to acid catalysis. Compared to the p-OMe substituent, the p-NO 2 group enhances the rate of formation of C and D by a factor of only 2.6. The same rate enhancement is observed in the reaction of pyridine with phenacyl bromides. Rates of reaction of a given phenacyl halide with pyridine and 2-aminopyridine are similar. It is concluded that the initial reaction is alkylation of the pyridine nitrogen atom to give C and that the other possible initial condensation product, the carbinolamine F, cannot be a kinetically significant intermediate. Reasons for preferred N-alkylation are presented. Recommendations for improved syntheses of imidazo[1,2- a]pyridines are included.