Preparation of 3-(alkylamino)imidazo[1,2-a]pyridine-2-carbaldehydes via Kornblum oxidation and unexpected ring-opening reactions of the corresponding alcohols under oxidative conditions.

Abstract

The first synthesis of 3-(alkylamino)imidazo[1,2-a]pyridine-2-carbaldehydes is reported. A Groebke-Blackburn-Bienaymé reaction between 2-aminopyridine derivatives, cyclohexyl isocyanide and glyoxylic acid in the presence of methanol and an acid catalyst gave the 2-ester derivatives that were reduced to give the corresponding alcohols. Mild Kornblum oxidation conditions, reaction in the presence of DMSO and NaHCO₃ under conventional or microwave heating to ≈100 °C, were applied to the bromides derived from these alcohols by treatment with PBr₃, resulting in the desired aldehydes which successfully underwent reductive amination reactions with 2-chloroaniline. Alternative oxidation conditions such as PCC, IBX or T. versicolor laccase applied to the alcohols led only to oxidative ring-opening to give oxalamide derivatives, with no aldehyde being isolated.