IR and NMR Reaction Monitoring Techniques for Nucleophilic Addition Reactions: In Situ Monitoring of the Addition of Benzimidazole to a Pyridinium Salt

Abstract

This study centers on the use of in situ FTIR spectroscopy and online NMR to study the nucleophilic addition of benzimidazole analogues to an N-methylpyridinium salt. The reaction consists of two stages. First, the protected benzimidazole was lithiated with LDA to form the C-2 lithiated benzimidazole. The lithiated benzimidazole was then added to the pyridinium salt to generate the coupled product. The lithiated benzimidazole was not thermally stable, so offline sampling was challenging. A good understanding of the reaction completion of the lithiation was needed for process understanding as well as to provide a basis to determine the fate of the lithiated benzimidazole through the entire addition sequence. In situ FTIR and online NMR provided online methods for monitoring the reaction sequence and studying the temperature-dependent stability of the lithiated benzimidazole.