A Base-Free, Low Temperature Click and Release Reaction for the In Situ Generation of Diazomethane

Diazomethane is a powerful reagent for numerous chemical reactions such as esterifications and the homologation of carboxylic acids. Unfortunately, the synthetic utility of diazomethane is severely limited by its toxicity and highly explosive nature. Diazald((R)) is typically used for ex situ synthesis, however it requires cumbersome and hazardous transfer of diazomethane from a caustic aqueous phase to the reaction medium. Herein, we present a low temperature and base-free insitu synthesis of diazomethane via a "click and release" reaction between an enamine and sulfonyl azide. Its utility is exemplified by the synthesis of diverse methyl esters in yields of up to 93%. Moreover, diazoketone synthesis from insitu generated diazomethane and acid chlorides was demonstrated for the first time. Finally, trideuteromethylation was achieved using acetone-d(6) as the deuterium source. We anticipate that this method will enable the safer use of diazomethane in organic synthesis and drug discovery programs.