Two-step synthesis of a-aryl a-diazoamides as versatile tools for chemical biology

Diazo compounds are highly attractive for their versatile reactivity in organic synthesis. Since the first discovery of diazomethane by Pechmann in 1894, the rich and tunable reactivity of diazo groups has been exploited to build functional chemical compounds via thermal, photochemical, or transition-metal-mediated carbenoid formation. Nevertheless, diazo compounds have not been utilized often in chemical biology. Recently, we demonstrated that α-aryl-α-diazoamides can serve as unprecedent “bioreversible” esterification reagents in physiological contexts. Specifically, aryl α-diazoamides can chemoselectively esterify carboxyl groups in proteins (ribonuclease A, green fluorescent protein, and cytochrome C), which can be reversely de-esterified by the action of intracellular esterases. The critical attribute of efficacious diazo compounds is their basicity, which leads to the abstraction of a proton from a carboxylic acid but not water and, thereby, to the esterification of carboxyl groups in an aqueous solution. Although this application of α-aryl-α-diazoamides has demonstrated promise, synthetic accessibility has been a major deterrent to progress. Therefore, we introduce a rapid synthetic route to generate α-aryl α-diazoamides in two steps under mild conditions. We successfully synthesized succinimide-functionalized aryl diazoacetates via Pd-catalyzed C−H arylation in the presence of a diazo moiety (10 examples, ≤95% yield) followed by amine displacement to generate α-aryl α-diazoamides in overall yields of up to 71% (16 examples). We further demonstrate that α-aryl α-diazoamides can label the carboxyl groups of small molecules and proteins in an aqueous solution. The versatility and facility of these synthetic routes expand the utility of diazo compounds in chemical biology.