Vicinal difunctionalization of nitriles: modular construction of N-alkyl amidines and late-stage modification

Abstract

Through vicinal difunctionalization of nitriles, a successful, innovative strategy for the synthesis of N-alkyl amidines is developed. This methodology capitalizes on commercially available nitriles, alcohols, and sulfonamides. The activation of alcohols by trifluoromethanesulfonic anhydride (Tf₂O) plays a pivotal role throughout the entire reaction process. In comparison to existing amidine synthesis methods, this strategy showcases notable advantages, including the avoidance of toxic and hazardous azides, the exclusion of transition metal catalysts, and the use of mild reaction conditions. Importantly, this methodology provides an effective approach for late-stage modification of complex molecules and drugs, holding promise for the construction of molecular libraries in drug discovery.