Pd-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine.

ABSTRACT

Acyl fluorides have recently gained a lot of attention as robust and versatile synthetic tools in synthetic chemistry. While several synthetic routes to acyl fluorides have been reported, a procedure involving direct insertion of the "fluoro-carbonyl" moiety using a single reagent has not yet been realized. Here we report the preparation of acyl fluorides by palladium-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine under CO-free conditions. 2-(difluoromethoxy)-5-nitropyridine is a stable, colorless solid that can be used as an alternative to the toxic gaseous formyl fluoride, which is commonly used under fluoride catalysis conditions. A wide variety of acyl fluorides are efficiently and safely obtained in high yield (up to 99%). A broad range of functional groups is tolerated under the optimized reaction conditions and the method can be applied to the late-stage fluoro-carbonylation of structurally complex Csp2-iodides, including bioactive derivatives, such as Fenofibrate, Isoxepac, and Tocopherol. Furthermore, the one-pot transformation of aryl-iodides, including drug-like molecules, into the corresponding amides by successive fluoro-carbonylation/amidation reactions, demonstrates the potential synthetic utility of this strategy.