Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides

We report a highly robust, general and stereoselective method for the synthesis of 3-(chloro­meth­yl­ene)­oxindoles from alkyne-tethered carbamoyl chlorides using PdCl2(PhCN)2 as the catalyst. The transformation involves a stereo- and regioselective chloro­pallad­ation of an internal alkyne to generate a nucleophilic vinyl PdII species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases and can be used to access biologically relevant oxindole cores. Through combined experimental and computational studies, we provide insight into stereo- and regioselectivity of the chloro­pallad­ation step, as well as the mechanism for the C–C bond forming process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a high valent PdIV species, which then undergoes facile C–C reductive elimination to form the final product. Overall, the transformation constitutes a formal PdII-catalyzed intramolecular alkyne chlorocarbamoylation reaction.