Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 138, Issue 43, Pages 14441-14448Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b08925
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Funding
- Alphora Inc.
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- University of Toronto (U of T)
- Canada Council for the Arts
- NSERC
- RWTH Aachen
- MIWF
- NRW
- Evonik Foundation
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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 Pd-II 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 Pd-IV species, which then undergoes facile C-C reductive elimination to form the final product. Overall, the transformation constitutes a formal Pd-II-catalyzed intramolecular alkyne chlorocarbamoylation reaction.
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