Rapid Access to β-Trifluoromethyl-Substituted Ketones: Harnessing Inductive Effects in Wacker-Type Oxidations of Internal Alkenes†
Michael M. Lerch
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorDr. Bill Morandi
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorZachary K. Wickens
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorCorresponding Author
Prof. Dr. Robert H. Grubbs
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)Search for more papers by this authorMichael M. Lerch
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorDr. Bill Morandi
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorZachary K. Wickens
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorCorresponding Author
Prof. Dr. Robert H. Grubbs
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)Search for more papers by this authorWe gratefully acknowledge financial support from the King Abdullah University of Science and Technology Centre in Development, King Fahd University of Petroleum and Minerals, and the NSF. Furthermore, we thank the Gordon and Betty Moore Foundation, the SNSF for a fellowship to B.M., and the Swiss Study Foundation for a fellowship to M.M.L.
Graphical Abstract
Synthetically highly desirable β-trifluoromethyl-substituted ketones can be rapidly accessed by a trifluoromethyl-directed Wacker oxidation starting from alkenes bearing an allylic trifluoromethyl group (see scheme). This effect seems to be dominantly inductive and can override coordinative effects. The reaction has a broad substrate scope and affords products in high yields and very high regioselectivity.
Abstract
We present a practical trifluoromethyl-directed Wacker-type oxidation of internal alkenes that enables rapid access to β-trifluoromethyl-substituted ketones. Allylic trifluoromethyl-substituted alkenes bearing a wide range of functional groups can be oxidized in high yield and regioselectivity. The distance dependence of the regioselectivity was established by systematic variation of the number of methylene units between the double bond and the trifluoromethyl group. The regioselectivity enforced by traditional directing groups could even be reversed by introduction of a competing trifluoromethyl group. Besides being a new powerful synthetic method to prepare fluorinated molecules, this work directly probes the role of inductive effects on nucleopalladation events.
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