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Published October 9, 2013 | Accepted Version + Supplemental Material
Journal Article Open

Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β‑Substituted Cyclic Enones: Insights from Computation and Experiment


Enantioselective conjugate additions of arylboronic acids to β-substituted cyclic enones have been previously reported from our laboratories. Air- and moisture-tolerant conditions were achieved with a catalyst derived in situ from palladium(II) trifluoroacetate and the chiral ligand (S)-t-BuPyOx. We now report a combined experimental and computational investigation on the mechanism, the nature of the active catalyst, the origins of the enantioselectivity, and the stereoelectronic effects of the ligand and the substrates of this transformation. Enantioselectivity is controlled primarily by steric repulsions between the t-Bu group of the chiral ligand and the α-methylene hydrogens of the enone substrate in the enantiodetermining carbopalladation step. Computations indicate that the reaction occurs via formation of a cationic arylpalladium(II) species, and subsequent carbopalladation of the enone olefin forms the key carbon–carbon bond. Studies of nonlinear effects and stoichiometric and catalytic reactions of isolated (PyOx)Pd(Ph)I complexes show that a monomeric arylpalladium–ligand complex is the active species in the selectivity-determining step. The addition of water and ammonium hexafluorophosphate synergistically increases the rate of the reaction, corroborating the hypothesis that a cationic palladium species is involved in the reaction pathway. These additives also allow the reaction to be performed at 40 °C and facilitate an expanded substrate scope.

Additional Information

© 2013 American Chemical Society. Received: February 20, 2013. Publication Date (Web): September 12, 2013. The authors thank NIH-NIGMS (B.M.S., R01 GM080269-01; K.N.H. GM36700), NSF (K.N.H., CHE-0548209), Caltech, Amgen, the American Chemical Society Division of Organic Chemistry (predoctoral fellowship J.C.H.), the Swiss National Science Foundation (postdoctoral fellowship M.G.), and the Japan Society for the Promotion of Science (postdoctoral fellowship K.K.) for financial support. A.N.M. is grateful for a research fellowship by the German National Academy of Sciences Leopoldina (LPDS 2011-12). Prof. Theodor Agapie (Caltech) is thanked for helpful discussions. Dr. David VanderVelde of the Caltech NMR facility is thanked for invaluable assistance with NMR experiments and helpful discussions. Lawrence Henling and Dr. Michael K. Takase (Caltech) are gratefully acknowledged for X-ray crystallographic structural determination. The Bruker KAPPA APEXII X-ray diffractometer was purchased via an NSF CRIF:MU award to the California Institute of Technology, CHE-0639094. The Varian 400 MHz NMR spectrometer at Caltech was purchased via an NIH grant (RR027690). Calculations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF. The authors declare no competing financial interest.

Attached Files

Accepted Version - nihms526312.pdf

Supplemental Material - ja401713g_si_001.pdf

Supplemental Material - ja401713g_si_002.pdf

Supplemental Material - ja401713g_si_003.cif


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August 19, 2023
October 25, 2023