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Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism

Cho, Hyungdo and Suematsu, Hidehiro and Oyala, Paul H. and Peters, Jonas C. and Fu, Gregory C. (2022) Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism. Journal of the American Chemical Society, 144 (10). pp. 4550-4558. ISSN 0002-7863. doi:10.1021/jacs.1c12749.

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Transition-metal catalysis of substitution reactions of alkyl electrophiles by nitrogen nucleophiles is beginning to emerge as a powerful strategy for synthesizing higher-order amines, as well as controlling their stereochemistry. Herein, we report that a readily accessible chiral copper catalyst (commercially available components) can achieve the photoinduced, enantioconvergent coupling of a variety of racemic tertiary alkyl electrophiles with aniline nucleophiles to generate a new C–N bond with good ee at the fully substituted stereocenter of the product; whereas this photoinduced, copper-catalyzed coupling proceeds at −78 °C, in the absence of light and catalyst, virtually no C–N bond formation is observed even upon heating to 80 °C. The mechanism of this new catalytic enantioconvergent substitution process has been interrogated with the aid of a wide array of tools, including the independent synthesis of proposed intermediates and reactivity studies, spectroscopic investigations featuring photophysical and EPR data, and DFT calculations. These studies led to the identification of three copper-based intermediates in the proposed catalytic cycle, including a chiral three-coordinate formally copper(II)–anilido (DFT analysis points to its formulation as a copper(I)–anilidyl radical) complex that serves as a persistent radical that couples with a tertiary organic radical to generate the desired C–N bond with good enantioselectivity.

Item Type:Article
Related URLs:
URLURL TypeDescription
Cho, Hyungdo0000-0001-6109-5742
Suematsu, Hidehiro0000-0002-9444-7254
Oyala, Paul H.0000-0002-8761-4667
Peters, Jonas C.0000-0002-6610-4414
Fu, Gregory C.0000-0002-0927-680X
Additional Information:© 2022 American Chemical Society. Received 3 December 2021. Published online 7 March 2022. This study is dedicated to Prof. K. Barry Sharpless on the occasion of his 80th birthday. Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences: R01-GM109194), the Korea Foundation for Advanced Studies (graduate research fellowship to H.C.), the National Science Foundation (support of the Caltech EPR Facility; NSF-1531940), the Arnold and Mabel Beckman Foundation (support of the Beckman Institute Laser Resource Center and the Molecular Materials Resource Center), and the Dow Next-Generation Educator Fund (grant to Caltech). We thank Dr. Bruce S. Brunschwig (Molecular Materials Resource Center), Dr. Mona Shahgoli (Mass Spectroscopy Facility), Dr. Michael K. Takase (X-ray Crystallography Facility), Dr. David Vander Velde (NMR Facility), Dr. Scott C. Virgil (Center for Catalysis and Chemical Synthesis), Dr. Jay R. Winkler (Beckman Institute Laser Resource Center), Dr. Caiyou Chen, Dr. Heejun Lee, Dr. Felix Schneck, Dr. Cooper Citek, Dr. Jaika Dörfler, Dr. Dylan J. Freas, Dr. Pablo Garrido Barros, Dr. Giuseppe Zuccarello, Dr. Suzanne M. Batiste, Christian M. Johansen, and Ammar Ibrahim for technical assistance and/or helpful discussions. The authors declare no competing financial interest. Accession Codes: CCDC 2098015–2098016, 2098018–2098019, 2098022, and 2125108 contain the supplementary crystallographic data for this paper.
Funding AgencyGrant Number
NIHR01 GM109194
Korea Foundation for Advanced StudiesUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
Dow Next Generation Educator FundUNSPECIFIED
Subject Keywords:Anions, Substitution reactions, Catalysts, Electrophiles, Alkyls
Issue or Number:10
Record Number:CaltechAUTHORS:20220307-188438000
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Official Citation:Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism. Hyungdo Cho, Hidehiro Suematsu, Paul H. Oyala, Jonas C. Peters, and Gregory C. Fu. Journal of the American Chemical Society 2022 144 (10), 4550-4558; DOI: 10.1021/jacs.1c12749
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113767
Deposited By: George Porter
Deposited On:08 Mar 2022 16:25
Last Modified:28 Mar 2022 22:39

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