CuH-Catalyzed Asymmetric Reductive Amidation of α,β-Unsaturated Carboxylic Acids
Achim Link, Yujing Zhou and Stephen L. Buchwald*
*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States,
Email: sbuchwal
mit.edu
A. Link, Y. Zhou, S. L. Buchwald, Org. Lett., 2020, 22, 5666-5670.
DOI: 10.1021/acs.orglett.0c02064
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Abstract
A direct enantioselective copper hydride (CuH)-catalyzed synthesis of β-chiral amides from α,β-unsaturated carboxylic acids and secondary amines under mild reaction conditions tolerates a variety of functional groups in the β-position including several heteroarenes. A subsequent iridium-catalyzed reduction to γ-chiral amines can be performed in the same flask.
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Details
The document discusses a study on the CuH-catalyzed asymmetric reductive amidation of α,β-unsaturated carboxylic acids to synthesize β-chiral amides. This method, developed by Achim Link, Yujing Zhou, and Stephen L. Buchwald, utilizes secondary amines and operates under mild conditions, tolerating various functional groups. The process involves the use of dimethoxy(methyl)silane (DMMS) or 1,1,3,3-tetramethyldisiloxane (TMDS) as hydride sources, achieving efficient amidation at room temperature or 40°C, respectively. The study highlights the method's ability to produce β-chiral amides with high enantioselectivity and good yields, even with complex substrates. Additionally, a one-pot synthesis of γ-chiral amines is demonstrated by adding Vaska’s complex and methanesulfonic acid to the reaction mixture, leading to the formation of γ-chiral amines with excellent yield and enantiomeric ratio. Mechanistic investigations suggest the formation of silyl ester intermediates, which are converted to the desired amides. This approach offers a streamlined, efficient route to β-chiral amides and γ-chiral amines, which are valuable in pharmaceuticals and biologically active molecules. The research was supported by the NIH and the Swiss National Science Foundation.
Key Words
1,4-reduction of α,β-unsaturated compounds, amides, dimethoxymethylsilane
ID: J54-Y2020
