Synthesis of C2-symmetric trans-2,6-diarylpiperidinones via aryl cuprate addition: an unexpected stereochemical outcome |
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Authors: | Christopher L Hamblett David L Sloman Bruce Adams Matthew G Stanton |
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Institution: | a Department of Drug Design and Optimization-Medicinal Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States b Department of Medicinal Chemistry, 126 Lincoln Avenue, PO Box 2000, Merck Research Laboratories, Rahway, NJ 07065, United States |
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Abstract: | An efficient procedure for the preparation of trans-2,6-diaryl piperidinones has been developed. Addition of aryl Grignard reagents to 2-aryl dihydropyridones under catalytic copper promoted conditions generates the trans isomer exclusively, an unprecedented stereochemical event. The X-ray structures of both starting material and product have been solved and shed light on the steric constraints and substrate geometry leading to the observed product. The reaction conditions tolerate a variety of aromatic nucleophiles to generate C2-symmetric products in good overall yields. |
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