Oxidative Amide Coupling from Functionally Diverse Alcohols and Amines Using Aerobic Copper/Nitroxyl Catalysis

The aerobic Cu/ABNO catalyzed oxidative coupling of alcohols and amines is highlighted in the synthesis of amide bonds in diverse drug‐like molecules (ABNO=9‐azabicyclo[3.3.1]nonane N‐oxyl). The robust method leverages the privileged reactivity of alcohols bearing electronegative hetero‐ atoms (O, F...

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Veröffentlicht in:Angewandte Chemie International Edition 2019-08, Vol.58 (35), p.12211-12215
Hauptverfasser: Piszel, Paige E., Vasilopoulos, Aristidis, Stahl, Shannon S.
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Sprache:eng
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Zusammenfassung:The aerobic Cu/ABNO catalyzed oxidative coupling of alcohols and amines is highlighted in the synthesis of amide bonds in diverse drug‐like molecules (ABNO=9‐azabicyclo[3.3.1]nonane N‐oxyl). The robust method leverages the privileged reactivity of alcohols bearing electronegative hetero‐ atoms (O, F, N, Cl) in the β‐position. The reaction tolerates over 20 unique functional groups and is demonstrated on a 15 mmol scale under air. Steric constraints of the catalyst allow for chemoselective amidation of primary amines in the presence of secondary amines. All catalyst components are commercially available, and the reaction proceeds under mild conditions with retention of stereocenters in both reaction partners, while producing only water as a by‐product. Cu/ABNO‐catalyzed oxidative amidation is shown to be highly effective in the cross coupling of complex alcohols and amines. The reactions exploit the unique reactivity of β‐heteroatom‐substituted alcohols to enable access to diverse products with pharmaceutically relevant functional groups.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201906130