One‐Pot Synthesis of Primary Amides From Benzylic, Heterobenzylic, and Cinnamyl Alcohols Through Biocatalytic Oxidation and Cu(II)‐Catalyzed Amidation

ABSTRACT

This article describes a one‐pot, two‐stage chemoenzymatic strategy for synthesizing aromatic, heteroaromatic, and α,β‐unsaturated primary amides from the corresponding alcohols. The approach combines our previously reported catalytically promiscuous oxidation of benzylic, heterobenzylic, and cinnamyl alcohols to nitriles—catalyzed by the M _3‐5 variant of galactose oxidase (GOx M _3‐5 ) from Fusarium sp.—with a Cu(II)‐catalyzed amidation using N , N ‐diethylhydroxylamine. Optimization studies showed that the concentration of Et ₂ NOH critically affects conversion and inhibits the enzyme, thereby preventing both steps from being performed concurrently and requiring their temporal separation into a two‐stage process. The substrate scope includes substituted benzyl alcohols, hydroxymethylpyridines, and cinnamyl alcohol, which were converted into the corresponding benzamides, pyridinecarboxamides, and cinnamamide, respectively, with conversions of 7%–70%, as determined by GC and HPLC. Selected reactions were scaled up to 20 mL, affording isolated yields of 38%–63%. Overall, the developed method expands the synthetic toolbox for primary amide synthesis and provides a chemoenzymatic alternative to traditional nitrile hydration or amidation approaches.