Efficient Synthesis Of Primary Benzamides From Benzyl Alcohols: A One-Pot, Two-Stage Chemoenzymatic Strategy

Amides are crucial compounds with widespread applications in the polymer, plastic, detergent, lubricant, pharmaceutical and agrochemical sectors.[1] Among them, primary benzamides hold importance in medicinal chemistry and serve as key intermediates in numerous transformations.[2] Nonetheless, traditional methods for their synthesis are often hampered by low atom economy, the need for reagent activation, high costs and undesirable side reactions.[3] In contrast to catalytic methods involving transition metals and enzymes (e.g. nitrile hydratases),[4] strategies combining the oxidation of alcohols followed by amidation are still underdeveloped. To this aim, a one-pot, two-stage (i.e., two steps separated in time) chemoenzymatic strategy was devised for the synthesis of primary benzamides from benzyl alcohols. This protocol combines an enzymatic oxidation step, catalyzed by a variant of the galactose oxidase from Fusarium sp. M3-5 (GOx),[5] and a Cu(II)-catalyzed amidation with N,N-diethylhydroxylamine (Scheme 1). Optimization revealed that Et2NOH plays a crucial role in the conversion rate but also inhibits GOx, thus preventing the two steps from running simultaneously. A variety of substituted benzyl alcohols were converted into the corresponding benzamides (9.2-70.3% conversion) and selected reactions were scaled up successfully (38-63% isolated yield). Scheme 1. Chemoenzymatic conversion of benzyl alcohols into primary benzamides (GOx-CFE stands for GOx cell free extract). [1] J. Boström, D. G. Brown, R. J. Young, G. M. Keserü, Nat. Rev. Drug Discov. 2018, 17, 709-727. [2] B. J. Monk et al., Ann. Oncol. 2024, 35, 981-992. [3] M. T. Sabatini, L. T. Boulton, H. F. Sneddon, T. D. Sheppard, Nat. Catal. 2019, 2, 10-17.