Lewis acid-mediated formamidation employing carbohydrates as synthons

Abstract

A practical formamidation using air as the sole oxidant and a Lewis acid as the catalyst, without the need for exogenous oxidants or stoichiometric additives, was developed. This catalytic system efficiently achieved N-formamidation of glucose with various amines under mild conditions, affording high yields of diverse N-formamides and a turnover number of 83 213, the highest value reported to date for analogous reactions. Isotope labeling experiments (D-, ¹³C₆-glucose, and ¹⁸O₂) confirmed that the carbon originated from glucose C1, the formyl hydrogen from the C–H bonds at glucose C2–C6, the N–H hydrogen from glucose hydroxyl groups, and the oxygen from O₂. The mechanistic study reveals that the Lewis acid not only promotes the dehydration–isomerization of glucose but also accelerates its selective oxidation by air, thereby driving the condensation–oxidation cascade reaction efficiently.