Lewis Acid-Mediated Formamidation Employing Carbohydrates as Synthons

Abstract

A practical formamidation method 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 Nformamidation of glucose with various amines under mild conditions, affording high yields of structurally diverse Nformamides 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 significantly accelerates its selective oxidation by air, thereby driving the condensation-oxidation cascade reaction efficiently.