Catalyst- and solvent-free Csp2–H functionalization of 4-hydroxycoumarins via C-3 dehydrogenative aza-coupling under ball-milling

Abstract

A one-pot procedure for the synthesis of biologically relevant coumarin hydrazones using a three-component reaction between 4-hydrocoumarins, primary aromatic amines and tert-butyl nitrite under ball-milling in the absence of any catalysts/additives and solvents has been developed. The mechanical force implements the C_sp²–H functionalization of 4-hydroxycoumarins via C-3 dehydrogenative aza-coupling with ease. The product was isolated by simple washing of the crude reaction residue with aqueous ethanol, followed by simple filtration. No chromatographic purification was required. Catalyst- and solvent-free reaction conditions, use of ball-milling as a green tool, lack of a need for chromatographic purification, broad substrate scope and tolerance for various functional groups, high yields of products at short reaction times (no more than 6 min), a clean reaction profile, and gram-scale synthetic applicability make this procedure green and cost-effective.