Amino Acid-Promoted Synthesis of 2H-Chromenes

The 2H-chromene heterocycle is found in numerous natural products and biologically active compounds of medicinal significance, making it a recognized privileged scaffold in drug discovery. In this work, aliphatic amino acids─particularly l-alanine─are employed to promote the synthesis of 2H-chromenes from nucleophilic phenols (resorcinols) and enals under heating in toluene or propyl acetate. These amino acids represent sustainable, biobased alternatives to oil-based amines, exhibiting comparable efficiency in this transformation. The reaction proved to be readily scalable and demonstrated a broad substrate scope. The reaction is proposed to proceed via an annulation reaction involving an electrophilic iminium intermediate, formed through the reaction of the amino acid with the enal substrate, which subsequently reacts with the nucleophilic phenol. Several natural products were synthesized in a single step from readily available materials─like Radula chromenes, cannabichromene, octandrenolone, α-xiloidone B, ranhuadujuanine B, precocenes, flindersine, arahypin-5, and arachidin-6─with some products successfully prepared on a multigram scale.