Tandem Diels-Alder Cycloaddition/Aromatization of Biomass-Derived 2-Methylfuran Toward Renewable N,N-Diethyl-3-Methylbenzamide.

Abstract

Biomass holds significant promise as a sustainable feedstock for replacing petrochemical products in green chemical synthesis. Among biomass-derived molecules, furan serves as a key building block for constructing diverse, high-value bioactive molecules. Herein, this study presents a highly chemoselective and regioselective Diels-Alder (D-A) reaction between biomass-derived monosubstituted furans and acrylamides, followed by aromatization, enabling the efficient synthesis of the bioactive molecule N,N-Diethyl-3-methylbenzamide (DEET) with excellent selectivity. Notably, the catalyst (Hf(OTf)4) serves not only as the Lewis acid center but also as a conformation-directing template and intermediate stabilizer in this reaction. Gram-scale syntheses were performed in both tubular and continuous-flow reactors, confirming the scalability of this process. This methodology offers broad applicability for the regioselective synthesis of multisubstituted aromatic products from biomass-derived furans, providing a novel approach for the high-value conversion of biomass into bioactive molecules.