Toward Greener Amide Synthesis: An Anisole-Based Route from Biomass-Derived Furoic Acid with Simplified Isolation

Amide bond formation is a crucial transformation in organic synthesis, and remains a challenge, particularly when aromatic animes are involved.¹ Herein, we present a mechanistic and operational study of an EDC/DMAP-mediated Steglich reaction² conducted entirely in anisole, a benign renewable solvent,³ using lignocellulosic biomass-derived furoic acid as a sustainable building block.⁴ Optimal reaction conditions (40 °C, 3 h) allowed the synthesis of ten N-phenylfuran-2-carboxamides in 28–83% yields. Structural and mechanistic evaluations revealed that reactivity in anisole is primarily dictated by steric control. Ortho-substituted anilines caused severe spatial repulsion toward the bulky acyl-pyridinium intermediate, yielding the lowest conversions (28–56%). Conversely, electronic effects proved secondary, as para-nitro substitution yielded 80%. Operationally, generating a protonatable tertiary urea by-product enabled clean isolation of amides via simple acid-base liquid-liquid extraction,⁵ completely avoiding chromatographic purification and consolidating a selective, chromatography-free, and eco-friendly route to biomass-derived functional heterocycles.