Decarboxylative carbonyl alkylative amination: A general and practical strategy for aliphatic amine synthesis

Aliphatic amines are ubiquitous core structural motifs in bioactive molecules including natural products, pharmaceuticals, and agrochemicals, driving ongoing demand for versatile, green, and practical synthetic strategies to construct complex aliphatic amines from inexpensive, readily available, structurally diverse feedstocks. Here, we report an iron-catalyzed decarboxylative carbonyl alkylative amination of aldehydes, amines, and carboxylic acids in HFIP under mild light irradiation at room temperature, with no additional additives and only CO₂ and H₂O as environmentally benign by-products. This protocol exhibits exceptional compatibility with sterically hindered substrates and a broad range of functional groups, enabling late-stage drug modification, hybrid drug conjugation, and pharmaceutical analog synthesis. EPR spectroscopy directly detected carbon- and nitrogen-centered radicals, corroborating the proposed mechanistic pathway where alkyl radicals add to in situ-generated iminium ions to form aminium radical cations. HFIP plays a critical role by accelerating aldehyde-amine condensation, shifting tautomeric equilibria toward reactive iminium ions, and lowering the activation barrier for the key radical addition step.