Replacing Metabolically Unstable Amides With Stable α‐Trifluoromethylamines via Decarboxylative Synthesis

Metabolically unstable amide bonds are a well-recognized liability in drug candidates. However, a general and practical strategy to rapidly access their stable bioisosteres directly from common synthetic intermediates is lacking. Here, we report a decarboxylative synthesis of α-trifluoromethylamines from widely available carboxylic acids. This method seamlessly integrates with existing synthetic routes, providing a modular platform for lead optimization. Mechanistically, this transformation is enabled by two key events: a tetramethyl guanidine (TMG)-promoted decarboxylation via an electron donor-acceptor (EDA) complex, and subsequent single-electron oxidation that activates the inert α-C─H bond of trifluoromethyl groups to generate α-CF₃/α-amino carbon radicals. The method exhibits broad functional group tolerance for a diverse range of carboxylic acids, from prevalent bioactive scaffolds such as amino acids, peptides, and uronic acids to complex drug motif itself. This capability enables the direct construction of N-aryl-substituted α-CF₃ amine bioisosteres using the exact carboxylic acid feedstocks from the original active molecules, thereby establishing a robust and practical approach for drug discovery.