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

ABSTRACT 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‐CF 3 /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‐CF 3 amine bioisosteres using the exact carboxylic acid feedstocks from the original active molecules, thereby establishing a robust and practical approach for drug discovery.