Pd-Catalyzed One-Pot Synthesis of Indole-3-carboxylic Acids via a Sequential Water-Mediated Nucleophilic Addition to Amides/Esters and Carbon–Heteroatom Cross-Coupling Reaction Strategy

Using 4-bromoindole-3-carboxylic acid derivatives (amides or esters) as substrates, this paper successfully developed a trace water-promoted, palladium-catalyzed “one-pot” reaction strategy for synthesizing 4-amino/alkoxyindole-3-carboxylic acid products. With PdCl2 (5 mol %) as the precatalyst, Xantphos as the ligand, and cesium pivalate as the additive, this synthetic method innovatively integrates nucleophilic substitution of amides/esters with Pd-catalyzed C–N or C–O cross-coupling into a single reaction system, achieving efficient synergy of multistep transformations. This approach facilitates a modular and rapid assembly of multisubstituted indole-3-carboxylic acids, exhibiting broad functional group compatibility while maintaining good reaction yields.