Regiodivergent N1- and C3-carboxylation of indoles

Abstract

Regioselective carboxylation of indoles using CO₂ remains a long-standing challenge, particularly for achieving controllable access to both N1- and C3-carboxylated products under unified conditions. Herein, we report a temperature-controlled, regiodivergent strategy for indole carboxylation enabled by cesium triphenylacetate as a mild CO₂-transfer reagent. This metal-free protocol allows selective N1- or C3-carboxylation from the same indole substrates simply by adjusting the reaction temperature and reagent loading, without external CO₂ pressure or strong bases. The method exhibits broad substrate scope, predictable regioselectivity, and good functional-group tolerance, and is readily applicable to near-stoichiometric ¹³C isotope labeling. Mechanistic studies reveal that reversible N1-carboxylation and temperature-dependent redistribution of a delocalized indolyl anion are responsible for the observed regioselectivity. This work establishes a unified and practical platform for regiodivergent indole carboxylation and introduces a distinct CO₂-transfer paradigm for regioselective C–H functionalization of heteroarenes.