Carbonate-promoted C-H carboxylation of electron-rich heteroarenes

C-H carboxylation is an attractive transformation for both streamlining synthesis and valorizing CO₂. The high bond strength and very low acidity of most C-H bonds, as well as the low reactivity of CO₂, present fundamental challenges for this chemistry. Conventional methods for carboxylation of electron-rich heteroarenes require very strong organic bases to effect C-H deprotonation. Here we show that alkali carbonates (M₂CO₃) dispersed in mesoporous TiO₂ supports (M₂CO₃/TiO₂) effect CO₃ ^2--promoted C-H carboxylation of thiophene- and indole-based heteroarenes in gas-solid reactions at 200-320 °C. M₂CO₃/TiO₂ materials are strong bases in this temperature regime, which enables deprotonation of very weakly acidic bonds in these substrates to generate reactive carbanions. In addition, we show that M₂CO₃/TiO₂ enables C3 carboxylation of indole substrates via an apparent electrophilic aromatic substitution mechanism. No carboxylations take place when M₂CO₃/TiO₂ is replaced with un-supported M₂CO₃, demonstrating the critical role of carbonate dispersion and disruption of the M₂CO₃ lattice. After carboxylation, treatment of the support-bound carboxylate products with dimethyl carbonate affords isolable esters and the M₂CO₃/TiO₂ material can be regenerated upon heating under vacuum. Our results provide the basis for a closed cycle for the esterification of heteroarenes with CO₂ and dimethyl carbonate.