Carbonate-promoted C-H Carboxylation of Electron-rich Heteroarenes

C-H carboxylation is an attractive transformation for both streamlining synthesis and valorizing CO. The high bond strength and very low acidity of most C-H bonds, as well as the low reactivity of CO, 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 (MCO) dispersed in mesoporous TiO supports (MCO/TiO) effect CO -promoted C-H carboxylation of thiophene- and indole-based heteroarenes in gas-solid reactions at 200-320 °C. MCO/TiO 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 MCO/TiO enables C3 carboxylation of indole substrates an apparent electrophilic aromatic substitution mechanism. No carboxylations take place when MCO/TiO is replaced with un-supported MCO, demonstrating the critical role of carbonate dispersion and disruption of the MCO lattice. After carboxylation, treatment of the support-bound carboxylate products with dimethyl carbonate affords isolable esters and the MCO/TiO material can be regenerated upon heating under vacuum. Our results provide the basis for a closed cycle for the esterification of heteroarenes with CO and dimethyl carbonate.