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

Abstract

C–H carboxylation is an attractive transformation for both streamlining synthesis and valorizing CO ₂. The high bond strength and very low acidity of most C–H bonds, as well as the low reactivity of CO ₂, 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 (M ₂CO ₃) dispersed in mesoporous TiO ₂ supports (M ₂CO ₃/TiO ₂) effect CO ₃ ²⁻-promoted C–H carboxylation of thiophene- and indole-based heteroarenes in gas–solid reactions at 200–320 °C. M ₂CO ₃/TiO ₂ 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 M ₂CO ₃/TiO ₂ enables C3 carboxylation of indole substrates via an apparent electrophilic aromatic substitution mechanism. No carboxylations take place when M ₂CO ₃/TiO ₂ is replaced with un-supported M ₂CO ₃, demonstrating the critical role of carbonate dispersion and disruption of the M ₂CO ₃ lattice. After carboxylation, treatment of the support-bound carboxylate products with dimethyl carbonate affords isolable esters and the M ₂CO ₃/TiO ₂ material can be regenerated upon heating under vacuum. Our results provide the basis for a closed cycle for the esterification of heteroarenes with CO ₂ and dimethyl carbonate.

Abstract

Carboxylation of heteroarenes with CO ₂ is achieved using alkali carbonate dispersed in mesoporous titania as a regenerable reagent.