Electrochemical Dearomative Dicarboxylation of Heterocycles with Highly Negative Reduction Potentials

The dearomative dicarboxylation of stable heteroaromatics using CO2 is highly challenging but represents a very powerful method for producing synthetically useful dicarboxylic acids, which can potentially be employed as intermediates of biologically active molecules such as natural products and drug leads. However, these types of transformations are still underdeveloped, and concise methodologies with high efficiency (e.g., high yield and high selectivity for dicarboxylations) have not been reported. We herein describe a new electrochemical protocol using the CO2 radical anion (E-1/2 of CO2 = -2.2 V in DMF and -2.3 V in CH3CN vs SCE) that produces unprecedented trans-oriented 2,3-dicarboxylic acids from N-Ac-, Boc-, and Ph-protected indoles that exhibit highly negative reduction potentials (-2.50 to -2.94 V). On the basis of the calculated reduction potentials, N-protected indoles with reduction potentials up to -3 V smoothly undergo the desired dicarboxylation. Other heteroaromatics, including benzofuran, benzothiophene, electron-deficient furans, thiophenes, 1,3-diphenylisobenzofuran, and N-Boc-pyrazole, also exhibit reduction potentials more positive than -3 V and served as effective substrates for such dicarboxylations. The dicarboxylated products thus obtained can be derivatized into useful synthetic intermediates for biologically active compounds in few steps. We also show how the dearomative monocarboxylation can be achieved selectively by choice of the electrolyte, solvent, and protic additive; this strategy was then applied to the synthesis of an octahydroindole-2-carboxylic acid (Oic) derivative, which is a useful proline analogue.

Automated summary

The dearomative dicarboxylation of stable heteroaromatics using CO2 is a challenging yet powerful method for producing useful dicarboxylic acids. This study introduces a new electrochemical protocol that utilizes CO2 radical anion to produce trans-oriented 2,3-dicarboxylic acids, which can be used as intermediates for biologically active compounds.