Electrochemical Dearomative Dicarboxylation of Heterocycles with Highly Negative Reduction Potentials

Abstract

The dearomative dicarboxylation of stable heteroaromatics using CO 2 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 CO 2 radical anion (E 1/2 of CO 2 = −2.2 V in DMF and −2.3 V in CH 3 CN 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, Nprotected 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.

Recent Advances in Electrocarboxylation with CO2

“…In 2022, Mita and co-workers reported the electrochemical dearomative dicarboxylation of heterocycles 44 under CO 2 atmosphere with high negative reduction potentials. [37] Prior to the experiments, they calculated the reduction potentials of the heterocycles to screen for substrates with reduction voltage more positive than À 3 V vs SCE, therefore the mechanism of dearomatization and carboxylation processes could be analyzed in a certain voltage range. Substrates with stable [4n + 2] π system such as N-Boc-indole, benzofuran, benzothiophene, Scheme 13.…”

Recent advances in the electrochemically mediated chemical transformation of carbon dioxide

“…In 2022, Maeda and co-workers reported electrochemical dicarboxylation reactions of heteroaromatics with CO 2 radical anions (Scheme 21). 43 The reaction was carried out at 0 °C using Mg as the sacrificial anode, Pt as the cathode, n -Bu 4 NClO 4 as the electrolyte, and CH 3 CN as the solvent with slow bubbling of CO 2 under constant-current electrolysis conditions at 9.4 mA cm −2 with 3 F mol −1 . Based on a series of control experiments and DFT calculations, a possible route was proposed.…”

Benzylic C(sp3)–H Bonds Play the Dual Role of Starting Material and Oxidation Inhibitor for Hydrazides in the Electrochemical Synthesis of Hydrazones

“…Nowadays, electrochemistry is an attractive detour in synthetic organic chemistry instead of prior conventional approaches. − Concerning this issue, hitherto, many efforts have been made to supersede greener electrochemical methods instead of operose chemicals ways. In contrast with traditional chemistry under highly active electrochemical conditions, persistent compounds could quickly generate reactive species and artfully produce target molecules. − One of the notable merits of using electrochemical approaches is avoiding using conventional chemical reagents in synthesizing organic molecules that generate many toxic or undesirable stoichiometric metal or nonmetallic byproducts. − The electrochemical organic synthesis technique, in contrast with chemical methods, has some prominent preferences. Some of the important advantages of electrochemical organic synthesis are easily cleanable and reusable surfaces of electrodes, environmentally benign oxidation way for producing reactive species, easily accessible instrumentation, and prevention of using high temperature and pressure in reaction conditions. − According to the mentioned advantages, the idea of designing an environmentally friendly electrochemical pathway as an appealing alternative for conventional synthetic approaches has long been demanded. − …”