Photoredox/HAT-Catalyzed Dearomative Nucleophilic Addition of the CO₂ Radical Anion to (Hetero)Aromatics

Abstract

The radical anion of CO 2 (CO 2 •− ) is a strongly nucleophilic radical species with rapidly emerging applications in contemporary organic chemistry. This radical species exhibits high reactivity in single-electron reduction reactions due to the concomitant release of stable CO 2 , or Giese-type reactions, especially for electron-deficient alkenes and styrene derivatives. In contrast to previous reports, we herein disclose the development of a robust method for the introduction of CO 2•− , which can be generated from cesium formate under photoredox/hydrogen atom transfer (HAT) catalysis, into stable heteroaromatics such as benzofuran, benzothiophene, and indole derivatives to afford synthetically useful α-oxy, α-thio, and α-amino acid derivatives in moderate to high yield. In addition, when using electron-deficient naphthalene derivatives, both single-electron reduction and Giese-type nucleophilic addition occur simultaneously to produce carboxylated tetrahydronaphthalene derivatives in good yield. Moreover, one of the tetrahydronaphthalenes that bear a cyano group was transformed into the corresponding γ-butyrolactam via reduction of the cyano functionality through hydrogenation followed by cyclization. To the best of our knowledge, these dearomative carboxylation reactions with metal formates under photoredox/HAT conditions are unprecedented, thus providing a synthetic option for the introduction of a C1 source into stable (hetero)aromatics.

Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation

“…54 This approach has been applied to activated alkene hydrocarboxylation; however, attempts to expand the scope of this process to unactivated alkenes have been categorically unsuccessful. 18,19,40,41 Nonetheless, we recognized that, in principle, this formate-based mechanistic manifold should be uniquely well-matched to address the specific challenges encountered by other approaches to unactivated alkene hydrocarboxylation. Based on our working mechanistic model, CO 2…”

“…Alkene hydrofunctionalization methods that exploit radical intermediates are a fundamental class of synthetic reactions. Radical reactivity offers a complementary regio- and chemoselectivity profile relative to polar pathways. , Despite anti-Markovnikov hydrobromination dating back a century, , the development of radical hydrofunctionalization reactions remains a contemporary area of investigation. − Our group has a particular interest in alkene hydrocarboxylation using radical intermediates. , Carboxylic acids are a readily diversifiable functional handle − and are themselves a common motif found in natural products, pharmaceuticals, and commodity chemicals. − We envision that a broad and general radical hydrocarboxylation reaction would offer a powerful complement to transition-metal-catalyzed methods, such as the numerous established CO-based approaches − and the emerging alternative technologies that proceed through migratory insertion into CO 2 . − However, established approaches to radical hydrocarboxylation have remained largely limited to activated alkenes (Figure A). ,,− Unactivated aliphatic alkenes are an abundant and important substrate class but remain more challenging to engage due to their attenuated reactivity. Indeed, in the past year, Yu and co-workers reported the first and only synthetic methodology that engages unactivated alkenes with CO 2 •– .…”

“…Our group and others , have recently reported a strategy that generates CO 2 •– from inexpensive formate salts via hydrogen atom abstraction (formate C­(sp 2 )–H BDE = 86 kcal/mol) . This approach has been applied to activated alkene hydrocarboxylation; however, attempts to expand the scope of this process to unactivated alkenes have been categorically unsuccessful. ,,, Nonetheless, we recognized that, in principle, this formate-based mechanistic manifold should be uniquely well-matched to address the specific challenges encountered by other approaches to unactivated alkene hydrocarboxylation. Based on our working mechanistic model, CO 2 •– generation is coupled to its consumption, which maintains a low steady-state concentration of the reactive radical intermediate (Figure B).…”

Revisiting the Electrochemical Carboxylation of Naphthalene with CO2: Selective Monocarboxylation of 2-Substituted Naphthalenes

“…In this method, the CO 2 radical anion derived from cesium formate acts as both a reductant and a CO 2 source to produce carboxylated tetrahydronaphthalene derivatives in good yield (eq 2 in Figure ). Encouraged by this light-promoted approach, we subsequently investigated electrochemical carboxylation using CO 2 as a C1 source. The CO 2 radical anion can also be generated through the electrochemical reduction of CO 2 .…”

“…Based on these findings, we would thus like to propose a plausible reaction pathway in Figure . Given that the reduction potential of 1a is −2.04 V, which is more positive than the reduction potential of CO 2 (−2.2 V), the single-electron reduction of 1a would likely occur before the reduction of CO 2 . The initial single-electron reduction should occur at the 1-position of the naphthalene ring supported by redox mediator M7 , even though M7 has a more negative reduction potential ( E 1/2 = −2.38 V in CH 3 CN vs SCE) than 1a (−2.04 V).…”