Polarity Transduction Enables the Formal Electronically Mismatched Radical Addition to Alkenes

Abstract

The formation of carbon–carbon bonds via the intermolecular addition of alkyl radicals to alkenes is a cornerstone of organic chemistry and plays a central role in synthesis. However, unless specific electrophilic radicals are involved, polarity matching requirements restrict the alkene component to be electron deficient. This limits the scope of a fundamentally important carbon–carbon bond forming process that could otherwise be more universally applied. Herein, we introduce a polarity transduction strategy that formally overcomes this electronic limitation. Vinyl sulfonium ions are demonstrated to react with carbon-centered radicals, giving adducts that undergo in situ or sequential nucleophilic displacement to provide products that would be inaccessible via traditional methods. The broad generality of this strategy is demonstrated through the derivatization of unmodified complex bioactive molecules.

Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation

“…Of particular note, an α-amino acid derivative was found to be compatible under the reaction conditions and could be transformed into the linear diacid product in high yield (13). Substrates bearing a variety of pendant heterocycles, including oxetanes (12), γ-lactones (14), piperidines (15,16), pyrans (17), and imidazoles (18), each underwent the desired transformation. Hydrocarboxylation proceeds smoothly across a series of sterically hindered substrates (11,12,(14)(15)(16)(17)19), which included fully substituted carbon centers in both cyclic (12) and acyclic systems (19).…”

“…Substrates bearing a variety of pendant heterocycles, including oxetanes (12), γ-lactones (14), piperidines (15,16), pyrans (17), and imidazoles (18), each underwent the desired transformation. Hydrocarboxylation proceeds smoothly across a series of sterically hindered substrates (11,12,(14)(15)(16)(17)19), which included fully substituted carbon centers in both cyclic (12) and acyclic systems (19). Moderate to high yields of the linear carboxylic acid products were obtained across a series of exocyclic and acyclic 1,1disubstituted alkene substrates upon gentle heating (20−22).…”

“…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 •– .…”

Oxetane Synthesis via Alcohol C–H Functionalization

“…As depicted in Scheme , luminescence quenching studies and electrochemical studies (see the Supporting Information for more details) suggest that this process proceeds through reductive quenching of photoexcited 4CzIPN* to mediate the formation of a quinuclidinium radical cation . This species undergoes HAT with activated H-bonded alcohol 1 , which leads to nucleophilic radical 4 that quickly adds to 2 to give radical cation 6 . Single-electron reduction of this intermediate closes the photoredox cycle and generates a transient ylide that quickly undergoes protonation to give 5 .…”

“…In such a strategy, the functional group LG within radical trap 2 would play the critical, dual role of modulating the alkene electronics to ensure polarity matching in the key addition of nucleophilic radical 4 while at the same time presenting an excellent leaving group ability to promote a challenging 4- exo - tet S N 2 cyclization . Our group has recently demonstrated that vinyl sulfonium ions readily participate in radical conjugate addition reactions, thereby giving highly reactive adducts that are prone to undergo intermolecular S N 2 reactions with nucleophiles. , Given its excellent leaving group ability, we envisioned that the cationic sulfonium functionality would provide alkene 2 with the unique combination of properties required to successfully realize the plan in Scheme c.…”