NHC-Catalyzed Radical Trifluoromethylation Enabled by Togni Reagent

Abstract

An unprecedented carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent was developed, thus providing the β-trifluoromethyl-α-substituted ketones with a broad scope and moderate to high chemical yields. Notably, this process includes a single-electron-transfer process and utilizes the persistent N-heterocycliccarbene-bound radical as a key intermediate to trigger the cascade radical cross-coupling.

Recent advances in N-heterocyclic carbene-based radical catalysis

“…In 2019 and 2020, the Li group, 26 the Wang group, 27 and the Yang and Wu group 28 reported the acyluoroalkylation of alkenes based on our NHC-catalyzed three-component coupling reaction, respectively (Schemes 15 and 16). Togni I reagent or peruoroalkylbromide instead of redox ester is used as an electron acceptor in the step of SET.…”

Light‐Driven Carbene Catalysis for the Synthesis of Aliphatic and α‐Amino Ketones

“…[12] In 2019, Ohmiya and co‐workers described the coupling of a persistent Breslow intermediate‐derived radical with a transient alkyl radical [13] . This pioneering example of thermal single‐electron NHC catalysis inspired the development of similar protocols by the groups of Li, [14] Wang, [15] and Hong, [16] among others [17]…”

“…[12] In 2019, Ohmiya and co-workers described the coupling of a persistent Breslow intermediate-derived radical with a transient alkyl radical. [13] This pioneering example of thermal single-electron NHC catalysis inspired the development of similar protocols by the groups of Li, [14] Wang, [15] and Hong, [16] among others. [17] Concurrent with this work, light-driven carbene methods by our group, [18] Hopkinson, [19] Studer, [20] and others demonstrated complementary reactivity to established two-electron carbene catalysis.…”

Single‐Electron Transfer Reactions Enabled by N‐Heterocyclic Carbene Organocatalysis

“…Moreover, this olefin difunctionalization strategy was successfully utilized in the late‐stage modification of several drug skeletons, further demonstrating its great synthetic practicality and generality. Later on, Wang's group reported a similar strategy, [30] and they found that the trifluoroalkylation reaction could be accelerated by using a trace amount of water as additive, which enabled the reaction to proceed efficiently at room temperature. However, the mechanism of water‐promoted acceleration remains unclear.…”

“…Recently,S tuder et al described aN HC/photoredox co-catalyzed three-component reactiono fb enzoyl fluorides 110,a lkenes, and CF 3 SO 2 Na to synthesize trifluoromethylated ketones (Scheme 24). [36] In contrast to the previouslyr eported radical trifluoromethylacylation pathway, [27,30] an alternative reductive SET strategy was appliedi nt his work by using CF 3 SO 2 Na as the electron donor.T he reactionm echanism was proposed. Upon visible light irradiation, the excited photocatalyst underwent reductiveq uenching by CF 3 SO 2 Na to form Ir II speciesa nd CF 3 SO 2 radical.…”