Radical Acylfluoroalkylation of Olefins through N‐Heterocyclic Carbene Organocatalysis

Abstract

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N‐heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late‐stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.

Carbotrifluoromethylations of C−C Multiple Bonds (Excluding Aryl‐ and Alkynyltrifluoromethylations)

“…The utilization of aromatic or heteroaromatic alkenes provided the corresponding products with good yields; however, in the case of aliphatic alkenes, only poor isolated yields were obtained (Scheme 65). Concerning the plausible mechanism of the reaction, similar to Han's and Wang's protocols, [57,58] the formation of the NHC‐bound intermediate was proposed.…”

“…The carbonyltrifluoromethylation of alkenes via three‐component coupling reactions, permitting the rapid assembly of more complex structures, has received intense interest in the last few years. In 2020, two very similar approaches were developed by Han [57] and Wang [58] for the radical acyltrifluoromethylation of styrene derivatives catalyzed by the NHC (N‐heterocyclic carbene) organocatalyst employing Togni's reagent and (hetero)aromatic aldehydes (Scheme 62a and Scheme 62b). In both protocols, the cycloheptane‐fused N ‐2,6‐diisopropylphenyl‐thiazolium salt as the NHC catalyst and Cs 2 CO 3 as the base were applied, leading to the desired aromatic and heteroaromatic compounds in good to excellent yields.…”

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

“…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.…”

“…Recently,L i, Han, and co-workers reported a three-component difunctionalization of alkenes by using difluoromethyl halides 74 as single-electrona cceptors as well as the alkylating reagents (Scheme 16). [27] The difluoromethyl radical could be efficiently generated throught he SET process between 74 and the Breslow intermediate, further undergoing a radicalr elay (for similarm echanisms,s ee Schemes 10 and 11). The electron-withdrawing group on difluoromethyl bromides, such as sulfonyl,e ster,a nd amide groups,i se ssential for the successo ft his chemistry.Avariety of difluoroketones 75 were obtainedi nm oderate to good yields.…”

“…The use of hypervalent iodine compounds as single-electron acceptorsi nN HC catalysis was first reported by Li, Han, and co-workers. [27] As shown in Scheme 18, To gni Ir eagent 78 was used as the trifluoromethyl radicals ource,f urnishing as pectrum of b-trifluoromethyl ketones 79 with outstanding results. This protocol tolerated aw ide scope of terminal alkenes, such as styrenes, vinyl ethers, vinyl esters, and unactivated olefins.…”