Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines

Abstract

Although great success has been achieved in asymmetric fluoroalkylation reactions via nucleophilic or electrophilic processes, the development of asymmetric radical versions of this type of reactions remains a formidable challenge because of the involvement of highly reactive radical species. Here we report a catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with commercially available fluoroalkylsulfonyl chlorides as the radical sources, providing a versatile platform to access four types of enantioenriched α-tertiary pyrrolidines bearing β-perfluorobutanyl, trifluoromethyl, difluoroacetyl and even difluoromethyl groups in excellent yields and with excellent enantioselectivity. The key to success is not only the introduction of the CuBr/chiral phosphoric acid dual-catalytic system but also the use of silver carbonate to suppress strong background and side hydroamination reactions caused by a stoichiometric amount of the in situ generated HCl. Broad substrate scope, excellent functional group tolerance and versatile functionalization of the products make this approach very practical and attractive.

Catalytic Asymmetric Radical Diamination of Alkenes

“…Thus, a mechanism involving an initial aminocupration followed by homolysis of the resultant C-Cu bond and subsequent coupling with an alkylaminyl radical is unlikely. 47,72 Overall, all these experimental observations as well as previous studies [26][27][28][29][30][31][32][33]47,48,52 favor our initial mechanistic proposal involving a process initiated by the intermolecular addition of aminyl radical to alkene, as shown in Scheme 1C.…”

“…To address these challenges, we became interested in the use of alkylaminyl radical as a key reactive intermediate for direct diamination of unactivated alkenes. [26][27][28] We envisioned that the Cu(I)-chiral phosphoric acid-catalyzed [29][30][31][32][33][34][35] asymmetric radical diamination of alkenes with electrophilic aminating reagents such as O-acylhydroxylamines, [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] if successful, would provide a direct, convenient, and powerful approach to enantio-enriched vicinal diamines bearing alkylamine moieties (Scheme 1B). via a single electron transfer process (Scheme 1C).…”

Rhodium‐Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

“…[19] More recently Liu and Stahl reported a related Cu-catalyzed benzylic cyanation. [20,21] Cu-catalyzed α-amination of amides [22] and difunctionalization of olefins [23] likely operate through similar inner-sphere mechanisms, although complete mechanistic details are not available.…”

Rhodium‐Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

“…[16,17] A third mechanism for enantioselective catalysis involving radical intermediates relies on inner-sphere bond formation from organometallic intermediates (Scheme 2c). [20,21] Copper-catalyzed a-amination of amides [22] and difunctionalization of olefins [23] most likely operate through similar inner-sphere mechanisms, although complete mechanistic details are not available. [18] In these transformations,asecondary radical probably combines with an alkyl metal species to provide ad ialkyl metal species 6.…”

“…[19] Liu and Stahl reported arelated coppercatalyzed benzylic cyanation. [20,21] Copper-catalyzed a-amination of amides [22] and difunctionalization of olefins [23] most likely operate through similar inner-sphere mechanisms, although complete mechanistic details are not available.…”