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.
Highlights
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
For the efficient collection of fundamental yet synthetically formidable chiral b-fluoroalkyl amine-building blocks directly from readily available materials and intrigued by our recent success in asymmetric radical aminotrifluoromethylation of alkenes using a dual-catalytic system of Cu(I) and CPA34, we envisaged the possibility of realizing an unprecedented asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with various fluoroalkylsulfonyl chlorides through such a dual-catalytic system (Fig. 1)
Several challenges are associated with the development of this reaction, such as (1) stoichiometric amount of strong achiral Brønsted acid HCl would be generated, which might result in strong background reactions against the chiral acid-catalysed process and lead to competitive hydroamination of alkene as previous report[40]; (2) it is not easy to search for a uniform catalytic system broadly applicable to a variety of electronically distinct fluoroalkylsulfonyl chlorides, such as perfluoroalkyl, trifluoromethyl, difluoroacetyl and even difluoromethyl radical precursors
Summary
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. We discovered that a dual-catalytic system[30,31,32,33] of Cu(I) and chiral phosphoric acid (CPA) could catalyse the asymmetric radical aminotrifluoromethylation of alkenes with Togni’s reagent as the CF3 radical source with excellent enantioselectivity[34] Given these facts, it is still very desirable to design and develop new effective catalytic systems for efficient and general challenging asymmetric radical fluoroalkylation reactions with versatile fluoroalkylating reagents. We describe our efforts toward the development of the dual Cu(I)/CPA-catalysed asymmetric radical intramolecular aminofluoroalkylation of alkenes with various fluoroalkylsulfonyl chlorides This mild protocol represents the general and broadly applicable platform enabling efficient access to four types of enantioenriched functionalized a-tertiary pyrrolidines bearing various b-fluoroalkyl groups with excellent yields and enantioselectivity (Fig. 1)
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