A Dual-Catalytic Strategy To Direct Asymmetric Radical Aminotrifluoromethylation of Alkenes

Abstract

A novel asymmetric radical aminotrifluoromethylation of alkenes has been developed for the first time, providing straightforward access to densely functionalized CF3-containing azaheterocycles bearing an α-tertiary stereocenter with excellent enantioselectivity. The key to success is not only the introduction of a Cu(I)/chiral phosphoric acid dual-catalytic system but also the use of urea with two acidic N-H as both the nucleophile and directing group. The utility of this method is illustrated by facile transformations of the products into other important compounds useful in organic synthesis and medicinal chemistry.

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

“…Unlike tethered substrates, the use of nonbranched substrates without the Thorpe–Ingold effects is generally far less studied in previous related process, probably due to the unfavourable entropy factor and proximity effects in the cyclic transition state of such processes48. It is more encouraging to note that the unbranched substrate 1s underwent the current aminoperfluoroalkylation reaction smoothly to deliver the desired product 3S in 60% yield with 85% ee under the same conditions, which was in sharp contrast to asymmetric radical aminotrifluoromethylation with Togni's reagent as the CF 3 source to give low product yield and ee in case of such a substrate34. Thus, the scope of this new reaction is substantially expanded.…”

“…In initial studies, however, treatment of 1a and 2a with the previously established asymmetric aminotrifluoromethylation conditions34 provided the desired product 3A in a poor yield with essentially no enantiocontrol, along with side hydroamination product 3AA in 56% yield (Table 1, entry 1). This might be attributed to the in situ generated stoichiometric amount of HCl, which may promote both the background and side reactions, which is in agreement with our initial assumption.…”

“…We then expanded the scope to the catalytic asymmetric radical aminotrifluoromethylation of alkenes34 in the presence of trifluoromethanesulfonyl chloride (CF 3 SO 2 Cl; 2d ) as the radical CF 3 source, considering the fact that, as compared with Togni's reagent, 2d is a bench stable and inexpensive radical CF 3 reagent and produces SO 2 and inorganic chloride as the by-products that could be removed effectively from the reaction mixture during the work-up. To our delight, under the otherwise identical reaction conditions, the reaction of N -alkenyl urea substrate 1a with 2d afforded trifluoromethyl-containing product 6A in 91% yield with 93% ee in the presence of 5 mol% of chiral catalyst ( S )- A1 , which showed markedly enhanced reactivity as compared with that using Togni's reagent as the CF 3 source (Table 5).…”

“…Buchwald succeeded in utilizing copper/bis(oxazoline) catalysts for asymmetric intramolecular oxytrifluoromethylation of alkenes with carboxylic acids with Togni's reagent, giving rise to good enantioselectivities (74–83% ee)2829. More recently, we discovered that a dual-catalytic system30313233 of Cu(I) and chiral phosphoric acid (CPA) could catalyse the asymmetric radical aminotrifluoromethylation of alkenes with Togni's reagent as the CF 3 radical source with excellent enantioselectivity34. Given these facts, it is still very desirable to design and develop new effective catalytic systems for efficient and general particularly challenging asymmetric radical fluoroalkylation reactions with versatile fluoroalkylating reagents.…”

“…For the efficient collection of fundamental yet synthetically formidable chiral β-fluoroalkyl amine-building blocks directly from readily available materials and particularly 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).…”