Diverse Synthesis of Chiral Trifluoromethylated Alkanes via Nickel-Catalyzed Enantioconvergent Reductive Hydroalkylation of Unactivated Olefins

Abstract

Here, we report a nickel-catalyzed enantioconvergent hydroalkylation of olefins with trifluoromethyl-containing α-alkyl halides for the synthesis of enantioenriched trifluoromethylated alkanes. This reaction employs readily available and bench-stable alkenes as alkyl coupling partners, featuring mild conditions, a broad substrate scope, and high functional group tolerance. The synthetic utility of this method is further demonstrated in the late-stage functionalization of a range of drug molecules and natural products.

Recent advances in transition metal-mediated trifluoromethylation reactions

“…Though other transition metals (except the discussed ones) have not been explored much in recent times for the construction of C(sp 3 )-CF 3 bonds in aliphatic or aromatic molecules, nickel and zinc have been reported for transition metalcatalysed trifluoromethylation by Wu's group and Wang's group in 2021, respectively. 68,69 3. Formation of C(sp 2 )-CF 3 bonds using transition metal complexes C(sp 2 )-H trifluoromethylation, similarly to the C(sp 3 )-H trifluoromethylation, has been deeply investigated using 3d, 4d and 5d transition metals.…”

“…Though other transition metals (except the discussed ones) have not been explored much in recent times for the construction of C(sp 3 )–CF 3 bonds in aliphatic or aromatic molecules, nickel and zinc have been reported for transition metal-catalysed trifluoromethylation by Wu's group and Wang's group in 2021, respectively. 68,69…”

Recent Advances in Nonprecious Metal Catalysis

“…Another limitation of the alcohol synthesis is the cryogenic conditions for the ketone reduction, which would require the implementation of systems beyond typical batch reactors (i.e., flow chemistry). Similarly, two nickel-catalyzed reductive couplings were also reported: reductive alkenylation of α-chlorosulfones with vinyl bromides by Wu, Sun, and co-workers and hydroalkylation of olefins with trifluoromethyl-containing α-alkyl halides by Wu, Ma, Tong, and co-workers …”

“…Similarly, two nickel-catalyzed reductive couplings were also reported: reductive alkenylation of α-chlorosulfones with vinyl bromides by Wu, Sun, and coworkers 10 and hydroalkylation of olefins with trifluoromethylcontaining α-alkyl halides by Wu, Ma, Tong, and co-workers. 11 Karadeolian and co-workers at Apotex Pharmachem reported a stereoselective synthesis of zuclomiphene using a Ni-catalyzed addition of aryl Grignards to 1,2-diphenylacetylene (Scheme 5). 12 All previously known methods for the synthesis of this drug require multiple crystallizations of this desired Z isomer from clomiphene citrate (a mixture of E and Z isomers that typically contains 40% Z isomer).…”

Catalytic Asymmetric Construction of CF3-Substituted Chiral sp3 Carbon Centers

“…The formed ArNi(II) species 45 initially reacts with Another approach to avoid the stoichiometric preparation of organometallic reagents is via the NiH-catalyzed asymmetric hydroalkylation of terminal alkenes 51 with compounds 30 (Scheme 17). 40 A catalytically generated alkylnickel species from alkene 51 and HSi(OMe) 3 undergoes an enantioselective cross-coupling reaction with 30 to form products 52 with high ee values. The proposed reaction mechanism involves SET-promoted alkyl radical intermediates and Ni(I)/(II)/(III) organometallic species, which is similar to the aforementioned pathways in Schemes 12 and 16.…”