Ligand‐Promoted, Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

Abstract

Comprehensive Summary While drug chirality remains one of the most important themes in medicinal chemistry and fluorine‐containing drugs have comprised large portion of global pharmaceutical market, the synthesis of fluorine‐containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped. Recent strategy of enantioconvergent cross‐coupling of trifluoromethylated alkyl halide has significantly updated previous toolbox that is dependent on additional functional group to achieve desired bond formation and highly enantioselective control. However, evident limitations were present in specific coupling candidate (sp2 carbon) and/or prerequisite heteroatom in trifluoroalkyl source for inducing effective stereoconvergent differentiation. Leveraging novel design of sterically hindered bisoxazoline ligand and drastic increase of molecular complexity of in situ generated sp3 coupling partner via metal‐hydride atom transfer, herein, we report a nickel‐catalyzed, highly enantioselective hydrotrifluoroalkylation of unactivated alkenes for diverse synthesis of enantioenriched aliphatic alkanes featuring trifluoromehylated stereogenic carbon. Excellent stereochemical control (mostly >95: 5 er), high catalytic reactivity, mild conditions, and broad substrate scope (40+ examples), enable convenient late‐stage asymmetric trifluoroalkylation of various biologically active complex molecules.

Palladium-catalyzed carbonylation with direct indole C-H activation involving HCFO-1233zd (E)

“…Subsequently, we screened the necessary additives for the reaction; we studied a total of seven additives, including sodium salt and potassium salt. The additive NaBr was the most effective in this reaction, with an isolated yield of 72% (Table 1, entries [14][15][16][17][18][19][20]. Finally, we selected different polar solvents and studied five different solvents.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] The incorporation of trifluoromethyl groups into organic molecules has thus received considerable attention, and significant progress has been achieved in the past decade. [14][15][16][17][18][19][20][21][22][23][24][25] Several top-selling drugs contain a CF 3 group, such asFluazuron, chlorfenapyr and pyridalyl. Among these trifluoromethylated substituted compounds,3-indolenone is an important class of compounds, especially those with trifluoromethyl substituents, which are particularly fluorinated indoles.…”

Catalytic Arylalkylation of Alkenyl Amines at Remote Sites via Directed Nickel Catalysis

“…Catalytic three component 1,2‐arylalkylation [ 34‐37 ] that incorporates alkyl units at the internal olefinic position via C(sp 3 )‐C(sp 3 ) [ 38‐46 ] coupling was considered one of the most challenging alkene difunctionalization reactions. Recently, our group developed a novel method for directed diarylation and arylalkylation of homoallylic amines via 5‐membered nickelacycle (Scheme 1B), [ 36 ] although the diastereoselectivity was rather low when reacting with internal alkenes.…”

Nickel-Catalyzed Remote Asymmetric Hydroalkylation of Alkenyl Ethers to Access Ethers of Chiral Dialkyl Carbinols

“…Recently, nickel-hydride-catalyzed alkene hydroalkylation has emerged as an attractive method to precisely construct C­(sp 3 )–C­(sp 3 ) bonds (Figure A) . Asymmetric hydroalkylation of (remote) unfunctionalized alkenes with racemic activated alkyl electrophiles were accessed via a radical pathway . Enantioselective oxidation addition or reductive elimination was responsible for generating enantioenriched products.…”