Catalytic Asymmetric Homologation of 4‐Substituted Cyclohexanones with CF₃CHN₂: Enantioselective Synthesis of α‐Trifluoromethyl Cycloheptanones

Abstract

Introduction of the trifluoromethyl group (CF 3 ) into organic molecules in an enantioselective manner has attracted significant attention, but still remains a challenging problem. We herein report a catalytic asymmetric trifluoromethylation of cyclic ketones via a Sc III /chiral bisoxazoline-catalyzed homologation reaction by employing 2,2,2-trifluorodiazoethane (CF 3 CHN 2 ) as the CF 3 source. This desymmetrization process is highly efficient and generates two chiral centers with excellent diastereoselectivity and enantioselectivity, affording chiral α-trifluoromethyl cyclic ketones in a straightforward manner.

Base-promoted anaerobic intramolecular cyclization synthesis of 4,5-disubstituted-1,2,3-thiadiazoles

“…Initially, we synthesized a series of N -tosylhydrazones based on the literature (Scheme S1; see the ESI† for details). 19 As expected, the procedure was applicable for substrates with both electron-donating and electron-withdrawing groups at the phenyl rings, providing N -tosylhydrazones in moderate to good yields. The procedure tolerated functional groups such as fluorine, chlorine, bromine, cyano, methoxy, and ester groups.…”

Enantioselective Synthesis of Secondary β-Trifluoromethyl Alcohols via Catalytic Asymmetric Reductive Trifluoroalkylation and Diastereoselective Reduction

“…Very recently, the Wang group reported an impressive work on Sc III -catalyzed homologation to achieve enantioselective synthesis of α-trifluoromethyl cycloheptanones by employing 2,2,2-trifluorodiazoethane as the CF 3 source, which could be transformed into the cyclic trifluoromethyl alcohols accordingly. 11 To address the issues and challenges of enantioselective synthesis of CF 3 -containing ketones and alcohols, herein (Figure 1E), we describe the work of nickel-catalyzed asymmetric reductive cross-coupling trifluoroalkylation of acyl chlorides for diverse synthesis of enantioenriched αtrifluoromethylated ketones. The sequential reduction of these α-trifluoromethylated ketones produced β-trifluoromethyl alcohols featuring adjacent stereocenters by a simple and efficient one-pot process.…”

“…To conquer the unsolved problems of racemization, we sought inspiration from the strategical disconnection of the C–C bond to result in a reductive cross-coupling of acyl chloride and trifluoroalkyl halide under neutral conditions, enabling the asymmetric construction of α-trifluoromethyl ketones for further stereoselective assembly of highly substituted β-trifluoromethyl alcohols (Figure C). Very recently, the Wang group reported an impressive work on Sc III -catalyzed homologation to achieve enantioselective synthesis of α-trifluoromethyl cycloheptanones by employing 2,2,2-trifluorodiazoethane as the CF 3 source, which could be transformed into the cyclic trifluoromethyl alcohols accordingly …”

Ring Expansion of Isatins via 1,2-Phospha-Brook Rearrangement: A Route to the Synthesis of 2-Quinolinone-Derived p-Quinone Methides

“…Overcoming some of these issues, another protocol involving diazo compounds has been used for decades for the homologation of one carbon into the ring or into the chain directly at carbonyl moieties . In spite of the stability issues of diazo compounds and challenges associated with the low regioselectivity of the product, it has been vastly used by researchers for the synthesis of ring expansion and chain elongation through appropriate substitution patterns in the starting ketone substrate.…”