Synthesis of chiral α-trifluoromethyl alcohols and ethers via enantioselective Hiyama cross-couplings of bisfunctionalized electrophiles

Abstract

Methods for synthesis of chiral organic compounds bearing trifluoromethyl-substituted stereocenters are of great interest for agrochemical and pharmaceutical labs and industries in their search for new bioactive materials. We report on employment of bisfunctionalized electrophiles, bearing both a trifluoromethyl and a functional group as direct substituents of the reactive center, in cross-coupling reactions. We exemplify this concept in the asymmetric synthesis of enantioenriched α-trifluoromethyl- and perfluoroalkyl-containing benzylic and allylic ethers and alcohols by nickel-catalyzed stereoconvergent Hiyama cross-coupling reaction. Substrate electrophiles are conveniently prepared in few steps from trifluoroacetic acid. The method represents a conceptually different approach to chiral CF3-substituted alcohols and ethers and allows for a rapid catalytic preparation of a wide range of these valuable compounds in high yields and enantioselectivity.

Facilitating the transmetalation step with aryl-zincates in nickel-catalyzed enantioselective arylation of secondary benzylic halides

“…However, the formation of the desired coupling product was not observed when lithium aryl boronates with ortho-methyl group ( 2i ) was subjected to the reaction conditions (Scheme 2, 3i ). Previously reported method for the preparation of enantio-enriched benzhydryl trifluoromethane derivatives typically required to use optically secondary α-(trifluoromethyl)benzyl tosylates to react with various aryl boronic acids in the presence of a palladium catalyst 19,29,33–36 , while Fu and coworker 37 reported a highly enantioselective nickel-catalyzed coupling of fluoroalkylated secondary alkyl bromide with aryl zinc chlorides (Fig. 1c).…”

“…Only recently, the nickel-catalyzed asymmetric couplings of racemic alkyl halides were successfully extended to other nucleophiles such as alkyl-9-BBN, aryl Grignard reagents, aryl zinc halides, aryl/vinyl silicates vinyl/alkynyl indium/zirconium/aluminum reagents (Fig. 1a) 6,14–19 .

Fig. 1Ni-catalyzed asymmetric cross-coupling of racemic secondary alkyl halides.

…”

Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides

“…All used boronic acids 2 and some aryl trialkoxysilanes 3 are commercially available and were purchased from appropriate vendors. 2-Bromo-2,2-difluoroacetamides [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], 1, 2-iodo-2,2-difluoroacetamides [ 54 ], aryl trialkoxysilanes 3 [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ], sulfonium salts 4 [ 65 , 66 , 67 ], and calixarenes L1 , L2 [ 68 , 69 ] are known compounds in the literature and were prepared according to the known literature, and the spectral data are identical with the corresponding literature. Copies 1 H and 13 C-NMR spectra are placed in Supplementary Materials .…”

Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands

“…The rising demand to access such compounds in an enantioselective manner has led to the development of several strategies. For example, contemporary methods include the enantioselective trifluoromethylation of aldehydes, the kinetic resolution of racemic 1‐aryl‐2,2,2‐trifluoroethanols as well as enantioselective Hiyama cross‐coupling reactions . However, to date, the most efficient and successful method is the enantioselective reduction of trifluoromethyl ketones, whereby different catalytic methods have been developed.…”

“…For example, contemporary methods include the enantioselectivet rifluoromethylation of aldehydes, [6] the kinetic resolution of racemic 1-aryl-2,2,2-trifluoroethanols [7,8] as well as enantioselective Hiyama cross-coupling reactions. [9] However,t od ate, the most efficient and successfulm ethod is the enantioselective reduction of trifluoromethyl ketones,w hereby different catalytic methods have been developed. These include chiralo xazoborolidine-catalyzed reductions, [10,11] enzymatic biocatalysis, [12][13][14] b-hydrogen transfer with diethylzinc, [15] homogenous transition-metal-cata-lyzed asymmetric hydrogenation (AH) and asymmetric transfer hydrogenation (ATH).…”