1-[3,5-BIS(TRIFLUOROMETHYL)PHENYL]ETHAN-1-OL

A 1 L oven-dried round-bottomed flask was charged with 102. [14 G] (0.4 mol, 1.0 eq) of 3', 5'-Bis (trifluoromethyl) acetophenone and 780 mL of anhydrous [DICHLOROMETHANE.] The resultant solution was transferred into a dry dropping funnel. An oven-dried 3L round-bottomed flask was cooled to-20 [XB0;C, ] and 20 mL of 1.0 M CBS catalyst (33) toluene solution was added via syringe, followed by 40 mL of 10. [0-10.] 3 M borane-methylsulfide complex. The 3', 5'-Bis (trifluoromethyl)- acetophenone solution was added dropwise through the dropping funnel. The addition was carried out over 2 days. During the addition, the temperature was maintained at-20 [XB0;C] with a cooling machine. Once the addition was finished, the reaction was monitored by TLC (EtOAc/Hexane = 1/4). When the starting material was completely consumed, 250 mL of methanol was added slowly. Hydrogen gas was emitted. The reaction solution was then concentrated to give a solid. The solid was dissolved in 500 mL of diethyl ether, then 45 mL of 2.0 M of hydrochloric acid in diethyl ether was added [SLOWLY AT-20 XB0;C.] A precipitate was formed. The reaction mixture was warmed to room temperature and stirred for 30-40 min. The mixture was filtered through a funnel and the filtrate was concentrated to give 101.5 g of a solid of 34 (yield 98.7percent). Chiral HPLC Chiral OD (Chiralcel) [COLUMN (HEXANE/IPA] = 98/2) showed 94.6percent.A 20 mL vial was charged with a stir bar and complex 4 (10 mg, 8.9 × 10–3 mmol). The substrate (4.43 × 10 mmol) was added and the mixture stirred. If the substrate was a liquid, the mixture was stirred until complex 4 had completely dissolved. i-PrOH (3.61 g) was added and the solution was stirred for 5 min. A stock solution of t-BuOK (20 mg, 0.18 mmol) in i-PrOH (0.98 g) was stirred until all the base had dissolved. This stock solution (0.1 g or 0.4 g, 2 and 8 equiv, respectively) was diluted with i-PrOH (1.0 g or 0.7 g, respectively) and added to the reaction vial to activate the precatalyst and start catalysis. Samples (0.1 mL) were taken via syringe and injected into Teflon-sealed GC vials prepared with wet, aerated i-PrOH to quench catalysis.Example 20 ; Asymmetric hydrogenation of 1-(3, 5-bis(trifluoromethyl)phenyl)-ethanone; To a solution of dichloro{(S)-2, 2'-bis[bis(4-dimethylamino-3, 5-dimethylphenyl)phosphino]-1, 1'-binaphthyl}ruthenium(II)-N, N-dimethylformamide complex (2.2 mg, 0.00195 mmoL) synthesized in Example 16, (2S)-(+)-1, 1-bis(4-methoxyphenyl)-3-methyl-1, 2-butanediamine (2.4 mg, 0.0078 mmoL) and potassium tert-butoxide (1.7 mg, 0.0156 mmoL) in 2-propanol (1 mL) was added a solution of 1-(3, 5-bis(trifluoromethyl)phenyl)-ethanone (0.05 g, 0.195 mmoL) in 2-propanol (1 mL). The mixture was subjected to hydrogenation under a 1.0 MPa hydrogen pressure at 25°C for 12 hr. The reaction mixture was analyzed by GC (column: CHIRASIL-DEX CB, 0.32 mmx25 m) to find a conversion ratio of 99.6percent and an optical purity of 94.6percent ee(R).A solution of the ketone in 2-propanol was added to a 50 mL Schlenk flask. After evacuating and refilling with argon, a mixture of the catalyst and base (eg. KO'Bu) was added. The resulting mixture was then injected into a 50 mL autoclave which had been previously placed under an atmosphere of hydrogen. The autoclave was pressurized with hydrogen gas and the reaction mixture was stirred at the desired temperature. The reaction progress was monitored by TLC. Upon completion of the reaction, the solvent was removed under vacuum and the mixture was filtered through a short pad of silica gel (ca. 6 cm) using hexane/ethyl acetate. The solvent was then removed from the filtrate affording the product.In a Schlenk tube sealed with a rubber septum under argon atmosphere the base (potassium tert-butoxide, 0.04 mmol) was added to a solution of precatalyst 4–7 (0.8 μmol) in 4 ml of 2-propanol and the system thermostated at 40°C or 82°C; then the ketone (0.8 mmol in 1ml of 2-propanol) was added in one portion ([sub]=0.16 M). GC analysis was performed taking 0.3 ml of reaction mixture, the sample was treated with ammonium chlorideThe transition metal complex catalyst uses structure VI; the base employs potassium carbonate; and the solvent uses methylene chloride. The molar ratio of the starting material 3, 5-bistrifluoromethylacetophenone (I) to the transition metal complex was 40, 000. Hydrolysis of R-3, 5-bistrifluoromethylphenethyl alcohol acetate The 8.51 g light yellow oily liquid obtained in Step 1 was added to 100 ml of methanol1N LiOH according to the volume ratio of 1: 1 prepared by the mixed solution, Heating reflux reaction, After 10 hours, The detection of R-3, 5-bistrifluoromethylphenylethanol acetate disappeared.The reaction solution was concentrated, The methanol was distilled off, The residual solution was extracted with dichloromethane, Dried, and concentrated to give 7.95 g of a pale yellow oily liquid.The mixture of n-hexane and ethyl acetate in a volume ratio of 10: 1 was obtained from 7.95 g of the light yellow oily liquid obtained in Step 2The solution was further purified by gel filtration.Eventually available 4.70G R-3, 5-bisbiphenylmethylethanol, After testing, The final product-wide R-3, 5_Bis (trifluoromethyl) phenylethanol had a 99.2percent. ValueEXAMPLE 4 EXAMPLE 4 EXAMPLE 4 EXAMPLE 4 [RhCp*CISodium formate was added to the water to make a 3.7M solution, which was then cooled to 10Experiment 2 - Biphasic Reduction of 3, 5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (SExperiment 2 - Biphasic Reduction of 3, 5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (SComparative Asymmetric hydrogenation of 1-(3, 5-bis(trifluoromethyl)phenyl)-ethanone To a solution of dichloro[(S)-2, 2'-bis(diphenylphosphino)-1, 1'-binaphthyl]ruthenium(II)-N, N-dimethylformamide complex (1.7 mg, 0.00195 mmoL) synthesized in the same method as in Example 16, (2S)-(+)-1, 1-bis(4-methoxyphenyl)-3-methyl-1, 2-butanediamine (2.4 mg, 0.0078 mmoL) and potassium tert-butoxide (1.7 mg, 0.0156 mmoL) in 2-propanol (1 mL) was added a solution of 1-(3, 5-bis(trifluoromethyl)phenyl)-ethanone (0.05 g, 0.195 mmoL) in 2-propanol (1 mL). The mixture was subjected to hydrogenation under a 1.0 MPa hydrogen pressure at 25°C for 12 hr. The reaction mixture was analyzed by GC (column: CHIRASIL-DEX CB, 0.32 mmx25 m) to find a conversion ratio of 60.8percent and an optical purity of 62.9percent ee(R).A solution of the ketone in 2-propanol was added to a 50 mL Schlenk flask. After evacuating and refilling with argon, a mixture of the catalyst and base (eg. KO'Bu) was added. The resulting mixture was then injected into a 50 mL autoclave which had been previously placed under an atmosphere of hydrogen. The autoclave was pressurized with hydrogen gas and the reaction mixture was stirred at the desired temperature. The reaction progress was monitored by TLC. Upon completion of the reaction, the solvent was removed under vacuum and the mixture was filtered through a short pad of silica gel (ca. 6 cm) using hexane/ethyl acetate. The solvent was then removed from the filtrate affording the product.Biotransformation using lyophilized powder of crude ChKRED20 was performed in 5 ml potassium phosphate buffer (100 mM, pH 7.0) containing 40percent (v/v) of 2-propanol, crude enzyme (2 g/l or10 g/l), and substrate (50–200 g/l). The reaction was carried outat 30°C for 24 h and terminated by extraction with ethyl acetate.The product was purified by silica gel column chromatographyand identified by 1H NMR analysis. The absolute configuration ofthe product was determined by comparing the optical rotationwith the literature data. Spectral data for the product (R)-3, 5-bis(trifluoromethyl)-1-phenylethanol (1b) were as follows: white solid; 1H NMR (600 MHz, CDCl3): 7.85 (s, 2H), 7.79 (s, 1H), 5.04–5.03(q, 1H, J = 6.6 Hz), 1.98 (br, OH), 1.55 (d, 3H, J = 6.6 Hz); [α]General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhClGeneral procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhClIn a Schlenk tube sealed with a rubber septum under argon atmosphere the base (potassium tert-butoxide, 0.04 mmol) was added to a solution of precatalyst 4–7 (0.8 μmol) in 4 ml of 2-propanol and the system thermostated at 40°C or 82°C; then the ketone (0.8 mmol in 1ml of 2-propanol) was added in one portion ([sub]=0.16 M). GC analysis was performed taking 0.3 ml of reaction mixture, the sample was treated with ammonium chlorideIn a Schlenk tube sealed with a rubber septum under argon atmosphere the base (potassium tert-butoxide, 0.04 mmol) was added to a solution of precatalyst 4–7 (0.8 μmol) in 4 ml of 2-propanol and the system thermostated at 40°C or 82°C; then the ketone (0.8 mmol in 1ml of 2-propanol) was added in one portion ([sub]=0.16 M). GC analysis was performed taking 0.3 ml of reaction mixture, the sample was treated with ammonium chlorideGeneral procedure: In a pressure tube, 0.5 molpercent of metal precursor [C16H24BF4Ir](2.48 mg, 0.005 mol) and 1 molpercent of chiral amine ligand (3.66 mg, 0.01 mmol) were dissolved in 2 mL of water and methanol (ratio1:1) and stirred at room temperature for 1 h under argon atmo-sphere. Then formic acid (2.5eq, 0.1 mL), sodium formate (2.5eq, 170 mg) and 1eq of ketone substrate (1 mmol) were introduced.The reaction mixture was stirred at 500 rpm and heated at 70C for22 h. After that, the tube was cooled to room temperature; and theorganic compound was extracted with either with ethyl acetate orCH2Cl2, then the solution was dried over Na2SO4, filtrated and con-centrated under reduced pressure. The crude material was purifiedby flash column chromatography on silica gel using cyclohex-ane/ethyl acetate as gradient eluent (90:10–7:3). After evaporation, alcohols were obtained as oil or solid. The products were identifiedby NMR. The conversion and the enantioselectivity were deter-mined by chiral GC or chiral HPLC analysis (Scheme 1).General procedure: First, two different cofactors NADH and NADPH were tested usingwhole cells biocatalysts to see which one could improve the activity ofKleADH. Reactions were conducted in 1 mL of triethanolamine buffer(100 mM, pH7.0) containing 10 mM substrates, 10 mM cofactors, and400 mg/mL recombinant wet cells at 30 °C with vigorous shaking for24 h. Then, a wide range of potential substrates were investigated toexplore the substrate specificity of KleADH. The substrates used in thisstudy were listed in Table. 2. Reactions were conducted in 1 mL oftriethanolamine buffer (100 mM, pH7.0) containing 10 mM substratesand 400 mg/mL recombinant wet cells at 30 °C with vigorous shakingfor 24 h. Then the aqueous phase was extracted by ethyl acetate andanalyzed by chiral HPLC or GC [30, 31].(1) primary crystals30g of the compound (21) was added 15mL of petroleum ether obtained in Preparation Example 5 embodiment taken, heated and stirred under argon at 46 deg.] C, dissolved; into an (R) -3, 5- bis (trifluoromethyl) phenethyl alcohol - seed, 45min after the seeding significantly smaller; after 1 hour, the seed disappeared; 3.5h, the white solid precipitated (bottom first precipitation); 10h later, no solid precipitation; suction dry, said weight 21g, yield 70.0percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 60.8percent.(2) secondary crystalsTake a crystalline compound obtained 30g, was added 105mL of petroleum ether, heated and stirred under argon for 48 , dissolved; into an (R) -3, 5- bis (trifluoromethyl) benzyl alcohol - seed, 45min after the seed was significantly smaller; after 1 hour, the seed disappeared; 3.5h, the white solid precipitated (bottom first precipitation); 10h later, no solid precipitation; suction drying, weighing 21g, income rate was 70.0percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 95.7percent.(3) three times crystallizedTaking a second resultant crystalline compound 30g, was added 105mL of petroleum ether, heated and stirred under argon for 46 , dissolved; into an (R) -3, 5- bis (trifluoromethyl) benzyl alcohol - seed, 45min after the seed was significantly smaller; after 1 hour, the seed disappeared; 3.5h, the white solid precipitated (bottom first precipitation); 10h later, no solid precipitation; suction drying, weighing 23g, income rate was 76.7percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 99.5percent.

Molecular Weight:258.16
XLogP3:3.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:1
Exact Mass:258.04793385
Monoisotopic Mass:258.04793385
Topological Polar Surface Area:20.2
Heavy Atom Count:17
Complexity:237
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes