* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium formate In methanol at 50℃; for 24 h; Inert atmosphere
Working Example 23; A ruthenium complex Ru(OTf)[(S,S)-iso-BuSO2dpen] (p-cymene) (1.4 mg, 0.002 mmol), potassium formate (1.0 g, 12 mmol), and 3',5'-bis(trifluoromethyl)acetophenone (2.56 g, 10 mmol, substrate/catalyst ratio=5000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. for 24 hours to give (S)-1-[3',5'-bis(trifluoromethyl)phenyl]ethanol at 100percent yield and 87.7percent ee optical purity.
93.5%
With sodium tetrahydroborate; dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at 0 - 5℃; for 0.5 h;
3',5'-bis(trifluoromethyl)acetophenone (3.1 ml in 17 ml) was passed through a syringe pump at 0-5°C for 2 hoursIn THF,17 millimoles) were added to5 ml of 2M (ie 10 mmol) of different borane reagent and 0.85 ml (5 molpercent vs. 3',5'-bis(trifluoromethyl)acetophenone)1M of a (R)-MeCBS toluene solution in a mixed solution.After stirring 3',5'-bis(trifluoromethyl)acetophenone for 30 minutes,Then, hydrochloric acid (1M, 4.2 ml) was added dropwise to the reaction solution to quench the reaction.The organic phase of the reaction solution was extracted with 20 ml of methyl tert-butyl ether.Wash the organic layer with water and saturated saline,Dry with anhydrous Na2SO4,At last,The organic phase is evaporated andGet the product.The resulting enantiomeric excess (percent ee) of (S)-1-[3,5-bis(trimethyl)phenyl]ethanol was determined by chiral HPLC.The results are shown in Table 5.Selective reduction of 3′,5′-bis(trifluoromethyl)acetophenone with BTHF as reducing agentThe resulting product has a low percent ee,and,Adding sodium borohydride has a great influence on the percent ee value of the product;In the selective reduction of 3′,5′-bis(trifluoromethyl)acetophenone with BDMS as reducing agent,The percent ee value is high,and,The presence of sodium borohydride did not reduce the percent ee value of the reaction
> 99 % ee
With NAD In isopropyl alcohol at 28℃; for 24 h; Sodium phosphate buffer
Geotrichum candidum BPCC 1118 was grown aerobically in shake flasks containing a mineral salts medium pH 7.2, supplemented with glucose (5g/litre), yeast extract (2g/litre) and 2-propanol (15g/litre). Cultures were incubated on a shaker at 28 degrees centigrade for 24 hours and the cells recovered by centrifugation. The recovered cell pellet was dehydrated by resuspension in 10 volumes of acetone, the cells were recovered by filtration and washed twice more with acetone before drying under vacuum to provide a free-flowing powder. Reactions were analysed by GC on a DB17 column (30m x 0.32mm), using a temperature gradient (initial temperature 80 degrees C held for 2.5 minutes, rising at 20 degrees per minute to 200 degrees) the starting material eluted at 3.8 minutes and the reduction product at 5.2 minutes. Chiral analysis was carried out by GC using a Chiraldex CB column (25m x 0.32mm) on a temperature gradient (initial temperature 80 degrees held for 5 minutes, rising at 10 degrees per minute to a final temperature of 180 degrees and held for 2 minutes), the (S)-enantiomer eluted at 12.3 minutes and the (R)-enantiomer at 12.7 minutes. The reduction of 3,5-bis- (trifluoromethyl)-acetophenone (20mg) was carried out in 2ml of sodium phosphate buffer (pH7.5) containing acetone dried Geotrichum candidum cells (100mg), EPO <DP n="28"/>nicotinamide adenine dinucleotide (1.5mg) and 2-propanol (2.6mg) incubated at 28 degrees centigrade for 24 hours, the reaction conversion was 65percent and the enantiomeric excess was >99percent (S).
92 % ee
With potassium <i>tert</i>-butylate; hydrogen In toluene; <i>tert</i>-butyl alcohol at 25 - 30℃; for 3 h; Autoclave
Accurately weighed amounts of (S5,S)-9 (0.9 mg, 1 μmol), solid KO-^-C4H9 (6 mg, 0.05 mmol) and sometimes derivatives [eg. PPh3 (0.3 mg, 1 μmol)] were placed in a pre-oven-dried (120 0C) 350-mL autoclave containing a magnetic stirring bar, and placed under high vacuum for at least 20 min before purging with argon. Freshly distilled solvent (toluene, 2.7 mL; t-BuOH, 0.3 mL) and purified ketones (1 mmol, S/C = 1,000) were placed into a pre-dried Schlenk and degassed by 3 cycles of freeze-and-thaw and then added to the autoclave under an Ar atmosphere. H2 was introduced under 20 atm pressure with several quick release-fill cycles before being set to 8 atm. The solution was vigorously stirred at 25 0C and H2 consumption monitored. The H2 was carefully released after a period of time, the solution passed through a short pad of silica gel and solvent removed under reduced pressure. The crude product mixture was analyzed by 1H NMR to determine conversion and chiral GC or HPLC to determine ee of the chiral alcohol products. The hydrogenation results are given in Table 5.
92 % ee
With potassium <i>tert</i>-butylate; hydrogen; triphenylphosphine In toluene; <i>tert</i>-butyl alcohol at 25 - 30℃; for 3 h;
Accurately weighed amounts of (SS,S)-9 (0.9 mg, 1 μmol), solid KO-t-C4H9 (6 mg, 0.05 mmol) and sometimes derivatives [e.g. PPh3 (0.3 mg, 1 μmol)] were placed in a pre-oven-dried (120° C.) 350-mL autoclave containing a magnetic stirring bar, and placed under high vacuum for at least 20 min before purging with argon. Freshly distilled solvent (toluene, 2.7 mL; t-BuOH, 0.3 mL) and purified ketones (1 mmol, S/C=1,000) were placed into a pre-dried Schlenk and degassed by 3 cycles of freeze-and-thaw and then added to the autoclave under an Ar atmosphere. H2 was introduced under 20 atm pressure with several quick release-fill cycles before being set to 8 atm. The solution was vigorously stirred at 25° C. and H2 consumption monitored. The H2 was carefully released after a period of time, the solution passed through a short pad of silica gel and solvent removed under reduced pressure. The crude product mixture was analyzed by 1H NMR to determine conversion and chiral GC or HPLC to determine ee of the chiral alcohol products. The hydrogenation results are given in Table 5. TABLE 5 Screening of aromatic substrates using complex (SS,S)-9a Entry subPPh3b t/h Conv. percent Ee percent (S) 1 acetophenone \\ 1 100 96 2 acetophenone 3eq 1 62 98 3 acetophenone 1eq 1 100 98 4 2-Me-acetophenone \\ 13.5 87 90 5 2-Me-acetophenone 1eq 8.5 74 97 6 4-MeO-acetophenone \\ 5 99 97 7 4-MeO-acetophenone 1eq 3 99 99.6 8 4-Br-acetophenone \\ 15 100 93 9 4-Br-acetophenone 1eq 6 99 98 10 4-F-acetophenone 1eq 9.5 100 98 11 4-Me-acetophenone 1eq 12 99 98 12 3-Br-acetophenone 1eq 1.5 99 98 133,5-CF3-acetophenone 1eq 3 100 92 14 1eq 5 100 99 15 1eq 2 99 99 16 1eq 10 90 98 17 1eq 3 97 91 18c 1eq 8 99 99 aConditions: Substrate/Catalyst/Base = 1000/1/50; VT = 3 mL, 25-30° C.bCompared to catalyst;cThe H2 pressure was 20 atm and the configuration of the product was R.
98.6 % ee
With [RuCl2((S,S)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane){(R,R)-2-(1H-benzo[d]imidazol-2-yl)cyclopentanamine}]; hydrogen; potassium carbonate In dichloromethane at 25℃; for 18 h; Autoclave; Inert atmosphere
The transition metal complex catalyst employs structure XI; 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 40,000.100L stainless steel autoclave, 3,5-bistrifluoromethylacetophenone (I) and methylene chloride were added and the catalyst was added under N2 atmosphere[RuCl2 ((S, S) -DIOP) {(R, R) -2- (1H-benzo [d] imidazol-2-yl) cyclopentanamine}](Transition metal complex) and potassium carbonate. After replacing the hydrogen, H2 to 60atm was charged. The reaction was stirred at 25 ° C. When the hydrogen pressure was constant (about 18 hours), the stirring was stopped and the H2 in the reaction kettle was vented. The reaction solution was sampled and subjected to a conventional post-treatment to obtain a solid product. The conversion of the reaction was 99.5percent as determined by liquid chromatography. The enantiomeric excess was 98.6percent and the absolute configuration was S configuration.
Reference：
[1] Patent: US2011/282077, 2011, A1, . Location in patent: Page/Page column 8
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 32, p. 7329 - 7332
[3] Tetrahedron Asymmetry, 2006, vol. 17, # 4, p. 554 - 559
[4] Patent: CN108059579, 2018, A, . Location in patent: Paragraph 0057-0061
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[7] Organic Process Research and Development, 2014, vol. 18, # 6, p. 793 - 800
[8] Tetrahedron Asymmetry, 2006, vol. 17, # 21, p. 3010 - 3014
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[10] Patent: WO2006/67395, 2006, A1, . Location in patent: Page/Page column 26-27
[11] Organic Letters, 2009, vol. 11, # 2, p. 305 - 308
[12] Patent: WO2009/149670, 2009, A1, . Location in patent: Page/Page column 21; 22
[13] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5888 - 5891
[14] Advanced Synthesis and Catalysis, 2010, vol. 352, # 14-15, p. 2621 - 2628
[15] Journal of Catalysis, 2011, vol. 278, # 1, p. 94 - 101
[16] Patent: US2011/92712, 2011, A1, . Location in patent: Page/Page column 9; 10
[17] Chemistry - A European Journal, 2011, vol. 17, # 50, p. 14234 - 14240
[18] Chemical Communications, 2016, vol. 52, # 30, p. 5289 - 5292
[19] Patent: CN105330517, 2016, A, . Location in patent: Paragraph 0066; 0067; 0068; 0069; 0070
[20] Organic and Biomolecular Chemistry, 2017, vol. 15, # 43, p. 9169 - 9175
4
[ 30071-93-3 ]
[ 225920-05-8 ]
[ 368-63-8 ]
Yield
Reaction Conditions
Operation in experiment
82 % ee
Stage #1: With formic acid; triethylamine In tetrahydrofuran at 20℃; for 1.75 h; Stage #2: With sodium hydroxide In tetrahydrofuran; water at 30℃;
[RhCp*CI2]2 and S1S-TsDPEN were charged to a split necked flask and the vessel placed under a nitrogen atmosphere. THF was charged to the vessel at ambient temperature with stirring and a nitrogen purge. To this was charged 3,5- bis(trifluoromethyl)acetophenone and the contents stirred for 15 mins. The TEAF (triethylamine/formic acid mixture) was then charged dropwise over 30 mins. The reaction was allowed to stir at 2O0C and the reaction monitored by GC (complete after approx 1 hour).The reaction was quenched by charging NaOH (2M) ensuring that the reaction temperature does not exceed 3O0C .The solution was stirred vigorously for 30 mins and allowed to settle for 30 mins. The lower organic layer was run off and fresh toluene charged to the separating vessel. The solution was stirred vigorously for 30 mins and allowed to settle for 30 mins and the lower organic layer was run off. The organic layers were combined and concentrated to 1/3 volume. This solution was used directly in the next stage. (Yield: >98percent, 82percent ee)
90.2 % ee
at 10℃; for 24.5 h;
Sodium formate was added to the water to make a 3.7M solution, which was then cooled to 100C. The Ir dimer was added and stirred for 20 minutes. The (S1S) TSDPEN was then added to the mixture and allowed to stir for 10 minutes prior to the addition of the ketone. The reaction was complete after 24hr. The suspension of product in aqueous solution was extracted twice with dichloromethane (2 x 40ml). The organic layers were combined and passed through a silica plug twice to remove the catalyst before being reduced in vacuo to yield the white, crystalline product (17.3g, 69percent yield). The combined organic layers can be used directly in the next stage without the need to isolate the product. Analysis by chiral GC (Chiralsil-Dex, 25m, 0.25 i.d., 0.25mm film) showed the product to be 90.2percent e.e (R).
83 % ee
With biphenyl; water; sodium formate In dichloromethane for 1.08333 h;
Experiment 2 - Biphasic Reduction of 3,5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (S1S1S)CSDPEN NaHCO2 A reaction flask was flushed through with nitrogen and charged with a solution of sodium formate (33.1g, 0.486mol, 5eq) in distilled water (131.4g, 7.3mol, 75eq). Rh or Ru metal-dimer (0.39mmol, 0.004eq of Rh2(Cp^2CI4 or Ru2(p-cymyl)2CI4) was added, followed by (S1S1S)CsDPEN ligand (0.332g, 0.77mmol, 0.008eq) and the aqueous mixture agitated under nitrogen for 20 minutes. EPO <DP n="26"/>An organic phase consisting of (3,5-bistrifluoromethyl)acetophenone (24.94g, 97.4mmol, 1eq) and biphenyl (0.3g, 1.93mmol, 0.02eq) in DCM (42.18g, 0.497mol, 5.1eq) was made up giving a total organic volume of 49.4ml. This organic solution was added to the aqueous whilst under agitation to form a well mixed, biphasic-aqueous continuous phase system, and the reaction allowed to proceed with GC sampling at regular intervals. Upon organic addition the solution changed from a pale orange to a red colour and any solids with low aqueous solubility dissolved. As reaction preceded the mixture slowly changed from a red to a dark brown colour, pH rose non-lineally from 7.0 to level out at 8.5. Reaction times were found to be 45 minutes for reaction using Rh-dimer and 700 minutes Ru-dimer. Reactions were worked up; agitation was ceased and the phases separated. The aqueous phase was washed with DCM (2x1 OmI) and the organic phases combined and washed with distilled water (2x1 OmI) followed by drying over anhydrous sodium sulphate and filtration. Next the dark brown solution was slurried with silica for 1 hour until the solution was clear, then the silica was filtered off and the solution concentrated in vacuo, to yield (3,5-Bistrifluoromethyl)phenylethanol as a white crystalline solid (17.15g, 66.4mmol, 68percent). Enantiomeric excess when using Rh-dimer was found to be 83.0percent and with Ru-dimer 81.5percent.(Note: biphenyl is present as an internal reference standard to assist in quantifying the GC results.)Experiment 3Experiment 2 was repeated except that the ligand was pre-dissolved. The reaction was carried out as above but Rh-dimer was added to aqueous formate solution and agitated for 5 minutes, then CsDPEN ligand was added pre-dissolved in DCM (10.0g, 118 mmol, 1.2 eq) and the mixture agitated for a further 15 minutes. Then solution of ketone/standard in DCM (32.18g, 379 mmol, 3.9 eq) was added and the reaction monitored. Results show that while the rate of hydrogenation is similar, there is increased conversion (conversion was increased from 90.7percent to 98.5percent).
81.5 % ee
With biphenyl; water; sodium formate In dichloromethane for 12 h;
Experiment 2 - Biphasic Reduction of 3,5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (S1S1S)CSDPEN NaHCO2 A reaction flask was flushed through with nitrogen and charged with a solution of sodium formate (33.1g, 0.486mol, 5eq) in distilled water (131.4g, 7.3mol, 75eq). Rh or Ru metal-dimer (0.39mmol, 0.004eq of Rh2(Cp^2CI4 or Ru2(p-cymyl)2CI4) was added, followed by (S1S1S)CsDPEN ligand (0.332g, 0.77mmol, 0.008eq) and the aqueous mixture agitated under nitrogen for 20 minutes. EPO <DP n="26"/>An organic phase consisting of (3,5-bistrifluoromethyl)acetophenone (24.94g, 97.4mmol, 1eq) and biphenyl (0.3g, 1.93mmol, 0.02eq) in DCM (42.18g, 0.497mol, 5.1eq) was made up giving a total organic volume of 49.4ml. This organic solution was added to the aqueous whilst under agitation to form a well mixed, biphasic-aqueous continuous phase system, and the reaction allowed to proceed with GC sampling at regular intervals. Upon organic addition the solution changed from a pale orange to a red colour and any solids with low aqueous solubility dissolved. As reaction preceded the mixture slowly changed from a red to a dark brown colour, pH rose non-lineally from 7.0 to level out at 8.5. Reaction times were found to be 45 minutes for reaction using Rh-dimer and 700 minutes Ru-dimer. Reactions were worked up; agitation was ceased and the phases separated. The aqueous phase was washed with DCM (2x1 OmI) and the organic phases combined and washed with distilled water (2x1 OmI) followed by drying over anhydrous sodium sulphate and filtration. Next the dark brown solution was slurried with silica for 1 hour until the solution was clear, then the silica was filtered off and the solution concentrated in vacuo, to yield (3,5-Bistrifluoromethyl)phenylethanol as a white crystalline solid (17.15g, 66.4mmol, 68percent). Enantiomeric excess when using Rh-dimer was found to be 83.0percent and with Ru-dimer 81.5percent.(Note: biphenyl is present as an internal reference standard to assist in quantifying the GC results.)Experiment 3Experiment 2 was repeated except that the ligand was pre-dissolved. The reaction was carried out as above but Rh-dimer was added to aqueous formate solution and agitated for 5 minutes, then CsDPEN ligand was added pre-dissolved in DCM (10.0g, 118 mmol, 1.2 eq) and the mixture agitated for a further 15 minutes. Then solution of ketone/standard in DCM (32.18g, 379 mmol, 3.9 eq) was added and the reaction monitored. Results show that while the rate of hydrogenation is similar, there is increased conversion (conversion was increased from 90.7percent to 98.5percent).
62.9 % ee
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 25℃; for 12 h;
Comparative Example 1; Asymmetric hydrogenation of 1-(3,5-bis(trifluoromethyl)phenyl)-ethanone [Show Image] 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).
70 % ee
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol for 3 h;
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.
> 99 % ee
With recombinant ketone reductase ChKRED20 from Chryseobacterium sp. CA49; isopropyl alcohol In aq. phosphate buffer at 30℃; for 24 h; Resolution of racemate; Enzymatic reaction
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]D22= +16.8 (c = 1.2, CHCl3); ee > 99percent {lit. [24] [α]D22= +16 (c = 1.204, CHCl3) for>99percent ee, R)}; retention times: tR(S) 7.3 min, tR(R) 8.4 min.
89 % ee
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate In water at 20℃; for 6 h;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2 . The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
89% ee
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate In water at 20℃; for 6 h; Green chemistry
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2. The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
83 % ee
With cis-[RuCl2((S)-8-amino-5,6,7,8-tetrahydroquinoline) ((2R,4R)-(-)-2,4-bis-(diphenylphosphine)pentane)]; potassium <i>tert</i>-butylate In isopropyl alcohol at 40℃; for 0.666667 h; Schlenk technique; Sealed tube; Inert atmosphere
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 chloride
28 % ee
With [RuCl2((R)-8-amino-5,6,7,8-tetrahydroquinoline) ((2R,5R)-(-)-2,5-bis-diphenylphosphin-3-hexene)]; potassium <i>tert</i>-butylate In isopropyl alcohol at 40℃; for 2 h; Schlenk technique; Sealed tube; Inert atmosphere
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 chloride
63 % ee
With bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate; formic acid; sodium formate; (1R,2R)-N1,N-di(naphthalen-1-yl)cyclohexane-1,2-diamine In methanol; water at 70℃; for 22 h; Inert atmosphere
General 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).
78.07 % ee
With Klebsiella oxytoca alcohol dehydrogenase overexpressed in Escherichia coli Rosetta (DE3); NADPH; NADH In aq. buffer at 30℃; for 24 h; Enzymatic reaction
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].
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5
[ 68120-60-5 ]
[ 225920-05-8 ]
Yield
Reaction Conditions
Operation in experiment
73.3%
at 50℃; for 5.25 h; Inert atmosphere
1, rac-3,5-bis (trifluoromethyl) phenethyl alcohol:Take 3,5-bis (trifluoromethyl) acetophenone 500g into the round bottom flask was added 30mL of ethanol, followed by stirring to dissolve, cooled to 0 deg.] C; and NaBH4350 g of, stirred for one hour at room temperature; heated to 35 , stirring was continued for 40min, TLC detection, the reaction was complete; quenched with water; extracted with ethylacetate three times, and concentrated to dryness; washed with petroleum ether, suction filtered.Product as a white powder, the product is a racemic mixture, weighed in 98percent yield.2, resolved by preferential crystallization (S) -3,5- bis (trifluoromethyl) phenethyl alcohol(1) primary crystalsStep 30g compound obtained in preparation to take on (2) was added 105mL of petroleum ether, heated and stirred under argon for 50 , dissolved; into an (S) -3,5- bis (trifluoromethyl) phenethyl alcohol seed , after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 19g a yield of 76.7percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 65.5percent.(2) secondary crystalsTake a crystalline compound obtained 30g, was added 105mL of petroleum ether, heated and stirred under argon for 40 , dissolved; into an (S) -3,5- bis (trifluoromethyl) phenethyl alcohol seed, after 45min, seed 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, yield 70.0percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 95.5percent.(3) three times crystallizedTaking a second resultant crystalline compound 30g, was added 105mL of petroleum ether, heated and stirred under argon for 50 , dissolved; into an (S) -3,5- bis (trifluoromethyl) phenethyl alcohol seed, after 45min seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 22g, yield 73.3percent; according to the aforementioned chromatographic conditions, chiral phase detection ee: 99.8percent.
Reference：
[1] Patent: CN105237346, 2016, A, . Location in patent: Paragraph 0085; 0086;0087; 0088; 0089; 0090; 0091; 0092-0095
[2] Advanced Synthesis and Catalysis, 2012, vol. 354, # 9, p. 1737 - 1742
[3] Chemical Communications, 2016, vol. 52, # 30, p. 5289 - 5292
6
[ 68120-60-5 ]
[ 30071-93-3 ]
[ 225920-05-8 ]
[ 368-63-8 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 11, p. 4600 - 4603
[RhCp*CI2]2 and S1S-TsDPEN were charged to a split necked flask and the vessel placed under a nitrogen atmosphere. THF was charged to the vessel at ambient temperature with stirring and a nitrogen purge. To this was charged 3,5- bis(trifluoromethyl)acetophenone and the contents stirred for 15 mins. The TEAF (triethylamine/formic acid mixture) was then charged dropwise over 30 mins. The reaction was allowed to stir at 2O0C and the reaction monitored by GC (complete after approx 1 hour).The reaction was quenched by charging NaOH (2M) ensuring that the reaction temperature does not exceed 3O0C .The solution was stirred vigorously for 30 mins and allowed to settle for 30 mins. The lower organic layer was run off and fresh toluene charged to the separating vessel. The solution was stirred vigorously for 30 mins and allowed to settle for 30 mins and the lower organic layer was run off. The organic layers were combined and concentrated to 1/3 volume. This solution was used directly in the next stage. (Yield: >98%, 82%ee)
With water; sodium formate;bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide; at 10℃; for 24.5h;Product distribution / selectivity;
Sodium formate was added to the water to make a 3.7M solution, which was then cooled to 100C. The Ir dimer was added and stirred for 20 minutes. The (S1S) TSDPEN was then added to the mixture and allowed to stir for 10 minutes prior to the addition of the ketone. The reaction was complete after 24hr. The suspension of product in aqueous solution was extracted twice with dichloromethane (2 x 40ml). The organic layers were combined and passed through a silica plug twice to remove the catalyst before being reduced in vacuo to yield the white, crystalline product (17.3g, 69% yield). The combined organic layers can be used directly in the next stage without the need to isolate the product. Analysis by chiral GC (Chiralsil-Dex, 25m, 0.25 i.d., 0.25mm film) showed the product to be 90.2% e.e (R).
With biphenyl; water; sodium formate;Ru2(p-cymyl)2Cl4; (S,S,S)-CsDPEN; tetrabutylammonium sulfate; In dichloromethane; for 1.08333h;pH 7.0 - 8.5;Product distribution / selectivity;
Experiment 2 was repeated using a phase transfer catalyst addition. The reaction was set up and allowed to run as before using the Ru-catalyst. After 60 minutes (Bu4N)2SO4PTC (5.66g of a 50% wt solution in water, 0.05 eq) was added. The reaction rate increased instantaneously. The increase was approx 520%.
With biphenyl; water; sodium formate;dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; (S,S,S)-CsDPEN; In dichloromethane; for 1.08333h;pH 7 - 8.5;Product distribution / selectivity;
Experiment 2 - Biphasic Reduction of 3,5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (S1S1S)CSDPEN NaHCO2 A reaction flask was flushed through with nitrogen and charged with a solution of sodium formate (33.1g, 0.486mol, 5eq) in distilled water (131.4g, 7.3mol, 75eq). Rh or Ru metal-dimer (0.39mmol, 0.004eq of Rh2(Cp^2CI4 or Ru2(p-cymyl)2CI4) was added, followed by (S1S1S)CsDPEN ligand (0.332g, 0.77mmol, 0.008eq) and the aqueous mixture agitated under nitrogen for 20 minutes. EPO <DP n="26"/>An organic phase consisting of (3,5-bistrifluoromethyl)acetophenone (24.94g, 97.4mmol, 1eq) and biphenyl (0.3g, 1.93mmol, 0.02eq) in DCM (42.18g, 0.497mol, 5.1eq) was made up giving a total organic volume of 49.4ml. This organic solution was added to the aqueous whilst under agitation to form a well mixed, biphasic-aqueous continuous phase system, and the reaction allowed to proceed with GC sampling at regular intervals. Upon organic addition the solution changed from a pale orange to a red colour and any solids with low aqueous solubility dissolved. As reaction preceded the mixture slowly changed from a red to a dark brown colour, pH rose non-lineally from 7.0 to level out at 8.5. Reaction times were found to be 45 minutes for reaction using Rh-dimer and 700 minutes Ru-dimer. Reactions were worked up; agitation was ceased and the phases separated. The aqueous phase was washed with DCM (2x1 OmI) and the organic phases combined and washed with distilled water (2x1 OmI) followed by drying over anhydrous sodium sulphate and filtration. Next the dark brown solution was slurried with silica for 1 hour until the solution was clear, then the silica was filtered off and the solution concentrated in vacuo, to yield (3,5-Bistrifluoromethyl)phenylethanol as a white crystalline solid (17.15g, 66.4mmol, 68%). Enantiomeric excess when using Rh-dimer was found to be 83.0% and with Ru-dimer 81.5%.(Note: biphenyl is present as an internal reference standard to assist in quantifying the GC results.)Experiment 3Experiment 2 was repeated except that the ligand was pre-dissolved. The reaction was carried out as above but Rh-dimer was added to aqueous formate solution and agitated for 5 minutes, then CsDPEN ligand was added pre-dissolved in DCM (10.0g, 118 mmol, 1.2 eq) and the mixture agitated for a further 15 minutes. Then solution of ketone/standard in DCM (32.18g, 379 mmol, 3.9 eq) was added and the reaction monitored. Results show that while the rate of hydrogenation is similar, there is increased conversion (conversion was increased from 90.7% to 98.5%).
With biphenyl; water; sodium formate;Ru2(p-cymyl)2Cl4; (S,S,S)-CsDPEN; In dichloromethane; for 12h;pH 7 - 8.5;Product distribution / selectivity;
Experiment 2 - Biphasic Reduction of 3,5-(bistrifluoromethyl)phenylacetophenoneTM dimer Rh/Ru (S1S1S)CSDPEN NaHCO2 A reaction flask was flushed through with nitrogen and charged with a solution of sodium formate (33.1g, 0.486mol, 5eq) in distilled water (131.4g, 7.3mol, 75eq). Rh or Ru metal-dimer (0.39mmol, 0.004eq of Rh2(Cp^2CI4 or Ru2(p-cymyl)2CI4) was added, followed by (S1S1S)CsDPEN ligand (0.332g, 0.77mmol, 0.008eq) and the aqueous mixture agitated under nitrogen for 20 minutes. EPO <DP n="26"/>An organic phase consisting of (3,5-bistrifluoromethyl)acetophenone (24.94g, 97.4mmol, 1eq) and biphenyl (0.3g, 1.93mmol, 0.02eq) in DCM (42.18g, 0.497mol, 5.1eq) was made up giving a total organic volume of 49.4ml. This organic solution was added to the aqueous whilst under agitation to form a well mixed, biphasic-aqueous continuous phase system, and the reaction allowed to proceed with GC sampling at regular intervals. Upon organic addition the solution changed from a pale orange to a red colour and any solids with low aqueous solubility dissolved. As reaction preceded the mixture slowly changed from a red to a dark brown colour, pH rose non-lineally from 7.0 to level out at 8.5. Reaction times were found to be 45 minutes for reaction using Rh-dimer and 700 minutes Ru-dimer. Reactions were worked up; agitation was ceased and the phases separated. The aqueous phase was washed with DCM (2x1 OmI) and the organic phases combined and washed with distilled water (2x1 OmI) followed by drying over anhydrous sodium sulphate and filtration. Next the dark brown solution was slurried with silica for 1 hour until the solution was clear, then the silica was filtered off and the solution concentrated in vacuo, to yield (3,5-Bistrifluoromethyl)phenylethanol as a white crystalline solid (17.15g, 66.4mmol, 68%). Enantiomeric excess when using Rh-dimer was found to be 83.0% and with Ru-dimer 81.5%.(Note: biphenyl is present as an internal reference standard to assist in quantifying the GC results.)Experiment 3Experiment 2 was repeated except that the ligand was pre-dissolved. The reaction was carried out as above but Rh-dimer was added to aqueous formate solution and agitated for 5 minutes, then CsDPEN ligand was added pre-dissolved in DCM (10.0g, 118 mmol, 1.2 eq) and the mixture agitated for a further 15 minutes. Then solution of ketone/standard in DCM (32.18g, 379 mmol, 3.9 eq) was added and the reaction monitored. Results show that while the rate of hydrogenation is similar, there is increased conversion (conversion was increased from 90.7% to 98.5%).
With formic acid; triethylamine;(1S,2S)-N-p-toluenesulfonyl-1,2-di(4-methoxyphenyl)ethylenediamine; [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; In N,N-dimethyl-formamide; at 40 - 60℃; for 20.1667h;Product distribution / selectivity;
Example 3: Use of mono-sulfonated diamines 5 for asymmetric transfer hvdroqenation; Test of transfer hvdroqenation catalysts on a mixture of ketones; EPO <DP n="11"/>Transfer hydrogenation catalysts bearing diamines 5 were prepared in situ and tested on pre¬ formed mixture of ketones in DMF. [Ru(p-cymene)CI2]2 (0.0025 mmol) or [RhCp*CI2]2 (0.0025 mmol) mono-sulfonated diamine (0.0055 mmol) 5 in anhydrous DMF (2 mL) were heated at 400C for 10 minutes under inert atmosphere (argon). A solution of five ketones (0.5 mL, 1 mmol in total, 0.2 mmol each) in DMF was added (S/C 40 with respect to each substrate), followed by 0.6 mL of formic acid/trietylamine 1/1 mixture and 1 mL of DMF. The reaction was heated overnight (20 hrs) at 6O0C and analysed by CG (ChiraDex CB column, 10 psi He, 1000C for 12 min, then to 18O0C at 1.5 C/min, then to 2000C at 5 C/min). For reference, the diamines tested were as follows; 5b, (S1S)-TsDAEN 5a, (R5R)-TsDTEN (S1S)-TsDPEN
With formic acid; triethylamine;(R,R)-TsDPEN; [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; In N,N-dimethyl-formamide; at 40 - 60℃; for 20.1667h;Product distribution / selectivity;
Example 3: Use of mono-sulfonated diamines 5 for asymmetric transfer hvdroqenation; Test of transfer hvdroqenation catalysts on a mixture of ketones; EPO <DP n="11"/>Transfer hydrogenation catalysts bearing diamines 5 were prepared in situ and tested on pre¬ formed mixture of ketones in DMF. [Ru(p-cymene)CI2]2 (0.0025 mmol) or [RhCp*CI2]2 (0.0025 mmol) mono-sulfonated diamine (0.0055 mmol) 5 in anhydrous DMF (2 mL) were heated at 400C for 10 minutes under inert atmosphere (argon). A solution of five ketones (0.5 mL, 1 mmol in total, 0.2 mmol each) in DMF was added (S/C 40 with respect to each substrate), followed by 0.6 mL of formic acid/trietylamine 1/1 mixture and 1 mL of DMF. The reaction was heated overnight (20 hrs) at 6O0C and analysed by CG (ChiraDex CB column, 10 psi He, 1000C for 12 min, then to 18O0C at 1.5 C/min, then to 2000C at 5 C/min). For reference, the diamines tested were as follows; 5b, (S1S)-TsDAEN 5a, (R5R)-TsDTEN (S1S)-TsDPEN
With formic acid; triethylamine;(1S,2S)-N-p-toluenesulfonyl-1,2-di(4-methoxyphenyl)ethylenediamine; [Cp*RhCl2]2; In N,N-dimethyl-formamide; at 40 - 60℃; for 20.1667h;Product distribution / selectivity;
Example 3: Use of mono-sulfonated diamines 5 for asymmetric transfer hvdroqenation; Test of transfer hvdroqenation catalysts on a mixture of ketones; EPO <DP n="11"/>Transfer hydrogenation catalysts bearing diamines 5 were prepared in situ and tested on pre¬ formed mixture of ketones in DMF. [Ru(p-cymene)CI2]2 (0.0025 mmol) or [RhCp*CI2]2 (0.0025 mmol) mono-sulfonated diamine (0.0055 mmol) 5 in anhydrous DMF (2 mL) were heated at 400C for 10 minutes under inert atmosphere (argon). A solution of five ketones (0.5 mL, 1 mmol in total, 0.2 mmol each) in DMF was added (S/C 40 with respect to each substrate), followed by 0.6 mL of formic acid/trietylamine 1/1 mixture and 1 mL of DMF. The reaction was heated overnight (20 hrs) at 6O0C and analysed by CG (ChiraDex CB column, 10 psi He, 1000C for 12 min, then to 18O0C at 1.5 C/min, then to 2000C at 5 C/min). For reference, the diamines tested were as follows; 5b, (S1S)-TsDAEN 5a, (R5R)-TsDTEN (S1S)-TsDPEN
With potassium tert-butylate; hydrogen;(S)-1-isopropyl-2,2-bis(4-methoxyphenyl)ethylenediamine; In isopropyl alcohol; at 25℃; under 7500.75 Torr; for 12h;Product distribution / selectivity;
Comparative Example 1; Asymmetric hydrogenation of 1-(3,5-bis(trifluoromethyl)phenyl)-ethanone [Show Image] 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 25C for 12 hr. The reaction mixture was analyzed by GC (column: CHIRASIL-DEX CB, 0.32 mmx25 m) to find a conversion ratio of 60.8% and an optical purity of 62.9%ee(R).
With potassium formate;Cp*IrCl[(S,S)-(C2H5)2CHCH2SO2dpen]; tetrabutylammomium bromide; In water; at 50℃; for 24h;Inert atmosphere;Product distribution / selectivity;
The reaction was carried out with the same conditions as in Comparative example C-9, except that 0.72 mg (1.0 mumol) of Cp*IrCl[(S,S)-(C2H5)2CHCH2SO2dpen] was used as the catalyst. GC analysis of the reaction product confirmed that 1-(3',5'-bis(trifluoromethyl)phenyl)ethanol with 84.2% ee optical purity was produced at 100% yield. Comparison with Comparative example C-9 indicated the superiority of this complex.
With potassium tert-butylate; hydrogen;RuCl2((S)-Ph-Garphos)((S)-DPEN); In isopropyl alcohol; under 8274.59 Torr; for 3h;
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.
With recombinant ketone reductase ChKRED20 from Chryseobacterium sp. CA49; isopropyl alcohol; In aq. phosphate buffer; at 30℃; for 24h;pH 7;Resolution of racemate; Enzymatic reaction;Kinetics;
Biotransformation using lyophilized powder of crude ChKRED20 was performed in 5 ml potassium phosphate buffer (100 mM, pH 7.0) containing 40% (v/v) of 2-propanol, crude enzyme (2 g/l or10 g/l), and substrate (50-200 g/l). The reaction was carried outat 30C 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); [alpha]D22= +16.8 (c = 1.2, CHCl3); ee > 99% {lit. [24] [alpha]D22= +16 (c = 1.204, CHCl3) for>99% ee, R)}; retention times: tR(S) 7.3 min, tR(R) 8.4 min.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate; In water; at 20℃; for 6h;Catalytic behavior;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2 . The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate; In water; at 20℃; for 6h;Green chemistry;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2. The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
With cis-[RuCl2((S)-8-amino-5,6,7,8-tetrahydroquinoline) ((2R,4R)-(-)-2,4-bis-(diphenylphosphine)pentane)]; potassium tert-butylate; In isopropyl alcohol; at 40℃; for 0.666667h;Schlenk technique; Sealed tube; Inert atmosphere;Catalytic behavior;
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 mumol) in 4 ml of 2-propanol and the system thermostated at 40C or 82C; 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 chloride
With [RuCl2((R)-8-amino-5,6,7,8-tetrahydroquinoline) ((2R,5R)-(-)-2,5-bis-diphenylphosphin-3-hexene)]; potassium tert-butylate; In isopropyl alcohol; at 40℃; for 2h;Schlenk technique; Sealed tube; Inert atmosphere;Catalytic behavior;
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 mumol) in 4 ml of 2-propanol and the system thermostated at 40C or 82C; 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 chloride
With bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate; formic acid; sodium formate; (1R,2R)-N1,N-di(naphthalen-1-yl)cyclohexane-1,2-diamine; In methanol; water; at 70℃; for 22h;Inert atmosphere;Catalytic behavior;
General procedure: In a pressure tube, 0.5 mol% of metal precursor [C16H24BF4Ir](2.48 mg, 0.005 mol) and 1 mol% 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).
With [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; hydrogen; sodium hydroxide; In tetrahydrofuran; at 95℃; under 18751.9 Torr; for 11h;Catalytic behavior;
Complex steps: The 0.0082g catalyst [RuCl 2 (C 10 H 14) 2] 2 and chiral ligand (S, S)-C 6 P 2 (NH) 2 (catalyst : = 1 the ligand [...] 1.9) into a 100 ml round-bottom flask, by adding tetrahydrofuran 50 ml, in 60 C magnetic stirring 60 min, the catalyst and ligand is fully dissolved complex; Reaction step: To 2500 ml of tetrahydrofuran is added in the reactor 1800 ml (organic solvent : = 90 the substrate [...] 1), then the 20 ml substrate 3,5-bis (trifluoromethyl) acetophenone and 0.738gNaOH (alkali :: = 90 the catalyst [...] 1) into a reaction kettle, then add the above-mentioned complex completion of the catalyst and ligand mixed solution 50 ml, replacement with hydrogen in the reactor 3 times, in order to ensure that the reaction is carried out under oxygen-free conditions. Opening stirring, the stirring rate set to 600r/min, hydrogen pressure of 2.5 MPa. After heating to 95 C and maintain a constant temperature, reaction 11h. Separating step: With the reaction liquid after the reaction the solvent is evaporated by the spin vaporization under reduced pressure, ethyl acetate and petroleum ether then used (the 1 [...] 8) as eluant on silica gel column to column separation in the catalyst and the unreacted substrate, after the liquid pressure reducing the spin vaporization crosses the column remove the eluant, pure product can be obtained. Removed from the kettle spirit after diluting the reaction solution with the chromatographic column for analysis. The obtained result is the conversion to 92.9%, the enantiomeric excess value of 88.3%.
With Klebsiella oxytoca alcohol dehydrogenase overexpressed in Escherichia coli Rosetta (DE3); NADPH; NADH; In aq. buffer; at 30℃; for 24h;Enzymatic reaction;
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].
With potassium tert-butylate; (Rc,Sp)-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diphenylphosphino)ferrocenylethylamine manganese; isopropyl alcohol; at 20℃; for 2h;Inert atmosphere;
General procedure: a) Add 1-acetylnaphthalene (0.17g, 1mmol), potassium tert-butoxide (22mg, 0.2mmol) and catalyst (7mg, 0.01mmol) to a 50ml round-bottomed flask, and then add them to the round-bottomed flask. 30 ml of isopropanol was replaced with nitrogen for 10 times, and the reaction was stirred. The reaction temperature was 20 C. The reaction was stopped after 2 hours of reaction. The reaction was detected by GC, and the conversion was determined to be 94%. The ee value measured by LC was 93%.
With potassium formate;Ru(OTf)[(S,S)-iso-BuSO2dpen](p-cymene); In methanol; at 50℃; for 24h;Inert atmosphere;
Working Example 23; A ruthenium complex Ru(OTf)[(S,S)-iso-BuSO2dpen] (p-cymene) (1.4 mg, 0.002 mmol), potassium formate (1.0 g, 12 mmol), and 3',5'-bis(trifluoromethyl)acetophenone (2.56 g, 10 mmol, substrate/catalyst ratio=5000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50 C. for 24 hours to give (S)-1-[3',5'-bis(trifluoromethyl)phenyl]ethanol at 100% yield and 87.7% ee optical purity.
93.5%
With sodium tetrahydroborate; dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; In tetrahydrofuran; toluene; at 0 - 5℃; for 0.5h;
3',5'-bis(trifluoromethyl)acetophenone (3.1 ml in 17 ml) was passed through a syringe pump at 0-5C for 2 hoursIn THF,17 millimoles) were added to5 ml of 2M (ie 10 mmol) of different borane reagent and 0.85 ml (5 mol% vs. 3',5'-bis(trifluoromethyl)acetophenone)1M of a (R)-MeCBS toluene solution in a mixed solution.After stirring 3',5'-bis(trifluoromethyl)acetophenone for 30 minutes,Then, hydrochloric acid (1M, 4.2 ml) was added dropwise to the reaction solution to quench the reaction.The organic phase of the reaction solution was extracted with 20 ml of methyl tert-butyl ether.Wash the organic layer with water and saturated saline,Dry with anhydrous Na2SO4,At last,The organic phase is evaporated andGet the product.The resulting enantiomeric excess (%ee) of (S)-1-[3,5-bis(trimethyl)phenyl]ethanol was determined by chiral HPLC.The results are shown in Table 5.Selective reduction of 3?,5?-bis(trifluoromethyl)acetophenone with BTHF as reducing agentThe resulting product has a low %ee,and,Adding sodium borohydride has a great influence on the % ee value of the product;In the selective reduction of 3?,5?-bis(trifluoromethyl)acetophenone with BDMS as reducing agent,The %ee value is high,and,The presence of sodium borohydride did not reduce the %ee value of the reaction
With NAD;Geotrichum candidum cells; In isopropyl alcohol; at 28℃; for 24h;pH 7.5;Sodium phosphate buffer;
Geotrichum candidum BPCC 1118 was grown aerobically in shake flasks containing a mineral salts medium pH 7.2, supplemented with glucose (5g/litre), yeast extract (2g/litre) and 2-propanol (15g/litre). Cultures were incubated on a shaker at 28 degrees centigrade for 24 hours and the cells recovered by centrifugation. The recovered cell pellet was dehydrated by resuspension in 10 volumes of acetone, the cells were recovered by filtration and washed twice more with acetone before drying under vacuum to provide a free-flowing powder. Reactions were analysed by GC on a DB17 column (30m x 0.32mm), using a temperature gradient (initial temperature 80 degrees C held for 2.5 minutes, rising at 20 degrees per minute to 200 degrees) the starting material eluted at 3.8 minutes and the reduction product at 5.2 minutes. Chiral analysis was carried out by GC using a Chiraldex CB column (25m x 0.32mm) on a temperature gradient (initial temperature 80 degrees held for 5 minutes, rising at 10 degrees per minute to a final temperature of 180 degrees and held for 2 minutes), the (S)-enantiomer eluted at 12.3 minutes and the (R)-enantiomer at 12.7 minutes. The reduction of 3,5-bis- (trifluoromethyl)-acetophenone (20mg) was carried out in 2ml of sodium phosphate buffer (pH7.5) containing acetone dried Geotrichum candidum cells (100mg), EPO <DP n="28"/>nicotinamide adenine dinucleotide (1.5mg) and 2-propanol (2.6mg) incubated at 28 degrees centigrade for 24 hours, the reaction conversion was 65% and the enantiomeric excess was >99% (S).
With potassium tert-butylate; hydrogen;trans-RuCl2[(S,S)-DIOP][(S)-Me-bimaH]; triphenylphosphine; In toluene; tert-butyl alcohol; at 25 - 30℃; under 6080.41 Torr; for 3h;Autoclave;Product distribution / selectivity;
Accurately weighed amounts of (S5,S)-9 (0.9 mg, 1 mumol), solid KO-^-C4H9 (6 mg, 0.05 mmol) and sometimes derivatives [eg. PPh3 (0.3 mg, 1 mumol)] were placed in a pre-oven-dried (120 0C) 350-mL autoclave containing a magnetic stirring bar, and placed under high vacuum for at least 20 min before purging with argon. Freshly distilled solvent (toluene, 2.7 mL; t-BuOH, 0.3 mL) and purified ketones (1 mmol, S/C = 1,000) were placed into a pre-dried Schlenk and degassed by 3 cycles of freeze-and-thaw and then added to the autoclave under an Ar atmosphere. H2 was introduced under 20 atm pressure with several quick release-fill cycles before being set to 8 atm. The solution was vigorously stirred at 25 0C and H2 consumption monitored. The H2 was carefully released after a period of time, the solution passed through a short pad of silica gel and solvent removed under reduced pressure. The crude product mixture was analyzed by 1H NMR to determine conversion and chiral GC or HPLC to determine ee of the chiral alcohol products. The hydrogenation results are given in Table 5.
With potassium tert-butylate; hydrogen; triphenylphosphine;trans-RuCl2[(S,S)-DIOP][(S)-Me-bimaH]; In toluene; tert-butyl alcohol; at 25 - 30℃; under 6080.41 Torr; for 3h;Product distribution / selectivity;
Accurately weighed amounts of (SS,S)-9 (0.9 mg, 1 mumol), solid KO-t-C4H9 (6 mg, 0.05 mmol) and sometimes derivatives [e.g. PPh3 (0.3 mg, 1 mumol)] were placed in a pre-oven-dried (120 C.) 350-mL autoclave containing a magnetic stirring bar, and placed under high vacuum for at least 20 min before purging with argon. Freshly distilled solvent (toluene, 2.7 mL; t-BuOH, 0.3 mL) and purified ketones (1 mmol, S/C=1,000) were placed into a pre-dried Schlenk and degassed by 3 cycles of freeze-and-thaw and then added to the autoclave under an Ar atmosphere. H2 was introduced under 20 atm pressure with several quick release-fill cycles before being set to 8 atm. The solution was vigorously stirred at 25 C. and H2 consumption monitored. The H2 was carefully released after a period of time, the solution passed through a short pad of silica gel and solvent removed under reduced pressure. The crude product mixture was analyzed by 1H NMR to determine conversion and chiral GC or HPLC to determine ee of the chiral alcohol products. The hydrogenation results are given in Table 5. TABLE 5 Screening of aromatic substrates using complex (SS,S)-9a Entry subPPh3b t/h Conv. % Ee % (S) 1 acetophenone 1 100 96 2 acetophenone 3eq 1 62 98 3 acetophenone 1eq 1 100 98 4 2-Me-acetophenone 13.5 87 90 5 2-Me-acetophenone 1eq 8.5 74 97 6 4-MeO-acetophenone 5 99 97 7 4-MeO-acetophenone 1eq 3 99 99.6 8 4-Br-acetophenone 15 100 93 9 4-Br-acetophenone 1eq 6 99 98 10 4-F-acetophenone 1eq 9.5 100 98 11 4-Me-acetophenone 1eq 12 99 98 12 3-Br-acetophenone 1eq 1.5 99 98 133,5-CF3-acetophenone 1eq 3 100 92 14 1eq 5 100 99 15 1eq 2 99 99 16 1eq 10 90 98 17 1eq 3 97 91 18c 1eq 8 99 99 aConditions: Substrate/Catalyst/Base = 1000/1/50; VT = 3 mL, 25-30 C.bCompared to catalyst;cThe H2 pressure was 20 atm and the configuration of the product was R.
With [RuCl2((S,S)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane){(R,R)-2-(1H-benzo[d]imidazol-2-yl)cyclopentanamine}]; hydrogen; potassium carbonate; In dichloromethane; at 25℃; under 45603.1 Torr; for 18h;Autoclave; Inert atmosphere;
The transition metal complex catalyst employs structure XI; 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 40,000.100L stainless steel autoclave, 3,5-bistrifluoromethylacetophenone (I) and methylene chloride were added and the catalyst was added under N2 atmosphere[RuCl2 ((S, S) -DIOP) {(R, R) -2- (1H-benzo [d] imidazol-2-yl) cyclopentanamine}](Transition metal complex) and potassium carbonate. After replacing the hydrogen, H2 to 60atm was charged. The reaction was stirred at 25 C. When the hydrogen pressure was constant (about 18 hours), the stirring was stopped and the H2 in the reaction kettle was vented. The reaction solution was sampled and subjected to a conventional post-treatment to obtain a solid product. The conversion of the reaction was 99.5% as determined by liquid chromatography. The enantiomeric excess was 98.6% and the absolute configuration was S configuration.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; cyclohexane; at 20℃; for 5.5h;
Step 3: Imidate Preparation FW mass volume mol equiv. Materials: (S)-BTBA 258.16 8.00 kg 31.0 1.0 CCl3CN 144.4 4.92 kg 3.42 L 34.07 1.1 DBU 152.24 92.2 mL 0.62 0.02 Cyclohexane 42.4 LCH2Cl2 8.6 L Procedure: To a 100 Liter Flask containing 27 L of a 4:1 mixture of cyclohexane/CH2Cl2 was added 8.0 Kg of (S)-BTBA as a solid and the sides of the flask were rinsed with an additional 10.3 L of 4:1 mixture of cyclohexane/CH2Cl2. To the resulting slurry was added 4.92 Kg (3.42 Liters) of trichloroacetonitrile followed by 92.2 mL of DBU. The reaction mixture was aged at rt for 5.5 h and assayed for completion. The reaction mixture was then transferred to a 100 Liter extractor rinsing the reaction flask with cyclohexane. The mixture was washed with 27 Liters of water and then with 27 liters of brine. The organic layer was then filtered over a small plug of Solka floc and azetropically distilled under reduced pressure (24 mmHg, internal temp<35 C.) and a final volume of 15 Liters and a Kf<200. Assay yield=12.00 Kg (96.2%).
96.2%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; cyclohexane; at 20℃; for 5.5h;
To a 100 Liter Flask containing 27 L of a 4:1 mixture of cyclohexane/CH2Cl2 was added 8.0 Kg of(S)-BTBA as a solid and the sides of the flask were rinsed with an additional 10.3 L of 4:1 mixture of cyclohexane/CH2Cl2. To the resulting slurry was added 4.92 Kg (3.42 Liters) of trichloroacetonitrile followed by 92.2 mL of DBU. The reaction mixture was aged at rt for 5.5 h and assayed for completion. The reaction mixture was then transferred to a 100 Liter extractor rinsing the reaction flask with cyclohexane. The mixture was washed with 27 Liters of water and then with 27 liters of brine. The organic layer was then filtered over a small plug of Solka floe and azetropically distilled under reduced pressure (24 mmHg, internal temp < 35 0C) and a final volume of -15 Liters and a Kf < 200. Assay yield = 12.00 Kg (96.2%).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In diethyl ether; at 0℃; for 2.41667h;
Step E (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate A solution of 25.82 g (100 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3 mL (20 mmol, 0.2 equiv) DBU was added to the reaction flask then the mixture was stirred at 0 C. for ten min. Slowly 15 mL (150 mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0 C. for 2 hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (<35 C.) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3"*10" pad) in two batches eluding with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a pale yellow oil. 1H-NMR (CDCl3): delta: 1.74 (3 H, d, J=6.5 Hz), 6.07 (1 H, q, J=6.5 Hz), 7.82 (1 H, s), 7.86 (2 H, s), 8.40 (1 H, br. s) ppm.
A solution of 25.82g (lOOmmol) of (lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethanol in 20OmL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3mL (20mmol, 0.2equiv) DBU was added to the reaction flask then the mixture was stirred at O0C for ten min. Slowly 15mL (150mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction EPO <DP n="22"/>was stirred at O0C for 2hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (< 350C) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3" X 10" pad) in two batches eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give the title compound as a pale yellow oil. 1H-NMR (CDCI3): D : 1.74 (d, 3H, 6.5Hz)5 6.07 (q, IH,6.5Hz), 7.82 (s, IH), 7.86 (s, 2H), 8.40 (br. s, IH) ppm.
With 1,8-diazabicyclo[5.4.0]undec-7-ene;
S-BTBA ((S)-1-[3,5-bis(trifluoromethyl)]phenylethanol)) (12) is reacted with trichloroacetonitrile (Sigma-Aldrich) in the presence of base 1,8-diazabicycloundec-7-ene (DBU) to produce imidate (13). HBF4 is used to catalyze the reaction of (11) with (13) to yield ether (14). Treatment with allylamine and bis-propylsulfonate cyclizes (14) to allylamine-protected pyrrolidine (15). Removal of the allyl protecting group with thiosalicylic acid and 1,4-bis(diphenylphosphino)butane (dppb), followed by bis(dibenzylideneacetone)palladium (Pd2(dba)3) and isolation with acetic acid gives crystalline (16). Finally, (16) is reacted with 1,3-cyclopentanedione (Sigma-Aldrich) in isopropyl alcohol to give Compound 1. Compound 1 is a white to off-white powder. It is freely soluble in methanol, soluble in ethanol, slightly soluble in isopropyl acetate, sparingly soluble in isopropyl alcohol, ethyl acetate, and acetonitrile, and insoluble in water.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In diethyl ether; at 0℃; for 2h;
A solution of 25. 82g (LOOMMOL) of (1S)-1- [3, 5-bis (trifluoromethyl) phenyl] ethanol in 200mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3mL (20mmol, 0.2equiv) DBU was added to the reaction flask then the mixture was stirred at 0C for ten min. Slowly l5mL (150MMOL, 1.5 equiv. ) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0C for 2hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (< 35 C) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3"X 10" pad) in two batches eluting with HEXANES/ETOAC (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give the title compound as a pale yellow OIL.
With diethylzinc;palladium diacetate; 1,4-di(diphenylphosphino)-butane;Product distribution / selectivity;
The moderate yield in the etherification was the result of an extremely reactive allylic ester, which underwent decomposition under the reaction conditions. Attenuation of the reactivity was achieved through the choice of a poorer leaving group, such as benzoate or naphthoate, which improved the yield of 4b to 73% yield. Naphthoate allylic ester (lib) was a crystalline solid, and was chosen for further development. An extensive screening of ligands revealed that although the Buchwald biaryl diphosphines were effective in the Pd-catalyzed etherification, equivalent results could be obtained with 1,3-diphenylphosphinopropane (dppp), which was considerably less expensive and more readily available. As a further improvement, the amount of alcohol 6b could be reduced to 1.0 equivalent with no effect on the assay yield of product. Under optimized conditions, allylic ether 4b was prepared in 80% yield and >99: 1 diastereomeric ratio (Scheme 3).; The conditions developed for the Pd-catalyzed allylic etherifcation were tolerant of a variety of alcohols, providing a diverse array of allylic ethers with complete retention of stereochemistry at the reacting center (Table 3). In the coupling of allylic ester lib with both enantiomers of alcohol 6b, only a modest difference in reactivity was observed; however in the case of more sterically encumbered alcohols, a clear "matched" and "mismatched" pairing was observed. Additionally, the coupling of allylic esters with achiral alcohols provided the expected allylic ethers in high enantiomeric ratios. The reaction was tolerant of a variety of electron withdrawing groups including esters, nitriles, and even ketones; however cyclic allylic esters lacking an electron withdrawing group at the 3-position were inactive in the allylic etherifcation.
(R)-1-[(1R,2R,3S)-3-{(R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy}-2-(4-fluorophenyl)cyclopentylmethyl]piperidine-3-carboxylic acid hydrochloride[ No CAS ]
() 3- (3-BROMO-4-FLUOROPHENYL)-4-VINYLTETRAHYDROPYRAN-2-OL (from step F) above; 10.32g, 0. 034MOL), (LR)-3, 5-bis (trifluoromethyl) phenylethanol (llg, 0. 042MOL), AMBERLYST (5G) and molecular sieves (8G) were suspended in dichloromethane (20mL) and the mixture was shaken at 40C for 3 days. The resulting yellow solution was filtered, concentrated in vacuo and was purified by chromatography on silica using 1-5% ethyl acetate in hexane as eluant to give A mixture of isomers 1-3 (which were retained) and the desired isomer 4 (3.6g, 20%) as a colourless oil. IH NMR (400 MHz, CDC13) : 8 7.69 (1H, s), 7.26-7. 21 (3H, m), 6. 98 (1H, t J 8. 4Hz), 6.91 (1H, m), 5.43 (1H, ddd, J 7. 1,10. 5,17. 4Hz), 4.95 (1H, Q, J 6.6Hz), 4.83 (1H, D, J 10.6Hz), 4. 80 (1H, D, J 17. 4HZ), 4.16 (1H, D, J 8. 3Hz), 4. 14 (1H, m), 3.56 (IH, M), 2.49 (1H, DD, J8. 3,11. 6Hz), 2. 38 (1E, M), 1.71-1. 60 (2EI, M), 1. 40 0 (3H, d, J 6.6Hz).
1, rac-3,5-bis (trifluoromethyl) phenethyl alcohol:Take 3,5-bis (trifluoromethyl) acetophenone 500g into the round bottom flask was added 30mL of ethanol, followed by stirring to dissolve, cooled to 0 deg.] C; and NaBH4350 g of, stirred for one hour at room temperature; heated to 35 , stirring was continued for 40min, TLC detection, the reaction was complete; quenched with water; extracted with ethylacetate three times, and concentrated to dryness; washed with petroleum ether, suction filtered.Product as a white powder, the product is a racemic mixture, weighed in 98% yield.2, resolved by preferential crystallization (S) -3,5- bis (trifluoromethyl) phenethyl alcohol(1) primary crystalsStep 30g compound obtained in preparation to take on (2) was added 105mL of petroleum ether, heated and stirred under argon for 50 , dissolved; into an (S) -3,5- bis (trifluoromethyl) phenethyl alcohol seed , after 45min, a seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 19g a yield of 76.7%; according to the aforementioned chromatographic conditions, chiral phase detection ee: 65.5%.(2) secondary crystalsTake a crystalline compound obtained 30g, was added 105mL of petroleum ether, heated and stirred under argon for 40 , dissolved; into an (S) -3,5- bis (trifluoromethyl) phenethyl alcohol seed, after 45min, seed 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, yield 70.0%; according to the aforementioned chromatographic conditions, chiral phase detection ee: 95.5%.(3) three times crystallizedTaking a second resultant crystalline compound 30g, was added 105mL of petroleum ether, heated and stirred under argon for 50 , dissolved; into an (S) -3,5- bis (trifluoromethyl) phenethyl alcohol seed, after 45min seed crystal was smaller; after 1 hour, the disappearance of seed; 3.5h, the precipitated white solid (precipitated to the bottom); 10H, no further solid separated; dry suction filtration, weighed 22g, yield 73.3%; according to the aforementioned chromatographic conditions, chiral phase detection ee: 99.8%.
In argon atmosphere, phosphorus tribromide (157.3 g, 0.58 mol) was added dropwise to (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (300 g, 1.16 mol, 96% ee) in a water bath at 20C or lower, and stirred for 30 minutes at 19 to 22C. The reaction liquid was cooled, hydrogen bromide (30% acetic acid solution) (228 mL, 1.16 mol) was added dropwise at 0C or lower, and stirred for 16 hours at 13 to 15C. The reaction liquid was added to ice water, and extracted with n-hexane (3 L x 2). The organic layers were combined, subsequently washed with saturated sodium bicarbonate water (3 L) and saturated saline solution (3 L), dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure (90 to 100 mm Hg), thereby obtaining 389.2 g of crude product. The crude product thus obtained was purified by column chromatography (silica gel 900 g, developing solvent: n-hexane), thereby obtaining 349.8 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) in the form of a colorless oil (yield: 93.8%). As described below, in the chiral HPLC analysis, the first peak appeared as the main peak, indicating that the 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl] ethane prepared in 1-(b) is also an (R)-enantiomer as that prepared in 1-(a). Chiral HPLC analysis: optical purity > 93.9% ee (main peak: first peak), degree of conversion: 97.8% 1H - NMR (CDCl3) delta : 2.08(3H,d,J=7.1Hz),5.21(1H,q,J=7.1Hz),7.81(1H,s),7.87(2H,s)
88.6%
With 1,2-dibromo-1,1,2,2-tetrachloroethane; triphenylphosphine; In toluene; at 0 - 20℃; for 1.16667h;Inert atmosphere;
Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), the solution was added with triphenylphosphine (6.1 g, 23.2 mmol) at 0C, and the mixture was stirred for 30 minutes. This reaction mixture was added dropwise with a solution of (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (5.0 g, 19.4 mmol, >99.5%ee) in toluene (12.5 mL) at 0C over 10 minutes or more, and then the mixture was warmed to room temperature, and stirred for 1 hour at the same temperature. The reaction mixture was added with n-hexane (25 mL), and the mixture was filtered through Celite. The filtrate was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, dried over sodium sulfate, and then evaporated under reduced pressure. The resulting residue was distilled under reduced pressure (56C, 0.7 mmHg) to obtain 5.52 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) as colorless oil (yield: 88.6%). Chiral HPLC analysis: optical purify >99.5%ee (main peak: first peak), conversion rate ?99% [alpha]D25 +59.1 (c = 1.03, CHCl3) 1H-NMR (CDCl3) delta: 2.08 (3H, d, J=7.1Hz), 5.21 (1H, q, J=7.1Hz), 7.81 (1H, s), 7.87 (2H, s)
88.6%
With 1,2-dibromo-1,1,2,2-tetrachloroethane; triphenylphosphine; In toluene; at 0 - 20℃; for 1.16667h;Inert atmosphere;
1-(a): Production 1 of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), and triphenylphosphine (6.1 g, 23.2 mmol) was then added to the obtained solution at 0 C., followed by stirring for 30 minutes. Thereafter, a toluene solution (12.5 mL) containing (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (5.0 g, 19.4 mmol, >99.5% ee) was added dropwise to the resulting solution at 0 C. over 10 or more minutes. Thereafter, the temperature of the mixed solution was increased to a room temperature, and the solution was then stirred at the same temperature as described above for 1 hour. Subsequently, n-hexane (25 mL) was added to the reaction solution, followed by filtration with Celite. The filtrate was successively washed with water, saturated sodium bicarbonate water, and saturated saline solution, and it was then dried over sodium sulfate. Thereafter, it was distilled away under a reduced pressure. The obtained residue was subjected to distillation under a reduced pressure (56 C., 0.7 mmHg) to obtain 5.52 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) in the form of a colorless oily product (yield: 88.6%). Chiral HPLC analysis: optical purity >99.5% ee (main peak: first peak), invert ratio ?99% [alpha]D25+59.1 (c=1.03, CHCl3) 1H-NMR (CDCl3) delta: 2.08 (3H, d, J=7.1 Hz), 5.21 (1H, q, J=7.1 Hz), 7.81 (1H, s), 7.87 (2H, s)
85%
Example 1-1 Under an argon atmosphere, (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1.0 g, 3.87 mmol, >99.5%ee) was added dropwise with phosphorus tribromide (0.52 g, 1.94 mmol) on a water bath at a temperature lower than 20C, and the mixture was stirred at 19 to 22C for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 0.76 mL, 3.87 mmol) at a temperature lower than 0C, and the mixture was stirred at 13 to 15C for 18 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (15 mL x 2). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL x 1) and then with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 8 g; developing solvent, n-hexane) to obtain 1.06 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil. Yield: 85% Chiral HPLC analysis: optical purity, 96.8%ee (first peak); conversion ratio, 97.3% 1H-NMR (CDCl3): delta 2.08 (3H, d, J = 7.1 Hz), 5.21 (1H, q, J = 7.1 Hz), 7.81 (1H, s), 7.87 (2H, s).
(S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With zinc trifluoromethanesulfonate; at 20℃;
General procedure: In a typical experimental procedure, to a mixture of alcohol/phenol (1mmol) and acetic anhydride (1.0mmol) or acyl chloride (1.0mmol) in dichloromethane solvent (2vol) or without solvent, Zn(OTf)2 (0.1mol%) was added. The reaction mixture was stirred at room temperature for the specified time. Completion of reaction was monitored by TLC, after quenching with a saturated solution of NaHCO3 and the products were extracted in to dichloromethane (3×10mL). The combined organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated in vacuum to obtain the product.
98%
With zinc trifluoromethanesulfonate; In dichloromethane; at 25℃; for 0.00277778h;
General procedure: In a typical experimentalprocedure, to a mixture of alcohol/phenol (1 mmol) and acetic anhydride (1.0mmol) in dichloromethane solvent (2 vol)/without solvent, Zn(OTf)2(0.01-0.1 mol %) was added. The reaction mixture was stirred at roomtemperature for the appropriate amount of time. Completion of reaction wasmonitored by TLC after quenching with a saturated solution of NaHCO3and the products were extracted in to dichloromethane (3 X 10.0 mL). Thecombined organic layer was washed with water, dried over anhydrous Na2SO4and concentrated under reduced pressure. All products were characterized bycomparison of their spectral data and physical prosperities with those ofauthentic samples.
1-(b): Production 2 of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane Under an argon atmosphere, phosphorus tribromide (157.3 g, 0.58 mol) was added dropwise to (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (300 g, 1.16 mol, 96% ee) at 20 C. or lower in a water bath, and the obtained mixture was then stirred at 19 C. to 22 C. for 30 minutes. Thereafter, the reaction solution was cooled, and hydrogen bromide (30% acetic acid solution) (228 mL, 1.16 mol) was added dropwise thereto at 0 C. or lower. The obtained mixture was stirred at 13 C. to 15 C. for 16 hours. Thereafter, the reaction solution was added to ice water, and was then extracted with n-hexane (3 L*2). The organic layers were gathered. The gathered organic layer was successively washed with saturated sodium bicarbonate water (3 L) and saturated saline solution (3 L), and was then dried over anhydrous magnesium sulfate. The resultant was concentrated under a reduced pressure (90 to 100 mmHg) to obtain 389.2 g of a crude product. The obtained crude product was purified by column chromatography (900 g of silica gel, developing solvent: n-hexane), to obtain 349.8 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) in the form of a colorless oily product (yield: 93.8%). Since the first peak appeared as a main peak in the chiral HPLC analysis, as shown below, 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane produced in 1-(b) above was also confirmed to be an (R)-form, as with the compound obtained in 1-(a) above. Chiral HPLC analysis: optical purity >93.9% ee (main peak: first peak); invert ratio: 97.8% 1H-NMR (CDCl3) delta: 2.08 (3H, d, J=7.1 Hz), 5.21 (1H, q, J=7.1 Hz), 7.81 (1H, s), 7.87 (2H, s)
With boron trifluoride diethyl etherate In tetrahydrofuran at -25 - -20℃; for 1h; Inert atmosphere;
4.S1
S1. Add 3.48g of APT003E and 20ml of tetrahydrofuran to a 100ml three-necked flask under nitrogen protection, dissolve the solution, stir and cool to -25°C, add boron trifluoride ether,Slowly add APT18 6.0g 16ml tetrahydrofuran, after the addition, react at -20°C for 1 hour, TLC detects the completion of the reaction (PE:EA=2:1), the reaction solution is heated to about 0°C, and 10% carbonic acid is added 3ml of sodium aqueous solution and 12ml of saturated brine were used to quench the reaction. The separated organic layer was evaporated to dryness under reduced pressure at 45°C, purified by column, PE:EA=60:1, the eluent was concentrated under reduced pressure to obtain 4.5g product , Namely APT19E;
Stage #1: With C36H28FeMnN2O3P(1+)*Br(1-); potassium carbonate In ethanol at 20℃; for 0.0833333h; Glovebox;
Stage #2: With hydrogen In ethanol at 50℃; for 16h; Glovebox; Autoclave;
16 Example 11 Asymmetric hydrogenation of acetophenone with Mn-PNN catalyst
General procedure: In the glove box, add Mn-Cat.1 catalyst (3.8mg, 0.005mmol) and substrate acetophenone (120mg, 1mmol) into a 5mL clear glass vial, then potassium carbonate (1.4 mg, 0.01 mmol) and absolute ethanol (3 mL) were added, and the mixture was stirred at room temperature for 5 min. Finally, the hydrogenation bottle was put into the autoclave, the hydrogen was replaced three times and then filled with 30 bar H2, and reacted at 50°C for 16h. After the reaction is completed, the hydrogen is released carefully, the solvent is spin-dried under reduced pressure, and the hydrogenated product (R)-1-phenylethanol is purified by silica gel column, a colorless and transparent liquid, >99% conversion, 95% yield, 77% ee,
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