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Chemical Structure| 30071-93-3
Chemical Structure| 30071-93-3
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Product Details of [ 30071-93-3 ]

CAS No. :30071-93-3 MDL No. :MFCD00009910
Formula : C10H6F6O Boiling Point : -
Linear Structure Formula :- InChI Key :MCYCSIKSZLARBD-UHFFFAOYSA-N
M.W : 256.14 Pubchem ID :121616
Synonyms :

Calculated chemistry of [ 30071-93-3 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 3
Num. H-bond acceptors : 7.0
Num. H-bond donors : 0.0
Molar Refractivity : 46.64
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.07 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.17
Log Po/w (XLOGP3) : 3.93
Log Po/w (WLOGP) : 6.23
Log Po/w (MLOGP) : 3.78
Log Po/w (SILICOS-IT) : 4.3
Consensus Log Po/w : 4.08

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.97
Solubility : 0.0276 mg/ml ; 0.000108 mol/l
Class : Soluble
Log S (Ali) : -3.99
Solubility : 0.0263 mg/ml ; 0.000103 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.51
Solubility : 0.00792 mg/ml ; 0.0000309 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.48

Safety of [ 30071-93-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 30071-93-3 ]

* 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.

  • Upstream synthesis route of [ 30071-93-3 ]
  • Downstream synthetic route of [ 30071-93-3 ]

[ 30071-93-3 ] Synthesis Path-Upstream   1~17

  • 1
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YieldReaction ConditionsOperation in experiment
63% With dihydrogen peroxide; trifluoroacetic anhydride In chloroform; water at 0 - 70℃; for 6.5 h; A mixture of 100 g (0.39 mol) of 3,5-bis(trifluoromethyl)acetophenone obtained above, 155.2 g of (0.74 mol) of trifluoroacetic anhydride and 400 ml of chloroform was stirred at 0°C in a nitrogen atmosphere.
After adding 19.7 g (0.52 mol) of a 90percent hydrogen peroxide aqueous solution from a dropping funnel over 30 min and stirring the mixture for one our, the temperature was raised to 70°C to proceed the reaction for 5 h.
After completion of the reaction, the temperature was returned to room temperature.
The reaction product solution was poured into a separating funnel containing a saturated brine and washed with water.
The organic phase separated was analyzed by gas chromatography.
It was confirmed that 57.5 g (0.25 mol) of the aimed 3,5-bis(trifluoromethyl)phenol was produced (yield: 67percent).
By vacuum distillation, 53.3 g (0.23 mol) of 3,5-bis(trifluoromethyl)phenol was isolated (yield: 63percent).
The purity determined by gas chromatography was 99percent or higher.
The results of ICP total elements analysis showed that none of Li, Na, K, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, V, Nb, Cr, Mo, W, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Al, In, Si, Sn, Pb, P, Sb and S were detected, and the content of each of group 1 and group 2 elements was 1 ppm or lower.
Reference: [1] Patent: EP1500641, 2005, A1, . Location in patent: Page 11
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YieldReaction ConditionsOperation in experiment
81%
Stage #1: With bis(trichloromethyl) carbonate; 4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine In dichloromethane at -10℃; for 1 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at -10℃; Inert atmosphere
General procedure: A solution of BTC (0.41 g, 1.39 mmol) in dry CH2Cl2 (5 mL) was cooled in an ice-salt bath under an atmosphere of N2. A solution of I (1.24 g, 4.17 mmol) in dry CH2Cl2 (5 mL) was added dropwise for 0.5 h, at −15 °C. Stirring was continued for 0.5 h, and a solution of benzyl alcohol (0.3 g, 2.78 mmol) in dry CH2Cl2 (5 mL) was added dropwise for 0.5 h, at−15 °C. After stirring for 0.5 h, Et3N (0.84 g, 8.34 mmol) was added slowly while the temperature should be controlled below −15 °C. When the reaction was completed, 10percent HCl solution in water was added dropwise until the pH of the reaction solution reached 2 under ice bath. The mixture was extracted with n-hexane or petroleum ether (10 mL x 2),decanted. The product was acquired after organic layer was concentrated and purified by flash chromatography (SiO2; n-hexane). (0.27 g, 92percent). The water layer was used for the recovery of V and the excess I.
Reference: [1] Synthetic Communications, 2016, vol. 46, # 10, p. 885 - 892
[2] Patent: WO2004/94358, 2004, A1, . Location in patent: Page 4-5
[3] Patent: WO2004/94358, 2004, A1, . Location in patent: Page 5
[4] European Journal of Organic Chemistry, 2018, vol. 2018, # 23, p. 3031 - 3035
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YieldReaction ConditionsOperation in experiment
82% With acetic anhydride; magnesium In tetrahydrofuran; water EXAMPLE 3
1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one
A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h).
The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C.
The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added.
The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL).
The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr).
The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
82% With acetic anhydride; magnesium In tetrahydrofuran; water EXAMPLE 3
1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one
A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h).
Alternatively, the Grignard initiation may be conducted at 0-20° C. to minimize the loss of solvent.
The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C.
The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added.
The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL).
The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr).
The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
82% With acetic anhydride; magnesium In tetrahydrofuran; water EXAMPLE 8
1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one
A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 h).
The mixture was aged for 30 min at reflux, cooled to RT and added over 1 h to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C.
The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added.
The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL).
The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr).
The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.
82% With sodium hydroxide; iodine; acetic anhydride; magnesium In tetrahydrofuran; water; acetonitrile EXAMPLE 2
1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one
To a 500 mL 3-neck round bottom flask equipped with an addition funnel, N2 inlet, and a Teflon coated thermocouple was added magnesium granules (5.10 g, 210 mmol) and THF (200 mL).
The mixture was heated to reflux. 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g, 98 mmol) was dissolved in 30 mL of THF. Some bromide solution (5 mL) was added to the gently refluxing magnesium slurry over 2 minutes to initiate the Grignard reaction.
Alternatively, the Grignard initiation may be conducted at 0-20° C. to minimize the loss of solvent.
After Grignard initiation, the remaining bromide was added over 1 hour.
An initial induction period of 5 minutes is generally permitted.
If the reaction does not initiate, another 5percent charge of bromide solution is added.
If the reaction still does not initiate after a bromide charge of 10percent, 100 mg of iodine is added.
The reaction exotherm was controlled by slowing or stopping the bromide addition if the reaction appeared too violent.
After complete bromide addition (~60 minutes), the dark brown solution was heated at gentle reflux for an additional 30 minutes.
The reaction was monitored by HPLC (sample preparation:
100 μL sample quenched into 3.5 mL of 1:1 THF:2N HCl, then diluted to 100 mL in 65:35 acetonitrile:pH 6 buffer).
Grignard formation was considered complete when the bromide level is less that 1 mol percent.
After cooling to ambient temperature in a water bath, the mixture was transferred via cannula to a 1L addition funnel. THF (10 mL) was used as rinse.
This solution was then added to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C. over 1 hr.
The dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added over 3 minutes.
The biphasic mixture was vigorously stirred while 50percent NaOH was added dropwise over 1 hr, until a pH of 8.0 was maintained for 5 minutes. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extraced with MTBE (3*150 mL).
The organic layers were combined and assayed (22.4 g ketone), then concentrated in vacuo at bath temperature of 32° C. (50-80 torr).
The concentrate was then distilled at atmospheric pressure and 20.7 g (82percent yield based on LC purity) of colorless oil was collected at 150-189° C., with the bulk collected at 187-189° C.
82% With acetic anhydride; magnesium In tetrahydrofuran; water EXAMPLE 3
1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1-one
A solution of 3,5-Bis(trifluoromethyl)bromobenzene (29.3 g) in 30 mL of THF was added to a mixture of magnesium granules (5.10 g) in THF (200 mL) heated at reflux (the reaction was initiated with approximately 5 mL of the bromide solution; the remainder was added slowly over 1 hour).
The mixture was aged for 30 minutes at reflux, cooled to room temperature and added over 1 hour to a solution of acetic anhydride (40 mL) in THF (40 mL) maintained at -15° C.
The resulting dark brown mixture was warmed to 10° C. in a water bath, and water (300 mL) was added.
The pH of the vigorously stirred biphasic mixture was adjusted to 8.0 using 50percent NaOH. MTBE (300 mL) was added, the layers were separated and the aqueous layer was further extracted with MTBE (3*150 mL).
The organic layers were combined and concentrated in vacuo (bath at 30-35° C.; 50-80 torr).
The concentrate was then distilled at atmospheric pressure to provide the pure product (20.7 g; 82percent yield) with a boiling point of 187-189° C.

Reference: [1] Patent: US2002/22725, 2002, A1,
[2] Patent: US2002/52494, 2002, A1,
[3] Patent: US2002/52493, 2002, A1,
[4] Patent: US6432952, 2002, B1,
[5] Patent: US6504066, 2003, B1,
[6] Patent: US2003/215456, 2003, A1,
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YieldReaction ConditionsOperation in experiment
77%
Stage #1: at 20℃; for 0.5 h;
Stage #2: at 65℃; for 1 h;
A mixture of 9.0 g (0.0345 mol) of 3,5-bis(trifluoromethyl)benzoyl fluoride obtained in the same manner as in Example 2 and 16 mL of HMPA was stirred at room temperature for 30 min.
After mixing 5 mL (0.0361 mol) of tetramethyltin and 14 mg (0.018 mol) of a palladium-phosphine catalyst (PhCH2Pd(PPh3)2Cl), the temperature was raised to 65°C.
After stirring for one hour, the temperature was lowered to room temperature and 20 mL of water was mixed to separate an organic phase.
After extracting the aqueous phase with 10 mL of diethyl ether, the collected organic solvent phase was washed four times with each 20 mL of water.
After dried over magnesium sulfate, the organic phase was analyzed by gas chromatography.
It was confirmed that 7.25 g (0.0283 mol) of the aimed 3,5-bis(trifluoromethyl)acetophenone was produced (yield: 82percent).
By vacuum distillation, 3,5-bis(trifluoromethyl)acetophenone was isolated (yield: 77percent).
Reference: [1] Patent: EP1500641, 2005, A1, . Location in patent: Page 10-11
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Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 9, p. 3695 - 3698
[2] Organic Syntheses, 2005, vol. 82, p. 115 - 119
[3] Patent: US2004/19243, 2004, A1, . Location in patent: Page 3
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Reference: [1] Patent: US2004/19243, 2004, A1, . Location in patent: Page 3
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Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 5, p. 1222 - 1226[2] Angew. Chem., 2018, vol. 130, # 5, p. 1236 - 1240,5
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Reference: [1] Patent: EP949243, 1999, A1,
  • 9
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Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 11, p. 4600 - 4603
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Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 9, p. 3695 - 3698
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Reference: [1] Patent: WO2004/85404, 2004, A1, . Location in patent: Page/Page column 70
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Reference: [1] Patent: US6350915, 2002, B1, . Location in patent: Example 2
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Reference: [1] Tetrahedron Letters, 1970, p. 4647 - 4650
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  • [ 127733-40-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3401 - 3406
[2] Organic Letters, 2003, vol. 5, # 7, p. 1007 - 1010
[3] Journal of the American Chemical Society, 1990, vol. 112, # 15, p. 5741 - 5747
[4] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5314 - 5327
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YieldReaction ConditionsOperation in experiment
100% 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.

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[4] Patent: CN108059579, 2018, A, . Location in patent: Paragraph 0057-0061
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[12] Patent: WO2009/149670, 2009, A1, . Location in patent: Page/Page column 21; 22
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YieldReaction ConditionsOperation 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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Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 11, p. 4600 - 4603
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