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Chemical Structure| 445-27-2
Chemical Structure| 445-27-2
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Product Details of [ 445-27-2 ]

CAS No. :445-27-2 MDL No. :MFCD00000320
Formula : C8H7FO Boiling Point : -
Linear Structure Formula :- InChI Key :QMATYTFXDIWACW-UHFFFAOYSA-N
M.W : 138.14 Pubchem ID :96744
Synonyms :
Chemical Name :1-(2-Fluorophenyl)ethanone

Calculated chemistry of [ 445-27-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 36.59
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.82 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.54
Log Po/w (XLOGP3) : 1.86
Log Po/w (WLOGP) : 2.45
Log Po/w (MLOGP) : 2.21
Log Po/w (SILICOS-IT) : 2.58
Consensus Log Po/w : 2.13

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.25
Solubility : 0.784 mg/ml ; 0.00567 mol/l
Class : Soluble
Log S (Ali) : -1.84
Solubility : 2.0 mg/ml ; 0.0145 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.98
Solubility : 0.144 mg/ml ; 0.00104 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 445-27-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 445-27-2 ]

* 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 [ 445-27-2 ]
  • Downstream synthetic route of [ 445-27-2 ]

[ 445-27-2 ] Synthesis Path-Upstream   1~27

  • 1
  • [ 445-27-2 ]
  • [ 655-15-2 ]
YieldReaction ConditionsOperation in experiment
97% at 20℃; for 2 h; Reference Example 33
2-bromo-1-(2-fluorophenyl)ethanone
To a solution of 1-(2-fluorophenyl)ethanone (15.1 g) in acetic acid (150 mL) was added bromine (5.8 mL).
The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure.
Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (22.91 g, yield 97percent).
1H-NMR (CDCl3) δ: 4.53 (2H, d, J=2.4 Hz), 7.13-7.20 (1H, m), 7.27-7.30 (1H, m), 7.54-7.61 (1H, m), 7.91-7.96 (1H, m).
97% With bromine In acetic acid at 20℃; for 2 h; To a solution of 1-(2-fluorophenyl)ethanone (15.1 g) in acetic acid (150 mL) was added bromine (5.8 mL). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 22.9 g, yield 97percent). 1H-NMR(CDCl3)δ:4.53(2H,d,J=2.4Hz), 7.13-7.20(1H,m), 7.27-7.30(1H,m), 7.54-7.61(1H,m), 7.91-7.96(1H,m).
85% With Oxone; ammonium bromide In methanol for 2 h; Reflux General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
80%
Stage #1: With aluminum (III) chloride In tert-butyl methyl ether at 0℃; for 0.25 h; Large scale
Stage #2: With N-Bromosuccinimide In tert-butyl methyl ether at 0 - 20℃; for 4 h; Large scale
250 kg of o-fluoroacetophenone and 500 liters of methyl tert-butyl ether were added to a 1000-liter reactor. Open the salt water system, stir to cool to 0 ° C, add 2.5kg of aluminum chloride, about 15min, after adding NBS 375kg (25kg each time to join), temperature control does not exceed 5 ° C. Plus finished, naturally warming to room temperature.After the reaction for 4 h, the dosing plate was monitored for no raw material, and the resulting solution was concentrated under reduced pressure to 50percent. A large amount of water was added to the substrate, the by-product was washed, the oil layer (lower layer), anhydrous Na2S04 Dry, filtered, filtrate under reduced pressure distillation, collecting 82 ~ 84 ° C (5mmHg) fractions, calculated yield of 80percent, 5percent higher than the small test
40% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 80℃; General procedure: A modified reaction route: NBS (1.2 equiv.) was added to a solution of appropriately substitutedacetophenones 9a–9l (1.0 equiv.) in CH3CN (15 mL) with p-TSA (0.2 equiv.). The solution washeated at 80 °C for 3-5 h until all the starting materials had been consumed (TLC monitored). Thereaction mass was poured in ice-cold water and extracted with DCM (3 × 20 mL). Anhydrous Na2SO4was added to the combined organic layer, filtered and the excess solvent was removed under reducedpressure. The resultant solid/ liquid obtained were washed with hexane to yield compounds 10a–10i.4,5
24% With N-Bromosuccinimide In ethyl acetate at 40℃; 10mmol 2-fluoroacetophenone is added to a 100mL round bottom flaskAnd 11mmol of N-bromosuccinimide (NBS),35mL of ethyl acetate dissolved,Then add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction was warmed to 40°C and reacted. After TLC tracks the reaction,The reaction solution was filtered to remove Amberlyst 15 ion exchange resin, and the filtrate was spin-dried.Column chromatography (eluent: petroleum ether/dichloromethane) gave white crystals in 24percent yield.

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  • 2
  • [ 445-27-2 ]
  • [ 655-15-2 ]
  • [ 1224739-02-9 ]
Reference: [1] Biochemistry, 2010, vol. 49, # 36, p. 7913 - 7919
  • 3
  • [ 445-27-2 ]
  • [ 445-28-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 33, p. 6359 - 6362
  • 4
  • [ 445-27-2 ]
  • [ 67500-19-0 ]
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[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 3, p. 673 - 683
  • 5
  • [ 445-27-2 ]
  • [ 105-58-8 ]
  • [ 1479-24-9 ]
YieldReaction ConditionsOperation in experiment
73% With sodium hydride In toluene; mineral oil General procedure: The substrate b-ketoesters 10 a–n were either purchased or synthesized following published procedures. Some benzoylacetates were commercially available. Ethyl 3-oxo-3-phenyl propanoate (10a) was purchased. The reaction of benzoylacetates 10 b–n was prepared as described in previous reports. 25–27 A solution of a substituted acetophenone 8 a–n (0.05 mol) dissolved in toluene (50 mL) was added dropwise to a solution containing diethyl carbonate (9) (0.10 mol) and sodium hydride (0.15 mol 60percent dispersion in mineral oil). The mixture was stirred at room temperature, and then refluxed for 30 min. The mixture was poured into ice water,acidified with glacial acetic acid, and extracted with EtOAc (3x100 mL). The EtOAc extract was then dried over anhydrous MgSO4. After removal of the solvent in vacuo, the crude products were purified by silica gel column chromatography eluting with dichloromethane to afford benzoylacetates 10 b–n. All synthetic compounds were in agreement with 1H NMR, 13C NMR, IR and mass spectroscopic data.
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[2] European Journal of Organic Chemistry, 2015, vol. 2015, # 17, p. 3656 - 3660
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 3922 - 3946
[4] Chemical Communications, 2017, vol. 53, # 58, p. 8136 - 8139
  • 6
  • [ 7789-21-1 ]
  • [ 98-86-2 ]
  • [ 445-27-2 ]
  • [ 18355-80-1 ]
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  • [ 69291-63-0 ]
  • [ 1979-36-8 ]
  • [ 455-36-7 ]
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  • [ 79110-05-7 ]
YieldReaction ConditionsOperation in experiment
97% at -42℃; for 0.5 h; To a mechanically stirred slurry of cone. H2S04 (93-98percent, 360 mL) at -42 °C were added dropwise l-(2-fluorophenyl)ethanone (90.0 g, 652 mmol) and a solution of fuming nitric acid (53.1 mL) in cone. H2S04 (129 mL). The slurry was stirred for 30 min at -42 °C. The mixture was slowly poured onto 1.3 kg of ice. To the mixture was added water (1 L). The product precipitated out of solution. After all of the ice melted, the product was collected via filtration. The solid was dissolved with EtOAc. The organic layer was washed with 5percent aq. Na2C03 (2x300 mL), water (1x300 mL), and brine (1x300 mL), dried over Na2S04, and filtered. The filtrate was concentrated to give l-(2-fluoro-5-nitrophenyl)ethanone (115 g, 97percent) as a yellow solid.
97%
Stage #1: at -40℃; for 1.08333 h;
Stage #2: Cooling with ice
Step 1 : Preparation of 1-(2-Fluoro-5-nitrophenyl)ethanone (2).A 2-L round-bottomed flask equipped with a mechanic stirrer was charged with concentrated H2S04 (360 mL) and cooled to -40 °C. 1 -(2-Fluorophenyl)ethanone 1 {90.0 g, 652 mmo.) was then added followed by addition of a mixture of fuming HN03 (53.1 mL) and concentrated H2S04 (129 mL) dropwise over 35 min. The resulting solution was stirred at -40 °C for 30 min and then slowly poured into ice (1.3 kg). The resulting mixture was diluted with water (1 L) and filtered. The filter cake was dissolved in EtOAc (1 L) and the filtrate was extracted with EtOAc (1 L). The combined organics were washed with 5percent aqueous sodium carbonate (2 x 300 mL), water (300 mL), and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2 (115 g, 97percent) as a yellow solid: 1H NMR (300 MHz, CDCI3) δ 8.79 (dd, J = 6.2, 2.9 Hz, 1 H), 8.41 (dt, J= 8.9, 3.4 Hz, 1 H), 7.34 (t, J= 9.3 Hz, 1 H), 2.71 (d, J = 4.8 Hz, 3H).
93.7% With sulfuric acid; nitric acid In water at -10 - 5℃; for 0.5 h; EXAMPLE 1160
Preparation of 3-Isopropyl-4-fluoroaniline
(As per WO 97/06136) In a three-necked 250 ML Morton flask with internal thermometer, addition funnel and stirbar, sulfuric acid (60 ML) was cooled to -10° C. 2'-fluoroacetophenone (17.9 g) was added at such a rate as to keep the internal temperature below 0° C.
The funnel was washed down with sulfuric acid (4 ML), and charged with HNO3 (9.5 ML)).This was added dropwise at such a rate that the internal temperature never exceeded 5° C.
These additions can be made more quickly if the addition funnel has an ice-jacket.Stirring continued at -10° C. 30 min.The mixture was then poured onto ice and extracted with ethyl acetate (2*) the combined extracts were washed (H2O, NaHCO3, NaCl), dried (K2CO3) filtered and stripped to an amber oil 22.3 gm=93.7percent
In a flame dried flask with nitrogen atmosphere and stirbar, KHMDS (11 mL, 0.5M in toluene) was added dropwise over 5 min to a stirred suspension of Ph3P+CH3Br- (2.34 gm) in THF (50 mL, dry) at -78° C. Yellow color appears as the addition proceeds. After 5 min at -78° C., the suspension was stirred at RT (5 min) then recooled to -78° C. The acetophenone (1.00 gm in 10 mL dry THF) was added dropwise over five minutes. Deep red color appears as the addition proceeds. After additional 2 min at -78° C., the system was allowed to warm to RT. After TLC (17percent EtOAc in hexanes) confirmed the consumption of starting materials, volatiles were removed and the residue suspended in cyclohexane (15 mL). Upon cooling, the solids were filtered off and discarded. The filtrate was purified by flash chromatography (30percent acetone in hexanes). Hydrogenation of this material over palladium on carbon (10percent w/w) in methanol (RT, 2 hrs) provides 3-isopropyl-4-fluoroaniline (quantitative).
115 g With nitric acid In sulfuric acid at -42℃; for 0.5 h; To a mechanically stirred slurry of cone. H2S04 (93-98percent, 360 mL) at -42 °C were added dropwise 2'-fluoro-acetophenone 45 (90.0 g, 652 mmol) and a solution of fuming nitric acid (53.1 mL) in cone. H2S04 (129 mL). The slurry was stirred for 30 min at -42 °C. The mixture was slowly poured onto 1.3 kg of ice. To the mixture was added water (1 L). The product precipitated out of solution. After all of the ice melted, the product was collected via filtration. The solid was dissolved with EtOAc. The organic layer was washed with 5percent a2C03 (2 x 300 mL), water (300 mL), and brine (300 mL), and dried over Na2S04. It was filtered, the filtrate was concentrated to give compound 46 (1 15 g) as a solid
115 g at -42℃; for 0.5 h; Step 1 (0672) To a mechanically stirred slurry of conc. H2SO4 (93-98percent, 360 mL) at −42° C. were added dropwise 2′-fluoro-acetophenone 45 (90.0 g, 652 mmol) and a solution of fuming nitric acid (53.1 mL) in conc. H2SO4 (129 mL). The slurry was stirred for 30 min at −42° C. The mixture was slowly poured onto 1.3 kg of ice. To the mixture was added water (1 L). The product precipitated out of solution. After all of the ice melted, the product was collected via filtration. The solid was dissolved with EtOAc. The organic layer was washed with 5percent Na2CO3 (2×300 mL), water (300 mL), and brine (300 mL), and dried over Na2SO4. It was filtered, the filtrate was concentrated to give compound 46 (115 g) as a solid.
10.8 kg
Stage #1: at -10 - 5℃; for 0.333333 h; Large scale
Stage #2: at -10℃; for 0.166667 h; Large scale
STEP 1 l-(2-fluoro-5-nitrophenyl)ethanone To a reactor (Rl) equipped with a temperature probe, nitrogen inlet, and agitator was charged H2S04 (91 kg). Agitation of Rl was begun, the internal temperature adjusted to 5 °C, and l-(2-fluorophenyl)ethanone (iii) (10.0 kg, 72.4 mol) was slowly charged. The internal temperature of Rl was then adjusted to -10 °C and the mixture agitated for 20 min. HNO3 (66- 67percent, 7.1 kg, 72.4 mol) was charged dropwise to Rl, maintaining the internal temperature, and the reaction agitated for 10 min. To a second reactor (R2) equipped with a temperature probe, nitrogen inlet, and agitator was charged water (300 kg). Agitation of R2 was begun and the internal temperature adjusted to 5 °C, at which point the reaction mixture from Rl was transferred to R2, maintaining the internal temperature. The mixture was stirred for 2 h and the resulting solids were collected and washed with water (40 kg) to provide l-(2-fluoro-5- nitrophenyl)ethanone (iv) (10.8 kg).
10 kg at -10℃; for 0.5 h; Inert atmosphere; Large scale To a reactor (Rl) equipped with a temperature probe, nitrogen inlet, and agitator was charged H2S04 (91 kg). Agitation of Rl was begun, the internal temperature adjusted to 5 °C, and l-(2-fluorophenyl)ethanone (iii) (10.0 kg, 72.4 mol) was slowly charged. The internal temperature of Rl was then adjusted to -10 °C and the mixture agitated for 20 min. HNO3 (66- 67percent, 7.1 kg, 72.4 mol) was charged dropwise to Rl , maintaining the internal temperature, and the reaction agitated for 10 min. To a second reactor (R2) equipped with a temperature probe, nitrogen inlet, and agitator was charged water (300 kg). Agitation of R2 was begun and the internal temperature adjusted to 5 °C, at which point the reaction mixture from Rl was transferred to R2, maintaining the internal temperature. The mixture was stirred for 2 h and the resulting solids were collected and washed with water (40 kg) to provide l-(2-fluoro-5- nitrophenyl)ethanone (iv) (10.8 kg).

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  • [ 162427-79-4 ]
YieldReaction ConditionsOperation in experiment
100% With RuBr2[(S,S)-2,4-bis(diphenylphosphino)pentane](2-picolylamine); potassium <i>tert</i>-butylate; hydrogen In ethanol at 40℃; for 19 h; Inert atmosphere; Autoclave General procedure: In an autoclave, 1.32 mg of RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) (1.29×10−3 mmol, S/C=10000) and 5.79 mg of potassium tert-butoxide (5.16×10−2 mmol) are placed, and replaced with argon gas. Under argon gas flow, 1.5 mL of acetophenone (12.9 mmol) and 2.9 mL of ethanol was added while measuring by a syringe, pressurized with hydrogen to 10 atm, stirred at 40° C. for 19 hours, then the reduction of the hydrogen pressure was confirmed and phenylethanol was obtained at 100percent yield. The optical purity was 88.0percent ee as measured by GC (CP-Chirasil-DEX CB (0.25 mml. D×25 m, DF=0.25 μm, from VARIAN), constant at 110° C., pressure: 102.0 kPa, column flow: 1.18 mL/min, vaporizing chamber temperature: 250° C., detector temperature: 275° C., the retention time of each enantiomer was: (R): 11.7 min, (S): 12.4 min), and (S) isomer has predominantly been generated.The reaction was carried out in similar way as Working Example 1 except that the complex was changed to RuBr2 [(S,S)-xylskewphos](pica), and the reaction solvent and substrate were changed as indicated in the Table below. The results are summarized in the Table below, which also describes the results from Comparative Example 1. Analysis conditions indicated in the Table is the same as the Table provided from Working Examples ito 6. From the results, it is clear that RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) has a better enantioselectivity as compared to RuBr2[(S,S)-xyl- skewphos] (pica) complex.
83.7 % ee With dodecacarbonyl-triangulo-triruthenium; (S,S)-N-{1,2-diphenyl-2-[(pyridin-2-ylmethyl)amino]ethyl}-4-methylbenzenesulfonamide In isopropyl alcohol at 80℃; for 48 h; Inert atmosphere; Schlenk technique General procedure: A mixture of catalyst (2 molpercent) and Ru3 (CO)12 (0.67 molpercent) in IPA (10 cm3) was stirred at 80 °C under an inert atmosphere in a schlenk tube for 30 min. To this solution, ketone (1 mmol) was added and the resulting mixture was stirred at 80 °Cfor 48 h. The reaction mixture was filtered through a short column of silica using (EtOAc:hexane 1:1), a small amount of the filtrate was dilluted in EtOAc and then injected on the GC to determine the conversion and enantiomeric excess.
89.8 % ee at 60℃; for 5 h; Schlenk technique General procedure: As Examples 20 to 35, hydrogen transfer reactions to ketones shown in Tables 1, 2, and 3 below were conducted by the same operation as in Examples 16 and 18. In these reactions, the catalyst ratios (S/C) were as shown in the tables, the reaction temperature was 60° C., and a formic acid-triethylamine (5:2) azeotrope was used as a hydrogen source in such an amount that the concentration of the substrate was 2 mol/L. The conversions and the optical purities were determined by analyzing the reaction liquids by GC after predetermined periods.; In addition, as Comparative Examples, results of reactions in which RuCl ((S,S)-Tsdpen) (mesitylene) was used in the same manner are also shown in each table. Note that, in these tables, conv. represents the conversion of the ketone substrate, selec. represents the selectivity for the target product, percent ee represents the optical purity, and S/C represents a value represented by the number of moles of the ketone substrate/the number of moles of the catalyst.
73 % ee With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate In water at 20℃; for 5 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.
73 % ee With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate In water at 20℃; for 5 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.
81 % ee
Stage #1: With dimethylsulfide borane complex; 3-(5-((3R,5S)-5-(hydroxydiphenylmethyl)pyrrolidin-3-yloxy)-5-oxopentyl)-1-methyl-1H-imidazol-3-ium hexafluorophosphate In tetrahydrofuran at 70℃; for 0.5 h; Inert atmosphere; Schlenk technique
Stage #2: With hydrogenchloride In waterInert atmosphere; Schlenk technique
General procedure: In a schlenk tube, BH3·SMe2(0.55 mmol, 275 L) was added inthe solution of IL 5 (28 mg, 10 molpercent) dissolved in THF (1 mL), undernitrogen atmosphere. The homogenous mixture was stirred andheated at 70C for 30 min. Later, a solution of ketone (0.5 mmolin THF (0.5 mL)) was added within 30 min. After the addition wascompleted, the solvent was evaporated under vacuum. An aqueoussolution of 1M HCl (5 mL) was added and the product was extractedwith DCM. The solvent was dried on anhydrous sodium sulfateand evaporated under reduced pressure. Crude residue was furtherpurified by column chromatography on silica gel using hexane-ethyl acetate as eluent. Enantiomeric excesses of all alcohols weredetermined by HPLC analysis using Chiralcel OD–H/AD–H chiralcolumn, isopropanol-n-hexane as mobile phase and HPLC condi-tions are given in SI.
74 % ee at 82℃; for 0.5 h; Inert atmosphere; Schlenk technique General procedure: Typical procedure for the catalytic hydrogen-transfer reaction: a solution of the Ru(II)-complexes 17–24 (0.005 mmol), KOH (0.025mmol) and the corresponding ketone (0.5 mmol) in degassed 2-propanol (5 mL) was refluxed until the reaction was completed. Periodically samples taken from the reaction medium were passed through acetone silica gel column and conversion rates were observed in gas chromatography, which were calculated based on unreacted ketone.

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  • 18
  • [ 445-27-2 ]
  • [ 171032-87-4 ]
YieldReaction ConditionsOperation in experiment
98% With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at 20℃; for 2 h; To anhydrous tetrahydrofuran (20 mL) was added (R)-2-methyl-CBS-oxazaborolidine (1.0 M, 2.9 mL) and borane dimethyl sulfide complex (10.0 M, 1.88 mL) and the mixture was stirred at ambient temperature for 1 h. To this mixture was then added dropwise a solution of 1-(2-fluorophenyl)ethanone (2.00 g, 14.5 mmol, 1.75 mL) in anhydrous tetrahydrofuran (5 mL). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was quenched by addition of methanol (20 mL) and concentrated in vacuo to afford the title compound as a colorless oil (2.00 g, 98percent yield) that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.53-7.49 (m, 1H), 7.28-7.24 (m, 1H), 7.20-7.16 (m, 1H), 7.04 (ddd, J=10.8, 8.2, 1.2 Hz, 1H), 5.23 (q, J=6.4 Hz, 1H), 1.54 (d, J=6.4 Hz, 3H), OH not observed.
92% With (R)-methyl oxazaborolidine; N,N-diethylaniline; diborane In <i>tert</i>-butyl alcohol at 45℃; for 1 h; First Step
Synthesis of (S)-1-(2-Fluorophenyl)ethanol
To a solution (60 mL) of (R)-methyl oxazaborolidine (0.32 g, 1.2 mmol) in tert-butyl alcohol, N,N-diethylaniline borane (2.6 g, 16 mmol) was added, and a solution (150 mL) of 1-(2-fluorophenyl)ethanone (2.0 g, 14 mmol) in tert-butyl alcohol was then added thereto at 45° C., and the resulting mixture was stirred.
One hour later, the reaction solution was cooled to room temperature, methanol was added thereto and the resultant was concentrated.
After 1.0 N hydrochloric acid was added thereto, the resultant was extracted with ethyl acetate, and the organic layer was washed with brine, then dried over anhydrous sodium sulfate and concentrated.
The obtained crude product was purified by silica gel column chromatography (hexane alone to hexane/ethyl acetate=85/15) to obtain the title compound (1.9 g; 92percent) as a colorless liquid.
1H-NMR (400 MHz, CDCl3)
δ: 1.52 (3H, d, J=6.8 Hz), 5.17-5.24 (1H, m), 6.98-7.05 (1H, m), 7.15 (1H, ddd, J=1.2, 7.6, 7.6 Hz), 7.21-7.28 (1H, m), 7.49 (1H, ddd, J=1.6, 7.6, 7.6 Hz).
74% at 35℃; for 36 h; Tris buffer; Microbiological reaction; Enzymatic reaction General procedure: The preparative scale (large scale) production of (S)-1-phenylethanol 1b from acetophenone 1a by immobilized C. laurentii EBK-19 cells was also achieved. The reduction of 1a was carried out in a 1000-mL Erlenmeyer flask using beads prepared as described in Section 4.4. The cells were activated by suspending the beads in 300 mL tris buffer containing 4percent glucose. After cell activation (3 h), acetophenone 1a (6 mM) was directly added to the mixture. During the 36 h reaction period, the beads were regularly separated by filtration, resuspended in tris buffer and glucose and reused for the same reaction without washing. At regular time intervals (36 h), the conversion and enantiomeric excess (ee) of the product were determined and the yields calculated. The run time of the beads was optimized for the production of 1b and found to be 27 days.
90.7 % ee With hydrogen; lithium hydroxide; (8R,9R)-9-amino(9-deoxy)epicinchonin In methanol at 25℃; for 3 h; Autoclave General procedure: Asymmetric hydrogenation of aromatic ketones was performed in a 60mL stainless steel autoclave with a magnetic stirred bar at room temperature, by using 9-amino(9-deoxy)epicinchonine as modifier, which is derived from cinchonine. In a typical run, the catalyst, chiral diamine, solvent, base and acetophenone were placed in the autoclave, followed by five purges hydrogen. The hydrogen pressure was thereafter increased to desired level. The mixture was stirred at room temperature for the appropriate duration.
99 % ee With bis(1,5-cyclooctadiene)diiridium(I) dichloride; C49H67FeN2O2PS; hydrogen; lithium tert-butoxide In isopropyl alcohol at 20℃; for 12 h; Inert atmosphere; Autoclave In a high-purity argon atmosphere,[Ir(COD)Cl]2 (3.4 mg, 0.005 mmol)The chiral ligand L6 (9.2 mg, 0.011 mmol) was dissolved in isopropanol (1 mL).Stirring for 3 hours at room temperature gives an orange clear solution.20 μL (0.001 molpercent) of this orange solution was taken with a microinjector.Add to a mixed system of o-fluoroacetophenone (2 mmol), isopropyl alcohol (2 mL) and lithium tert-butoxide (1 mol percent).The reaction system was placed in an autoclave and stirred at room temperature under H2 (20 atm) for 12 hours.The solvent was removed under reduced pressure and the column was separated by chromatography (silica gel, eluent: ethyl acetate).The pure product 1-o-fluorophenylethanol was analyzed by HPLC and the ee value was found to be 99percent.

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[3] Patent: CN106243008, 2016, A,
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Reference: [1] Patent: EP2336107, 2015, B1,
[2] Patent: CN108558831, 2018, A,
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Reference: [1] Patent: US2015/238558, 2015, A1,
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  • 27
  • [ 445-27-2 ]
  • [ 1402412-84-3 ]
YieldReaction ConditionsOperation in experiment
3.80 g
Stage #1: With pyridinium hydrobromide perbromide In toluene at 20℃; for 3.5 h; Inert atmosphere; Cooling with ice
Stage #2: With potassium fluoride; 18-crown-6 ether In acetonitrile at 90 - 100℃; for 35 h;
Step 1 [0276] To pyridinium bromide perbromide (25.7 g) was added toluene (60 mL) under nitrogen atmosphere, stirred for 10 minutes under ice-cooling. To the mixture was added Compound 48 (10 g), stirred at room temperature for 3.5 hours, and quenched with an aqueous sodium carbonate solution. The organic layer was washed with water and brine and dried over magnesium sulfate. After the extract was filtered, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (100 mL). To the solution were added potassium fluoride (16.82 g) and 18-crown-ether (1.91 g), and stirred at 90° C. for 12 hours. After stirring at 100° C. for 23 hours, the solvent was evaporated under reduced pressure. To the residue was added water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The extract was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 49 (3.80 g). [0277] 1H-NMR (CDCl3) δ: 5.36 (1H, d, J=3.7 Hz), 5.51 (1H, d, J=3.7 Hz), 7.17 (1H, dd, J=11.1, 8.3 Hz), 7.30 (1H, t, J=7.5 Hz), 7.56-7.63 (1H, m), 8.00-8.06 (1H, m).
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