* 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.
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.
Reference：
[1] Patent: US2009/156642, 2009, A1, . Location in patent: Page/Page column 40
[2] Patent: EP2196459, 2010, A1, . Location in patent: Page/Page column 78
[3] Tetrahedron Letters, 2012, vol. 53, # 2, p. 191 - 195
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 20, p. 3763 - 3772
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
[6] Patent: CN106431871, 2017, A, . Location in patent: Paragraph 0023-0025
[7] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 2861 - 2864
[8] Angewandte Chemie - International Edition, 2013, vol. 52, # 29, p. 7509 - 7513[9] Angew. Chem., 2013, vol. 125, # 29, p. 7657 - 7661,5
[10] Patent: CN107629022, 2018, A, . Location in patent: Paragraph 0447; 0448; 0449; 0450
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 1, p. 123 - 149
[12] Journal of Organic Chemistry, 1990, vol. 55, # 6, p. 1796 - 1801
[13] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
[14] Arzneimittel-Forschung/Drug Research, 2001, vol. 51, # 7, p. 569 - 573
[15] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1291 - 1295
[16] Patent: US6346532, 2002, B1, . Location in patent: Page column 15
[17] Patent: US5053509, 1991, A,
[18] Patent: US2007/60623, 2007, A1, . Location in patent: Page/Page column 20
[19] Synthesis, 2008, # 6, p. 891 - 896
[20] Patent: US2009/203705, 2009, A1, . Location in patent: Page/Page column 45
[21] Tetrahedron Letters, 2010, vol. 51, # 28, p. 3613 - 3615
[22] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 131-132
[23] Patent: WO2012/27965, 2012, A1, . Location in patent: Page/Page column 22-23
[24] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 403 - 412
[25] Advanced Synthesis and Catalysis, 2013, vol. 355, # 18, p. 3570 - 3574
[26] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 2, p. 692 - 702
[27] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 1, p. 16 - 24
[28] Chemical Communications, 2014, vol. 50, # 51, p. 6726 - 6728
[29] MedChemComm, 2015, vol. 6, # 6, p. 1036 - 1042
[30] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0243
[31] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 8, p. 1166 - 1173
[32] Organic and Biomolecular Chemistry, 2016, vol. 14, # 34, p. 8026 - 8029
[33] Patent: CN105315279, 2016, A, . Location in patent: Paragraph 0160
[34] Patent: CN105669586, 2016, A, . Location in patent: Paragraph 0053
[35] Journal of the American Chemical Society, 2016, vol. 138, # 35, p. 11093 - 11096
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[37] Journal of Medicinal Chemistry, 2017, vol. 60, # 4, p. 1591 - 1597
[38] Patent: JP2016/88894, 2016, A, . Location in patent: Paragraph 0214; 0215
[39] Organic Letters, 2017, vol. 19, # 8, p. 1994 - 1997
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[42] Patent: TW2017/38323, 2017, A, . Location in patent: Paragraph 0214
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Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 33, p. 6359 - 6362
4
[ 445-27-2 ]
[ 67500-19-0 ]
Reference：
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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 ]
Yield
Reaction Conditions
Operation 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.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5064 - 5075
[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
Reference：
[1] Russian Journal of Organic Chemistry, 2003, vol. 39, # 11, p. 1581 - 1586
8
[ 445-27-2 ]
[ 79110-05-7 ]
Yield
Reaction Conditions
Operation 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).
Reference：
[1] Patent: WO2012/139425, 2012, A1, . Location in patent: Page/Page column 117
[2] Patent: WO2011/44184, 2011, A1, . Location in patent: Page/Page column 99-100
[3] Patent: US2004/122237, 2004, A1, . Location in patent: Page 388
[4] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 3, p. 673 - 683
[5] Patent: US2002/151715, 2002, A1,
[6] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1246 - 1252
[7] Australian Journal of Chemistry, 1981, vol. 34, # 4, p. 839 - 853
[8] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1725 - 1728
[9] Patent: EP2147914, 2010, A1, . Location in patent: Page/Page column 28-29
[10] Patent: EP2151435, 2010, A1, . Location in patent: Page/Page column 71
[11] Patent: WO2013/28670, 2013, A1, . Location in patent: Page/Page column 95
[12] Patent: US9181236, 2015, B2, . Location in patent: Page/Page column 106; 107
[13] Patent: WO2015/187437, 2015, A1, . Location in patent: Page/Page column 48
[14] Patent: WO2016/25364, 2016, A1, . Location in patent: Page/Page column 17-18
[15] Patent: WO2016/44120, 2016, A1, . Location in patent: Page/Page column 48-49
[16] Patent: WO2016/53767, 2016, A1, . Location in patent: Page/Page column 17; 18
9
[ 445-27-2 ]
[ 93102-96-6 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 6, p. 1796 - 1801
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 6, p. 788 - 792
[2] Journal of Fluorine Chemistry, 1990, vol. 49, # 1, p. 67 - 73
[3] Advanced Synthesis and Catalysis, 2011, vol. 353, # 11-12, p. 2085 - 2092
[4] Advanced Synthesis and Catalysis, 2011, vol. 353, # 11-12, p. 2085 - 2092
[5] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5314 - 5327
[6] Angewandte Chemie - International Edition, 2014, vol. 53, # 40, p. 10714 - 10717[7] Angew. Chem., 2015, vol. 126, # 40, p. 10890 - 10893,4
[8] Green Chemistry, 2017, vol. 19, # 2, p. 474 - 480
12
[ 445-27-2 ]
[ 68285-25-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 45, p. 8960 - 8962,3
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 45, p. 8960 - 8962
13
[ 445-27-2 ]
[ 87227-77-8 ]
[ 109-97-7 ]
[ 68285-25-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 10, p. 1618 - 1624
14
[ 462-94-2 ]
[ 445-27-2 ]
[ 505-18-0 ]
[ 68285-25-6 ]
Reference：
[1] Green Chemistry, 2017, vol. 19, # 2, p. 361 - 366
15
[ 124-20-9 ]
[ 445-27-2 ]
[ 68285-25-6 ]
[ 57672-23-8 ]
Reference：
[1] Green Chemistry, 2017, vol. 19, # 2, p. 361 - 366
16
[ 445-27-2 ]
[ 405931-46-6 ]
Reference：
[1] Australian Journal of Chemistry, 1984, vol. 37, # 7, p. 1437 - 1446
17
[ 445-27-2 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Yield
Reaction Conditions
Operation 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.
Reference：
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18
[ 445-27-2 ]
[ 171032-87-4 ]
Yield
Reaction Conditions
Operation 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.
Reference：
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[3] Patent: US2018/162868, 2018, A1, . Location in patent: Paragraph 1572-1573
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[6] Journal of Organic Chemistry, 1998, vol. 63, # 24, p. 8957 - 8964
[7] Patent: US2014/128606, 2014, A1, . Location in patent: Paragraph 0174; 0175; 0176; 0177
[8] Organic Letters, 2018, vol. 20, # 4, p. 1110 - 1113
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[12] Tetrahedron Asymmetry, 2007, vol. 18, # 19, p. 2332 - 2335
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[14] Organic and Biomolecular Chemistry, 2016, vol. 14, # 13, p. 3404 - 3408
[15] ACS Catalysis, 2018, vol. 8, # 9, p. 8020 - 8026
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[29] Patent: CN107722068, 2018, A, . Location in patent: Paragraph 0079; 0080; 0081; 0082
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19
[ 445-26-1 ]
[ 445-27-2 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Reference：
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20
[ 445-27-2 ]
[ 67-63-0 ]
[ 67-64-1 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 35, p. 10843 - 10846
21
[ 445-27-2 ]
[ 74788-44-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 245 - 252
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[6] Green Chemistry, 2017, vol. 19, # 2, p. 474 - 480
[7] Molecules, 2014, vol. 19, # 12, p. 21386 - 21397
22
[ 445-27-2 ]
[ 267401-33-2 ]
Reference：
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23
[ 445-27-2 ]
[ 881674-56-2 ]
Reference：
[1] Patent: EP2336107, 2015, B1,
[2] Patent: CN106432191, 2017, A,
[3] Patent: CN106243008, 2016, A,
[4] Patent: CN108558831, 2018, A,
Reference：
[1] Patent: CN106432191, 2017, A,
[2] Patent: CN107162949, 2017, A,
[3] Patent: CN108558831, 2018, A,
27
[ 445-27-2 ]
[ 1402412-84-3 ]
Yield
Reaction Conditions
Operation 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).
With potassium carbonate In water at 130℃; for 0.666667h; Microwave irradiation;
1-[2’-(Pyrrolidin-1”-yl)phenyl]ethan-1-one (1b)
Following method A, the title compound was isolated. A mixture of 2-fluoroacetophenone (5.00 g, 36.20 mmol, 4.40 mL), pyrrolidine (2.57 g,36.20 mmol, 3.02 mL) and K2CO3 (5.00 g, 36.20 mmol) in 20 mL water was irradiated at 130 °Cfor 40 minutes. Brown oil (6.05 g, 88%). 1H NMR: (400 MHz, chloroform-d): 7.51 (1H, dd, J 7.8,1.6 Hz, H - 6’), 7.32 (1H, tm, J 8.6 Hz, H - 4’), 6.82 (1H, d, J 8.5 Hz, H - 3’), 6.74 (1H, tm, J7.8 Hz, H - 5’), 3.15 - 3.11 (4H, m, H - 2”, 5”), 2.60 (3H, s, H - 2), 1.97 - 1.93 (4H, m, H - 3”,4”). Before using for the synthesis of the vinyl compound (method B1) the crude product was purified by column chromatography (n-hexane/EtOAc 8:1). Yellow oil (76%).
47%
With potassium carbonate In N,N-dimethyl-formamide at 140℃;
With potassium carbonate In N,N-dimethyl-formamide at 152℃;
With potassium carbonate In dimethyl sulfoxide at 100℃; for 16h;
34.1 Step 1
To a stirred solution of compound 2 ’-Fluoro acetophenone (30 g, 0.22 mol, 1 eq) and piperidine (19.6 g, 0.23 mol, 1.05 eq) in DMSO (200 mL) was added K2CO3 (45.5 g, 0.33 mol, 1.5 eq). The reaction was stirred at 100 °C for 16 h. TLC showed the reaction was completed. The mixture was cooled to room temperature and poured into water (1 L), extracted with ethyl acetate (400 mL*4). The combined organic layers were washed with brine (300 mLX3), dried with Na2SO4, filtered and concentrated in vacuum to give compound 34A (42 g, Y=94.2%) as a yellow oil, which was used directly for the next step without further purification.
94.2%
With potassium carbonate In dimethyl sulfoxide at 100℃; for 16h;
34.1 Step 1
To a stirred solution of compound 2 ’-Fluoro acetophenone (30 g, 0.22 mol, 1 eq) and piperidine (19.6 g, 0.23 mol, 1.05 eq) in DMSO (200 mL) was added K2CO3 (45.5 g, 0.33 mol, 1.5 eq). The reaction was stirred at 100 °C for 16 h. TLC showed the reaction was completed. The mixture was cooled to room temperature and poured into water (1 L), extracted with ethyl acetate (400 mL*4). The combined organic layers were washed with brine (300 mLX3), dried with Na2SO4, filtered and concentrated in vacuum to give compound 34A (42 g, Y=94.2%) as a yellow oil, which was used directly for the next step without further purification.
92%
With potassium carbonate In water monomer at 130℃; for 0.5h; Microwave irradiation;
1-[2’-(Piperidin-1”-yl)phenyl]ethan-1-one (1c)
Following method A, the title compound was isolated. A mixture of 2-fluoroacetophenone (5.00 g, 36.20 mmol, 4.40 mL), piperidine (2.98 g,36.20 mmol, 3.46 mL) and K2CO3 (5.00 g, 36.20 mmol) in 30 mL water was irradiated at 130 °Cfor 30 minutes. Yellow oil (6.53 g, 92%). 1H NMR: (500 MHz, chloroform-d): 7.41 - 7.39 (1H,dm, J 7.5 Hz, H - 6’), 7.39 - 7.36 (1H, m, H - 4’), 7.06 - 7.05 (1H, dm, J 7.5 Hz, H - 3’), 7.03 -7.00 (1H, m, H - 5’), 2.95 - 2.93 (4H, m, H - 2”, 6”), 2.67 (3H, s, H - 2), 1.73 - 1.69 (4H, m, H -3”, 5”), 1.57 - 1.56 (2H, m, H - 4”).
80%
With potassium carbonate In dimethyl sulfoxide for 8h;
64%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 12h; Inert atmosphere;
52%
With potassium carbonate In N,N-dimethyl-formamide at 152℃; for 24h;
47%
With potassium carbonate In N,N-dimethyl-formamide at 140℃;
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 12h;
33 2-bromo-1-(2-fluorophenyl)ethanone
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 97%). 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 2h;
19
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 97%). 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).
95%
With copper(I) bromide In ethyl acetate at 80℃;
1 Preparation of 2-bromo-1-(2-fluorophenyl)ethan-1-one (Intermediate II-1)
3.5 g of 2'-fluoroacetophenone was dissolved in 60 ml of ethyl acetate, 11.3 g of copper bromide was added, and then heated to 80 ° C to react overnight. After completion of the reaction, the reaction solution was cooled to room temperature, filtered and concentrated, and the residue was subjected to silica gel column chromatography, to give compound of formula II-1, 5.2 g of a yellow oil, 95% yield
94%
With copper(ll) bromide In ethyl acetate for 3h; Reflux;
85%
With Oxone; ammonium bromide In methanol for 2h; Reflux; regioselective reaction;
2. General procedure
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 (3×25 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.
83%
With aluminium trichloride; bromine In diethyl ether at 0℃; for 3h;
81%
With copper(ll) bromide In chloroform; ethyl acetate at 85℃; for 3h;
80%
Stage #1: 2'-Fluoroacetophenone With aluminum (III) chloride In tert-butyl methyl ether at 0℃; for 0.25h; Large scale;
Stage #2: With N-Bromosuccinimide In tert-butyl methyl ether at 0 - 20℃; for 4h; Large scale;
1
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 50%. 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 80%, 5% higher than the small test
40%
With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 80℃;
4.1 General procedure for the synthesis of 2-bromo-1-substituted phenylethanone 10a-10i
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 copper(ll) bromide In chloroform; ethyl acetate Inert atmosphere; Reflux;
24%
With N-Bromosuccinimide In ethyl acetate at 40℃;
38.1 38.1 Preparation of α-bromo-2-fluoroacetophenone
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 24% yield.
20%
With bromine In dichloromethane at 25℃; for 2h;
36.7 g
With copper(ll) bromide In chloroform; ethyl acetate Heating;
With bromine In 1,4-dioxane; diethyl ether for 1h;
With bromine In chloroform Photolysis;
With bromine In diethyl ether at 20℃;
With mono(N,N,N-trimethylbenzenaminium) tribromide In tetrahydrofuran at 20℃; for 0.5h;
9 REFERENTIAL EXAMPLE 9
To a solution of 0.96 g of 2-fluoroacetophenone in 20 ml of tetrahydrofuran was added 2.65 g of benzyltrimethylammonium tribromide. The reaction mixture was stirred at room temperature for 30 minutes, insoluble matters were filtered off, and the solvent was concentrated in vacuo.
9 EXAMPLE 9
Starting with 2'-fluoroacetophenone (20 g), 2'-fluoro-2-bromoacetophenone (32.6 g) is obtained in the form of a greenish oil, which is used without further purification for the subsequent steps.
With copper(ll) bromide In ethyl acetate for 4h; Heating / reflux;
4
Reference Example 4 ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate; To a solution of 2'-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL) was added copper (II) bromide (92.6 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude 2-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogen phosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→4:1) to give the title compound as an oil (yield 64.0 g, yield about 100%). 1H-NMR (CDCl3) δ: 1.35 (3H, t, J=7.2 Hz), 3.55-3.80 (2H, m), 4.11 (1H, t, J=6.0 Hz), 4.24-4.34 (2H, m), 7.15-7.29 (2H, m), 7.55-7.62 (1H, m), 7.94 (1H, dt, J=7.5, 1.8 Hz).
With bromine In various solvent(s) at 35℃; for 1.5h;
With bromine In diethyl ether at 20℃; for 2h;
2-Bromo-1-(2-fluorophenyl)ethanone
2-Bromo-1-(2-fluorophenyl)ethanone 1-(2-fluorophenyl)ethanone (1 g, 7.24 mmol) was dissolved in Et2O (30 ml). Bromine (0.373 ml, 7.24 mmol) was added portion wise, and the resulting red solution was stirred at r.t. for 2 hours. The reaction mixture was taken up with Et2O (200 ml), washed with a saturated NaHCO3 aq solution (3*100 ml), dried over Na2SO4, filtered and concentrated to give a crude which was used in the next step without any further purification (1.8 g). 1H NMR (400 MHz, CDCl3): δ 4.56 (d, 2H), 7.16-7.24 (m, 1H), 7.28-7.33 (m, 1H), 7.57-7.65 (m, 1H), 7.93-8.00 (m, 1H).
With copper(ll) bromide In chloroform; ethyl acetate Reflux;
With copper(ll) bromide In ethyl acetate for 4h; Heating / reflux;
With bromine In diethyl ether at 0 - 20℃;
7.7a
To a solution of l-(2-fluorophenyl)ethanone (1.5 g) in diethyl ether (30 mL) cooled at 0 °C was added bromine (0.587 mL) dropwise. The mixture was allowed to warm to room temperature. After stirring for 1.5 hours, most of the starting material was consumed. Solvent was removed in vacuo to afford 2-bromo-l-(2-fluorophenyl)ethanone (2.432 g) as an orange oil. MS(ES+) m/z 217 (MH+).
With toluene-4-sulfonic acid; N,N'-dibromohydantoin In methanol at 30℃; for 8h;
5.2. General procedure for the preparation of compounds 2
General procedure: To a solution of the appropriate acetophenone 1 and p-toluenesulfonic acid (15 mmol) in dry methanol (20 mL), dibromohydantoin (15 mmol), diluted in methanol (20 mL) was added dropwise and the mixture was stirred for 8 h at 30 °C. After the completion of the reaction, excess solvent was removed under reduced pressure. Ice water was added to the residue. The precipitated solid was filtered, and washed with ethanol. The resulting crude solid was directly used in the next step without purification.
With copper(ll) bromide In chloroform; ethyl acetate for 8h; Reflux;
With bromine In diethyl ether
With N-Bromosuccinimide; toluene-4-sulfonic acid In water; acetonitrile Reflux;
With copper(ll) bromide In chloroform; ethyl acetate for 8h; Reflux;
With tetrabutylammomium bromide In acetonitrile at 20℃;
With copper(ll) bromide In ethyl acetate for 4h; Reflux;
69 Ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate
Reference Example 69 Ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate To a solution of 2'-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL), copper (II) bromide (92.6 g) was added, and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 1-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil.
With hydrogen bromide; bromine; acetic acid at 0 - 5℃;
General procedure to obtainα-bromoacetophenonederivatives
General procedure: General procedure to obtainα-bromoacetophenonederivatives Acetophenone derivative (10 mmol) was solved in acetic acid(50 mL) and hydrobromic acid (0.5 mL) mixture. Bromine(10 mmol, 0.52 mL) was added dropwise to this mixture at 0-5°Ctemperatureandthemixturewasstirredfor6-7h.Afterthisperiod, the mixture was poured into ice-water, collapsed portionwas filtrated and after dryness it was crystallized from ethanol.
With copper(ll) bromide In chloroform; ethyl acetate for 2h; Reflux;
With N-Bromosuccinimide; toluene-4-sulfonic acid In ethyl acetate at 20℃; for 12h;
14
0.20g (1.5mmol) 2- fluoroacetophenone, 0.27g (1.5mmol) N- bromosuccinimide and 0.03g (0.15mmol) of p-toluenesulfonic acid dissolved in 15mL ethyl acetate and stirred at room temperature 12 hours, TLC tracking, completion of the reaction, deionized water (3 × 10mL) and washed, the organic solvent was removed under reduced pressure to give the crude product α- bromo-2-fluoroacetophenone, 95% yield without purification It was used directly in the next reaction.
With copper(ll) bromide In chloroform; ethyl acetate at 90℃; for 3h;
100mL single-mouth flask, equipped with a reflux condenser, was added cupric bromide (8.934g, 40mmol), 2- fluoroacetophenone (2.762g, 20mmol). Add chloroform 10mL, ethyl acetate 10mL. Move to 90 deg.C oil bath react for 3H; cooled to room temperature, the solid was filtered to give a liquid after spin dry column to give α-bromo-2-fluoroacetophenone.
With bromine In acetic acid at 20℃; Inert atmosphere;
With toluene-4-sulfonic acid In methanol at 23℃;
With tetrabutylammomium bromide; bromine In chloroform at 20℃; for 2h;
With hydrogen bromide; bromine In ethyl acetate at 20℃; for 0.5h; Inert atmosphere;
1
The following reaction, is carried out in a nitrogen atmosphere. In a flask equipped with a stirrer and cooling tubes, 2' nitroacetophenone (tokyo chemical company) alkylfluoro -15 parts and ethyl acetate 105 part, 0.15 part to 48% hydrobromic acid, dropping hypobromous 17.9 part at room temperature. Thereafter, 30 minutes to react at room temperature. The reaction solution of about 1% aqueous solution of sodium sulfite, sodium hydrogen carbonate, about 7% washed with an aqueous, organic layer. The organic layer is water, washed with 10% saline, by vacuum concentrator 2-bromo -2'-fluoropyrimidine corallite nitroacetophenone obtained as a liquid
With bromine In chloroform at 0 - 25℃; for 6h; Inert atmosphere;
With copper(ll) bromide In ethyl acetate for 4h; Reflux;
S.7. Ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate(9d)
General procedure: A mixture of compound 8d (28.6 g, 207 mmol) and CuBr2 (92.6 g, 415 mmol) in EtOAc (400 mL) was refluxed for 4h, and filtered after cooling. The filtrate was concentrated in vacuo to obtainan crude oil of 2-bromo-1-(2-fluorophenyl)ethanone
With copper(ll) bromide In ethanol at 60℃;
With hydrogen bromide; bromine In ethyl acetate at 20℃; for 0.5h; Inert atmosphere;
1
The following reaction was performed under a nitrogen atmosphere.2'-fluoroacetophenone (manufactured by Tokyo Chemical Industry Co., Ltd.) 15 parts and ethyl acetate 105 parts,48% Hydrobromic Acid0.15 parts fed into a flask with a cooling tube and stirring device,Bromine 17.9 parts were dripped at room temperature.Thereafter, the reaction was allowed to proceed at room temperature for 30 minutes.The reaction solution was made up of about 1% aqueous sodium sulfite,Then wash it with about 7% sodium bicarbonate solution.Separate the organic layer.Wash the organic layer with water and 10% saline solution.Obtained as a pale yellow liquid by concentration under reduced pressure2-Bromo-2'-fluoroacetophenone.
With copper(ll) bromide In ethyl acetate at 20℃; for 24h;
With bromine In diethyl ether at 0 - 20℃;
With copper(ll) bromide In chloroform; ethyl acetate for 2h; Reflux;
With N-Bromosuccinimide; toluene-4-sulfonic acid In chloroform at 20℃; for 24h;
3.1.4 General procedure for the synthesis of b1-b5
General procedure: To a solution of acetophenone (3mmol) in CHCl3 were added p-TsOH·H2O (100mg, 0.53mmol) and N-bromosuccinimide (NBS, 214mg, 3.6mmol). The mixture was stirred at room temperature for 24h. The aqueous mixture was extracted with ether (50mL). The organic layer was dried (Na2SO4), after filtration, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether and CH2Cl2, 2:1) to obtain white solid. To a solution of the white solid in DMF (50mL), NaN3 (143mg, 2.2mmol) was added. After stirred at r.t for 3h, the solid was disappeared completely. Added ascorbic acid (528mg, 3mmol) and anhydrous K2CO3 (414mg, 3mmol) into the reaction solution, stirred at r.t for 30min. Then added the intermediate 2 (680mg, 2mmol) and CuSO4·5H2O (625mg, 2.5mmol) into the reaction solution, stirred at r.t for 3h. Method as described in 4.1.2.2 (acidified to pH 5-6 and extracted with EtOAc, washed with brine solution, dried over anhydrous Na2SO4, filtered, and concentrated). The residues of b1-b5, were purified by flash column chromatography (CHCl3/Petroleum ether/mehanol=1/1, v/v) [30] (white crystal or powder, yield 36-80% for this step reaction, Scheme 1).
With copper(ll) bromide In ethyl acetate at 80℃; Inert atmosphere;
General procedure: To a solution of 2-ethoxyacetophenone (4.71 g, 28.7 mmol) inAcOEt was added copper bromide (7.37 g, 31.6 mmol). The solutionwas heated at 80 °C under nitrogen protection. When the solid in theflask turned from black to white, the solution was cooled to roomtemperature. The solid was removed by filtration. The filter cake waswashed with AcOEt. The combined filtrates were concentrated in vacuoto afford G (6.14 g, 88.08%) which was used directly in the next stepwithout purification.
With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 90℃;
With bromine In methanol
With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 90℃; Inert atmosphere;
2.1 Synthesis of substituted bromoacetone
General procedure: A mixture of N-bromosuccinimide (NBS, 2.94 g, 16.5 mmol, 1.1 equiv), p-toluenesulfonic acid(TsOH, 3.10 g, 18 mmol, 1.2 equiv) were added to substituted acyl (S1, 15 mmol, 1.0 equiv), then thereaction stirred at 90 oC for overnight. The reaction solvent was distilled off under reduced pressure,then neutralize the reaction with 5 mL of NaHCO3 saturated solution, dissolved in DCM (50 mL) andwashed with H2O (3×30 mL), dried over Na2SO4, then concentrated to give the substitutedbromoacetone (S2) as a white solid. The crude mixture S2 did not need to be purified and go to thenext reaction step directly
With copper(ll) bromide In ethyl acetate for 5h; Schlenk technique; Inert atmosphere; Reflux;
Stage #1: 2'-Fluoroacetophenone With toluene-4-sulfonic acid In ethyl acetate for 0.166667h; Inert atmosphere;
Stage #2: With N-Bromosuccinimide In ethyl acetate at 25℃; for 24h; Inert atmosphere;
With copper(ll) bromide In ethyl acetate Reflux;
With tetra-N-butylammonium tribromide In tetrahydrofuran at 20 - 30℃;
1.1 (1) 2-Fluoro-α-bromoacetophenone
Add 160ml of tetrahydrofuran and 2-fluoroacetophenone (40g, 0.29mol) to the 500ml reaction flask, stir until completely dissolved, add tetrabutylammonium tribromide (153.8g, 0.319mol), and stir at 20~30°C for 5~6h.The reaction solution was concentrated at 40-45°C.250 ml of ethyl acetate was added to the concentrated solution, followed by washing with water (80 ml×3).The organic phase was dried with anhydrous sodium sulfate and filtered to obtain ethyl acetate solution of 2-fluoro-α-bromoacetophenone, which was directly used in the next reaction.
With C40H37ClN2PRuS(1+)*C24H20B(1-); isopropyl alcohol; potassium hydroxide; at 82℃; for 2h;Catalytic behavior;
General procedure: The mixture of a ketone (0.2 mmol) and base (0.08 mmol)containingthe catalyst (0.1 mol%) in 2-propanol (6 ml) was stirred at82 C. After the reactionwas complete, diethyl ether could be addedto the mixture and extract the ruthenium complexes followed byfiltration and neutralized with 1N HCl, washed with water anddried over anhydrous Na2SO4. Conversion obtained is related to theresidual unreacted ketone. Percentage of conversionwas calculatedby using GC method of the crude mixture and compared with theauthentic samples. Acetone was identified as only by-product in allthe cases. As the catalyst is stable in all organic solvents and it canbe recovered and the work up process is also very simple for thiscatalytic system.
80%
With Al(3+)*C3H7O(1-)*C50H66O4(2-); isopropyl alcohol; In hexane; toluene; at 20℃; for 12h;
General procedure for conducting MPV reduction: In 5 mL of anhydrous toluene (freshly distilled over sodium benzophenone ketyl), 1,3-bis-substituted calix[4]arene (e.g., for 1,3-bispropoxy calix[4]arene, 73 mg, 0.1 mmol, 10 mol%) is dissolved. To this solution, Me3Al (40 muL, 0.1 mmol, 10 mol%, 25% w/w solution in hexane) is added under Ar. Gaseous methane bubbles indicate the formation of methylaluminum calix[4]arene complex, which upon treatment with alcohol forms the active MPV catalyst and evolves methane. A 5 mL solution of alcohol (e.g., 300 muL, 240 mg, 4 mmol, 4 equiv. anhydrous 2-propanol) and substrate ketone (e.g., 155 mg, 1 mmol, 1 equiv. alpha-chloroacetophenone) in toluene is added. The reaction is subsequently performed at room temperature and is monitored by 1H NMR spectroscopy.
40%
With titanium(IV) isopropylate; In methanol; at 20℃; for 72h;UV-irradiation; Inert atmosphere;
General procedure: Argon gas was passed through a mixture of 0.75 mmol (1 equiv) ketone in 6 mL of methanol containing 0.5 equiv titanium(IV) catalyst of the type TiCln(OiPr)4-n (n = 0-4) for 15 min. The degassed solution was irradiated with UV light (254-300 nm) for 72 h at room temperature. After irradiation, the solution was poured into water and extracted four times with CH2Cl2. The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure. The residual was purified via column chromatography.
With sodium tetrahydroborate;
A solution of CF2CFRe(CO)5 (100 mg, 0.245 mmol) in 0.5 ml THF was added to a suspension of PhCCNa in 1 ml THF, prepared in a Schlenk flask from [(Me3Si)2N]Na (46 mg, 0.25 mmol) and PhCCH (27 mg, 0.26 mmol). Samples of the reaction solution were taken for the NMR and IR analysis and to the rest of it solid Y(OTf)3 (64 mg, 0.122 mmol) was added under stirring in two portions, a sample for IR and NMR being taken in between and after the addition of the second portion. IR spectrum indicated the presence of CF2CFRe(CO)5 band (2147 cm-1), and two new bands (2107 and 2099 cm-1), the latter subsequently identified as belonging to 7. Reaction mixture was diluted with CH2Cl2 (3 ml) and filtered through an alumina pad. Part of the reaction mixture was separated on a Silufol UV-254 TLC plate, using a CH2Cl2-petroleum ether, 1:5 as an eluent. The second yellow band (Rf = 0.3) after solvent removal afforded 4 mg of complex 7 as a yellow solid. 1H NMR (acetone-d6): delta 9.67 (s, br, 1H, NH); 8.26 (s, br, 1H, NH); 7.78 (d, 2h); 7.62 (t, 1H); 7.55 (t, 2H); 5.63 (t, 1H, JHF = 2.7 Hz); 1.48 (s, 9H). 19F NMR (Et2O): delta -70.4 (m, 1F); -141.6 (m, 1F). IR (THF): nu 1544 (s) CO; 1941 (vs), 1985 (sh), 1996 (vs), 2099 (s) CO. EIMS (direct inlet) 70 eV, m/z (rel. int.): 507 [M]+ (10), 479 [M-CO]+ (10), 451 [M-2CO]+ (20), 423 [M-3CO]+ (10), 395 [M-4CO]+ (30), 103 [PhC2H2]+ (100).
93%Spectr.
With C24H20B(1-)*C40H43NO2PRuS(1+); isopropyl alcohol; potassium hydroxide; at 80℃; for 8h;Inert atmosphere;Catalytic behavior;
General procedure: In a dry two-necked round bottom flask under an atmosphere of nitrogen were placed an appropriate amount of catalyst 1-5 (0.01 mmol), (0.025 mmol) of KOH and (10 mmol) of aryl ketone in 2-propanol (10 ml) was added and the resulting mixture was refluxed under an atmosphere of nitrogen and the course of the reaction was monitored by 1H NMR analysis. After completion of the reaction, the solvent was removed under reduced pressure. The catalyst was removed by the addition of 15 ml of ether (b.p., 40-60 C) followed by filtration and subsequent neutralization with dilute HCl. The combined organic fractions were dried over anhydrous Na2SO4. The solvent was distilled off to obtain a crude mixture containing ketone and its hydrogenated product. Percentage conversion was calculated by 1H NMR spectra of the crude mixture. The only side product formed is acetone, which is easily removed by distillation during workup.
With sodium tetrahydroborate; In methanol; at 20℃;Schlenk technique;
General procedure: The ketone (1mmol) was dissolved in MeOH (5cm3) in a schlenk tube, then NaBH4 (3mmol) was added slowly and the mixture was stirred at r.t. for o/n. The solvent was removed and the mixture was dissolved in DCM (10 cm3), washed with water (10cm3), filtered and solvent removed. a small amount of the residue was dilluted inEtOAc and then injected on the GC to determine the conversion.
With [(2-(benzoimidazol-2-yl)-6-(3,5-dimethylpyrazol-1-yl)pyridine)RuCl2(PPh3)]; potassium tert-butylate; acetone; In methanol; at 56℃; under 750.075 Torr; for 0.5h;Inert atmosphere;Catalytic behavior;
General procedure: The catalyst solutionwas prepared by dissolving complex 3(36.1 mg,0.05mmol) in methanol (5.0 mL).Under a nitrogen atmosphere, the mixture of an alcohol substrate (2.0 mmol) and1.0 mL of the catalyst solution (0.01mmol) in 20mL acetone was stirred at 56 Cfor 10 minutes. tBuOK(22.4mg, 0.2 mmol)was then added to initiate the reaction.At the stated time, 0.1 mL of the reaction mixture was sampled and immediately diluted with 0.5 mL acetone pre-cooled-to-0 C for GC or NMR analysis. After the reaction was complete, the reaction mixture was condensed under reduced pressure and subject to purification by flash silica gel column chromatography to afford the corresponding ketone product, which was identified by comparison with the authentic sample through NMR and GC analysis.
72%
With tert.-butylhydroperoxide; In water; at 100℃; for 24h;
General procedure: Caution. tert-Butyl hydroperoxide is an exceptionally dangerous chemical that is highly reactive, flammable, and toxic. It is corrosive to skin and mucous membranes and causes respiratory distress when inhaled. A solution of secondary alcohol (1 mmol) and 70% TBHP (6 or 10 equiv.) was stirred at 100 C for 24 h. The reaction mixture was quenched with the saturated solution of sodium thiosulfate (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined dichloromethane extracts were dried over anhydrous Na2SO4 and filtered, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE or PE/EtOAc as the eluent to obtain the desired products.
With sodium hypochlorite; N-Bromosuccinimide; [(R,R)-(N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato)]manganese(III) chloride; In dichloromethane; water; at 25℃; for 0.17h;
General procedure: In a typical experiment an alcohol (1 mmol), salen-Mn(III) complex (0.02 mmol), NBS (0.13 mmol), and CH2Cl2 (2 mL) was loaded into a 5 mL flask at room temperature. NaOCl (2.3 mmol) was added dropwise within 10 min and progress of the reaction was monitored by GC. Upon completion of the process the reaction mixture was treated twice with10 mL of 10% NaHSO3 solution and the organic phase was dried over anhydrous sodium sulfate and filtered off. The solvent was removed by distillation. The residue was distilled under low pressure.
With oxygen; at 120℃; for 12h;
Add 0.5 mmol of 1-phenylethanol to the test tube.Add 1.5 mmol of dipropylene glycol dimethyl ether to the oxygen balloon.Reaction at 120 C for 12 hours,By gas chromatography, the reaction was complete,To the reaction system, sodium formate 2.5 mmol was added.Add 0.0025 mmol of Catalyst B and add 4 mL of methanol:water (3:1).Nitrogen replacement 3 times, 50 C reaction 12h, after the end of the reaction, washed with water,The aqueous phase was extracted three times with ethyl acetate.Column chromatography separation (petroleum ether: ethyl acetate = 10:1),(S)-1-ethanol (57.3 mg) was obtained in a yield of 93%.The ee value is 95%.
Example 39; Preparation of Intermediate Compound 39D; Step A - Synthesis of Compound 39B; A mixture of ortho-fluoroacetophenone (39A, 3.45 g; 25 mmol) and guanidine carbonate (2 eq; 9.0 g) was prepared in 250 mL of N,N-dimethyl acetamide, set to stir, and heated at 135 oC under nitrogen purge overnight. The solvent was removed under reduced pressure and diluted with ethyl acetate (600 mL). The solution was washed with water (2x100 <n="178"/>mL) and brine (40 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was dissolved in methylene dichloride, loaded on silica gel and dried under reduced pressure. The material was purified on ISCO (80 g column; 0-70% THF in Hexanes). Fractions containing product were collected and concentrated under reduced pressure to afford product 39B as a creme colored solid (880 mg; 22%)
22%
In N,N-dimethyl acetamide; at 135℃;
Example 20; Preparation of Intermediate Compound 2OD; Step A - Synthesis of Compound 2OB; A mixture of ortho-fluoroacetophenone (2OA, 3.45 g; 25 mmol) and guanidine carbonate (2 eq; 9.0 g) was prepared in 250 mL of N,N-dimethyl acetamide, set to stir, and heated at 135 oC under nitrogen purge overnight. The solvent was removed under reduced pressure and diluted with ethyl acetate (600 mL). The solution was washed with water (2x100 mL) and brine (40 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was dissolved in methylene dichloride, loaded on silica gel and dried under reduced pressure. The material was purified on ISCO (80 g column; 0-70% THF in Hexanes). Fractions containing product were collected and concentrated under reduced pressure to afford product 2OB as a creme colored solid (880 mg; 22%)
22%
In N,N-dimethyl acetamide; at 135℃;
Example 22; Preparation of Intermediate Compound 22D; Step A - Synthesis of Compound 22B; <n="192"/>A mixture of ortho-fluoroacetophenone (22A, 3.45 g; 25 mmol) and guanidine carbonate (2 eq; 9.0 g) was prepared in 250 mL of N,N-dimethyl acetamide, set to stir, and heated at 135 oC under nitrogen purge overnight. The solvent was removed under reduced pressure and diluted with ethyl acetate (600 mL). The solution was washed with water (2x100 mL) and brine (40 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The solid was dissolved in methylene dichloride, loaded on silica gel and dried under reduced pressure. The material was purified on ISCO (80 g column; 0-70% THF in Hexanes). Fractions containing product were collected and concentrated in vacuo to afford product 22B as a creme colored solid (880 mg; 22%)
With RuBr2[(S,S)-2,4-bis(diphenylphosphino)pentane](2-picolylamine); potassium tert-butylate; hydrogen; In ethanol; at 40℃; under 7600.51 Torr; for 19h;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 100% yield. The optical purity was 88.0% ee as measured by GC (CP-Chirasil-DEX CB (0.25 mml. D×25 m, DF=0.25 mum, 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.
With (S,S)-DPENDS; C36H24Cl2O18P2RuS6(6-)*6Na(1+); hydrogen; potassium hydroxide; In water; at 30℃; under 37503.8 Torr; for 3h;Autoclave;
General procedure: To a 60 mL stainless autoclave with a glass liner and magnetic stirrer were added PEG-400, H2O, RuCl2(TPPTS)2, (S,S)-DPENDS, KOH, and reactant. Hydrogen was introduced to the desired pressure after the reaction mixture had been purged with H2 five times. The products were extracted by n-hexane and analyzed by GC-960 with a FID detector and beta-DEX120 capillary column (30 m × 0.25 mm, 0.25 mum film) at 115 C. The enantiomeric excess (ee value) was calculated from the equation: ee (%) = 100 × (R - S)/(R + S).
With dodecacarbonyl-triangulo-triruthenium; (S,S)-N-{1,2-diphenyl-2-[(pyridin-2-ylmethyl)amino]ethyl}-4-methylbenzenesulfonamide; In isopropyl alcohol; at 80℃; for 48h;Inert atmosphere; Schlenk technique;
General procedure: A mixture of catalyst (2 mol%) and Ru3 (CO)12 (0.67 mol%) 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.
With formic acid; (S,S)-RuCl(eta6-CH3C6H4CH2CH2CH2CH2NHCH(C6H5)CH(C6H5)NSO2Ts); C32H35ClN2O2RuS; triethylamine; at 60℃; for 5h;Schlenk technique;Catalytic behavior;
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, % 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.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate; In water; at 20℃; for 5h;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 5h;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.
General procedure: In a schlenk tube, BH3·SMe2(0.55 mmol, 275 L) was added inthe solution of IL 5 (28 mg, 10 mol%) 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.
With (2R)-2-[benzyl([6-({benzyl[(1R)-2-[(diphenylphosphanyl)oxy]-1-phenylethyl]amino}methyl)pyridin-2-yl]methyl})amino]-2-phenylethyl diphenylphosphinite bis(dichloro-eta6-p-cymeneruthenium(II)); isopropyl alcohol; potassium hydroxide; at 82℃; for 0.5h;Inert atmosphere; Schlenk technique;Catalytic behavior;
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.
With [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); sodium formate; In methanol; water; at 50℃; for 12h;Green chemistry;
0.5 mmol of 1-(2-fluorophenyl)ethanol was added to the test tube, 1.5 mmol of dipropylene glycol dimethyl ether was added to the oxygen balloon, and the reaction was completed at 120 C for 12 hours until the reaction was completed, and sodium formate was added to the reaction system, 2.5 mmol. Then add 0.0025 mmol of catalyst B, add 4 mL of methanol:water (3:1), replace with nitrogen three times, react at 50 C for 12 h, wash with water after the reaction, extract the aqueous phase with ethyl acetate three times, and concentrate the organic phase to dry Column chromatography (petroleum ether: ethyl acetate = 10:1) gave (S)-1-(2-fluorophenyl)ethanol (61.6 mg), yield 88%, ee value 86%. HPLC separation conditions: chiral column OD-H column, mobile phase: n-hexane / isopropanol = 98: 2 (volume ratio), flow rate: 1.0 ml / min, wavelength: 254 nm, temperature, 25 C, t1 = 11.82min, t2=12.72min;
With glucose dehydrogenase; D-glucose; NAD; acetophenone reductase from Geotrichum candidum NBRC 4597 (Trp288Ala mutant); In aq. buffer; at 30℃; for 14h;pH 7.2;Enzymatic reaction;Kinetics;
General procedure: Reductions were performed in 50 mL of 100 mM HEPES-NaOH buffer (pH 7.2) consisting of1.4 mM NAD+, 0.23-0.39 mmol of 2a-13a, cofactor regeneration reagent written in Table S1, and purified GcAPRD with the amount written in Table S1. Reactions were done for 14 h at 30C with a rotational speed of 130 rpm. The product was extracted with diethyl ether, dried over MgSO4, and evaporated under reduced pressure. Silica gel column chromatography (hexane:ethyl acetate 4:1) were performed to give the corresponding chiral alcohols 2b-13b.
With triethylamine; sodium iodide In acetonitrile at 20℃; Inert atmosphere;
6 Methods of Compounds of Formula VI
Add acetonitrile to the reaction flask to start stirring,Compound V (13.8 g, 0.1 mol) and sodium iodide (18.0 g, 0.12 mol) were added,Nitrogen replacement three times, stirring at room temperature,Triethylamine and trimethylchlorosilane (13.0 g, 0.12 mol) were added to the system,Stir at room temperature,Cool down to below 0°C,The temperature should not exceed 0°C,Saturated ammonium chloride solution and petroleum ether were added to the system, and the layers were separated. The aqueous phase was washed twice with petroleum ether, the organic phase was combined and washed with ice water and saturated ammonium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until there was no fraction.The residue was purified by vacuum distillation to obtain 20.4 g of compound VI with a yield of 97%.
84%
With triethylamine; sodium iodide In acetonitrile at 20℃; Inert atmosphere;
With lithium diisopropyl amide at -78 - 20℃; for 3h;
Stage #1: 2'-Fluoroacetophenone With sodium iodide In acetonitrile at 20℃; for 0.0833333h; Inert atmosphere;
Stage #2: chloro-trimethyl-silane With triethylamine In acetonitrile at 20℃; Inert atmosphere;
Stage #1: 2'-Fluoroacetophenone With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: chloro-trimethyl-silane In tetrahydrofuran
Stage #1: 2'-Fluoroacetophenone With sodium iodide In acetonitrile at 20℃; for 0.0833333h; Inert atmosphere;
Stage #2: chloro-trimethyl-silane With triethylamine In acetonitrile at 20℃; Inert atmosphere;
Stage #1: 2'-Fluoroacetophenone With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 0.25h;
Stage #2: chloro-trimethyl-silane In tetrahydrofuran for 2h;
Example56 N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methyl-1H-indazol-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (56) 3-methyl-1H-indazole (56a) To a solution of 1- (2-fluorophenyl) ethanone (20 g, 0.14 mol) in ethane-1, 2-diol (70 ml) was added hydrazine hydrate (4.7 ml, 0.15 mol) at r.t while maintaining this temperature for 2 h , and then was heated to 150 for overnight. The mixture was cooled to r.t, quenched with water (200 ml) and extrated with DCM (200 mL) . The organic layers were combined and washed with water (200 mL × 2) and brine (200 mL) , dried over anhydrous sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:20) to give 3-methyl-1H-indazole (56a) as brown solid (7 g, 37) . MS-ESI (m/z) : 133 [M + 1]+
With hydrazine; In ethylene glycol; at 20 - 165℃; for 42h;
EXAMPLE 32; 3-Methylindazole (32-2); A stirred solution of 2.0 g (14.48 mmol) of 2-fluoroacetophenone (32-1) in 10 mL of ethylene glycol under nitrogen was treated with 473 uL (15.06 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165 C. for 40 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and conc. in vacuo. Purification of the crude material by recrystallization from hexanes/CHCl3 gave the desired product 32-2 as a tan solid. 1H NMR (DMSO-d6): delta 7.70 (d, 1H), 7.42 (m, 2H), 7.17 (dd, 1H), 2.60 (s, 3H).
With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; In tetrahydrofuran; at 20℃; for 2h;
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, 98% yield) that was used without further purification: 1H NMR (400 MHz, CDCl3) delta 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 tert-butyl alcohol; at 45℃; for 1h;
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; 92%) as a colorless liquid. 1H-NMR (400 MHz, CDCl3) delta: 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).
77%
With acetophenone reductase from Geotrichum candidum NBRC 4597; NAD; isopropyl alcohol; In aq. buffer; at 30℃; for 14h;pH 7.2;Enzymatic reaction;Kinetics;
General procedure: Reductions were performed in 50 mL of 100 mM HEPES-NaOH buffer (pH 7.2) consisting of1.4 mM NAD+, 0.23-0.39 mmol of 2a-13a, cofactor regeneration reagent written in Table S1, and purified GcAPRD with the amount written in Table S1. Reactions were done for 14 h at 30C with a rotational speed of 130 rpm. The product was extracted with diethyl ether, dried over MgSO4, and evaporated under reduced pressure. Silica gel column chromatography (hexane:ethyl acetate 4:1) were performed to give the corresponding chiral alcohols 2b-13b.
74%
With D-glucose; at 35℃; for 36h;pH 7.5;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 4% 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.
With hydrogen; lithium hydroxide; (8R,9R)-9-amino(9-deoxy)epicinchonin; In methanol; at 25℃; under 45004.5 Torr; for 3h;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.
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; C49H67FeN2O2PS; hydrogen; lithium tert-butoxide; In isopropyl alcohol; at 20℃; under 15201.0 Torr; for 12h;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 muL (0.001 mol%) 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 %).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 99%.
With potassium carbonate In N,N-dimethyl-formamide Heating;
61%
With potassium carbonate In N,N-dimethyl-formamide at 120 - 150℃;
General synthesis of intermediates M1, M3, M14 and M16
General procedure: 5-Fluoro-2,3-dihydro-1H-inden-1-one, 1-(4-fluorophenyl)ethan-1-one, 7-fluoro-2,3-dihydro-1H-inden-1-one, or 1-(2-fluorophenyl)ethan-1-one was treated as starting material. The starting material (5 mmol), tert-butyl piperazine-1-carboxylate (15 mmol) and K2CO3 (4.5 mmol) were added to DMF (15 mL), and the reaction mixture was heated to 120-150 °C overnight. After cooling to room temperature, the mixture was extracted with EtOAc (100 mL 3) and washed with water (100 mL 3) to remove the DMF. The organic layer was washed with brine, dried over Na2SO4 and evaporated at reduced pressure. The residue was purified by column chromatography, eluted with a mixture of ethyl acetate and petroleum to afford the intermediates M1, M3, M14 and M16.
4.1.2. General procedure for synthesis of 2-amino-4-(substituted phenyl)-1,3-thiazoles (3a-k)
General procedure: A mixture of thiourea (50 mmol), the corresponding acetophenone (25 mmol) and iodine (25 mmol) is stirred at 100 °C for 8 h.Then the reaction mixture is cooled, extracted with diethyl ether toremove excess of acetophenone, and then washed with aqueous sodium thiosulfate to remove excess iodine and later with cold water. The crude product is dissolved in hot water, filtered to remove sulphone, and the filtrate is basified with aqueous Na2CO3to yield the corresponding 2-amino-4-(substituted-phenyl)-1,3-thiazole. The crude product is purified by recrystallization from alcohol.
52%
With iodine; dimethyl sulfoxide at 80℃; for 12h; Schlenk technique;
I2-catalyzed coupling reaction of ketones and thiourea: general procedure
General procedure: A Schlenk tube (20 mL) was charged with ketone 1 (4 mmol),thiourea (2) (2 mmol), I2 (0.4 mmol) and DMSO (4 mL). Thetube was sealed with a rubber septum and the reaction mixturewas stirred at 80 °C for 12 h. After completion of thereaction, the mixture was cooled to room temperature. Ethylacetate (20 mL) and a saturated solution of NaHCO3 (20 mL)were added and the organic layer was separated. The aqueousphase was extracted with ethyl acetate (3 × 10 mL). Thecombined organic layer was washed with a saturated solutionof NaCl (20 mL) and then dried over anhydrous Na2SO4.After filtration, the solvent was removed under reduced pressure.The crude mixture was purified by chromatography onsilica gel to yield the desired products.
51.7%
With iodine In dimethyl sulfoxide at 80℃; for 12h;
3 Example 3
Add 0.553 g (4 mmol) of o-fluoroacetophenone to the reaction tube containing the stirring magnet.Thiourea 0.152g (2mmol),0.051 g (0.4 mmol) of iodine and 4 ml of DMSO.Place the reaction tube in an oil bath at 80 ° C.The reaction was stirred for 12 h.After the reaction, the reaction solution was treated with a saturated NaHCO3 solution (20 mL).An additional 30 ml of water was added and extracted three times with 20 mL of ethyl acetate.The extract was washed with water and saturated NaCl solution, and dried over anhydrous Na2SO4.The solvent was removed under reduced pressure on a rotary evaporator, and the residue was separated by silica gel column chromatography.Eluted with petroleum ether / ethyl acetate (5: 1 by volume),2-amino-4-o-fluorophenylthiazole (0.201 g) was obtained in a yield of 51.7%.
12%
With iodine at 100℃;
With iodine at 100℃; for 8h;
General procedure for synthesis of 2-amino-4-(substituted-phenyl)-1,3-thiazoles
General procedure: A mixture of thiourea (7, 50 mmol), the corresponding acetophenone (6, 25 mmol) and iodine(25 mmol) is stirred at 100 °C for 8 h. Then the reaction mixture is cooled, extracted with diethylether to remove excess of acetophenone, and then washed with aqueous sodium thiosulfate to remove excess iodine and later with cold water. The crude product is dissolved in hot water, filtered to remove sulphone, and the filtrate is basified with aqueous Na2CO3 to yield the corresponding 2-amino-4-(substituted-phenyl)-1,3-thiazole (5). The crude product is purified by recrystallization from alcohol. The synthesis and spectral data of compounds 5a-i have been reported by us earlier [2]. The data in respect of compounds 5j-l is described here.
Stage #1: 2'-Fluoroacetophenone; thiourea With bromine In ethanol for 2h;
Stage #2: In ethanol for 12h; Reflux;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃;
94.7%
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 25℃; for 4h;
19 Example 19: Preparation of 2-fluoroacetophenone oxime
Add 2-fluoroacetophenone (10.0g, 72.4mmol) to a 250mL reaction flask. hydroxylamine hydrochloride (7.5g, 108.6mmol), ethanol 80mL,then a 20% aqueous sodium hydroxide solution (21.7 g, 108.6 mmol) was added dropwise,The reaction was carried out at 25 ° C for 4 hours. after the reaction, the solvent was distilled off under reduced pressure, washed with water, filtered with suction, and dried.10.5 g of 2-fluoroacetophenone oxime was obtained as a white solid with a yield of 94.7%.
72%
With pyridine; hydroxylamine hydrochloride In methanol at 25 - 50℃; for 2h;
1.1 Step 1: 1-(2-Fluorophenyl)ethanone oxime
1-(2-fluorophenyl)ethenone (10 g, 1.0 eq) was taken in methanol (300 ml) and hydroxyl amine hydrochloride (7.54 g, 1.8 eq) was added. Pyridine (33.45 g, 2 eq) was added drop wise at 25 °C. Reaction mixture was stirred at 50 °C for 2 hr. Reaction was monitored using LCMS & TLC. Methanol was evaporated under vacuum. Crude mass was diluted with water (200 ml) and it was extracted with ethyl acetate (3 x 100 ml). Combined organic layer was again washed with water and brine. Organic layer was dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by flash column chromatography. Pure compound was eluted with 0% to 20% ethyl acetate (EtOAc) in heptane. Evaporation of solvent afforded 8 g title compound as white solid (Yield 72%).1H NMR 300 MHz, DMSO-d6: δ 11.4 (s ,1 H), 7.46- 7.41 (m, 2 H), 7.27-7.23 (m, 2H), 2.14 (s, 3H).
72%
With pyridine; hydroxylamine hydrochloride In methanol at 50℃; for 2h;
1.1 Step 1: 1-(2-Fluorophenyl)ethanone oxime
1-(2-fluorophenyl)ethenone (10 g, 1.0 eq) was taken in methanol (300 ml) and hydroxyl amine hydrochloride (7.54 g, 1.8 eq) was added. Pyridine (33.45 g, 2 eq) was added drop wise at 25 °C. Reaction mixture was stirred at 50 °C for 2 hr. Reaction was monitored using LCMS & TLC. Methanol was evaporated under vacuum. Crude mass was diluted with water (200 ml) and it was extracted with ethyl acetate (3 x 100 ml). Combined organic layer was again washed with water and brine. Organic layer was dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by flash column chromatography. Pure compound was eluted with 0% to 20% ethyl acetate (EtOAc) in heptane. Evaporation of solvent afforded 8 g title compound as white solid (Yield 72%). 1H NMR 300 MHz, DMSO-d6: d 11.4 (s ,1 H), 7.46- 7.41 (m, 2 H), 7.27-7.23 (m, 2H), 2.14 (s, 3H).
72%
With pyridine; hydroxylamine hydrochloride In methanol at 50℃; for 2h;
1.1 Step 1: 1-(2-Fluorophenyl)ethanone oxime
-(2-fluorophenyl)ethenone (10 g, 1.0 eq) was taken in methanol (300 ml) and hydroxyl amine hydrochloride (7.54 g, 1.8 eq) was added. Pyridine (33.45 g, 2 eq) was added drop wise at 25 °C. Reaction mixture was stirred at 50 °C for 2 hr. Reaction was monitored using LCMS & TLC. Methanol was evaporated under vacuum. Crude mass was diluted with water (200 ml) and it was extracted with ethyl acetate (3 x 100 ml). Combined organic layer was again washed with water and brine. Organic layer was dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by flash column chromatography. Pure compound was eluted with 0% to 20% ethyl acetate (EtOAc) in heptane. Evaporation of solvent afforded 8 g title compound as white solid (Yield 72%). 1H NMR 300 MHz, DMSO-d6: d 11.4 (s ,1 H), 7.46- 7.41 (m, 2 H), 7.27-7.23 (m, 2H), 2.14 (s, 3H).
72%
With pyridine; hydroxylamine hydrochloride In methanol at 25 - 50℃; for 2h;
1.1 Step 1: 1-(2-Fluorophenyl)ethanone oxime
1-(2-fluorophenyl)ethenone (10 g, 1.0 eq) was taken in methanol (300 ml) and hydroxyl amine hydrochloride (7.54 g, 1.8 eq) was added. Pyridine (33.45 g, 2 eq) was added drop wise at 25 °C. Reaction mixture was stirred at 50 °C for 2 hr. Reaction was monitored using LCMS & TLC. Methanol was evaporated under vacuum. Crude mass was diluted with water (200 ml) and it was extracted with ethyl acetate (3 x 100 ml). Combined organic layer was again washed with water and brine. Organic layer was dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by flash column chromatography. Pure compound was eluted with 0% to 20% ethyl acetate (EtOAc) in heptane. Evaporation of solvent afforded 8 g title compound as white solid (Yield 72%).1H NMR 300 MHz, DMSO-d6: δ 11.4 (s ,1 H), 7.46- 7.41 (m, 2 H), 7.27-7.23 (m, 2H), 2.14 (s, 3H).
With hydroxylamine hydrochloride; sodium acetate In ethanol; water Heating;
With hydroxylamine hydrochloride; triethylamine In ethanol at 120℃; for 0.333333h; Microwave irradiation;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 20h; Reflux;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 20℃; for 20h; Reflux;
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 0 - 20℃;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water for 1h; Reflux;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 100℃;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 100℃;
With hydroxylamine hydrochloride; sodium hydroxide In ethanol at 20℃; Cooling with ice;
2
In 50 ml three-mouth flask add o-fluoroacetophenone 0.552 g, hydroxylamine hydrochloride 0.347 g, 15 ml ethanol as a solvent, under the condition of ice bath stirring, dropping 0.5 mol/L sodium hydroxide solution to the reaction solution to pH 9 after, stirring the reaction overnight at room temperature. By extraction, water washing, and drying to obtain o-fluoroacetophenone oxime.
With hydroxylamine hydrochloride; sodium acetate In ethanol; water Reflux; Inert atmosphere; Schlenk technique;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃; for 2h;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃; for 2h;
With hydroxylamine hydrochloride; sodium acetate In methanol at 60℃; for 2h;
With hydroxylamine hydrochloride; sodium acetate In methanol at 80℃; for 3h; Inert atmosphere;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃; for 2h;
With hydroxylamine hydrochloride; sodium acetate In ethanol at 95℃; Inert atmosphere; Glovebox;
With ammonium acetate; sodium cyanoborohydride; In methanol; at 20℃; for 12h;
1-(2-methylphenyl)ethanone (0.50 mL, 3.73 mmol) and ammonium acetate (2.88 g, 37.3 mmol) were dissolved in methanol (20 mL). To the stirred solution was added slowly a solution of NaCNBH3 (0.79 g, 11.2 mmol) dissolved in methanol (15 mL) through a dropping funnel. The whole mixture was stirred at room temperature. After stirring for 12 h, solvent was removed by using rotary evaporator. The residue was dissolved in ethyl acetate and then the solution was treated with 6 N HCl solution to makethe solution to be acidic (pH = 12-13). The two layers were separated and then 6 N NaOH solutionwas added to the separated aqueous solution to make the solution to be basic (pH = 11-12). The basic aqueous solution was extracted with ethyl acetate twice and then combined organic solution was dried over anhydrous Na2SO4. Solvent was removed by using rotary evaporator to afford an intermediateamine B, 1-(2-methylphenyl)ethylamine (Ar = 2-methylphenyl, R1 = CH3, compound B in Figure 5) (0.21 g, 46% yield).
194
Production Example 194 3-(2-Fluorophenyl)-1H-pyrazole 4.17 g of the title compound (yellow oil) was obtained from 3.25 g of 2'-fluoroacetophenone by the same method as in Production Example 3.1H-NMR (CDCl3) δ: 6.74(dd, J=2.0, 2.0Hz, 1H), 7.17(ddd, J=11.6, 8.0, 1.2Hz, 1H), 7.21(ddd, J=7.6, 7.6, 1.2Hz, 1H), 7.28-7.34(m, 1H), 7.66 (d, J=2.0Hz, 1H), 7.82(ddd, J=7.6, 7.6, 1.6Hz, 1H)
(E)-1-(2-fluorophenyl)-3-phenyl-2-propen-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: 2'-Fluoroacetophenone With sodium hydroxide In ethanol; water at 0℃; for 0.0833333h;
Stage #2: benzaldehyde In ethanol; water for 0.0833333h;
83%
Stage #1: 2'-Fluoroacetophenone With sodium hydroxide In ethanol; water at 20℃; for 0.166667h;
Stage #2: benzaldehyde In ethanol; water at 20℃;
8.2 General procedure for the preparation of intermediates 39a-39g, 39i-39k
General procedure: The substituted aryl methyl ketone (1.0 mmol), an aqueous solution of 10% sodium hydroxide (2.5 mmol) and ethanol (5 mL) were charged into a 50 mL flask, and the mixture was stirred at room temperature for 10 min, followed by addition of substituted aryl aldehyde (1.05 mmol). The reaction mixture was then stirred at room temperature and monitored using TLC with 5% ethyl acetate/petroleum ether as the solvent system until all reactants disappeared. The mixture was extracted with ethyl acetate three times, and the combined organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was recrystallized from anhydrous ethanol, except for 39i and 39a, which were directly used in the next step without purification.
With triethylamine In neat (no solvent) at 20 - 40℃; for 2h; Green chemistry;
General Procedure for the Synthesis of Compounds 3a-3q
General procedure: A mixture of substituted ketones 1 (11 mmol), phosphite 2 (10 mmol), and triethylamine(10 mmol) were stirred from ambient temperature to 40 °C for 2 h. The crude product was collected by filtration and recrystallized from ethyl acetate to afford pureα-hydroxyphosphonates 3.
83%
With titanium(IV) isopropylate at 60℃; for 0.5h; Neat (no solvent); Inert atmosphere;
56%
With triethylamine In neat (no solvent) at 25℃; for 3h;
Stage #1: 2'-Fluoroacetophenone; carbonic acid dimethyl ester With sodium hydride In toluene; mineral oil Reflux;
Stage #2: With acetic acid In water; toluene; mineral oil
1.1
Step 1 : methyl 3 -(2 -fluorophenyl)- 3 -oxopropanoate2-fluoroacetophenone was added dropwise at reflux to a stirred suspension of NaH (60% suspension in mineral oil, 2.5 eq.) and dimethyl carbonate (2.5 eq.) in dry Toluene (1.3 M). The resulting mixture was refluxed for further 30 min then allowed to cool down to RT. A solution of HOAc in H2O (1 :4 v/v) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted twice with Et2O. The combined organic layers were washed with sat. aq. K2CO3, dried and evaporated. The residue was purified by silica gel chromatography eluting with PE/EtOAc 80:20 to afford the title compound (55%). 1H NMR (300 MHz, CDCI3, 300 K, ketone/enol in 4:1 ratio; only the major species is described) δ 3.75, (s, 3H), 4.00(s, IH), 4.01 (s, IH), 7.08-7.28 (m, 2H), 7.40-7.60 (m, IH), 7.87-7.97 (m, IH).
With potassium acetate In ethanol at 25℃; for 16h;
75
Example 75 2-(2-Fluoro-phenyl)-5-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-1H-indole N-(4-Bromo-phenyl)-N'-[1-(2-fluoro-phenyl)-eth-(E)-ylidene]-hydrazine: To a solution of 1-(2-fluoro-phenyl)-ethanone (3.1 g, 22 mmol) and (4-bromophenyl)-hydrazine (5.0 g, 22 mmol) in EtOH was added KOAc (2.2 g, 22 mmol) and stirred at 25° C. for 16 hrs. The reaction mixture was extracted with hexanes (4*50 mL) and the organic phase was washed with brine, dried over Na2SO4 and concentrated to give N-(4-bromo-phenyl)-N'-[1-(2-fluoro-phenyl)-eth-(E)-ylidene]-hydrazine (5.5 g, 80%).
1-[3-(2-trimethylsilanylethyl)biphenyl-2-yl]ethanone[ No CAS ]
1-[1,1';3',1"]terphenyl-2'-yl-ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 79%
2: 8%
With carbonyl bis(hydrido)tris(triphenylphosphine)ruthenium(II) In toluene at 130℃; for 24h;
General procedure for ruthenium-catalyzed C-F arylation:
General procedure: To a 20-mL J-Young tube was added ruthenium complex 3 (0.2 mmol) and arylboronate 2 (2 mmol). n-Eicosane (0.4 mmol) was also added when the yield was determined by GC analysis. The J-Young tube was brought into a glove box filled with nitrogen, and cesium floride, trimethylvinylsilane, toluene, and fluorinated aromatic ketone 1 was introduced into the tube. The J-Young tube was then taken out of the glove box and heated at 130 °C in an oil bath for 24 h. GC analysis was performed after the reaction mixture was cooled to rt. To isolate the arylation product, volatile materials were removed from the mixture by rotary evaporator, and the resulting material was passed through a short column of basic alumina using dichloromethane to remove unreacted arylboronate 2. The resulting material was concentrated again by rotary evaporator and then passed through a silica gel column using hexane with ethyl acetate as eluents.
With titanium(IV) tetraethanolate In toluene at 80℃; for 4h; Inert atmosphere;
77%
With titanium(IV) tetraethanolate In toluene at 80℃; for 7h;
74%
With titanium(IV) tetraethanolate In tetrahydrofuran at 50℃; for 15h; Inert atmosphere;
A2.1
Synthesis of the Intermediate Sulfinyl Imine A2.1 (R7H)A solution of 1-(2-fluorophenyl)ethanone (20 g, 145 mmol) in tetrahydrofuran (250 ml) was treated under an inert atmosphere at room temperature with (R)-(+)-tert-butylsulfinamide (21.1 g, 174 mmol) followed by the addition of titanium(IV)ethoxide (66.1 g, 290 mmol). The solution was stirred at 50° C. for 15 hours. For the workup, the dark brown solution was cooled to room temperature, then poured into a saturated solution of ammonium chloride. After addition of ethyl acetate, the mixture was stirred vigorously for 15 minutes. After separation of the layers, the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulphate and evaporated at reduced pressure. Purification of the crude product by chromatography on silica gel using a 4:1-mixture of cyclohexane and ethyl acetate yielded the (R)-E-N(1-(2-fluorophenyl)ethylidene)-2-methylpropane-sulfinamide (25.9 g, 74% of theory) as a brown oil. MS (ISP): m/z=242.3 [M+H]+.
74%
With titanium(IV) tetraethanolate In tetrahydrofuran at 50℃; for 15h; Inert atmosphere;
Synthesis of the intermediate sulfinyl imine A2.1 (R7 = H)A solution of l-(2-fluorophenyl)ethanone (20 g, 145 mmol) in tetrahydrofuran (250 ml) was treated under an inert atmosphere at room temperature with (R)-(+)-tert-butylsulfinamide (21.1 g, 174 mmol) followed by the addition of titanium(IV)ethoxide (66.1 g, 290 mmol). The solution was stirred at 50 °C for 15 hours. For the workup, the dark brown solution was cooled to room temperature, then poured into a saturated solution of ammonium chloride. After addition of ethyl acetate, the mixture was stirred vigorously for 15 minutes. After separation of the layers, the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulphate and evaporated at reduced pressure. Purification of the crude product by chromatography on silica gel using a 4: l-mixture of cyclohexane and ethyl acetate yielded the (R)-E-N(l-(2-fluorophenyl)ethylidene)-2- methylpropane-sulfinamide (25.9 g, 74% of theory) as a brown oil. MS (ISP): m/z = 242.3 [M+H]+.
With titanium(IV) tetraethanolate In tetrahydrofuran for 5h; Reflux;
To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone Al (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 °C, treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cylohexane/ethyl acetate to give the pure sulfinyl imine A2.Intermediate A2AStarting from l-(2-fluorophenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [l-(2-fluorophenyl)-(E)-ethylidene] -amide was obtained as pale brown oil. MS (ISP): m/z = 242.3 [M+H]+.
With titanium(IV) tetraethanolate In tetrahydrofuran; ethyl acetate for 5h; Reflux;
Synthesis of the Intermediate Sulfinyl Imines A2 General Procedure To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone A1 (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22° C., treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cylohexane/ethyl acetate to give the pure sulfinyl imine A2. Intermediate A2A Starting from 1-(2-fluorophenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluorophenyl)-(E)-ethylidene]-amide was obtained as pale brown oil. MS (ISP): m/z=242.3 [M+H]-.
With titanium(IV) tetraethanolate In tetrahydrofuran for 5h; Reflux;
Synthesis of the intermediate sulfinyl imines B2 General Procedure To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone B1 (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22° C., treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuum. The residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give the pure sulfinyl imine B2. Intermediate B2A Starting from 1-(2-fluoro-phenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-phenyl)-eth-(E)-ylidene]-amide was obtained as pale brown oil. MS (ISP): m/z=242.2 [M+H]+.
With titanium(IV) tetraethanolate In tetrahydrofuran for 5h; Reflux;
Synthesis of the intermediate sulfinyl imines A2General ProcedureTo a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone A1 (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22° C., treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cylohexane/ethyl acetate to give the pure sulfinyl imine A2.Intermediate A2A Starting from 1-(2-fluorophenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluorophenyl)-(E)-ethylidene]-amide was obtained as pale brown oil. MS (ISP): m/z=242.3 [M+H]+.
With titanium(IV) tetraethanolate In tetrahydrofuran for 5h; Reflux;
Synthesis of the intermediate sulfinyl imines A2 General procedureTo a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone Al (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 °C, treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cylohexane/ethyl acetate to give the pure sulfinyl imine A2.Intermediate A2AStarting from l-(2-fluorophenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [l-(2-fluorophenyl)-(/^-ethylidene] -amide was obtained as pale brown oil. MS (ISP): m/z = 242.3 [M+H]+.
With titanium(IV) tetraethanolate In tetrahydrofuran for 5h; Reflux;
To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone Bl (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 °C, treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuum. The residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give the pure sulfinyl imine B2.Intermediate B2AStarting from l-(2-fluoro-phenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [l-(2-fluoro-phenyl)-eth-(E)-ylidene]-amide was obtained as pale brown oil. MS (ISP): m/z = 242.2 [M+H]+.
With titanium(IV) tetraethanolate In tetrahydrofuran for 5h; Reflux;
Synthesis of the Intermediate Sulfinyl Imines A2
To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in THF (350 ml) was added subsequently the ketone A1 (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22° C., treated with brine (400 ml), the suspension was stirred for 10 min and filtered over dicalite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica using cylohexane/ethyl acetate to give the pure sulfinyl imine A2. Starting from 1-(2-fluorophenyl)-ethanone, the product (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluorophenyl)-(E)-ethylidene]-amide was obtained as pale brown oil. MS (ISP): m/z=242.3 [M+H] +.
With titanium(IV) tetraethanolate In tetrahydrofuran at 50 - 70℃; Inert atmosphere;
With copper(II) sulfate; acetyl chloride In dichloromethane at 20℃; for 3h;
Typical experimental procedure for the one-pot synthesis of bromo alkyne (4d)
General procedure: A round bottom flask is charged with propargyl derivative of 2-hydroxy benzaldehyde (320 mg, 2 mmol), 4-chloro acetophenone (309.18 mg, 2 mmol), acetyl chloride (2 mL), 3-bromopropionitrile (1 mL) and copper sulfate (100 mg) and kept under stirring for 3h at room temperature. The progress of the reaction was monitored by TLC analysis at regular intervals. After 3h, the mixture was quenched with cold water. The solid residue separated was collected and purified by passing it through a silica gel column. Elution of the column with petroleum ether (60-80 °C) / ethyl acetate (9: 1 v/v) afforded 4d (664.13 mg, 74%).
With hydrogenchloride; sodium dichromate In water monomer at 95℃; for 6h;
2 Example 2 This example provides the synthesis of 2-(2-fluorobenzene)-2-glyoxylic acid
The specific synthesis operation method is the same as that in Example 1, specifically: 1-(2-fluorobenzene)e-1-one (1 mmol) and 50 mL of trifluorotoluene are added to the flask,Stir to dissolve 1-(2-fluorobenzene) ethyl-1-one in trifluorotoluene, then add 2N HCl (0.5mL),Then, sodium dichromate (0.30g) was added under acidic conditions, heated to 95°C and reacted under reflux at this temperature for 6h.After the reaction, the trifluorotoluene in the system was removed, and sodium hydroxide was added to the aqueous phase to adjust the aqueous phase to pH 9 to remove impurities,Then add hydrochloric acid to the water phase to adjust the pH of the water phase to 3 and extract,Recrystallization of petroleum ether gave the product 2-(2-fluorobenzene)-2-glyoxylic acid in 88% yield.
65%
With pyridine; selenium(IV) dioxide at 90 - 110℃; for 5h;
2. Synthesis of α-Aryl Ketone Acids 1
General procedure: The substituted phenylglyoxylic acid were prepared from oxidation of corresponding acetophenone with SeO2: acetophenone (5 mmol), SeO2 (6 mmol), 20 mL of pyridine were added in a 50 mL round-bottom flask. The reaction was carried out at 110 °C for 1 hour, then temperature was lowered to 90 °C and the reaction was continued stirring at this temperature for 4 hours. The desired products were isolated by silica-gel columnchromatography in excellent yield (40%-79%).
50%
With pyridine; selenium(IV) dioxide at 90 - 110℃; for 4h; Inert atmosphere;
44%
With pyridine; selenium(IV) dioxide at 110℃; for 12h; Inert atmosphere;
With selenium(IV) dioxide Inert atmosphere;
With pyridine; selenium(IV) dioxide
With pyridine; selenium(IV) dioxide at 100℃; for 15h; Inert atmosphere;
With pyridine; selenium(IV) dioxide at 90 - 110℃; for 5h;
With pyridine; selenium(IV) dioxide at 90 - 110℃; for 5h;
With selenium(IV) dioxide
83 %Chromat.
With nitrosyl-sulphuric acid; sulfuric acid; water monomer at 50℃; for 9h; Inert atmosphere;
11 Example 11 (One Example of Embodiment 1 of Step B)
Under nitrogen atmosphere, at room temperature, to nitrosyl sulfuric acid (35% by weight content, moisture content 14.7%, sulfuric acid solution) 153.0 g was added 2′-fluoroacetophenone 15.0 g at 50° C. over 8 hours, and the mixture was stirred for additional 1 hour. To the resulting mixture was added dropwise water 45.9 g, followed by addition of sodium chloride 7.7 g, and the mixture was extracted with toluene 120.2 g at 80° C. The resulting organic layers were analyzed with high-performance liquid chromatography to confirm that a toluene solution 124.0 g containing the desired product 2-fluorobenzoyl formic acid 14.7 g was obtained (the desired product yield: 83%)
12 g
Stage #1: 2'-Fluoroacetophenone With pyridine; selenium(IV) dioxide at 100℃; for 2h; Inert atmosphere;
Stage #2: With hydrogenchloride; water monomer
1
Compound 1-1 (10 g, 72.4 mmol), pyridine (200 mL) and selenium dioxide (16 g, 144.8 mmol) were added to a three-necked flask.React at 100°C for 2 hours under nitrogen protection.After the completion of the reaction, suction filtration, the filtrate was spin-dried, then 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate.The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered with suction, and spin-dried to obtain an off-white solid 1-2 (12g).
With pyridine; selenium(IV) dioxide at 90 - 110℃; for 5h; Inert atmosphere;
With pyridine; selenium(IV) dioxide at 110℃; for 16h;
With pyridine; selenium(IV) dioxide at 90 - 110℃; for 5h; Inert atmosphere;
With selenium(IV) dioxide In pyridine at 90 - 110℃; for 5h;
With pyridine; selenium(IV) dioxide at 110℃; for 16h;
2.1.2 Oxidation of the corresponding aryl-ketones:
General procedure: In a dry flask, flushed with nitrogen, aryl-ketone (1 equiv, 8 mmol) and selenium dioxide (2 equiv, 1.78 g, 16 mmol) were added followed by anhydrous pyridine (4 mL). The reaction mixture was then stirred at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution containing precipitated selenium was filtered using a Buchner funnel, and the residue was washed with EtOAc (60 mL). The filtrate was treated with 1M aqueous NaOH (30 mL) and the aqueous layer was separated. This procedure was repeated 3 times and the aqueous layers were combined, then acidified with 1M aqueous HCl (pH=1.5). Thus, the mixture was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to provide the corresponding α-ketoacid. Expected glyoxylic acid was isolated with quantitative yield (>99%) and was pure enough (>98%) to be used without further purification. Compounds 1h was obtained by this oxidation.
With ethanol; sodium In N,N-dimethyl-formamide at 0 - 45℃; for 1.75h;
95 Preparation 28 Ethyl 2,4-dioxo-4-phenylbutanoate
General procedure: In a three-necked flask acetophenone (5 g, 41.61 mmol) and diethyl oxalate (6.76 mL, 50 mmol) were dissolved in anhydrous DMF (65 mL) at 0°C and NaH 60% (2 g, 83.25 mmol) was slowly added, mixture was stirred at 0°C for 15 min and 30 min more at r.t before heating at 45°C for 1 h. Reaction was poured onto water-acetic acid and product extracted with ethyl acetate. Organic layers were combined, washed with water and brine, dried over magnesium sulphate, filtered and concentrated to yield the title compound as an oil (62% yield). LRMS: m/z 221 (M+1)+ Retention time: 6.30 min (Method B); Obtained (87%) from 1-(2-fluorophenyl)ethanone and diethyl oxalate following the procedure described in Preparation 28, preparing the NaH in situ with Na in ethanol. LRMS: m/z 239 (M+1)+ Retention time: 6.28 min (Method B)
Stage #1: 2'-Fluoroacetophenone With lithium hexamethyldisilazane at 0℃; for 0.5h;
Stage #2: oxalic acid diethyl ester at 20℃;
Ethyl 2,4-dioxo-4-phenylbutanoate (28b):
General procedure: To a stirred solution of acetophenone (27b) (2.0 g, 16.5 mmol)inMTBE (30 mL) was added lithium hexamethyldisilazide (1.3M, 12.7 mL, 16.5 mmol) dropwise at 0 C;After addition, the reaction mixture was stirred at 0 °C for 0.5 h and diethyl oxalate (3.0 g, 20.8 mmol) wasadded dropwise. Then, the mixture was stirred at room temperature overnight. TLC analysis showedreaction was complete and the reaction mixture was extracted with H2O (20 mL). The aqueous layerwas separated, acidified by hydrochloric acid (1M) to pH6 and extracted by ethyl acetate (10 mL 2).The combined organic layer was concentrated in vacuum to give 28b as yellow oil, which was used fornext step without further purification (3.4 g, 92.7% yield).
With sodium In ethanol at 20 - 80℃; for 16.5h; Cooling with ice;
With sodium In ethanol at 0 - 20℃; for 15h;
With sodium ethanolate In ethanol at 0 - 20℃; for 15h;
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 20℃; for 24h; Cooling with ice;
3. General Procedure for Synthesis of ketoximes (1a-z)
General procedure: To a 50 mL round bottom flask, ketone (10.0 mmol) and hydroxylamine hydrochloride (15.0mmol) were added in 25 mL ethanol/ water (4:1). A quantity of NaOH solution was added topH=9 in ice bath, stirred at room temperature for 24 hours. The mixture was then extracted withethyl acetate (3 × 20 mL). The combined organic extracts were dried over Mg2SO4andconcentrated under reduced pressure. The ketoxime products were obtained by recrystallization ofS4ethyl acetate or petroleum ether.
92%
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 0 - 20℃; for 24h;
General Procedure for Synthesis of ketoximes (1a-1zd)
General procedure: To a 50 mL round bottom flask, ketone (10.0 mmol) and hydroxylamine hydrochloride (15.0mmol) were added in 25 mL ethanol/ water (4:1). A quantity of NaOH solution was added top H=9 in ice bath, stirred at room temperature for 24 hours. The mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over Mg2SO4 and concentrated under reduced pressure. The ketoxime products were obtained by recrystallization of ethyl acetate or petroleum ether.
72%
With pyridine; hydroxylamine hydrochloride In methanol at 25 - 50℃; for 2h;
1.1 Step 1: 1-(2-Fluorophenyl)ethanone oxime
1-(2-fluorophenyl)ethenone (10 g, 1.0 eq) was taken in methanol (300 ml) and hydroxyl amine hydrochloride (7.54 g, 1.8 eq) was added. Pyridine (33.45 g, 2 eq) was added drop wise at 25 °C. Reaction mixture was stirred at 50 °C for 2 hr. Reaction was monitored using LCMS & TLC. Methanol was evaporated under vacuum. Crude mass was diluted with water (200 ml) and it was extracted with ethyl acetate (3 x 100 ml). Combined organic layer was again washed with water and brine. Organic layer was dried over sodium sulphate and concentrated under vacuum. Crude compound was purified by flash column chromatography. Pure compound was eluted with 0% to 20% ethyl acetate (EtOAc) in heptane. Evaporation of solvent afforded 8 g title compound as white solid (Yield 72%). 1H NMR 300 MHz, DMSO-d6: d 11.4 (s ,1 H), 7.46- 7.41 (m, 2 H), 7.27-7.23 (m, 2H), 2.14 (s, 3H).
52%
With hydroxylamine hydrochloride; sodium carbonate In ethanol; water Reflux;
With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 95℃;
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 60% 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.
Sodium hydride (1.74 g, 72.4 mmmol) was taken in dry THF (30 mL) in a 100 mL round bottom flask under N2 and cooled it down to 0 C. To it was added a solution of 1-(2-fluorophenyl)ethan-1-one (5.0 g, 36.2 mmol) in THF (5 mL). The reaction mixture was stirred at rt for 30 min followed by the addition of diethyl carbonate (17.5 mL, 144.8 mmol). The reaction mixture was then stirred at rt for 12 h. Ice-cooled water was added dropwise to quench the reaction. It was extracted with EtOAc (3 * 75 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was triturated with Et2O afford 2i as a brown liquid (4.0 g, 52%). MS (ESI) m/z 211.17 [M+H+].
With ammonium hydroxide In ethanol; water at 60℃; for 5.5h;
A4c A4c: (RS)-5-(2-Fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione
A4c: (RS)-5-(2-Fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione A mixture of freshly distilled 1-(2-fluorophenyl)ethanone (27.6 g, 24.6 ml, 200 mmol, Eq: 1.00), potassium cyanide (15.6 g, 240 mmol, Eq: 1.20), ammonium carbonate (96.1 g, 1.00 mol, Eq:5.00) and ammonium hydroxide (25%) (130 g, 145 ml, 931 mmol, Eq: 4.65) in ethanol (250 ml) and water (200 ml) was stirred at 60 °C for 5.5 h. The ethanol was removed in vacuum, thencooled to 0 °C, cautiously acidified the residue to pH 1, the precipitate was filtered off, washed with dilute HC1 and dried at 50 °C first at rotary evaporator, then at high vacuum to give the 5- (2-fluorophenyl)-5-methylimidazolidine-2,4-dione (40.4 g, 194 mmol, 97.0 % yield) as a white solid. MS (ISN): m/z = 207.5 [M-Hf.
97%
With ammonium hydroxide In ethanol; water at 60℃; for 5.5h;
A4c A4c: (RS)-5-(2-Fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione
A mixture of freshly distilled 1-(2-fluorophenyl)ethanone (27.6 g, 24.6 ml, 200 mmol, Eq: 1.00), potassium cyanide (15.6 g, 240 mmol, Eq: 1.20), ammonium carbonate (96.1 g, 1.00 mol, Eq: 5.00) and ammonium hydroxide (25%) (130 g, 145 ml, 931 mmol, Eq: 4.65) in ethanol (250 ml) and water (200 ml) was stirred at 60 °C for 5.5 h. The ethanol was removed in vacuum, then cooled to 0 °C, cautiously acidified the residue to pH 1, the precipitate was filtered off, washed with dilute HCl and dried at 50 °C first at rotary evaporator, then at high vacuum to give the 5-(2-fluorophenyl)-5-methylimidazolidine-2,4-dione (40.4 g, 194 mmol, 97.0 % yield) as a white solid. MS (ISN): m/z = 207.5 [M-H]-.
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h;
General procedure: 4.2.1 Ethyl 2,5-dimethylpyrazolo[1,5-a]quinoline-3-carboxylate (5a) Condition A: A mixture of 2-fluoroacetophenone 3a (138 mg, 1.00 mmol), 1H-pyrazole 2a (202 mg, 1.20 mmol) and K2CO3 (420 mg, 3.00 mmol) in DMF (5.0 mL) was stirred at 120 C for 16 h. After monitoring the end of the reaction on TLC, the mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water twice, dried over MgSO4 and the solvent was removed in vacuo to afford a residue. The residue was purified by flash column chromatography (hexane:EtOAc=5:1) on silica gel to afford 5a (92.0 mg, 34% yield). Condition B: The reaction was carried out with Cs2CO3 instead of K2CO3 under the same conditions as that of Condition A to afford 5a (210 mg, 78% yield).
4-(2-(2-fluorophenyl)-2-oxoethyl)-3-phenyl-1,2,4-oxadiazol-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium carbonate; In acetone; at 50℃; for 12h;
General procedure: A suspension of phenacyl bromide (597 mg, 3.00 mmol),<strong>[1456-22-0]3-phenyl-1,2,4-oxadiazol-5(4H)-one</strong> (584 mg, 3.60 mmol), K2CO3 (498 mg, 3.60 mmol) inacetone (10 mL) was stirred at 50 C for 12 h. The reaction mixture was quenched with H2Oand extracted with EtOAc three times. The combined organic filtered through Celite, and thefiltrate was concentrated under vacuum. The residue was subjected to columnchromatography on silica gel (hexane/EtOAc = 3/1 to 1/1) to give 730 mg of4-(2-oxo-2-phenylethyl)-<strong>[1456-22-0]3-phenyl-1,2,4-oxadiazol-5(4H)-one</strong> (3a; 2.60 mmol, 87% yield) as apale yellow solid
With bis-[(trifluoroacetoxy)iodo]benzene; potassium hydroxide In water monomer; dimethyl sulfoxide at 85℃; for 10h;
4.2. Synthesis
General procedure: A mixture of 2H-benzothiazole 1 (0.45 mmol), aryl methyl ketone 2 (0.30 mmol), KOH (1 equiv., 0.30 mmol), and PIFA (2 equiv., 0.60 mmol) was heated at 85 °C in DMSO/H2O(v/v, 3/1, 2 mL) for 10 h. After cooling to room temperature, the reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane (3 10 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel,petroleum ether/ethyl acetate, 20:1 to 8:1) to give products 3aa-3bs.
77%
With bis-[(trifluoroacetoxy)iodo]benzene; potassium hydroxide In water monomer; dimethyl sulfoxide at 85℃; for 10h;
4.2. Synthesis
General procedure: A mixture of 2H-benzothiazole 1 (0.45 mmol), aryl methyl ketone 2 (0.30 mmol), KOH (1 equiv., 0.30 mmol), and PIFA (2 equiv., 0.60 mmol) was heated at 85 °C in DMSO/H2O(v/v, 3/1, 2 mL) for 10 h. After cooling to room temperature, the reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane (3 10 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel,petroleum ether/ethyl acetate, 20:1 to 8:1) to give products 3aa-3bs.
76%
With copper (I) iodide; hydrogen tetrafluoroborate In water monomer; dimethyl sulfoxide at 130℃; for 9h; Inert atmosphere; Sealed tube; chemoselective reaction;
General procedure: A solutionof carboxylic acid (1 mmol), ketone (1 mmol, if required) and TFAA (0.85 mL, 6 mmol) in dichloromethane (1 mL) was stirred for 15 min at rt. The required quantity of triflic acid (usually 44 muL, 0.5 mmol) was then added, and the resulting solution was stirred at rt for 1-4 h (24 h for 3v and 3w) under the conditions indicated in Scheme 1, Scheme 2, Table 1, and Table 2 (TLC monitoring). The reaction mixture was evaporated under reduced pressure, and after quenching with water, the residue was redissolved in dichloromethane (10 mL), washed with 5% NaHCO3 (2 × 3 mL), water (2 × 3 mL), and dried over MgSO4. The solvent was removed in vacuum, andthe crude reaction mixture was purified by silica gel chromatography (n-hexane/CH2Cl2/MeOH).
(E)-1-(2-fluorophenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
General procedure: A 50 mL flask was charged with substituted acetophenone (5 mmol) and a solution of sodium hydroxide (10 mmol) in a 4:1 (v/v) mixture of ethanol/H2O (25 mL), and the resulting mixture was stirred at room temperature for 5 min. A substituted benzaldehyde (5 mmol) was then added to the reaction, and the resulting mixture was stirred at room temperature. The reaction was then monitored byTLC using ethyl acetate/petroleum ether (1:4 or 1:2 v/v) as the solvent system. Upon completion of the reaction, the crude product was filtered off and recrystallized from a mixture of dichloromethane and ethanol or purified by column chromatography over silica gel eluting with a mixture of petroleum ether and ethyl acetate to give the pure product.
(E)-ethyl 3-(2-fluorophenyl)but-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 2'-Fluoroacetophenone In tetrahydrofuran; mineral oil at 0 - 20℃; for 18h; Inert atmosphere;
48%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃;
Stage #2: 2'-Fluoroacetophenone In tetrahydrofuran at 0℃;
44%
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: 2'-Fluoroacetophenone In tetrahydrofuran at 20℃;
4.1.1 General procedure for preparation of compounds b1~b9
General procedure: The THF solution with diethyl (ethoxyacetyl)phosphonate (1.1 equiv) was addedto the solution of NaH (1.1 equiv.) in dried THF (20 mL) at 0 oC and the solution wasstirred for 30 min at this temperature. Then compounds a~a17 (1 equiv.) were addedand the mixture was stirred at room temperature until the TLC showed the reactionwas completed. Then the reaction was quenched with H2O, was extracted with aceticether, washed with brine, dried (Na2SO4), filtered, and concentrated to give the crudeproducts. And the crude products were purified with column chromatography to givecompounds b1~b9.
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 2.08333h; Inert atmosphere;
Stage #2: 2'-Fluoroacetophenone In tetrahydrofuran; mineral oil Inert atmosphere; Reflux;
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 3h;
Stage #2: 2'-Fluoroacetophenone In tetrahydrofuran; mineral oil at 20℃;
Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h;
Stage #2: 2'-Fluoroacetophenone In tetrahydrofuran; mineral oil at 0 - 25℃;
With titanium(IV) tetraethanolate In tetrahydrofuran at 80℃; for 18h;
1NTERMEDIATE: (R)-N-[ 1 -(2-fluorophenyl)ethylidene]-2-methyl-propane-2-sulfinamide
To a solution of 1 -(2-fluorophenyl)ethanone (100 g, 723.9 mmol) and (R)-2-methylpropane- 2-sulfinamide (105.28 g, 868.68 mmol) in THF (2.00 L) was added tetraethoxytitanium (330.26 g, 1.45 mol).The solution was warmed to 80°C and stirred for 18 hours. The reaction was quenched by water (500 mL), then extracted with ethyl acetate (500 mL, 4 times). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100- 200 mesh silica gel, petroleum ether/ethyl acetate=10/l, 5/1) to give (R)-N-[l -(2- fluorophenyl)ethylidene]-2-methyl-propane-2-sulfinamide (150 g, 86% yield).
77.3%
With titanium(IV) tetraethanolate In tetrahydrofuran at 85℃; for 14h;
INTERMEDIATE: (R)-N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
To a solution of 1 -(2-fluorophenyl)ethanone (25.0 g, 181 mmol) in THF (500 mL) was added Ti(OEt)4 (82.6 g, 362.0 mmol) and (R)-2-methylpropane-2-sulfinamide (26.3 g, 217 mmol). The mixture was stirred at 85 °C for 14 hours. The reaction mixture was quenched with water (200 mL) and then filtered and the filtrate was extracted with ethyl acetate (3 χ 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was combined with four similar batches (25 g reactant 1 -(2-fluorophenyl)ethanone for each batch), the mixture was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 5:1 ). (R)-N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (135.0 g, 77.3% yield) was obtained.
77.3%
With titanium(IV) tetraethanolate In tetrahydrofuran at 85℃; for 14h;
To a solution of 1-(2-fluorophenyl)ethanone (25.0 g, 181 mmol) in THF (500 ml.) was added Ti(OEt)4 (82.6 g, 362.0 mmol) and (R)-2-methylpropane-2-sulfinamide (26.3 g, 217 mmol). The mixture was stirred at 85 °C for 14 hours. The reaction mixture was quenched with water (200 ml.) and then filtered and the filtrate was extracted with ethyl acetate (3 χ 200 ml_). The combined organic layers were washed with brine (100 ml_), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was combined with four similar batches (25 g reactant 1 -(2-fluorophenyl)ethanone for each batch), the mixture was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 5:1 ). (R)-/V-(1 -(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (135.0 g, 77.3% yield) was obtained.
70.8%
With titanium(IV) tetraethanolate In tetrahydrofuran Molecular sieve; Reflux;
(R)-N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
1-(2-Fluorophenyl)ethanone (15 g, 109 mmol) and (R)-2-methylpropane-2-sulfinamide (15.79 g, 130 mmol) were placed in a round bottom flask fitted with a reflux condenser. Tetrahydrofuran (90 ml) (dried over 4A MS) was added followed by Ti(OEt)4 (49.5 g, 217 mmol) and the resulting yellow solution was stirred at gentle reflux overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and brine (100 mL) was added dropwise while stirring vigorously. The addition of brine resulted in immidiate formation of copious amounts of a white precipitate. After 10 min stirring at room temperature the suspension was filtered through a plug of celite using ethyl acetate for elution. The filtrate was transferred to a separation funnel, the layers were separated, and the organic layer was washed with brine (150 mL). The organic layer was dried over MgS04, filtered and concentrated under reduced pressure and was purified using a CombiFlash system (330 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→70:30) to afford (R)-N-(1 -(2-fluorophenyl)ethylidene)-2- methylpropane-2-sulfinamide (20.6 g, 70.8 % yield) 1 H NMR (600 MHz, CDCI3) δ 7.69 (t, J = 7.1 Hz, 1 H), 7.43 (dd, J = 13.0, 6.0 Hz, 1 H), 7.18 (td, J = 7.7, 1 .0 Hz, 1 H), 7.1 1 (ddd, J = 1 1 .3, 8.3, 0.8 Hz, 1 H), 2.78 (d, J = 3.4 Hz, 3H), 1 .32 (s, 9H).
With titanium(IV) isopropylate In tetrahydrofuran at 73℃; for 15h; Inert atmosphere;
1.A N-((R)-1-(2-Fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
To a solution of 1-(2-fluorophenyl)ethanone (6.84 g, 49.5 mmol) in anhydrous THF (50 mL) at rt was added Ti(iOPr)4 (25 mL) followed by solid (R)-tert-butyl sulfinamide (5.00 g, 41.3 mmol, source: Oakwood) under N2 atm (Reference: Syn. Comm., 39:1451-1456 (2009); Tet. Lett., 40:6709-6712 (1999)). The reaction mixture was heated at 73° C. for 15 h, cooled to -70° C. and treated with NaBH4 (1.6 g). The reaction mixture was stirred for 7 h, slowly warmed to -10° C. and slowly diluted with MeOH (20 mL) followed by EtOAc and brine. The solid that formed was filtered through a pad of CELITE, washed with EtOAc and the filtrate was concentrated in vacuo to obtain 10.1 g of crude mixture of products. This material was purified by column chromatography (eluting with hexanes/EtOAc) to obtain the title compound (4.35 g, 43.3% yield) as a white solid. 1H NMR (CDCl3) δ 7.38 (td, J=7.6, 1.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.18-7.11 (m, 1H), 7.05 (ddd, J=10.6, 8.2, 1.2 Hz, 1H), 4.81 (dd, J=6.6, 5.3 Hz, 1H), 3.54 (d, J=4.4 Hz, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.24 (s, 9H); MS(ESI+) m/z 244.2 (M+H)+.
With titanium(IV) tetraethanolate In tetrahydrofuran for 16h; Reflux;
1-(3,5-dichlorophenyl)-3-(2-fluorophenyl)-1,3-propanedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In tetrahydrofuran; mineral oil; for 24.0h;Reflux;
Step A: Preparation of 1 -(3,5 -dichlorophenyl)-3 -(2-fluorophenyl)- 1,3 -propanedioneTo a solution of tetrahydrofuran (20 mL) and sodium hydride (60% dispersion in mineral oil, 0.35 g, 8.7 mmol) was added 2?-fluoroacetophenone (0.59 mL, 4.9 mmol), followed by <strong>[2905-67-1]3,5-dichlorobenzoic acid methyl ester</strong> (1.0 g, 4.9 mmol). The mixture was heated at reflux for 24 h. After cooling to ambient temperature, 1 N aqueous hydrochloricacid was added, and the mixture was extracted three times with dichloromethane. The extracts were combined, dried with Mg504 and filtered. The filtrate was concentrated to give a tan solid (1.8 g), which was used without further purification.
With silver trifluoromethanesulfonate; In water; acetic acid; at 110℃; for 6.0h;Schlenk technique;
General procedure: To a 25mL Schlenk tube, AuSBA-15 (6wt%, 20mg), AgOTf (0.05mmol) was added to a solution of phenylacetylene (1.0mmol) in HOAc/H2O (3.0mL, 15:1) under ambient air, the resulting mixture was stirred for 6hat 110C. It was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure and purified of the crude product by column chromatography on silica-gel afforded the desired compound.
80%
With p-toluenesulfonic acid monohydrate; acetic acid; In dichloromethane; at 80℃; for 8.0h;Sealed tube;
General procedure: The corresponding alkyne (1 mmol) was added to a solution of p-toluenesulfonic acidmonohydrate (1 mmol, 0.190 g), acetic acid (0.5 mL) in CH2Cl2 (1.0 mL). Thereaction was then sealed and stirred at the indicated temperature (oC) and for theindicated amount of times (h) in Table 2. After completion, saturated aqueousNaHCO3 (10 mL) was added to quench the reaction and then extracted with CH2Cl2(10 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo. Theresidue was purified by column chromatography to give the pure product. Forsubstrates 1j. 1l, 1n, 1p and 1q, DCE was used as solvent in consideration ofoperation convenience.
With chloro(1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene)gold(I); water; silver trifluoromethanesulfonate; In methanol; at 120℃; for 6.0h;
The <strong>[766-49-4]1-ethynyl-2-fluorobenzene</strong> (120 mg, 1.0 mmol), cat. [Au] (6 mg, 1 muM %), AgOTf (2.6 mg, 1 muM %), water (36 mg, 2 mmol) and methanol (1 ml) are added to the 25 mL of Claisen tube or. After closing the reaction at 120 C for 6 hours, cooling to room temperature. Then adding formic acid amine (315 mg, 5 mmol) and cat. [Rh] (6.2 mg, 1 mmol %), the reaction mixture in oil bath heated to 80 C, reaction 12 hours, cooling to room temperature. Rotary evaporation of the solvent and add a certain amount of ethyl acetate and water extraction, the organic phase of the resulting product after concentrated hydrochloric acid the reflux process, rotary evaporation to remove the solvent, the final petroleum ether washing and filtering to obtain the pure target compound, yield: 81%
N-(1-(2-fluorophenyl)ethylidene)prop-2-en-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With acetic acid In ethanol at 50℃; for 6h;
1 Example 1 Preparation of Compound IV:
In a 2000 ml reaction flask,Join2-Fluoroacetophenone138g,Allylamine 114 g,Anhydrous ethanol 966ml,Glacial acetic acid 10ml,The reaction system was heated to 50 ° C,Insulation reaction 6h,After TLC detection reaction is complete,Cooled to room temperature,There is a lot of solid precipitation,Stir for 1h,And then cooled to 0 ~ 10 ,Insulation 1h,Filter,The filter cake is rinsed with cold ethanol,dry,165 g of a white solid,I.e. compound IV,Yield 93%.
93%
With acetic acid In ethanol at 50℃; for 6h;
1 Example 1 Preparation of Compound IV
In 2000ml reaction flask was added 2-fluoroacetophenone 138g, allyl amine 114 g, anhydrous ethanol 966ml, glacial acetic acid 10ml, the reaction system was warmed to 50 °C, incubated for 6h, TLC detection reaction is completed After cooling to room temperature, a large number of solid precipitation, stirring 1h, then cooled to 0 ~ 10 °C, incubated 1h, suction filtration, the filter cake was rinsed with cold ethanol and dried to give 165g of a white solid, Compound IV, yield 93%.
With pyridoxal 5'-phosphate; beta-nicotinamide adenine dinucleotide hydrate; In dimethyl sulfoxide; at 37℃; for 16h;pH 9.0;Green chemistry; Enzymatic reaction;
General procedure: cascadeThe reductive amination of ketones using the AlRed/PtxD cas-cade system were carried out in 2 mL Eppendorf tubes in a finalvolume of 0.5 mL. To a mixture containing 50 mM HEPES bufferand 1 mM PLP was added 7.5 mM n-butylamine and 5 mM ketonein DMSO, 1 mM NAD(P)+, 100 mM Na2HPO3·5H2O, with Ec-YghD(1 mg/mL), PtxD (1 mg/mL) and 2 mg/mL of purified SpuC enzyme.The reactions were placed in a shaking incubator at 37C and250 rpm for 16 h. The reactions were quenched by addition of 2 MNaOH (50 L), followed by extraction with methyl tert-butyl ether(300 L). The organic phase was dried on MgSO4and analysedon normal phase chiral HPLC, using analytical methods previouslydescribed [5].
(S)-1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
To a solution of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (300 mg, 1.75 mmol) in anhydrous DMA (3 mL), cooled at 0 C under a N2atmosphere, NaH (60 wt% dispersion in mineral oil, 175 mg, 4.38 mmol) was added portionwise. After stirring at 0 C for 30 min, a solution of 1-(2-fluorophenyl)ethan-1-one (0.21 mL, 1.75 mmol) in anhydrous DMA (3 mL) was added and the reaction mixture was stirred at 50 C for 2 h. It was cooled to 0 C and then NH4Cl sat. sol. was carefully added. The aqueous phase was extracted with EtOAc and the combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (166 mg, 33% yield).
With 4-mesityl-2,6-diphenylpyrylium tetrafluoroborate; ketoreductase-P1-A04; oxygen; NADPH In water; acetonitrile at 23℃; for 24h; Irradiation; Enzymatic reaction;
74%Chromat.
With oxygen; fluorescein In acetonitrile at 20℃; for 12h; Irradiation;
General procedure for the preparation of 2
General procedure: Dry 5 mL pressure test tube was charged with 1 (0.2 mmol), fluorescein (10 mol%), MeCN (1.0 mL). Then replace the gas with oxygen at least three times and light irradiation (425 nm) at room temperature for 12 h. After the reaction was completed, it was extracted with ethyl acetate, filtered, detected by TLC, and then applied to silica gel column chromatography (EtOAc: PE = 1: 30)
74%Chromat.
With oxygen; fluorescein In acetonitrile at 20℃; for 12h; Irradiation; Green chemistry;
General procedure for the preparation of 2
General procedure: Dry 5 mL pressure test tube was charged with 1 (0.2 mmol), fluorescein (10 mol%), MeCN (1.0 mL). Then replace the gas with oxygen at least three times and light irradiation (425 nm) at room temperature for 12 h. After the reaction was completed, it was extracted with ethyl acetate, filtered, detected by TLC, and then applied to silica gel column chromatography (EtOAc: PE = 1: 30)
With potassium carbonate In N,N-dimethyl-formamide at 100℃;
5
In a 100 mL round bottom flask, 4 mmol of the compound represented by formula (D) (for specific substituents, see Table 2) and 6 mmol of the compound represented by formula (E) (for specific substituents, see Table 2)And 8 mmol of anhydrous potassium carbonate, 10 mL of DMF was added, and the temperature was raised to 100 ° C.TLC monitors the reaction of the raw materials after the reaction is complete and stops the reaction. After adding 50 mL of ether, washing twice with 30 mL of 2M NaOH and then once with 50 mL of saturated brineThe solvent was removed under reduced pressure to obtain a compound represented by the formula (F).
With potassium carbonate In N,N-dimethyl-formamide Reflux;
With dihydrogen peroxide; C21H24Cl2N4O9Pd In water at 80℃; regioselective reaction;
4.4 General Procedure for the Wacker OxidationReaction in the Presence of the GPT-Pdor GPT-Pt Catalyst
General procedure: The Wacker oxidation reaction was performed in a 10 mLround-bottomed flask where olefins (1.0 mmol), H2O2(2.0 mmol), GPT-Pd or GPT-Pt catalyst (1 mol% withrespect to olefins) and water (2 mL) were charged and stirredat 80 °C under air. The reaction progress was monitoredby TLC. After completion of the reaction, the mixture wasallowed to cool to room temperature. Then the aqueousphase was extracted with CH2Cl23 times (3 × 2 mL). Thenthe combined organic layers were dried over anhydrousNa2SO4,concentrated under vacuum and purified by columnchromatography (n-hexane/ethyl acetate, 10:1) to afford thedesired product.
70%
With tert.-butylhydroperoxide; C21H19N5Pd(2+)*2BF4(1-) In decane; acetonitrile at 45℃; for 30h;
46%
With manganese(II) bromide; water; lithium perchlorate; copper dichloride In acetonitrile at 60℃; for 8h; Sealed tube; Inert atmosphere; Electrochemical reaction; regioselective reaction;
82.3 %Chromat.
With oxygen; potassium carbonate; isopropyl alcohol at 150℃; for 6h; regioselective reaction;
(E)-1-(2-fluorophenyl)-3-(2,4-dichlorothiazol-5-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With hydrogenchloride; acetic acid In ethanol Reflux;
General protocol for the synthesis of thiazole-chalcone hybrids (1-20)
General procedure: Initially,1 mmol of 2,4-dichlorothiazole-5-carboxaldehyde was dissolved in a mixture of glacialacetic acid (4 mL) and concentrated hydrochloric acid (2 mL) [60]. To the above solution,1 mmol of corresponding aromatic ketone dissolved in 10 mL of ethanol was transferredand refluxed for 4-6 h. After completion of the reaction, the precipitate of the target compoundwas separated by filtration and washed thoroughly with cold water (50 mL 2)and dried in a desiccator (Scheme 1). The crude precipitate was purified by columnchromatography on silica gel using a mixture of hexane and ethyl acetate (2-25%).
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