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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 321-28-8 * Storage: {[proInfo.prStorage]}
* 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：
[1] Journal of Organic Chemistry, 1953, vol. 18, p. 910,914
6
[ 321-28-8 ]
[ 351-54-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
[2] Chimica Therapeutica, 1968, vol. 3, p. 1 - 9
[3] Patent: US6028116, 2000, A,
[4] Patent: US5401774, 1995, A,
[5] Patent: EP485172, 1992, A2,
[6] Patent: US6232312, 2001, B1,
7
[ 321-28-8 ]
[ 1191-17-9 ]
[ 351-54-2 ]
Reference：
[1] Patent: US5998477, 1999, A,
[2] Patent: US5696159, 1997, A,
[3] Patent: US5776962, 1998, A,
8
[ 321-28-8 ]
[ 100-97-0 ]
[ 351-54-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 2003, vol. 123, # 1, p. 101 - 108
9
[ 321-28-8 ]
[ 75-36-5 ]
[ 455-91-4 ]
Yield
Reaction Conditions
Operation in experiment
95.2%
Stage #1: With aluminum (III) chloride In dichloromethane at 5 - 10℃; for 0.166667 h; Cooling with ice Stage #2: at 5℃; for 1 h;
Under ice bath conditions,6.38 g (48 mmol) of aluminum trichloride and 40 mlDichloromethane is put into a 100ml round bottom flask, stirred and dissolved4.68 g (60 mmol) of acetyl chloride, maintaining the temperature at 5 to 10° C., stirring at 5° C. for 10 minutes, followed by dropwise addition of 2-fluoroanisole 5.04 g(40 mmol). The mixture is stirred at 5°C for 1 hour and then poured into 100 ml of ice-water. The aqueous layer is extracted with dichloromethane (2 x 30 ml). The combined organic phases are washed with water (2 x 30 ml), dried over anhydrous magnesium sulphate, filtered, and petroleum ether is used. The product was recrystallized from ethyl acetate in 92.4percent yield.
92%
Stage #1: With aluminum (III) chloride In chloroform at 5 - 10℃; for 0.166667 h; Stage #2: at 0 - 10℃; for 1 h;
Step 1: Preparation of 3'-fluoro-4'-methoxy-acetophenone. acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 ML), maintaining the temperature between 5-10° C. The mixture was stirred for 10 minutes at 5 ° C. before the dropwise addition of 2-fluoroanisole (62.6 g, 0.5 mol).. The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L).. The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 ML).. The combined organic layers were washed with water (2*150 ML), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 ML. Hexanes were added and a white solid formed which was isolated by filtration and air dried.. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92percent) of material suitable for use in the next step: mp 92-94° C.
75%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 1 h; Stage #2: at 20℃; for 16 h;
D2. 1 -( 3 -Fluoro-4-methoxy-ρhenvD-ethanoneTo a slurry of AICI3 (63.5g, 0.476mol) in dry dichloromethane (500ml) under nitrogen was added acetyl chloride (37.3g, 0.476mol) and the mixture was stirred for Ih at room temperature. To this was added a solution of l-fluoro-2-methoxybenzene (50g, 0.396mol) in dichloromethane (200ml) and the mixture was stirred at room temperature for 16h. This was then poured into ice-water (2L) and extracted with dichloromethane. The organic layer was washed with water, brine and dried. The solvent was removed under vacuum to afford 50g (75percent) of the title compound.
Reference：
[1] Patent: CN107686465, 2018, A, . Location in patent: Paragraph 0041; 0053; 0054
[2] Patent: US6342510, 2002, B1, . Location in patent: Page column 28
[3] Patent: US5098602, 1992, A,
[4] Patent: WO2006/136829, 2006, A2, . Location in patent: Page/Page column 123
[5] Journal of Organic Chemistry, 1953, vol. 18, p. 910,914
[6] Patent: US6376528, 2002, B1,
[7] Patent: US6407140, 2002, B1,
[8] Patent: US5990148, 1999, A,
[9] Patent: US6136839, 2000, A,
[10] Patent: US5521207, 1996, A,
[11] Patent: US5700816, 1997, A,
[12] Patent: US5756529, 1998, A,
[13] Patent: US5756529, 1998, A,
[14] Patent: US5760068, 1998, A,
[15] Patent: US5760068, 1998, A,
[16] Patent: US6172096, 2001, B2,
10
[ 321-28-8 ]
[ 455-91-4 ]
Reference：
[1] Patent: US5180520, 1993, A,
[2] Patent: US5422037, 1995, A,
11
[ 321-28-8 ]
[ 108-24-7 ]
[ 455-91-4 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 350,353
12
[ 75-15-0 ]
[ 7446-70-0 ]
[ 321-28-8 ]
[ 108-24-7 ]
[ 455-91-4 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 350,353
13
[ 321-28-8 ]
[ 454-16-0 ]
[ 455-93-6 ]
[ 484-94-6 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
14
[ 321-28-8 ]
[ 455-93-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
[2] Journal of the Chemical Society, 1926, p. 1332
[3] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 1583[5] Chem.Abstr., 1947, p. 6274
[6] Journal of the American Chemical Society, 1941, vol. 63, p. 609
[7] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
[8] Patent: US4431807, 1984, A,
15
[ 321-28-8 ]
[ 454-16-0 ]
[ 455-93-6 ]
[ 484-94-6 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
16
[ 321-28-8 ]
[ 455-93-6 ]
[ 484-94-6 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
17
[ 321-28-8 ]
[ 344-78-5 ]
[ 455-93-6 ]
Reference：
[1] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[2] Journal of the Chemical Society, 1926, p. 1332
18
[ 321-28-8 ]
[ 7697-37-2 ]
[ 108-24-7 ]
[ 455-93-6 ]
Reference：
[1] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[2] Journal of the Chemical Society, 1926, p. 1332
[3] Journal of the Chemical Society, 1940, p. 810
[4] Journal of the American Chemical Society, 1940, vol. 62, p. 350,353
19
[ 321-28-8 ]
[ 7697-37-2 ]
[ 344-78-5 ]
[ 455-93-6 ]
Reference：
[1] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[2] Journal of the Chemical Society, 1926, p. 1332
[3] Journal of the Chemical Society, 1940, p. 810
20
[ 373-91-1 ]
[ 100-66-3 ]
[ 459-60-9 ]
[ 321-28-8 ]
[ 710-18-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 2012, vol. 140, p. 43 - 48
21
[ 321-28-8 ]
[ 366-99-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
[3] Journal of the American Chemical Society, 1941, vol. 63, p. 609
[4] Chemische Berichte, 1933, vol. 66, p. 1180,1183
[5] Chemische Berichte, 1933, vol. 66, p. 1180,1183
22
[ 321-28-8 ]
[ 350-29-8 ]
Reference：
[1] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
23
[ 321-28-8 ]
[ 404-90-0 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 296 - 306
Reference：
[1] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
26
[ 321-28-8 ]
[ 151-50-8 ]
[ 331-62-4 ]
Reference：
[1] Tetrahedron, 1977, vol. 33, p. 779 - 786
27
[ 50-00-0 ]
[ 321-28-8 ]
[ 331-61-3 ]
Reference：
[1] DRP/DRBP Org.Chem.,
28
[ 321-28-8 ]
[ 452-11-9 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 609
29
[ 321-28-8 ]
[ 2357-52-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With sodium bicarbonate; bromine; sodium hydrogensulfite In chloroform; water
Synthesis of 3-fluoro-4-methoxybromobenzene Into a flask of 5 l were charged 384 g (3.04 mol) of 2-fluoroanisole and 2.5 l of chloroform, to which was added dropwise 504 g (3.16 mol) of bromine over about 3 hours while cooling on an ice water bath at 10° C. The resulting mixture was stirred at room temperature over a night and heated under reflux for 8 hours. After the air cooling, the product was added with 1 l of water and 50 g of sodium bisulfite and sufficiently shaken to separate into two layers. The resulting organic layer was washed with an aqueous solution of 5percent sodium hydrogen carbonate and further with 1 l of water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and distilled under a reduced pressure (4 mmHg, bp: 93-°96° C.) to obtain 585 g (yield: 94percent) of 3-fluoro-4-methoxybromobenzene.
92.3%
With sodium hydroxide; bromine In chloroform
(a) Synthesis of STR7 A reaction vessel was charged with 128 g (1.016 mol) of 2-fluoroanisole and 250 ml of chloroform. To this mixture was added dropwise under agitation at room temperature 177 g (1.106 mol) of bromine over the period of at least 3 hours. The reaction liquid was poured into a diluted aqueous solution of NaOH, and the chloroform layer was separated, washed with a solution of edible salt and dried over Glauber's salt. The solvent was distilled off and the residue was distilled under reduced pressure to obtain 2-fluoro-4-bromoanisole. Yield 192 g (yield rate: 92.3percent) b.p. 107°-116° C./25-31 mmHg
91%
With sodium hydroxide; bromine In chloroform
(a) Synthesis of 3-fluoro-4-methoxybenzamidine hydrochloride: 306 g of 2-fluoroanisole was dissolved in 750 ml of chloroform. To the resulting solution, was added dropwise 389 g of bromine under stirring at room temperature. After the completion of the addition, the reaction mixture was heated under reflux for nine hours and then allowed to cool to room temperature. The mixture was washed with 500 ml of a 5percent aqueous solution of sodium hydroxide and then the organic layer was washed with 500 ml portions of water thrice. The organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by distillation (main fraction: 14 mmHg, 98°-100° C.) to thereby give 454 g of 2-fluoro-4-bromoanisole. Yield: 91percent.
86%
With N-Bromosuccinimide In acetonitrile at 70℃; for 3 h;
The crude product (1.0 g, 7.9 mmol) was dissolved in acetonitrile (15 mL) and N-bromosuccinimide (1.4 g, 8.7 mmol) was added and reacted at 70 ° C for 3 h. After the reaction was completed, most of the acetonitrile was distilled off, 30 mL of water was added, the mixture was stirred for 10 min and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous magnesium sulfate and separated by column chromatography (pure petroleum ether as eluent) The brominated product (intermediate A_2c) was obtained as a light yellow oily liquid (1.4 g, yield 86percent) oA-2c: SH (300 MHz; CDCl 3) 7.23-7.16 (2H, m), 6.82 (D, J = 8.7Hz), 3.86 (3H, s); δ (75ΜΗζ; CDC13) 152.3 (d, Jc, F = 249.0Hz), 147.1 (d, 119.6 (d, J = 21.1 Hz), 114.6 (d, J = 2.2 Hz), 111.9 (d, J = 8.2 Hz), 56.4
73.4%
With sodium hydroxide; bromine In chloroform; water
Example 21 [Synthesis of 3'-fluoro-4'-dodecyloxybiphenyl-4-carboxylic acid] 2-Fluoroanisole (266 g) was dissolved in 700 ml of chloroform and 337 g of bromine was added dropwise to the solution. The mixture was reacted under reflux at 67° to 68° C. for 1 hour, subsequently left to cool, washed with a 5percent aqueous solution of sodium hydroxide and then with water, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled (95° to 96° C./12 mmHg) to obtain 317 g of 4-bromo-2-fluoroanisole (yield 73.4percent).
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
[2] Patent: US5098602, 1992, A,
[3] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579
[4] Patent: US5397504, 1995, A,
[5] Patent: US4997942, 1991, A,
[6] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[7] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0082; 0083; 0085
[8] Patent: US4828754, 1989, A,
[9] Journal fuer Praktische Chemie (Leipzig), 1935, vol. <2> 143, p. 18,24
[10] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
[11] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4790 - 4798
30
[ 321-28-8 ]
[ 454-16-0 ]
[ 455-93-6 ]
[ 484-94-6 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
[2] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
31
[ 321-28-8 ]
[ 455-93-6 ]
[ 484-94-6 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
32
[ 321-28-8 ]
[ 458-09-3 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 296 - 306
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
[3] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
[4] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
33
[ 321-28-8 ]
[ 452-14-2 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 296 - 306
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
With chlorosulfonic acid In chloroform at 20℃; for 14 h;
A stirred solution of 2-fluoroanisole (33.7 mL, 301 MMOL) in chloroform (250 mL) was cooled to 0°C and treated drop-wise with chlorosulfonic acid (50.0 mL, 752 MMOL). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (700 mL) and the separated, aqueous phase extracted with chloroform (2 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated IN VACUO TO YIELD 3-FLUORO-4- METHOXYBENZENESULFONYL CHLORIDE as a fine, white solid (58.6 g, 87percent), m. p. 80°C ; 1H NMR (400 MHz, DMSO-d6) 5 : 7.32 (m, 1H), 7.25 (dd, J= 11.5, 2.0 Hz, 1H), 7.05 (t, J = 8. 5 HZ, 1 H), 3.78 (s, 3H).
Stage #1: With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 2 h; Stage #2: at -78℃; for 0.166667 h; Stage #3: With acetic acid In tetrahydrofuran; cyclohexane; water at 20℃;
A solution of 2 fluoro-anisole (6. 0 g, 47 mmol) and N, N, N', N'-teteramethylethylenediamine in THF (250 mL) was cooled to-78°C and treated dropwise with sec-butyl lithium (1.3 M/CYCLOHEXANE, 37.9 mL, 49 mmol). The mixture was stirred for 2 hours at- 78°C and then treated with dimethylformamide (3.6 mL, 47 mmol). Stirring continued for an additional 10 minutes and then acetic acid (20 mL) followed by water (150 mL) was added to the reaction. The reaction was warmed to ambient temperature and then diluted with ethyl acetate. The organic layer was extracted first with IN HCL, and then with brine. The solution was dried over MgSO4 and concentrated under reduced pressure to afford crude 2 flouro-3- methoxybenzaldehyde (4.7 g, 64percent). In a manner analogous to that described in Intermediate 13,2 flouro-3-methoxybenzaldehyde (4.7 g, 30 mmol), malonic acid (4.76 g, 45 mmol), pyridine (50 mL) and piperidine (1. 5 mL) afforded the title product (2.5g, 42percent). IH-NMR- (400 MHZ, D6 DMSO) 8, 7.65 (d, J=16. 1HZ, LH), 7. 34 (m, LH), 7.18 (m, 2H), 6.58 (d, J= 16. 1Hz, 1H), 3.83 (s, 3H).
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 14, p. 3145 - 3147
38
[ 100-66-3 ]
[ 459-60-9 ]
[ 321-28-8 ]
[ 134364-69-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 2004, vol. 125, # 12, p. 1873 - 1877
39
[ 321-28-8 ]
[ 124-38-9 ]
[ 137654-20-7 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1271 - 1275
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 18, p. 2115 - 2118
[3] Patent: WO2004/11443, 2004, A1, . Location in patent: Page 122
40
[ 321-28-8 ]
[ 137654-20-7 ]
Yield
Reaction Conditions
Operation in experiment
51%
With n-butyllithium; potassium <i>tert</i>-butylate In tetrahydrofuran; water
Step 1. Preparation of 2-fluoro-3-methoxybenzoic acid. A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours. The reaction was poured into a 2 L Erlenmeyer flask containing dry ice and warmed to room temperature. Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51percent) as a yellow solid: mp 155°-160° C.; 1 H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19 F NMR (acetone-d6) 300 MHz -134.04(m). Mass spectrum: M+H=171.
Step 1: 3-(3-fluoro-4-methoxybenzoyl)propionic acid Intermediate 351-Fluoro-2-methoxybenzene (7 mL, 0.062 mol) and succinic anhydride (6.93 g, 0.0692 mol) were dissolved in methylene chloride (100 mL). The resulting solution was cooled in an ice-water bath for 20 min. Aluminum trichloride (18.3 g, 0.137 mol) was then added in portions. Upon completion of addition, the mixture was heated at 65 C. in an oil bath for 2 h and then cooled to room temperature and allowed to stir overnight. The reaction mixture was poured onto ice and 200 mL 1N HCl was added. A white precipitate formed which was isolated by suction filtration. The filter cake was dried under suction and then further dried under vacuum to provide the title compound as a white solid (12.703 g, 90%). LC-MS: (FA) ES- 225; NMR (400 MHz, CD3OD) delta ppm 7.86 (ddd, J=8.6, 2.1, 1.14 Hz, 1H), 7.72 (dd, J=12.1, 2.1 Hz, 1H), 7.20 (dd, J=8.5, 8.5 Hz, 1H), 3.95 (s, 3H), 3.28-3.23 (m, 2H), 2.71-2.66 (m, 2H).
2-Fluoro-4-nitroanisole (IX) To a cold (-2), stirred solution of 285 g. (2.26 mol) of 2-fluoroanisole in 1.1 L of acetic anhydride was added, dropwise, 114 mL of fuming nitric acid (sp. gr. 1.59) at such a rate that the reaction temperature remained between -2 and 0. The reaction mixture was stirred for 5 hours at this temperature then poured into 4.0 L of water. The suspension was stirred for 1.5 hours, stored for 15 hours, then extracted with methylene chloride (2*1.0 L). The combined extracts were washed with water (2*500 mL), dried over anhydrous magnesium sulfate, then concentrated in vacuo (475 g.). Crystallization from ethanol gave 147.4 g. (38%) of material suitable for further transformation. Additional material (34.5 g.) was obtained from three scouting runs. Analytically pure product (5.2 g.; 63.4% recovery) was obtained by recrystallizing 8.2 g of the material from 200 mL of ethanol; mp, 105-106 (Literature, R. C. Elderfield et al., J. Am. Chem. Soc., 68, 1584 (1946)). Anal. Calcd for C7 H6 FNO3 (percent): C, 49.13; H, 3.53; F, 11.10; N, 8.19. Found: C, 49.07; H, 3.52; F, 11.02; N, 8.19.
With sodium bicarbonate; bromine; sodium hydrogensulfite; In chloroform; water;
Synthesis of 3-fluoro-4-methoxybromobenzene Into a flask of 5 l were charged 384 g (3.04 mol) of <strong>[321-28-8]2-fluoroanisole</strong> and 2.5 l of chloroform, to which was added dropwise 504 g (3.16 mol) of bromine over about 3 hours while cooling on an ice water bath at 10 C. The resulting mixture was stirred at room temperature over a night and heated under reflux for 8 hours. After the air cooling, the product was added with 1 l of water and 50 g of sodium bisulfite and sufficiently shaken to separate into two layers. The resulting organic layer was washed with an aqueous solution of 5% sodium hydrogen carbonate and further with 1 l of water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and distilled under a reduced pressure (4 mmHg, bp: 93-96 C.) to obtain 585 g (yield: 94%) of 3-fluoro-4-methoxybromobenzene.
92.3%
With sodium hydroxide; bromine; In chloroform;
(a) Synthesis of STR7 A reaction vessel was charged with 128 g (1.016 mol) of <strong>[321-28-8]2-fluoroanisole</strong> and 250 ml of chloroform. To this mixture was added dropwise under agitation at room temperature 177 g (1.106 mol) of bromine over the period of at least 3 hours. The reaction liquid was poured into a diluted aqueous solution of NaOH, and the chloroform layer was separated, washed with a solution of edible salt and dried over Glauber's salt. The solvent was distilled off and the residue was distilled under reduced pressure to obtain 2-fluoro-4-bromoanisole. Yield 192 g (yield rate: 92.3%) b.p. 107-116 C./25-31 mmHg
91%
With sodium hydroxide; bromine; In chloroform;
(a) Synthesis of 3-fluoro-4-methoxybenzamidine hydrochloride: 306 g of <strong>[321-28-8]2-fluoroanisole</strong> was dissolved in 750 ml of chloroform. To the resulting solution, was added dropwise 389 g of bromine under stirring at room temperature. After the completion of the addition, the reaction mixture was heated under reflux for nine hours and then allowed to cool to room temperature. The mixture was washed with 500 ml of a 5% aqueous solution of sodium hydroxide and then the organic layer was washed with 500 ml portions of water thrice. The organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by distillation (main fraction: 14 mmHg, 98-100 C.) to thereby give 454 g of 2-fluoro-4-bromoanisole. Yield: 91%.
86%
With N-Bromosuccinimide; In acetonitrile; at 70℃; for 3h;
The crude product (1.0 g, 7.9 mmol) was dissolved in acetonitrile (15 mL) and N-bromosuccinimide (1.4 g, 8.7 mmol) was added and reacted at 70 C for 3 h. After the reaction was completed, most of the acetonitrile was distilled off, 30 mL of water was added, the mixture was stirred for 10 min and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous magnesium sulfate and separated by column chromatography (pure petroleum ether as eluent) The brominated product (intermediate A_2c) was obtained as a light yellow oily liquid (1.4 g, yield 86%) oA-2c: SH (300 MHz; CDCl 3) 7.23-7.16 (2H, m), 6.82 (D, J = 8.7Hz), 3.86 (3H, s); delta (75MuEtazeta; CDC13) 152.3 (d, Jc, F = 249.0Hz), 147.1 (d, 119.6 (d, J = 21.1 Hz), 114.6 (d, J = 2.2 Hz), 111.9 (d, J = 8.2 Hz), 56.4
73.4%
With sodium hydroxide; bromine; In chloroform; water;
Example 21 [Synthesis of 3'-fluoro-4'-dodecyloxybiphenyl-4-carboxylic acid] 2-Fluoroanisole (266 g) was dissolved in 700 ml of chloroform and 337 g of bromine was added dropwise to the solution. The mixture was reacted under reflux at 67 to 68 C. for 1 hour, subsequently left to cool, washed with a 5% aqueous solution of sodium hydroxide and then with water, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled (95 to 96 C./12 mmHg) to obtain 317 g of 4-bromo-<strong>[321-28-8]2-fluoroanisole</strong> (yield 73.4%).
Step 1 1-(3-fluoro-4-methoxyphenyl)-1-hexanone Aluminum chloride (6.5 g, 48.8 mmol) was added to a stirred mixture of <strong>[321-28-8]1-fluoro-2-methoxybenzene</strong> (5.0 mL, 44.4 mmol) and hexanoyl chloride (7.5 mL, 53.3 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 45 minutes and then partitioned between EtOAc (100 mL) and water (100 mL). The EtOAc layer was washed with water (100 mL), aqueous K2CO3 (100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-fluoro-4-methoxyphenyl)-1-hexanone (9 g) as a solid.
EXAMPLE 1 Preparation of 1-(3-Fluoro-4-Methoxy-Phenyl)-Hexan-1-One; 2-Fluoroanisole (3.15 g, 25.0 mmol) is dissolved in dry dichloromethane (25 mL). While stirring the resulting solution under nitrogen, aluminum chloride is added (3.92 g, 29.4 mmol). This solution is cooled with a cold water bath and hexanoyl chloride (3.87 g, 28.8 mmol) is added drop wise such that the internal temperature is maintained at or below 20 C. Upon complete of addition, the reaction is stirred 30 minutes at room temperature. The dark orange solution is cooled to -10 C. and slowly quenched by the addition of water (25.0 mL) while keeping the internal temperature below 0 C. The mixture is transferred to a separatory funnel, the organic layer (bottom) is collected and the aqueous discarded. The organic solution is then washed with 5N NaOH (12.5 mL) and again with water (12.5 mL). The crude organic is concentrated by vacuum distillation and diluted with heptane to a final volume of about 20 mL. The slurry is heated until all solids are dissolved and allowed to cool to room temperature. The product crystallizes upon cooling. The slurry is further cooled to 0 to 5 C. for one hour and filtered. The wet cake is washed with cold (0 C.) heptane (2×2.5 mL) and the product dried under vacuum.
Under ice bath conditions,6.38 g (48 mmol) of aluminum trichloride and 40 mlDichloromethane is put into a 100ml round bottom flask, stirred and dissolved4.68 g (60 mmol) of acetyl chloride, maintaining the temperature at 5 to 10 C., stirring at 5 C. for 10 minutes, followed by dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> 5.04 g(40 mmol). The mixture is stirred at 5C for 1 hour and then poured into 100 ml of ice-water. The aqueous layer is extracted with dichloromethane (2 x 30 ml). The combined organic phases are washed with water (2 x 30 ml), dried over anhydrous magnesium sulphate, filtered, and petroleum ether is used. The product was recrystallized from ethyl acetate in 92.4% yield.
92%
Step 1: Preparation of 3'-fluoro-4'-methoxy-acetophenone. acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 ML), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol).. The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L).. The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 ML).. The combined organic layers were washed with water (2*150 ML), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 ML. Hexanes were added and a white solid formed which was isolated by filtration and air dried.. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.
88%
aluminium trichloride; In dichloromethane;
Synthesis of 3-fluoro-4-methoxyacetophenone To a solution of 700 ml of dried methylene chloride and 157 g of acetyl chloride was added dropwise 267 g of anhydrous aluminum chloride over 30 minutes with stirring while holding temperature at 15-25 C., which were further stirred at room temperature for about 2 hours. Separately, a solution of 206 g of o-fluoroanisole and 170 ml of dried methylene chloride was cooled on an ice water bath, to which was added dropwise the previously prepared solution of acetyl chloride and aluminum chloride in methylene chloride over about 2.5 hours. The resulting mixture was further stirred on the ice water bath for 1 hour and at room temperature for 1 hour. The resulting reaction mixture was poured into 1.4 l of ice water and separated into two layers. The extraction with 400 ml of methylene chloride on aqueous layer was repeated two times, and thereafter the organic layers were gathered, washed with water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and dried to obtain a light brown crystal. This crystal was recrystallized with ethanol to obtain 242 g (yield: 88%) of a white crystal having a melting point of 89.5-90.0 C.
75%
D2. 1 -( 3 -Fluoro-4-methoxy-rhohenvD-ethanoneTo a slurry of AICI3 (63.5g, 0.476mol) in dry dichloromethane (500ml) under nitrogen was added acetyl chloride (37.3g, 0.476mol) and the mixture was stirred for Ih at room temperature. To this was added a solution of l-fluoro-2-methoxybenzene (50g, 0.396mol) in dichloromethane (200ml) and the mixture was stirred at room temperature for 16h. This was then poured into ice-water (2L) and extracted with dichloromethane. The organic layer was washed with water, brine and dried. The solvent was removed under vacuum to afford 50g (75%) of the title compound.
aluminium trichloride; In chloroform;
Step 1 Preparation of 3'-fluoro-4'-methoxy-acetophenone Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford material suitable for use in the next step (77.2 g, 92%): mp 92-94 C.
aluminium trichloride; In chloroform;
Step 1: Preparation of 3'-fluoro-4'-methoxy-acetophenone. Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford material suitable for use in the next step (77.2 g, 92%): mp 92-94 C.
aluminium trichloride; In chloroform;
Step 1: Preparation of 3'-fluoro-4'-methoxy-acetophenone. Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.
aluminium trichloride; In chloroform;
Step 1 Preparation of 3'-fluoro-4'-methoxy-acetophenone Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.
aluminium trichloride; In chloroform;
Step 1 Preparation of 3'-Fluoro-4'-methoxyacetophenone Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition at 5-10 C. of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacou to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.; 1 H NMR (D6 -DMSO) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
aluminium trichloride; In chloroform;
Step 1 Preparation of 3'-fluoro-4'-methoxy-acetophenone Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.
aluminium trichloride; In chloroform;
Step 1 Preparation of 3'-fluoro-4'-methoxyacetophenone Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition at 5-10 C. of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.; 1 H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
aluminium trichloride; In chloroform;
Step 1. Preparation of 3'-fluoro-4'-methoxyacetophenone Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution was added acetyl chloride (51.0 g, 0.65 mol) dropwise, maintaining the temperature between 5-10 C. The mixture was allowed to stir for 10 minutes. at 5 C. before the dropwise addition at 5-10 C. of <strong>[321-28-8]2-fluoroanisole</strong> (63.06 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with methylene chloride (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over magnesium sulfate, and concentrated to 300 mL. Hexanes were added and a white solid (77.2 g, 92%) was crystallized from the mixture: mp 92-94 C.; 1 H NMR (d6 -DMSO) 7.8 (m, 2H), 7.3 (t, J=8.7 Hz, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
aluminium trichloride; In chloroform;
Step 1. Preparation of 3'-fluoro-4'-methoxyacetophenone Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution was added acetyl chloride (51.0 g, 0.65 mol) dropwise, maintaining the temperature between 5-10 C. The mixture was allowed to stir for 10 minutes at 5 C. before the dropwise addition at 5-10 C. of <strong>[321-28-8]2-fluoroanisole</strong> (63.06 g, 0.5 mol. The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with methylene chloride (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over magnesium sulfate, and concentrated to 300 mL. Hexanes crystallized from the mixture: mp 92-94 C.; 1 H NMR (d6 -DMSO) 7.8 (m, 2H), 7.3 (t, J=8.7Hz, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
aluminium trichloride; In chloroform;
Step 1: Preparation of 3'-fluoro-4'-methoxy-acetophenone Aluminum chloride, (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition at 5-10 C. of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94 C.; 1 H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
aluminium trichloride; In chloroform;
Step 1: Preparation of 3'-fluoro-4'-methoxy-acetophenone. Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10 C. The mixture was stirred for 10 minutes at 5 C. before the dropwise addition of <strong>[321-28-8]2-fluoroanisole</strong> (62.6 g, 0.5 mol). The mixture was stirred at 0-10 C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2*250 mL). The combined organic layers were washed with water (2*150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford material suitable for use in the next step (77.2 g, 92%): mp 92-94 C.
Step 1: Preparation of 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one. A suspension of aluminum chloride (9.4 g, 70.5 mmol) in a solution of <strong>[321-28-8]2-fluoroanisole</strong> (6.6 mL, 58.8 mmol) and anhydrous chloroform (200 mL) was cooled to 0 C. under a blanket of dry nitrogen. A solution of phenylacetyl chloride (8.6 mL, 64.7 mmol) in anhydrous chloroform (50 mL) was added to the vigorously stirred suspension over 20 minutes keeping the reaction temperature <5 C. The yellowish solution was stirred at 0 C. for 1 hour, poured into ice (200 mL) and stirred without temperature control for 16 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic solution was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from boiling hexane to yield, upon filtration and drying, 1-(3-fluoro-4 methoxyphenyl)-2-phenyl-ethan-1-one (12.9 g, 90%) as white crystals: 1 H NMR (CDCl3 /300 MHz) delta 7.82-7.72 (m, 2H), 7.35-7.24 (m, 5H), 6.98 (dd, J=8.46, 8.26 Hz, 1H), 4.22 (s, 2H), 3.94 (s, 3H). 19 F NMR (CDCl3 /282.2 MHz) -134.875 (m).
aluminium trichloride; In dichloromethane;
Step 1. Preparation of 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one. Aluminum chloride (42.17 g, 316 mmol) and dichloromethane (350 mL) were cooled to 2 C. and phenylacetylchloride (40.50 g, 262 mmol) in dichloromethane (30 mL) was added. 2-Fluoroanisole (32.77 g, 260 mmol) in dichloromethane (30 mL) was added. The cooling bath was removed, and the mixture was stirred for 1 hour. The reaction mixture was poured into concentrated HCl (150 mL), filtered through diatomaceous earth, washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. A white solid was obtained by crystallization from dichloromethane/hexane (29.2 g, 46%): mp 105-106 C.
aluminium trichloride; In chloroform;
Step 1: Preparation of 1-(3-fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one. In a 500 mL, 3-neck round-bottom flask, equipped with a pressure equalizing dropping funnel, thermometer, gas inlet tube and provisions for magnetic stirring, a suspension of aluminum chloride (9.4 g, 70.5 mmol) in a solution of <strong>[321-28-8]2-fluoroanisole</strong> (6.6 mL, 58.8 mmol) and anhydrous chloroform (200 mL) was cooled to 0 C. under a blanket of dry nitrogen. A solution of phenylacetyl chloride (8.6 mL, 64.7 mmol) in anhydrous chloroform (50 mL) was added to the vigorously stirred suspension over 20 minutes keeping the reaction temperature <5 C. The yellowish solution was stirred at 0 C. for 1 hour, then poured into ice (200 mL) and stirred without temperature control for 16 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic solution was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from boiling hexane to yield, upon filtration and drying, 12.9 g (90%) of 1-(3-fluoro-4 methoxyphenyl)-2-phenyl-ethan-1-one as white crystals: 1 H NMR (CDCl3 /300 MHz) delta 7.82-7.72 (m, 2H), 7.35-7.24 (m, 5H), 6.98 (dd, J=8.46, 8.26 Hz, 1H), 4.22 (s, 2H), 3.94 (s, 3H). 19 F NMR (CDCl3 /282.2 MHz) -134,875 (m).
With aluminum (III) chloride; In dichloromethane; at -10 - 20℃;
To a stirring suspension consisting of aluminum trichloride (15.9 g) in dichloromethane (200 mL) cooled to an internal temperature of -10 C. under a nitrogen atmosphere is added <strong>[321-28-8]2-fluoroanisole</strong> (10 g) over one minute. Phenylacetyl chloride (11.6 mL) is subsequently added to the mixture at a rate that maintained the internal temperature below 0 C. The reaction mixture is allowed to warm to room temperature overnight. Water (100 mL) is cautiously added to the stirring mixture. The layers are subsequently separated and the dichloromethane layer is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate and washed with water, 1 M sodium hydroxide, water, and brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 1-(3-fluoro-4-methoxy-phenyl)-2-phenyl-ethanone (14.1 g.)
With potassium hydroxide; In dimethyl sulfoxide; at 130℃; for 16h;
General procedure: A mixture of 2-fluorobenzamide (1a, 69.5 mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16 h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture was extracted with ethyl acetate three times (3 * 10 mL). The combined organic phases were dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05 in volume) to afford 2aa as a white solid in 80% yield (60.7 mg).
D 1. 1 -Fluoro-2-methoxy-benzeneTo a slurry of NaH (28.8g, O.?Omol) in dry DMF (500ml) at 0 0C was added 2-fluoro phenol (5Og, 0.446mol) slowly over a period of 30min and stirred for Ih at room EPO <DP n="125"/>temperature. To this was added methyl iodide (19Og, 1.33mol) and the reaction mixture was stirred for 16h under nitrogen and poured into ice-water (1.5L). The product was extracted with ethyl acetate (2 x 200ml), washed with water, brine and dried. The solvent was removed under vacuum to afford 55g (98%) of the title compound.
With potassium hexamethylsilazane; In toluene; at 60℃; for 5h;
A mixture of <strong>[321-28-8]2-fluoroanisole</strong> (1.78 mL, 15.9 mmol), cyclopropanecarbonitrile (4.68 mL, 63.6 mmol), and KHMDS (0.5 M solution in toluene, 50 mL, 24 mmol) was stirred and heated to 60 C. under N2. After 5 h, the mixture was allowed to cool to room temperature, then treated with 1 N HCl and extracted twice with toluene. The toluene extracts were combined, washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo. The oily residue was dissolved in CH2Cl2 and purified by chromatography on silica gel (gradient 3:1 hexanes/CH2Cl2 to CH2Cl2) to provide compound 6 (530 mg, 21%) as a clear, colorless oil: 1H NMR (300 MHz, CDCl3) delta 7.19-7.34 (m, 2H), 6.88-6.93 (m, 2H), 3.93 (s, 3H), 1.58-1.63 (m, 2H), 1.23-1.27 (m, 2H).
[PENTAMETHYLENEDIETHYLENETETRAMINE] (31. [2ML)] was added to a solution of 2-fluoroanisole [(15.] 0g) in THF [(450ML).] The reaction mixture was cooled [TO-78C] and n-butyllithium (59. [6ML,] 2. 5M solution in hexanes) was added dropwise. Stirring was maintained for 2h before the solution was added in a dropwise fashion to a flask containing solid carbon dioxide pellets. Upon complete addition (30min) the mixture was allowed to warm to room temperature before removal of the volatiles in vacuo. The residue was dissolved in 10% sodium hydroxide solution [(300ML)] and extracted with Et20 (3x). The aqueous was acidified to pH 1 with concentrated hydrochloric acid before extracting with DCM. The organics were washed with [H20,] dried (MgS04) and concentrated in vacuo to afford the subtitle compound as a yellow solid. Yield: 7. [1G.] [LH NMR 6 (CDC13)] 7.50 [(1H,] [M),] 7.12 (2H, [M),] 3.91 (3H, s).
1.0 g, 1.0 equiv. of the compound of formula II is dissolved in 2 mL of THF solution;After adding 1.2 equiv. of diisopropylamino lithium in THF to the reactor, cooling, cooling to -78 C, the THF solution of the compound of formula II is added dropwise to the reaction system. After the dropwise addition, the temperature of the reaction solution is raised to -50 C.Insulation reaction for 1 h,During the heat preservation reaction, carbon dioxide is introduced into the reaction system until the TLC detection reaction is complete;After the reaction was completed, the reaction mixture was partitioned between ethyl acetate and 1N aqueous hydrochloric acid.The organic phase was separated and the organic phase was washed with brine and dried over sodium sulfate.Finally, the solvent is concentrated to dryness, and the residue is purified by column chromatography to give the compound of formula VI.
A mixture of <strong>[321-28-8]2-fluoroanisole</strong> (1.8 ml, 15.85 mmol), pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran (10 mL) is stirred at -78 C. A 2.5 M solution of r°-butyllithium in hexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solution is stirred at -78 C 2 hr. Trimethylborate (2 mL, 17.45 mmol) is added and the reaction is warmed to room temperature and stirred 1 hr. Acetic acid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30 % solution of hydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture is stirred rapidly 18 hr at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate (3 X 50 mL). The combined extracts are dried over magnesium sulfate, filtered and concetrated to about 10 mL volume. The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes: ethyl acetate to give the title compound (1.65 g, 73 %) as a colorless oil. MS ES 141 m-1.
(A) 3-Fluoro-4-methoxybenzaldehyde A solution of titanium tetrachloride (182 g, 0.96 mol, 1.2 equiv.) and alpha,alpha, -dichloromethylmethyl ether (110 g, 0.96 mol) in an equal volume of methylene chloride is slowly added (30 minutes) to a solution of o-fluoroanisole (101 g, 0.80 mol) in dry methylene chloride (50 ml) at 10-20 C. The mixture is stirred at room temperature for one hour, is poured over crushed ice water and ether (1 l) with stirring. This mixture is stirred under nitrogen until solution occurs. The organic layer is extracted with water, aqueous sodium bicarbonate, and is dried (MgSO4). The solvent is evaporated at 30 C. The residual oil is vacuum-distilled through a jacketed Vigreux column to give 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121 C. (10 mm Hg) Rf 0.6 on a silica-gel G plate with methylene chloride.
titanium tetrachloride; In dichloromethane;
(A) 3-fluoro-4-methoxybenzaldehyde. To a solution of o-fluoroanisole, 101 g. (0.80 mole) in 500 ml. dry methylene chloride is added dropwise over 30 minutes a solution of titanium tetrachloride, 182 g. (0.96 mole, 1.2 equiv.) and alpha,alpha-dichloromethylmethyl ether, 110 g. (0.96 mole) in an equal volume of methylene chloride. The temperature is maintained at 10-20 C. with an ice-bath. The mixture is stirred at room temperature for 1 hour longer and then poured over crushed ice-water with stirring. Ether (1l.) is added, and the mixture stirred under nitrogen until solution occurs. The organic layer is extracted with water (3*), sodium bicarbonate solution (3*) and dried (MgSO4). The solvent is evaporated off at 30 to give crude product as an oil. The oil is vacuum distilled through a jacketed Vigreux column when it gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121 C., at 10 mm. Hg; Rf 0.6 on a silica-gel G plate with methylene chloride.
titanium tetrachloride; In dichloromethane;
(A) 3-fluoro-4-methoxybenzaldehyde. To a solution of o-fluoroanisole, 101 g. (0.80 mole) in 500 ml. dry methylene chloride is added dropwise over 30 minutes a solution of titanium tetrachloride, 182 g. (0.96 mole, 1.2 equiv.) and alpha,alpha-dichloromethylmethyl ether, 110 g. (0.96 mole) in an equal volume of methylene chloride. The temperature is maintained at 10-20 C. with an ice-bath. The mixture is stirred at room temperature for 1 hour longer and then poured over crushed ice-water with stirring. Ether (1 l.) is added,and the mixture stirred under nitrogen until solution occurs. The organic layer is extracted with water (3X), sodium bicarbonate solution (3X) and dried (MgSO4). The solvent is evaporated off at 30 to give crude product as an oil. The oil is vacuum distilled through a jacketed Vigreux column when it gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121 C, at 10 mm. Hg; Rf0.6 on a silica-gel G plate with methylene chloride.
titanium tetrachloride; In dichloromethane;
(A) 3-fluoro-4-methoxybenzaldehyde To a solution of o-fluoroanisole, 101 g. (0.80 mole) in 500 ml. dry methylene chloride is added dropwise over 30 minutes a solution of titanium tetrachloride, 182 g. (0.96 mole, 1.2 equiv.) and alpha,alpha-dichloromethylmethyl ether, 110 g. (0.96 mole) in an equal volume of methylene chloride. The temperature is maintained at 10-20 C. with an ice-bath. The mixture is stirred at room temperature for 1 hour longer and then poured over crushed ice-water with stirring. Ether (1 l.) is added, and the mixture stirred under nitrogen until solution occurs. The organic layer is extracted with water (3*), sodium bicarbonate solution (3*) and dried (MgSO4). The solvent is evaporated off at 30 to give crude product as an oil. The oil is vacuum distilled through a jacketed Vigreoux column when it gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121 C., at 10 mm. Hg; Rf 0.6 on a silica-gel G plate with methylene chloride.
Multi-step reaction with 3 steps
1: benzene; HCl / Erwaermen des Reaktionsgemisches mit AlCl3 auf 40-50grad und anschliessendes Erhitzen mit wss.HCl
2: concentrated sulfuric acid; nitric acid / -10 °C
3: potassium permanganate; water
Initially, <strong>[321-28-8]2-fluoroanisole</strong> (II) was used to synthesize 3-fluoro-4-methoxyacetophenone (III). AlCl3 (0.6 mol) and acetic anhydride (0.4 mol) were placed in 250 ml of dry dicloromethane. The 2-fluoroanisol (0.2 mol) was added dropwise over a period of 30 minutes to the reaction mixture which was then stirred with a magnetic stir bar for two hours. The reaction was judged complete by TLC. The reaction mixture was then poured in ice and stirred for one hour. The CH2 Cl2 layer was separated and the water layer was extracted twice with CH2 Cl2. Organic layers were combined and washed with 3N HCl and water, dried with MgSO4 and passed through a thick pad of silica. The solvent was rotary evaporated to obtain the crude product, which was crystallized from 7% (v/v) ethyl acetate in hexanes to obtain 70% yield of the crystallized product, 3-fluoro-4-methoxyacetophenone (III).
70%
With acetic anhydride;AlCl3;
Initially, <strong>[321-28-8]2-fluoroanisole</strong> (II) was used to synthesize 3-fluoro-4-methoxyacetophenone (III). AlCl3 (0.6 mol) and acetic anhydride (0.4 mol) were placed in 250 ml of dry dicloromethane. The 2-fluoroanisol (0.2 mol) was added dropwise over a period of 30 minutes to the reaction mixture which was then stirred with a magnetic stir bar for two hours. The reaction was judged complete by TLC. The reaction mixture was then poured in ice and stirred for one hour. The CH2 Cl2 layer was separated and the water layer was extracted twice with CH2 Cl2. Organic layers were combined and washed with 3N HCl and water, dried with MgSO4 and passed through a thick pad of silica. The solvent was rotary evaporated to obtain the crude product, which was crystallized from 7% (v/v) ethyl acetate in hexanes to obtain 70% yield of the crystallized product, 3-fluoro-4-methoxyacetophenone (III).
With aluminum (III) chloride; In dichloromethane; at 20℃; for 2.5h;Cooling with ice;
Preparation Example 7 Preparation of 3'-fluoro-4'-methoxy-2-(4-methoxyphenyl)acetophenone thionyl chloride (3.57 g) was added to a solution of 4-methoxyphenylacetic acid (3.32 g, 19.98 mmol) in benzene (30 ml).. After the mixture was heated under reflux for 3 hours, the solvent was distilled off.. To the residue, methylene chloride (50 ml) and <strong>[321-28-8]2-fluoroanisole</strong> (2.10 g) were added.. Under ice cooling, aluminum chloride (13.32 g) was added, followed by stirring for 30 minutes.. The mixture was then stirred at room temperature for 2 hours.. The reaction mixture was added to ice water, followed by extraction with methylene chloride.. The extract was dried over anhydrous sodium sulfate.. The solvent was distilled off under reduced pressure.. The residue so obtained was separated and purified by chromatography on a silica gel column and was then crystallized form ethyl acetate-hexane, whereby the title compound (2.27 g, 49.6%) was obtained as colorless prisms. Melting point: 141.7-142.7 C. Mass (m/Z): 274 (M+).. 1H-NMR (CDCl3) delta: 3.78(3H,s), 3.94(3H,s), 4.15(2H,s), 6.86(2H,d,J=8.7 Hz), 6.98(1H,dd,J=8.5 Hz,J=8.5 Hz), 7.17(2H,d,J=8.7 Hz), 7.73(1H,dd,J=12.0 Hz,J=2.2 Hz), 7.79(1H,ddd,J=8.5 Hz,J=2.2 Hz,J=1.0 Hz). IR (KBr) cm-1: 1681,1613,1516,1436,1286,1254,1223,1177, 1132,1034,1014,889,809,787.
With chlorosulfonic acid; In chloroform; at 20℃; for 14h;
A stirred solution of <strong>[321-28-8]2-fluoroanisole</strong> (33.7 mL, 301 MMOL) in chloroform (250 mL) was cooled to 0C and treated drop-wise with chlorosulfonic acid (50.0 mL, 752 MMOL). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (700 mL) and the separated, aqueous phase extracted with chloroform (2 x 200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated IN VACUO TO YIELD 3-FLUORO-4- METHOXYBENZENESULFONYL CHLORIDE as a fine, white solid (58.6 g, 87%), m. p. 80C ; 1H NMR (400 MHz, DMSO-d6) 5 : 7.32 (m, 1H), 7.25 (dd, J= 11.5, 2.0 Hz, 1H), 7.05 (t, J = 8. 5 HZ, 1 H), 3.78 (s, 3H).
Step A 2-Fluoro-3-methoxyphenylboronic acid n-Butyl lithium (20 mL, 2.5M) was added to a solution of tetramethylpiperidine (8.44 mL, 50 mmol) in THF (125 mL) at -78 C. The reaction mixture was stirred at -78 C. for 1.5 hours. 2-Fluoroanisole (6.31 g, 50 mmol) was added and the mixture was stirred for 8 hours at -78 C. Trimethyl borate (6.17 mL, 55 mmol) was added and the reaction mixture was allowed to warm slowly to room temperature overnight. The mixture was poured into 1N HCl (250 mL). Extraction with EtOAc followed by evaporation gave a sticky solid which was triturated with hexanes to give product (2.19 g, 26% yield).
With n-butyllithium; potassium tert-butylate; In tetrahydrofuran; water;
Step 1. Preparation of 2-fluoro-3-methoxybenzoic acid. A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78 C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours. The reaction was poured into a 2 L Erlenmeyer flask containing dry ice and warmed to room temperature. Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51%) as a yellow solid: mp 155-160 C.; 1 H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19 F NMR (acetone-d6) 300 MHz -134.04(m). Mass spectrum: M+H=171.
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃;
General procedure: To a solution of the selected anisole or biphenyl (13.0mmol) in 30mL of dry CH2Cl2 at 0 C, p-toluoylchloride (2g, 13.0mmol), and AlCl3 (3g, 22.05mmol) were added and the mixture was stirred at rt overnight. After addition of ice, the mixture was diluted with CH2Cl2, washed with NaHCO3 saturated solution, dried and evaporated to dryness.
With Selectfluor; In acetonitrile; at 50℃; for 0.5h;
[00577] With the arylpalladium(II) complexes in hand, the electrophilic reagentSELECTFLUOR " (2) was determined to be the most suitable fluorination source to obtain the arylfluorides 5a-m in stoichiometric reactions from 4a-m regiospecifically in 31-82% isolated yield (Table 3). The scope of this fluorination reaction includes a variety of functional-group- containing arenes, most notably arenes with protic functionality (5d, 5g) that is not compatible with nucleophilic aromatic substitution reactions due to the high basicity of the fluoride ion in anhydrous solvents. Additionally, electron-rich arenes (5b, 5g, 5h), which cannot be synthesized through nucleophilic displacement, are accessible. Electrophilic aromatic fluorination has been reported using conventional fluorination regimes, such as the use of elemental fluorine, but the regioselectivity in these cases is typically poor. The fluorination reaction presented herein affords electron-rich arylfluorides regiospecifically. The scope was further extended to electron-poor (5e, 51) and heteroarenes (5m) and tolerates ortho substitution (5k). The reaction proceeds in 30 minutes under mild conditions (acetonitrile, 50 0C). Acetonitrile can be substituted for acetone as reaction solvent and the yields remain similar. No special care was taken to exclude moisture or air during manipulation; the reactions can be performed in open containers and the yields of the isolated products remained the same. The optimal temperature for the fluorination reaction was determined to be 50 0C; the reactions proceed at 23 0C, but inferior yields of product were obtained.
A solution of 2 fluoro-anisole (6. 0 g, 47 mmol) and N, N, N', N'-teteramethylethylenediamine in THF (250 mL) was cooled to-78C and treated dropwise with sec-butyl lithium (1.3 M/CYCLOHEXANE, 37.9 mL, 49 mmol). The mixture was stirred for 2 hours at- 78C and then treated with dimethylformamide (3.6 mL, 47 mmol). Stirring continued for an additional 10 minutes and then acetic acid (20 mL) followed by water (150 mL) was added to the reaction. The reaction was warmed to ambient temperature and then diluted with ethyl acetate. The organic layer was extracted first with IN HCL, and then with brine. The solution was dried over MgSO4 and concentrated under reduced pressure to afford crude 2 flouro-3- methoxybenzaldehyde (4.7 g, 64%). In a manner analogous to that described in Intermediate 13,2 flouro-3-methoxybenzaldehyde (4.7 g, 30 mmol), malonic acid (4.76 g, 45 mmol), pyridine (50 mL) and piperidine (1. 5 mL) afforded the title product (2.5g, 42%). IH-NMR- (400 MHZ, D6 DMSO) 8, 7.65 (d, J=16. 1HZ, LH), 7. 34 (m, LH), 7.18 (m, 2H), 6.58 (d, J= 16. 1Hz, 1H), 3.83 (s, 3H).
57.3%
Add 3-fluoroanisole (85.0g, 0.67mol), tetrahydrofuran (3540mL), tetramethylethylenediamine (78.3g, 0.67mol) at room temperature,Replace with nitrogen three times, turn on stirring,Cooled to -50 ~ -78 , was added dropwise a solution of sec-butyllithium (870mL, 1.3M), after the addition was complete stirring incubated 2 to 3 hours, a solution of N, N- dimethylformamide (67.5g, 0.92 mol), heat and stir for 1 hour,After the reaction was completed, a 13% acetic acid aqueous solution (1464 g) was added dropwise at -50 to -78 C, and the layers were separated. The aqueous phase was extracted with ethyl acetate (350 mL * 3), and the organic phases were combined.After washing with water (500mL), 1N hydrochloric acid,The organic phase is concentrated to no droplets,A pale yellow mixture was obtained and crystallized from methyl tert-butyl ether (150 mL) to give a white solid,Drying gave compound II (57.7 g, 57.3%).
2-Fluoro-3-methaxybenzaldehyde 2-Fluoroanisole (2.24 mL) was dissolved in THF (25 mL) under an argon atmosphere, and an n-butyl lithium, (2.71 mol/L hexane solution, 7.38 mL) and N,N,N', N', N'-pentamethyldiethylene triamine (4.20 mL) were added thereto at -78C, followed by stirring at -78C for 2 hours. Then, DMF (2.41 mL) was added thereto at -78C, followed by stirring at room temperature for 1.5 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the extracted layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain the desired product (2.36 g) as a yellow powder. 1H-NMR (CDCl3, 400 MHz): delta 3.94 (3H, s), 7.16-7.44 (3H, m), 10.39 (1H, s).
A solution of 2-fluoro-anisole (6.0 g, 47 mmol) and N, N, Nu', '- tetramethylethylenediamine in THF (250 mL) was cooled to - 78 C and treated dropwise with sec -butyl lithium (1.3 M in cyclohexane, 38 mL, 49 mmol). The mixture was stirred for 2 h at - 78 C and then treated with dimethylformamide (3.6 mL, 47 mmol). Stirring continued for an additional 10 min and then acetic acid (20 mL) followed by water (150 mL) was added to the mixture. The mixture was warmed to ambient temperature and then diluted with ethyl acetate. The organic layer was washed with 1 M HCI, and brine. The organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude 2-flouro-3-methoxybenzaldehyde (4.7 g, yield 64%) as a yellow solid. NMR (400 MHz, CDC13) (ppm) 10.40 (s, 1H), 7.45-7.40 (m, 1H), 7.23-7.18 (m, 2H), 3.94 (s, 3H).
The mixture of 2-chloro-5-nitrobenzoyl chloride (4.0 g, 18.18 mmol), <strong>[321-28-8]2-fluoroanisole</strong> (5.0 mL) and AlCl3 (3.63 g, 27.27 mmol) was stirred at room temperature for 24 h. The reaction mixture was poured into 10% HCl aqueous solution cooled in ice bath, which was extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 1) and dried over anhydrous Na2SO4. The crude product was provided after evaporation and recrystalized with EtOAc to give compound 2b as white solid (5.40 g, 96%); mp 113-115 C; 1H NMR (DMSO-d6) delta (ppm): 8.41 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H, ArH), 8.35 (d, J = 2.4 Hz, 1H, ArH), 7.88 (d, J = 8.7 Hz, 1H, ArH), 7.60-7.67 (m, 2H, ArH), 7.28 (t, J = 8.4 Hz, 1H, ArH), 4.01 (s, 3H, OCH3); HRMS (ESI): m/z, Calcd for C14H10ClFNO4 [M+H+]: 310.0277, Found 310.0297.
In 1,2-dichlorotrifluoroethyl-trifluoromethylether; at -40℃;Inert atmosphere;
General procedure: The procedure consists of bubbling a stream of hypofluorite (5.5 NL/h: He = 80%, FTM = 18.5%, COF2 = 1.5%) into a solution of the aromatic compounds maintained at the desired temperature (-30 C; -80 C) in a semi-batch method [57].The solubility of the aromatic compounds was measured by carrying out a cloud-point measurement in selected solvents. All the aromatics tested (alpha,alpha,alpha-trifluoro-toluene, toluene, benzene, chloro-benzene, methoxybenzene) are soluble at concentrations between 4% and 5% in the chloro-fluoro-ether (CF3OCFClCF2Cl) used as reaction solvent.A cylinder containing 150 ml of a diluted (3%) solution of the aromatic substrate in 1,2-dichlorotrifluoroethyl-trifluoromethyl-ether (CF3OCFClCF2Cl) was prepared at room temperature. This solution was then poured in the 250 ml stainless steel stirred reactor, cooled at -40 C and then stripped with helium for 15 min to eliminate the dissolved air since oxygen strongly interacts with radical based mechanisms.Subsequently the hypofluorite stream was bubbled in the reactor kept at -40 C under vigorous mechanical stirring. For one mole of aromatic substrate only 0.05-0.88 mol of hypofluorite were added, obtaining only a partial conversion of the aromatics.
potassium 3-methoxyphenyltrifluoroborate[ No CAS ]
[ 459-60-9 ]
[ 321-28-8 ]
Yield
Reaction Conditions
Operation in experiment
1: 25 %Spectr.
2: 15 %Spectr.
With iron(III) chloride; potassium fluoride; Selectfluor In ethyl acetate at 55℃; Overall yield = 40 %Spectr.;
1-Fluoro-4-methoxybenzene (2a) and 1-Fluoro-2-methoxybenzene(3a) (Table 4, Entry 8)
General procedure: FeCl3 (60.8 mg, 0.375 mmol, 1.5 equiv), Selectfluor (177 mg, 0.5mmol, 2.0 equiv), and KF (43.6 mg, 0.75 mmol, 3.0 equiv) wereweighed into a 10-mL microwave vial. EtOAc (2.5 mL) was added, andthe vial was sealed with a septum. The mixture stirred at 25 °C for 5min. Then, potassium aryltrifluoroborate (0.25 mmol, 1.0 equiv) wasadded to the mixture, and the vial was sealed with microwave capand the mixture stirred at 55 °C for 10-15 h. The resulting solutionwas cooled to r.t.The volatile products were not isolated and their yields were determinedonly by 19F NMR of the reaction mixture. For the compoundsreported with 19F NMR yields, 4-fluorobenzonitrile (0.25 mmol) wasadded as reference to the mixture, stirred for 5 min, and then dilutedwith t-BuOMe or hexane (2.5 mL) and H2O (3.0 mL). The layers wereseparated and an organic aliquot was withdrawn for the 19F NMRmeasurement in either in CDCl3 or DMSO-d6. The 19F NMR spectroscopicdata were identical to those reported previously in the literature.The identity of the product was further confirmed by GC-MSanalysis. For the compounds reported as isolated yields, the mixture was dilutedwith t-BuOMe or hexane (2.5 mL) and H2O (4.0 mL). Then organicphase was separated, the aqueous phase was extracted with t-BuOMe(2 × 5 mL). The combined organic phases were dried (anhyd Na2SO4),the solvent was removed at 1.0 bar and the residue was purified bycolumn chromatography (Combiflash, hexanes) to afford the desiredcompounds. The identity of the product was confirmed by 1H NMRand GC-MS analyses.
2,6,11-trifluoro-3,7,10-trimethoxytriphenylene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With trifluorormethanesulfonic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 1,2-dichloro-ethane; at 20℃; for 10h;Inert atmosphere;
General procedure: An oven-dried 20 mL scintillation vial, equipped with a magnetic stir-bar, was charged with the starting material (1.0 equiv), DDQ (1.0 equiv), trifluoromethanesulfonic acid (1.4% v/v, 3.0 equiv), and 1,2-dichloroethane (0.05 M). The reaction mixture was then allowed to stir at ambient temperature for 10 h. After this time, methanol (0.05M) was added, and the solution was then allowed to stir at ambient temperature for an additional hour. Upon addition of the methanol, some solids precipitated out of the solution. Then, the solvent was removed from the heterogeneous mixture under reduced pressure. The crude material was purified by either recrystallization (methanol/DCM) or silica-gel column chromatography (hexanes/DCM) to give the title compounds.
With 1,10-Phenanthroline; potassium carbonate; Selectfluor; copper(l) chloride; In nitromethane; at 90℃; for 6h;Sealed tube;
General procedure: To a 5 mL screw-capped vial equipped with a 15×10 mm spinvane triangular-shaped Teflon stirbar, simple arene 1(0.5 mmol), saccharin (1.0 mmol), Selectfluor (1.0 mmol), K2CO3 (1.0 mmol) and CuCl (0.1 mmol) were added in nitromethane (3.0 mL). The mixture was sealed with aTeflon-lined cap and stirred at 90 C for 6.0 h (monitoredby TLC), extracted with dichloromethane (5×3 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel column chromatography to give aromatic amine 2. The characterizations of aromatic amines 2 and 4 were listed in the Supporting Information online.
With potassium carbonate; In tetrahydrofuran; at 50℃; for 1h;
Dissolve o-fluorophenol (4.0 g, 35.7 mmol) in tetrahydrofuran (30 mL) and add potassium carbonate (18.5 g, 0.13 mol) and dimethylsulfate (4.2 mL, 44.3 mmol) Reaction 1h, TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure (water pump) to give a pale yellow oily liquid (Intermediate A-1c) (3.74 g, Yield 83%). delta H (300 MHz; CDCl 3) 7.07-6.84 (4H, m), 3.87 (3H, s)
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; C20H28N4O2Pd(2+)*2BF4(1-); In acetonitrile; at 23℃; for 24h;
General procedure: A 100 ml pressure tube was charged with palladium complex 1 (13.6 mg, 21.4 mumol, 2.50 mol%), Ru(bipy)3(PF6)2 (55.2 mg, 64.2 mumol, 7.50 mol%) and <strong>[140681-55-6]Selectfluor</strong> (455 mg, 1.28 mmol, 1.50 equiv.). Acetonitrile (4.3 ml, 0.20 M) was added, followed by toluene (91.1 mul, 0.856 mmol, 1.00 equiv.) via a syringe. The reaction mixture was stirred at 23 C for 24 hours. Saturated aqueous sodium thiosulfate (8.6 ml) and water (8.6 ml) were added, the pressure tube was sealed and the reaction mixture was stirred at 100 C for two hours. After cooling to 23 C, the reaction mixture was transferred to a separatory funnel. Dichloromethane (20 ml) and ethylenediamine (1.5 ml) were added and the organic layer was washed with 6 M aqueous sodium hydroxide (5 ml). The aqueous layer was extracted with dichloromethane (2 × 10 ml). The combined organic layers were extracted with 1 M aqueous hydrochloric acid (2 × 15 ml). Ethylenediamine (5.0 ml) was added to the combined acidic aqueous layers, followed by basification with 6 M aqueous sodium hydroxide (8 ml). The basic aqueous layer was extracted with dichloromethane (3 × 15 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford a red oil. The residue was purified by chromatography on silica gel, eluting with a solvent mixture of dichloromethane/methanol/28% aqueous ammonium hydroxide (97.5/2.0/0.5 v/v/v) to afford 119 mg of the title compound as a yellow oil (79% yield).
(5-bromo-2-chlorophenyl)-(3-fluoro-4-methoxy-phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With aluminum (III) chloride; In dichloromethane; at 20 - 30℃; for 4h;
5-Bromo-2-chlorobenzoyl chloride 9b (124 g, 0.49 mol)Was dissolved in dichloromethane (600 mL)Cooled to -5 C,<strong>[321-28-8]2-fluoroanisole</strong> (61.8 g, 0.49 mol) was added,Anhydrous aluminum chloride (133 g, 1.0 mol) was added in portions,The resulting mixture was stirred at room temperature for 4 hours.The reaction solution is poured into crushed ice,Extracted with dichloromethane (400 mL x 2)The combined organic phases were washed successively with saturated sodium bicarbonate solution (300 mL)And saturated brine (300 mL)Dried over anhydrous sodium sulfate,Concentrated under reduced pressure,To the residue was added anhydrous ethanol (500 mL) and stirred at 0 C for 30 minutes. The solid was collected by suction filtration,The title compound 9c was obtained as a white solid (129 g, 77%).
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; In diethyl ether; at -78 - 20℃; for 6h;
(1) 1.0 g, 1 equiv. of the compound of formula II was dissolved in a constant pressure dropping funnel using 5 mL of diethyl ether to prepare a diethyl ether solution of the compound of formula II, and set aside;The ethyl chloroacetate of 1 equiv. was dissolved in a constant pressure dropping funnel using diethyl ether (3 mL) in diethyl ether.(2) Add 1.2 eq. of n-butyllithium in diethyl ether to the reactor in the form of a compound of formula II, cool to -78 C, add 1.2 equiv. of TMEDA, stir and disperse, and then step (1) The diethyl ether solution of the compound II was added dropwise to the reaction system, and the reaction system was heated to -50 C after the dropwise addition.After stirring for 1 h, the mixture was cooled to -78 C;(3) The ethyl ether solution of ethyl chloroacetate in the step (1) is added dropwise to the reaction system, and after the dropwise addition, the reaction system is slowly raised to room temperature, and the temperature is raised.The mixture was partitioned between ethyl acetate and 1N aqueous HCl. To obtain a compound of formula VI,Yield 52.2%,
(1) 1.0 g, 1 equiv. of the compound of formula II was dissolved in a constant pressure dropping funnel using 5 mL of THF, and a solution of 1.6 equiv. of diisopropylamino lithium in THF was added to the reactor as a compound of formula II. Medium, stirring and cooling to -78 CAfter that, the THF solution of the compound of the formula II is added dropwise to the reactor, and the reaction system is heated to -50 C, and the mixture is kept under stirring for 1 hour;(2) Ethyl glyoxylate was dissolved in 7 mL of toluene, added to the reactor, stirred under heat for 2 h, and the reaction system was cooled to room temperature;(3) 10 mL of ethyl acetate and 1N hydrochloric acid solution were separately added to the reactor, and after extraction, the organic layer was separated, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness and concentrated. After separation by column chromatography, ethyl 2-(2-fluoro-3-methoxyphenyl)-2-hydroxyacetate of the formula I was obtained in a yield of 85%.
1.5 g, 1.0 equiv. of the compound of formula II was dissolved in 8 mL of THF solution for use. After adding 1.4 equiv. of diisopropylamide lithium in THF to the reactor, and cooling and cooling to -85 C, A solution of the compound of the formula II in THF is added dropwise to the reaction system, and the mixture is dropped. After the reaction solution was heated to -55 C, the reaction was kept for 1.5 h. During the heat preservation reaction, ethylene oxide is introduced into the reaction system until the TLC detection reaction is complete; after the reaction was completed, the reaction mixture was partitioned between ethyl acetate and 0.5N aqueous hydrochloric acid. The organic phase was separated and the organic phase was washed with brine and dried over sodium sulfate. Finally concentrate the solvent to dryness, The residue is chromatographed to give the compound of formula VI, The yield is 88.6%.
With 3,6?di?tert?butyl?9?mesityl?10?phenylacridin?10?ium tetrafluoroborate; In 1,2-dichloro-ethane; at 25℃; for 48h;Irradiation; Inert atmosphere;
1-Fluoro-2-methoxybenzene a13 (0.0126 g, 0.10 mmol), acridine photosensitizer (A) (0.0029 g, 0.005 mmol) and L-valine ethyl ester b1 were added sequentially under argon protection. 0.0218 g, 0.15 mmol), 1,2-dichloroethane (DCE) 2.0 mL.The reaction was irradiated for 48 hours under a 6W blue light at room temperature.After completion of the reaction, the solvent was evaporated under reduced pressure and purified by column chromatography, eluting solvent: (V) petroleum ether / (V) ethyl acetate = 20/1.A yellow liquid (30) (0.0188 g, 95%) was obtained.
In a 500 ml three-necked flask, 15.56 g of pentamethyl-di- (ethylene) triamine and 200 ml of THF were added. 35.2 ml of n-BuLi was added dropwise at -78 C. After stirring for 40 minutes, 10 g of <strong>[321-28-8]2-fluoroanisole</strong> was added dropwise. After stirring at -78 C for 1 hour, 100 ml of 22.84 g of a THF solution was added dropwise. After stirring at -78 C for 2 hours, the reaction solution was warmed to room temperature, quenched with 400 ml of a saturated ammonium chloride solution, and the organic phase was removed by rotary evaporation. To the residue, 200 ml of ethyl acetate was added, and the organic phase was washed with a saturated solution of sodium thiosulfite and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 18.16 g of a yellow liquid (yield 90.89%).
With 3,6‐di‐tert‐butyl‐9‐(2,6‐dimethylphenyl)‐10‐(4‐(trifluoromethyl)phenyl)acridin‐10‐iumtetrafluoroborate; sodium hydrogencarbonate In 2,2,2-trifluoroethanol at 45 - 50℃; for 18h; Irradiation; Inert atmosphere; Sealed tube;
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