* 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 the American Chemical Society, 2000, vol. 122, # 4, p. 712 - 713
2
[ 10272-07-8 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
[2] Patent: WO2011/17125, 2011, A1, . Location in patent: Page/Page column 109
3
[ 20469-65-2 ]
[ 52189-63-6 ]
Reference:
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 12, p. 2219 - 2222
4
[ 17275-82-0 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
5
[ 99-10-5 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
6
[ 17213-58-0 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
7
[ 75996-26-8 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
8
[ 51707-38-1 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
9
[ 1132-21-4 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
10
[ 17213-57-9 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
11
[ 54132-76-2 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
12
[ 72470-95-2 ]
[ 52189-63-6 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
13
[ 52189-63-6 ]
[ 75996-29-1 ]
Yield
Reaction Conditions
Operation in experiment
97%
With boron tribromide In dichloromethane at -30 - 25℃;
[00154] A solution of dimethoxy fluorobenzene (1) (10 g, 64 mmol ) in dry dichloromethane (40 mL) was cooled to -30 °C. To the cooled solution was added a solution of BBr3 (35.93 mL, 384 mmol ) in 60 mL of DCM slowly (in drops) over 30 min. After completion of addition, the reaction mixture was allowed to reach 25 °C and stirred for 12 h. After completion of reaction (by TLC using 30percent ethyl acetate and pet ether as eluting solvent), reaction mixture was cooled to 0 °C and then slowly quenched with water and stirred for 30 min at 25 °C. The reaction mixture was extracted with dichloromethane (3 x 100 mL) and the combined organic layer was washed with sodium bicarbonate, dried over Na2S04 and concentrated to get the product (2) as light brown solid. Yield: 8g (97percent)
97%
With boron tribromide In dichloromethaneCooling with acetone-dry ice
[0321} Preparation of 5-fluorobenzene- 1 ,3-diol: To a solution of 1 -fluoro-3 ,5-dimethoxybenzene (2.0 g, 12.8 mmol) in dichloromethane (50 mL) cooled in a dry ice/acetone bath was added a solution of boron tribromide (2.8 mL, 29.0 mmol) in dichloromethane (50 mL) dropwise over half an hour. The reaction mixture was stirred over night during which reaction temperature raised to room temperature, and then cooled in a ice/water bath. 60 mL of methanol was added slowly.Organic solvents were evaporated under vaccum. The residue was extracted between ethyl acetate and aqueous sodium bicarbonate. The ethyl acetate phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 0-40percent ethyl acetate in hexanes to give desired product (1.6 g, 97percent yield) LC-MS: 127 (M-H).
93%
With boron tribromide In dichloromethane at -30℃; for 2 h;
To a -30° C. solution of 1-fluoro-3,5-dimethoxybenzene (1.56 g, 10 mmol) in 10 mL of CH2Cl2 was added 10 mL of BBr3/CH2Cl2 at while the solution was stirring. The reaction mixture was stirred at -30° C. for 2 h and then allowed to warm up to RT overnight. To the reaction mixture was added water and the product was extracted with EtOAc (3*10 mL). The organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, then the combined organic layers were concentrated under reduced pressure to afford a crude product. The residue was purified by flash chromatography (1:1 EtOAc/hexanes) to give 5-fluorobenzene-1,3-diol as a yellow solid (1.2 g, 93percent). MS (ES+) C6H5FO2 requires: 128. found: 129 [M+H]+.
Reference:
[1] Patent: WO2013/90921, 2013, A1, . Location in patent: Paragraph 00154
[2] Patent: WO2014/153000, 2014, A1, . Location in patent: Paragraph 0321
[3] Patent: US2016/60260, 2016, A1, . Location in patent: Paragraph 0237
[4] Journal of Organic Chemistry, 1997, vol. 62, # 19, p. 6469 - 6475
[5] Journal of Materials Chemistry, 2002, vol. 12, # 5, p. 1316 - 1324
[6] Journal of Organic Chemistry, 1999, vol. 64, # 26, p. 9719 - 9721
[7] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1658 - 1666
[8] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 6, p. 1504 - 1507
[9] Patent: US6162931, 2000, A,
[10] Patent: WO2013/177668, 2013, A1, . Location in patent: Page/Page column 55-56
[11] Patent: WO2014/5217, 2014, A1, . Location in patent: Page/Page column 24; 25
[12] Patent: WO2014/29007, 2014, A1, . Location in patent: Paragraph 22; 23; 24
14
[ 52189-63-6 ]
[ 850793-25-8 ]
Yield
Reaction Conditions
Operation in experiment
67%
With boron tribromide In dichloromethane at -15 - 20℃; for 1.66 h;
EXAMPLE 50; 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzonitrile; Step 1: 3-fluoro-5-methoxyphenol (50-1); Under nitrogen atmosphere, 1-fluoro-3,5-dimethoxybenzene (25 g, 160 mmol) was diluted in CH2Cl2 (200 mL, 0.8M) and then cooled to -15° C. Next, BBr3 (176 mL, 176 mmol, 1M in CH2Cl2) was slowly added to the reaction mixture. The reaction mixture was stirred at -15° C. for one and a half hours and at room temperature for 10 minutes. The reaction mixture was then cooled to 0° C. and slowly quenched with water (150 mL). The aqueous layer was then extracted with methylene chloride (3.x.100 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (1percent-30percent EtOAc/Hexanes) gave the mono demethylated product (50-1) (15 g, 67percent).
54%
Stage #1: With boron tribromide In dichloromethane at 0 - 20℃; for 22 h; Stage #2: With ammonia In dichloromethane; water at 20℃; for 1.5 h;
Boron tribromide (1 M in dichloromethane, 9mL, 89.985mmol) was added drop wise to an ice- cooled solution of 3,5-dimethoxy fluorobenzene (3ml, 22,496mmol) in dichloromethane (2OmL) and the mixture was stirred at O0C to room temperature for 4 hours. The solution was cooled to O0C, further boron tribromide (4ml, 44.992mmol) was added and stirring continued, warming to room temperature for an additional 18 hours. The reaction was quenched with 0.88 ammonia solution and stirred at room temperature for 90 minutes. The organic layer was separated and extracted with 2N sodium hydroxide (30ml), which was then acidified to pH1 by drop wise addition of concentrated hydrochloric acid. The aqueous layer was then re- extracted with dichloromethane (3x15mL), the combined organic solution was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 54percent yield, 1.72g. 1HNMR(400MHz, CD3OD) δ: 3.72(s, 3H), 6.07-6.15(m, 3H)
53%
With boron tribromide In dichloromethane at -78 - 0℃;
Example 53 3- {4- [3-Fluoro-5- (2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}- propionic acid Step A 3-Fluoro-5-methoxy-phenol A-78 °C solution of l-fluoro-3, 5-dimethoxybenzene (4. 98 g, 31.9 mmol) in dry CH2C12 (50 mL) is treated with a 1 M CH2C12 solution of boron tribromide (128 mL, 128 mmol), and the mixture is warmed to 0 °C and stirred under N2. Upon completion, the mixture is poured into ice water and extracted with Et2O. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 5/1 to 1/1 to hexanes/ethyl acetate to afford 2.40 g (53percent) of the title compound. Rf= 0.49 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDCl3). MS (ES-) m/z mass calculated for C7H702F 142, found 141 (M-1,100percent).
With boron tribromide; In dichloromethane; at -30 - 25℃;
[00154] A solution of dimethoxy fluorobenzene (1) (10 g, 64 mmol ) in dry dichloromethane (40 mL) was cooled to -30 C. To the cooled solution was added a solution of BBr3 (35.93 mL, 384 mmol ) in 60 mL of DCM slowly (in drops) over 30 min. After completion of addition, the reaction mixture was allowed to reach 25 C and stirred for 12 h. After completion of reaction (by TLC using 30% ethyl acetate and pet ether as eluting solvent), reaction mixture was cooled to 0 C and then slowly quenched with water and stirred for 30 min at 25 C. The reaction mixture was extracted with dichloromethane (3 x 100 mL) and the combined organic layer was washed with sodium bicarbonate, dried over Na2S04 and concentrated to get the product (2) as light brown solid. Yield: 8g (97%)
97%
With boron tribromide; In dichloromethane;Cooling with acetone-dry ice;
[0321} Preparation of 5-fluorobenzene- 1 ,3-diol: To a solution of 1 -fluoro-3 ,5-dimethoxybenzene (2.0 g, 12.8 mmol) in dichloromethane (50 mL) cooled in a dry ice/acetone bath was added a solution of boron tribromide (2.8 mL, 29.0 mmol) in dichloromethane (50 mL) dropwise over half an hour. The reaction mixture was stirred over night during which reaction temperature raised to room temperature, and then cooled in a ice/water bath. 60 mL of methanol was added slowly.Organic solvents were evaporated under vaccum. The residue was extracted between ethyl acetate and aqueous sodium bicarbonate. The ethyl acetate phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 0-40% ethyl acetate in hexanes to give desired product (1.6 g, 97% yield) LC-MS: 127 (M-H).
93%
With boron tribromide; In dichloromethane; at -30℃; for 2h;
To a -30 C. solution of <strong>[52189-63-6]1-fluoro-3,5-dimethoxybenzene</strong> (1.56 g, 10 mmol) in 10 mL of CH2Cl2 was added 10 mL of BBr3/CH2Cl2 at while the solution was stirring. The reaction mixture was stirred at -30 C. for 2 h and then allowed to warm up to RT overnight. To the reaction mixture was added water and the product was extracted with EtOAc (3*10 mL). The organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, then the combined organic layers were concentrated under reduced pressure to afford a crude product. The residue was purified by flash chromatography (1:1 EtOAc/hexanes) to give 5-fluorobenzene-1,3-diol as a yellow solid (1.2 g, 93%). MS (ES+) C6H5FO2 requires: 128. found: 129 [M+H]+.
90.4%
With boron tribromide; In dichloromethane; at 20℃;Cooling with ice;
Step A: The compound <strong>[52189-63-6]1,3-dimethoxy-5-fluorobenzene</strong> (6.50 g, 41.6 mmol) was dissolved in dichloromethane (65 ml).Boron tribromide (24.0 g, 95.7 mmol) was added dropwise under ice-water bath. After the addition was completed, the mixture was warmed to room temperature and stirring was continued overnight. Add the reaction droplets to the ice water,Adjust the pH to 7-8 with saturated sodium bicarbonate solution.The organic layer was washed with brine (100 mL) The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:20 to 1:10) to give 5-fluorobenzene-1,3-diol ( 93) (4.82g),The yield was 90.4%.
3.69 g (92%)
Example 16 Preparation of 5-fluororesorcinol (16) Using general method E, <strong>[52189-63-6]3,5-dimethoxyfluorobenzene</strong> (5.0 g, 32.0 mmol, Aldrich) gives Compound 16 as 3.69 g (92%) of a colorless crystalline solid: m.p. 134-136 C.; 1 H-NMR (d6 -DMSO) 9.60 (s, 2H), 6.05 (s, 1H), 5.97 (d, 2H). 19 F-NMR (d6 -DMSO) 108.26 (t, J=11.1 Hz,). Anal. calc. for C6 H5 FO2: C, 56.26; H, 3.93. Found: C, 56.33; H, 3.98.
With boron tribromide; In dichloromethane; at 0 - 20℃; for 19h;
Step 5: Intermediate 29-f To a solution of l-fluoro-3,5-dimethoxybenzene (12.5 g, 80 mmol) in dichloromethane (80 ml), cooled to 0C, was added 1.0 M solution of boron tribromide in dichloromethane (200 ml, 200 mmol), drop wise over a period of 30 minutes. The reaction was stirred for 1 hour at 0C and then slowly warmed to room temperature and stirred for 18 hours. The reaction was cooled to 0C and quenched by the slow addition of MeOH and water. After stirring at room temperature for 1 hour the mixture was filtered and volatiles were removed in vacuo. Ethyl acetate was added to the residue; a precipitate formed and was collected by filtration to provide intermediate 29-f as an orange solid
With boron tribromide; In dichloromethane; at 0 - 20℃; for 19h;
To a solution of <strong>[52189-63-6]1-fluoro-3,5-dimethoxybenzene</strong> (12.5 g, 80.0 mmol) in dichloromethane (80 ml), cooled to 0 C, was added a 1.0 M solution of BBr3 in dichloromethane (200 ml, 200 mmol), dropwise over a 30 minutes period. The reaction was stirred for 1 hour at 0 C and then slowly warmed to room temperature and stirred for 18 hours. The reaction was cooled to 0 C and quenched by slow addition of MeOH and water. After stirring at room temperature for 1 hour the mixture was filtered and volatiles were removed in vacuo. The solid was washed twice with ethyl acetate; the filtrate was concentrated in vacuo to provide intermediate 8-b as an orange solid.
With boron tribromide; In dichloromethane; at 0 - 20℃; for 19.5h;
Step 4: Intermediate 5-f: To a solution of 1-fiuoro-3,5-dimethoxybenzene (12.5 g, 80 mmol) in dichloromethane (80 ml) cooled to 0C was added dropwise over a period of 30 minutes a 1.0 M solution of BBr3 in dichloromethane (200 ml, 200 mmol). The reaction was stirred for 1 hour at 0C and then slowly warmed to room temperature and stirred for 18 hours. The reaction was cooled to 0C and quenched by slow addition of MeOH and water. After stirring at room temperature for 1 hour the mixture was filtered and volatiles were removed under reduced pressure. Ethyl acetate was added to the residue; a precipitate formed and was collected by filtration to provide intermediate 5-f as orange solid
1.2 g
With boron tribromide; In dichloromethane; at 20℃;
Weigh 1.5g of <strong>[52189-63-6]1-fluoro-3,5-dimethoxybenzene</strong> and dissolve it with CH2Cl2.40 ml of BBr3/CH2Cl2 solution was added dropwise under ice bath, and reacted at room temperature overnight.After the end, the excess boron tribromide is quenched with methanol.Add ice water, stir, distill off most of the CH2Cl2 under reduced pressure, and extract the aqueous phase three times with ethyl acetate.The ethyl acetate layer was combined, dried with saturated brine, and EtOAc evaporated.The product was obtained in an amount of 1.2 g, which was used without further purification.
With tetrafluoroboric acid; sodium nitrite; In water; at 20℃; for 0.5h;
Step 1: 1 -Fluoro-3 ,5-dimethoxybenzene[0360] To a mixture of 3,5-dimethoxybenzenamine (6.12 g, 40.0 mmol) and tetrafluoroboric acid (8% solution, 70 mL) was added dropwise a solution of sodium nitrite (2.84 g, 41.2 mmol) in water (10 mL). After stirring at room temperature for 30 min, the reaction mixture was filtered. The solid was collected and washed with water (2x10 mL) and dried under high vacuum. The resulting red solid was suspended in dry hexane (50 mL) and heated to reflux for 2 hr. The mixture was filtered and the filtrate was concentrated to give the crude product as a yellow oil (3.03 g, Yield: 48.5%). MS (ESI) m/z = 157 [M + H]+.
With boron tribromide; In dichloromethane; at -15 - 20℃; for 1.66h;
EXAMPLE 50; 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzonitrile; Step 1: 3-fluoro-5-methoxyphenol (50-1); Under nitrogen atmosphere, <strong>[52189-63-6]1-fluoro-3,5-dimethoxybenzene</strong> (25 g, 160 mmol) was diluted in CH2Cl2 (200 mL, 0.8M) and then cooled to -15 C. Next, BBr3 (176 mL, 176 mmol, 1M in CH2Cl2) was slowly added to the reaction mixture. The reaction mixture was stirred at -15 C. for one and a half hours and at room temperature for 10 minutes. The reaction mixture was then cooled to 0 C. and slowly quenched with water (150 mL). The aqueous layer was then extracted with methylene chloride (3×100 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (1%-30% EtOAc/Hexanes) gave the mono demethylated product (50-1) (15 g, 67%).
54%
Boron tribromide (1 M in dichloromethane, 9mL, 89.985mmol) was added drop wise to an ice- cooled solution of <strong>[52189-63-6]3,5-dimethoxy fluorobenzene</strong> (3ml, 22,496mmol) in dichloromethane (2OmL) and the mixture was stirred at O0C to room temperature for 4 hours. The solution was cooled to O0C, further boron tribromide (4ml, 44.992mmol) was added and stirring continued, warming to room temperature for an additional 18 hours. The reaction was quenched with 0.88 ammonia solution and stirred at room temperature for 90 minutes. The organic layer was separated and extracted with 2N sodium hydroxide (30ml), which was then acidified to pH1 by drop wise addition of concentrated hydrochloric acid. The aqueous layer was then re- extracted with dichloromethane (3x15mL), the combined organic solution was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 54% yield, 1.72g. 1HNMR(400MHz, CD3OD) delta: 3.72(s, 3H), 6.07-6.15(m, 3H)
53%
With boron tribromide; In dichloromethane; at -78 - 0℃;
Example 53 3- {4- [3-Fluoro-5- (2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}- propionic acid Step A 3-Fluoro-5-methoxy-phenol A-78 C solution of l-fluoro-3, 5-dimethoxybenzene (4. 98 g, 31.9 mmol) in dry CH2C12 (50 mL) is treated with a 1 M CH2C12 solution of boron tribromide (128 mL, 128 mmol), and the mixture is warmed to 0 C and stirred under N2. Upon completion, the mixture is poured into ice water and extracted with Et2O. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 5/1 to 1/1 to hexanes/ethyl acetate to afford 2.40 g (53%) of the title compound. Rf= 0.49 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDCl3). MS (ES-) m/z mass calculated for C7H702F 142, found 141 (M-1,100%).
Step 5: Intermediate 29-f [0173] To a solution of <strong>[52189-63-6]1-fluoro-3,5-dimethoxybenzene</strong> (12.5 g, 80 mmol) in dichloromethane (80 ml), cooled to 0 C., was added 1.0 M solution of boron tribromide in dichloromethane (200 ml, 200 mmol), drop wise over a period of 30 minutes. The reaction was stirred for 1 hour at 0 C. and then slowly warmed to room temperature and stirred for 18 hours. The reaction was cooled to 0 C. and quenched by the slow addition of MeOH and water. After stirring at room temperature for 1 hour the mixture was filtered and volatiles were removed in vacuo. Ethyl acetate was added to the residue; a precipitate formed and was collected by filtration to provide intermediate 29-f as an orange solid.
...presented by the following formula (4) which can respectively correspond to the formula (1) can be obtained. (D) Fluorine substituted aromatic compound represented by the formula (4) corresponding to the hydroxy compound wherein X1 is a substituent of the group (a) in the formula(1): ... 2-methoxyfluorobenzene, 3-methoxyfluorobenzene, 4-methoxyfluorobenzene, 2-ethoxyfluorobenzene, 3-ethoxyfluorobenzene, 4-ethoxyfluorobenzene, 2,3-dimethoxyfluorobenzene, 2,6-dimethoxyfluorobenzene, 3,4-dimethoxyfluorobenzene, 3,5-dimethoxyfluorobenzene, 2-fluorobiphenyl, 3-fluorobiphenyl, 4-fluorobiphenyl, 2,6-diphenylfluorobenzene, 4-phenoxyfluorobenzene, 2-nitrofluorobenzene, 3-nitrofluorobenzene, 4-nitrofluorobenzene, ...
62
[ 79-03-8 ]
[ 52189-63-6 ]
[ 864866-61-5 ]
Yield
Reaction Conditions
Operation in experiment
With aluminum (III) chloride;zinc(II) chloride; In 1,2-dichloro-ethane; at -10 - 20℃; for 2h;
Under nitrogen atmosphere, 5 ml solution of dichloroethane with 2 g of <strong>[52189-63-6]3,5-dimethoxy-1-fluorobenzene</strong>, and 5 ml solution of dichloroethane with 1.3 mg of propionyl chloride were dropped sequentiallly at -10C to 40 ml solution of dichloroethane with 2.4 g of alumimium trichloride and 240 mg of zinc dichloride, and the mixture was stirred at room temperature for 2 hours. 20 % hydrochloric acid aqueous solution was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=5/1), to obtain 1.5 g of the above compound as a white solid.
aluminium trichloride; Zinc chloride; In 1,1-dichloroethane; 1,2-dichloro-ethane;
Synthesis of 1-(2-fluoro-6-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone To 1,2-dichloroethane (40 mL) were added anhydrous aluminum chloride (4.27 g) and zinc chloride (436 mg), followed by stirring 15 min. Under ice-cooling, a solution of <strong>[52189-63-6]1,3-dimethoxy-5-fluorobenzene</strong> (5 g) in 1,2-dichloroethane (15 mL) was added. The mixture was cooled to -10 C. and 4-methoxyphenylacetyl chloride (4.9 mL) in dichloroethane (10 mL) was added drop-wise. The mixture was stirred 30 min at -10 C., and 1 h at room temperature and then heated to reflux for 2 h. The mixture was cooled at 0 C., poured carefully into ice-water and extracted twice with dichloromethane. The dichloromethane layer was dried over MgSO4 and evaporated in vacuo to give the title compound (9.1 g); 1H NMR (CDCl3): 13.23 (s, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.24 (d, 1H, J=2.1 Hz), 6.18 (dd, 1H, J=13.8 Hz, J'=2.1 Hz), 4.20 (d, 2H, J=3.9 Hz), 3.82 (s, 3H), 3.80 (s, 3H); MS: 291 (MH+); containing 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)-2-(4-methoxyphenyl)ethanone as a by-product. 1H NMR (CDCl3): 13.62 (s, 1H), 7.2-6.0 (6H), 4.29 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H).
EXAMPLE 12 Method of Forming a 1-(2,6-dimethoxy-4-fluorophenyl)-2-methylpropan-1-one Intermediate to a Photoinitiator of the Present Invention The following reaction was carried out as detailed below: Into a 1-liter, three-necked round-bottom flask was placed 20.0 g (0.13 mole) of <strong>[52189-63-6]1,3-dimethoxy-5-fluorobenzene</strong>, 13.6 g (0.0.13 mole) of 2-methylpropanoyl chloride, and 100 ml of nitrobenzene. The mixture was flushed with argon and an equal molar amount of AlCl3 (17.2 g) was added to the reaction mixture while stirring at 5C. The mixture was stirred at a temperature of 5C for about 1 hour after the addition of the AlCl3. The reaction mixture was then mixed with about 100 ml of distilled water and extracted with dichloromethane. The organic layer was washed with NaHCO3 solution, salt water, and then dried. The solvent was removed by vacuum to yield the final productproduct, 1-(2,6-dimethoxy-4-fluorophenyl)-2-methylpropan-1-one. The yield of the reaction was 22.8 g of product (77%).
Preparation of 4-Fluoro-2,6-dimethoxybenzaldehyde: Phosphorous oxychloride (1.8 mL, 19.3 mmol) was added slowly to a well-stirred mixture of <strong>[52189-63-6]1-fluoro-3,5-dimethoxy benzene</strong> (2.6 mL, 19.25 mmol) and N,N-dimethylformamide (2.5 mL, 20 mmol) while temperature was kept below -5 C. Stirring was continued at room temperature for 1.5 h and at 60 C. for another 2 h. Reaction completion was monitored by TLC. The reaction mixture was cooled and hydrolyzed with ice-water (60 mL). The resulting suspension was neutralized by addition of 5N NaOH, extracted with ethyl acetate (2×30 mL), the aqueous phase was adjusted to pH 10 by 5N NaOH and re-extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The dried solution was concentrated to get the crude product which on purification by column chromatography afforded a colorless pure product. Yield: 75%; white solid mp 79-81 C. 1H NMR: delta 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.25 (S, 2H, Ar-H), 10.24 (s, 1H, CHO). Anal. Calcd for C18H19FO5S: C, 58.70, H, 4.92. Found: C, 58.64, H, 4.91.
EXAMPLE FORTY-SEVEN: Synthesis of l-iodo-l'^'-triisopropyl-S^- dimethoxybiphenyl; l-iodo-l'^'-triisopropyl-S^-dimethoxybiphenyl. An oven-dried three-neck 500 mL round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.8 g, 116 mmol), was fitted with a reflux condenser, glass stopper, <n="142"/>and rubber septum. The flask was purged with argon and then THF (45 rnL) and 2,4,6- triisopropylbromobenzene (11.4 mL, 45 mmol) were added via syringe. The reaction mixture was heated to reflux and 1 ,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried 2 L round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (200 mL) and 3,5- dimethoxyfluorobenzene (3 mL, 22.5 mmol) were added to the flask via syringe. The reaction mixture was cooled to -78 0C and n-BuLi (2.5 M in Hexane, 9.2 mL, 23 mmol) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at -78 0C for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0 0C and a solution of Iodine in THF (1 M, 50 mL, 50 mmol) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgSO4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was triturated with hexanes and filtered to give the desired product as an off- white solid (5.059 g, 48%).
methyl 3-[5-(2-fluoro-4,6-dimethoxybenzoyl)-2-isobutoxyphenyl] propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.00 g of 4-isobutoxy-3-(3-methoxy-3-oxopropyl) benzoic acid was dissolved in 60 ML of methylene chloride, and after the consecutive addition thereto of 20 muL of N,N-dimethylformamide and 2.8 ML of oxalyl chloride at room temperature, the resultant mixture was stirred for 3 hours at room temperature.. After the reaction mixture was cooled to -30 C, followed by the consecutive addition thereto of 5.17 g of aluminum chloride and 3.68 g of <strong>[52189-63-6]1-fluoro-3,5-dimethoxybenzene</strong>, this mixture was stirred for 30 minutes in an ice bath.. The reaction mixture was poured into an iced 6M hydrochloric acid for the separation of the organic phase therefrom.. After the resultant organic phase was washed with 6M hydrochloric acid, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure.. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 5.40 g of methyl 3-[5-(2-fluoro-4,6-dimethoxybenzoyl)-2-isobutoxyphenyl] propanoate as colorless oil. NMR(400MHz,CDCl3) delta value: 1.05(6H,d,J=6.8Hz), 2.10-2.17(1H,m), 2.61(2H,t,J=7.8Hz), 2.96(2H,t,J=7.8Hz), 3.66(3H,s), 3.72(3H,s), 3.80(2H,d,J=6.4Hz), 3.85(3H,s), 6.28-6.32(2H,m), 6.82(1H,d,J=8.4Hz), 7.69-7.73(2H,m)
Step 2: 2-Fluoro-4,6-dimethoxybenzaldehyde[0361] To a solution of l-fluoro-3,5-dimethoxybenzene (3.12 g, 20.0 mmol) inDMF (15 mL) was added dropwise phosphoryl trichloride (1.55 mL) at O0C. The reaction mixture was stirred at room temperature overnight and poured onto ice. The resulting mixture was extracted with ethyl acetate (2x50 mL) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE = 1/8) to give the title compound as a yellow solid (2.75 g, Yield: 74.6%). 1U NMR (400 MHz, DMSO- d) delta 10.15 (s, IH), 6.52-6.56 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H). MS (ESI) m/z = 185 [M + H]+.