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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 128-08-5 * 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] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
2
[ 128-08-5 ]
[ 616-44-4 ]
[ 14282-76-9 ]
Reference:
[1] Patent: EP308170, 1989, A1,
3
[ 56-23-5 ]
[ 128-08-5 ]
[ 616-44-4 ]
[ 14282-76-9 ]
Reference:
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 4018
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 1201,1203
4
[ 554-14-3 ]
[ 56-23-5 ]
[ 128-08-5 ]
[ 94-36-0 ]
[ 45438-73-1 ]
Reference:
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1201,1203
5
[ 872-31-1 ]
[ 128-08-5 ]
[ 3140-93-0 ]
Reference:
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
6
[ 554-14-3 ]
[ 56-23-5 ]
[ 128-08-5 ]
[ 765-58-2 ]
Reference:
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1201,1203
7
[ 1003-09-4 ]
[ 128-08-5 ]
[ 3141-27-3 ]
Reference:
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
Reference:
[1] Russian Journal of Organic Chemistry, 2001, vol. 37, # 10, p. 1503 - 1504
[2] Journal of the American Chemical Society, 2018, vol. 140, # 19, p. 6039 - 6043
[3] Russian Journal of Organic Chemistry, 2018, vol. 54, # 1, p. 131 - 138[4] Zh. Org. Khim., 2018, vol. 54, # 1, p. 131 - 138,8
10
[ 88-15-3 ]
[ 128-08-5 ]
[ 5370-25-2 ]
Reference:
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
11
[ 128-08-5 ]
[ 95-15-8 ]
[ 7342-82-7 ]
Reference:
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
12
[ 128-08-5 ]
[ 5407-87-4 ]
[ 89856-44-0 ]
Reference:
[1] Patent: US5693812, 1997, A,
13
[ 128-08-5 ]
[ 274-09-9 ]
[ 67-66-3 ]
[ 2635-13-4 ]
Reference:
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 908
14
[ 56-23-5 ]
[ 128-08-5 ]
[ 493-08-3 ]
[ 94-36-0 ]
[ 3875-78-3 ]
Reference:
[1] Annales de Chimie (Cachan, France), 1954, vol. <12> 9, p. 431,363
15
[ 2810-04-0 ]
[ 128-08-5 ]
[ 5751-83-7 ]
Reference:
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
16
[ 56-23-5 ]
[ 128-08-5 ]
[ 21785-09-1 ]
[ 94-36-0 ]
[ 22395-22-8 ]
Reference:
[1] Proceedings - Indian Academy of Sciences, Section A, 1952, # 36, p. 134,137
17
[ 56-23-5 ]
[ 128-08-5 ]
[ 104-93-8 ]
[ 94-36-0 ]
[ 2746-25-0 ]
Reference:
[1] Huaxue Xuebao, 1959, vol. 25, p. 277,285[2] Chem.Abstr., 1960, p. 17306
18
[ 128-08-5 ]
[ 2835-77-0 ]
[ 39859-36-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0 - 20℃;
2-benzoyl-4-bromoaniline Pathway 2: 2-aminobenzophenone (1 eq., 5 mmol, 0.986 g) is dissolved in dichloromethane at 0° C. N-bromosuccinimide (1 eq., 5 mmol, 0.890 g) is then added in small portions. The temperature of the reaction mixture is allowed to return to ambient temperature over approximately two hours. The reaction mixture is then evaporated and 2-benzoyl-4-bromoaniline is quantitatively obtained. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.63 (d, J=7.2 Hz, 2H, 2′), 7.56 (s, 1H, 6), 7.55-7.54 (d, J=2.4 Hz, 1H, 4′), 7.50-7.47 (t, J=7.6 Hz, 2H, 3′), 7.38-7.35 (q, J=8.8-2.4 Hz, 1H, 4), 6.66-6.64 (d, J=8.4 Hz, 1H, 3), 6.09 (s, 2H, NH2). MS (ES) m/z 276 (M+H+), 198, 105.
Reference:
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 973
20
[ 128-08-5 ]
[ 110-83-8 ]
[ 18926-24-4 ]
[ 3540-84-9 ]
[ 82469-57-6 ]
[ 1521-51-3 ]
Reference:
[1] Journal of the American Chemical Society, 1982, vol. 104, # 25, p. 7267 - 7274
21
[ 56-23-5 ]
[ 128-08-5 ]
[ 110-83-8 ]
[ 1521-51-3 ]
Reference:
[1] Journal of the Chemical Society, 1958, p. 3727
[2] Justus Liebigs Annalen der Chemie, 1942, vol. 551, p. 115
22
[ 128-08-5 ]
[ 110-83-8 ]
[ 1521-51-3 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1942, vol. 551, p. 115
23
[ 128-08-5 ]
[ 99-04-7 ]
[ 123-56-8 ]
[ 6515-58-8 ]
Yield
Reaction Conditions
Operation in experiment
61%
for 2.75 h; Irradiation; Heating / reflux
Synthesis of 3-bromomethylbenzoic acid: In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75percent power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75percent power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to-20 °C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to-20 °C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3 x 300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61percent) of 3- bromomethylbenzoic acid as a white crystalline power.
Reference:
[1] Iowa State College Journal of Science, 1946, vol. 21, p. 44[2] Chem.Abstr., 1947, p. 3045
35
[ 128-08-5 ]
[ 922-67-8 ]
[ 23680-40-2 ]
Yield
Reaction Conditions
Operation in experiment
88%
With silver nitrate In acetone at 20℃; for 6 h;
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N- bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65C, about 25 mm Hg) into a dry ICE/ACETONE cooled receiver to give 83.7 g (88percent) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BRO2 : C, 29.48 ; H, 1.86. Found: C, 29.09 ; H, 1.97.
Third Step Synthesis of 4-(Bromomethyl)benxoic acid (III) STR18 13.6 g (100 mmol) of p-toluic acid STR19 17.8 g (100 mmol) of N-bromo succinoimide STR20 and 1 g (4.1 mmol) of dibenzoyl peroxide were suspended in 125 ml of carbon tetrachloride, and the mixture was heated under vigorous stirring and reacted under reflux (oil bath 93° C., inner temp. 74° C.) for 2 hours to obtain a reaction mixture of yellow milky liquid. The reaction mixture was cooled in an ice bath, and the precipitated crystalline product was filtered and washed with hexane. The crystalline product was further washed with water, and recrystallized from ethanol to obtain 14.6 g of white needle crystals of 4-(bromomethyl)benzoic acid (III). Yield 67.7percent.
Reference:
[1] Patent: US5143644, 1992, A,
40
[ 128-08-5 ]
[ 120-12-7 ]
[ 1564-64-3 ]
Reference:
[1] Acta Chimica Academiae Scientiarum Hungaricae, 1958, vol. 15, p. 183,186
41
[ 56-23-5 ]
[ 128-08-5 ]
[ 85-01-8 ]
[ 573-17-1 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1944, vol. 556, p. 1,7
Reference:
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 4327,4329
44
[ 128-08-5 ]
[ 83-32-9 ]
[ 68-12-2 ]
[ 2051-98-1 ]
Reference:
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 4327,4329
45
[ 128-08-5 ]
[ 533-18-6 ]
[ 704-65-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
With 2,2'-azobis(isobutyronitrile); o-methylphenylacetic acid In cyclohexane at 80℃; for 0.5 h;
60.07 g of [2-(bromoethyl)phenyl] acetate, 400 mmol of 2-methylphenylacetic acid,106.8 g of N-bromosuccinimide and 500 ml of cyclohexane were added to a 1 L flask and added with vigorous stirring3.284 g of azobisisobutyronitrile and stir for 30 minutes,Mixing was stirred at 80C until no further conversion was observed. Work-up after reaction: then cooled to room temperature, the precipitate was removed by filtration and the filtrate was washed with cyclohexane to give compound S6-5 in 90percent yield.
Reference:
[1] Patent: CN107573360, 2018, A, . Location in patent: Paragraph 0017; 0019; 0027
46
[ 56-23-5 ]
[ 128-08-5 ]
[ 129-00-0 ]
[ 1714-29-0 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
47
[ 128-08-5 ]
[ 129-00-0 ]
[ 71-43-2 ]
[ 1714-29-0 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
48
[ 128-08-5 ]
[ 95-48-7 ]
[ 13319-71-6 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 17, p. 3187 - 3194
49
[ 128-08-5 ]
[ 100-12-9 ]
[ 19935-81-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
With dibenzoyl peroxide In tetrachloromethane for 1 h; Heating / reflux
A mixture of 1-ethyl-4-nitro-benzene (3.4 mL, 25 mmol), N-bromosuccinimide (4.38 g, 24.6 mmol) and benzoylperoxide (0.04g, 0.18 mmol) in carbon tetrachloride (30 mL) was refluxed 1h, cooled and filtered, washing with 1:1 ethyl acetate : hexanes. The filtrate was evaporated and purified by flash chromatography (SiO2) eluted with 2:98 ethyl acetate : hexanes to provide 1-(1-bromo-ethyl)-4-nitro-benzene (5.18 g, 90percent yield) as a yellow oil. 1H-NMR (CDCl3, 500 MHz) 8.22 (d, 2H), 7.62 (d, 2H), 5.22 (q, 1H), 2.08 (d, 3H) ppm; HPLC (Method A) 3.837 min.
Reference:
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 4327,4329
53
[ 128-08-5 ]
[ 86-73-7 ]
[ 109-63-7 ]
[ 71-43-2 ]
[ 1133-80-8 ]
Reference:
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 4327,4329
54
[ 56-23-5 ]
[ 128-08-5 ]
[ 93-04-9 ]
[ 3401-47-6 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1944, vol. 556, p. 1,7
55
[ 56-23-5 ]
[ 128-08-5 ]
[ 86-73-7 ]
[ 1940-57-4 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 895
[3] Justus Liebigs Annalen der Chemie, 1944, vol. 555, p. 133,137,144
56
[ 128-08-5 ]
[ 86-73-7 ]
[ 7726-95-6 ]
[ 71-43-2 ]
[ 1940-57-4 ]
Reference:
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1948, vol. 226, p. 87
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 895
[3] Justus Liebigs Annalen der Chemie, 1944, vol. 555, p. 133,137,144
57
[ 128-08-5 ]
[ 2216-69-5 ]
[ 5467-58-3 ]
Reference:
[1] Patent: US2011/108827, 2011, A1,
58
[ 56-23-5 ]
[ 128-08-5 ]
[ 2216-69-5 ]
[ 5467-58-3 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1944, vol. 556, p. 1,7
Reference:
[1] Patent: US2002/95041, 2002, A1,
[2] Patent: US5962490, 1999, A,
[3] Patent: US5594021, 1997, A,
72
[ 128-08-5 ]
[ 367-30-6 ]
[ 112279-60-4 ]
Reference:
[1] Patent: US5888421, 1999, A,
73
[ 1468-83-3 ]
[ 128-08-5 ]
[ 59227-67-7 ]
Reference:
[1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1988, vol. 27, # 6, p. 538 - 539
74
[ 128-08-5 ]
[ 105942-09-4 ]
Reference:
[1] Patent: US5849736, 1998, A,
75
[ 128-08-5 ]
[ 59382-59-1 ]
[ 98475-07-1 ]
Reference:
[1] Patent: US2018/334443, 2018, A1,
76
[ 128-08-5 ]
[ 195062-57-8 ]
[ 138500-85-3 ]
Yield
Reaction Conditions
Operation in experiment
76.1%
With 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 14 h; Reflux
P-toluene boronic acid pinacol ester (10.91 g, 50.0 mmol),Bromosuccinimide (NBS, 9.91 g, 55.0 mmol),Azobisisobutyronitrile (AIBN, 0.44 g, 2.0 mmol) was dissolved in dry carbon tetrachloride (CCl4, 200 mL).It was stirred at reflux for 14 hours, filtered, the solvent was removed by rotary evaporation, and the ethyl acetate (200 mL) was dissolved.After washing once with distilled water (100 mL) and saturated aqueous sodium chloride solution (100 mL), it was dried over anhydrous sodium sulfate.Spin-steaming, finally using petroleum ether as eluent to cross the column,4-Bromomethylphenylboronic acid pinacol ester (11.30 g, yield 76.1percent) was isolated.
Reference:
[1] Patent: CN107417714, 2017, A, . Location in patent: Paragraph 0056; 0057; 0061
[2] Dalton Transactions, 2016, vol. 45, # 35, p. 13726 - 13741
Reference:
[1] Chemical Communications, 2017, vol. 53, # 14, p. 2218 - 2221
80
[ 128-08-5 ]
[ 7424-72-8 ]
[ 474688-73-8 ]
Reference:
[1] Patent: US2007/152565, 2007, A1,
81
[ 128-08-5 ]
[ 79669-50-4 ]
[ 79670-17-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
With 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4 h; Heating / reflux
Place 5-bromo-2-methyl-benzoic acid (1.0 g, 4.7 mmol) in a 200 mL flask under an N2 atmosphere and add methanol via syringe. Add a 2M solution of diazomethyl- trimethyl-silane in hexane (3.5 mL, 23.0 mmol) drop wise over 10 minutes and stir for 1 hour at room temperature. Add glacial acetic acid (16 mL) and stir for 45 minutes. Dilute with ethyl acetate (100 mL) and wash with 1M aqueous sodium hydroxide solution (30 mL), saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). Dry the organic layer (Na2SO4), filter and concentrate in vacuo to obtain 1.01 g of 5-bromo-2- methyl-benzoic acid methyl ester (99 percent). Place 5-bromo-2-methyl-benzoic acid methyl ester (1.04 g, 4.5 mmol) in a 50 mL flask under a N2 atmosphere and add carbon tetrachloride (15 mL). Add N-bromo- succinamide (1.49 g, 8.3 mmol) and 2,2'-azobisisobutyronitrile (40 mg, 0.2 mmol) and fit flask with a condenser and reflux for 4 hours. Cool to room temperature and filter. Concentrate the filtrate and pre-adsorb the crude product onto silica gel. Chromatograph the residue on a Si02 column eluting with dichloromethane in hexane (0 to 50percent) to obtain 977 mg of 5-bromo-2-bromomethyl-benzoic acid methyl ester (70percent). Using 5-bromo-2-bromomethyl-benzoic acid methyl ester (0. 984 g, 3.20 mmol) and the procedure described in the I st paragraph for the alternative procedure for 5- (4,4, 5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -2, 3-dihydro-isoindol-1-one, prepare 509 mg of the title compound (75 percent).
General procedure: To a solution of 3-anisyl pinacol borane (50 mg, 0.21 mmol)in DMF (1 mL) was added N-bromosuccinimide (82 mg, 0.46 mmol). After stirring at room temperature for 14 h, resultant solution was treated with 10percent Na2S2O3aq (10 ml) and was extracted with Et2O (10 ml3). The combined organic phase was washed with H2O (10 ml2) and brine (10 ml1) and dried over MgSO4. After removal of solvent under reduced pressure, the residue was chromatographed on silica gel with Hexane to afford 2-bromo-5-methoxyphenyl pinacol borate (57.3 mg, 87percent yield) as colorless oil
In dimethylformamide [DMF]; N,N-dimethyl-formamide;
Example 13 Preparation of 2-bromo-<strong>[632-15-5]3,4-dimethylthiophene</strong>: A solution of N-bromosuccinimide (NBS) (41.85 g, 0.24 mol) in 150 mL of DMF was added dropwise into a flask containing <strong>[632-15-5]3,4-dimethylthiophene</strong> (30.0 g, 0.267 mol) in dimethylformamide (DMF) (300 mL) at 0 C. over a period of 1 h. After the addition, the cooling bath was removed and the resulting mixture was stirred for 2 h at room temperature. The mixture was quenched with ice-water (300 mL) and extracted with ether (50 mL) three times. The combined organic extracts were washed with water, and dried over MgSO4. Solvent removal followed by fractional vacuum distillation yielded the product 2-bromo-<strong>[632-15-5]3,4-dimethylthiophene</strong> as a pale yellow liquid (35.0 g, 70%). 1H NMR (CDCl3) delta 6.88 (1H, s), 2.20 (3H, s), 2.12 (3H, s).
With dibenzoyl peroxide; In tetrachloromethane; for 1.0h;Heating / reflux;
A mixture of 1-ethyl-4-nitro-benzene (3.4 mL, 25 mmol), N-bromosuccinimide (4.38 g, 24.6 mmol) and benzoylperoxide (0.04g, 0.18 mmol) in carbon tetrachloride (30 mL) was refluxed 1h, cooled and filtered, washing with 1:1 ethyl acetate : hexanes. The filtrate was evaporated and purified by flash chromatography (SiO2) eluted with 2:98 ethyl acetate : hexanes to provide 1-(1-bromo-ethyl)-4-nitro-benzene (5.18 g, 90% yield) as a yellow oil. 1H-NMR (CDCl3, 500 MHz) 8.22 (d, 2H), 7.62 (d, 2H), 5.22 (q, 1H), 2.08 (d, 3H) ppm; HPLC (Method A) 3.837 min.
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N- bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65C, about 25 mm Hg) into a dry ICE/ACETONE cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BRO2 : C, 29.48 ; H, 1.86. Found: C, 29.09 ; H, 1.97.
2,2'-azobis(isobutyronitrile); In benzene; at 20℃; for 0.5h;Heating / reflux;
(1) 2.08 g of <strong>[37830-90-3]4,5-dimethyl-1,3-dioxol-2-one</strong> was dissolved in 24 mL of benzene, to which 3.25 g of N-bromosuccinimide and 86 mg of 2,2'-azobis(isobutyronitrile) were added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and consequently, a solution of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in benzene was obtained.(2) 3.00 g of methyl 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 15 mL of methanol and 15 mL of tetrahydrofuran, to which a solution of 1.08 g of potassium hydroxide in 4.5 mL of water was added, and this mixture was stirred for one hour at room temperature, and then the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 40 mL of N,N-dimethylformamide, to which 3.60 g of potassium carbonate was added. Then, the benzene solution prepared in (1) was added thereto, and was stirred for one hour at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; toluene:ethyl acetate=5:1] to yield 1.58 g of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[3-(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate as yellow oil. NMR(400MHz,CDCl3) delta value: 1.5-2.0(8H,m), 2.16(3H,s), 2.75(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz), 3.65(3H,s), 4.5-5.0(3H,m), 5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.47(1H,d,J=2.4Hz), 6.95(1H,d,J=8.4Hz), 7.35(1H,dd,J=8.4,1.2Hz), 7.4-7.6(4H,m), 7.72(1H,d,J=8.0Hz), 12.67(1H,s).
A solution of <strong>[1078-28-0]6-methoxy-2-methylquinoline</strong> (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to [0-3C] followed by portion-wise addition of N-bromo- succinimidyl (200 g, 1.12 mol) over a period of 30 minutes while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 h. The reaction was then quenched by a 10% [NAHS03] solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N [NAOH] (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 h then filtered, washed with water (2 x 1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid. Rf = 0.39 (3: 7) EtOAc: heptane [;'H] NMR (DMSO) [8] 8.30 (d, J=6.5 Hz, [1H),] 7.98 (d, J=6.9 Hz, [1H),] 7.70 (d, J=7.0 Hz, 1 H), 7.47 (d, J=6.5 Hz, [1 H),] 4.02 (s, 3H), 2.66 (s, 3H); Elemental Analysis for: [CT HT0NOBR] Calc'd : C 52.40 H 3.97 N 5.56 Found: C 52.13 H 3.94 N 5.61
With 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Heating / reflux;
Place 5-bromo-2-methyl-benzoic acid (1.0 g, 4.7 mmol) in a 200 mL flask under an N2 atmosphere and add methanol via syringe. Add a 2M solution of diazomethyl- trimethyl-silane in hexane (3.5 mL, 23.0 mmol) drop wise over 10 minutes and stir for 1 hour at room temperature. Add glacial acetic acid (16 mL) and stir for 45 minutes. Dilute with ethyl acetate (100 mL) and wash with 1M aqueous sodium hydroxide solution (30 mL), saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). Dry the organic layer (Na2SO4), filter and concentrate in vacuo to obtain 1.01 g of 5-bromo-2- methyl-benzoic acid methyl ester (99 %). Place <strong>[79669-50-4]5-bromo-2-methyl-benzoic acid methyl ester</strong> (1.04 g, 4.5 mmol) in a 50 mL flask under a N2 atmosphere and add carbon tetrachloride (15 mL). Add N-bromo- succinamide (1.49 g, 8.3 mmol) and 2,2'-azobisisobutyronitrile (40 mg, 0.2 mmol) and fit flask with a condenser and reflux for 4 hours. Cool to room temperature and filter. Concentrate the filtrate and pre-adsorb the crude product onto silica gel. Chromatograph the residue on a Si02 column eluting with dichloromethane in hexane (0 to 50%) to obtain 977 mg of 5-bromo-2-bromomethyl-benzoic acid methyl ester (70%). Using 5-bromo-2-bromomethyl-benzoic acid methyl ester (0. 984 g, 3.20 mmol) and the procedure described in the I st paragraph for the alternative procedure for 5- (4,4, 5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -2, 3-dihydro-isoindol-1-one, prepare 509 mg of the title compound (75 %).
Step D Preparation of 4-bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified chromatography (silica gel, 5-10% EtOAc/hexane. 1H NMR (CDCl3) delta 7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
In dichloromethane;
Step D Preparation of 4-Bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile, as described in Step C above, (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified after chromatography (silica gel, 5-10% EtOAc/hexane). 1H NMR (CDCl3) delta 7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
In dichloromethane;
Step D Preparation of 4-Bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile, as described in Step C above, (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified after chromatography (silica gel, 5-10% EtOAc/hexane). 1H NMR (CDCl3) delta 7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
In dichloromethane;
Step D: Preparation of 4-bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified by chromatography (silica gel, 5-10% EtOAc/hexane. 1H NMR (CDCl3) d 7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
In dichloromethane;
Step D Preparation of 4-Bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified chromatography (silica gel, 5-10% EtOAc/hexane. 1H NMR (CDCl3) d 7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
In dichloromethane;
Step D Preparation of 4-Bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile, as described in Step C above, (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified after chromatography (silica gel, 5-10% EtOAc/hexane). 1H NMR (CDCl3) delta7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
In dichloromethane;
Step D Preparation of 4-Bromomethyl-2-fluoro-benzonitrile N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0 C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to -20 C. then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile, as described in Step C above, (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0 C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified after chromatography (silica gel, 5-10% EtOAc/hexane). 1H NMR (CDCl3) delta 7.61 (dd, 1H, J=8, 8 Hz), 7.26-7.30 (m, 2H), 4.45 (s, 2H).
Step 34a To a dry flask is added methyl 1-methyl-1H-pyrrole-2-carboxylate (12.0 g, 86.4 mmol) and 150 mL of dry CH2Cl2, and the flask is wrapped in foil and purged with nitrogen. N-Bromosuccinimide (16.2 g, 90.7 mmol) is added in one portion and the mixture is stirred at rt for 0.5 h. The reaction mixture is washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Fractional distillation gives 12.0 g of methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate as a yellow oil (64% yield). MS for C7H8NO2Br (ESI) (M)+m/z 217.1.
Step 5.1 4-Bromo-2,5-difluoroaniline. N-Bromosuccinimide (28.50 g, 0.160 mol) is added in small quantities over 1.5 hours to a stirred, cooled (-10 to 0 C.) solution of 2,5-difluoroaniline (20.00 g, 0.155 mol) in dry dichloromethane under dry nitrogen. This mixture is stirred at 0 C. for 2 hours (glc analysis revealing a complete reaction), and the red solution then washed with a large amount of water (*2) and dried (MgSO4). The solvent is removed in vacuo to afford a red solid with a yield of 32.19 g (100%).
With potassium carbonate; In tetrachloromethane; ethyl acetate; acetone;
Example 2 Synthesis of 1,3-Dimethoxy-4-Bromo-2-Fluorobenzene (12) <strong>[103068-40-2]2-fluoro resorcinol</strong> (prepared according to Patrick, T. B., et al., J. Org. Chem (1986), 51, 3242-4) (12.8 g, 100 mmol), potassium carbonate (42 g, 0.3 mol), and methyl iodide (25 mL, 0.4 mol) were mixed with acetone (300 mL) and refluxed for 6 hrs. The reaction was poured into ice-water (500 mL) and extracted in ethyl acetate (500 mL). The ethyl acetate was washed with water (200 mL*2), and brine (200 mL*1), dried over sodium sulfate, filtered, and solvent was removed to yield 14.2 grams (91%) of 1,3-dimethoxy 2-fluoro benzene. This fluoro-benzene intermediate (23.19 g, 148.5 mmoL), N-bromo succinimide (26.52 g, 149 mmol), and 300 uL of 70% aqueous perchloric acid (Aldrich Chemical, 3.4 mmoL) were mixed in carbon tetrachloride (100 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and solvent was removed to obtain a yellow oil. The oil was subjected to silica-gel chromatography (silica gel, hexane mobile phase) to yield 33.28 grams (95%) of the 1,3-dimethoxy-4-bromo-2-fluorobenzene 12 compound as a yellow oil.
In tetrahydrofuran; tetrachloromethane; petroleum;
This product (185 g) was dissolved in carbon tetrachloride (1250 ml). N-Bromosuccinimide (159.3) was added and the mixture heated under reflux for 3 hours. The reaction mixture was then cooled and worked up to give a light brown oil. The crude product was triturated with a 10% solution of di-isopropyl ether in light petroleum to give methyl (E)-3-methoxy-2-[(2-bromomethyl)phenyl]prop-2-enoate, m.p. 87-90 C. 2-Mercaptobenzothiazole (101.87 g) in tetrahydrofuran (600 ml) was added dropwise with stirring to a petrol washed suspension of sodium hydride (from 18.42 g of 80% dispersion in oil), in tetrahydrofuran (200 ml). The mixture was heated under reflux for 30 minutes and cooled to room temperature. A solution of the bromomethyl compound (175 g) in tetrahydrofuran (1000 ml) was added over one hour and the mixture stirred for 5 hours at room temperature. Aqueous tetrahydrofuran was added to quench the reaction and the mixture was evaporated. The residue was worked up in conventional manner to give methyl (E)-2-[2-[[(2-benzothiazolyl)thio]-methyl]phenyl]-3-methoxy-2-propenoate, m.p. 77-78. (Compound 1).
4-(Bromomethyl)-3-chlorobenzenesulphonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With dibenzoyl peroxide; In tetrachloromethane; hexane; ethyl acetate;
(a) 3-Chloro-4-bromomethylphenylsulphonyl chloride N-Bromosuccinimide (13.76 g, 76 mmol) was added to a stirred solution of <strong>[42413-03-6]3-chloro-4-toluenesulphonyl chloride</strong> (12 g, 76 mmol) in CCl4 (120 ml) under argon. After one hour benzoyl peroxide (0.92 g, 3.8 mmol) was added and the reaction mixture refluxed overnight. The mixture was allowed to cool, the resulting white precipitate filtered off and the filtrate evaporated to a yellow oil. Purification of the residue by chromatography over silica gel (3% ethyl acetate in hexane) afforded 3-chloro-4-bromomethylphenylsulphonyl chloride (3.3 g, 14%) as a colourless oil. deltaH 8.30-7.05 (3H, m), 4.62 (2H, s).
This product (185 g) was dissolved in carbon tetrachloride (1250 ml). N-Bromosuccinimide (159.3 g) was added and the mixture heated under reflux for 3 hours. The reaction mixture was then cooled and worked up to give a light brown oil. The crude product was triturated with a 10% solution of di-isopropyl ether in light petroleum to give methyl (E)-3-methoxy-2-[2-(bromomethyl)phenyl]prop-2-enoate, m.p. 87-90 C., (Intermediate A).
ethyl 5-(bromomethyl)thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dibenzoyl peroxide;SiO2; In water; ethyl acetate; benzene;
Ethyl 5-bromomethyl-2-thiophenecarboxylate N-Bromosuccinimide (23.5 g, 132 mmol), benzoyl peroxide (0.26 g) and 90 mL of benzene were brought to reflux under argon. Ethyl 5-methyl-2-thiophenecarboxylate (22.5 g, 132 mmol) was added dropwise through an addition funnel and the resulting mixture was refluxed for 6 hours and then cooled to room temperature and stirred for 16 hours. The mixture was treated with 50 mL of water and extracted with 3*75 mL ether. The ether extracts were combined and washed with 75 mL saturated aqueous NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residual oil purified by flash chromatography (SiO2, 99:1, ethyl acetate in hexanes) to give the title compound as a clear, yellow oil. PMR (CDCl3): delta1.37 (3H, t, J=7.3 Hz), 4.35 (2H, q, J=7.3 Hz), 4.68 (3H, s), 7.09 (1H, d, J =4.0 Hz), 7.64 (1H, d, J =4.0 Hz).
With dibenzoyl peroxide; In water; benzene;
Ethyl 5-bromomethyl-2-thiophenecarboxylate (Compound 21) N-Bromosuccinimide (23.5 g, 132 mmol), benzoyl peroxide (0.26 g) and 90 mL of benzene were brought to reflux under argon. Ethyl 5-methyl-2-thiophenecarboxylate (Compound 20, 22.5 g, 132 mmol) was added dropwise through an addition funnel and the resulting mixture was refluxed for 6 hours and then cooled to room temperature and stirred for 16 hours. The mixture was treated with 50 mL of water and extracted with 3*75 mL ether. The ether extracts were combined and washed with 75 mL saturated aqueous NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residual oil purified by flash chromatography (SiO2, 99:1, hexane:ethyl acetate) to give the title compound as a clear, yellow oil. PMR (CDCl3): delta1.37 (3H, t, J=7.3 Hz), 4.35 (2H, q, J=7.3 Hz), 4.68 (3H, s), 7.09 (1H, d, J=4.0 Hz), 7.64 (1H, d, J=4.0 Hz).
1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
130 g (70.2%)
With dibenzoyl peroxide; In tetrachloromethane;
a) A mixture of 129 g of <strong>[38560-96-2]2-chloro-1,3-dimethyl-5-nitrobenzene</strong>, 125 g of 1-bromo-2,5-pyrrolidinedione, 12 g of dibenzoyl peroxide and 1200 ml of tetrachloromethane was stirred for 2 hours at reflux temperature using a water separator. Twice there was added an extra portion of 20 g of dibenzoyl peroxide during a refiuxing period of 29 hours. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2 Cl2 /hexane 50:50). The eluent of the desired fraction was evaporated, yielding 130 g (70.2%) of 1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene (interre. 5).
2-Bromomelatonin (4k). N-bromo succinimide (0.89 g, 5 mmol) was added to a solution of melatonin (1.16 g, 5 mmol) in acetic acid (20 mL). The reaction mixture was stirred under N2 at room temperature for 4 h, then cooled at 0 C., neutralized with a 50% solution of NaOH and extracted with ethyl acetate. The combined organic layers were washed with NaCl solution, dried (Na2 SO4) and concentrated. Purification by flash chromatography (silica gel; ethyl acetate/cyclohexane 6:4) and crystallization gave 0.467 g (30% yield) of 4k as white solid, mp 141-142 C. IR numax: 3460, 3300, 1650. 1 H NMR: 1.99 (s, 3H, COCH3); 2.92(t, 2H, beta -CH2), 3.54(q, 2H, alpha-CH2), 3.86(s, 3H, OCH3), 5.53(br s, 1H, NH), 6.85-7.23(m, 3Harom), 8.15(br s, 1H, NHindole).
Step A Preparation of 2-amino-5-bromo-4,6-lutidine STR4 2-Amino-4,6-lutidine (101.0 g, 0.827 mole) is dissolved in acetone at 25 C. and the solution cooled to -15 C. N-Bromosuccinimide (137.5 g, 0.778 mole) is added in 10*13.75 g portions over 1.5 hours, maintaining a temperature of -10 C. After addition is complete, the slurry is aged at -10 C. for 0.5 hours. Water (1820 mL) is added over 0.5 hours, allowing the temperature to rise to 20-25 C. The resulting slurry is recooled to 5-10 C. and aged for 1 hour then filtered and the product washed with cold water (500 mL, 5-10 C.) and dried under vacuum to yield 141.3 g of 2-amino-5-bromolutidine (4) at a purity of 96.9% (HPLC wt %) for a yield of 82.3%. The crystallization as described removes succinimide (water soluble), 2-amino-4,6-lutidine (3) (water soluble) and 2-amino-3-bromo-4,6-lutidine (10).
Part C: 2-Fluoro-4-cyanobenzylbromide N-Bromosuccinimide (9.6 g, 54 mmol) and the part B substrate (7.3 g, 54 mmol) were heated under reflux in CCl4 (100 mL) under N2 with irradiation with a high intensity visible lamp for 2 h. After cooling to ambient temp., the mixture was filtered through a Celite pad and concentrated in vacuo. The crude product was recrystallized from hot cyclohexane (4*) to yield 4.5 g of off-white needles; mp 75-77 C.; IR(KBr) 2236 cm-1; HRMS, e/z Calc. for (M+H)+: 213.9668. Found: 213.9660.
(b) N-Bromosuccinimide (3.2 g.) and benzoyl peroxide (0.005 g.) were added to a solution of <strong>[3556-60-3]3-methoxy-4-methylbenzonitrile</strong> (2.65 g.) in dry carbon tetrachloride (90 ml.). The mixture was heated to reflux for 15 minutes using a 250 watt tungsten lamp. The cooled reaction mixture was diluted with petrolum ether (b.p. 60-80 C., 90 ml.), insoluble material removed by filtration, and the filtrate evaporated. The solid residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 4-bromomethyl-3-methoxybenzonitrile (W) (2.64 g., 65%) as a white solid, m.p. 87-91 C.
With dibenzoyl peroxide; In tetrachloromethane;
(b) N-Bromosuccinimide (3.2 g.) and benzoyl peroxide (0.005 g.) were added to a solution of <strong>[3556-60-3]3-methoxy-4-methylbenzonitrile</strong> (2.65 g.) in dry carbon tetrachloride (90 ml.). The mixture was heated to reflux for 15 minutes using a 250 watt tungsten lamp. The cooled reaction mixture was diluted with petrolum ether (b.p. 60-80C., 90 ml.), insoluble material removed by filtration, and the filtrate evaporated. The solid residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 4-bromomethyl-3-methoxybenzonitrile (W) (2.64 g., 65%) as a white solid, m.p. 87-91C.
4-Carbomethoxy-3-methoxybenzyl bromide N-Bromosuccinimide (45.3 g) was added to methyl 2-methoxy-4-methylbenzoate (45.8 g) in carbon tetrachloride (~11) containing a trace of dibenzoyl peroxide. The suspension was heated under reflux until no orange colour persisted, then cooled, filtered and the filtrate evaporated to give the title compound, bp 136-144/7 mm. tau(CDCl3) 6.17 (3H, s), 6.13 (3H, s), 5.59 (2H, s), 2.9-3.15 (2H, m), 2.3 (1H, d, J=8 Hz).
(1) 2-Amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole. 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole(0.87g, 5.6mmol) was dissolved in carbon tetrachloride(9mL). N-Bromosuccinimide(1.00g, 5.6mmol) was added, and the mixture was stirred at room temparature for 1 hour. Hexane was added to the reaction mixture, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel(hexane:ethyl acetate=2:1) to give the title compound(1.23g, 93.7%) as a yellowish gray powder. 1H-NMR(CDCl3): delta 1.39(9H, s), 4.81(2H, brs).
The quinazolinone used as starting material was obtained as follows:- A mixture of <strong>[18731-19-6]3,4-dihydro-2,6-dimethylquinazolin-4-one</strong> (20 g), N -bromosuccinimide (21.3 g), benzoyl peroxide (100 mg) and chloroform (600 ml) was heated to 50C for 6 hours during which time the mixture was illuminated by the light from a 250 Watt light bulb. The mixture was cooled. The precipitated product was separated by filtration of the mixture, washed with chloroform (2 x 50 ml) and dried. There was thus obtained 6-bromomethyl-3,4-dihydro-2-methylquinazolin-4-one, m.p.> 330C.
4. 2-Chloro-3-bromo-6-aminopyrazine and 2-amino-3-bromo-6-chloropyrazine A solution of 2-chloro-6-aminopyrazine (20 g, 0.15 mole) in chloroform (1940 ml) was stirred at -5° C. to 0° C. N-Bromosuccinimide (27.58 g, 0.15 mole) was added in portions maintaining the temperature between -5 and 0° C. The mixture was warmed to room temperature and stirred for 3.50 hrs. The mixture was then washed with aqueous saturated sodium bicarbonate (1*300 ml), then water (1*500 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was purified by 'flash chromatography' using chloroform as the eluent. Yield of 2-chloro-3-bromo-6-aminopyrazine 13.89 g (43percent), M.p. 146-147° C. Yield of 2-amino-3-bromo-6-chloropyrazine 4.90 g (15percent), M.p. 124-125° C.
With dibenzoyl peroxide; In tetrachloromethane; hexane; toluene;
Step 3 Preparation of 5-chloro-2-bromomethylbenzoxazole A solution of the benzoxazole (1.3 g) (Step 2) in CCl4 (15 mL) was treated with N-bromosuccinimide (NBS) (1.5 g) and benzoyl peroxide (38 mg) at reflux using a U.V. lamp for 24 hours. Filtration, evaporation, and flash chromatography of the residue using 1:1 hexane/toluene afforded the title compound which was used as such for the next step.
With 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Heating / reflux;
N-Bromosuccinimide and AIBN were added to a carbon tetrachloride solution of 2-fluoro-4-methylbenzonitrile, followed by heating under reflux to obtain 4-(bromomethyl)-2-fluorobenzonitrile. By allowing this to react with morpholine in DMF in the presence of potassium carbonate, 2-fluoro-4-(morpholin-4-ylmethyl)benzonitrile was obtained. In DMF and in the presence of potassium carbonate, this was allowed to react with cyclohexanamine at 160C for 30 minutes while carrying out microwave irradiation. By post-treating the reaction liquid, 2-(cyclohexylamino)-4-(morpholin-4-ylmethyl)benzonitrile was obtained.
Example 13A3 -Bromo- 1 H-indazole-5 -carbaldehydeTo a solution of 20 g (137 mmol) lH-indazole-5-carbaldehyde in acetonitrile (580 ml), 28 g (157 mmol) l-bromopyrrolidine-2,5-dione were added over 20 min at room temperature. The resulting suspension was stirred under reflux for 30 min, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1500 ml), and the solution was washed with water and with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate. After filtration, the precipitate was dried under vacuum to yield the title compound as a white solid (30.9 g, 75% of th.).LC-MS (method 4): Rt = 0.77 min; MS (ESIpos): m/z = 225 (M+Eta)+ 1H-NMR (400 MHz, DMSOd6): delta = 15.01 (br. s, IH), 10.09 (s, IH), 8.29 (s, IH), 7.91 (d, IH), 7.73 (d, IH) ppm.
1-a. Synthesis of 1-bromo-4-methoxynaphthalene 1-Bromo-4-methoxynaphthalene was synthesized as follows. 1-Methoxynaphthalene (250 g, 1.58 mol) and acetonitrile (3500 mL) were stirred in a 10 L round-bottom flask. After adding bromosuccinimide (253.1 g, 1.42 mol), the mixture was added stirred for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was stirred in hexane (1 L) and then filtered. Concentration of the filtrate under reduced pressure followed by column purification using hexane yielded a liquid product (345.2 g, 1.46 mol, 92.1%).
Dibenzo[b,d]furan-4-amine (33.4 g, 182 mmol) was dissolved in DMF (300 mL) and cooled to 0 C. by ice bath. 1-bromopyrrolidine-2,5-dione (68.1 g, 383 mmol) was dissolved in DMF (300 mL) and added into the reaction solution dropwise. After the addition, the reaction was stirred at room temperature overnight. Then the reaction mixture was diluted by EtOAc and washed by 10% LiCl solution three times and saturated sodium bicarbonate twice. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified with silica gel column (<15% EtOAc in hexane) to give red brown solid 1,3-dibromo<strong>[50548-43-1]dibenzo[b,d]furan-4-amine</strong> (76 g, 122% yield, containing some succinimide).
6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With DIEA;Pd(PPh3)4; PdCl2(PPh3)2; In 1,4-dioxane; ethanol; deoxofluor; water; ethyl acetate; N,N-dimethyl-formamide; toluene; acetonitrile;
2,7-Dibromo-fluoren-9-one (4.0 g, 11.8 mmol) was suspended in deoxofluor (12 mL) at room temperature and EtOH (4 drops) was added. The stirred suspension was heated at T=90 C. for 24 hours (CAUTION: Use of deoxofluor at elevated temperatures, as described above, is cautioned as rapid and violent exotherms may occur). The reaction was cooled to room temperature and poured onto ice containing sodium bicarbonate. A solid formed and was collected via filtration. The crude material was taken into EtOAc and was washed with aqueous HCl (1M) and brine. The solution was dried over sodium sulfate. Filtration and evaporation of solvents gave crude product, which was purified by silica gel chromatography (eluent: EtOAc/hexanes) to yield the product (3.2 g). 19F-NMR: 282 MHz, (dmso-d6) delta: -111.6 ppm. Before using the material in the next step, it was exposed as a solution in EtOAc to charcoal. 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester: <strong>[1229603-71-7]2,7-Dibromo-9,9-difluoro-9H-fluorene</strong> (372 mg, 1.04 mmol), Pd(PPh3)4 (30.0 mg, 0.026 mmol), PdCl2(PPh3)2 (18.2 mg, 0.026 mmol), As(PPh3)3 (5.0 mg) were dissolved in dioxane (10 mL) under an argon atmosphere. Ethoxyvinyl-tributyl tin (376.4 mg, 1.04 mmol) was added. The mixture was heated for 140 minutes at 85 C. (oil bath). The reaction was cooled to room temperature. N-bromo succinimide (177 mg, 1.0 mmol) was added followed by water (2 mL). The reaction was stirred at room temperature for 3 hours, after which the majority of the dioxane was removed in vacuo. The crude reaction mixture was diluted with EtOAc and was washed with water. All volatiles were removed in vacuo. Toluene was added and all volatiles were removed in vacuo for a second time. The crude material was dissolved in DMF/MeCN (2 mL, 1:1) at room temperature. A solution of N-Cbz-4-cyclopropyl (L) Proline (0.84 mmol) and DIEA (268 mg, 2.08 mmol) in MeCN (2 mL) was added and stirring at room temperature was continued. After 14 hours, most of the MeCN was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with aqueous HCl (1M), aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product (176 mg). LCMS-ESI+: calc'd for C30H24BrF2NO5: 596.4 (M+); Found: 595.2/597.2 (M+H+). 6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester:
Preparation of methyl 2-bromo-2-(3-fluorophenyl)acetate (I15) Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield).
Synthesis of 2-bromo-5-fluoro-4-nitroanilineA flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C.At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap.The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight.The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved.A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).
a) 2,7-Dibromo-9,9-dimethyl-9,10-dihydroacridine N-Bromosuccinimide (94.5 g, 531 mmol) is added in portions to a solution of 9,9-dimethyl-9,10-dihydroacridine (CAS 6267-02-3, 45 g, 252 mmol) in chloroform (1000 ml) at 0 C. with exclusion of light, and the mixture is stirred at this temperature for 2 h. 500 ml of water are subsequently added to the mixture. After phase separation, the organic phase is washed with water, and the aqueous phase is extracted with chloroform. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in ethyl acetate and filtered through silica gel. The crude product is subsequently recrystallized from heptane. Yield: 64.7 g (176 mmol), 70% of theory, colourless solid.
pinacol 2,6-dibromo-3,5-dimethoxypnehylboronate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In N,N-dimethyl-formamide; at 20℃; for 14h;
General procedure: To a solution of 3-anisyl pinacol borane (50 mg, 0.21 mmol)in DMF (1 mL) was added N-bromosuccinimide (82 mg, 0.46 mmol). After stirring at room temperature for 14 h, resultant solution was treated with 10% Na2S2O3aq (10 ml) and was extracted with Et2O (10 ml3). The combined organic phase was washed with H2O (10 ml2) and brine (10 ml1) and dried over MgSO4. After removal of solvent under reduced pressure, the residue was chromatographed on silica gel with Hexane to afford 2-bromo-5-methoxyphenyl pinacol borate (57.3 mg, 87% yield) as colorless oil
General procedure: To a solution of 3-anisyl pinacol borane (50 mg, 0.21 mmol)in DMF (1 mL) was added N-bromosuccinimide (82 mg, 0.46 mmol). After stirring at room temperature for 14 h, resultant solution was treated with 10% Na2S2O3aq (10 ml) and was extracted with Et2O (10 ml3). The combined organic phase was washed with H2O (10 ml2) and brine (10 ml1) and dried over MgSO4. After removal of solvent under reduced pressure, the residue was chromatographed on silica gel with Hexane to afford 2-bromo-5-methoxyphenyl pinacol borate (57.3 mg, 87% yield) as colorless oil
General procedure: To a solution of 3-anisyl pinacol borane (50 mg, 0.21 mmol)in DMF (1 mL) was added N-bromosuccinimide (82 mg, 0.46 mmol). After stirring at room temperature for 14 h, resultant solution was treated with 10% Na2S2O3aq (10 ml) and was extracted with Et2O (10 ml3). The combined organic phase was washed with H2O (10 ml2) and brine (10 ml1) and dried over MgSO4. After removal of solvent under reduced pressure, the residue was chromatographed on silica gel with Hexane to afford 2-bromo-5-methoxyphenyl pinacol borate (57.3 mg, 87% yield) as colorless oil
General procedure: To a solution of 3-anisyl pinacol borane (50 mg, 0.21 mmol)in DMF (1 mL) was added N-bromosuccinimide (82 mg, 0.46 mmol). After stirring at room temperature for 14 h, resultant solution was treated with 10% Na2S2O3aq (10 ml) and was extracted with Et2O (10 ml3). The combined organic phase was washed with H2O (10 ml2) and brine (10 ml1) and dried over MgSO4. After removal of solvent under reduced pressure, the residue was chromatographed on silica gel with Hexane to afford 2-bromo-5-methoxyphenyl pinacol borate (57.3 mg, 87% yield) as colorless oil
With azobisisobutyronitrile; In chloroform; for 4.5h;Reflux;
To the mixture of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (3.6 g, 20 mmol) in CC14 (320 ml) was added 1-bromopyrrolidine-2,5-dione (3600 mg, 20 mmol) and (E)-2,2?-(diazene- 1,2-diyl)bis(2-methylpropanenitrile) (190 mg, 1.2 mmol). The resulting mixture was heated at reflux for 4.5 hrs. After filtration through celite and washing of the pad with DCM, the combined filtrate was concentrated and the residue was purified on silica gel column usingEtOAc/hexane as eluting solvents to give 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole. LC/MS:(M+1): 256.83, 258.84, 260.88.
sodium (4'-methyl-2,2'-bipyridin-4-yl)methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium sulfate; dibenzoyl peroxide; In tetrachloromethane; water;
3. Synthesis of a mono-anionic ligand (salt form): sodium (4'-methyl-2,2'-bipyridin-4-yl)methanesulfonate (6) To 4,4'-dimethyl-2,2'-bipyridine (20 g, 108.5 mmol) in 400 mL of anhydrous tetrachloromethane was added 19 g (106.8 mmol) of N-Bromosuccinimide and 2.6 g of benzoyl peroxide. The mixture was refluxed overnight and cooled to room temperature. The solid was removed by filtration and the filtrate concentrated by rotary-evaporation. The column chromatography with triethylamine treated silica column afforded 6 g of 4-(bromomethyl)-4'-methyl-2,2'-bipyridine (5), which was mixed with 4.9 g (38.9 mmol) of Na2SO3 in 100 mL of water. The cloudy mixture was refluxed for six hours. When it was still hot, the supernatant was concentrated to about 30 mL and cooled to room temperature. The yellow precipitate was collected by filtration and washed with dichloromethane to afford 3.6 g of 4'-methyl-2,2'-bipyridin-4-yl)methanesulfonate (6). 1H NMR (D2O, 400 MHz, See ) delta 8.81 (1H), 8.67 (1H), 8.44 (1H), 8.30 (1H), 7.88 (1H), 7.76 (1H), 4.42 (2H), 2.73 (3H).
With dibenzoyl peroxide; In acetonitrile; at 90℃; for 4h;
To a solution of E6 (40 g, 183 mmol) in MeCN (400 mL) was added NBS (35.9 g, 202 mmol), BPO (444 mg, 1.83 mmol). The reaction mixture was stirred at 90C for 4 hours to give a brown mixture. LCMS showed the desired MS. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL*2). The organic layer was washed with water (100 mL*4), brine (100 mL*3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give E7 (57 g, crude) as brown oil.
With 2,2'-azobis(isobutyronitrile); In toluene; at 70℃; for 1h;
Add to the reaction flask<strong>[1128-54-7]3-methyl-1-phenyl-1H-pyrazole</strong> (0.50 g, 0.003 mol)Toluene 5 ml,Heating up to 70 ,To the reaction solution was added N-bromosuccinimide (0.40 g, 0.003 mol)Azobisisobutyronitrile (catalytic amount),Plus,The reaction solution was heated to reflux,The reaction was refluxed for 1 hour.After the reaction is cooled to below 30 C,The reaction solution was poured into 50 ml of water,Extracted with 3 x 50 ml of ethyl acetate,The resulting organic phase was washed with saturated aqueous sodium bicarbonate solution (50 ml)Saturated aqueous sodium chloride solution (50 ml)Dried over anhydrous magnesium sulfate,After concentration under reduced pressure,The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 100)To give 0.40 g of 3-bromomethyl-1-phenyl-1H-pyrazole as a yellow oil in 56% yield.
With 2,2'-azobis(isobutyronitrile); o-methylphenylacetic acid; In cyclohexane; at 80℃; for 0.5h;
60.07 g of [2-(bromoethyl)phenyl] acetate, 400 mmol of 2-methylphenylacetic acid,106.8 g of N-bromosuccinimide and 500 ml of cyclohexane were added to a 1 L flask and added with vigorous stirring3.284 g of azobisisobutyronitrile and stir for 30 minutes,Mixing was stirred at 80C until no further conversion was observed. Work-up after reaction: then cooled to room temperature, the precipitate was removed by filtration and the filtrate was washed with cyclohexane to give compound S6-5 in 90% yield.
In chloroform; N,N-dimethyl-formamide; at 20.0℃; for 10h;
To 0.025 g (0.0296 mmol) of copper tetraphenylporphyrin in a mixture of 10 mL ofCHCl3 and 1mL of DMF was added 0.105 g (0.592 mmol) of NBS and stirred at roomtemperature for 10 h. The reaction mixture was evaporated to a minimum 10 mL ofDMF, H2O and NaClsolid was added. Dark brown precipitate was filtered off, washedwith water and dried, then chromatographed on Al2O3 with CHCl3, and precipitatedfrom C25OH. Yield: 68% (0.026 g, 0.0199 mmol). Mass spectrum, m/z (Irel, %) 1306.6(98) [M]+ was calculated for C44H20N4Br8Cu - 1307.5. UV-vis spectrum in CHCl3, lambda, nm(log epsilon)626 sh., 581 (4.33), 467 (5.21), 447 sh
Procedure K: To a mixture of 4<strong>[1211540-79-2]2,3-dihydro-1H-pyrrolo[3,2-b]pyridine</strong> (crude 5.0 g, 22.9 mmol) in THF (20 mL) at 0 C, was added NBS (25.2 mg, 1.1 mmol) within 20 min. The reaction mixture was stirred at RT for 10 h. It was then diluted with IPA and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA 4:1, v/v) to give 5-bromo-<strong>[1211540-79-2]2,3-dihydro-1H-pyrrolo[3,2-b]pyridine</strong> as a red solid (1.5 g, 33%). LC-MS (ESI): m/z (M)+ = 199.07, 201.06