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Structure of 66192-24-3 * 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.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2 h; Heating / reflux
20.5 g (100 mmol) of 2-bromo-5-chlorotoluene was dissolved in 200 ml of carbon tetrachloride, 0.2 g (1 mmol) of AIBN and 19.6 g (110 mmol) of N-bromosuccinimide were added thereto, the resulting mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and with 50 ml of a brine solution, dried over anhydrous MgS04, and distilled under a reduced pressure to obtain an oil containing a small amount of the starting material. The oil was dissolved in 20 ml of hexane, and recrystallized at room temperature to obtain ' 22.7 g (yield 80percent) of 2-bromo-l-bromomethyl-5-chlorobenzene. 1H NMR (300 MHz, CDC13) d 7.50 (d, 1H, J= 8.7 Hz), 7.45 (d, 1H, J= 2.4 Hz), 7.15 (dd, 1H, J= 8.7 Hz, 2.4 Hz), 4.53 (s, 2H)
45%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4 h; Heating / reflux
Step 1: l-bromo-2-(bromomethyl)-4-chlorobenzene; l-bromo-2-(bromomethyl)-4-chlorobenzene was prepared according to literature precedent (J. Am. Chem. Soc. 2002, 124 (7), 1354): a suspension of l-bromo-2-methyl-4-chlorobenzene (1 eq), NBS (1 eq) and benzoyl peroxide (0.004 eq) in CCl4 (0.7 M) was heated at reflux for 4 h. The reaction was then filtered whilst hot and the volatiles reduced in vacuo. PE was added, and the resultant precipitate filtered off and dried in vacuo to afford the title compound (45 percent).
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 31, p. 6404 - 6409
[2] Patent: WO2005/123054, 2005, A1, . Location in patent: Page/Page column 25
[3] Patent: WO2006/46030, 2006, A2, . Location in patent: Page/Page column 28
[4] Organic Letters, 2015, vol. 17, # 19, p. 4654 - 4657
[5] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 19, p. 2903 - 2909
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4721 - 4736
[7] Patent: EP1842846, 2007, A1, . Location in patent: Page/Page column 51
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 336 - 343
[9] Patent: EP2020405, 2009, A1, . Location in patent: Page/Page column 68
[10] Heterocycles, 2010, vol. 80, # 1, p. 669 - 677
[11] Patent: WO2006/14357, 2006, A1, . Location in patent: Page/Page column 87
[12] Patent: EP1826201, 2007, A1, . Location in patent: Page/Page column 34-35
[13] Chemistry - A European Journal, 2012, vol. 18, # 16, p. 4859 - 4865
[14] Patent: WO2017/35354, 2017, A1, . Location in patent: Page/Page column 100; 101
[15] Patent: WO2007/79186, 2007, A2, . Location in patent: Page/Page column 77
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 8, p. 2722 - 2730
6
[ 66192-24-3 ]
[ 174265-12-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
With 4-methylmorpholine N-oxide In acetonitrile at 0℃; for 2 h; Molecular sieve
Step 2: 2-bromo-5-chlorobenzaldehyde; 2-bromo-5-chlorobenzaldehyde was prepared according to literature precedent (/. Am. Chem. Soc. 2002, 124 (7), 1354): a mixture of activated powdered 4A molecular sieves (800 mg/mmol substrate), N- methylmorpholine-N-oxide (2 eq) and 2-bromomethyl-5-chlorobenzaldehyde (1 eq) in MeCN (0.16 M) was stirred at 0 0C for 2 h. The reaction was then filtered through a pad of celite and concentrated in vacuo to afford the title compound (92 percent)
Reference：
[1] Patent: WO2006/46030, 2006, A2, . Location in patent: Page/Page column 28
[2] Journal of the American Chemical Society, 2002, vol. 124, # 7, p. 1354 - 1363
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h;
7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-l(2H)-oneTo a stirred solution of 7-hydroxy-l-tetralone (13.9 g, 85.7 mmol) and l-bromo-2- (bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5- chlorobenzyloxy)-3,4-dihydronaphthalen-l(2H)-one (27.8 g, 89percent yield) was isolated by filtration.
89%
With potassium carbonate In N,N-dimethyl-formamide for 18 h; Inert atmosphere
To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)- (27.8 g, 89percent yield) was isolated by filtration.
89%
With potassium carbonate In N,N-dimethyl-d6-formamide at 20℃; for 18 h; Inert atmosphere
7-(2-Bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 89percent yield) was isolated by filtration.
28 g
With potassium carbonate In N,N-dimethyl-formamide for 18 h; Inert atmosphere
In 850 ml of dimethylformamide,25.6 g (90.0 mmol) of 1-bromo-2-(bromomethyl)-4-chlorobenzene (iv-1) and 13.9 g (85.7 mmol) of 7-hydroxy-1-tetralone () iv- are sequentially added. 2, stir to dissolve; add 24g under stirring(172 mmol) potassium carbonate. Argon and stirred for 18 hours. Add 1 L of ethyl acetate, wash the organics with water (3X300 mL) 3 times, and wash once with 300 mL of brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, 500 ml was reduced, stirred for 1 hour, filtered and dried. 28 g of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (iv-3) was obtained.
28 g
With potassium carbonate In N,N-dimethyl-formamide for 18 h; Inert atmosphere
The first step: In 850 ml of dimethylformamide,Add 25.6g (90.0mmol) in order1-Bromo-2-(bromomethyl)-4-chlorobenzene(iv-1) and 13.9 g (85.7 mmol) of 7-hydroxy-1-tetralone () iv-2, stirring to dissolve; 24 g (172 mmol) of potassium carbonate was added under stirring. Argon and stirred for 18 hours. Add 1 L of ethyl acetate, wash the organics with water (3X300 mL) 3 times, and wash once with 300 mL of brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, evaporated to dryness in vacuo, 500 ml of methanol was added, stirred for 1 hour, filtered, and dried.Obtained 28 g of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalene-1(2H)-one (iv-3).
Reference：
[1] Patent: WO2013/75029, 2013, A1, . Location in patent: Page/Page column 53-55
[2] Patent: US2013/309196, 2013, A1, . Location in patent: Paragraph 0205
[3] Patent: US2014/178336, 2014, A1, . Location in patent: Paragraph 0234
[4] Patent: US2015/361073, 2015, A1, . Location in patent: Paragraph 0433
[5] Patent: CN107540679, 2018, A, . Location in patent: Paragraph 0031; 0032
[6] Patent: CN107556324, 2018, A, . Location in patent: Paragraph 0030-0032
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2h;Heating / reflux;
20.5 g (100 mmol) of <strong>[14495-51-3]2-bromo-5-chlorotoluene</strong> was dissolved in 200 ml of carbon tetrachloride, 0.2 g (1 mmol) of AIBN and 19.6 g (110 mmol) of N-bromosuccinimide were added thereto, the resulting mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and with 50 ml of a brine solution, dried over anhydrous MgS04, and distilled under a reduced pressure to obtain an oil containing a small amount of the starting material. The oil was dissolved in 20 ml of hexane, and recrystallized at room temperature to obtain ' 22.7 g (yield 80%) of 2-bromo-l-bromomethyl-5-chlorobenzene. ¹H NMR (300 MHz, CDC13) d 7.50 (d, 1H, J= 8.7 Hz), 7.45 (d, 1H, J= 2.4 Hz), 7.15 (dd, 1H, J= 8.7 Hz, 2.4 Hz), 4.53 (s, 2H)
71%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 24h;Reflux;
Take a 500 ml double neck round bottom bottle and place it in a stirrer and a reflux tube. After drying, it is filled with nitrogen. First, add compound A-2 (20.548 g, 1.0 equivalent) and NBS (N-bromosuccinimide). , 19.5778 g, 1.1 eq.), and AIBN (azobisisobutyronitrile, 0.821 g, 0.5 mol%), followed by the addition of carbon tetrachloride (250 ml) and stirred for 10 minutes, finally heated to reflux and reacted After 24 hours; after the temperature was warmed, water (200 ml) was added, followed by extraction with ethyl acetate (3×200 ml), and the obtained extract was sequentially dried over magnesium sulfate, filtered and dried. Purification (ethyl acetate / hexanes, 1/10) gave Intermediate 1-2 (20.191 g, yield 71%).
45%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Heating / reflux;
Step 1: l-bromo-2-(bromomethyl)-4-chlorobenzene; l-bromo-2-(bromomethyl)-4-chlorobenzene was prepared according to literature precedent (J. Am. Chem. Soc. 2002, 124 (7), 1354): a suspension of l-bromo-2-methyl-4-chlorobenzene (1 eq), NBS (1 eq) and benzoyl peroxide (0.004 eq) in CCl4 (0.7 M) was heated at reflux for 4 h. The reaction was then filtered whilst hot and the volatiles reduced in vacuo. PE was added, and the resultant precipitate filtered off and dried in vacuo to afford the title compound (45 %).
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;
2-Bromo-5-chlorotoluene (8.26 ml) and N-bromosuccinimide (11.03 g) in carbontetrachloride (50 ml) were treated with a catalytic amount of benzoylperoxide (100 mg) and heated under reflux until the reaction had reached completion as monitored by TLC. The reaction mixture was then allowed to cool and filtered. The filtrate was washed twice with water and brine, dried over sodium sulfate and concentrated in vacuo.
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;
Intermediate 22a): [Show Image] 2-Bromo-5-chlorotoluene (8.26 ml) and N-bromosuccinimide (11.03 g) in carbon-tetrachloride (50 ml) were treated with a catalytic amount of benzoylperoxide (100 mg) and heated under reflux until the reaction had reached completion as monitored by TLC. The reaction mixture was then allowed to cool and filtered. The filtrate was washed twice with water and brine, dried over sodium sulfate and concentrated in vacuo.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Heating / reflux;
A mixture of <strong>[14495-51-3]2-bromo-5-chloro-toluene</strong> (2.00 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol) and catalyticamount of AffiN in carbon tetrachloride (50 ml) was stirred under refluxing conditions for 4 h. TLC(EtOAc-.hexane = 5:95) showed no starting material. The mixture was filtered and the filtrate wasconcentrated. The title compound was obtained as a white solid after flash column using EtOAc:hexane =5:95 as the elute.lH NMR (CDCls, 500 MHz) 5 7.53 (d, J = 9.0 Hz,lH), 7.47 (d, J =2.5 Hz, 1H), 7.18(dd, J = 8.5, 2.5 Hz, IH), 4.60 (s, 2H).
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;
2-Bromo-5-chlorotoluene (8.26 ml) and N-bromosuccinimide (11.03 g) in carbontetrachloride (50 ml) were treated with a catalytic amount of benzoylperoxide (100 mg) and heated under reflux until the reaction had reached completion as monitored by TLC. The reaction mixture was then allowed to cool and filtered. The filtrate was washed twice with water and brine, dried over sodium sulfate and concentrated in vacuo.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 12h;
A solution of l-bromo-4-chloro-2-methylbenzene (3.00 g, 14.60 mmol, 1.00 eq), NBS (2.34 g, 13.14 mmol 0.90 eq) and AIBN (239.75 mg, 1.46 mmol, 0.10 eq) in CC14 (20.00 mL) was stirred at 90C for 12 hrs. The solution was concentrated under vacuum to give a crude product 1-bromo- 2-(bromomethyl.)-4-chl.orobenzene (5.40 g, crude) as a yellow solid which was used directly in the next step without further purification.
With N-Bromosuccinimide;di-t-butyldiazene; In tetrachloromethane; for 4h;Heating / reflux;
A mixture of <strong>[14495-51-3]2-bromo-5-chloro-toluene</strong> (2.00 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol) and catalytic amount of AIBN in carbon tetrachloride (50 ml) was heated to and maintained at reflux for 4 h. TLC (EtOAc:hexane / 5:95) showed no starting material. The mixture was filtered and the filtrate was concentrated. The title compound was obtained as a white solid (2.20 g) after flash column using EtOAc:hexane / 5:95 as the eluant.'H NMR (CDCl3, 500 MHz) delta 7.53 (d, J= 9.0 Hz,lH), 7.47 (d3 J=2.5 Hz, IH), 7.18 (dd, J= 8.5, 2.5 Hz, IH), 4.60 (s, 2H).
With potassium carbonate; In acetonitrile; for 15.0h;Heating / reflux;
1.42 g (5 mmol) of the compound obtained in Step 1 was dissolved in 20 ml of acetonitrile, 1.38 g (10 mmol) of K2C03 and 0.84 g (5 mmol) of <strong>[51980-60-0]4-(2-methoxyethoxy)phenol</strong> were added thereto, which was refluxed for 15 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added thereto. The resulting mixture was washed twice with water, dried over anhydrous MgS04, and concentrated under a reduced pressure. The concentrate was subjected to column chromatography using 20% ethyl acetate/hexane to obtain 1.76 g (yield 95 %) of 1-(2-bromo-5-chlorobenzyloxy)-4-(2-methoxyethoxy)benzene.
With N-Bromosuccinimide; potassium carbonate; In N-methyl-acetamide;
EXAMPLE 4 Production of Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate 2-Bromo-5-chlorobenzyl bromide prepared from <strong>[14495-51-3]2-bromo-5-chlorotoluene</strong> (50 g), N-bromosuccinimide and N,N'-azobisisobutyronitrile, and ethyl 1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate (50 g) obtained in Example 3 were suspended in dimethylformamide (300 ml). Potassium carbonate (38 g) was added and the mixture was stirred for 1 hr at 80 C. with heating. The reaction mixture was allowed to cool and then added to a mixed solvent of water-ethyl acetate.
To a solution of (4S,5R>5-[3,5-bis(trifluoromethyl) phenyl]-4-methyl-l,3-oxazolidin-2-one (0.050 g,0.16 mmol) in THF (1 ml) at 0C, NaH (7.6 mg, 0.19 mmol, 60%) was added. The mixture was stirred at0C for 30 min. The title compound from Step A (0.059 g, 0.21 mmol) was added. The whole mixturewas stirred at 0C for 1 h and warmed to room temperature for 4 h. The reaction was quenched withsaturated ammonium chloride. The organic was extracted with ethyl acetate (3 x 15 ml). The combinedethyl acetate layers were washed with brine and dried over sodium sulfate. The title compound wasobtained after preparative TLC purification using EtOAc:hexane = 2:8 as the elute. IH NMR (CDC13,500 MHz) 5 7.92 (s, IH), 7.82 (s, 2H), 7.55 (d, J = 8.5 Hz, IH), 7.43 (d, J = 2.5 Hz, IH), 7.23 (dd, J =8.5, 2.5 Hz, IH), 5.77 (d, / = 8.0 Hz, 1H),4.86 (d, J = 16.0 Hz, IH), 4.36 (d, J = 16.0 Hz, IH), 4.11 (m,ffl),0.82(d,J = 6.5Hz, 3H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 48h;Inert atmosphere; Reflux;
Intermediate 6: 2:1 Mixture of 2-(bromomethyl)-4-chloro-1-iodobenzene and 1- bromo-2-(bromomethyl)-4-chlorobenzene; Lambda/-bromosuccinimide (6.34 g, 35.6 mmol) was weighed into a flask and carbon tetrachloride (200 ml) was added followed by <strong>[23399-70-4]4-chloro-1-iodo-2-methylbenzene</strong> (8.57 g, 33.9 mmol, Fluorochem Ltd). The reaction mixture was stirred and dibenzoyl peroxide (0.822 g, 3.39 mmol) was added in one portion. The apparatus was then flushed three times with nitrogen and heated to reflux with vigorous stirring. After approximately 46 h at reflux, the reaction was allowed to cool to room temperature. The reaction mixture was filtered to remove the insoluble material and washed with aqueous sodium sulfite solution. The carbon tetrachloride layer was dried over sodium sulfate and evaporated to give a crude product as a pale yellow oil which crystallised on standing. The crude product was triturated with cyclohexane. The white insoluble material (1.30 g) was retained. The soluble material was then loaded onto 50 g silica SPE (pre-conditioned with cyclohexane) and was eluted with cyclohexane. Two product batches were obtained from this purification. The slower running material was obtained as a clear liquid which crystallised on standing to give the title compounds as a 2:1 mixture of 2- (bromomethyl)-4-chloro-1-iodobenzene and 1-bromo-2-(bromomethyl)-4- chlorobenzene (1.99 g).The faster running material (2.07 g) was combined with the triturated material (1.30 g) and was re-purified on 50 g silica SPE eluting with cyclohexane, exactly as before. A second batch of the title compounds, again as a 2:1 of 2-(bromomethyl)-4-chloro-1- iodobenzene and 1-bromo-2-(bromomethyl)-4-chlorobenzene (2.38 g) was obtained; LCMS: (System 2) tRET = 1 -37 min (no ions detected).
With copper(l) iodide; caesium carbonate; L-proline; In N,N-dimethyl-formamide; at 110℃; for 20h;Inert atmosphere;
General procedure: An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, 2-mercaptobenzimidazole 1a (125 mg, 0.5 mmol), isothiocyanatobenzene 2a (75 mg, 0.5 mmol), Cs2CO3 (652 mg, 2.0 mmol), CuI (10 mg, 0.05 mmol, 10 mol %), L-Proline (16.5 mg, 0.10 mmol, 20 mol %). The tube was evacuated and backfilled with N2 (this procedure was repeated 3 times). Under a counter flow of N2, DMF (2.0 mL) was added by syringe and the mixture was pre-stirred for several minutes. The tube was sealed and the mixture was allowed to stir at 110 C for 20 h. The reaction was stopped and cooled to room temperature. Then the cooled reaction mixture was dissolved in H2O and extracted with Et2O. The combined organic layer was dried (MgSO4), then concentrated by rotatory evaporation. The crude residue was purified by column chromatography on silica gel using petroleum/ethyl acetate as eluent to give a yellow solid of benzimidazobenzothiazine (3a) (97.7 mg, 82%).
With copper(l) iodide; caesium carbonate; <i>L</i>-proline In N,N-dimethyl-formamide at 110℃; for 20h; Inert atmosphere;
(A) Typical Experimental Procedure Experimental Procedure for Copper-Catalyzed One-Pot Synthesis of benzimidazobenzothiazine (3a) (Table 2, entry 1).
General procedure: An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, 2-mercaptobenzimidazole 1a (125 mg, 0.5 mmol), isothiocyanatobenzene 2a (75 mg, 0.5 mmol), Cs2CO3 (652 mg, 2.0 mmol), CuI (10 mg, 0.05 mmol, 10 mol %), L-Proline (16.5 mg, 0.10 mmol, 20 mol %). The tube was evacuated and backfilled with N2 (this procedure was repeated 3 times). Under a counter flow of N2, DMF (2.0 mL) was added by syringe and the mixture was pre-stirred for several minutes. The tube was sealed and the mixture was allowed to stir at 110 °C for 20 h. The reaction was stopped and cooled to room temperature. Then the cooled reaction mixture was dissolved in H2O and extracted with Et2O. The combined organic layer was dried (MgSO4), then concentrated by rotatory evaporation. The crude residue was purified by column chromatography on silica gel using petroleum/ethyl acetate as eluent to give a yellow solid of benzimidazobenzothiazine (3a) (97.7 mg, 82%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-l(2H)-oneTo a stirred solution of 7-hydroxy-l-tetralone (13.9 g, 85.7 mmol) and l-bromo-2- (bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5- chlorobenzyloxy)-3,4-dihydronaphthalen-l(2H)-one (27.8 g, 89% yield) was isolated by filtration.
89%
With potassium carbonate; In N,N-dimethyl-formamide; for 18h;Inert atmosphere;
To a stirred solution of <strong>[22009-38-7]7-hydroxy-1-tetralone</strong> (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)- (27.8 g, 89% yield) was isolated by filtration.
89%
With potassium carbonate; In N,N-dimethyl-d6-formamide; at 20℃; for 18h;Inert atmosphere;
7-(2-Bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one To a stirred solution of <strong>[22009-38-7]7-hydroxy-1-tetralone</strong> (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 89% yield) was isolated by filtration.
With potassium carbonate; In N,N-dimethyl acetamide; at 20℃;
To a mixture of <strong>[22009-38-7]7-hydroxy-3,4-dihydronaphthalen-1(2H)-one</strong> (Compound (N)) (1.0 g) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.75 g) (Compound (5-1)) and N,N-dimethylacetamide (5 mL) at ambient temperature was added potassium carbonate (1.28 g). After complete conversion, the mixture was diluted with water (10 mL) and the mixture was filtered. The filter cake was washed with water and the isolated solids dried under reduced pressure at 50 C. to afford 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (Compound (5-2)). HRMS (ESI+ MS/MS) Calculated for C17H15BrClO2 m/z (M+H): 364.9944, and 366.9923. Found: 364.9947, and 366.9948. 1H NMR (400 MHz, CDCl3) delta 7.62 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.24-7.11 (m, 3H), 5.10 (s, 2H), 2.98-2.86 (m, 2H), 2.70-2.60 (m, 2H), 2.21-2.06 (m, 2H).
28 g
With potassium carbonate; In N,N-dimethyl-formamide; for 18h;Inert atmosphere;
In 850 ml of dimethylformamide,25.6 g (90.0 mmol) of 1-bromo-2-(bromomethyl)-4-chlorobenzene (iv-1) and 13.9 g (85.7 mmol) of <strong>[22009-38-7]7-hydroxy-1-tetralone</strong> () iv- are sequentially added. 2, stir to dissolve; add 24g under stirring(172 mmol) potassium carbonate. Argon and stirred for 18 hours. Add 1 L of ethyl acetate, wash the organics with water (3X300 mL) 3 times, and wash once with 300 mL of brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, 500 ml was reduced, stirred for 1 hour, filtered and dried. 28 g of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (iv-3) was obtained.
28 g
With potassium carbonate; In N,N-dimethyl-formamide; for 18h;Inert atmosphere;
The first step: In 850 ml of dimethylformamide,Add 25.6g (90.0mmol) in order1-Bromo-2-(bromomethyl)-4-chlorobenzene(iv-1) and 13.9 g (85.7 mmol) of <strong>[22009-38-7]7-hydroxy-1-tetralone</strong> () iv-2, stirring to dissolve; 24 g (172 mmol) of potassium carbonate was added under stirring. Argon and stirred for 18 hours. Add 1 L of ethyl acetate, wash the organics with water (3X300 mL) 3 times, and wash once with 300 mL of brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, evaporated to dryness in vacuo, 500 ml of methanol was added, stirred for 1 hour, filtered, and dried.Obtained 28 g of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalene-1(2H)-one (iv-3).
With potassium carbonate; In N,N-dimethyl-formamide; for 1h;Inert atmosphere;
5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-l(2//)-oneTo a stirred solution of 5 -hydroxy- 1-tetralone (2.0 g, 12.3 mmol) and l-bromo-2- (bromomethyl)-4-chlorobenzene (3.6 g, 12.7 mmol) in dimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1 mmol). The reaction was stirred under argon for 1 hour then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (100 mL) and the suspension was agitated for thirty minutes. 5-(2-bromo-5- chlorobenzyloxy)-3,4-dihydronaphthalen-l(2H)-one (4.25 g, 94% yield) was isolated by filtration.
94%
With potassium carbonate; In N,N-dimethyl-formamide; for 1h;Inert atmosphere;
To a stirred solution of 5-hydroxy-1-tetralone (2.0 g, 12.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (3.6 g, 12.7 mmol) in dimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1 mmol). The reaction was stirred under argon for 1 hour then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (100 mL) and the suspension was agitated for thirty minutes. 5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (4.25 g, 94% yield) was isolated by filtration.
2-(2-bromo-5-chlorobenzyl)-2H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 60h;
2H-<strong>[288-36-8]1 ,2,3-Triazole</strong> (0.486 g, 7.03 mmol) was added to a suspension of potassium carbonate(1.166 g, 8.44 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (2 g, 7.03 mmol) inDMF (15 mL) and the resulting mixture stirred at room temperature for 60 h. The reactionwas poured into water (150 mL) and extracted with ethyl acetate (3x100 mL). The combined organics were washed with water (100 mL), dried over sodium sulphate, filtered and concentrated in vacuo. Purification was carried out by silica gel column chromatography eluting with a gradient of iso-hexane to 75% ethyl acetate in iso-hexane. The productfractions were combined and evaporated in vacuo to give the title compound as a whitesolid;1H NMR (400 MHz, ODd3) O 7.73 (2H, 5), 7.55 (1H, d), 7.19, (1H, dd), 6.87 (1H, m), 5.74(2H, 5).
4-((2-bromo-5-chlorobenzyl)oxy)-1-methyl-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 50℃; for 20h;Inert atmosphere;
General procedure: To a cold (0 °C, ice bath) solution of 1-alkyl-1H-pyrazol-4-ol (3.5 g, 35.7 mmol) and potassium carbonate (5.2 g, 37.5 mmol, 1.05 eq.) in N,N-dimethylformamide (118.9 mL, 0.3 M) was slowly added benzyl chloride (4.3 mL, 37.5 mmol, 1.05 eq.). The reaction mixture was stirred at 0-25 °C for 2 h and 50 °C for 18 h. The reaction mixture was diluted with ethyl acetate (500 mL) and water (500 mL). The aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were washed with water (250 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography.
10-chloro-4-oxo-4H,8H-pyrido[3,2,1-de]phenanthridine-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: 2-bromo-5-chlorobenzyl bromide; ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;
Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 20 - 80℃; for 3h; Inert atmosphere;
Phenanthridinone Derivatives 7 and 9; General Procedure
General procedure: A mixture of the appropriate quinolone 1 (1 mmol), 2-bromobenzylbromide 5 or 8 (1.5 mmol), and K2CO3 (2 mmol) in anhydDMF (3 mL) was stirred at 80 °C for 2 h, then cooled to r.t. TBAB(1.5 equiv), K2CO3 (1.5 equiv), and Pd(OAc)2 (10 mol %) wereadded to the reaction vessel under argon, and the mixture washeated at 80 °C for 3 h. When the reaction was complete, themixture was cooled and diluted with H2O then extracted withEtOAc. The combined organic extracts were washed with H2Oand brine, dried (Na2SO4), filtered, and concentrated. Theresidue was purified by column chromatography [silica gel,CHCl3-MeOH (9:1)].
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