Methyl (4-bromophenyl)acetate

Pale Yellow Oil

Preparation Example 26-1 methyl(4-bromophenyl)acetate Preparative Step A; A solution of commercially available (4-bromophenyl)-acetic acid (4.05 g) and ion exchange resin IR-120(HPreparation of Intermediate methyl 2-(4-bromoohenyl)-2-methylorooanoate (1D-D; A solution of 4-bromophenylacetic acid (10g, 47mmol) in methanol (194ml, 46.5/W) and sulfuric acid (2.48ml, 46.5mmol) was heated to reflux for 16 hours. Reaction was concentrated, diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. Organic was dried over sodium sulfate, filtered and concentrated to give methyl 2-(4-bromophenyl)acetate (10.63g , 100percent) as a colorless oil.1 H NMR (400 MHz, CHLOROFORM-d) d ppm 3.56 (s, 2 H) 3.68 (s, 3 H) 7.14 (d, J=8.59 Hz, 2 H) 7.43 (d, J=8.59 Hz, 2 H)Concentrated sulfuric acid (30 ml) was added to a solution of (4-bromophenyl)acetic acid (101 g, 468 mmol) in methanol (1000 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and, after ethyl acetate was added to the residue, the mixture was successively washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=5/1) to obtain methyl (4-bromophenyl)acetate (107 g, yield: 100percent). A mixture of 2-(4-bromophenyl)acetic acid (10 g, 46.5 mmol) in MeOH (100 mL, with 2 mL of conc. H2504) was refluxed for 4 h. The mixture was concentrated and diluted with EtOAc. The organic was washed with water and brine, dried and concentrated to give the title product (10.6 g, yield 100percent). MS (ES+) C9H9BrO2 requires: 229 found 230 [M+H].Methyl 2-(4-bromophenyl)acetate. To a solution of 2-(4-bromophenyl)acetic acid (10 g, 46.7 mmol) in menthol was added thionyl chloride (8.34 g, 70.07 mmol) dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated, and obtained methyl 2-(4-bromophenyl)acetate (10.5 g, 99.8percent).General procedure: (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.percent sulfonic acid (0.28 mL) inmethanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted withsaturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combinedextracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (38) (1.13 g, 99percent yield) as a colorless oil. The crude product was used without purification. (Step 2)10 A solution of 38 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide11 (1.16 g, 5.88 mmol) in acetonitrile(9.8 mL) was treated with DBU (1.10 mL, 7.36 mmol) at 0 °C and the mixture was stirred for overnight at roomtemperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Theresidue was purified by chromatography on silica gel (n-hexane/ethyl acetate = 10/1 as the eluent) to afford 2a(1.22 g, 98percent yield) as an orange solid.(Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.percent sulfonic acid (0.28 mL) in methanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (18) (1.13 g, 99percent yield) as a colorless oil. The crude product was used without purification. (Step 2)4 A solution of 18 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide5 (1.16 g, 5.88mmol) in acetonitrile (9.8 mL) was treated with DBU (1.10 mL, 7.36 mmol) at 0 °C and the mixture was stirred for overnight at room temperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (n-hexane/ethyl acetate= 10/1 as the eluent) to afford 4 (1.22 g, 98percent yield) as an orange solidTo a solution of 2-(4-bromophenyl)acetic acid (10 g, 46.7 mmol) in menthol was added thionyl chloride (8.34 g, 70.07 mmol) dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated, and obtained methyl 2-(4-bromophenyl)acetate (10.5 g, 99.8percent).Sulfuric acid (56.5 mL) was very slowly added to a solution of 206.6 g of 4- bromophenyl acetic acid in methanol (800 mL). After completion of the addition, the mixture was heated to reflux for 2h. The reflux condenser was replaced by a distillation head and 400 mL of methanol was atmospherically distilled. The temperature was the reduced to 50 Step 3: 4-Bromophenyl acetic acid methyl ester Sulfuric acid (56.5 mL) was very slowly added to a solution of 206.6 g of 4-bromophenyl acetic acid in methanol (800 mL). After completion of the addition, the mixture was heated to reflux for 2h. The reflux condenser was replaced by a distillation head and 400 mL of methanol was atmospherically distilled. The temperature was the reduced to 50 °C and the reaction stirred for additional 16h, when the mixture was then cooled to room temperature and partitioned between dichloromethane (1 L) and water (600 mL). The organic phase was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Concentration under reduced pressure provided 220. lg (98percent yield) colorless oil. HNMR: CDCI6.2.3 4-Bromophenylacetic acid (4.9 g, 22.79 mmol) in methanol (15 mL) and sulfuric acid (0.05 mL, 0.9 mmol) was heated to 75° C. for 2 hours. Add 500g of p-bromophenylacetic acid to the 5.0L reaction flaskAnd 250g of solid acid catalyst, Add 2.7 L of methanol, Stirring, Reflux reaction for 5.5 h;The reaction solution was cooled to 25 ° C.Filtering and recovering the solid acid catalyst, The filtrate obtained is subjected to reduced pressure distillation, Remove methanol, Add 2.0 L of toluene and stir to dissolve.Wash the toluene with water, Concentrated under reduced pressure, 505.6g of intermediate 1, The yield was 95.0percent.2-(4-Bromophenyl) acetic acid (10.0 g, 46.5 mmol, 1.0 equiv) was dissolved in methanol (30 mL). Concentrated H2S04 (7 mL) was added drop wise at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.5a (10 g, 94 percent yield). 1H NMR (400 MHz, DMSO) 6 7.52 (d, J= 8.4 Hz, 2H), 7.26 (t, J= 14.0 Hz, 2H), 3.69 (s, 2H), 3.62 (s, 3H).To a stirred solution of 100 g 4-bromophenylacetic acid (8, 0.46 mol) in 300 cm3 methanol, 30 cm3 sulfuric acid was added in 1 h. The reaction mass was heated to 70 C and the temperature maintained until the completion of the reaction (monitored by HPLC). After completion of the reaction, methanol was distilled under reduced pressure at70 C, the resulting solution was cooled to 25–30 C, diluted with 200 cm3 water and the product was extracted into 300 cm3 dichloromethane. The dichloromethane layer was washed with 5percent solution of sodium bicarbonate and concentrated under reduced pressure to offer 9 as lightbrown oil. Yield: 101 g (94.83percent); purity by HPLC: 99percent;b.p.: 265–270 C. The spectral data of compound 9 werefound to agree with the reported data [8].To a solution of 2-(4-bromophenyl)acetic acid (5.0 g, 23.25 mmol) in methanol (50 mL) was added catalytic amount of thionyl chloride at room temperature under nitrogen atmosphere, the solution was refluxed for 2 hours, methanol was removed under vacuum to get methyl 2-(4-bromophenyl)acetate (37) (5 g, 94 percent) as pale yellow liquid; (4-bromophenyl)acetic acid (10 g, 1 eq) was dissolved in methanol. 10 ml conc. HTo a solution of 4-bromophenylacetic acid, 7-c, (10 g, 47 mmol) in methanol (100 mL) was added SOC12 (3.4 mL, 47 mmol) dropwise under a nitrogen atmosphere in an ice-water bath. After stirred in the ice- water bath for 30 min, the resulting solution was refluxed with stirring overnight. The cooled reaction solution was concentrated and treated with cooled saturated NaHCC'3 solution. The layers were separated and the aqueous layer was extracted by EA. Combined organic layers were washed by brine, dried over Na2SC'4 and concentrated to afford the title compound, 7-d, as pink oil (9.0 g, 85percent).1H NMR (300 MHz, CDCI3) 53.58 (s, 2H), 3.69 (s, 3H), 7.15 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H).Step C: Methyl 2-f4-bromophenvD acetate (7-d) To a solution of 4-bromophenylacetic acid, 7-c, (10 g, 47 mmol) in methanol (100 mL) was added SOC12 (3.4 mL, 47 mmol) dropwise under a nitrogen atmosphere in an ice-water bath. After stirred in the ice-water bath for 30 min, the resulting solution was refluxed with stirring overnight. The cooled reaction solution was concentrated and treated with cooled saturated NaHC03 solution. The layers were separated and the aqueous layer was extracted by EA. Combined organic layers were washed by brine, dried over Na2S04 and concentrated to afford the title compound, 7-d, as pink oil (9.0 g, 85percent). NMR (300 MHz, CDCI3) 83.58 (s, 2H), 3.69 (s, 3H), 7.15 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H).To a stirred solution of compound XCVI-1 (20 g, 93.5 mmol) in MeOH (200 mL) was added S0C1Concentrated sulfuric acid (1.0 mL, 18.4 mmol) was added dropwise over 15 minutes to a stirred solution of 2-(4-bromophenyl)acetic acid (4.0 g, 18.6 mol) in methanol (40 mL) and the resulting mixture heated to reflux for 4 hours. The solution was allowed to cool to room temperature and the solvents evaporated under reduced pressure. Saturated NaHCC>3 solution was added to the residue to adjust the pH to -8, then the aqueous phase was extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried (Na2S0Step 1: Step 1: General procedure: Carboxylic acid (0.5 mmol) and MImC (2a, 1.0 mmol) were placed in a dry 20 mL vial with a Teflon tape-coated thread. A magnetic stirbar was added, followed by dry MeCN (1.0 mL), and the vial was quickly sealed with a plastic cap (gas is evolved during the course of the reaction. All experiments should be performed behind a blast shield if a sealed container is used.). The reaction mixture was then stirred at 23 °C for 15 min and then heated to 80 °C using a heating block for 24 h. The mixture was cooled to room temperature and then the vial was carefully opened (CAUTION: vial under pressure.). The volatiles were removed in vacuo, the resulting residue was dissolved in diethyl ether (20 mL), and then washed with 1 M HCl (10 mL). The aqueous layer was back-extracted with diethyl ether (20 mL) and the organic fractions were combined, washed with a saturated solution of NaHCOGeneral procedure: A stirred solution of the appropriate bromophenyl alkanoic acid(1 eq) in MeOH (25 mL)was treated with H2SO4 (0.1 eq of a conc. aq.solution) and heated at reflux for 18 h. The resultant solution wascooled to room temperature and concentrated under reducedpressure. The resultant oil was diluted with NaHCO3 (50 mL of a sat.aq. solution) and subsequently extracted with diethyl ether(3 25 mL). The combined organics were washed with brine(1 100 mL), dried (MgSO4), filtered and concentrated underreduced pressure to give the desired methyl ester:A.

Molecular Weight:229.07
XLogP3:2.5
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:227.97859
Monoisotopic Mass:227.97859
Topological Polar Surface Area:26.3
Heavy Atom Count:12
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes