Methyl alpha-bromo-2-chlorophenylacetate

To a stirred solution of the Methyl 2-chlorophenylacetate (0, 86 ml; 5, 31 mmol) in dichloromethane (10, 2 ml; 159 mmol) are added N- bromosuccinimide (1 .04 g; 5.84 mmol) and azobisisobutyronitrile (43, 6 mg; 0, 27 mmol) at room temperature and the mixture is stirred at 100 °C for 16 h under argon atmosphere. The reaction mixture is cooled down to room temperature. The mixture is diluted with diethyl ether and filtered. The filtrate is evaporated to dryness. The oily residue containing solid (0456) succinimid is diluted with heptane and filtered again. The solvent is removed to afford Bromo-(2-chloro-phenyl)-acetic acid methyl ester (1 .38 g; 4.56 mmol; 86 percent of theory). (0457) 1 H NMR (500 MHz, Chloroform-d) δ 7.69 (dd, J = 7.6, 1 .8 Hz, 1 H), 7.31 (dd, J = 7.6, 1 .7 Hz, 1 H), 7.24 (td, J = 7.6, 1 .7 Hz, 1 H), 7.21 (dd, J = 7.5, 1 .8 Hz, 1 H), 5.84 (s, 1 H), 3.74 (s, 3H).To a stirred solution of the Methyl 2-chlorophenylacetate (0, 86 ml; 5, 31 mmol) in dichloromethane (10, 2 ml; 159 mmol) are added N- bromosuccinimide (1.04 g; 5.84 mmol) and azobisisobutyronitrile (43, 6 mg; 0, 27 mmol) at room temperature and the mixture is stirred at 100 °C for 16 h under argon atmosphere. The reaction mixture is cooled down to room temperature. The mixture is diluted with diethyl ether and filtered. The filtrate is evaporated to dryness. The oily residue containing solid succinimid is diluted with heptane and filtered again. The solvent is removed to afford Bromo-(2-chloro-phenyl)-acetic acid methyl ester (1.38 g; 4.56 mmol; 86 percent of theory). 1H NMR (500 MHz, Chloroform-d) δ 7.69 (dd, J = 7.6, 1.8 Hz, 1H), 7.31 (dd, J = 7.6, 1.7 Hz, 1H), 7.24 (td, J = 7.6, 1.7 Hz, 1H), 7.21 (dd, J = 7.5, 1.8 Hz, 1H), 5.84 (s, 1H), 3.74 (s, 3H).Preparation of Alpha Bromo O-Chloro phenyl acetic acid methyl ester (A)100 gm of alpha bromo O-chloro phenyl acetic acid (B), methanol (365 ml) and concentrated sulphuric acid (54.5 gm) were charged in a reaction vessel at 25-30° C and the reaction mixture was then heated to reflux. The reflux was maintained at 65-66 ° C for 7 hours. The formation of alpha bromo O-chloro phenyl acetic acid methyl ester was monitored on TLC. After the formation of alpha bromo O-chloro phenyl acetic acid methyl ester the reaction mixture was distilled at 50-55° C under vacuum. Water was added to the concentrated mass and the aqueous layer was extracted twice with toluene (175ml). The toluene layer was distilled under vacuum to get the concentrated mass of alpha bromo o-chloro phenyl acetic acid methyl ester. Yield: 97.8 gm, percent Yield: 93General procedure: Methyl 2-hydroxy-2-phenylacetate 7a (5.00 g, 30 mmol) was dissolved in CHClStep A Step A Step A: Methanol (1 mL) was added to toluene (10 mL) under an argon atmosphere at room temperature. The flask was cooled in a water bath and 2M(trimethylsilyl)diazo methane (5 mL, 10 mmol) was added, followed by a-bromo-2- chlorophenyl acetic acid (2.2 g, 8.81 mmol) in portions over 5 minutes. After 10 additional minutes, the toluene/methanol was removed under reduced pressure. The crude oil was purified by MPLC (companion) on a silica cartridge (40 g) with a gradient of ethyl acetate in heptane (10percent to 50percent) over 20 minutes. The product containing fractions were combined, concentrated, and dried under high vacuum for 1 hour at room temperature to provide bromo-(2-chlorophenyl)-acetic acid methyl ester (2.0 g, 86percent yield) as a clear liquid that solidified at low temperatures (-10 °C). 1H NMR (300 MHz, CDCIGeneral procedure: Methyl 2-hydroxy-2-phenylacetate 7a (5.00 g, 30 mmol) was dissolved in CHCl3 (50 ml) and 2 equivalents of PBr3 (8.09 ml, 60 mmol). This was then stirred at r.t. for 4 days. Upon completion the reaction was washed with water (50 ml), dried (MgSO4) and then passed through a silica pad. The CHCl3 was removed to give the title compound as a clear oil, 5.00 g (26 mmol, 75%).2-Hydroxy-4-methoxybenzaldehyde (800 mg; 5, 26 mmol) and bromo-(2- chloro-phenyl)-acetic acid methyl ester (1 , 39 g; 5.26 mmol) are dissolved in dimethylformamide (26, 6 ml; 342 mmol). To the solution is added potassium carbonate (3, 63 g; 26, 3 mmol). The mixture is stirred at 100 C for 2 h. The mixture is cooled to 25 C and portioned to ethyl acetate and HCI (1 N, aq.). The organic layer is separated, washed with brine and dried over MgSO4. Evaporation of solvent gave brownish oily intermediate. The residue is dissolved in ethanol (21 , 4 ml; 368 mmol). To the solution is added potassium hydroxide (2, 66 g; 47, 3 mmol) and the mixture is heated to 100 C for 2 h. The mixture is cooled to ambient temperature and acidified with HCI (cone). A solid precipitates which is collected and recrystallized from ethanol to yield 2-(2-Chloro-phenyl)-6-methoxy- benzofuran (500 mg; 1 , 93 mmol; 37 % of theory). (0463) 1 H NMR (500 MHz, Chloroform-d) delta 8.04 (dd, J = 7.9, 1 .8 Hz, 1 H), 7.54 - 7.46 (m, 3H), 7.39 (t, J = 7.7 Hz, 1 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 8.5 Hz, 1 H), 3.91 (d, J = 1 .4 Hz, 3H).