1-bromo-4-(2-methoxyethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Bromophenyl)ethanol (2.0 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60% in oil) (0.44 g) was added under ice-cooling. After gradually warming to room temperature, the mixture was stirred for 2 hr, and methyl iodide (2.1 g) was added again under ice-cooling. After gradually warming to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1) to give the title compound (1.2 g) as a colorless oil. cooling cooling After gradually warming to room temperature the mixture was stirred overnight the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethynyltrimethylsilane (3.42 g, 34.9 mmol) was added via syringe to a mixture of 1-bromo-4-(2-methoxyethyl)benzene (5 g, 23.25 mmol), bis(triphenylphosphine)palladium dichloride (0.326 g, 0.465 mmol), triphenylphosphine (0.305 g, 1.162 mmol) and copper(I) iodide (0.089 g, 0.465 mmol) in piperidine (25 mL). The mixture was heated to 100° C. for 1 h under a nitrogen atmosphere, then cooled and concentrated under vacuum. The residue was taken up in ethyl acetate (70 mL), filtered and concentrated to give the crude product that was then purified by flash chromatography on silica gel (ISCO 120 g column, 0-20% ethyl acetate in n-heptane as the eluent). Product (4.36 g) was obtained as a brown oil (MS: (M+H)+=233.3). cooled concentrated under vacuum filtered concentrated to give the crude product that was then purified by flash chromatography on silica gel (ISCO 120 g column, 0-20% ethyl acetate in n-heptane as the eluent)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-bromo-4-(2-methoxyethyl)benzene (1 g, 4.6 mmole) in THF (15 mL) at −78° C. was added dropwise BuLi (2.5M in hexane) (2.4 mL, 6 mmole). After stirring at −78° C. for 20 min, trimethyl borate (0.62 g, 6 mmole) was added to the mixture at −78° C. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. 2N HCl was added to the reaction mixture and stirred for 2 h. The mixture was extracted with ether, washed with water, dried over MgSO4, and filtered. Hexane was added to the ether solution. Solid was precipitated and collected by filtration. The solid was used in the next step without purification. MS (ESI) m/z: Calc: 180.0 (M+). Found: 181.3 (M++1). The mixture was slowly warmed to room temperature stirred at room temperature for 1 h stirred for 2 h The mixture was extracted with ether washed with water dried over MgSO4 filtered Hexane was added to the ether solution Solid was precipitated collected by filtration The solid was used in the next step without purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in anhydrous THF (10 mL) was added NaH (60% oil dispersion, 0.2 g, 5 mmol). The mixture was stirred at room temperature for 30 min and cooled to −0° C. Iodomethane (920 mg, 6.5 mmole) was added slowly to the mixture and stirred for 8 h. The reaction mixture was then quenched by adding water, extracted with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a colorless (1 g, 93% yield). 1H NMR (CDCl3, 400 MHz): 7.39 (d, 2H), 7.08 (d, 2H), 3.56 (t, 2H), 3.33 (s, 3H), 2.82 (t, 2H); MS (ESI) m/z. Calc. 215.1 (M+). Found: 216.3 (M′+1), 218.1 (M++3). cooled to −0° C stirred for 8 h The reaction mixture was then quenched by adding water extracted with ethyl acetate The combined organic extracts were dried over MgSO4 filtered concentrated The residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In THF (100 ml) was dissolved 4-bromophenethyl alcohol (10 g). To the mixture was added under ice-cooling 65% sodium hydride (1.7 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise under ice-cooling iodomethane (3.7 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 1-bromo-4-(2-methoxyethyl)benzene (8.3 g). In THF (100 ml) was dissolved 1-bromo-4-(2-methoxyethyl)benzene (8.2 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (26.0 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (11.8 g) in THF (12 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (40 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(2-methoxyethyl)phenyl borate (3.7 g). To the mixture was added under ice- To the mixture was added dropwise under ice- the mixture was stirred at room temperature for 1.5 hours the mixture was extracted with ethyl acetate washed with saturated brine dried with magnesium sulfate Under reduced pressure, the solvent was evaporated the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3-necked 50 mL flask fitted with two septa and a nitrogen balloon was added 800 mg (20 mmol) of 60% NaH dispersed in mineral oil. The oil was removed by washing and decanting with hexanes (3×5 mL), using a pipette and keeping a positive pressure of N2 over the flask. Next, 5 mL of THF was added, the suspension was cooled with an ice bath, then a solution of 2.01 g (10.0 mmol) of 4-bromophenethanol in 5 mL of THF was added via cannula. The ice bath was removed, and the mixture was stirred for 10 min, then 700 mL (11 mmol) of iodomethane was added. The mixture was stirred at ambient temperature for 1 h, then 1 mL of H2O was added to quench the excess NaH. The reaction was poured into 50 mL of H2O, then extracted with diethyl ether (3×20 mL). The combined ether layers were back extracted with brine (1×20 mL), dried over MgSO4, filtered, and concentrated to 2.08 g (97%) of a colorless oil. To a solution of 1.03 g (4.78 mmol) of the above 4-(2-methoxy)ethylbromobenzene in 10 mL of THF was added 400 mg of magnesium turnings, and a crystal of I2. The mixture was heated to reflux under N2 for 5 min, then cooled to ambient temperature. The Grignard reagent was transferred via syringe to a 50 mL 3-necked flask under N2. A balloon of C02 was opened over the reaction, and the red color quickly faded to yellow. After stirring for 1 h at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in 20 mL of H2O and acidified with 12M HCl to pH=1, then extracted with diethyl ether (3×10 mL). The combined ether layers were back extracted with 2M NaOH (3×5 mL), then the combined NaOH layers were extracted with diethyl ether (2×5 mL). The basic layers were treated with 12M HCl until pH=1, then the product was extracted with ethyl acetate (2×5 mL). The combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated to 427 mg (50%) of 4-(2-methoxy)ethylbenzoic acid as a yellow solid. The yellow impurity did not interfere with any subsequent reactions. To a 3-necked 50 mL flask fitted with two septa dispersed in mineral oil The oil was removed by washing decanting with hexanes (3×5 mL) Next, 5 mL of THF was added the suspension was cooled with an ice bath The ice bath was removed The mixture was stirred at ambient temperature for 1 h to quench the excess NaH The reaction was poured into 50 mL of H2O extracted with diethyl ether (3×20 mL) The combined ether layers were back extracted with brine (1×20 mL) dried over MgSO4 filtered concentrated to 2.08 g (97%) of a colorless oil The mixture was heated to reflux under N2 for 5 min A balloon of C02 was opened over the reaction After stirring for 1 h at ambient temperature the reaction was concentrated in vacuo extracted with diethyl ether (3×10 mL) The combined ether layers were back extracted with 2M NaOH (3×5 mL) the combined NaOH layers were extracted with diethyl ether (2×5 mL) The basic layers were treated with 12M HCl until pH=1 the product was extracted with ethyl acetate (2×5 mL) The combined ethyl acetate layers were back extracted with brine (1×5 mL) dried over MgSO4 filtered concentrated to 427 mg (50%) of 4-(2-methoxy)ethylbenzoic acid as a yellow solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Bromophenyl)ethanol (2.0 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60% in oil) (0.44 g) was added under ice-cooling. After gradually warming to room temperature, the mixture was stirred for 2 hr, and methyl iodide (2.1 g) was added again under ice-cooling. After gradually warming to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1) to give the title compound (1.2 g) as a colorless oil. cooling cooling After gradually warming to room temperature the mixture was stirred overnight the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1)