4-bromo-2-(bromomethyl)-1-methoxybenzene

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: To a solution of (5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1 M in dichloromethane, 9.2 mL, 9.2 mmol). The ice bath was removed and the reaction stirred for 15 min. The reaction was concentrated, poured onto cold saturated sodium bicarbonate, extracted with pentane, dried over magnesium sulfate, and concentrated to give 1.15 g (89%) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.44 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.9, 6.1 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.7, 133.6, 132.8, 128.4, 112.8, 112.7, 56.0, 27.5. The ice bath was removed The reaction was concentrated poured onto cold saturated sodium bicarbonate extracted with pentane dried over magnesium sulfate concentrated to give 1.15 g (89%) as a white crystalline solid

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

Procedure: To a solution of 2-methyl-thiophene-3-carboxylic acid (8.01 g, 56.0 mmol, 1.0 equiv) in THF (56 mL) at −78° C. was added a solution of lithium diisopropylamide (LDA; 2M, 56 mL, 112.0 mmol, 2 equiv). The orange solution was allowed to stir for 1 hr and then a solution of 4-bromo-2-bromomethyl-1-methoxybenzene (17 g, 73 mmol, 1.3 equiv) in THF (50 mL) was added dropwise via cannula. The solution was allowed to stir at −78° C. for one hour and then warmed to room temperature. The reaction was quenched by the addition of water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. Addition of methanol caused precipitation of a white solid, which was filtered and dried to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophene-3-carboxylic acid (5.3 g, 15.5 mmol, 27%). 1H NMR (300 MHz, d6-DMSO) δ 12.59 (s, 1H), 7.31 (dd, J=8.7, 5.7 Hz, 1H), 7.26 (dd, J=6.6, 5.4 Hz, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.27-3.35 (m, 2H), and 2.79-2.88 (m, 2H). LCMS ES− 339 (M−1), 341 (M+1). to stir at −78° C. for one hour The reaction was quenched by the addition of water and ethyl acetate The phases were separated the organic phase was washed with brine dried over Na2SO4 filtered concentrated to give a yellow oil precipitation of a white solid, which was filtered dried

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

Procedure: To a solution of (5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1 M in dichloromethane, 9.2 mL, 9.2 mmol). The ice bath was removed and the reaction stirred for 15 min. The reaction was concentrated, poured onto cold saturated sodium bicarbonate, extracted with pentane, dried over magnesium sulfate, and concentrated to give 1.15 g (89%) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.44 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.9, 6.1 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.7, 133.6, 132.8, 128.4, 112.8, 112.7, 56.0, 27.5. The ice bath was removed The reaction was concentrated poured onto cold saturated sodium bicarbonate extracted with pentane dried over magnesium sulfate concentrated to give 1.15 g (89%) as a white crystalline solid

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

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 4-bromo-2-(bromomethyl)-1-methoxybenzene (500 mg, 1.786 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (700 mg, 85% yield). 1H NMR (500 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.34-7.29 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 4.47 (s, 2H), 3.88 (s, 2H), 3.71 (s, 3H), 2.78 (t, J=6.7 Hz, 2H), 1.82 (t, J=6.7 Hz, 2H), 1.38 (s, 9H), 1.34 (s, 6H). LRMS [ESI, MH−] m/z calcd for C25H33BrNO6S 554.12, found 554.1. The reaction mixture was filtered rinsed alternatively by dichloromethane and methanol The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography

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

Procedure: To a solution of 2-methyl-thiophene-3-carboxylic acid (8.01 g, 56.0 mmol, 1.0 equiv) in THF (56 mL) at −78° C. was added a solution of lithium diisopropylamide (LDA; 2M, 56 mL, 112.0 mmol, 2 equiv). The orange solution was allowed to stir for 1 hr and then a solution of 4-bromo-2-bromomethyl-1-methoxybenzene (17 g, 73 mmol, 1.3 equiv) in THF (50 mL) was added dropwise via cannula. The solution was allowed to stir at −78° C. for one hour and then warmed to room temperature. The reaction was quenched by the addition of water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. Addition of methanol caused precipitation of a white solid, which was filtered and dried to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophene-3-carboxylic acid (5.3 g, 15.5 mmol, 27%). 1H NMR (300 MHz, d6-DMSO) δ 12.59 (s, 1H), 7.31 (dd, J=8.7, 5.7 Hz, 1H), 7.26 (dd, J=6.6, 5.4 Hz, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.27-3.35 (m, 2H), and 2.79-2.88 (m, 2H). LCMS ES− 339 (M−1), 341 (M+1). to stir at −78° C. for one hour The reaction was quenched by the addition of water and ethyl acetate The phases were separated the organic phase was washed with brine dried over Na2SO4 filtered concentrated to give a yellow oil precipitation of a white solid, which was filtered dried

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

Procedure: To a solution of 2-methyl-thiophene-3-carboxylic acid (8.01 g, 56.0 mmol, 1.0 equiv) in THF (56 mL) at −78° C. was added a solution of lithium diisopropylamide (LDA; 2M, 56 mL, 112.0 mmol, 2 equiv). The orange solution was allowed to stir for 1 hr and then a solution of 4-bromo-2-bromomethyl-1-methoxybenzene (17 g, 73 mmol, 1.3 equiv) in THF (50 mL) was added dropwise via cannula. The solution was allowed to stir at −78° C. for one hour and then warmed to room temperature. The reaction was quenched by the addition of water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. Addition of methanol caused precipitation of a white solid, which was filtered and dried to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophene-3-carboxylic acid (5.3 g, 15.5 mmol, 27%). 1H NMR (300 MHz, d6-DMSO) δ 12.59 (s, 1H), 7.31 (dd, J=8.7, 5.7 Hz, 1H), 7.26 (dd, J=6.6, 5.4 Hz, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.27-3.35 (m, 2H), and 2.79-2.88 (m, 2H). LCMS ES− 339 (M−1), 341 (M+1). to stir at −78° C. for one hour The reaction was quenched by the addition of water and ethyl acetate The phases were separated the organic phase was washed with brine dried over Na2SO4 filtered concentrated to give a yellow oil precipitation of a white solid, which was filtered dried

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

Procedure: To a solution of (5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1 M in dichloromethane, 9.2 mL, 9.2 mmol). The ice bath was removed and the reaction stirred for 15 min. The reaction was concentrated, poured onto cold saturated sodium bicarbonate, extracted with pentane, dried over magnesium sulfate, and concentrated to give 1.15 g (89%) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.44 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.9, 6.1 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.7, 133.6, 132.8, 128.4, 112.8, 112.7, 56.0, 27.5. The ice bath was removed The reaction was concentrated poured onto cold saturated sodium bicarbonate extracted with pentane dried over magnesium sulfate concentrated to give 1.15 g (89%) as a white crystalline solid

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