3-fluoro-4-iodoaniline

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 stirred solution of 4-iodo 3-fluoro aniline (2.25 g, 9.49 mmol) in THF (25 ml) at 0° C. to −5° C., CuI (90 mg, 0.47 mmol) and Et3N (3.5 ml, 25.62 mmol) were added. The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C. Addition of Pd(dppf)Cl2.CH2Cl2 (346 mg, 0.47 mmol) and purging was continued. After 10 minutes, cyclopropyl acetylene (0.72 ml, 8.54 mmol) was added at −5° C. and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (200 mL), filtered through celite pad, washed with ether (2×25 mL). The filtrate was concentrated and the residue purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to afford title compound as pale brown liquid (750 mg, 45%). The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C Addition of Pd(dppf)Cl2 filtered through celite pad washed with ether (2×25 mL) The filtrate was concentrated the residue purified by column chromatography (100-200 mesh silica gel)

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

Procedure: To a stirred solution of 4-iodo 3-fluoro aniline (2.25 g, 9.49 mmol) in THF (25 ml) at 0° C. to −5° C., CuI (90 mg, 0.47 mmol) and Et3N (3.5 ml, 25.62 mmol) were added. The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C. Addition of Pd(dppf)Cl2.CH2Cl2 (346 mg, 0.47 mmol) and purging was continued. After 10 minutes, cyclopropyl acetylene (0.72 ml, 8.54 mmol) was added at −5° C. and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (200 mL), filtered through celite pad, washed with ether (2×25 mL). The filtrate was concentrated and the residue purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to afford title compound as pale brown liquid (750 mg, 45%). The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C Addition of Pd(dppf)Cl2 filtered through celite pad washed with ether (2×25 mL) The filtrate was concentrated the residue purified by column chromatography (100-200 mesh silica gel)

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

Procedure: To a stirred solution of 4-iodo 3-fluoro aniline (2.25 g, 9.49 mmol) in THF (25 ml) at 0° C. to −5° C., CuI (90 mg, 0.47 mmol) and Et3N (3.5 ml, 25.62 mmol) were added. The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C. Addition of Pd(dppf)Cl2.CH2Cl2 (346 mg, 0.47 mmol) and purging was continued. After 10 minutes, cyclopropyl acetylene (0.72 ml, 8.54 mmol) was added at −5° C. and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (200 mL), filtered through celite pad, washed with ether (2×25 mL). The filtrate was concentrated and the residue purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to afford title compound as pale brown liquid (750 mg, 45%). The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C Addition of Pd(dppf)Cl2 filtered through celite pad washed with ether (2×25 mL) The filtrate was concentrated the residue purified by column chromatography (100-200 mesh silica gel)

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

Procedure: 3-Fluoro-4-iodoaniline (15.36 g, 0.069 M) and concentrated hydrochloric acid (18.51 g) were dissolved in a mixture of water (30 ml) and ice (30 g). The solution was treated at 0–5° with a solution of sodium nitrite (4.81 g, 0.07 M) in water (15 ml). The pH of the resulting red-brown solution was adjusted to 5–6 by the addition of sodium acetate (6.05 g, 0.044 M). To the solution of formaldoxime was added sodium acetate (45.38 g, 0.333 M), hydrated copper sulfate (1.72 g, 6.9 mM) and sodium sulfite (0.275 g, 2.18 mM), giving a deep green solution, which was cooled to 10–15°. The solution of the diazonium salt was then slowly introduced with vigorous stirring, and stirring continued for 1 hour. The mixture was extracted with diethyl ether (3×100 ml), the combined extracts washed with water (100 ml), and dried (magnesium sulfate). The residue after filtration and evaporation was chromatographed in four portions on 50 g silica Mega Bond Elut® columns, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (3.52 g). giving a deep green solution, which was cooled to 10–15° The mixture was extracted with diethyl ether (3×100 ml) the combined extracts washed with water (100 ml) dried (magnesium sulfate) The residue after filtration and evaporation was chromatographed in four portions on 50 g silica Mega Bond Elut® columns eluting with a gradient from dichloromethane to 5% methanol in dichloromethane

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

Procedure: In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1 dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40 minutes, followed by addition of 1-cyclohexenyl boronic acid pinacol ester (2.7 mL, 2.61 g, 12.56 mmol). Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added followed by degassing for another 5 minutes. The pressure tube was sealed and warmed at 100° C. for 18 hours. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na2SO4) and stirred with 3-(mercaptopropyl) silica gel for 1 hour. Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (1.16 g, 63%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.00 (m, 1 H), 6.37 (m, 2 H), 5.84 (s, 1 H), 3.71 (br s, 2 H), 2.32 (m, 2 H), 2.17 (m, 2 H), 1.73 (m, 2 H), 1.65 (m, 2 H); MS (+DCI) m/z (rel abundance) 192 (100, M+H). sparge for 40 minutes Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added by degassing for another 5 minutes The pressure tube was sealed The mixture was cooled diluted with ethyl acetate followed by extraction with water and saturated sodium chloride solution The solution was dried (Na2SO4) Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge eluting with 10-100% ethyl acetate in hexanes

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

Procedure: To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The mixture was quenched by addition of water and the organic layer was extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1 H), 6.42 (dd, J=9.9, 2.5 Hz, 1 H), 6.27 (dd, J=8.5, 2.5 Hz; 1 H), 3.81 (s, 2 H); MS+ESI m/z (rel abundance) 238 (100, M+H). The mixture was quenched by addition of water the organic layer was extracted with water (2×) Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge eluting with 10-100% ethyl acetate in hexanes

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

Procedure: In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1 dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40 minutes, followed by addition of 1-cyclohexenyl boronic acid pinacol ester (2.7 mL, 2.61 g, 12.56 mmol). Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added followed by degassing for another 5 minutes. The pressure tube was sealed and warmed at 100° C. for 18 hours. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na2SO4) and stirred with 3-(mercaptopropyl) silica gel for 1 hour. Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (1.16 g, 63%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.00 (m, 1H), 6.37 (m, 2H), 5.84 (s, 1H), 3.71 (br s, 2H), 2.32 (m, 2H), 2.17 (m, 2H), 1.73 (m, 2H), 1.65 (m, 2H); MS (+DCI) m/z (rel abundance) 192 (100, M+H). sparge for 40 minutes Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added by degassing for another 5 minutes The pressure tube was sealed The mixture was cooled diluted with ethyl acetate followed by extraction with water and saturated sodium chloride solution The solution was dried (Na2SO4) Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge eluting with 10-100% ethyl acetate in hexanes

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

Procedure: To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The mixture was quenched by addition of water and the organic layer was extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1H), 6.42 (dd, J=9.9, 2.5 Hz, 1H), 6.27 (dd, J=8.5, 2.5 Hz, 1H), 3.81 (s, 2H); MS+ESI m/z (rel abundance) 238 (100, M+H). The mixture was quenched by addition of water the organic layer was extracted with water (2×) Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge eluting with 10-100% ethyl acetate in hexanes

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

Procedure: A solution of compound 143 (13.67 g, 57.7 mmol) in 1,4-dioxane (100 mL) was treated with BOC2O (13.83 g, 63.4 mmol, 1.1 equiv) and DMAP (700.0 mg, 5.8 mmol, 0.1 equiv) at room temperature. The resulting reaction mixture was then warmed up to refluxing for 4 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was treated with H2O (100 mL) and EtOAc (100 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, desired (3-fluoro-4-iodo-phenyl)-carbamic acid tert-butyl ester (compound 144, 18.67 g, 19.44 g theoretical, 96%) as pale-yellow oil, which solidified upon standing in vacuo at room temperature and was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For compound 144: C11H13FINO2, LCMS (EI) m/e 338 (M++H). The resulting reaction mixture was then warmed up to refluxing for 4 h The two layers were separated the aqueous layer was extracted with EtOAc (2×100 mL) The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL) dried over MgSO4 concentrated in vacuo The residue was further dried in vacuo