methyl 4-chloro-3-iodobenzoate

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

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

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

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A dry flask was charged with 4-chloro-3-iodo-benzoic acid methyl ester (5.0 g, 16.9 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (35 mL) was added, and the solution cooled to −40° C.; then isopropylmagnesium chloride (8.85 mL, 2.0 M in diethyl ether, 17.7 mmol) was added slowly over 20 min keeping the temperature below −40° C. On completion of the addition the reaction mixture was stirred at −40° C. for 45 min. A THF solution of ZnCl2 (2.32 g, 17.0 mmol, 0.9 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (3.7 g, 17 mmol) and Cu(OAc)2 (68 mg, 0.34 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:6 as the eluent to give the title compound as yellow solid. the flask was evaporated filled with argon Dry THF (35 mL) was added the temperature below −40° C On completion of the addition the reaction mixture The reaction mixture was stirred at 0° C. for 20 min to warm to room temperature shaken separated The aqueous phase was extracted with more EtOAc dried (MgSO4) filtered concentrated in vacuo to afford the crude product The crude product was purified by flash chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-3-iodo-benzoic acid (5.31 g, 18.8 mmol) was dissolved in methanol (50 mL) and concentrated sulfuric acid (3 mL) was carefully added. The solution was stirred at 80° C. for 4 hours, then cooled to room temperature and the volatile organics were removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-10% EtOAc in hexanes) to yield 5.32 g (95%) of the title compound as an oil. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.94 (s, 3H). cooled to room temperature the volatile organics were removed under reduced pressure The residue was partitioned between EtOAc (50 mL) and water (50 mL) the organic layer was washed with brine dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by flash chromatography (SiO2; 0-10% EtOAc in hexanes)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere of nitrogen, a mixture of methyl 4-chloro-3-iodobenzoate (200 mg, 0.68 mmol, 1.00 equiv), 1-ethynyl-4-fluorobenzene (243 mg, 2.02 mmol, 3.00 equiv), Pd(PPh3)2Cl2 (94.6 mg, 0.14 mmol, 0.20 equiv), CuI (13 mg, 0.07 mmol, 0.10 equiv), tetrahydrofuran (12 mL), and triethylamine (4 mL) was stirred overnight at 70° C. in an oil bath. The solids were filtered out, and the filtrate was concentrated in vacuo. The residue was purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:100)) resulting in 130 mg (67%) of methyl 4-chloro-3-(2-(4-fluorophenyl)ethynyl)benzoate as a white solid. The solids were filtered out the filtrate was concentrated in vacuo The residue was purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:100)) resulting in 130 mg (67%) of methyl 4-chloro-3-(2-(4-fluorophenyl)ethynyl)benzoate as a white solid

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

Procedure: A solution of 4-chloro-3-iodobenzoic acid (500 mg, 1.77 mmol, 1.00 equiv), methanol (20 mL), and concentrated sulfuric acid (0.35 g, 2.00 equiv) was heated to reflux overnight in an oil bath. The resulting mixture was concentrated in vacuo and diluted with 50 mL of ethyl acetate. The organic layer was washed with 3×20 mL of water and 3×20 mL of saturated aqueous sodium carbonate. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo, resulting in 0.52 g (99%) of methyl 4-chloro-3-iodobenzoate as a white solid. to reflux overnight in an oil bath The resulting mixture was concentrated in vacuo diluted with 50 mL of ethyl acetate The organic layer was washed with 3×20 mL of water and 3×20 mL of saturated aqueous sodium carbonate The mixture was dried over anhydrous sodium sulfate concentrated in vacuo resulting in 0.52 g (99%) of methyl 4-chloro-3-iodobenzoate as a white solid

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A dry flask was charged with 4-chloro-3-iodo-benzoic acid methyl ester (5.0 g, 16.9 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (35 mL) was added, and the solution cooled to −40° C.; then isopropylmagnesium chloride (8.85 mL, 2.0 M in diethyl ether, 17.7 mmol) was added slowly over 20 min keeping the temperature below −40° C. On completion of the addition the reaction mixture was stirred at −40° C. for 45 min. A THF solution of ZnCl2 (2.32 g, 17.0 mmol, 0.9 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (3.7 g, 17 mmol) and Cu(OAc)2 (68 mg, 0.34 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:6 as the eluent to give the title compound as yellow solid. the flask was evaporated filled with argon Dry THF (35 mL) was added the temperature below −40° C On completion of the addition the reaction mixture The reaction mixture was stirred at 0° C. for 20 min to warm to room temperature shaken separated The aqueous phase was extracted with more EtOAc dried (MgSO4) filtered concentrated in vacuo to afford the crude product The crude product was purified by flash chromatography