2-chloro-1-fluoro-4-methoxybenzene

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

Procedure: To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro-4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285. filtered through Celite The filtrate was washed with water, brine dried concentrated The crude product was purified by crystallization from ether/petroleum ether

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

Procedure: A solution of 2-Chloro-1-fluoro-4-methoxy-benzene (10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+). the mixture was refluxed for 40 hours the layers were separated The mixture was washed with water dried over MgSO4 filtered concentrated to a solid (2.8 g)

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

Procedure: A solution of 2-Chloro-1-fluoro-4-methoxy-benzene (10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+). the mixture was refluxed for 40 hours the layers were separated The mixture was washed with water dried over MgSO4 filtered concentrated to a solid (2.8 g)

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

Procedure: To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro-4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285. filtered through Celite The filtrate was washed with water, brine dried concentrated The crude product was purified by crystallization from ether/petroleum ether

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

Procedure: To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro-4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285. filtered through Celite The filtrate was washed with water, brine dried concentrated The crude product was purified by crystallization from ether/petroleum ether

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

Procedure: To a solution of 3-chloro-4-fluoroanisole (28.5 g, 178 mmol) in t-butyl methyl ether (200 mL, dried over anhydrous MgSO4) at −78° C. was added 2.5 M n-butyl lithium in hexanes (107 mL, 267.5 mmol). After 3 h, methyl formate (18.76 mL) was added drop-wise while keeping the temperature below −60° C. The reaction mixture was quenched with sat. aq. ammonium chloride (250 mL) after 45 minutes and the organic layer was separated. The aq. layer was extracted with ethyl acetate (2×100 mL) and the combined organic layer was washed with water (200 mL) followed by brine, dried (Na2SO4) and concentrated to give a residue which on trituration with hexanes gave solids. The solids were filtered, taken again in hexanes and heated over steam bath. It was cooled, the light yellow desired product filtered and air dried to give the title compound. 1H NMR (400 MHz, CDCl3): δ=10.48 (d, J=0.8 Hz, 1H), 7.31 (dd, J=9.4, 7.8 Hz, 1H), 6.88 (dd, J=7.8, 3.8 Hz, 1H), 3.92 (s, 3H). the temperature below −60° C The reaction mixture was quenched with sat. aq. ammonium chloride (250 mL) after 45 minutes the organic layer was separated The aq. layer was extracted with ethyl acetate (2×100 mL) the combined organic layer was washed with water (200 mL) dried (Na2SO4) concentrated to give a residue which on trituration with hexanes gave solids The solids were filtered heated over steam bath It was cooled the light yellow desired product filtered air dried

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

Procedure: Silver trifluoroacetate (23.2 g, 105.0 mmol) was added to a solution of 2-chloro-1-fluoro-4-methoxy-benzene (5 g, 29.2 mmols) in chloroform (250 ml), followed by iodine (15.8 g, 62.2 mmol) in several portions. The mixture was stirred at room temperature for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 1-chloro-2-fluoro-4-iodo-5-methoxy-benzene (6.8 g, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.83 (s, 3H), 7.22 (d, 1H), 7.88 (d, 1H). filtered through Celite The filtrate was washed with water, brine dried with Na2SO4 decanted concentrated to dryness

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

Procedure: A round-bottom flask was charged with 2-chloro-1-fluoro-4-methoxybenzene (Alfa Aesar, Ward Hill, Mass., 2.714 g, 16.90 mmol), DCM (24.86 ml), AcOH (24.86 ml), and sulfuric acid (0.496 ml, 9.30 mmol) to give a solution. n-iodosuccinimide (3.80 g, 16.90 mmol) was added in a single portion. TLC showed what appeared to be conversion of the starting material to a slightly higher, move UV-active spot. The mixture was diluted with DCM, washed with water (2×), washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-10% EtOAc/Heptane) to give 3.409 g of a clear oil. This oil was used directly in the next reaction without further purification. to give a solution washed with water (2×) washed with saturated aq. sodium thiosulfate dried over sodium sulfate filtered concentrated The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-10% EtOAc/Heptane)

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

Procedure: To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285. filtered through Celite The filtrate was washed with water, brine dried concentrated The crude product was purified by crystallization from ether/petroleum ether

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

Procedure: To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro-4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285. filtered through Celite The filtrate was washed with water, brine dried concentrated The crude product was purified by crystallization from ether/petroleum ether

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

Procedure: A solution of 2-Chloro-1-fluoro-4-methoxy-benzene (10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+). the mixture was refluxed for 40 hours the layers were separated The mixture was washed with water dried over MgSO4 filtered concentrated to a solid (2.8 g)