(2,6-dibromo-4-fluorophenyl)methyl acetate

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:0.00; pressure:0.00; stir:

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

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 2,6-dibromo-4-fluorobenzyl acetate 101C (2.34 g, 7.2 mmol), 119b (500 mg, 2.4 mmol), and cesium carbonate (1.6 g, 4.8 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (140 mg, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium(0) (220 mg, 0.24 mmol) were added and the reaction mixture was heated at 100° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous layer was separated and extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column eluting with 3:1 petroleum ether/ethyl acetate to afford 119c (632 mg, 58%) as a yellow solid. MS: [M+H]+ 453.2 A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer reflux condenser After bubbling nitrogen through the resulting mixture for 30 minutes After this time the reaction was cooled to room temperature filtered The filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL) The aqueous layer was separated extracted with ethyl acetate (3×70 mL) The combined organic layer was washed with brine (30 mL) dried over sodium sulfate The drying agent was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by silica-gel column eluting with 3:1 petroleum ether/ethyl acetate

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

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 2,6-dibromo-4-fluorobenzyl acetate 101C (2.34 g, 7.2 mmol), 119b (500 mg, 2.4 mmol), and cesium carbonate (1.6 g, 4.8 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (140 mg, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium(0) (220 mg, 0.24 mmol) were added and the reaction mixture was heated at 100° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous layer was separated and extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column eluting with 3:1 petroleum ether/ethyl acetate to afford 119c (632 mg, 58%) as a yellow solid. MS: [M+H]+ 453.2 A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer reflux condenser After bubbling nitrogen through the resulting mixture for 30 minutes After this time the reaction was cooled to room temperature filtered The filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL) The aqueous layer was separated extracted with ethyl acetate (3×70 mL) The combined organic layer was washed with brine (30 mL) dried over sodium sulfate The drying agent was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by silica-gel column eluting with 3:1 petroleum ether/ethyl acetate

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

Procedure: A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 115k (3.8 g, 20 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101c (20.0 g, 61 mmol), XantPhos (1.16 g, 2.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.83 g, 2.0 mmol), Cs2CO3 (16.3 g, 50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask and the reaction mixture was heated at 100° C. for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 115l as a white solid (5.2 g, 60%). MS: [M+H]+ 435. 1H NMR (500 MHz, DMSO-d6) δ 7.71-7.69 (m, 1H), 7.49-7.47 (m, 1H), 6.52 (s, 1H), 5.01 (m, 2H), 4.18 (m, 2H), 4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 2H), 1.98 (s, 3H), 1.77 (m, 2H), 1.68 (m, 2H). A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer The system was evacuated refilled with N2 A reflux condenser was attached to the flask The mixture was cooled to room temperature filtered The filtrate was concentrated under reduced pressure the resulting residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate

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

Procedure: A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 115k (3.8 g, 20 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101c (20.0 g, 61 mmol), XantPhos (1.16 g, 2.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.83 g, 2.0 mmol), Cs2CO3 (16.3 g, 50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask and the reaction mixture was heated at 100° C. for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 115l as a white solid (5.2 g, 60%). MS: [M+H]+ 435. 1H NMR (500 MHz, DMSO-d6) δ 7.71-7.69 (m, 1H), 7.49-7.47 (m, 1H), 6.52 (s, 1H), 5.01 (m, 2H), 4.18 (m, 2H), 4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 2H), 1.98 (s, 3H), 1.77 (m, 2H), 1.68 (m, 2H). A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer The system was evacuated refilled with N2 A reflux condenser was attached to the flask The mixture was cooled to room temperature filtered The filtrate was concentrated under reduced pressure the resulting residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate

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

Procedure: A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 1,4-dioxane (40 mL), 113o (890 mg, 3.94 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101c (3847 mg, 11.8 mmol), Pd2(dba)3 (180 mg, 0.197 mmol), XantPhos (227 mg, 0.394 mmol), and cesium carbonate (2.57 g, 7.88 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 16 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 113p (1100 mg, 62%) as a white solid. MS-ESI: [M+H]+ 471.1. A 100-mL round-bottomed flask equipped with a reflux condenser After three cycles of vacuum/argon flush It was then filtered the filtrate was evaporated under reduced pressure The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate

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

Procedure: A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 104j (3.8 g, 20 mmol), 104m (20 g, 60 mmol), XantPhos (1.2 g, 2 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.8 g, 2 mmol), Cs2CO3 (16 g, 50 mmol), and 1,4-dioxane (120 mL). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 16 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 104n as a white solid (5.2 g, 60%). MS: [M+H]+ 435. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (dd, J=3, 1H), 7.48 (dd, J=3, 1H), 6.52 (s, 1H), 5.01 (m, 2H), 4.18 (m, 2H), 4.02 (m, 1H), 3.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 2H), 1.98 (s, 3H), 1.77 (m, 2H), 1.68 (m, 2H). A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer The system was evacuated refilled with N2 A reflux condenser was attached to the flask Then, the mixture was cooled to room temperature filtered The filtrate was concentrated under reduced pressure the resulting residue was purified by flash column chromatography eluting with 5:1 petroleum ether/ethyl acetate

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

Procedure: To a solution of (2,6-dibromo-4-fluorophenyl)methanol (1041) (20 g, 71 mmol) in CH2Cl2 (500 mL) at 0° C. was added pyridine (8.4 g, 107 mmol) and acetyl chloride (8.3 g, 107 mmol). The mixture was stirred at room temperature for 5 h. TLC showed the start material disappeared. The reaction was evaporated in vacuum and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 104m as a white solid (20 g, 87%). MS: [M-Oac]+ 267. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J=7.5, 2H), 5.38 (s, 2H), 2.10 (s, 3H) The reaction was evaporated in vacuum the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1)

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

Procedure: A sealed tube was equipped with a magnetic stirrer and charged with 103e (740 mg, 3.6 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101c (2.4 g, 7.2 mmol) and cesium carbonate (2.6 g, 7.9 mmol) in 1,4-dioxane (36 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (250 mg, 0.43 mmol) and tris(dibenzylideneacetone) dipalladium(0) (260 mg, 0.29 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, H2O (50 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of 100% hexanes-100% Ethyl acetate to afford a 56% yield (910 mg) of 103f. A sealed tube was equipped with a magnetic stirrer After bubbling nitrogen through the solution for 30 min The aqueous layer was separated extracted with ethyl acetate (2×50 mL) The combined organic extracts were washed with brine (100 mL) dried over sodium sulfate The resulting residue was purified by column chromatography eluting with a gradient of 100% hexanes-100% Ethyl acetate