2-ethenyl-1,4-difluorobenzene

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

Procedure: A round bottom flask was charged with 1,4-difluoro-2-vinylbenzene (1 g, 7.14 mmol), 5-bromo-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.69 g, 8.92 mmol), and DMF (27 mL). The resulting mixture was purged with a stream of oxygen for 10 min. To this was added sodium carbonate (1.89 g, 17.8 mmol) and palladium (II) acetate (0.128 g, 0.571 mmol) as a solid in a single portion. The reaction was purged with oxygen for 5 min. The reaction was fitted with a balloon of oxygen and stirred at room temperature overnight. In the morning, the reaction was diluted with ethyl acetate and poured into water. The mixture was treated with excess celite and filtered to remove solids. The organic layer was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (10% EtOAc/Hex) gave 409 mg (17%). 1H NMR (CDCl3) δ: 8.16-8.22 (m, 1H), 8.13 (dd, J=8.2, 2.4 Hz, 1H), 7.29-7.39 (m, 2H), 7.06-7.20 (m, 2H), 6.97-7.06 (m, 1H). 19F NMR (CDCl3) δ: −74.07 (d, J=8.7 Hz, 1F), −118.78 (d, J=8.7 Hz, 1F), −123.39 (br. s., 1F). Mass spec.: 314.1 (MH)+. The resulting mixture was purged with a stream of oxygen for 10 min The reaction was purged with oxygen for 5 min The reaction was fitted with a balloon of oxygen In the morning, the reaction was diluted with ethyl acetate poured into water The mixture was treated with excess celite and filtered to remove solids The organic layer was washed with water (2×) brine, dried over magnesium sulfate concentrated Column chromatography (10% EtOAc/Hex) gave 409 mg (17%)

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

Procedure: A round bottom flask was charged with 1,4-difluoro-2-vinylbenzene (1 g, 7.14 mmol), 5-bromo-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.69 g, 8.92 mmol), and DMF (27 mL). The resulting mixture was purged with a stream of oxygen for 10 min. To this was added sodium carbonate (1.89 g, 17.8 mmol) and palladium (II) acetate (0.128 g, 0.571 mmol) as a solid in a single portion. The reaction was purged with oxygen for 5 min. The reaction was fitted with a balloon of oxygen and stirred at room temperature overnight. In the morning, the reaction was diluted with ethyl acetate and poured into water. The mixture was treated with excess celite and filtered to remove solids. The organic layer was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (10% EtOAc/Hex) gave 409 mg (17%). 1H NMR (CDCl3) δ: 8.16-8.22 (m, 1H), 8.13 (dd, J=8.2, 2.4 Hz, 1H), 7.29-7.39 (m, 2H), 7.06-7.20 (m, 2H), 6.97-7.06 (m, 1H). 19F NMR (CDCl3) δ: −74.07 (d, J=8.7 Hz, 1F), −118.78 (d, J=8.7 Hz, 1F), −123.39 (br. s., 1F). Mass spec.: 314.1 (MH)+. The resulting mixture was purged with a stream of oxygen for 10 min The reaction was purged with oxygen for 5 min The reaction was fitted with a balloon of oxygen In the morning, the reaction was diluted with ethyl acetate poured into water The mixture was treated with excess celite and filtered to remove solids The organic layer was washed with water (2×) brine, dried over magnesium sulfate concentrated Column chromatography (10% EtOAc/Hex) gave 409 mg (17%)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-bromo-5-fluoropyridin-4-ylboronic acid (1.569 g, 7.14 mmol) and 1,4-difluoro-2-vinylbenzene (1 g, 7.14 mmol) in dimethylformamide (20 mL) was flushed with a balloon of oxygen. To this was added sodium carbonate (1.51 g, 14.3 mmol) and palladium(II) acetate (0.16 g, 0.71 mmol) as solids in one portion. The flask was flushed with another balloon of oxygen and fitted with a balloon of oxygen. The reaction was warmed to 50° C. After 1 h, the reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g). This process was repeated twice more (total boronic acid addition=6.3 g). The reaction was cooled to room temperature, diluted with ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid. 1H NMR (CDCl3) Shift: 8.28 (d, J=1.8 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.49 (d, J=16.5 Hz, 1H), 7.33 (ddd, J=8.9, 5.8, 3.1 Hz, 1H), 7.17 (d, J=16.8 Hz, 1H), 6.98-7.14 (m, 2H). 19F NMR (CDCl3) Shift: −118.54 (d, J=13.0 Hz, 1F), −122.71 (br. s., 1F), −135.71 (br. s., 1F). Mass spec.: 314.0 (MH)+. was flushed with a balloon of oxygen The flask was flushed with another balloon of oxygen fitted with a balloon of oxygen the reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g) (total boronic acid addition=6.3 g) The reaction was cooled to room temperature diluted with ether washed with water (3×) brine, dried over magnesium sulfate concentrated Column chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-bromo-5-fluoropyridin-4-ylboronic acid (1.569 g, 7.14 mmol) and 1,4-difluoro-2-vinylbenzene (1 g, 7.14 mmol) in dimethylformamide (20 mL) was flushed with a balloon of oxygen. To this was added sodium carbonate (1.51 g, 14.3 mmol) and palladium(II) acetate (0.16 g, 0.71 mmol) as solids in one portion. The flask was flushed with another balloon of oxygen and fitted with a balloon of oxygen. The reaction was warmed to 50° C. After 1 h, the reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g). This process was repeated twice more (total boronic acid addition=6.3 g). The reaction was cooled to room temperature, diluted with ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid. 1H NMR (CDCl3) Shift: 8.28 (d, J=1.8 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.49 (d, J=16.5 Hz, 1H), 7.33 (ddd, J=8.9, 5.8, 3.1 Hz, 1H), 7.17 (d, J=16.8 Hz, 1H), 6.98-7.14 (m, 2H). 19F NMR (CDCl3) Shift: −118.54 (d, J=13.0 Hz, 1F), −122.71 (br. s., 1F), −135.71 (br. s., 1F). Mass spec.: 314.0 (MH)+. was flushed with a balloon of oxygen The flask was flushed with another balloon of oxygen fitted with a balloon of oxygen the reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g) (total boronic acid addition=6.3 g) The reaction was cooled to room temperature diluted with ether washed with water (3×) brine, dried over magnesium sulfate concentrated Column chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of methyltriphenylphosphonium bromide (26.4 g, 73.9 mmol) in tetrahydrofuran (350 mL) at 0° C. was added nBuLi (2.5M in hexane, 29.6 mL, 73.9 mmol). After addition was complete, the reaction was stirred at 0° C. for 10 min. To this was added 2,5-difluorobenzaldehyde (5.35 mL, 49.3 mmol). The ice bath was removed, and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride. The reaction was poured into ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5% EtOAc/Hex) gave 2.1 g (30%) as a colorless oil. 1H NMR (CDCl3) Shift: 7.20 (ddd, J=9.2, 5.9, 3.2 Hz, 1H), 7.02 (td, J=9.3, 4.6 Hz, 1H), 6.90-6.97 (m, 1H), 6.86 (dd, J=17.7, 11.3 Hz, 1H), 5.84 (d, J=17.7 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H). 13C NMR (CDCl3) Shift: 158.6, 156.3, 128.6, 126.8, 117.6, 116.8, 115.6, 113.0. 19F NMR (CDCl3) Shift: −120.17-119.46 (m, 1F), −125.20 (d, J=17.3 Hz, 1F). After addition The ice bath was removed stirring continued for 1 h The reaction was quenched by addition of saturated ammonium chloride The reaction was poured into ether washed with water (3×) brine, dried over magnesium sulfate concentrated Column chromatography (2.5% EtOAc/Hex) gave 2.1 g (30%) as a colorless oil