2-bromo-5-fluorobenzonitrile

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:0.00; pressure:0.00; stir:

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

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

Procedure: To a degassed solution of 1-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethanone (12 g, 45.43 mmol), 2-bromo-5-fluorobenzonitrile (9.09 g, 5.28 ml, 45.44 mmol), potassium fluoride (7.92 g, 136.31 mmol) and tris(dibenzylideneacetone)palladium(0) (0.834 g, 0.908 mmol) in THF (200 ml) and water (10 ml) was added tri-tert butylphosphine (10% weight solution) (0.368 g, 3.63 ml, 1.817 mmol). The reaction was heated at 70° C. for 14 h then allowed to cool to ambient temperature. The reaction was partitioned between water (200 ml) and ether (300 ml). The aqueous phase was extracted with ether (150 ml) and the combined organics washed with brine (200 ml), dried (MgSO4), filtered and evaporated to give a brown solid. The solid was dissolved in DCM and adsorbed onto silica. The crude product was chromatographed on silica (5-20% EtOAc in isohexane) to give the title product as a white solid (6.8 g): δH (400 MHz, CDCl3) 2.63 (3H, s), 7.31 (1H, t, J 9.0 Hz), 7.40-7.44 (1H, m), 7.50-7.53 (2H, m), 8.02-8.10 (2H, m). to cool to ambient temperature The reaction was partitioned between water (200 ml) and ether (300 ml) The aqueous phase was extracted with ether (150 ml) the combined organics washed with brine (200 ml) dried (MgSO4) filtered evaporated to give a brown solid The crude product was chromatographed on silica (5-20% EtOAc in isohexane)

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

Procedure: To a degassed solution of 1-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethanone (12 g, 45.43 mmol), 2-bromo-5-fluorobenzonitrile (9.09 g, 5.28 ml, 45.44 mmol), potassium fluoride (7.92 g, 136.31 mmol) and tris(dibenzylideneacetone)palladium(0) (0.834 g, 0.908 mmol) in THF (200 ml) and water (10 ml) was added tri-tert butylphosphine (10% weight solution) (0.368 g, 3.63 ml, 1.817 mmol). The reaction was heated at 70° C. for 14 h then allowed to cool to ambient temperature. The reaction was partitioned between water (200 ml) and ether (300 ml). The aqueous phase was extracted with ether (150 ml) and the combined organics washed with brine (200 ml), dried (MgSO4), filtered and evaporated to give a brown solid. The solid was dissolved in DCM and adsorbed onto silica. The crude product was chromatographed on silica (5-20% EtOAc in isohexane) to give the title product as a white solid (6.8 g): δH (400 MHz, CDCl3) 2.63 (3H, s), 7.31 (1H, t, J 9.0 Hz), 7.40-7.44 (1H, m), 7.50-7.53 (2H, m), 8.02-8.10 (2H, m). to cool to ambient temperature The reaction was partitioned between water (200 ml) and ether (300 ml) The aqueous phase was extracted with ether (150 ml) the combined organics washed with brine (200 ml) dried (MgSO4) filtered evaporated to give a brown solid The crude product was chromatographed on silica (5-20% EtOAc in isohexane)

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

Procedure: 2-Bromo-5-fluorobenzonitrile was coupled with 3-nitrophenylboronic acid by the method of Example 7, part c) to yield 4-fluoro-3′-nitrobiphenyl-2-carbonitrile, which was reduced to 3′-amino-4-fluorobiphenyl-2-carbonitrile by the method of Example 5, part b). This was converted into 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 7 parts e) and f), using bis(pinacolato)diboron instead of bis(neopentyl glycolato)diboron. The product was isolated as a brown oil which solidified on standing. δH (400 MHz, CDCl3) 1.36 (12H, s), 7.35 (1H, td, J 8.2 and 2.7), 7.44-7.54 (3H, m), 7.65 (1H, dt, J 8.2 and 1.7), 7.88-7.90 (2H, m)

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

Procedure: 2-Bromo-5-fluorobenzonitrile was coupled with 3-nitrophenylboronic acid by the method of Example 7, part c) to yield 4-fluoro-3′-nitrobiphenyl-2-carbonitrile, which was reduced to 3′-amino-4-fluorobiphenyl-2-carbonitrile by the method of Example 5, part b). This was converted into 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 7 parts e) and f), using bis(pinacolato)diboron instead of bis(neopentyl glycolato)diboron. The product was isolated as a brown oil which solidified on standing. δH (400 MHz, CDCl3) 1.36 (12H, s), 7.35 (1H, td, J 8.2 and 2.7), 7.44-7.54 (3H, m), 7.65 (1H, dt, J 8.2 and 1.7), 7.88-7.90 (2H, m)

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

Procedure: 2-Bromo-5-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 7 part c) to give 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.38-7.56 (4H, m), 8.33-8.40 (2H, m).

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

Procedure: 2-Bromo-5-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 7 part c) to give 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.38-7.56 (4H, m), 8.33-8.40 (2H, m).