1-bromo-2,3-difluorobenzene

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:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (7.86 grams (g), 78 mmol) was dissolved in tetrahydrofuran (THF; 104 mL) and cooled to −75° C. utilizing a dry ice/acetone bath. A solution of n-BuLi (2.5 M in hexanes; 22.80 mL, 57.0 mmol) was added dropwise, and the solution was again cooled to −75° C. 1-Bromo-2,3-difluorobenzene (10 g, 51.8 mmol) was dissolved in THF (25.9 mL), and the solution was added dropwise keeping the temperature below −60° C. The reaction mixture was then allowed to warm to −15° C. before cooling again to −75° C. TMSCl (7.29 mL, 57.0 mmol) was then added dropwise, and the reaction mixture was allowed to warm to 25° C. and then concentrated under vacuum. The residue was partitioned between ethyl acetate (EtOAc) and H2O. The organic phase was washed twice more with H2O and concentrated. Kugelrohr distillation at 88° C. provided the product in greater purity but an impurity was distilling at that temperature. Kugelrohr distillation of that purified distillate at 75° C. led to purer product but some product was left in the pot. This process yielded the title compound as a clear oil (3.0 g, 21.83%, 90% purity): 1H NMR (300 MHz, CDCl3) δ 7.28 (ddd, J=7.8, 5.2, 1.3 Hz, 1H), 6.98 (ddd, J=8.0, 4.8, 1.9 Hz, 1H), 0.32 (s, 9H); EIMS m/z 264, 266. the solution was again cooled to −75° C the solution was added dropwise the temperature below −60° C to warm to −15° C. before cooling again to −75° C to warm to 25° C. concentrated under vacuum The residue was partitioned between ethyl acetate (EtOAc) and H2O The organic phase was washed twice more with H2O concentrated Kugelrohr distillation at 88° C. provided the product in greater purity an impurity was distilling at that temperature Kugelrohr distillation of that purified distillate at 75° C. some product was left in the pot

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-bromo-2,3-difluorobenzene (0.232 mL, 2.073 mmol), aniline (0.208 mL, 2.280 mmol), Pd2(dba)3 (95 mg, 0.104 mmol), BINAP (194 mg, 0.311 mmol), sodium tert-butoxide (299 mg, 3.11 mmol), and toluene (3 mL) in a sealed vessel under argon was heated in an oil bath at 110° C. overnight. The reaction mixture was filtered through a plug of celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the title compound as a light brown oil (411 mg). LCMS m/z=206.1 [M+H]+; 1H NMR (400 MHz, Methanol-d4) δ ppm 6.53-6.64 (m, 1H), 6.80-6.88 (m, 2H), 6.88-6.95 (m, 1H), 6.95-7.03 (m, 2H), 7.11-7.19 (m, 2H). The reaction mixture was filtered through a plug of celite The filtrate was concentrated the residue was purified by silica gel column chromatography

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

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

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

Procedure: To a solution of 2,3-difluorobromobenzene (471 ml, 4.206 mmol) in dry THF (20 mL) was added a solution of n-butyl lithium (1.6M in hexanes, 2.63 mL) at −78° C. The resulting yellow solution was stirred at the same temperature for 70 minutes, then a solution of 2-trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (0.500 g, 1.28 mmol) in dry THF (20 mL), was added dropwise via a cannula. The red-orange solution was allowed to warm over 60 minutes. Saturated NH4Cl was added and the mixture was stirred for 25 minutes before extracting with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography (CH2Cl2/CH3CN 4/1) to give 390 mg of an orange solid. (69%). MS(FAB), NMR. to warm over 60 minutes the mixture was stirred for 25 minutes before extracting with EtOAc The organic layer was washed with brine dried (Na2SO4) concentrated in vacuo purified by column chromatography (CH2Cl2/CH3CN 4/1)

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

Procedure: To a solution of 2,3-difluorobromobenzene (471 ml, 4.206 mmol) in dry THF (20 mL) was added a solution of n-butyl lithium (1.6M in hexanes, 2.63 mL) at −78° C. The resulting yellow solution was stirred at the same temperature for 70 minutes, then a solution of 2-trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (0.500 g, 1.28 mmol) in dry THF (20 mL), was added dropwise via a cannula. The red-orange solution was allowed to warm over 60 minutes. Saturated NH4Cl was added and the mixture was stirred for 25 minutes before extracting with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography (CH2Cl2/CH3CN 4/1) to give 390 mg of an orange solid. (69%). MS(FAB), NMR. to warm over 60 minutes the mixture was stirred for 25 minutes before extracting with EtOAc The organic layer was washed with brine dried (Na2SO4) concentrated in vacuo purified by column chromatography (CH2Cl2/CH3CN 4/1)