3-bromo-2-fluoroaniline

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: 1-Bromo-2-fluoro-3-nitro-benzene (3 g, 13.64 mmol), iron (2.28 g, 40.91 mmol), water (34.39 ml, 1909 mmol) and acetic acid (11.7 ml, 204.55 mmol) were added to ethanol (60 ml) and heated to reflux for 2 h. The reaction mixture was then filtered through Celite and evaporated. Water was added and the solution was made basic by the addition of 2 N NaOH, followed by extraction with DCM. The organic layers were washed with water and brine, dried with Na2SO4 evaporated to dryness and the crude product was obtained and used without further purification. Yield: 1.46 g, 56% heated to reflux for 2 h The reaction mixture was then filtered through Celite evaporated Water was added the solution was made basic by the addition of 2 N NaOH followed by extraction with DCM The organic layers were washed with water and brine dried with Na2SO4 evaporated to dryness

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

Procedure: This material was prepared from 1-bromo-2-fluoro-3-nitrobenzene, following the procedure used for SM-9, step 2 (94%): LCMS (m/z) 189.9, tR=0.74 minute; 1H NMR (300 MHz, CDCl3) δ 3.81 (br s, 2H) 6.64-6.75 (m, 1H) 6.80 (t, J=8.2 Hz, 1H) 6.84-6.95 (m, 1H).

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

Procedure: This material was prepared from 1-bromo-2-fluoro-3-nitrobenzene, following the procedure used for SM-9, step 2 (94%): LCMS(m/z) 189.9, tR=0.74 minute; 1H NMR (300 MHz, CDCl3) δ 3.81 (br s, 2H) 6.64-6.75 (m, 1H) 6.80 (t, J=8.2 Hz, 1H) 6.84-6.95 (m, 1H).

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 400 mg (2.10 mmol) of 3-bromo-2-fluoroaniline, 809.42 mg (6.32 mmol) of tert-butyl acrylate and 1.47 ml (10.53 mmol) of triethylamine were initially charged in 2.4 ml of DMF. The reaction vessel was evacuated three times and in each case vented with argon. 47.26 mg (0.21 mmol) of palladium(II) acetate and 128.14 mg (0.42 mmol) of tri-2-tolylphosphine were then added, and the reaction vessel was evacuated two more times and again vented with argon. The mixture was stirred at 145° C. overnight. The reaction mixture was then cooled, added to saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 210 mg (42% of theory) of the title compound. The reaction vessel was evacuated three times the reaction vessel was evacuated two more times The reaction mixture was then cooled added to saturated ammonium chloride solution extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient)

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 400 mg (2.10 mmol) of 3-bromo-2-fluoroaniline, 809.42 mg (6.32 mmol) of tert-butyl acrylate and 1.47 ml (10.53 mmol) of triethylamine were initially charged in 2.4 ml of DMF. The reaction vessel was evacuated three times and in each case vented with argon. 47.26 mg (0.21 mmol) of palladium(II) acetate and 128.14 mg (0.42 mmol) of tri-2-tolylphosphine were then added, and the reaction vessel was evacuated two more times and again vented with argon. The mixture was stirred at 145° C. overnight. The reaction mixture was then cooled, added to saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 210 mg (42% of theory) of the title compound. The reaction vessel was evacuated three times the reaction vessel was evacuated two more times The reaction mixture was then cooled added to saturated ammonium chloride solution extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient)

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

Procedure: Under argon, 1.0 g (4.54 mmol) of 3-bromo-2-fluoronitrobenzene was initially charged in 5 ml of dioxane, and 4.3 g (22.72 mmol) of tin(II) chloride and a few drops of 1 N hydrochloric acid were added. After 2 h of stirring, the reaction mixture was concentrated on a rotary evaporator and the residue was taken up in ethyl acetate. The organic phase was washed with 1 N aqueous sodium hydroxide solution, water and saturated sodium chloride solution and then dried over magnesium sulfate and concentrated. This gave 826 mg (95% of theory) of the title compound. the reaction mixture was concentrated on a rotary evaporator The organic phase was washed with 1 N aqueous sodium hydroxide solution, water and saturated sodium chloride solution dried over magnesium sulfate concentrated

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

Procedure: A solution of 3-bromo-2-fluoroaniline (Intermediate 34-1, 160 mg, 0.842 mmol) and DIEA (0.368 mL, 2.105 mmol) in DCM (3 mL) was stirred at ca. −5° C. and treated with methanesulfonyl chloride (0.098 mL, 1.263 mmol) and stirred at that temperature for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to provide N-(3-bromo-2-fluorophenyl)-N-(methylsulfonyl)methanesulfonamide as a yellow solid (308 mg, quantitative), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.70 (1H, ddd, J=8.1, 6.4, 1.5 Hz), 7.33 (1H, ddd, J=8.1, 6.5, 1.6 Hz), 7.15 (1H, td, J=8.1, 1.4 Hz), 3.46 (6H, s). Mass spectrum m/z 363, 365 (M+NH4)+. The mixture was partitioned between DCM and NaHCO3 (aq) The organic phase was washed with brine dried concentrated

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

Procedure: A solution of 3-bromo-2-fluoroaniline (Intermediate 34-1, 160 mg, 0.842 mmol) and DIEA (0.368 mL, 2.105 mmol) in DCM (3 mL) was stirred at ca. −5° C. and treated with methanesulfonyl chloride (0.098 mL, 1.263 mmol) and stirred at that temperature for 2 h. The mixture was partitioned between DCM and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to provide N-(3-bromo-2-fluorophenyl)-N-(methylsulfonyl)methanesulfonamide as a yellow solid (308 mg, quantitative), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.70 (1H, ddd, J=8.1, 6.4, 1.5 Hz), 7.33 (1H, ddd, J=8.1, 6.5, 1.6 Hz), 7.15 (1H, td, J=8.1, 1.4 Hz), 3.46 (6H, s). Mass spectrum m/z 363, 365 (M+NH4)+. The mixture was partitioned between DCM and NaHCO3 (aq) The organic phase was washed with brine dried concentrated

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

Procedure: A solution of 1-bromo-2-fluoro-3-nitrobenzene (1.10 g, 5.00 mmol) in ethanol-acetic acid-water (2:2:1) (25 mL) was treated with iron powder (1.396 g, 25.0 mmol) and the mixture was heated at reflux for 1 h. The mixture was cooled to rt and filtered through a Celite pad. The filtrate was concentrated and the residue was partitioned between EtOAc and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to provide 3-bromo-2-fluoroaniline as a brown oil (880 mg, 93%). 1H NMR (400 MHz, chloroform-d) δ 6.85-6.92 (1H, m), 6.80 (1H, td, J=8.0, 1.2 Hz), 6.66-6.73 (1H, m), 3.81 (2H, br. s.). the mixture was heated at reflux for 1 h filtered through a Celite pad The filtrate was concentrated the residue was partitioned between EtOAc and NaHCO3 (aq) The organic phase was washed with brine dried concentrated

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

Procedure: This material was prepared from 1-bromo-2-fluoro-3-nitrobenzene, following the procedure used for SM-9, step 2 (94%): LCMS (m/z) 189.9, tR=0.74 minute; 1H NMR (300 MHz, CDCl3) δ 3.81 (br s, 2H) 6.64-6.75 (m, 1H) 6.80 (t, J=8.2 Hz, 1H) 6.84-6.95 (m, 1H).