2-bromo-4-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:

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

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

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): δ 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), δ 6.982 (td, J=8.4 Hz, J=2 Hz 1H), δ 5.540 (bs, 1H), δ 3.590 (bs, 1H). aged for an additional 30 minutes to 1 hour The mixture was filtered washed with dichloromethane The resulting solid was dissolved in 1.0M HCl extracted 3 times with dichloromethane dried overnight to give 3.53 g (83% yield)

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

Procedure: To a solution of 2-bromo-4-fluoroaniline (5.0 g, 26.3 mmol) in DMF/water (80/20 v/v, 65.8 ml) under an atmosphere of nitrogen were added 4-(methanesulfonyl)phenylboronic acid (7.9 g, 39.5 mmol), tris(4,6-dimethyl-3-sulfanatophenyl)phosphine trisodium salt hydrate (2.6 g, 4.0 mmol), palladium(II) acetate (0.3 g, 1.3 mmol), and diisopropyl amine (11.3 ml, 79.0 mmol). The reaction was allowed to stir at 50° C. for 2.5 h. The reaction was diluted with EtOAc and washed with 3M LiCl (3×), water, and brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-fluoro-4′-(methylsulfonyl)-1,1′-biphenyl-2-amine as a yellow solid (95%). LCMS (M+H) 266.1. 1H NMR (400 MHz, CD3OD) δ 8.02 (m, 2H), 7.65 (m, 2H), 7.05 (dd, J=8.6, 6.2 Hz, 1H), 6.57-6.47 (m, 2H), 3.86 (s, 2H), 3.11 (s, 3H). washed with 3M LiCl (3×), water, and brine The organic portion was dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: 2-Bromo-4-fluorobenzenamine (10 g, 52.6 mmol) was weighed into a round bottom flask, and dissolved in 40 mL of 6N HCl. The reaction mixture was then heated to reflux, followed by drop-wise addition of (E)-but-2-enal (4.578 mL, 55.3 mmol) mixed with 1.0 mL deionized water over 25 minutes. Following complete addition the reaction was heated at 100° C. for an additional 35 minutes, until all the 2-bromo-4-fluorobenzenamine had been consumed. The reaction was cooled to ambient temperature, followed by addition of 50 mL of Et2O. The reaction was stirred for 5 minutes followed by removal of Et2O by partitioning. The aqueous layer was replaced into the original reaction flask and ZnCl2 (3.586 g, 26.3 mmol) was then added in two portions followed by cooling to 0° C. over 30 minutes. The pH of the crude reaction mixture was then adjusted to pH=8.0 using concentrated NH4OH. The crude mixture was then extracted with Et2O, followed by ethyl acetate. The combined organics were then dried over Na2SO4, and then concentrated in vacuo, affording the desired product as a brown solid (10.7 g, 85% yield). MS APCI (+) m/z 240.2 and 242.2 (M+1 of each Br isotope) detected. The reaction mixture was then heated to reflux mixed with 1.0 mL over 25 minutes addition the reaction had been consumed followed by addition of 50 mL of Et2O followed by removal of Et2O by partitioning was then added in two portions by cooling to 0° C. over 30 minutes The pH of the crude reaction mixture The crude mixture was then extracted with Et2O The combined organics were then dried over Na2SO4 concentrated in vacuo

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

Procedure: 2-Bromo-4-fluorobenzenamine (10 g, 52.6 mmol) was weighed into a round bottom flask, and dissolved in 40 ml, of 6N HCl. The reaction mixture was then heated to reflux, followed by drop-wise addition of (E)-but-2-enal (4.578 mL, 55.3 mmol) mixed with 1.0 mL deionized water over 25 minutes. Following complete addition the reaction was heated at 100° C. for an additional 35 minutes, until all the 2-bromo-4-fluorobenzenamine had been consumed. The reaction was cooled to ambient temperature, followed by addition of 50 mL of Et2O. The reaction was stirred for 5 minutes followed by removal of Et2O by partitioning. The aqueous layer was replaced into the original reaction flask and ZnCl2 (3.586 g, 26.3 mmol) was then added in two portions followed by cooling to 0° C. over 30 minutes. The pH of the crude reaction mixture was then adjusted to pH=8.0 using concentrated NH4OH. The crude mixture was then extracted with Et2O, followed by ethyl acetate. The combined organics were then dried over Na2SO4, and then concentrated in vacuo, affording the desired product as a brown solid (10.7 g, 85% yield). MS APCI (+) m/z 240.2 and 242.2 (M+1 of each Br isotope) detected. The reaction mixture was then heated to reflux mixed with 1.0 mL over 25 minutes addition the reaction had been consumed followed by addition of 50 mL of Et2O followed by removal of Et2O by partitioning was then added in two portions by cooling to 0° C. over 30 minutes The pH of the crude reaction mixture The crude mixture was then extracted with Et2O The combined organics were then dried over Na2SO4 concentrated in vacuo

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

Procedure: The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 260 mg of 2-bromo-4-fluoroaniline in place of the 2,4-difluoroaniline. 310 mg of N-(2-bromo-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following: The product is prepared

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrakis(triphenylphosphine)palladium (289 mg, 0.250 mmol), potassium carbonate (829 mg, 6.00 mmol), water (4 mL) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (722 mg, 3.00 mmol) were successively added to a solution of 2-bromo-4-fluoroaniline (950 mg, 5.00 mmol) in 1,2-dimethoxyethane (10 mL) under an argon atmosphere. The mixture was heated to an external temperature of 105° C. and stirred for 7 hr. The mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to afford 2-ethenyl-4-fluoroaniline as a reddish brown oil (458 mg). washed with brine dried over anhydrous sodium sulfate Thereafter, the desiccant was filtered off followed by concentration under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1)

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrakis(triphenylphosphine)palladium (289 mg, 0.250 mmol), potassium carbonate (829 mg, 6.00 mmol), water (4 mL) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (722 mg, 3.00 mmol) were successively added to a solution of 2-bromo-4-fluoroaniline (950 mg, 5.00 mmol) in 1,2-dimethoxyethane (10 mL) under an argon atmosphere. The mixture was heated to an external temperature of 105° C. and stirred for 7 hr. The mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to afford 2-ethenyl-4-fluoroaniline as a reddish brown oil (458 mg). washed with brine dried over anhydrous sodium sulfate Thereafter, the desiccant was filtered off followed by concentration under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1)