N-(4-bromophenyl)-2-chloroacetamide

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:; See reaction.notes.procedure_details.

Procedure: N-(4-Bromo-phenyl)-2-chloro-acetamide (0.3 g, 1.21 mmol) was dissolved in anhydrous toluene (10 ml). Pyrrolidine (0.3 ml, 3.63 mmol) was added dropwise to the mixture, which was then heated to reflux and stirred overnight. The toluene was removed under reduced pressure and the residue was dissolved in ethyl acetate. Saturated ammonium chloride was added and the aqueous layer was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Yield 0.22 g, 65%. LCMS method: 2, RT: 2.62 min; MI: 283-285 [M+1]. was then heated to reflux The toluene was removed under reduced pressure the residue was dissolved in ethyl acetate Saturated ammonium chloride was added the aqueous layer was extracted twice with ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: N-(4-Bromo-phenyl)-2-chloro-acetamide (0.3 g, 1.21 mmol) was dissolved in anhydrous toluene (10 ml). Pyrrolidine (0.3 ml, 3.63 mmol) was added dropwise to the mixture, which was then heated to reflux and stirred overnight. The toluene was removed under reduced pressure and the residue was dissolved in ethyl acetate. Saturated ammonium chloride was added and the aqueous layer was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Yield 0.22 g, 65%. LCMS method: 2, RT: 2.62 min; MI: 283-285 [M+1]. was then heated to reflux The toluene was removed under reduced pressure the residue was dissolved in ethyl acetate Saturated ammonium chloride was added the aqueous layer was extracted twice with ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of compound 7a (496 mg, 2 mmol), K2CO3 (553 mg, 4 mmol), and KI (66 mg, 0.4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc (3:1) to provide the intermediate 7b (100 mg, 0.3 mmol, 16% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (broad s, 1H), 7.56-7.46 (m, 4H), 6.94-6.87 (m, 2H), 6.87-6.80 (m, 2H), 4.57 (s, 2H). was added to the mixture under argon The reaction mixture was heated After cooling to room temperature the solvent was evaporated the residue was quenched with 100 mL water The mixture was then extracted with EtOAc the combined organic layer was washed with water brine, and dried over Na2SO4 The solvent was evaporated the residue was purified by silica gel column chromatography with hexane/EtOAc (3:1)

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

Procedure: 4-bromoaniline (1.72 g, 10 mmol) was dissolved in 50 mL dichloromethane. Pyridine (cat.) was added and then 2-chloroacetyl chloride (800 uL, 10 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hr. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give the intermediate 7a (1.03 g, 4 mmol, 42% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.24 (broad s, 1H), 7.54-7.44 (m, 4H), 4.21 (s, 2H). The reaction was quenched with water the aqueous layer was extracted with dichloromethane (2×25 mL) The combined organic layer was washed with water brine, and dried over Na2SO4 The solvent was evaporated

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

Procedure: A mixture of 5-Ethyl-5-(1-methylethyl)-2,4-imidazolidinedione, (CAS #98492-91-2 (50 mg, 0.29 mmol), N-(4-bromophenyl)-2-chloro-acetamide (CAS #2564-02-5) (80 mg, 0.32 mmol), K2CO3 (48 mg, 0.35 mmol) in acetone was stirred at ambient temperature for 18 h. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and solvent removed. The crude product was purified by preparative TLC. The title compound was isolated as white solid. The mixture was extracted with EtOAc the organic layer was washed with brine dried over MgSO4 filtered solvent removed The crude product was purified by preparative TLC

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add potassium carbonate (2.1 g, 15.5 mmol) and pyrrolidine (9.65 mL, 116 mmol) to a solution of N-(4-bromophenyl)-2-chloroacetamide (2.0 g, 7.7 mmol) in acetonitrile (78 mL) at RT. Heat the mixture at 80° C. for 4 h. Cool the mixture to RT, dilute with CH2Cl2, and wash with brine and water. Dry the organic layer over Na2SO4, filter, and concentrate to give 2.17 g (99%) of the title compound. LC-ES/MS m/z (79Br) 283.0 [M+H]+. Cool the mixture to RT wash with brine and water Dry the organic layer over Na2SO4 filter concentrate