2-bromo-3-methylaniline

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: 2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material. ##STR34##

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

Procedure: To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (3.00 g, 6.43 mmol) in dichloromethane (50 mL) with N,N-dimethylformamide (2 drops) was added oxalyl chloride (1.13 mL, 12.9 mmol) drop wise. The reaction mixture was stirred at room temperature for 1 hour, and then it was concentrated. The concentrate is taken up in tetrahydrofuran (50 mL) and 2-bromo-3-methyl aniline (1.33 g, 7.07 mmol) was added in tetrahydrofuran (5 mL) and diisopropylethylamine (5.62 mL, 36.2 mmol). The solution is heated to 70° C. for 2 hours. The mixture was then cooled to 50° C. and piperazine (1.66 g, 19.3 mmol) was added. The reaction mixture stirred for 16 hours before concentration onto silica gel. Purification via flash chromatography (0-20% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54-7.71 (m, 1H), 7.06-7.31 (m, 2H), 3.62-3.98 (m, 2H), 2.26-3.45 (m, 10H), 0.87-1.05 (m, 9H); MS (APCI+) m/z 412, 414 (M+H)+. it was concentrated The solution is heated to 70° C. for 2 hours The mixture was then cooled to 50° C. The reaction mixture stirred for 16 hours before concentration onto silica gel Purification via flash chromatography (0-20% methanol/dichloromethane)

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

Procedure: To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (3.00 g, 6.43 mmol) in dichloromethane (50 mL) with N,N-dimethylformamide (2 drops) was added oxalyl chloride (1.13 mL, 12.9 mmol) drop wise. The reaction mixture was stirred at room temperature for 1 hour, and then it was concentrated. The concentrate is taken up in tetrahydrofuran (50 mL) and 2-bromo-3-methyl aniline (1.33 g, 7.07 mmol) was added in tetrahydrofuran (5 mL) and diisopropylethylamine (5.62 mL, 36.2 mmol). The solution is heated to 70° C. for 2 hours. The mixture was then cooled to 50° C. and piperazine (1.66 g, 19.3 mmol) was added. The reaction mixture stirred for 16 hours before concentration onto silica gel. Purification via flash chromatography (0-20% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54-7.71 (m, 1H), 7.06-7.31 (m, 2H), 3.62-3.98 (m, 2H), 2.26-3.45 (m, 10H), 0.87-1.05 (m, 9H); MS (APCI+) m/z 412, 414 (M+H)+. it was concentrated The solution is heated to 70° C. for 2 hours The mixture was then cooled to 50° C. The reaction mixture stirred for 16 hours before concentration onto silica gel Purification via flash chromatography (0-20% methanol/dichloromethane)

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

Procedure: To a solution of lithium perchlorate (2.13 g, 20 mmol) in diethyl ether (4 mL) was added 1,2-epoxy-2-methylpropane (0.195 mL, 2.2 mmol), followed by 2-bromo-3-methylaniline (0.250 mL, 2 mmol) under an atmosphere of nitrogen gas. The reaction mixture was stirred overnight at RT. Water was added dropwise, and the product was extracted from the reaction mixture with DCM. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc). 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol was obtained as a clear colorless oil. the product was extracted from the reaction mixture with DCM The organic phase was dried over MgSO4 The solvent was removed under reduced pressure the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc)

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

Procedure: To a solution of lithium perchlorate (2.13 g, 20 mmol) in diethyl ether (4 mL) was added 1,2-epoxy-2-methylpropane (0.195 mL, 2.2 mmol), followed by 2-bromo-3-methylaniline (0.250 mL, 2 mmol) under an atmosphere of nitrogen gas. The reaction mixture was stirred overnight at RT. Water was added dropwise, and the product was extracted from the reaction mixture with DCM. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc). 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol was obtained as a clear colorless oil. the product was extracted from the reaction mixture with DCM The organic phase was dried over MgSO4 The solvent was removed under reduced pressure the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc)

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

Procedure: To a stirred slurry of NaH (60% in mineral oil) (0.435 mL, 10.00 mmol) in THF (5 ml) was added dropwise a solution of 2-bromo-3-methylaniline (0.625 mL, 5 mmol) in THF (1 ml). After 15 min, (2-bromoethoxy)-tert-butyldimethylsilane (1.07 mL, 5 mmol) was added and the reaction mixture was stirred for 48 h. The reaction was quenched with water, partitioned between EtOAc and aqueous saturated ammonium chloride. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-10% EtOAc/hexanes). 2-Bromo-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methylaniline was isolated as a yellow oil. The reaction was quenched with water partitioned between EtOAc and aqueous saturated ammonium chloride The aqueous layer was extracted with EtOAc the combined organic layers were dried over MgSO4 The solvent was removed under reduced pressure the remaining residue was purified by flash chromatography (0-10% EtOAc/hexanes)

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

Procedure: 2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material. ##STR34##

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

Procedure: 2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4 methylphenylhydrazine hydrochloride in Example 7, except using 2-bromo-3-methylaniline as starting material. ##STR52##

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

Procedure: 2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material.

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

Procedure: The procedure described in Example 3: step b was followed using 2-bromo-3-methyl-phenylamine (185 mg, 1.0 mmol, Example 25: step a), PdCl2(PPh3)2 (70.2 mg, 0.1 mmol), dioxane (3 mL), and Et3N (729 μL, 6 mmol), 4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolane (453 μL, 3 mmol). Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue yielded the title compound (94 mg, 40%) as a yellow solid. ESI-MS (m/z): Calcd. for C13H20BNO2: 234.1 (M+H) found: 234.1. Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue