6-bromonaphthalene-1,2-diamine

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

Procedure: To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g) extracted with EtOAc/H2O (150 mL) The organic layer was dried over Na2SO4 filtered concentrated purified by silica gel chromatography (2:1 EtOAc:petroleum ether)

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

Procedure: To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g) extracted with EtOAc/H2O (150 mL) The organic layer was dried over Na2SO4 filtered concentrated purified by silica gel chromatography (2:1 EtOAc:petroleum ether)

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

Procedure: To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g) extracted with EtOAc/H2O (150 mL) The organic layer was dried over Na2SO4 filtered concentrated purified by silica gel chromatography (2:1 EtOAc:petroleum ether)

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

Procedure: To a mixture of 6-bromo-1-nitronaphthalen-2-amine (11.6 g, 43.4 mmol) in ethanol (430 mL) under argon was added Raney Nickel (˜5 g, NOTE: no effort was made to remove the water from the nickel). Hydrogen gas was bubbled through the reaction mixture for 2 minutes. The reaction was stirred under an atmosphere of hydrogen at room temperature. After 16 hours, the Raney Nickel was removed by filtration over Celite and rinsed with ethyl acetate. The filtrate was thoroughly concentrated to yield 6-bromonaphthalene-1,2-diamine (9.2 g, 88% yield). to remove the water from the nickel) Hydrogen gas was bubbled through the reaction mixture for 2 minutes the Raney Nickel was removed by filtration over Celite rinsed with ethyl acetate The filtrate was thoroughly concentrated

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

Procedure: To a solution of 6-bromonaphthalene-1,2-diamine (1.08 g, 4.56 mmol), and (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.10 g, 4.56 mmol) and HATU (2.08 g, 5.47 mmol) in methylene chloride (45 mL) was added DIPEA (3.98 mL, 22.79 mmol). The mixture was stirred at room temperature for two hours. Upon completion, the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate twice. The combined organic layers were washed with brine, concentrated, and purified by normal phase chromatography (30-80% ethyl acetate (5% MeOH) in hexanes) to give (1S,3S,4R)-tert-butyl 3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.01 g, 95%). LCMS-ESI+: calc'd for C22H26BrN3O3: 459.12 (M+); Found: 460.9 (M+H+). Upon completion, the reaction was concentrated in vacuo diluted with ethyl acetate washed with water The aqueous layer was back extracted with ethyl acetate twice The combined organic layers were washed with brine concentrated purified by normal phase chromatography (30-80% ethyl acetate (5% MeOH) in hexanes)

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

Procedure: To a solution of 2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (0.08 g, 0.34 mmol) in CH2Cl2 (3.5 mL) was added 6-Bromo-naphthalene-1,2-diamine (0.09 g, 0.041 mmol), HATU (0.16 g, 0.43 mmol), and DIPEA (0.3 mL, 1.72 mmol). The resulting solution was stirred at room temperature for 1.5 h and diluted with EtOAc. The organic layer was washed with H2O and brine. The aqueous layers were back extracted with EtOAc. The combined organic layers were dried over Na2SO4 and separated. The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (2% MeOH) in hexanes) to provide an oil that was dissolved in AcOH (7.0 mL). The solution was stirred at 40° C. (external, oil bath) for 2 h. The solution was diluted with EtOAc and slowly basified with saturated sodium bicarbonate and NaOH (2N). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (2% MeOH) in hexanes) to provide 3-(7-Bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.15 g, 97%). LCMS-ESI+: calc'd for C21H22BrN3O2: 427.09 (M+); Found: 428.35 (M+H+). The organic layer was washed with H2O and brine The aqueous layers were back extracted with EtOAc The combined organic layers were dried over Na2SO4 separated The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (2% MeOH) in hexanes) to provide an oil that The solution was stirred at 40° C. (external, oil bath) for 2 h The organic layer was separated dried over Na2SO4 concentrated The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (2% MeOH) in hexanes)

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

Procedure: To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g) extracted with EtOAc/H2O (150 mL) The organic layer was dried over Na2SO4 filtered concentrated purified by silica gel chromatography (2:1 EtOAc:petroleum ether)