tert-butyl N-[(4-bromophenyl)methyl]carbamate

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

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

Procedure: In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H). The reaction mixture was filtered through a bed of celite the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL) The filtrate was concentrated to remove most of the DMF The residue was treated with water (50 mL) a white emulsion formed This mixture was extracted with ethyl acetate (4×25 mL) dried over Na2SO4 the solvent was evaporated

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 117 (286 mg, 1.0 mmol) in anhydrous DMF (3.0 mL) was added sodium hydride (NaH, 60% oil dispersion, 48.0 mg, 1.2 mmol, 1.2 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 30 min before 1-bromo-3-fluoropropane 118 (170 mg, 1.2 mmol, 1.2 equiv) was added. The reaction mixture was subsequently warmed to 50-60° C. and stirred for 24 hours. The reaction mixture was then quenched with water (10 mL), and the resulting aqueous solution was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10-15% EtOAc/hexane gradient elution) to afford the desired (4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115 (158 mg, 46% yield) as a colorless oil. was added The reaction mixture was then quenched with water (10 mL) the resulting aqueous solution was extracted with EtOAc (2×20 mL) The combined organic extracts were washed with water (10 mL) and saturated aqueous NaCl (10 mL) dried over MgSO4 concentrated in vacuo The residue was purified by column chromatography (10-15% EtOAc/hexane gradient elution)

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

Procedure: A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL) and water (5 mL) was treated with BOC2O (2.40 g, 11.0 mmol, 1.1 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (4-bromo-benzyl)-carbamic acid tert-butyl ester 117 (2.60 g, 90.9% yield) as a colorless oil. The two layers were separated the aqueous layer was extracted with EtOAc (20 mL) The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL) dried over MgSO4 concentrated in vacuo The residue was further dried in vacuo

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: A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (3.21 g) and N-tert-butoxycarbonyl-4-bromobenzylamine (2.86 g) was cooled to −78° C. To the solution kas gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (31 ml). To the mixture were then added water (100 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography. followed by crystallization. The crystals were collected to give 2-amino-4′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) as a pale yellow crystalline product. The organic layer was washed with water dried over anhydrous MgSO4 The solvent was then distilled off the residue was purified by means of a silica gel column chromatography followed by crystallization The crystals were collected

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

Procedure: A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (3.21 g) and N-tert-butoxycarbonyl-4-bromobenzylamine (2.86 g) was cooled to −78° C. To the solution kas gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (31 ml). To the mixture were then added water (100 ml) and acetic acid ethyl ester (100 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography. followed by crystallization. The crystals were collected to give 2-amino-4′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) as a pale yellow crystalline product. The organic layer was washed with water dried over anhydrous MgSO4 The solvent was then distilled off the residue was purified by means of a silica gel column chromatography followed by crystallization The crystals were collected

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprised of N-cyanomethyl-4-methyl-2-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentanamide (250 mg, 0.702 mmol), tert-butyl 4-bromobenzylcarbamate (303 mg, 1.053 mmol), sodium bicarbonate (1.1 mL, 2.11 mmol), palladium(II) chloride (18 mg, 0.0211 mmol) and DMF (15.8 mL) was stirred under nitrogen at between 80-85° C. until the reaction was complete. The mixture was diluted with water and the product was extracted with diethyl ether (3×). The combined extracts were washed with brine, dried (MgSO4) and then concentrated in vacuo. The product was purified from the residue by flash chromatography over silica gel (ethyl acetate/hexanes) to provide tert-butyl 3′-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylmethylcarbamate (252 mg, 0.576 mmol). 1H NMR (400 MHz, d6-DMSO): δ 8.79 (br s, 1H), 7.58-7.26 (m, 9H), 4.16 (d, J=5.2 Hz, 2H), 4.11 (br s, 2H), 3.67 (dd, J=7.2, 7.2 Hz, 1H), 1.95-1.91 (m, 1H), 1.57-1.53 (m, 1H), 1.40-1.33 (m, 10H), 0.88 (dd, J=6.7, 6.7 Hz, 6H); MS (−ESI) m/z 434.6 (M−H)−. the product was extracted with diethyl ether (3×) The combined extracts were washed with brine dried (MgSO4) concentrated in vacuo The product was purified from the residue by flash chromatography over silica gel (ethyl acetate/hexanes)

Conditions: temp:82.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprised of N-cyanomethyl-4-methyl-2-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentanamide (250 mg, 0.702 mmol), tert-butyl 4-bromobenzylcarbamate (303 mg, 1.053 mmol), sodium bicarbonate (1.1 mL, 2.11 mmol), palladium(II) chloride (18 mg, 0.0211 mmol) and DMF (15.8 mL) was stirred under nitrogen at between 80-85° C. until the reaction was complete. The mixture was diluted with water and the product was extracted with diethyl ether (3×). The combined extracts were washed with brine, dried (MgSO4) and then concentrated in vacuo. The product was purified from the residue by flash chromatography over silica gel (ethyl acetate/hexanes) to provide tert-butyl 3′-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylmethylcarbamate (252 mg, 0.576 mmol). 1H NMR (400 MHz, d6-DMSO): δ 8.79 (br s, 1H), 7.58-7.26 (m, 9H), 4.16 (d, J=5.2 Hz, 2H), 4.11 (br s, 2H), 3.67 (dd, J=7.2, 7.2 Hz, 1H), 1.95-1.91 (m, 1H), 1.57-1.53 (m, 1H), 1.40-1.33 (m, 10H), 0.88 (dd, J=6.7, 6.7 Hz, 6H); MS (−ESI) m/z 434.6 (M−H)−. the product was extracted with diethyl ether (3×) The combined extracts were washed with brine dried (MgSO4) concentrated in vacuo The product was purified from the residue by flash chromatography over silica gel (ethyl acetate/hexanes)

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

Procedure: In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H). The reaction mixture was filtered through a bed of celite the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL) The filtrate was concentrated to remove most of the DMF The residue was treated with water (50 mL) a white emulsion formed This mixture was extracted with ethyl acetate (4×25 mL) dried over Na2SO4 the solvent was evaporated

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

Procedure: In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H). The reaction mixture was filtered through a bed of celite the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL) The filtrate was concentrated to remove most of the DMF The residue was treated with water (50 mL) a white emulsion formed This mixture was extracted with ethyl acetate (4×25 mL) dried over Na2SO4 the solvent was evaporated