4-bromo-2-methylbenzaldehyde

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: The title compound was prepared from crude 4-bromo-2-methylbenzaldehyde (D91) and 1,1-dimethylethyl methylcarbamate (D83) using a method similar to that described for D84 in Description 84. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.76 (1H, d), 7.28 (1H, dd), 7.19 (1H, d), 3.31 (3H, s), 2.66 (3H, s), 1.49 (9H, s).

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

Procedure: The title compound was prepared from crude 4-bromo-2-methylbenzaldehyde (D91) and 1,1-dimethylethyl methylcarbamate (D83) using a method similar to that described for D84 in Description 84. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.76 (1H, d), 7.28 (1H, dd), 7.19 (1H, d), 3.31 (3H, s), 2.66 (3H, s), 1.49 (9H, s).

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

Procedure: To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 5° C. for 30 minutes then MeOH (3 mL) and 2 M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ˜19 h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil (1.81 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.65 (1H, d), 7.50 (1H, dd), 7.43 (1H, m), 2.64 (3H, s). The mixture was stirred for ˜19 h then concentrated in vacuo The residue was re-dissolved in water/EtOAc The organic layer was dried concentrated

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

Procedure: The compound was synthesized as in Example 3.1 using 2-methyl-4-bromobenzaldehyde (113 mg, 0.57 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (113 mg, 0.69 mmol) in place of hexylboronic acid to give 2-methyl-4-butylbenzaldehyde (34 mg, 35%). Used without further characterization.

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

Procedure: The title compound was prepared from crude 4-bromo-2-methylbenzaldehyde (D91) and 1,1-dimethylethyl methylcarbamate (D83) using a method similar to that described for D84 in Description 84. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.76 (1H, d), 7.28 (1H, dd), 7.19 (1H, d), 3.31 (3H, s), 2.66 (3H, s), 1.49 (9H, s).

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

Procedure: To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 5° C. for 30 minutes then MeOH (3 mL) and 2M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ˜19 h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil (1.81 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.65 (1H, d), 7.50 (1H, dd), 7.43 (1H, m), 2.64 (3H, s). The mixture was stirred for ˜19 h then concentrated in vacuo The residue was re-dissolved in water/EtOAc The organic layer was dried concentrated

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

Procedure: To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 5° C. for 30 minutes then MeOH (3 mL) and 2M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ˜19 h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil (1.81 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.65 (1H, d), 7.50 (1H, dd), 7.43 (1H, m), 2.64 (3H, s). The mixture was stirred for ˜19 h then concentrated in vacuo The residue was re-dissolved in water/EtOAc The organic layer was dried concentrated

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

Procedure: A 500 mL round-bottom flask was charged with 4-bromo-2-methylbenzaldehyde (8.00 g, 40.2 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (9.40 g, 50.5 mmol, 1.26 equiv), triethylamine (6.50 g, 64.2 mmol, 1.60 equiv) and dichloroethane (200 mL). The resulting solution was stirred for 30 min at room temperature. Solid sodium triacetoxyborohydride (27.0 g, 127 mmol, 3.17 equiv) was added. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic layers were combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3) to yield 10.0 g (67% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 369 [M+H]+. The resulting solution was stirred overnight at room temperature The reaction was then quenched by the addition of water (100 mL) The resulting solution was extracted with dichloromethane (3×200 mL) washed with brine (2×200 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3)

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

Procedure: A 250 mL round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (2.80 g, 15.0 mmol, 1.00 equiv), 4-bromo-2-methylbenzaldehyde (3.28 g, 16.5 mmol, 1.10 equiv), dichloromethane (80 mL). Triethylamine (4.56 g, 45.1 mmol, 3.00 equiv) was added. The resulting solution was stirred for 30 mins at room temperature. Sodium triacetoxyborohydride (9.60 g, 45.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (100 mL). The resulting solution was extracted with dichloromethane (3×60 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 5.70 g (98% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 369 [M+H]+. The resulting solution was stirred overnight at room temperature The resulting solution was extracted with dichloromethane (3×60 mL) dried over Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80)