(3-propan-2-yloxyphenyl)methanamine

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: Following a procedure analogous to that for the synthesis of Example 106, (3-isopropoxyphenyl)methanamine (Matrix, 200 mg, 1.21 mmol) and butyraldehyde (110 μL, 1.21 mmol) were converted to the title compound (43 mg, 16%). 1H NMR (CDCl3) δ 7.29-7.17 (m, 1H), 6.99-6.74 (m, 3H), 4.57 (td, J=6.1, 12.1 Hz, 1H), 3.80 (s, 2H), 2.65 (t, J=7.3 Hz, 2H), 1.63-1.50 (m, 2H), 1.40-1.24 (m, 8H), 0.90 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 222.2 (M+H)+.

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

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

Procedure: A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (156 mg, 0.601 mmol), 1-(3-isopropoxyphenyl)methanamine (116 mg, 0.702 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (113 mg, 0.181 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (6 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-isopropoxy-benzylamino)-2H-phthalazin-1-one (45 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 1.22 (d, 6H), 4.40 (d, 2H), 4.57 (quintet, 1H), 6.80 (m, 2H), 6.91 (m, 2H), 7.16 (dd, 1H), 7.22 (t, 1H), 7.64 (t, 1H), 7.92 (d, 1H), 12.34 (s, 1H) ppm; m/z (M+1) 344.01. to cool washed with water The organic layer was washed with sat.aq NaHCO3, brine and dried (Na2SO4)

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

Procedure: A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (156 mg, 0.601 mmol), 1-(3-isopropoxyphenyl)methanamine (116 mg, 0.702 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (113 mg, 0.181 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (6 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-isopropoxy-benzylamino)-2H-phthalazin-1-one (45 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 1.22 (d, 6H), 4.40 (d, 2H), 4.57 (quintet, 1H), 6.80 (m, 2H), 6.91 (m, 2H), 7.16 (dd, 1H), 7.22 (t, 1H), 7.64 (t, 1H), 7.92 (d, 1H), 12.34 (s, 1H) ppm; m/z (M+1) 344.01. to cool washed with water The organic layer was washed with sat.aq NaHCO3, brine and dried (Na2SO4)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an alternative preparation, AlCl3 (15 g, 0.11 mole) was added to a 3-necked flask equipped with a jacketed addition funnel, flushed with argon and cooled in an ice bath. Crotonyl chloride (21 g, 200 mmol) was added dropwise while keeping the temperature of the reaction below 15° C. The resulting light yellow solution was stirred for 15 min before the ice bath was replaced with an ethyleneglycol/dry ice bath and the solution cooled to −20° C. Vinylsilane (21.1 ml, 220 mmol) was added dropwise from the ice-cooled jacketed addition funnel keeping the temperature of the reaction below −20° C. The reaction was stirred for 3 hr and then added quickly to a slurry of 200 mL saturated aqueous sodium/potassium tartrate solution, 200 g K2CO3, 300 mL ice and 500 mL ether. The slurry was stirred vigorously for 30 min then filtered through celite. The organic layer was separated, dried over Na2SO4, filtered and carefully concentrated. The oil was dissolved in 200 mL CH3CN and added dropwise to a cooled (0° C.) suspension of 3-(isopropoxy)benzylamine (30 g, 180 mmol) in a mixture of 2M aq NaHCO3 (100 mL) and CH3CN (30 mL). The reaction was stirred at rt overnight and partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting oil was chromatographed on silica eluting with 0-50% EtOAc/Hexanes. was added to a 3-necked flask equipped with a jacketed addition funnel flushed with argon cooled in an ice bath the temperature of the reaction below 15° C was replaced with an ethyleneglycol/dry ice bath cooled addition funnel the temperature of the reaction below −20° C The slurry was stirred vigorously for 30 min then filtered through celite The organic layer was separated dried over Na2SO4 filtered carefully concentrated The oil was dissolved in 200 mL CH3CN added dropwise to a cooled The reaction was stirred at rt overnight partitioned between water and EtOAc The organic layer was dried over Na2SO4 filtered concentrated The resulting oil was chromatographed on silica eluting with 0-50% EtOAc/Hexanes

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

Procedure: A 500 mL Parr bottle was flushed with argon, then 3-isopropoxybenzonitrile (32 g, 198 mmol) was added and diluted with 150 mL EtOH. The reaction was charged with ˜2 mL of an aq. slurry of Raney Nickel, then affixed to a Parr hydrogenation apparatus. The flask was evacuated and flushed with N2 three times before being charged with 40 psi H2. The flask was allowed to shake for 3 hr over which time the flask was recharged to 40 psi and consumption of gas ceased. HPLC/MS showed no starting material so the catalyst was carefully filtered without drying and washed with EtOH. The filtrate was concentrated and purified on an Isco automated system affixed with a Biotage Flash 40(M) cartridge eluted with 0-5% (MeOH+0.5M NH3) in CH2Cl2 over 30 min at 40 mL/min to give the product. A 500 mL Parr bottle was flushed with argon The flask was evacuated flushed with N2 three times before being charged with 40 psi H2 the flask was recharged to 40 psi and consumption of gas was carefully filtered without drying washed with EtOH The filtrate was concentrated purified on an Isco automated system eluted with 0-5% (MeOH+0.5M NH3) in CH2Cl2 over 30 min at 40 mL/min to give the product

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

Procedure: Following a procedure analogous to that for the synthesis of Example 106, (3-isopropoxyphenyl)methanamine (Matrix, 200 mg, 1.21 mmol) and butyraldehyde (110 μL, 1.21 mmol) were converted to the title compound (43 mg, 16%). 1H NMR (CDCl3) δ 7.29-7.17 (m, 1H), 6.99-6.74 (m, 3H), 4.57 (td, J=6.1, 12.1 Hz, 1H), 3.80 (s, 2H), 2.65 (t, J=7.3 Hz, 2H), 1.63-1.50 (m, 2H), 1.40-1.24 (m, 8H), 0.90 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 222.2 (M+H)+.