tert-butyl 8-bromo-4-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask containing tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5) (316 mg, 0.957 mmol) was added TRIETHYLAMINE (0.6 mL, 4.30 mmol), followed by degassed anhydrous MeOH (6 mL) & DMSO (3 mL). This mixture was then degassed by bubbling N2 through with a vent needle while stirring for ˜5 minutes. Then added PdOAc2 (57 mg, 0.254 mmol) & DPPP (83 mg, 0.201 mmol) as solids in 1 portion. A balloon containing CARBON MONOXIDE (536 mg, 19.14 mmol) was then attached and the reaction was purged 3× (vacuum/CO), then the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO. Followed by LC/MS. After 22 hours, the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield 2-tert-butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate (24-6). HRMS [M+H]: calculated; 310.1449, observed; 310.1439. by degassed anhydrous MeOH (6 mL) & DMSO (3 mL) This mixture was then degassed by bubbling N2 through with a vent needle the reaction was purged 3× (vacuum/CO) the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO After 22 hours washed with saturated NaHCO3 organics dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO) desired fractions concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask containing tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5) (316 mg, 0.957 mmol) was added TRIETHYLAMINE (0.6 mL, 4.30 mmol), followed by degassed anhydrous MeOH (6 mL) & DMSO (3 mL). This mixture was then degassed by bubbling N2 through with a vent needle while stirring for ˜5 minutes. Then added PdOAc2 (57 mg, 0.254 mmol) & DPPP (83 mg, 0.201 mmol) as solids in 1 portion. A balloon containing CARBON MONOXIDE (536 mg, 19.14 mmol) was then attached and the reaction was purged 3× (vacuum/CO), then the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO. Followed by LC/MS. After 22 hours, the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield 2-tert-butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate (24-6). HRMS [M+H]: calculated; 310.1449, observed; 310.1439. by degassed anhydrous MeOH (6 mL) & DMSO (3 mL) This mixture was then degassed by bubbling N2 through with a vent needle the reaction was purged 3× (vacuum/CO) the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO After 22 hours washed with saturated NaHCO3 organics dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO) desired fractions concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask containing tert-butyl 8-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-4) (622 mg, 1.895 mmol) was added anhydrous DCM (10 ml). The reaction mixture was then capped & cooled to −78 C (dry ice/acetone bath) while stirring under N2. Then added DAST (1.4 ml, 10.60 mmol) at −78 C. The reaction mixture was then stirred at −78 C. Followed by LC/MS. After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), then permitted to warm to room temperature, then the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated to yield. Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5). The reaction mixture was then capped The reaction mixture was then stirred at −78 C After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), washed with saturated NaHCO3 organics dried over Na2SO4 filtered concentrated to yield Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO) desired fractions concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask containing tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5) (316 mg, 0.957 mmol) was added TRIETHYLAMINE (0.6 mL, 4.30 mmol), followed by degassed anhydrous MeOH (6 mL) & DMSO (3 mL). This mixture was then degassed by bubbling N2 through with a vent needle while stirring for ˜5 minutes. Then added PdOAc2 (57 mg, 0.254 mmol) & DPPP (83 mg, 0.201 mmol) as solids in 1 portion. A balloon containing CARBON MONOXIDE (536 mg, 19.14 mmol) was then attached and the reaction was purged 3× (vacuum/CO), then the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO. Followed by LC/MS. After 22 hours, the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield 2-tert-butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate (24-6). HRMS [M+H]: calculated; 310.1449, observed; 310.1439. by degassed anhydrous MeOH (6 mL) & DMSO (3 mL) This mixture was then degassed by bubbling N2 through with a vent needle the reaction was purged 3× (vacuum/CO) the reaction mixture (clear tan, became darker with heat) was heated to 80 C while stirring in a hot oil bath in the hood under an atmosphere of CO After 22 hours washed with saturated NaHCO3 organics dried over Na2SO4 filtered concentrated Purification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO) desired fractions concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask containing tert-butyl 8-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-4) (622 mg, 1.895 mmol) was added anhydrous DCM (10 ml). The reaction mixture was then capped & cooled to −78 C (dry ice/acetone bath) while stirring under N2. Then added DAST (1.4 ml, 10.60 mmol) at −78 C. The reaction mixture was then stirred at −78 C. Followed by LC/MS. After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), then permitted to warm to room temperature, then the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated to yield. Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5). The reaction mixture was then capped The reaction mixture was then stirred at −78 C After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), washed with saturated NaHCO3 organics dried over Na2SO4 filtered concentrated to yield Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO) desired fractions concentrated