Triethylamine → 2-tert-Butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate

HRID 920243Notes

Reaction equation

HRID 920243 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[F:19].C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C]=O>>[F:19][CH:7]1[C:6]2[C:11](=[C:2]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=[CH:4][CH:5]=2)[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1

Participants

5

Reactant 4

HCID 8471TriethylamineHCID 812191,3-Bis(diphenylphosphino)propaneHCID 89526335tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylateHCID 178418416HCID 178418416, compound

Product 1

HCID 895258942-tert-Butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate

Procedure

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.

Workup

  1. customby degassed anhydrous MeOH (6 mL) & DMSO (3 mL)
  2. customThis mixture was then degassed
  3. customby bubbling N2 through with a vent needle
  4. customthe reaction was purged 3× (vacuum/CO)
  5. temperaturethe reaction mixture (clear tan, became darker with heat)
  6. temperaturewas heated to 80 C
  7. stirringwhile stirring in a hot oil bath in the hood under an atmosphere of CO
  8. waitAfter 22 hours
  9. washwashed with saturated NaHCO3
  10. dry with materialorganics dried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customPurification by silica gel chromatography (0-40% EtOAc/Hex; 40 g ISCO)
  14. concentrationdesired fractions concentrated

Sources & evidence

ORD record
ord-eb69ff1394774c4d9316079f61b9f075
Source dataset
uspto-grants-2016_03
Patent number
US09273040B2

Reaction notes

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