1-Bromo-3-chlorobenzene → 2-tert-butyl 3-methyl 6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylate

HRID 2081119Notes

Reaction equation

HRID 2081119 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]([C:19]([O:21][CH3:22])=[O:20])[CH2:5]2.[Cl:23][C:24]1[CH:25]=[C:26](Br)[CH:27]=[CH:28][CH:29]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.C(OC)(C)(C)C.Cl[Cu]>[Cl:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:6]([C:19]([O:21][CH3:22])=[O:20])[CH2:5]2

Participants

8

Reactant 4

HCID 79281-Bromo-3-chlorobenzeneHCID 10796Cesium carbonateHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 577645552-tert-Butyl 3-methyl 6-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate

Product 1

HCID 536292952-tert-butyl 3-methyl 6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylateYield 50.1%

Reagents, catalysts & solvents 3

HCID 62652Cuprous chlorideCatalystHCID 13387N-methyl-2-pyrrolidoneSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
120 °C

Procedure

2-Tert-butyl 3-methyl 6-hydroxy-3,4-dihydroisoquinoline-2, 3(1H)-dicarboxylate (200 mg, 0.65 mmol), m-chloro-phenyl bromide (103 mg, 0.54 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (TMHD, 10 mg, 0.054 mmol), Cs2CO3 (326 mg, 1.00 mmol), and CuCl (27 mg, 0.27 mmol) were mixed together in NMP (1 mL) and heated to 120° C. for 6 h. The reaction was then diluted with methyl tert-butyl ether (MTBE) and filtered over celite. The filtrate was washed with 1 N HCl, 1 N NaOH, and brine. The organic was dried over Na2SO4 and concentrated before loading on a Biotage silica column (12 m) and eluting with 10% Acetone/Hexanes to give 2-tert-butyl 3-methyl 6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate as a pale yellow oil (113 mg, 50%). This material was then taken up in 1 mL of a mixture of THF/H2O (3:1) and LiOH (70 mg, 1.62 mmol) was added. The reaction stirred overnight at rt, before it was concentrated and quenched with 1 N HCl. The product was then extracted with EtOAc (3×). The combined extracts were dried over Na2SO4 and concentrated to give a pale yellow foam (100 mg, 92%). MS m/e 402.9 (M−−H),

Workup

  1. filtrationfiltered over celite
  2. washThe filtrate was washed with 1 N HCl, 1 N NaOH, and brine
  3. dry with materialThe organic was dried over Na2SO4
  4. concentrationconcentrated before loading on a Biotage silica column (12 m)
  5. washeluting with 10% Acetone/Hexanes

Sources & evidence

ORD record
ord-bbf49782c2ff4900a152f6945f3be6eb
Source dataset
uspto-grants-2011_04
Patent number
US07932277B2

Reaction notes

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