Ethanol → 6-Thiophen-3-yl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

HRID 2227836Notes

Reaction equation

HRID 2227836 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

9

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 581760Thiophene-3-boronic acidHCID 10091216Tert-butyl 6-(trifluoromethylsulfonyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Product 1

HCID 697341956-Thiophen-3-yl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl esterYield 101.1%

Reagents, catalysts & solvents 4

HCID 821241,4-Bis(diphenylphosphino)butaneCatalystHCID 498840Bis(benzonitrile)palladium chlorideCatalystHCID 1140TolueneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of bis(benzonitrile)palladium(II) chloride (30 mg, 0.079 mmol) and 1,4-bis(diphenylphosphino)butane (33.6 mg, 0.079 mmol) in toluene (3 mL) was stirred at room temperature for 20 min. To this mixture was added 6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (300 mg, 0.79 mmol, Synth. Commun. 1995, 25, 3255), thiophene-3-boronic acid (131 mg, 1.02 mmol), 1 M aqueous sodium carbonate (1.57 mL, 1.57 mmol), and ethanol (2 mL). This dark mixture was heated to reflux with stirring under nitrogen overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered through Celite, evaporated, and purified by flash column chromatography (hexanes→5% ethyl acetate/hexanes) to give 252 mg (100%) of the title compound of Example 248, Step A as a pale yellow waxy solid. 1H NMR (CDCl3, 250 MHz) δ7.47-7.38 (c, 5H), 7.14 (d, 1H), 4.60 (s, 2H), 3.72-3.64 (c, 2H), 2.95-2.82 (c, 2H), 1.52 (s, 9H); MS (TS) 316 (MH+).

Workup

  1. temperatureThis dark mixture was heated
  2. temperatureto reflux
  3. stirringwith stirring under nitrogen overnight
  4. temperaturecooled to room temperature
  5. extractionextracted with ethyl acetate (4×)
  6. dry with materialThe combined organic extracts were dried over sodium sulfate
  7. filtrationfiltered through Celite
  8. customevaporated
  9. custompurified by flash column chromatography (hexanes→5% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-c3bbec863fd04ca189cfffe5f62c543c
Source dataset
uspto-grants-2002_07
Patent number
US06414149B1

Reaction notes

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