Water → (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

HRID 537249Notes

Reaction equation

HRID 537249 reaction equation
Br[C:2]1[N:3]=[C:4]([Si:7]([CH3:10])([CH3:9])[CH3:8])[S:5][CH:6]=1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36](OC)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1.O>CCOCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36]([C:2]5[N:3]=[C:4]([Si:7]([CH3:10])([CH3:9])[CH3:8])[S:5][CH:6]=5)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1

Participants

6

Reactant 4

HCID 962WaterHCID 43403994-Bromo-2-(trimethylsilyl)-1,3-thiazoleHCID 583333606-O-tert-butyl 4a-O-methyl 1-(4-fluorophenyl)-4,5,7,8-tetrahydropyrazolo(3,4-g)isoquinoline-4a,6-dicarboxylateHCID 178418339Butyllithium

Product 1

HCID 86709984(R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateYield 23.5%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent3×

Conditions

Temperature
-78 °C

Procedure

A solution of 4-bromo-2-(trimethylsilyl)thiazole (304 μl, 1.784 mmol) in dry ether (2 mL) was added to a solution of butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dry ether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. then slowly warmed to −50° C. over 2 hours. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a pale yellow foamy solid (76 mg). LCMS (Method F, ES-API): RT 2.65 min, m+H=553.3.

Workup

  1. stirringthe reaction mixture was stirred for 0.5 hour at −78° C.
  2. temperaturethen slowly warmed to −50° C. over 2 hours
  3. stirringthe reaction mixture was stirred at room temperature for 10 minutes
  4. extractionThe aqueous layer was extracted with ethyl acetate (3×15 mL)
  5. washThe combined organic extracts were washed with brine (20 mL)
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give a dark orange oil
  10. customThe crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane)

Sources & evidence

ORD record
ord-6e7d7256e31a4f928e5762318ec1ed55
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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