8-Hydroxyquinoline → 1-(1-(2,2-Dimethoxyethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one

HRID 2390434Notes

Reaction equation

HRID 2390434 reaction equation
[CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](I)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:32])([F:33])[F:17])=[CH:24][CH:23]=4)=[CH:26][C:27]3=[O:31])=[CH:11][CH:12]=2)[CH:7]=[N:6]1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 497584672-Hydroxy-4-(4-trifluoromethylphenyl)pyridineHCID 576255361-(2,2-Dimethoxyethyl)-5-iodo-1H-indazole

Product 1

HCID 576255431-(1-(2,2-Dimethoxyethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-oneYield 79%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
115 °C

Procedure

A suspension of 1-(2,2-dimethoxyethyl)-5-iodo-1H-indazole (458 mg, 1.38 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (330 mg, 1.38 mmol), Cs2CO3 (997 mg, 3.06 mmol), 8-hydroxyquinoline (42 mg, 0.29 mmol) and CuI (311 g, 163 mmol) in DMSO (5 mL) was evacuated for 30 minutes under high vacuum then backfilled with argon. The mixture was stirred under argon at 115° C. for 15 h and then allowed to cool. The mixture was diluted with 10% NH4OH in H2O (40 mL) and extracted with EtOAc (4×50 mL). The organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 95:5) followed by a second purification by flash chromatography (silica gel, CH2Cl2/MeOH, 97.5:2.5) gave the title compound (482 mg, 79%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.75-7.73 (m, 5H), 7.61 (d, J=8.9 Hz, 1H), 7.52 (d, J=7.1 Hz, 1H), 7.45 (dd, J=8.9, 1.8 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.52 (dd, J=7.1, 1.9 Hz, 1H), 4.78 (t, J=5.3 Hz, 1H), 4.52 (d, J=5.3 Hz, 2H), 3.39 (s, 6H); ESI MS m/z 444 [M+H]+.

Workup

  1. customwas evacuated for 30 minutes under high vacuum
  2. temperatureto cool
  3. additionThe mixture was diluted with 10% NH4OH in H2O (40 mL)
  4. extractionextracted with EtOAc (4×50 mL)
  5. washThe organics were washed with brine (50 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customPurification by flash chromatography (silica gel, CH2Cl2/MeOH, 95:5)
  10. customfollowed by a second purification by flash chromatography (silica gel, CH2Cl2/MeOH, 97.5:2.5)

Sources & evidence

ORD record
ord-507e6741b6d043f6ba791bb83b953dca
Source dataset
uspto-grants-2012_09
Patent number
US08273770B2

Reaction notes

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