8-Hydroxyquinoline → tert-Butyl 9-methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-b]pyridine-6-carboxylate

HRID 882042Notes

Reaction equation

HRID 882042 reaction equation
Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:38])([F:39])[F:23])=[CH:30][CH:29]=4)=[CH:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 497584672-Hydroxy-4-(4-trifluoromethylphenyl)pyridineHCID 71551310tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-b]pyridine-6-carboxylate

Product 1

HCID 86667081tert-Butyl 9-methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-b]pyridine-6-carboxylateYield 65.1%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
130 °C

Procedure

tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.15 g, 0.41 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (98 mg, 0.41 mmol), and Cs2CO3 (0.15 g, 0.45 mmol) were suspended in DMSO (2.4 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.12 mmol) and copper iodide (94 mg, 0.49 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting solution was stirred at ambient temperature for 30 min, extracted with CH2Cl2 (3×20 mL), and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (4×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 48 mL, increased to 50:50 over 240 mL and held for 48 mL; increased to 0:100 over 120 mL) gave the title compound (0.14 g, 63%) as a yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 8.09-8.80 (m, 4H), 7.88 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 6.77 (dd, J=7.5, 2.1 Hz, 1H), 4.59 (s, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.70 (s, 3H), 2.90 (t, J=4.8 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 525 [M+H]+.

Workup

  1. customthe air was removed under vacuum for 15 min
  2. additionwere added to the suspension
  3. customThe evacuation/Ar flushing process
  4. temperatureThe mixture was cooled
  5. additiondiluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL)
  6. extractionextracted with CH2Cl2 (3×20 mL)
  7. washwashed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (4×20 mL)
  8. dry with materialThe resulting organic solution was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated to dryness under reduced pressure
  11. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 48 mL, increased to 50:50 over 240 mL and held for 48 mL; increased to 0:100 over 120 mL)

Sources & evidence

ORD record
ord-31e64ef566654fed8c829f2460c80ad5
Source dataset
uspto-grants-2015_03
Patent number
US08993765B2

Reaction notes

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