8-Hydroxyquinoline → tert-Butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

HRID 474989Notes

Reaction equation

HRID 474989 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]3[C:9]4[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=4[N:7]([CH3:22])[C:6]=3[N:23]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

7

Reactant 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 36077244-Benzyloxy-2(1H)-pyridoneHCID 86649551tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

Product 1

HCID 66869329tert-Butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylateYield 70.4%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
130 °C

Procedure

A suspension of tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.15 g, 0.40 mmol), 4-benzyloxypyridinone (80 mg, 0.40 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) in DMSO (2.3 mL) was placed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (91 mg, 0.48 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 (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (40 mL) and washed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (2×30 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 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (141 mg, 70%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.98-7.95 (m, 1H), 7.81-7.79 (m, 1H), 7.49-7.37 (m, 5H), 7.30-7.27 (m, 1H), 6.15 (dd, J=7.8, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.58 (br s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.4 Hz, 2H), 3.03-3.01 (m, 2H), 1.98-1.93 (m, 2H), 1.35-1.27 (m, 9H); ESI MS m/z 501 [M+H]+.

Workup

  1. additionwere added to the suspension
  2. customThe evacuation/Ar flushing process
  3. temperatureThe mixture was cooled
  4. additiondiluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL)
  5. filtrationThe resulting solids were collected by filtration
  6. dissolutiondissolved in CH2Cl2 (40 mL)
  7. washwashed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (2×30 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 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes)

Sources & evidence

ORD record
ord-dc447051524741b18430cccc6e6680b1
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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