Cesium carbonate → Tetra-hydro-quinoline derivative 4

HRID 1051595Notes

Reaction equation

HRID 1051595 reaction equation
Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][OH:35])[CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[OH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:2]2[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]3)[CH:29]=[N:30]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 457888552-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olHCID 118086263(S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone

Product 1

HCID 118076127Tetra-hydro-quinoline derivative 4Yield 86%

Reagents, catalysts & solvents 3

HCID 72376365[2-(2-Aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphaneCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.050 g, 0.153 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.055 g, 0.230 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (0.012 g, 0.015 mmol), and cesium carbonate (0.150 g, 0.460 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 2.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane followed by 10% methanol-ethyl acetate) to afford (S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.047 g, 86%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.48 Hz, 3H), 1.03 (d, J=6.45 Hz, 3H), 1.23 (m, 1H), 1.64-1.80 (m, 2H), 2.07 (s, 3H), 2.18-2.38 (m, 2H), 2.75-2.90 (m, 1H), 3.50-3.65 (m, 2H), 3.68-3.80 (m, 2H), 4.17 (t, J=5.57 Hz, 2H), 4.62 (m, 1H), 4.84-4.94 (m, 1H), 7.12 (br d, J=8.21 Hz, 1H), 7.38 (d, J=8.50 Hz, 1H), 7.85 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 358 [M+H]+. The following examples were made according to the procedure outlined for Example 24:

Workup

  1. filtrationThe reaction mixture was filtered through Celite
  2. concentrationconcentrated
  3. customto afford an orange oil
  4. customThis material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane followed by 10% methanol-ethyl acetate)

Sources & evidence

ORD record
ord-4f81d3bc65474c30879f0a534251f3f6
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

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