Triethylamine → 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-phenylquinolin-2-amine

HRID 1055937Notes

Reaction equation

HRID 1055937 reaction equation
CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:23][C:24]1[C:25]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[C:34](=O)[CH3:35]>C(Cl)Cl>[Si:8]([O:15][C:34]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[N:26]=[C:25]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:24]([CH3:23])=[CH:33]2)=[CH2:35])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 123564tert-Butyldimethylsilyl trifluoromethanesulphonateHCID 897818941-(3-Methyl-2-(phenylamino)quinolin-8-yl)ethanone

Product 1

HCID 897820018-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-phenylquinolin-2-amine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Et3N (0.241 mL, 1.728 mmol) and TBSOTf (0.318 mL, 1.383 mmol, added dropwise, over 2 min) were sequentially added to a solution of 1-(3-methyl-2-(phenylamino)quinolin-8-yl)ethanone (Example 105c; 308.1 mg, 0.691 mmol) in DCM (3.5 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. The mixture was then partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-phenylquinolin-2-amine (450.0 mg) as a yellow-orange solid. This material was taken up in THF (3.50 mL), water (0.199 mL, 11.06 mmol) and NBS (123 mg, 0.691 mmol) were sequentially added at 0° C., and the resulting solution was stirred at 0° C. for 2 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), and then dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 2-bromo-1-(3-methyl-2-(phenylamino)quinolin-8-yl)ethanone (404.1 mg) as a yellow-orange solid. NH4OAc (213 mg, 2.77 mmol) and 4-ethoxy-5-ethyl-5,6-dihydropyridin-2(1H)-one (prepared according to Synthesis 2007, 3185-3190; 140 mg, 0.830 mmol) were added to the resulting solid. The mixture was taken up in EtOH (3.5 mL) and heated in a sealed flask under argon at 50° C. for 16 h. The mixture was then cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and sat. aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished rac-7-ethyl-2-(3-methyl-2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (80.6 mg, 0.203 mmol, 29% yield) as a yellow solid: 1H NMR (400 MHz, CD Cl3) δ ppm 12.34 (1H, br. s.), 7.96 (1H, dd, J=7.5, 1.1 Hz), 7.83 (1H, s), 7.52 (2H, d, J=7.6 Hz), 7.45 (1H, dd, J=7.8, 1.0 Hz), 7.41 (2H, t, J=7.8 Hz), 7.30 (1H, t, J=7.7 Hz), 7.21 (1H, t, J=7.5 Hz), 7.10 (1H, d, J=2.2 Hz), 6.44 (1H, br. s.), 5.22 (1H, br. s.), 3.63 (1H, ddd, J=12.0, 5.5, 2.1 Hz), 3.23 (1H, ddd, J=12.0, 6.2, 3.1 Hz), 2.46-2.54 (1H, m), 2.45 (3H, s), 1.14-1.23 (1H, m), 1.02-1.12 (1H, m), 0.65 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 397.2 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralcel AD-H (250×21 mm, 5 μm), 55% liquid CO2/45% MeOH (+20 mM NH3), 60 mL/min) separately afforded 7-ethyl-2-(3-methyl-2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, first-eluting enantiomer (117; 27.0 mg, 0.068 mmol) and 7-ethyl-2-(3-methyl-2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, second eluting enantiomer (118; 27.8 mg, 0.070 mmol).

Workup

  1. customThe mixture was then partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL)
  2. customThe organic layer was separated
  3. extractionthe aq. layer was extracted with DCM (2×20 mL)
  4. dry with materialThe combined organic extracts were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-62d2a5d18d8140e5abbcdce4bbfeef48
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

Loading…