Cesium carbonate → 5-(5,5-Dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile

HRID 1776359Notes

Reaction equation

HRID 1776359 reaction equation
Br[C:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[C:15]#[N:16].CC1(C)C(C)(C)OB([C:28]2[CH:45]=[CH:44][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:5]1([CH3:9])[O:4][C:3]([C:10]2[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:44][CH:45]=2)[C:6]1=[O:7]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 583680032-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinolineHCID 593548145-(3-Bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile

Product 1

HCID 445944675-(5,5-Dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A solution of 5-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.15 g, 0.465 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.17 g, 0.465 mmol), and Cs2CO3 (0.75 g, 2.32 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.76 g, 0.090 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 2 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (125 mg, 58%( as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43 (d, J=8.5 Hz, 1 H), 8.02 (t, J=7.9 Hz, 2 H), 7.90 (s, 1 H), 7.81-7.77 (m, 2 H), 7.70 (d, J=8.2 Hz, 1 H), 7.62 (t, J=8.2 Hz, 1 H), 7.32 (d, J=8.1 Hz, 1 H), 7.19 (d, J=7.4 Hz, 2 H), 7.12 (d, J=7.5 Hz, 2 H), 5.40 (s, 2 H), 3.95 (s, 3H), 1.46 (s, 6 H). MS: [M+Na]: m/z=499.3, [M+H]: m/z=477.2. HPLC: 98%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).

Workup

  1. customthe solution was again degassed
  2. temperatureThe reaction was then refluxed for 2 h
  3. filtrationfiltered through a pad of Celite®
  4. additionthe filtrate was diluted with EtOAc (40 mL)
  5. washThe combined organic layers were washed with water (20 mL) and brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto obtain the crude product
  10. customThe crude material was purified via silica gel column chromatography

Sources & evidence

ORD record
ord-ff1baad654ab4f9098c8f806d23b53b0
Source dataset
uspto-grants-2016_02
Patent number
US09265767B2

Reaction notes

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