Ethyl Acrylate → 3-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-acrylic acid ethyl ester

HRID 1877429Notes

Reaction equation

HRID 1877429 reaction equation
Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:45][C:41](=[O:44])[CH:42]=[CH:43][C:2]1[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:28][C:29]=1[Cl:30])[CH3:47]

Participants

7

Reactant 4

HCID 8821Ethyl AcrylateHCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 59294468[2-(4-Bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

Product 1

HCID 673681563-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenyl}-acrylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 7854PropionitrileSolvent

Conditions

Temperature
95 °C

Procedure

To a degassed solution of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (500 mg, 0.96 mmol, 1.0 equiv; Example 163) in propionitrile (10 mL) under Ar was added N-ethyldiisopropylamine (373 mg, 491 μL, 2.89 mmol, 3.0 equiv; [CAS RN 7087-68-5]), ethyl acrylate (0.58 g, 0.63 mL, 5.78 mmol, 6.0 equiv; [CAS RN 140-88-5]), palladium(II) acetate (22 mg, 0.10 mmol, 0.1 equiv; [CAS RN 3375-31-3]) and tri-o-tolyl-phosphane (59 mg, 0.19 mmol, 0.2 equiv; [CAS RN 6163-58-2]). The reaction mixture was heated to 95° C. over night. The crude reaction was filtered over Celite®, a sat. solution of NaCl (50 mL) added and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 320 mg (62%) of the title compound as a yellow foam. MS (ISN): 538.3 [M+H]+.

Workup

  1. customThe crude reaction
  2. filtrationwas filtered over Celite®
  3. additiona sat. solution of NaCl (50 mL) added
  4. extractionextracted with ethyl acetate (3×50 mL)
  5. dry with materialThe combined organic phases were dried over Na2SO4
  6. customthe product purified by silica column chromatography
  7. washeluting with a gradient of heptane/ethyl acetate affording 320 mg (62%) of the title compound as a yellow foam

Sources & evidence

ORD record
ord-1167f646b3034143913e5568e4041b2f
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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