tert-Butyl acrylate → (E)-3-(4-Ethoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid tert-butyl ester

HRID 1362058Notes

Reaction equation

HRID 1362058 reaction equation
[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[C:14](Br)[CH:15]=[N:16][C:10]=2[NH:9][C:8](=[O:18])[CH2:7]1)[CH3:2].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:25]([O:24][C:20](=[O:23])/[CH:21]=[CH:22]/[C:14]1[CH:15]=[N:16][C:10]2[NH:9][C:8](=[O:18])[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:12][C:11]=2[CH:13]=1)([CH3:28])([CH3:27])[CH3:26]

Participants

8

Reactant 4

HCID 15458tert-Butyl acrylateHCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 59456907(7-Bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid ethyl ester

Product 1

HCID 59456982(E)-3-(4-Ethoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid tert-butyl esterYield 39%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 7854PropionitrileSolvent

Procedure

A suspension of (7-Bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid ethyl ester (6.18 g, 17.4 mmol) in propionitrile (70 mL) and DMF (17 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with tert-butyl acrylate (10.2 mL, 69.6 mmol) and (i-Pr)2EtN (6.4 mL, 37 mmol) and was then de-oxygenated with Ar for 10 min. Pd(OAc)2 (0.39 g, 1.7 mmol) and P(o-tol)3 (1.06 mg, 3.48 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. After heating to reflux for 14 h, the mixture was allowed to cool and then concentrated in vacuo. The resulting residue was diluted with CH2Cl2 and filtered through Celite. The orange filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL) and washed with H2O (100 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) and again by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (2.55 g, 39%) as an off-white solid: MS (ESI) m/e 376 (M+H)+.

Workup

  1. waitde-oxygenated with Ar for 10 min
  2. customfor 5 min
  3. temperatureAfter heating
  4. temperatureto reflux for 14 h
  5. temperatureto cool
  6. concentrationconcentrated in vacuo
  7. additionThe resulting residue was diluted with CH2Cl2
  8. filtrationfiltered through Celite
  9. concentrationThe orange filtrate was concentrated in vacuo
  10. additionThe resulting residue was diluted with EtOAc (200 mL)
  11. washwashed with H2O (100 mL)
  12. extractionThe aqueous layer was extracted with EtOAc (2×100 mL)
  13. washThe combined organic layers were washed with H2O (2×100 mL) and brine (100 mL)
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. customthe solvent was removed in vacuo
  17. customPurification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3)

Sources & evidence

ORD record
ord-a2d99f2f89724db9952e25a6335d0a1e
Source dataset
uspto-grants-2011_02
Patent number
US07879872B2

Reaction notes

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