Diisopropylethylamine → 3-(7,7-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-3-yl)-N-methyl-N-[1-(R)-(3-methyl-benzofuran-2-yl)-ethyl]acrylamide

HRID 1879965Notes

Reaction equation

HRID 1879965 reaction equation
[CH3:1][N:2]([C@@H:7]([C:9]1[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])[CH3:8])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:20]1[CH:33]=[N:32][C:23]2[NH:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:22]=2[CH:21]=1.CCN(C(C)C)C(C)C>C(C#N)C.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:29][C:26]1([CH3:30])[C:25](=[O:31])[NH:24][C:23]2[N:32]=[CH:33][C:20]([CH:5]=[CH:4][C:3]([N:2]([CH3:1])[C@@H:7]([C:9]3[O:10][C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]=3[CH3:14])[CH3:8])=[O:6])=[CH:21][C:22]=2[O:28][CH2:27]1

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 59332837(R)-N-methyl-N-[1-(3-methyl-benzofuran-2-yl)-ethyl]acrylamideHCID 593328468-bromo-3,3-dimethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one

Product 1

HCID 684140103-(7,7-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-3-yl)-N-methyl-N-[1-(R)-(3-methyl-benzofuran-2-yl)-ethyl]acrylamideYield 26%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 7854PropionitrileSolvent

Procedure

A suspension of (R)—N-methyl-N-[1-(3-methyl-benzofuran-2-yl)-ethyl]acrylamide (328 mg, 1.35 mmol), 3-bromo-7,7-dimethyl-6,7-dihydro-9H-5-oxa-1,9-diaza-benzocyclohepten-8-one (400 mg, 1.48 mmol), (o-tol)3P (132 mg, 0.43 mmol) and DIEA (0.3 mL, 1.6 mmol) in EtCN (10 mL) and DMF (5 mL) was deoxygenated with argon for 30 min. Pd(OAc)2 (50 mg, 0.22 mmol) was added, the mixture was deoxygenated again with argon for 20 min and the mixture was heated to reflux overnight. The mixture was cooled to room temperature and partitioned between EtOAc and water. The residue was suspended in Et2O and then sonicated to give a solid. The solid was collected by filtration. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) and sonication in Et2O gave the title compound (150 mg, 26%) as a white solid: 1H NMR (300 MHz, DMSO-d6) 10.13 (s, 1H), 8.27 (s, 1H), 8.01-7.89 (m, 1H), 7.58-7.50 (m, 3H), 7.32-7.18 (m, 3H), 6.19-5.99 (m, 1H), 4.07 (s, 2H), 3.04-2.79 (m, 3H), 2.18 (s, 3H), 1.64-1.54 (m, 3H), 1.19 (s, 6H); MS (ESI) m/e 434 (M+H)+.

Workup

  1. customwas deoxygenated with argon for 30 min
  2. customthe mixture was deoxygenated again with argon for 20 min
  3. temperaturethe mixture was heated
  4. temperatureto reflux overnight
  5. custompartitioned between EtOAc and water
  6. customsonicated
  7. customto give a solid
  8. filtrationThe solid was collected by filtration
  9. customPurification
  10. customby column chromatography (silica gel, 1:1 hexanes/EtOAc) and sonication in Et2O

Sources & evidence

ORD record
ord-f1f4ac99d7444fcb9c70e545088b2e14
Source dataset
uspto-grants-2012_11
Patent number
US08318720B2

Reaction notes

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