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 340820Notes

Reaction equation

HRID 340820 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 (1.32 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 partitinned 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) δ10.13 (s, 1H), 8.27 (s, 1H), 8.0.1-7.89 (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), 248 (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. customsonicated
  6. customto give a solid
  7. filtrationThe solid was collected by filtration
  8. customPurification
  9. customby column chromatography (silica gel, 1:1 hexanes/EtOAc) and sonication in Et2O

Sources & evidence

ORD record
ord-1b089e6533b84a0bab3d817da869c343
Source dataset
uspto-grants-2014_11
Patent number
US08895545B2

Reaction notes

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