Tri-o-tolylphosphine → (E)-3-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide

HRID 2097082Notes

Reaction equation

HRID 2097082 reaction equation
[CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:37]=[N:36][C:35]2[NH:34][C:33](=[O:38])[C:32]([CH3:40])([CH3:39])[O:31][C:30]=2[CH:29]=1.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]>[CH3:39][C:32]1([CH3:40])[O:31][C:30]2[CH:29]=[C:28](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[O:9][C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[C:12]=3[CH3:13])=[O:6])[CH:37]=[N:36][C:35]=2[NH:34][C:33]1=[O:38]

Participants

8

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 577420407-bromo-2,2-dimethyl-2H,3H,4H-pyrido(3,2-b)(1,4)oxazin-3-oneHCID 57742103N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide

Product 1

HCID 16659989(E)-3-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamideYield 46%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 7854PropionitrileSolvent

Procedure

A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.231 g, 1.01 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.28 mL, 1.64 mmol) and 7-bromo-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.200 g, 0.775 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.017 g, 0.078 mmol) and P(o-tol)3 (0.047 g, 0.15 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with H2O (100 mL). The resulting solids were collected by filtration and washed with Et2O (50 mL). Residual palladium was removed by silica gel plug (silica gel, 95:5, CH2Cl2/MeOH) the resulting solution concentrated to reveal a light orange solid. The solid was triturated with Et2O and dried to give the title compound (0.14 g, 46%) as a light pink solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.20-8.19 (m, 1H), 7.97-7.93 (m, 1H), 7.57-7.48 (m, 3H), 7.28-7.23 (m, 3H), 5.00-4.78 (m, 2H), 3.17-2.92 (m, 3H), 2.62 (s, 3H), 1.44 (m, 6H); MS (ESI) m/e 406 (M+H)+.

Workup

  1. customThe solution was deoxygenated with Ar for 20 min
  2. customthe solution was deoxygenated again with Ar for 10 min
  3. temperatureThe mixture was heated
  4. temperatureto reflux for 18 h
  5. temperatureto cool
  6. additionThe mixture was diluted with H2O (100 mL)
  7. filtrationThe resulting solids were collected by filtration
  8. washwashed with Et2O (50 mL)
  9. customResidual palladium was removed by silica gel plug (silica gel, 95:5, CH2Cl2/MeOH) the resulting solution
  10. concentrationconcentrated
  11. customThe solid was triturated with Et2O
  12. customdried

Sources & evidence

ORD record
ord-65817e46a7304361ac8272eb9ed02af9
Source dataset
uspto-grants-2013_05
Patent number
US08450307B2

Reaction notes

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