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

HRID 1362336Notes

Reaction equation

HRID 1362336 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][CH2:33][C:32]([CH3:39])([CH3:38])[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].C(Cl)Cl.CO>[CH3:38][C:32]1([CH3:39])[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][CH2:33]1

Participants

9

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 57742103N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamideHCID 592775797-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

Product 1

HCID 16659991(E)-3-(2,2-Dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamideYield 59%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 7854PropionitrileSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.190 g, 0.637 mmol) in propionitrile (3 mL) and DMF (0.6 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.23 mL, 1.33 mmol) and 7-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (0.154 g, 0.828 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.014 g, 0.063 mmol) and P(o-tol)3 (0.038 g, 0.12 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 2 h, then allowed to cool. The mixture was diluted with H2O (200 mL) and the solution was washed with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried (Na2SO4) and concentrated to give a dark green oil. Column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.14 g, 59%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.56-7.54 (m, 1H), 7.51-7.47 (m, 2H), 7.41-7.38 (m, 1H), 7.32 (br s, 1H), 7.29-6.93 (m, 3H), 4.95-4.76 (m, 2H), 3.19 (m, 2H), 3.14-2.90 (m, 3H), 2.25 (s, 3H), 1.26 (s, 6H); MS (ESI) m/e 392 (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 2 h
  5. temperatureto cool
  6. additionThe mixture was diluted with H2O (200 mL)
  7. washthe solution was washed with EtOAc (3×50 mL)
  8. washThe combined organic layers were washed with brine (2×30 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated
  11. customto give a dark green oil

Sources & evidence

ORD record
ord-6de1e4bb9b284163a184cc74f68b857b
Source dataset
uspto-grants-2011_02
Patent number
US07879872B2

Reaction notes

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