Tri-o-tolylphosphine → (E)-N-(3-Isopropyl-2-propoxybenzyl)-N-methyl-3-(2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide

HRID 1362293Notes

Reaction equation

HRID 1362293 reaction equation
[CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=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]>[CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])/[CH:10]=[CH:11]/[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1)([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 59277555N-(3-Isopropyl-2-propoxybenzyl)-N-methylacrylamideHCID 594569547-Bromo-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one

Product 1

HCID 16659658(E)-N-(3-Isopropyl-2-propoxybenzyl)-N-methyl-3-(2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamideYield 33%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 7854PropionitrileSolvent

Procedure

A solution of N-(3-isopropyl-2-propoxybenzyl)-N-methylacrylamide (0.385 g, 1.40 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.39 mL, 2.25 mmol) and 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.07 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.10 mmol) and P(o-tol)3 (0.065 g, 0.21 mmol) were then added and the solution deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with H2O (30 mL) and the mixture was washed with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.15 g, 33%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.08-10.05 (m, 1H), 8.45-8.39 (m, 1H), 8.03-7.93 (m, 1H), 7.55-7.49 (m, 1H), 7.32-7.20 (m, 2H), 7.13-7.04 (m, 1H), 6.88-6.86 (m, 1H), 4.81-4.66 (m, 2H), 3.91-3.86 (m, 2H), 3.76-3.69 (m, 2H), 3.63-3.60 (m, 2H), 3.30-3.25 (m, 1H), 3.12-2.90 (m, 4H), 1.83-1.75 (m, 2H), 1.24-1.17 (m, 6H), 1.06-1.01 (m, 3H).

Workup

  1. customThe solution was deoxygenated with Ar for 20 min
  2. customthe solution deoxygenated with Ar for 20 min
  3. temperatureThe solution was heated
  4. temperatureto reflux for 18 h
  5. temperatureto cool
  6. additionThe solution was diluted with H2O (30 mL)
  7. washthe mixture was washed with EtOAc (3×50 mL)
  8. washThe combined organics were washed with brine (2×100 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated
  11. customPurification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 95:5)

Sources & evidence

ORD record
ord-397d718ff40d46da8549e97d9b0d4e07
Source dataset
uspto-grants-2011_02
Patent number
US07879872B2

Reaction notes

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