Dimethylformamide → (E)-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-thiophen-3-yl-acrylamide

HRID 2250872Notes

Reaction equation

HRID 2250872 reaction equation
[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:44]=[C:43]3[C:39]([CH2:40][CH2:41][N:42]3[C:45](=[O:47])[CH3:46])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:45]([N:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([N:35]([CH:32]3[CH2:31][CH2:30][N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:34][CH2:33]3)[C:8](=[O:10])/[CH:7]=[CH:6]/[C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:44]=2)[CH2:40][CH2:41]1)(=[O:47])[CH3:46]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 735793(2E)-3-(3-Thienyl)-2-propenoic acidHCID 27611281-Acetyl-N-(1-benzylpiperidin-4-yl)-indolin-6-amine

Product 1

HCID 11294696(E)-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-thiophen-3-yl-acrylamideYield 85%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a mixture of trans-3-thiophen-3-yl-acrylic acid (66 mg, 0.43 mmol) and oxalyl chloride (45 μL, 0.52 mmol) in 2 mL of CH2Cl2 was added a catalytic amount of DMF. After stirring at rt for 2 h, the mixture was concentrated in vacuo. The resulting crude acid chloride was dissolved in CH2Cl2 and treated with TEA (80 μL, 0.58 mmol) and 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.100 g, 0.286 mmol). After stirring for 4 h, the mixture was washed with satd. aq. NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/hexanes) afforded 118 mg (64%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.02 (br s, 1H), 7.83 (d, J=15.7 Hz, 1H), 7.39-7.16 (m, 8H), 6.94-6.93 (m, 1H), 6.73-6.72 (m, 1H), 5.97 (d, J=15.7 Hz, 1H), 4.74-4.70 (m, 1H), 4.17-4.13 (m, 2H), 3.45 (br s, 2H), 3.28-3.23 (m, 2H), 2.88 (br s, 3H), 2.23 (s, 3H), 2.13 (m, 2H), 1.88-1.76 (m, 3H). MS: exact mass calculated for C29H18N3O2, 485.21; m/z found, 486.2 [M+H]+, 508.1 [M+Na]+.

Workup

  1. concentrationthe mixture was concentrated in vacuo
  2. dissolutionThe resulting crude acid chloride was dissolved in CH2Cl2
  3. stirringAfter stirring for 4 h
  4. washthe mixture was washed with satd
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification by silica gel chromatography (60% EtOAc/hexanes)

Sources & evidence

ORD record
ord-af04899ca4de46769e1646d05d05c6b5
Source dataset
uspto-grants-2008_01
Patent number
US07317025B2

Reaction notes

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