tert-Butyl acrylate → (E)-Benzyl 4-(4-(3-tert-butoxy-3-oxoprop-1-enyl)-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate

HRID 528924Notes

Reaction equation

HRID 528924 reaction equation
Br[C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7].[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[CH:48]=[CH2:49]>CN(C=O)C.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:52]([O:51][C:47](=[O:50])/[CH:48]=[CH:49]/[C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:42][CH2:43][CH2:44][CH3:45])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7])([CH3:55])([CH3:54])[CH3:53]

Participants

6

Reactant 2

HCID 15458tert-Butyl acrylateHCID 71062156Benzyl 4-(4-bromo-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate2×

Product 1

HCID 71062592(E)-Benzyl 4-(4-(3-tert-butoxy-3-oxoprop-1-enyl)-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoateYield 50%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
140 °C

Procedure

To a solution of benzyl 4-(4-bromo-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 164A, 80 mg, 0.12 mmol) in DMF (580 μL) and Et3N (580 μL) was added (PPh3)2PdCl2 (8 mg, 0.012 mmol) followed by tert-butyl acrylate (58 μL, 0.40 mmol). The reaction mixture was purged with N2 for 5 min and then heated at 140° C. overnight. The reaction mixture was poured into a separatory funnel containing 1N aq. HCl solution and EtOAc. The organic layer was washed 1N aq. HCl solution (2×) and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 0% to 35% EtOAc/hexanes) to provide the title compound (42 mg, 50%) as a colorless oil. MS(ESI+) m/z 733.5 (M+H)+.

Workup

  1. customThe reaction mixture was purged with N2 for 5 min
  2. additionThe reaction mixture was poured into a separatory funnel
  3. additioncontaining 1N aq. HCl solution and EtOAc
  4. washThe organic layer was washed 1N aq. HCl solution (2×)
  5. extractionthe aqueous layer was extracted with EtOAc (3×)
  6. washThe combined organic extracts were washed with sat. aq. NaHCO3 solution
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by flash chromatography (gradient from 0% to 35% EtOAc/hexanes)

Sources & evidence

ORD record
ord-8a7293510f9c4e6c91071d013ed97a7b
Source dataset
uspto-grants-2016_05
Patent number
US09346795B2

Reaction notes

Loading…