Tri-o-tolylphosphine → (E)-tert-butyl 6-(3-oxo-3-(pyrrolidin-1-yl) prop-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

HRID 2174576Notes

Reaction equation

HRID 2174576 reaction equation
CCN(C(C)C)C(C)C.Br[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14]2.[N:28]1([C:33](=[O:36])[CH:34]=[CH2:35])[CH2:32][CH2:31][CH2:30][CH2:29]1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C>[O:36]=[C:33]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)/[CH:34]=[CH:35]/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14]2

Participants

6

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 1820551-(Pyrrolidin-1-yl)prop-2-en-1-oneHCID 49761184tert-Butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate

Product 1

HCID 89602353(E)-tert-butyl 6-(3-oxo-3-(pyrrolidin-1-yl) prop-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateYield 54%

Reagents, catalysts & solvents 1

HCID 86641869DMF propionitrileSolvent

Conditions

Temperature
110 °C

Procedure

DIPEA (1.44 ml, 8.36 mmol) was added to a solution of 125a (650 mg, 2.09 mmol), 125b (287 mg, 2.29 mmol), Pd-(OAc)2 (46 mg, 0.21 mmol) and P(o-tol)3 (127 mg, 0.42 mmol) in propionitrile/DMF (8 ml/2 ml) and the reaction mixture was purged with nitrogen for 10 minutes, then was heated at 110° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was cooled to 20-35° C. and filtered on celite. The filtrate was concentrated and resultant residue diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (30 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/pet ether as an eluent to get the desired compound as an off-white solid (400 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=6.8 Hz, 2H), 7.41 (d, J=15.7 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.94 (d, J=15.7 Hz, 1H), 4.56-4.46 (m, 2H), 3.63 (t, J=6.6 Hz, is 2H), 3.55 (t, J=5.9 Hz, 2H), 3.41-3.34 (m, 2H), 2.79 (t, J=5.9 Hz, 2H), 1.96-1.88 (m, 2H); 1.87-1.76 (m, 2H), 1.43 (s, 9H).

Workup

  1. customthe reaction mixture was purged with nitrogen for 10 minutes
  2. temperaturethe mixture was cooled to 20-35° C.
  3. filtrationfiltered on celite
  4. concentrationThe filtrate was concentrated
  5. additionresultant residue diluted with water (30 ml)
  6. extractionextracted with ethyl acetate (2×30 ml)
  7. washThe combined organic layers were washed with brine (30 ml)
  8. dry with materialby drying over anhydrous Na2SO4
  9. filtrationfiltering
  10. customThe filtrate was rotary evaporated
  11. customto get residue which
  12. customwas purified by column chromatography
  13. additiona mixture of 50% ethyl acetate/pet ether as an eluent

Sources & evidence

ORD record
ord-869ff5d9f521402e960701d25c3abf24
Source dataset
uspto-grants-2015_06
Patent number
US09062002B2

Reaction notes

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