Tricyclohexylphosphine → tert-butyl(R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate

HRID 472893Notes

Reaction equation

HRID 472893 reaction equation
[CH:1]([C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[CH2:2].Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:21]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:26]1[CH2:27][CH2:28][CH:23]([O:22][C:20]2[CH:21]=[C:16](/[CH:2]=[CH:1]/[C@H:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)[CH:17]=[N:18][CH:19]=2)[CH2:24][CH2:25]1

Participants

8

Reactant 4

HCID 75806TricyclohexylphosphineHCID 81531DiisopropylethylamineHCID 219640263-Bromo-5-[(oxan-4-yl)oxy]pyridineHCID 46222798(R)-tert-Butyl 3-vinylpyrrolidine-1-carboxylate

Product 1

HCID 58057079tert-butyl(R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylateYield 82.7%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of tert-butyl (R)-3-vinylpyrrolidine-1-carboxylate 9 (7.00 g, 35.5 mmol), 3-bromo-5-(tetrahydro-2H-pyran-4-yloxy)pyridine 12 (10.0 g, 38.8 mmol), palladium acetate (0.40 g, 1.8 mmol), tricyclohexylphosphine (1.0 g, 3.57 mmol) and diisopropylethylamine (15 mL) in 1-methyl-2-pyrrolidinone (130 mL) was stirred at 130° C. for 17 h. The reaction was cooled to ambient temperature, diluted with water (800 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography using 60-100% ethyl acetate in hexanes. This product was further purified on reverse phase HPLC using 0.05% trifluoroacetic acid in acetonitrile and 0.05% trifluoroacetic acid in water to obtain tert-butyl (R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (11.0 g) as a gum. 1H-NMR (CDCl3, 400 MHz): δ 8.41 (s, 1 H), 8.37 (d, J=2.3 Hz, 1 H), 7.68 (s, 1 H), 6.48 d, J=16.1 Hz, 1 H), 6.43 (dd, J=16.0, 6.4 Hz, 1 H), 4.71-4.66 (m, 1 H), 4.02-3.96 (m, 2 H), 3.68-3.52 (m, 4 H), 3.44-3.34 (m, 1 H), 3.28-3.15 (m, 1 H), 3.09-2.98 (m, 1 H), 2.18-2.04 (m, 3 H), 1.90-1.78 (m, 3 H), 1.48 (s, 9 H)

Workup

  1. temperatureThe reaction was cooled to ambient temperature
  2. extractionextracted with ethyl acetate (2×200 mL)
  3. dry with materialThe combined organic extracts were dried over sodium sulfate
  4. concentrationconcentrated
  5. custompurified by silica gel column chromatography
  6. customThis product was further purified on reverse phase

Sources & evidence

ORD record
ord-8d5681efade74775b54397765c19ef27
Source dataset
uspto-grants-2014_01
Patent number
US08633227B2

Reaction notes

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