Ethyl Acetate → 4-(5-(4-(2,5-Bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2-yl)morpholine

HRID 1470981Notes

Reaction equation

HRID 1470981 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[N:43][CH:44]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>C1COCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][CH2:10][CH:9]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([C:39]3[CH:40]=[CH:41][C:42]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[N:43][CH:44]=3)=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 62657Potassium Phosphate, TribasicHCID 27953634-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl)morpholineHCID 866491071-(4-Bromophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine

Product 1

HCID 867623254-(5-(4-(2,5-Bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2-yl)morpholineYield 93.3%

Reagents, catalysts & solvents 3

HCID 178454861HCID 178454861, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

In a microwave tube (size L, 20 mL) purged with nitrogen and sealed with a rubber septum, dissolved the product of Example 86A (160 mg, 0.342 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (153 mg, 0.512 mmol) in THF (6 mL), added a solution of potassium phosphate (176 mg, 0.803 mmol) in water (2 mL), and sparged the reaction solution with S nitrogen for 5 min. Added 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (12.02 mg, 0.018 mmol) and stirred at 25° C. for 15 min. During this process, the reaction darkened quickly to a brown color. Diluted the reaction with EtOAc (50 mL), washed with brine (10 mL), dried the organic phase over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. Dissolved the residue in CH2Cl2 and purified by flash chromatography (silica gel, Alltech Extract-Clean 10 g column, 20% EtOAc/CH2Cl2) to afford the title compound as a solid (176 mg, 93%) as a mixture of stereoisomers. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.82-1.94 (m, 2H), 2.53-2.62 (m, 2H), 3.37-3.47 (m, 4H), 3.64-3.74 (m, 4H), 5.03 (t, J=5.37 Hz, 2H), 6.40 (d, J=8.89 Hz, 2H), 6.82 (d, J=9.00 Hz, 1H), 7.34 (d, J=8.78 Hz, 2H), 7.69 (dd, J=8.84, 2.55 Hz, 1H), 7.83 (d, J=8.78 Hz, 4H), 8.28 (d, J=8.78 Hz, 4H), 8.29-8.31 (m, 1H); MS (ESI+) m/z 552 (M+H)+.

Workup

  1. customIn a microwave tube (size L, 20 mL) purged with nitrogen
  2. customsealed with a rubber septum
  3. customsparged the reaction solution with S nitrogen for 5 min
  4. additionDiluted
  5. washwashed with brine (10 mL)
  6. dry with materialdried the organic phase over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated by rotary evaporation
  9. dissolutionDissolved the residue in CH2Cl2
  10. custompurified by flash chromatography (silica gel, Alltech Extract-Clean 10 g column, 20% EtOAc/CH2Cl2)

Sources & evidence

ORD record
ord-d7b37ea1ef1342978e0f9fa943130adf
Source dataset
uspto-grants-2015_04
Patent number
US09006387B2

Reaction notes

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