Dichloromethane → 4-[(4-Benzo[b]thien-7-yl-6-fluoro-3-pyridinyl)methyl]morpholine

HRID 561023Notes

Reaction equation

HRID 561023 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4](I)[CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:17]1=2.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CC#N.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:4]3[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=3[CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:17]1=2

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 666739762-(Benzo[b]thiophen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 66738088HCID 66738088, compound

Product 1

HCID 669978574-[(4-Benzo[b]thien-7-yl-6-fluoro-3-pyridinyl)methyl]morpholineYield 87.3%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

Combine 4-(6-fluoro-4-iodo-pyridin-3-ylmethyl)-morpholine (0.48 g, 1.5 mmol), 2-benzo[b]thiophen-7-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.47 g, 1.8 mmol) and sodium carbonate (0.39 g, 3.75 mmol) in CH3CN (8 mL) and water (4 mL). Purge the mixture with nitrogen for 5 min. Add [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (5.0 mg, 0.6 mmol) and purge with nitrogen for an additional 5 min. Heat the mixture at 120° C. for 10 min in microwave reactor and cool to room temperature. Dilute the reaction mixture with ethyl acetate, wash with water and saturated aqueous sodium chloride. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give a crude mixture. Purify by column chromatography (0.1% to 1% 2 M ammonia in methanol/dichloromethane) to afford the title compound (0.43 g, 87%). MS (ES) m/z 329 [M+1]+.

Workup

  1. customPurge the mixture with nitrogen for 5 min
  2. temperaturecool to room temperature
  3. washwash with water and saturated aqueous sodium chloride
  4. customSeparate the organic layer
  5. dry with materialdry over magnesium sulfate
  6. filtrationFilter
  7. concentrationconcentrate in vacuo
  8. customto give a crude mixture
  9. customPurify by column chromatography (0.1% to 1% 2 M ammonia in methanol/dichloromethane)

Sources & evidence

ORD record
ord-7f11e92f331944d5aaf19f429c7d1d82
Source dataset
uspto-grants-2011_11
Patent number
US08063212B2

Reaction notes

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