Tetrahydrofuran → 3-tert-butoxycarbonyl-7-chloro-6-(5-cyclohexyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041368Notes

Reaction equation

HRID 2041368 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[Br-].[CH:30]1([Zn+])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1COCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:20]2[C:10]([S:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:7][N:6]=3)=[C:11]([Cl:28])[CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 576562493-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 178418970HCID 178418970, compound

Product 1

HCID 667067593-tert-butoxycarbonyl-7-chloro-6-(5-cyclohexyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 32%

Reagents, catalysts & solvents 1

HCID 53485975CID 53485975Catalyst

Conditions

Temperature
60 °C

Procedure

To a mixture of 6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (146 mg, 0.30 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (12 mg, 0.015 mmol) under dry nitrogen add with stirring a solution of 0.5 M cyclohexylzinc bromide in THF (3.0 mL, 1.5 mmol). Degas, purge with dry nitrogen, and stir overnight at 60° C. Cool to ambient temperature, dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(5-cyclohexyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (46 mg, 32%). MS (APCI+) m/z: 487 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (APCI+) m/z: 387 (M+H)+.

Workup

  1. additionadd
  2. customDegas
  3. custompurge with dry nitrogen
  4. temperatureCool to ambient temperature
  5. additiondilute with EtOAc
  6. washwash with water
  7. dry with materialdry over anhydrous MgSO4
  8. concentrationconcentrate in vacuo
  9. customPurify by chromatography on silica gel eluting with hexane/EtOAc (5:1)

Sources & evidence

ORD record
ord-07f466ddba5044f8b8f54d6367cd7690
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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