Dichloromethane → N-{4-[4-(4-chlorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1-benzothien-2-yl]pyridin-2-yl}acetamide

HRID 1615489Notes

Reaction equation

HRID 1615489 reaction equation
Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[C:5]=2[CH:6]=1.O1CCOCC1.C[Sn](C)(C)[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=1.ClCCl>CCOC(C)=O.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]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2([OH:11])[C:5]3[CH:6]=[C:2]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=4)[S:3][C:4]=3[CH2:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 312751,4-DioxaneHCID 59529632N-(4-(trimethylstannyl)pyridin-2-yl)acetamideHCID 681832292-Bromo-4-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-ol

Product 1

HCID 68182981N-{4-[4-(4-chlorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1-benzothien-2-yl]pyridin-2-yl}acetamideYield 10%

Reagents, catalysts & solvents 2

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

Procedure

In a 100 mL round bottomed flask were placed 2-bromo-4-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (640 mg, 1.9 mmol) and 1,4-dioxane (10 mL). To the mixture were added N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (925 mg, 3.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (198 mg, 0.242 mmol). The mixture was refluxed for 16 hr with vigorous stirring. The mixture was allowed to cool to rt and then diluted with EtOAc (100 mL). The resulting solution was washed with H2O (50 mL×2). The combined aqueous phases were extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (50 mL) and dried over MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography, eluting with a 30% to 100% EtOAc/hexane to obtain crude title compound (ca 500 mg). About 100 mg of this material was purified by HPLC (AA) to obtain pure title compound (74 mg; 10%). LCMS: (AA) ES+ 399, 401; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.51 (br s, 1H), 8.23 (s, 1H), 8.20 (d, 1H), 7.36 (d, 2H), 7.30 (d, 2H), 7.19 (dd, 1H), 7.14 (s, 1H), 5.85 (s, 1H), 2.83-2.90 (m, 2H), 2.07 (s, 3H), 1.85-2.01 (m, 3H), 1.65-1.70 (m, 1H).

Workup

  1. customIn a 100 mL round bottomed flask were placed
  2. temperatureThe mixture was refluxed for 16 hr with vigorous stirring
  3. washThe resulting solution was washed with H2O (50 mL×2)
  4. extractionThe combined aqueous phases were extracted with EtOAc (50 mL×2)
  5. washThe combined organic phases were washed with brine (50 mL)
  6. dry with materialdried over MgSO4
  7. customInsoluble materials were removed by filtration
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe residue was purified by pre-packed silica gel (40 g) column chromatography
  10. washeluting with a 30% to 100% EtOAc/hexane
  11. customto obtain crude title compound (ca 500 mg)
  12. customAbout 100 mg of this material was purified by HPLC (AA)

Sources & evidence

ORD record
ord-e840a850f62145f292f28eb848e7eb86
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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