1,4-Dioxane → N-(4-(4-(4-chlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)pyridin-2-yl)acetamide

HRID 1615502Notes

Reaction equation

HRID 1615502 reaction equation
Br[C:2]1[S:6][C:5]2[C:7](=[O:17])[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=1.O1CCOCC1.[Cl-].[Li+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=4)[S:6][C:5]=3[C:7](=[O:17])[CH2:8]2)=[CH:11][CH:12]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 433294Lithium ChlorideHCID 59529632N-(4-(trimethylstannyl)pyridin-2-yl)acetamideHCID 681829442-bromo-4-(4-chlorophenyl)-4H-cyclopenta[b]thiophen-6(5H)-one

Product 1

HCID 56971355N-(4-(4-(4-chlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)pyridin-2-yl)acetamideYield 81.5%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
90 °C

Procedure

To a 20 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.046 g, 0.141 mmol) and N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.063 g, 0.211 mmol) in anhydrous 1,4-dioxane (2.00 mL, 25.63 mmol) was degassed for 10 minutes. Lithium chloride (0.018 g, 0.42 mmol) and copper(I) iodide (0.008 g, 0.043 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (2.00 mL) and extracted with EtOAc (2.00 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica gel and then purified using an ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.044 g, 78%) as a yellow oil. LC/MS (AA) ES+ 383, 385. 1H NMR (dmso-d6, 400 MHz): δ 10.68 (s, 1H), 8.40 (s, 1H), 8.36 (d, 1H), 7.66 (s, 1H), 7.50 (dd, 1H), 7.42-7.40 (m, 2H), 7.30-7.28 (m, 2H), 4.72 (dd, 1H), 3.48 (dd, 1H), 2.82 (dd, 1H), 2.11 (s, 3H).

Workup

  1. customwas degassed for 10 minutes
  2. temperatureThe reaction was cooled to ambient temperature
  3. customquenched by the addition of a saturated aqueous solution of sodium bicarbonate (2.00 mL)
  4. extractionextracted with EtOAc (2.00 mL×3)
  5. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. dry with materialThe crude material was dry
  9. custompurified
  10. customan ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min)

Sources & evidence

ORD record
ord-f76955b90113439eb396cc4c7223fcc0
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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