Morpholine → 4-(4-chlorophenyl)-2-morpholino-4H-cyclopenta[b]thiophen-6(5H)-one

HRID 1615501Notes

Reaction equation

HRID 1615501 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.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:6][C:5]=3[C:7](=[O:17])[CH2:8]2)=[CH:11][CH:12]=1

Participants

7

Reactant 5

HCID 8083MorpholineHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 681829442-bromo-4-(4-chlorophenyl)-4H-cyclopenta[b]thiophen-6(5H)-one

Product 1

HCID 569711194-(4-chlorophenyl)-2-morpholino-4H-cyclopenta[b]thiophen-6(5H)-oneYield 57.6%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
140 °C

Procedure

To a 10-20 mL microwave vial was added a solution of 2-bromo-4-(4-chlorophenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.150 g, 0.458 mmol) and morpholine (0.120 mL, 1.374 mmol) in anhydrous 1,4-dioxane (8.00 mL, 102.5 mmol) and degassed under nitrogen for 10 min. Cesium carbonate (0.694 g, 2.130 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.080 g, 0.137 mmol) was added followed by tris(dibenzylideneacetone)dipalladium(0) (0.042 g, 0.046 mmol). The reaction mixture was sealed and heated via microwave to 140° C. and allowed to stir for 1 hour. The reaction was cooled to ambient temperature and quenched by the addition of a solution of saturated aqueous solution of sodium bicarbonate (10.0 mL) and extracted with EtOAc (10.0 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 (0.088 g, 49%) as a brown oil. LC/MS (AA) ES+ 334, 336. 1H NMR (dmso-d6, 400 MHz): δ 7.38 (d, 2H), 7.19 (d, 2H), 6.04 (s, 1H), 4.48 (dd, 1H), 3.69-3.68 (m, 4H), 3.27-3.19 (m, 6H).

Workup

  1. customdegassed under nitrogen for 10 min
  2. customThe reaction mixture was sealed
  3. temperatureThe reaction was cooled to ambient temperature
  4. customquenched by the addition of a solution of saturated aqueous solution of sodium bicarbonate (10.0 mL)
  5. extractionextracted with EtOAc (10.0 mL×3)
  6. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. dry with materialThe crude material was dry
  10. custompurified
  11. customan ISCO (12 g cartridge, gradient hexanes to 100% EtOAc over 30 min)

Sources & evidence

ORD record
ord-9ce072a1fc6b4ee8a0e72dd29d5b5d77
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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