Morpholine → methyl 4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate

HRID 1615562Notes

Reaction equation

HRID 1615562 reaction equation
Br[C:2]1[S:6][C:5]2[C:7](=[O:22])[CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=3)[C:4]=2[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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:17][C:12]1[CH:11]=[C:10]([CH:9]2[C:4]3[CH:3]=[C:2]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[S:6][C:5]=3[C:7](=[O:22])[CH:8]2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:16]

Participants

7

Reactant 4

HCID 8083MorpholineHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 68183335methyl 2-bromo-4-(3,4-dichlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate

Product 1

HCID 68183248methyl 4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylateYield 0.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of methyl 2-bromo-4-(3,4-dichlorophenyl)-6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (0.25 g, 0.59 mmol), morpholine (0.26 g, 2.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (26.9 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.0 mg, 0.06 mmol) and cesium carbonate (0.58 g, 1.76 mmol) in 1,4-dioxane (5.96 mL) was heated at 80° C. under argon for 3 h. And the temperature was raised to 100° C. and maintained overnight. The mixture was dryloaded on silica gel and purified by column chromatography (12 g cartridge, gradient hexanes to 60% EtOAc in hexanes) and then preparative HPLC to afford the product as a white solid (0.8 mg, 0.3%). LCMS: (FA) ES+ 426, 428, 430. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 6.99 (dd, J=8.0, 2.1 Hz, 1H), 5.77 (s, 1H), 4.73 (d, J=3.2 Hz, 1H), 3.86-3.76 (m, 7H), 3.67 (d, J=3.2 Hz, 1H), 3.35-3.26 (m, 4H).

Workup

  1. temperatureAnd the temperature was raised to 100° C.
  2. temperaturemaintained overnight
  3. custompurified by column chromatography (12 g cartridge, gradient hexanes to 60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-3b3a948b27fd4ab49cd00886a76dc843
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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