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Dichloromethane → 5-[3,5-Dichloro-4-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester

HRID 2235326
Notes
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Reaction equation

HRID 2235326 reaction equation
[CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C([Li])CCC.FC(F)(F)S(O[C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH2:29][CH:30]2[CH2:34][CH2:33][N:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:31]2=[O:41])=[C:24]([Cl:42])[CH:23]=1)(=O)=O.ClCCl>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:23]=[C:24]([Cl:42])[C:25]([CH2:29][CH:30]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[C:31]3=[O:41])=[C:26]([Cl:28])[CH:27]=2)=[CH:8][CH:9]=1)=[O:4]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 605713Methyl 5-bromothiophene-2-carboxylateHCID 592994213,5-Dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonateHCID 178418339Butyllithium

Product 1

HCID 592993875-[3,5-Dichloro-4-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester
Yield 16.1%

Reagents, catalysts & solvents 4

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (Preparation 86) (552.5 mg, 2.5 mmol) in 5 mL of THF, add n-butyl lithium (1.6 M, 1,56 mL, 2.5 mmol) at −78° C. and stir at that temperature for 30 min. Add anhydrous zinc chloride (455 mg, 4.0 mmol) and keep in −78° C. for 30 min, and then warm up to room temp. After stirring at room temp for 30 min, add 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (593 mg, 1.25 mmol). Add 1,1′-bis(diphenylphosphino) ferrocene)dichloroplladium and complex with dichloromethane (102 mg, 0.125 mmol) with 1.0 mL of THF. After heating to reflux for 5 hours. cool the reaction to room temp. Dilute with ethyl acetate, wash with water, separate the organic layer, and dry over anhydrous sodium sulfate. Purify the crude material by flash chromatography on silica gel using hexane:ethyl acetate (10:1.5) as eluent to give 94 mg of the title compound LC/MS (API) m/z: 466.0 (M+1).

Workup

  1. stirringAfter stirring at room temp for 30 min
  2. temperatureAfter heating
  3. temperatureto reflux for 5 hours
  4. temperaturecool
  5. customthe reaction to room temp
  6. washwash with water
  7. customseparate the organic layer
  8. dry with materialdry over anhydrous sodium sulfate
  9. customPurify the crude material by flash chromatography on silica gel

Sources & evidence

ORD record
ord-a86bd04c3f7e4ca6b7fd29940e934a21
Source dataset
uspto-grants-2010_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07713979B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes