2,5-Dichlorophenol → Tert-butyl 4-(2-(2,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine-1-carboxylate

HRID 244364Notes

Reaction equation

HRID 244364 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=[O:24])=[O:23].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=[O:24])=[O:23]

Participants

9

Reactant 5

HCID 662,5-DichlorophenolHCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 2855718-Crown-6HCID 59260816Tert-butyl 4-(2-chloro-5-nitrophenylsulfonyl)piperazine-1-carboxylate

Product 1

HCID 66770240Tert-butyl 4-(2-(2,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine-1-carboxylateYield 11.6%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
75 °C

Procedure

To a solution of 2,5-dichlorophenol (0.414 g, 2.54 mmol) in THF (20.00 mL) stirred in an ice bath was added NaH (0.101 g, 2.54 mmol) slowly. After addition, the mixture was stirred for 5 min. Compound 38 (0.790 g, 1.95 mmol) was then added and the resulting reaction mixture was heated to 75° C. overnight. The reaction was monitored by HPLC. However, the reaction was not complete after 16 hrs (HPLC), so THF was evaporated and 18-crown-6 (1.057 g, 4.00 mmol), DMF (15 mL), and K2CO3 (0.553 g, 4.00 mmol) were added. The reaction mixture was heated to 100° C. for another 16 hrs, at which time HPLC indicated that the reaction was complete by absence of starting material. The reaction mixture was cooled to room temperature, and water (0.250 mL) was added. The reaction mixture was extracted thrice with EtOAc. Combined extracts were washed sequentially with 1N NaOH, water, and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residual was dissolved in a minimal amount of DCM and purified with chromatography using a gradient of 5 to 30% EtOAc in hexanes. Pure fractions were combined and evaporated in vacuo. The resulting solid was triturated with DCM and hexanes, and then filtered to afford compound 39 as a white/yellow powder (0.120 g, 100% HPLC purity, 10.0% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.59 (d, J=2 Hz, 1H), 8.42 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.66 (d, J=3 Hz, 1H), 7.50 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 3.40 (m, 4H), 3.25 (m, 4H), 1.37 (s, 9H).

Workup

  1. additionAfter addition
  2. customthe resulting reaction mixture
  3. waitHowever, the reaction was not complete after 16 hrs
  4. custom(HPLC), so THF was evaporated
  5. temperatureThe reaction mixture was heated to 100° C. for another 16 hrs, at which time HPLC
  6. temperatureThe reaction mixture was cooled to room temperature
  7. extractionThe reaction mixture was extracted thrice with EtOAc
  8. washCombined extracts were washed sequentially with 1N NaOH, water, and brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. dissolutionThe residual was dissolved in a minimal amount of DCM
  13. custompurified with chromatography
  14. customevaporated in vacuo
  15. customThe resulting solid was triturated with DCM and hexanes
  16. filtrationfiltered

Sources & evidence

ORD record
ord-62bff06ba83346e088a3dedd9ffa3919
Source dataset
uspto-grants-2014_02
Patent number
US08658642B2

Reaction notes

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