Methyl morpholine oxide → HCID 11645212, compound

HRID 2235265Notes

Reaction equation

HRID 2235265 reaction equation
Br[C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].B1(B2OCC(C)(C)CO2)OCC(C)(C)C[O:23]1.CC([O-])=O.[K+].C[N+]1([O-])CCOCC1.S(=O)(O)[O-].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([OH:23])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16]

Participants

8

Reactant 5

HCID 82029Methyl morpholine oxideHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 11632109HCID 11632109, compoundHCID 23665763Sodium Bisulfite

Product 1

HCID 11645212HCID 11645212, compoundYield 27%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

Charge a flask with 3-(2-bromo-6-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 56) (210 mg, 0.57 mmol), bis(neopentyl glycolato)diboron (150 mg, 0.68 mmol), KOAc (200 mg, 2.0 mmol) and Pd(dppf)Cl2 (23 mg, 0.03 mmol) and purge with nitrogen. Add DMSO (5 mL) and plunge into an 80° C. oil bath and stir under nitrogen for 24 hours. Cool to room temperature and pour into water. Extract with ether. Dry over sodium sulfate, filter and concentrate. Dissolve residue in 1N NaOH (10 mL) and stir at room temperature overnight. Extract water with ether and acidify the aqueous layer with HCl. Extract with ether, dry over sodium sulfate, filter and concentrate. Dissolve residue in THF (5 mL) and add N-methyl morpholine N-oxide (200 mg, 1.7 mmol) and heat to reflux for 6 hours. Cool to room temperature and pour into saturated aqueous sodium bisulfite. Extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (3:1 to 1:1 hexanes:ethyl acetate). Triturate the recovered material with 2:1 hexanes:ethyl acetate to afford 47 mg (27%) of the title compound as a white solid. Mass spectrum (apci) m/z=308.1 (M+H).

Workup

  1. custompurge with nitrogen
  2. temperatureCool to room temperature
  3. additionpour into water
  4. extractionExtract with ether
  5. dry with materialDry over sodium sulfate
  6. filtrationfilter
  7. concentrationconcentrate
  8. stirringDissolve residue in 1N NaOH (10 mL) and stir at room temperature overnight
  9. extractionExtract with ether
  10. dry with materialdry over sodium sulfate
  11. filtrationfilter
  12. concentrationconcentrate
  13. temperatureheat
  14. temperatureto reflux for 6 hours
  15. temperatureCool to room temperature
  16. extractionExtract with methylene chloride
  17. dry with materialDry over sodium sulfate
  18. filtrationfilter
  19. concentrationconcentrate
  20. customPurify over silica gel (3:1 to 1:1 hexanes:ethyl acetate)
  21. customTriturate the recovered material with 2:1 hexanes

Sources & evidence

ORD record
ord-4023db4e315e4f4b92003c82c626b8c6
Source dataset
uspto-grants-2010_05
Patent number
US07713979B2

Reaction notes

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