Triethylamine → 3-Fluoro-4-(3-hydroxy-3-methyl-1-azetidinyl)nitrobenzene

HRID 1418660Notes

Reaction equation

HRID 1418660 reaction equation
Cl.C1(C(C2C=CC=CC=2)[N:9]2[CH2:12][C:11]([CH3:14])([OH:13])[CH2:10]2)C=CC=CC=1.C(N(CC)CC)C.P([O-])([O-])(O)=O.[K+].[K+].[F:35][C:36]1[CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[CH:39]=[CH:40][C:41]=1F>CS(C)=O.[OH-].[OH-].[Pd+2].O.ClCCl.CCCCCC.C(OCC)(=O)C.CO.O1CCCC1>[F:35][C:36]1[CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[CH:39]=[CH:40][C:41]=1[N:9]1[CH2:12][C:11]([OH:13])([CH3:14])[CH2:10]1

Participants

11

Reactant 4

HCID 8471TriethylamineHCID 24450Potassium Phosphate, DibasicHCID 1230531,2-Difluoro-4-nitrobenzeneHCID 144051211-(Diphenylmethyl)-3-methylazetidin-3-ol hydrochloride

Product 1

HCID 543624403-Fluoro-4-(3-hydroxy-3-methyl-1-azetidinyl)nitrobenzeneYield 98%

Reagents, catalysts & solvents 6

HCID 9942167Palladium hydroxideCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 21226206Ethyl acetate hexaneSolvent2×HCID 21899815MeOH tetrahydrofuranSolvent

Procedure

A solution of 1-(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride (3.00 g, 10.4 mmol) in 2:1 methanol/tetrahydrofuran (60 mL) was treated with triethylamine (1.00 g, 1.40 mL, 10.4 mmol) and then palladium hydroxide/carbon (0.300 g) under a N2 stream. The mixture was shaken on a Parr apparatus under 40 psi H2. TLC analysis (2:1 hexane/ethyl acetate) after 2.5 h revealed the hydrogenolysis to be complete. The reaction mixture was filtered through Celite® (dichloromethane wash) and the filtrate concentrated under reduced pressure to give an oil which was immediately taken-up in dry dimethyl sulfoxide (15 mL) and treated with dipotassium hydrogen phosphate (3.40 g, 19.8 mmol) and 3,4-difluoronitrobenzene (1.60 g, 1.10 mL, 9.9 mmol) at ambient temperature under N2. After stirring 16 hours at his temperature, TLC analysis (2:1 hexane/ethyl acetate) revealed the reaction to be essentially complete. The reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL) and water (150 mL). After shaking, the organic phase was separated. The aqueous phase was back-extracted with dichloromethane and the combined organic extracts washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to an oil. Chromatography over silica gel, eluting with 3:1 hexane/ethyl acetate, afforded, after concentration of appropriate fractions, 2.15 g (98%) of the title compound as an orange solid with mp 109°-110° C. and MS(EI) 226 (M+).

Workup

  1. filtrationThe reaction mixture was filtered through Celite® (dichloromethane wash)
  2. concentrationthe filtrate concentrated under reduced pressure
  3. customto give an oil which
  4. customthe reaction
  5. stirringAfter shaking
  6. customthe organic phase was separated
  7. extractionThe aqueous phase was back-extracted with dichloromethane
  8. washthe combined organic extracts washed with water
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo to an oil
  12. washChromatography over silica gel, eluting with 3:1 hexane/ethyl acetate
  13. customafforded

Sources & evidence

ORD record
ord-8eeb739b74874d83b95685c7f7409b41
Source dataset
uspto-grants-1999_03
Patent number
US05883093

Reaction notes

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