Dichloromethane → 3,3-Difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclobutanol

HRID 2040757Notes

Reaction equation

HRID 2040757 reaction equation
[F:1][C:2]1([F:8])[CH2:7][C:4]2([O:6][CH2:5]2)[CH2:3]1.C(Cl)Cl.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O-:23].[K+]>CC#N.O.CCOC(C)=O>[F:1][C:2]1([F:8])[CH2:7][C:4]([CH2:5][O:23][C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[O:13][CH3:12])([OH:6])[CH2:3]1

Participants

6

Reactant 3

HCID 6344DichloromethaneHCID 14144719Potassium 2-methoxy-4-nitrophenolateHCID 579888155,5-Difluoro-1-oxaspiro(2.3)hexane

Product 1

HCID 579888303,3-Difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclobutanolYield 64.5%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

A mixture of 5,5-difluoro-1-oxaspiro[2.3]hexane+3 eq. CH2Cl2 (22.52 g, 0.06 mol), potassium 2-methoxy-4-nitrophenolate (12.43 g, 0.060 mol) prepared in Part E and NaH2PO4.H2O (7.45 g, 0.054 mol) in 50 mL MeCN-water (85:15) was heated at 130° C. in a steel bomb for 3.5 h. The reaction mixture was diluted with EtOAc, washed with 5% Na2CO3, dried (MgSO4) and concentrated. The crude product was recrystallized from ca. 150 mL MTBE giving 3,3-difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclobutanol (11.2 g, 0.039 mol, 64.5% yield) as a light yellow solid. An additional 1.2 g of a slightly less pure desired product was obtained upon concentration of the mother liquor to ca. 50 mL. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1H, dd, J=8.94, 2.64 Hz), 7.76 (1H, d, J=2.77 Hz), 6.95 (1H, d, J=9.06 Hz), 4.16 (2H, s), 3.94 (3H, s), 3.36 (1H, s), 2.73-2.92 (4H, m).

Workup

  1. washwashed with 5% Na2CO3
  2. dry with materialdried (MgSO4)
  3. concentrationconcentrated
  4. customThe crude product was recrystallized from ca. 150 mL MTBE

Sources & evidence

ORD record
ord-f282c8c08b4e4851850070af79a2460f
Source dataset
uspto-grants-2013_11
Patent number
US08580959B2

Reaction notes

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