Trifluoroacetic acid → 4-(2,4-Difluorobenzyloxy)pyridine-1-oxide

HRID 1866970Notes

Reaction equation

HRID 1866970 reaction equation
[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[N+]([C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][CH:15]=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)C(O)=O>CN(C)C=O.C(#N)C.O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:5][C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][CH:15]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 143004-Nitropyridine N-oxideHCID 918672,4-Difluorobenzyl alcohol

Product 1

HCID 220502194-(2,4-Difluorobenzyloxy)pyridine-1-oxideYield 96%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

2,4-difluorobenzyl alcohol (100. g, 0.694 mol) and 4-nitropyridine N-oxide (98. g, 0.700 mol)are combined with 250 g Cs2CO3 (1.1 eq) in 2.5 L anhydrous dimethylformamide and heated to 80° C. with stirring. The reaction was followed by 19F-NMR (crude reaction mixture with external D2O reference) and complete after 40 h. The mixture was filtered hot; product crystallized out on cooling. 90.21 g (55%) of white plates were collected by filtration and washed with diethyl ether. The mother liquor was diluted with 2.5 L diethyl ether and stored in the freezer overnight, yielding a second crop 68.76 g (41%, combined yield 96%). 1H-NMR (400 MHz, DMSO-d6) δ 8.06 (m, 2H), 7.61 (quartet, J=8.45 Hz, 1H), 7.30 (t, J=10.37 Hz, 1H), 7.12, (t, J=8.45 Hz, 1H), 7.09 (d, J=5.06 Hz, 2H), 5.14 (s, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.43 (quintet, J=7.78 Hz, 1F), −113.82 (quartet, J=9.55 Hz, 1F). LC/MS tr=3.90 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 238 (M+H).

Workup

  1. customreaction mixture with external D2O reference) and complete after 40 h
  2. filtrationThe mixture was filtered hot
  3. customproduct crystallized out
  4. temperatureon cooling
  5. filtration90.21 g (55%) of white plates were collected by filtration
  6. washwashed with diethyl ether
  7. additionThe mother liquor was diluted with 2.5 L diethyl ether
  8. customstored in the freezer overnight
  9. customyielding a second crop 68.76 g (41%, combined yield 96%)

Sources & evidence

ORD record
ord-9716f14279d5463abef04813e2fe23ff
Source dataset
uspto-grants-2009_12
Patent number
US07629363B2

Reaction notes

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