2,2-Difluoro-2-(fluorosulfonyl)acetic acid → Ethyl 6-difluoromethoxymethylpyridine-2-carboxylate

HRID 2207566

Reaction equation

HRID 2207566 reaction equation
[F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][CH:14]=1>CC#N.[Cu]I>[F:1][CH:2]([F:10])[O:11][CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][CH:14]=1

Participants

5

Reactant 2

HCID 27375162,2-Difluoro-2-(fluorosulfonyl)acetic acidHCID 109211412-Pyridinecarboxylic acid, 6-(hydroxymethyl)-, ethyl ester

Product 1

HCID 66718372Ethyl 6-difluoromethoxymethylpyridine-2-carboxylateYield 13%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6342AcetonitrileSolvent

Procedure

2,2-Difluoro-2-(fluorosulfonyl)acetic acid (495 mL, 4.79 mmol) was added dropwise to a solution of ethyl 6-hydroxymethylpyridine-2-carboxylate (800 mg, 4.79 mmol) and CuI (91 mg, 0.479 mmol) in MeCN (10 mL) at room temperature at a rate to maintain the internal temperature <30° C. The mixture was stirred for a further 20 min at room temperature, poured onto brine/water and extracted with EtOAc (×3). The combined extracts were dried (MgSO4), filtered, evaporated and purified by column chromatography (4:1 to 2:1, isohexane:EtOAc) to give the title compound (130 mg, 13%) as a colorless oil; NMR δH (400 MHz, CDCl3) 8.01 (1H, d, J 7.5 Hz), 7.89 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 7.5 Hz), 6.41 (1H, t, J 74.0 Hz), 5.14 (2H, s), 4.49 (2H, q, J 7.0 Hz), 1.44 (3H, t, J 7.0H); (M+H)+ 232.

Workup

  1. temperatureto maintain the internal temperature <30° C
  2. additionpoured onto brine/water
  3. extractionextracted with EtOAc (×3)
  4. dry with materialThe combined extracts were dried (MgSO4)
  5. filtrationfiltered
  6. customevaporated
  7. custompurified by column chromatography (4:1 to 2:1, isohexane:EtOAc)

Sources & evidence

ORD record
ord-2d1c22284e88425181549ff89db4af20
Source dataset
uspto-grants-2016_06
Patent number
US09376443B2

Linked notes

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