Sodium bis(trimethylsilyl)amide → Tert-butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutanecarboxylate

HRID 2048094Notes

Reaction equation

HRID 2048094 reaction equation
[Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1([F:21])[CH2:13][CH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C:10]([F:21])([F:9])[CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 27628183-Chloro-2-fluoropyridineHCID 58042504Cyclobutanecarboxylic acid, 3,3-difluoro-, 1,1-dimethylethyl ester

Product 1

HCID 58042374Tert-butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutanecarboxylateYield 44%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A solution of 3-chloro-2-fluoropyridine (500 mg, 3.8 mmol) and tert-butyl 3,3-difluorocyclobutanecarboxylate (Preparation 227, 877 mg, 4.6 mmol) in toluene (13 mL) was cooled to 0° C. A solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1M solution in THF, 5.7 mL, 5.7 mmol) was added dropwise. The reaction mixture was stirred for 20 minutes at the same temperature, and then allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with 1N aqueous citric acid solution (3×15 mL), then brine (3×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as yellow oil which was purified by silica gel column chromatography eluting with 0-20% EtOAc in heptane to give the title compound (505 mg, 44%) as colourless oil.

Workup

  1. stirringstirred for 4 hours
  2. customThe reaction was quenched with saturated aqueous NH4Cl solution
  3. extractionextracted with EtOAc (3×20 mL)
  4. washThe combined organic extracts were washed with 1N aqueous citric acid solution (3×15 mL)
  5. dry with materialThe organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give a crude product as yellow oil which
  9. customwas purified by silica gel column chromatography
  10. washeluting with 0-20% EtOAc in heptane

Sources & evidence

ORD record
ord-2d00b6f4e52b45f3be164d7764cc72dd
Source dataset
uspto-grants-2013_11
Patent number
US08592629B2

Reaction notes

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