Cesium carbonate → 5-(3,3-Difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile

HRID 1480287Notes

Reaction equation

HRID 1480287 reaction equation
Br[C:2]1[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl.[F:17][C:18]1([F:22])[CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[F:17][C:18]1([F:22])[CH2:21][N:20]([C:2]2[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:19]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 902033795-Bromo-4-(2,2,2-trifluoroethoxy)picolinonitrile

Product 1

HCID 902032995-(3,3-Difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrileYield 78.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonitrile (example 78c, 587 mg, 2.09 mmol) in dry toluene (10 ml) in a schlenk tube was added 3,3-difluoroazetidine hydrochloride (298 mg, 2.3 mmol), cesium carbonate (1.36 g, 4.18 mmol), palladium diacetate (46.9 mg, 209 μmol) and BINAP (130 mg, 209 μmol). The reaction mixture was stirred at 120° C. for 1 hour. The reaction mixture was filtered over a pad of celite and the filtrate was diluted with ethylacetate. The organic phase was extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (480 mg, 78%). MS (ESI, m/z): 294.2 (M+H+).

Workup

  1. filtrationThe reaction mixture was filtered over a pad of celite
  2. additionthe filtrate was diluted with ethylacetate
  3. extractionThe organic phase was extracted with a 1M aqueous solution of sodium bicarbonate
  4. dry with materialThe organic phase was dried over sodium sulfate
  5. customevaporated down to dryness
  6. customThe crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient

Sources & evidence

ORD record
ord-bbeabb260d3946b39ccd2850af87b62e
Source dataset
uspto-grants-2016_08
Patent number
US09409866B2

Reaction notes

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