Nitrogen → 5-(But-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 1254447Notes

Reaction equation

HRID 1254447 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[C:24]([Si](C)(C)C)#[C:25][CH2:26][CH3:27].N#N>CCOC(C)=O.O.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC(N(C)C)=O>[C:24]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:6]=[CH:5]2)#[C:25][CH2:26][CH3:27]

Participants

11

Reactant 4

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 439261-ButynyltrimethylsilaneHCID 667932045-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Product 1

HCID 667933445-(But-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 52.2%

Reagents, catalysts & solvents 6

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

Nitrogen was bubbled into a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7.5 g, 25.33 mmol) and DMA (100 mL). After 5 min, CuI (241 mg, 1.27 mmol), Pd(OAc)2 (284 mg, 1.27 mmol), dppf (704 mg, 1.27 mmol), K2CO3 (4.89 g, 35.46 mmol), and but-1-yn-1-yltrimethylsilane (4.46 g, 35.46 mmol) were added sequentially with continued N2 bubbling. The resulting mixture was heated at 80° C. for 10 h under N2. The reaction mixture was diluted with EtOAc (250 mL) and H2O (200 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (1:30 EtOAc/petroleum ether) to give the pure product as a yellow solid (3.6 g) and an impure product (2 g; further purified to give additional 1.47 g). 1H NMR (300 MHz, DMSO-d6): δ 8.19 (d, 1H), 7.68 (d, 1H), 7.26 (dd, 1H), 5.79 (dd, 1H), 3.92-3.87 (m, 1H), 3.69-3.60 (m, 1H), 2.47-2.34 (m, 1H), 2.43 (q, 2H), 2.07-2.02 (m, 2H), 1.76-1.69 (m, 1H), 1.57-1.50 (m, 2H), 1.17 (t, 3H); LCMS: 273 (M+H)+.

Workup

  1. filtrationfiltered
  2. customThe organic layer of the filtrate was separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×100 mL)
  4. washThe combined organic layers were washed with brine (3×50 mL)
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationconcentrated
  7. custompurified by silica gel chromatography (1:30 EtOAc/petroleum ether)

Sources & evidence

ORD record
ord-04273c676dc94257b47d258e1733f0d4
Source dataset
uspto-grants-2013_06
Patent number
US08455534B2

Reaction notes

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