Nitrogen → 5-(Cyclobutylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 2069582Notes

Reaction equation

HRID 2069582 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH:23]1([C:27]#[C:28][Si](C)(C)C)[CH2:26][CH2:25][CH2:24]1.N#N>[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>[CH:23]1([C:27]#[C:28][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:26][CH2:25][CH2:24]1

Participants

9

Reactant 4

HCID 947NitrogenHCID 10796Cesium carbonateHCID 534338265-bromo-1-(oxan-2-yl)-1H-indazole2×HCID 66793217(Cyclobutylethynyl)trimethylsilane2×

Product 1

HCID 667938035-(Cyclobutylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 71%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
80 °C

Procedure

A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 42) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+.

Workup

  1. customwas bubbled through the mixture
  2. temperatureThe reaction mixture was cooled to room temperature
  3. additiondiluted with EtOAc (100 mL) and H2O (100 mL)
  4. filtrationfiltered
  5. customThe organic layer of the filtrate was separated
  6. extractionthe aqueous layer was extracted with additional EtOAc (2×50 mL)
  7. washThe combined organic layers were washed with brine (3×100 mL)
  8. dry with materialdried over anhydrous Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified on a silica gel column

Sources & evidence

ORD record
ord-66a96bb6a1fa4ad4b43df7f912a39b1e
Source dataset
uspto-grants-2012_10
Patent number
US08299112B2

Reaction notes

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