Nitrogen → 5-(1-Butyn-1-yl)-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 1254450Notes

Reaction equation

HRID 1254450 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]=[C:5]2[F:17].C([O-])([O-])=O.[Cs+].[Cs+].[C:24]([Si](C)(C)C)#[C:25][CH2:26][CH3:27].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>[C:24]([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]=[C:5]2[F:17])#[C:25][CH2:26][CH3:27]

Participants

9

Reactant 4

HCID 947NitrogenHCID 10796Cesium carbonateHCID 439261-Butynyltrimethylsilane2×HCID 667932975-Bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole2×

Product 1

HCID 667932855-(1-Butyn-1-yl)-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 69.2%

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-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.2 g, 20.7 mmol; Intermediate 39), DMA (20 mL), CuI (393.3 mg, 2.07 mmol), Pd(OAc)2 (465.0 mg, 2.07 mmol), dppf (1.1 g, 2.07 mmol), Cs2CO3 (10.8 g, 33.1 mmol), and but-1-yn-1-yltrimethylsilane (3.4 g, 26.9 mmol; Intermediate 35) sequentially while N2 was bubbled through the solution. The resulting mixture was heated at 80° C. for 10 h under N2. The reaction mixture was diluted with EtOAc (350 mL) and H2O (300 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with 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 EtOAc in petroleum ether (1:30) to afford the title compound as a yellow solid (3.9 g, yield 69.1%). 1H NMR (DMSO-d6, 400 MHz): δ 7.76-7.71 (m, 2H), 7.49 (d, 1H), 5.79 (dd, 1H), 3.88-3.85 (m, 1H), 3.74-3.71 (m, 1H), 2.44 (q, 2H), 2.24-2.21 (m, 1H), 2.01-1.91 (m, 2H), 1.70-1.65 (m, 1H), 1.57-1.54 (m, 2H), 1.18 (t, 3H); LCMS: 273 (M+H)+.

Workup

  1. customwas bubbled through the solution
  2. additionThe reaction mixture was diluted with EtOAc (350 mL) and H2O (300 mL)
  3. filtrationfiltered
  4. customThe organic layer of the filtrate was separated
  5. extractionthe aqueous layer was extracted with EtOAc (2×50 mL)
  6. washThe combined organic layers were washed with brine (3×100 mL)
  7. dry with materialdried over anhydrous Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified on a silica gel column

Sources & evidence

ORD record
ord-bf68d30f5e494b138bd8387d59f726ac
Source dataset
uspto-grants-2013_06
Patent number
US08455534B2

Reaction notes

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