Iodoethane → 5-(But-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 1254419Notes

Reaction equation

HRID 1254419 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)#[CH:2].[CH2:18]1COC[CH2:19]1.CN(CCN(C)C)C.[Li]CCCC.ICC>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)#[C:2][CH2:18][CH3:19]

Participants

5

Reactant 4

HCID 6340IodoethaneHCID 86588997Thf tmedaHCID 866633655-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole2×HCID 178418339Butyllithium

Product 1

HCID 667932705-(But-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Conditions

Temperature
-78 °C

Procedure

A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a N2 inlet was charged with 5-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.2 g, 18.6 mmol; Intermediate 2) and anhydrous THF/TMEDA (9:1, 93 mL). This solution was cooled to −78° C. in an IPA/dry ice bath, and n-BuLi (17.4 mL solution in hexanes, 27.84 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred for 30 minutes at −78° C., and then iodoethane (2.23 mL, 27.84 mmol) was added dropwise over 5 minutes. The mixture was gradually warmed to room temperature, stirred for 1 h, and then heated at 40° C. overnight. Upon completion by LCMS, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (100 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-10% ethyl acetate in hexanes) to give the title compound (1.42 g) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.69 (d, 1H), 7.39 (d, 1H), 5.84 (dd, 1H), 3.89-3.86 (m, 1H), 3.76-3.72 (m, 1H), 2.45-2.36 (m, 3H), 2.04-1.94 (m, 2H), 1.74 (m, 1H), 1.57-1.20 (m, 2H), 1.16 (t, 3H); LCMS: 255 (M+H)+.

Workup

  1. customA 250-mL round-bottom flask equipped with a magnetic stir bar
  2. temperatureThe mixture was gradually warmed to room temperature
  3. stirringstirred for 1 h
  4. temperatureheated at 40° C. overnight
  5. temperatureUpon completion by LCMS, the reaction mixture was cooled to room temperature
  6. customquenched with water (100 mL)
  7. extractionextracted with ethyl acetate (2×100 mL)
  8. washThe combined organics were washed with water (100 mL)
  9. washwashed with brine (50 mL)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. custompurified by silica gel chromatography (0-10% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-14e7e8073f6948b68518143250901a9f
Source dataset
uspto-grants-2013_06
Patent number
US08455534B2

Reaction notes

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