Ammonium Chloride → 1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-4,5-dicarbonitrile

HRID 1851132Notes

Reaction equation

HRID 1851132 reaction equation
[NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].F[C:10]1[C:11]([C:20]#[C:21][Si](C)(C)C)=[C:12]([C:18]#[N:19])[C:13](=[CH:16][CH:17]=1)[C:14]#[N:15].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>[Cu]I.CN(C=O)C.O.CS(C)=O>[OH:5][C:3]([CH3:6])([CH3:4])[C:2]([N:1]1[C:10]2[C:11](=[C:12]([C:18]#[N:19])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH:20]=[CH:21]1)([CH3:8])[CH3:7]

Participants

9

Reactant 4

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 157085323-Amino-2,3-dimethylbutan-2-olHCID 86709187HCID 86709187, compound

Product 1

HCID 867091891-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-4,5-dicarbonitrileYield 8%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

An oven-dried vial was charged with 3-amino-2,3-dimethylbutan-2-ol (Example 35A) (0.063 g, 0.540 mmol), and 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.109 g, 0.45 mmol) and sealed with a rubber septum. DIEA (0.157 mL, 0.900 mmol) and anhyd DMSO (2 mL) were added via syringe and the mixture was stirred at rt under N2. After 18 h, the temperature was increased to 60° C. and stirring continued an additional 30 h. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo to a dark, oily residue. An oven-dried vial was charged with the residue, followed by CuI (0.043 g, 0.225 mmol) and sealed with a rubber septum. Anhyd DMF (3 mL) was added via syringe and the septum was replaced with a PTFE-faced crimp top. The mixture was subjected to microwave heating (140° C.) for 20 min. The mixture was poured into satd NH4Cl and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) followed by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording 1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0093 g, 8% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J=9.0, 0.8 Hz, 1H), 7.65 (d, J=3.5 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 6.81 (dd, J=3.5, 0.8 Hz, 1H), 1.88 (s, 6H), 1.21 (s, 6H); MS (LCMS ES+) m/z 268 ([M+H]+, 29%), 309 ({[M+H]+MeCN}+, 100%).

Workup

  1. customsealed with a rubber septum
  2. temperaturethe temperature was increased to 60° C.
  3. stirringstirring
  4. waitcontinued an additional 30 h
  5. temperatureUpon cooling the mixture
  6. extractionextracted with EtOAc (×3)
  7. washCombined organics were washed (water, brine)
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated in vacuo to a dark, oily residue
  10. additionAn oven-dried vial was charged with the residue
  11. customsealed with a rubber septum
  12. temperatureheating (140° C.) for 20 min
  13. extractionextracted with EtOAc (×3)
  14. washCombined organics were washed (water, brine)
  15. dry with materialdried over Na2SO4
  16. concentrationconcentrated in vacuo
  17. customThe residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-fabed0b00f114e1788b4ffc3388397eb
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

Loading…