N,N'-Dimethylethylenediamine → 6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indole

HRID 522772Notes

Reaction equation

HRID 522772 reaction equation
[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 62657Potassium Phosphate, TribasicHCID 125652014-Bromo-1-ethyl-1H-pyrazoleHCID 226127456-chloro-7-fluoro-1H-indole

Product 1

HCID 1181041956-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indoleYield 36%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8058HexaneSolvent

Conditions

Temperature
140 °C

Procedure

To a stirred solution of 6-chloro-7-fluoro-1H-indole 8 (400 mg, 2.36 mmol) in toluene (10 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (Step 3 above; 414 mg, 2.36 mmol), potassium phosphate (1.25 g, 5.91 mmol), N,N′-dimethylethylenediamine (84 mg, 0.95 mmol) and Cu(I)I (45 mg, 0.24 mmol) at RT under inert atmosphere. The resulted solution was purged with argon and sealed the tube. The reaction mixture was then heated to 140° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, diluted with hexane (10 mL) and filtered through a short pad of celite. The filtrate was washed with water (2×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 8-10% EtOAc/Hexanes) to afford compound 9 (224 mg, 36%) as a light brown thick liquid. 1H NMR (500 MHz, CDCl3): δ 7.64 (s, 1H), 7.61 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.12-7.07 (m, 2H), 6.60-6.59 (m, 1H), 4.22 (q, J=7.5 Hz, 2H), 1.55 (t, J=7.5 Hz, 3H); LC-MS (ESI): 94.7%; m/z 264.1 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 3.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).

Workup

  1. customThe resulted solution was purged with argon
  2. customsealed the tube
  3. customAfter completion of the reaction (monitored by TLC)
  4. temperaturethe reaction mixture was cooled to RT
  5. filtrationfiltered through a short pad of celite
  6. washThe filtrate was washed with water (2×10 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto obtain the crude
  11. customThe crude was purified (silica gel chromatography; 8-10% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-579afc187e574b8aa18d4fdbc77b32f0
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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