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

HRID 522758Notes

Reaction equation

HRID 522758 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.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:27]2[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=2)=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 62657Potassium Phosphate, TribasicHCID 218597074-Bromo-1-propyl-1H-pyrazole2×HCID 226127456-chloro-7-fluoro-1H-indole

Product 1

HCID 1181042006-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indoleYield 72.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

To a stirred solution of compound 2 (1.1 g, 6.48 mmol) in toluene (15 mL) under inert atmosphere were added N,N′-dimethyl ethylene diamine (229 mg, 2.60 mmol), potassium phosphate (3.44 g, 16.27 mmol), 4-bromo-1-propyl-1H-pyrazole (Intermediate B; 1.21 g, 6.50 mmol), CuI (124 mg, 0.65 mmol) at RT, degassed under argon for 15 min; heated to 140° C. and stirred for 20 h in sealed tube. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (30 mL), filtered and the filtrate was concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 8-10% EtOAc/Hexanes to afford compound 3 (1.3 g, 72%) as brown liquid. 1H NMR (500 MHz, CDCl3): δ 7.64 (s, 1H), 7.60 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.12-7.07 (m, 2H), 6.60 (s, 1H), 4.13 (t, J=7.0 Hz, 2H), 1.99-1.91 (m, 2H), 0.97 (t, J=8.0 Hz, 3H); LC-MS (ESI): 93.5%; m/z 278.2 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.08 min; 5 mM NH4OAc: ACN; 0.8 mL/min).

Workup

  1. customdegassed under argon for 15 min
  2. customafter completion of the reaction
  3. filtrationfiltered
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. customto obtain the crude
  6. customThis was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-c61f8296ebf540a0b53e0e6a4c592361
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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