Dimethylformamide → 6-(5,7-Dichloro-2,3-dihydro-1h-indol-1-yl)-4-(1-ethylpropyl)-4,5-dihydro-5-oxo-2-pyrazinecarbonitrile

HRID 2251047Notes

Reaction equation

HRID 2251047 reaction equation
Br[C:2]1[N:3]=[C:4]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=3[Cl:23])[CH2:16][CH2:15]2)[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=1.[CH3:25][N:26](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:19]1[CH:18]=[C:17]2[C:22](=[C:21]([Cl:23])[CH:20]=1)[N:14]([C:4]1[C:5](=[O:13])[N:6]([CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:7]=[C:2]([C:25]#[N:26])[N:3]=1)[CH2:15][CH2:16]2

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 102246635-Bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone

Product 1

HCID 99698106-(5,7-Dichloro-2,3-dihydro-1h-indol-1-yl)-4-(1-ethylpropyl)-4,5-dihydro-5-oxo-2-pyrazinecarbonitrileYield 21%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
175 °C

Procedure

A solution of 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) (100 mg, 0.23 mmol), zinc cyanide (32 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium(0) (32 mg, 25 μmol) in dimethylforamide (3 ml) was degassed with nitrogen and heated to 175° C. in a microwave for 5 min. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×2). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a crude residue. Purification by HPLC (reverse phase C18, 95% water in acetonitrile containing 0.1% trifluroacetic acid to 5% water in acetonitrile containing 0.1% trifluroacetic acid, flow rate 18 ml/min, retention time 38.4 min) gave the product (18 mg, 21%) as a yellow solid. mp 197-199° C.; 1H NMR (300 MHz, CDCl3): δ 7.27 (s, 1 H), 7.19 (d, J=2.2 Hz, 1H), 7.14 (d, J=1.8 Hz, 1 H), 4.82-4.77 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.15 (t, J=7.7 Hz, 2 H), 1.92-1.78 (m, 2 H), 1.75-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C18H19N4OCl2 (M+H)+: 377.0936; Found m/z 377.0910.

Workup

  1. extractionextracted with ethyl acetate (5 mL×2)
  2. dry with materialThe combined organic extracts were dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customto give a crude residue
  6. customPurification by HPLC (reverse phase C18, 95% water in acetonitrile containing 0.1% trifluroacetic acid to 5% water in acetonitrile containing 0.1% trifluroacetic acid, flow rate 18 ml/min, retention time 38.4 min)

Sources & evidence

ORD record
ord-251e447c0a864dd1a30d382ec931c494
Source dataset
uspto-grants-2008_01
Patent number
US07319100B2

Reaction notes

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