Sodium hydride → 3-(4-Chlorophenylmethyl)-5-(4-(4-methylpiperazin-1-yl)-1H-indol-2-yl)-1,2,4-oxadiazole

HRID 1383330Notes

Reaction equation

HRID 1383330 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:11][OH:12])[NH2:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[C:25]([C:31](OC2C=CC(F)=CC=2)=O)[NH:26]3)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[N:10]=[C:31]([C:25]3[NH:26][C:27]4[C:23]([CH:24]=3)=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)[CH:30]=[CH:29][CH:28]=4)[O:12][N:11]=2)=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 2493452-(4-chlorophenyl)-N'-hydroxyethanimidamideHCID 516892Sodium BicarbonateHCID 211875494-methyl-1-(2-(4-fluorophenoxycarbonyl)-1H-indol-4-yl)piperazine

Product 1

HCID 1360453253-(4-Chlorophenylmethyl)-5-(4-(4-methylpiperazin-1-yl)-1H-indol-2-yl)-1,2,4-oxadiazoleYield 4.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of (4-chlorophenyl)acetamidoxime (2.21 g from above, assumed 10 mmol, 15 equivalents) and sodium hydride (60% in oil, 0.460 g, 11.5 mmol, 17 equivalents) in anhydrous tetrahydrofuran (25 mL) was added crude 4-methyl-1-(2-(4-fluorophenoxycarbonyl)-1H-indol4-yl)piperazine (0.225 g from above, assumed 0.68 mmol), and the resulting reaction mixture was heated at reflux under nitrogen for 6 hours. A saturated solution of sodium hydrogen carbonate (25 mL) was added, and the resulting aqueous mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 25 g) and elution with methylene chloride/methanol/ammonium hydroxide [10:1:0.1] to afford the title compound (0.013 g, 0.03 mmol, 4%) as an off-white foam: 13C NMR (acetone-d6) δ170.3, 169.5, 147.2, 139.7, 135.0, 132.3, 130.7, 128.5, 126.2, 121.5, 119.9, 107.0, 106.4, 106.2, 55.3, 51.2, 45.5, 31.0; LRMS (m/z, relative intensity) 409 ([M+ with 37Cl], 30), 408 (27), 407 ([M+ with 35Cl], 100), 392 (7), 337 (23), 322 (16), 170 (16), 70 (41); HRMS calculated for C22H22ClN5O [with 35Cl] 407.1516, found 407.1516.

Workup

  1. customthe resulting reaction mixture
  2. temperaturewas heated
  3. temperatureat reflux under nitrogen for 6 hours
  4. extractionthe resulting aqueous mixture was extracted with ethyl acetate (2×25 mL)
  5. dry with materialdried (magnesium sulfate)
  6. customevaporated under reduced pressure
  7. customThe residue was chromatographed
  8. washsilica gel (approximately 25 g) and elution with methylene chloride/methanol/ammonium hydroxide [10:1:0.1]

Sources & evidence

ORD record
ord-f4feef2d5474426f91cef6f23e9d4f0e
Source dataset
uspto-grants-2001_07
Patent number
US06255306B1

Reaction notes

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