Acetic Acid → 1-(3-Nitrophenyl)piperazin-2-one

HRID 1889979Notes

Reaction equation

HRID 1889979 reaction equation
N1CCNCC1=O.IC1C=CC=C([N+]([O-])=O)C=1.[N+:18]([C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]2=[O:33])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[CH:34](=[O:36])[CH3:35].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N+:18]([C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]2=[O:33])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[CH2:31]([N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:34](=[O:36])[CH2:35]1)[CH3:32]

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 177AcetaldehydeHCID 125741-Iodo-3-nitrobenzeneHCID 231360Piperazin-2-oneHCID 5003444Sodium cyanoborohydrideHCID 110639881-(3-Nitrophenyl)piperazin-2-one

Product 2

HCID 110639881-(3-Nitrophenyl)piperazin-2-oneHCID 674788074-Ethyl-1-(3-nitro-phenyl)-piperazin-2-one

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

205 a) 1-(3-nitro-phenyl)-piperazin-2-one was prepared from piperazin-2-one (1.00 g, 9.99 mmol) and 1-iodo-3-nitro-benzene (3.00 g, 12.0 mmol) in a manner analogous to Example 204a. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 3.77 (t, J=4.9 Hz, 2H), 3.74 (s, 2H), 3.28 (t, J=4.8 Hz, 2H). MS=222 (MH)+. 205 b) To a solution of 1-(3-nitro-phenyl)-piperazin-2-one (0.629 g, 2.84 mmol), acetaldehyde (0.20 mL, 3.6 mmol) and acetic acid (0.50 mL, 8.8 mmol) in methanol (10 mL) at room temperature was added solid Sodium cyanoborohydride (0.27 g, 4.3 mmol) in small portions. The mixture was stirred for 18 hours at room temperature. The mixture was evaporated and cold water was slowly added to the residue. The mixture was stirred for 15 minutes and then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→5% methanol:dichloromethane). 4-Ethyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a yellow-orange viscous oil (0.497 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 3.81-3.76 (m, 2H), 3.37-3.33 (m, 2H), 2.89-2.84 (m, 2H), 2.60-2.53 (m, 2H), 1.20-1.14 (m, 3H). 205 c) 1-(3-Amino-phenyl)-4-ethyl-piperazin-2-one was prepared from 4-ethyl-1-(3-nitro-phenyl)-piperazin-2-one (0.497 g, 1.99 mmol) in a manner analogous to Example 111a. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.17 (t, J=7.7 Hz, 1H), 6.67-6.57 (m, 3H), 3.71 (br s, 2H), 3.69-3.63 (m, 2H), 3.30 (s, 2H), 2.82-2.77 (m, 2H), 2.53 (q, J=6.8 Hz, 2H), 1.19-1.12 (m, 3H). MS=220 (MH)+. 205 d) 4-Ethyl-1-{3-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-ethyl-piperazin-2-one (79.0 mg, 0.360 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.059 g, 37%). MP=210-212° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.76 (s, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.42-7.34 (m, 2H), 7.04 (t, J=6.5 Hz. 1H), 6.96-6.92 (m, 2H), 3.80-3.75 (m, 2H), 3.36 (s, 2H), 3.10 (s, 3H), 2.88-2.83 (m, 2H), 2.58 (q, J=7.0 Hz, 2H), 1.18 (t, J=6.4 Hz, 3H). MS=491 (MH)+.

Workup

  1. customThe mixture was evaporated
  2. additioncold water was slowly added to the residue
  3. stirringThe mixture was stirred for 15 minutes
  4. extractionextracted with dichloromethane (3×20 mL)
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified via chromatography
  9. custompurification apparatus (silica gel column 40 g and 0%→5% methanol:dichloromethane)

Sources & evidence

ORD record
ord-a9029e07f5144419a3c48d1ce079203a
Source dataset
uspto-grants-2013_08
Patent number
US08501936B2

Reaction notes

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