Cesium carbonate → 4-(6-Nitropyridin-3-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester

HRID 1772139Notes

Reaction equation

HRID 1772139 reaction equation
[N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(OCC)(=O)C.O>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][C:12]2=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 8176205-Bromo-2-nitropyridineHCID 3157178Tert-butyl 3-oxopiperazine-1-carboxylate

Product 1

HCID 592909524-(6-Nitropyridin-3-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl esterYield 96.2%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-nitro-5-bromopyridine (1.00 g, 5.00 mmol), 2-oxo-4-(tert-butoxycarbonyl)piperazine (1.01 g, 5.00 mmol), cesium carbonate (3.58 g, 11.0 mmol) and 1,4-dioxane (40 mL). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (246 mg, 0.425 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (230 mg, 0.250 mmol) were added, and the reaction mixture was heated at reflux for 6 h. Water (30 mL) and ethyl acetate (150 mL) were added after the reaction mixture was cooled to room temperature. The resulting mixture was filtered through a bed of Celite 521. The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and purified by column chromatography to afford a 96% yield (1.55 g) of 121a as an amber oil: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=8.7 Hz), 8.15 (dd, 1H, J=8.7, 2.4 Hz), 4.33 (s, 1H), 3.89 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 323.1 (M+H).

Workup

  1. customA 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting solution for 30 min
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 6 h
  6. filtrationThe resulting mixture was filtered through a bed of Celite 521
  7. customThe organic layer of the filtrate was separated
  8. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
  9. washThe combined organic layers were washed with brine (30 mL)
  10. dry with materialdried over sodium sulfate
  11. custompurified by column chromatography

Sources & evidence

ORD record
ord-d3d57991ae9641e7a5c846f0697c8596
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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