Cesium carbonate → 2-(Fluoromethyl)-1-methyl-4-(6-nitropyridin-3-yl)piperazine

HRID 1919158Notes

Reaction equation

HRID 1919158 reaction equation
[F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH3:9].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>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].O1CCOCC1>[F:1][CH2:2][CH:3]1[CH2:8][N:7]([C:11]2[CH:16]=[N:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]1[CH3:9]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 8176205-Bromo-2-nitropyridineHCID 197772702-(Fluoromethyl)-1-methylpiperazine

Product 1

HCID 580437532-(Fluoromethyl)-1-methyl-4-(6-nitropyridin-3-yl)piperazineYield 84.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 336d (1.6 g, 12.1 mmol), 5-bromo-2-nitropyridine (3.7 g, 18.2 mmol), and cesium carbonate (9.9 g, 30.2 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (700 mg, 0.12 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (550 mg, 0.06 mmol) were added. After three cycles of vacuum/argon flash, the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, filtered, and concentrated to afford a black solid as a crude product, which was further purified by column chromatography eluting with 100:1 methylene chloride/methanol to afford 336e as a yellow solid (2.6 g, 76%). MS: [M+H]+ 255. 1H NMR (500 MHz, MeOD) δ 8.20 (m, 2H), 7.52 (dd, J=9, 1H), 4.72 (m, 0.5H), 4.64 (m, 1H), 4.56 (m, 0.5H), 4.01 (m, 1H), 3.94 (m, 1H), 3.19 (m, 1H), 3.06 (m, 1H), 3.00 (m, 1H), 2.50 (m, 2H), 2.46 (s, 3H).

Workup

  1. customA 100-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. temperatureAfter three cycles of vacuum/argon flash, the reaction mixture was heated
  5. temperatureat reflux for 15 h
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto afford a black solid as a crude product, which
  9. customwas further purified by column chromatography
  10. washeluting with 100:1 methylene chloride/methanol

Sources & evidence

ORD record
ord-3c2a85b37041404c9d340b3076f2ff77
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

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