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

HRID 1026429Notes

Reaction equation

HRID 1026429 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]>[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

6

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 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 111d (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(dibenzyl-ideneacetone)dipalladium(0) (550 mg, 0.06 mmol) were added, and 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 the crude product. Then it was purified on silica gel (DCM:MeOH=100:1) to afford 111e as a yellow solid (2.6 g, yield 76%). 1H NMR (500 MHz, MeOD) δ 8.20 (dd, J=12.5 Hz, 2H), 7.51 (dd, J=9.0 Hz, 1H), 4.74-4.54 (m, 2H), 4.03-3.92 (m, 2H), 3.20 (m, 1H), 3.09-2.99 (m, 2H), 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. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 15 h
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto afford a black solid as the crude product
  9. customThen it was purified on silica gel (DCM:MeOH=100:1)

Sources & evidence

ORD record
ord-268860c7111347daa333335c86f2ddd0
Source dataset
uspto-grants-2014_05
Patent number
US08729072B2

Reaction notes

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