Dimethylformamide → Methyl 6-chloro-3-methylpyrazine-2-carboxylate

HRID 627689Notes

Reaction equation

HRID 627689 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][N:10]=1)=[O:4].[CH3:13][O:14][C:15]([C:17]1[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N+:18]=1[O-])=[O:16].P(Cl)(Cl)([Cl:27])=O.CN(C=O)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:27][C:8]1[N:7]=[C:6]([CH3:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:10][CH:9]=1.[Cl:27][C:19]1[N:18]=[C:17]([C:15]([O:14][CH3:13])=[O:16])[C:22]([CH3:23])=[N:21][CH:20]=1

Participants

7

Reactant 3

HCID 6228DimethylformamideHCID 24813Phosphorus oxychlorideHCID 86728143Methyl 3-methyl-1-oxidopyrazin-1-ium-2-carboxylate;methyl 3-methyl-4-oxidopyrazin-4-ium-2-carboxylate

Product 2

HCID 57992035Methyl 6-chloro-3-methylpyrazine-2-carboxylateYield 106%HCID 72218580Methyl 5-chloro-3-methylpyrazine-2-carboxylateYield 48.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of mixture of 2-(methoxycarbonyl)-3-methylpyrazine 1-oxide compound with 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (1:1) (5.1 g, 15.17 mmol) in toluene (50 mL) was cooled to 0° C. To the mixture was added phosphorus oxychloride (2.78 ml, 30.3 mmol) under nitrogen followed by n,n′-dimethylformamide (0.117 ml, 1.517 mmol). The reaction mixture was stirred at room temperature for 4 h and then was heated to 65° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc and washed with saturated NaHCO3 solution. The aqueous layer was back-extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The mixture was purified with ISCO (0% to 50% EtOAc/Hexanes) to afford both isomers: methyl 5-chloro-3-methylpyrazine-2-carboxylate (0.68 g, 48.1% yield) and methyl 6-chloro-3-methylpyrazine-2-carboxylate (1.5 g, 106% yield).

Workup

  1. temperaturewas heated to 65° C. for 18 h
  2. temperatureThe mixture was cooled to room temperature
  3. washwashed with saturated NaHCO3 solution
  4. extractionThe aqueous layer was back-extracted with EtOAc
  5. dry with materialThe combined organic extracts were dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe mixture was purified with ISCO (0% to 50% EtOAc/Hexanes)
  9. customto afford both isomers

Sources & evidence

ORD record
ord-302116827bbc4f6da8e88938c8ff13c7
Source dataset
uspto-grants-2016_04
Patent number
US09309263B2

Reaction notes

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