Tetrahydrofuran → Methyl 5-bromo-6-methylnicotinate

HRID 468918Notes

Reaction equation

HRID 468918 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Br.O1CCC[CH2:14]1.C[Mg]Br>C1COCC1.C1(C)C=CC=CC=1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[CH3:14]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 12677292Methyl 5,6-dibromonicotinateHCID 178418573HCID 178418573, compound2×

Product 1

HCID 58001778Methyl 5-bromo-6-methylnicotinateYield 44%

Reagents, catalysts & solvents 2

HCID 2724937Dichloro(1,1'-(1,3-propanediyl)bis(1,1-diphenylphosphine-kappaP))nickelCatalystHCID 22635083Tetrahydrofuran tolueneSolvent2×

Procedure

To a solution of methyl 5,6-dibromopyridine-3-carboxylate (0.5122 g; 1.737 mmol) in tetrahydrofuran (10.0 mL; 123 mmol) at 0° C. (using an oven-dried flask) was added 1,3-bis(diphenylphosphino)propane nickel(II) chloride (98.0 mg; 0.179 mmol). After 5 minutes, methylmagnesium bromide (1.4 mol/L) in THF:toluene (1:3) (1.6 mL; 2.2 mmol) was added dropwise. After addition was complete, the reaction mixture was stirred at room temperature. After 8 hours, methylmagnesium bromide (1.4 mol/L) in THF:toluene (1:3) (1.0 mL) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic portion was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-30% ethyl acetate in dichloromethane) to yield 174.1 mg (44%) of the title compound. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=1.4 Hz, 1H), 8.39 (d, J=1.4 Hz, 1H), 3.89 (s, 4H), 2.67 (s, 4H).

Workup

  1. additionAfter addition
  2. waitAfter 8 hours
  3. stirringthe reaction stirred at room temperature overnight
  4. customThe reaction mixture was quenched with saturated aqueous NH4Cl
  5. extractionextracted with ethyl acetate
  6. dry with materialThe organic portion was dried over MgSO4
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-30% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-f17084abf7f74af78efc5e4ff1ba3adc
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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