Methyl iodide → 6-Isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

HRID 749088Notes

Reaction equation

HRID 749088 reaction equation
[C:1]([C:3]1[C:4](=O)NC(C)=C[CH:8]=1)#[N:2].[CH:11]([N-:14]C(C)C)(C)C.[Li+].CI.[OH-].[Na+].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:11]([C:26]1[C:27](=[O:23])[NH:2][C:1]([CH:3]([CH3:4])[CH3:8])=[CH:24][CH:25]=1)#[N:14]

Participants

6

Reactant 5

HCID 6328Methyl iodideHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 779193-Pyridinecarbonitrile, 1,2-dihydro-6-methyl-2-oxo-HCID 2724682Lithium diisopropylamide

Product 1

HCID 105831136-Isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrileYield 18%

Procedure

A solution of 3-cyano-6-methyl-2(1H)-pyridinone (10.0 g, 74.6 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to −78° C. under nitrogen and reacted slowly with lithium diisopropylamide solution (40 mL of 1.4 M and 85 mL of 2.0 M, 226 mmol total) via syringe. After warring to 0° C. and stirring 2 hours, methyl iodide (10 mL, 160 mmol) was added and the reaction stirred 18 hours at ambient temperature. The reaction was poured into 0.67 N NaOH (300 mL), the phases separated, the aqueous layer washed with diethyl ether, and the combined organic layers extracted with water. The combined aqueous layers were acidified to pH 4 with 6 N HCl and extracted with methylene chloride, and the methylene chloride layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (1:1 methylene chloride:ethyl acetate) giving the title compound as a light yellow solid (2.15 g, 18%). 1H NMR (300 MHz, CDCl3) δ 13.25 (br s, 1H), 7.84 (d, 1H, J=7.5 Hz), 6.23 (d, 1H, J=7.5 Hz), 3.00 (septet, 1H, J=7.0 Hz), 1.36 (s, 3H), 1.34 (s, 3H). Also recovered from the column was the mono-methylated side-product 3-cyano-6-ethyl-2(1H)pyridinone (5.50 g, 50%), which was used to make the title compound in Example 97. 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=7.5 Hz, 1H), 6.23 (d, J=7.4 Hz, 1H), 2.76 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.5 Hz, 3H).

Workup

  1. customAfter warring to 0° C.
  2. stirringthe reaction stirred 18 hours at ambient temperature
  3. customthe phases separated
  4. washthe aqueous layer washed with diethyl ether
  5. extractionthe combined organic layers extracted with water
  6. extractionextracted with methylene chloride
  7. washthe methylene chloride layer was washed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated in vacuo
  11. customthe residue purified by flash column chromatography (1:1 methylene chloride:ethyl acetate)

Sources & evidence

ORD record
ord-1204b504f0234322997fd91078c09b71
Source dataset
uspto-grants-2008_07
Patent number
US07402586B2

Reaction notes

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