Propanal → 5-Methoxy-3-methylquinoline

HRID 495430Notes

Reaction equation

HRID 495430 reaction equation
[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)[C:2]([CH3:5])([CH3:4])C.C([Li])(CC)C.C1CCCCC1.CN(C)C=O.C(=O)CC.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1>O1CCCC1>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]2[C:9]=1[CH:5]=[C:2]([CH3:4])[CH:1]=[N:7]2

Participants

9

Reactant 7

HCID 527PropanalHCID 1140TolueneHCID 6228DimethylformamideHCID 8078CyclohexaneHCID 546358N-(3-methoxyphenyl)pivalamideHCID 3251421Potassium bis(trimethylsilyl)amideHCID 178418400CID 53628100

Product 1

HCID 157236185-Methoxy-3-methylquinolineYield 5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
2.5 °C

Procedure

To a stirred solution of N-pivaloyl-3-methoxyaniline (4.14 g, 20 mmol) in dry tetrahydrofuran (80 mL) at 0° C. under argon was added a solution of sec-butyllithium in cyclohexane (1.4 M, 35.7 mL, 50 mmol), dropwise over 0.2 h (T≦0° C.) and the resulting mixture was stirred at 0-5° C. for 2 h. The mixture was cooled to −5° C. then dry N,N-dimethylformamide (2.3 mL, 30 mmol) was added dropwise, and the resulting solution stirred at 0° C. for 1 h then at 20° C. for 20 h. The mixture was cooled to 0° C. and propionaldehyde (1.17 g, 20.2 mmol) was added dropwise followed by a solution of potassium hexamethyldisilazide in toluene (0.5 M, 80 mL, 40 mmol) dropwise over 0.2 h. The mixture was stirred at 0° C. for 0.25 h, then at 20° C. for 2 h and at 30° C. for 1 h. The resulting mixture was partitioned between saturated aqueous NH4Cl (200 mL) and ether (3×50 mL), and the combined organic extracts dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue on silica with 20-100% ether in hexane gradient elution gave 5-methoxy-3-methylquinoline (0.16 g, 5%) as an oil. A mixture of 5-methoxy-3-methylquinoline (0.16 g, 0.92 mmol) and pyridine hydrochloride (0.064 g, 5.5 mmol) was heated under argon at 200° C. with stirring for 2.5 h, then cooled and partitioned between saturated aqueous NaHCO3 (30 mL) and dichloromethane (5×30 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by chromatography on silica eluting with ethyl acetate to give the title compound (0.089 g, 60%) as a solid.

Workup

  1. temperatureThe mixture was cooled to −5° C.
  2. stirringthe resulting solution stirred at 0° C. for 1 h
  3. waitat 20° C. for 20 h
  4. temperatureThe mixture was cooled to 0° C.
  5. stirringThe mixture was stirred at 0° C. for 0.25 h
  6. waitat 20° C. for 2 h
  7. waitat 30° C. for 1 h
  8. customThe resulting mixture was partitioned between saturated aqueous NH4Cl (200 mL) and ether (3×50 mL)
  9. dry with materialthe combined organic extracts dried (Na2SO4)
  10. customevaporated in vacuo
  11. washChromatography of the residue on silica with 20-100% ether in hexane gradient elution

Sources & evidence

ORD record
ord-3ab06a02bb8e46ac8b34ec430c6e363d
Source dataset
uspto-grants-2005_09
Patent number
US06939871B2

Reaction notes

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