Cyanomethylenetributylphosphorane

Used Chemicals

• 3,4-Dihydro-7-hydroxy-2(1H)-quinolinone [D3599]
• 4-(2-Hydroxyethyl)morpholine [H0244]
• Cyanomethylenetributylphosphorane (= Tsunoda Reagent) [C1500]
• Toluene

Procedure

To a solution of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (500 mg, 3.06 mmol), 4-(2-hydroxyethyl)morpholine (0.45 mL, 3.7 mmol, 1.2 eq.) in toluene (15 mL) was added Tsunoda reagent (1.0 mL, 3.8 mmol, 1.25 eq.) at r.t. and the mixture was stirred at 100 °C for 3 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (dichloromethane:methanol = 1:0 - 10:1 on silica gel) to give 1 as a white solid (790 mg, 93%).

Experimenter’s Comments

The reaction mixture was monitored by UPLC.

Analytical Data

Compound 1

¹H NMR (270 MHz, DMSO-d6); δ 9.97 (s, 1H), 7.41 (d, 1H, J = 7.8 Hz), 6.49 (d, 1H, J = 8.1 Hz), 6.43 (d, 1H, J = 1.9 Hz), 4.00 (t, 2H, J = 5.7 Hz), 3.59-3.55 (m, 4H), 2.78 (t, 2H, J = 7.3 Hz), 2.65 (t, 2H, J = 5.7 Hz), 2.46-2.33 (m, 6H).

Lead Reference

• Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy
• Ó. M. Bautista-Aguilera, L. Ismaili, M. Chioua, R. Andrys, M. Schmidt, P. Bzonek, M. Á. Martínez-Grau, C. D. Beadle, T. Vetman, F. López-Muñoz, I. Iriepa, B. Refouvelet, K. Musilek, J. Marco-Contelles, Int. J. Mol. Sci. 2020, 21, 3913.

References

• Carbon-carbon bond formation with new Mitsunobu reagents
• T. Tsunoda, M. Nagaku, C. Nagino, Y. Kawamura, F. Ozaki, H. Hioki, S. Ito, Tetrahedron Lett. 1995, 36, 2531.
• Formation of heterocycles by the Mitsunobu reaction. Stereoselective synthesis of (+)-α-skytanthine
• T. Tsunoda, F. Ozaki, N. Shirakata, Y. Tamaoka, H. Yamamoto, S. Ito, Tetrahedron Lett. 1996, 37, 2463.