Regioselective Condensation of Alkylidenephosphoranes to N-Methoxy- and N-Anilino-1H isoindole-1,3-(2H)-diones

Abstract

Treatment of 2-methoxyisoindoline-1,3-dione with resonance-stabilized alkylidenephosphoranes afforded the corresponding monoalkenes as the sole reaction product, in ∼58–63% yields, whereas more than 80% yields of the same monoolefin products were obtained when the reactions were carried out under microwave conditions. Similarly, 2-(phenylamino)isoindoline-1,3-dione reacted under either thermal or microwave conditions to give only the corresponding monoalkene derivatives. The alkene products from both substrates were further reduced to the corresponding isoindoles using Zn-dust in EtOH. Prediction of the designed compounds and the in vivo anti-inflammation activity of the products in the rat adjuvant model were also studied. The work is the first demonstration of the anti-inflammatory activity of phthalimide derivatives.

GRAPHICAL ABSTRACT

Keywords:

• Alkylidenephosphoranes
• inflammatory inhibition
• N-substituted phthalimides
• olefination

ACKNOWLEDGMENTS

Financial support from the Egyptian Academy of Scientific Research and Technology is gratefully acknowledged. We thank the National Central Laboratory of Toxicology, Cairo, Egypt, for carrying out the pharmacological screening.

Notes

^a Data are means of at least two independent determinations with 6 animals in each group (in a dose of 50 mg/kg body weight), and the deviation in absorbance values was less than 10%.

^b A = Indomethacin (used as a reference standard).

^c (SEM: standard error of the mean) statistical significance of results was established using the Student's t-test (***) P < 0.001; (**) P < 0.01; (*) P < 0.05. The anti-inflammatory activity (prediction results * > ** > ***) was expressed as percentage inhibition of edema volume in treated animals in comparison with the control group as described in the experimental section.