Construction Of Isoindolinone By Cascade Reaction Of Multiynes With Imidazole Derivatives

The Catalyst-Free Hexadehydro-Diels–Alder (HDDA) Reaction ofvarious substituted tetraynes and imidazoles derivatives were described inthis paper. Heterocyclic compounds with nitrogen atom in the ringusually are drug intermediates and with some desirable biological activity.Therefore, the nitrogen containing heterocyclic synthesis receivedextensive attention of chemists. The imidazole ring structure existswidely in biological molecules since the electrophilic aromaticsubstitution reaction of imidazole would be more easily than other1,3-diazole. Many important biological molecules contain imidazolefunctional groups, which play also important roles of many drugs.Isoindolinone skeleton with potential antitumor activity is a kind ofimportant pharmaceutical intermediates and of potentially importantpharmaceutical application prospect, draw a growing interest in thesynthesis of these compounds.The HDDA cyclization reactions of palladium-catalyzed tetraynesderivatives and imidazole derivatives were discussed. Through theoptimization of the reaction conditions, we developed a mild catalyst-freesynthesis of isoindolone skeleton compounds in high yields. This methodwas simple, also accorded with the requirement of atom economy ofgreen chemistry. Different substituted imidazole(R1-C3H2N2，R1=CH3,，CH2CH3，CH2CH2CH3，CH2CH2CH2CH3，CH2CH=CH2) derivativesreact with tetraynes under O2atmosphere. Imidazole derivatives andtetraynes substrates could be effectively react at100℃produced21polycyclic compounds with isoindolinone skeleton structure. Weproposed the plausible mechanism of the reaction, tetraynes substratesformed benzyne intermediates by self-cyclization then reacted with imidazole derivatives to get the unstable bridge-ring compounds throughthe HDDA reaction. The unstable bridge-ring compounds were easy to beoxidized to take off HCN for isoindolones skeleton structure. It is foundthat the electron-withdrawing group whether in imidazole derivatives ortetraynes substrates, had promoting effect in the reaction. All productswere characterized by1H NMR,13C NMR, IR, and HRMS, structure ofone of the products was also confirmed by X-ray single crystal structureanalysis.