Purine-Directed Palladium-Catalyzed C-H Bond Activation

Purine, purine nucleosides and their derivatives belong to a special class of aromatic heterocycle compounds. Since they are found to behave a wide range of biological and pharmaceutical activities, the derivatives of purine and purine nucleosides have attracted much interest. Currently, chemical synthesis is the main access to the derivatives of purine and purine nucleosides. In recent years, many research teams devote themselves to the modification of purine and purine nucleosides. As a result, chemical synthesis methods have made tremendous progress and thus provide strong support for the development of purine's and purine nucleosides'drugs that may preferably cure human diseases.The chemical synthesis methods of the derivatives of purine and purine nucleosides which people have developed in recent years can be concisely concluded in three kinds, namely, SN2Ar reaction (aromatic nucleophilic substituted reaction), transition metal-catalyzed cross-coupling reaction, transition metal-catalyzed C-H bond activation. Generally speaking, SN2Ar reaction is mainly limited to synthesize the derivatives of nucleophilic reagents substituted at C6 or C2 site of purine. Moreover, the range of nucleophilic reagents in SN2Ar reaction is rather narrow, such as HN(R1)R2, RNH2,HOR, HSR and so on. Additionally, the functional groups lying in the structures of these nucleophilic reagents tend to disturb the desired reaction. Transition metal-catalyzed cross-coupling reaction presents as a complementary tool to the synthesis of the derivatives of purine and purine nucleosides in comparison to SN2Ar reaction. A variety of C-heteroatom bonds can be conveniently constructed via transition metal such as Pd, Ni, Fe-catalyzed cross-coupling reaction, thus obtaining a series of desired purine's derivatives. The conditions of cross-coupling reaction however, are rather rigorous. For example, the reaction usually employs notable metals such as Pd, Ni as the catalysts and requires various auxiliary ligands such as organic phosphine. Furthermore, the involved organometallic reagents tend to require to be stepwise prepared and are sensitive to air and moisture. To overcome these shortcomings, organic chemists also have developed a transition metal-catalyzed C-H bond activation method for the synthesis of purine's and purine nucleosides'derivatives. This method have the virtue of directness and convenience, which not only dispenses with the pre-activation of C-H bond to C-X (X= Cl, Br, I, OTf, etc) bond, but also employs easily available electrophilic or nucleophilic reagents instead of organometallic reagents. Notably, the hydroxyl group which lies in the sugar entity of purine nucleosides doesn't need not to be protected in some cases. Unfortunately, this method is limited to the modification of C2, C6 and C8 sites of purine. Moreover, the reaction proceeds sluggishly and usually requires some ligands under the method.In last decades, substrate-directed transition metal-catalyzed C-H bond activation has become a hot topic in the research and has been widely applied in the field of organic synthesis. This approach can be easily conducted under mild conditions and the high regioselectivity, stereoselectivity as well as yield can be also obtained in the presence of auxiliary ligands. As we know, purine molecule behaves multiple nitrogen atoms, and we envisioned that purine may offer a nitrogen atom to effectively bind to the metal center, and thus selectively delivers the catalyst to a proximal C-H bond. To the best knowledge of us, there have no reports that purine severs as a directing group for metal-catalyzed C-H bond activation. Consequently, applying substrate-directed transition metal-catalyzed C-H activation to the modification of purine and purine nucleosides not only severs as an important complementary for the above synthesis methods, but also becomes a challenging task for us.We herein report that purine functions as a directing group for palladium-catalyzed aryl C-H bond functionalizations and Heck reaction. With the assist of purine, highly regioselective construction of C-X (X= Cl, Br) and C-OR of C6-aryl substituent and the regiospecific arylation of N9-allyl substituent in purine's structure have been achieved, and the double bonds of terminal olefins don't migrate, which provides a facile method for the modification of purine and purine nucleosides. At the same time, we elucidate the likely reaction mechanism based on related literatures and our preliminary study. We have synthesized thirty six compounds which had never been reported before via the newly developed methods. The structures of all target products are characterized by 1H NMR, 13C NMR and HRMS. In addition, some new purine compounds not only enrich the world of purine and purine nucleosides, but also may potentially behave application in activities.