Purine-Directed Palladium-Catalyzed Arylation Of C6-Arylpurine(Nucleosides)

C⁶-modified purines and purine nucleosides exhibit a variety of biological activities and have attracted much interest in recent years. For example, N⁶- substituted adenine derivatives have the ability of inhibiting the growth of fungus and plant. S⁶-substituted purine derivatives behave antitumor activity and are usually used as immunity reagent for treating Leukaemia. 6-halopurines are not only the starting materials of synthesizing various anti-tumor and antiviral pharmaceuticals, but also themselves behave some biological activities. For example, C⁶-floropenciclovir exhibits antitumor activity and most of C⁶-alkyl, arylpurines have the ability of inhibiting the growth of cell.Traditionally, the synthetic maneuvers to them can be mainly attributed to two kinds. One method is SN2Ar reaction via attacking of prefunctionalized nucleophiles, which provides a very facile access to the construction of C⁶-O, C⁶-S, C⁶-N, C⁶-P bond and so on. Another is transition metal such Palladium, Nickel, Ferrous-catalyzed cross-coupling reactions of organostin, organoboron, organozinc, organomagnesium reagents with 6-halopurines (i.e. Stille, Suzuki, Negishi, Kumada cross coupling), which emerge as a powerful tool for efficiently constructing C⁶-C bond of purine. Both of the two methods are problematic and complementary to each other. Firstly, nucleophiles applicable for SN2Ar reaction of purines are very limited. Furthermore, functional groups lying in such nucleophiles tend to interfere into the desired transformation. Secondly, prefunctionalized organometallic reagents bear some shortcomings such as difficulty in preparation, experimental operation as well as sensitivity to moisture and air.Over the past decade, substrate-directed metal-catalyzed C-H bond activation has attracted much interest and made great progress. Such reaction directly transforms C-H bond to the C-M bond with the assist of directing group and dispenses with the transformation of C-H bond to C-X bond. Consequently, the reaction routes have been shortened. In conclusion, directed C-H activation bears the virtues such as easy operation, high selectivity, high yield and auxiliary ligand-free. To the best knowledge of us, there have no reports on purine-directed metal-catalyzed C-H bond activation so far. As such, application of substrate-directed C-H bond activation to purines and purine nucleosides remains a critical challenge.In this paper, we firstly report that highly regioselective construction of CAr-CAr, CAr-X (Cl, Br), C_Ar-OAc and C_Ar-OR among C⁶-aryl purines and purine nucleosides via purine-directed palladium-catalyzed C_Ar-H bond activation, which presents a facile approach to modified purines and purine nuclesides. At the same time, based on analysis on the experimental results and referring to related literatures, we elucidate the possible reaction mechanism. Besides, some new products both enrich the world of purines and purine nucleosides and potentially behave biological activities. Structures of all the terminal products and most of reaction intermediates are characterized by ¹H NMR, ¹³C NMR, HRMS.