N-9 Alkylation Of Purine Derivatives Based On Radical Oxidative Coupling Reaction

The structure of acyclic nucleosides consists of bases and side chains,the modified purine nucleoside analogue has unique biological activity and has wide application in clinical as antiviral and antitumor chemotherapy nucleoside drugs.Therefore,efficient and highly selective synthesis of purine nucleoside analogues is a key area of research in the field of organic methodology.In the past,traditional methods for synthesizing purine nucleoside analogues mainly included:substitution reactions,addition reactions,etc.However,these methods usually require preactivation of the reaction substrates and the reaction conditions are harsh,resulting in many by-products,low selectivity and low atomic economy.In recent years,the direct functionalization of C-H bond has developed rapidly and is an efficient method for the synthesis of C-C,C-N,C-O and C-S bonds.The method does not require complicated pre-activation of the reaction substrate,and the transition metal can be used as a catalyst to chelate with the substrate to activate the C-H bond of the substrate.With the continuous development of C-H direct functionalization,cross dehydrogenation coupling reaction?CDC?has become an important area of interest for researchers due to its high atom economy and wide range of applications.Oxidative coupling reaction,one of the CDC methods,reaction process involves free radicals,is a green and efficient way in line with atomic economy.Therefore,it is an important research method of synthetic chemistry.In our work,6-chloropurine and tetrahydrofuran?THF?were used as reaction substrates for the oxidative coupling reaction.The optimal reaction conditions were selected by screening reaction conditions:TBAI as a catalyst,TBHP as an oxidant,readily available and inexpensive alkyl ethers and benzyl compounds were used as the alkylating agent and also used as the solvent,purine derivatives reacted with the alkylating agent in an air atmosphere at 90oC for 12 hours to obtain a series of purine N-9 alkylation products.This catalytic system has wide applicability of substrates,purine rings bearing the electron donating groups or electron withdrawing groups at the C-2 and C-6 positions do not affect the smooth progress of the reaction.Even the amino and methylthio groups at the C-6 position of purine rings could be tolerated under the oxidative conditions.In addition,both cyclic and chain ethers were suitable reaction substrates for this transformation.Toluene derivatives with electron-donating substituents furnished higher yields of desired products than with electron-withdrawing substituents.Moreover,the coupling reaction proceeded successfully when employing benzylic substrates with steric hindrance.It worth noting that the reaction can smoothly performed on a gram-scale and obtain the desired products with good yield.To determine the product structure,we used ¹H NMR,¹³C NMR,IR,HR-MS,and single crystal analysis methods.And the single-crystal data confirmed that the purine alkylation occurred at the N-9position.In addition,to elucidate the mechanism of this coupling reaction,several control experiments were carried out.We detected and captured free radical intermediates,but did not detect the presence of iodo compounds intermediates.Combined the control experimental results with the previous research results,we proposed a possible reaction mechanism:a free radical intermediate transformed into an oxonium ion or a benzyl cation via a single electron transfer in the reaction process.