Metal-Free Catalyzed Highly Regioselective Functionalization Of Purines Skeleton

The purine derivatives is a kind of very important compound.Adenine and guanine are two structures in nucleic acid of human beings.Meanwhile purine-8-ones compounds have great medicinal benefits because they are the vital component part of many natural purine nucleosides.A large amount of purine nucleosides with different modified groups play an inportant role because of their unique value such as antivirus,antitumor and antihypertensive.Therefore,scientists have fucused on the study of purine nucleosides analogues in the past few decades.People's final mission is to build up purine nucleosides analogues with innovtive structures and explore their potential physiological and pharmacological application.Previously,the troditional methods of synthesizing purine nucleosides mainly included alkylation reaction,Michael addition reaction,ring-opening reaction with cyclic compounds,Mitsunobu reaction,allylation reaction and so on.However,these syntheses mentioned above have suffered from substrate preactivation,expensive reagents,low reaction selectivity and hard reaction condition.Recently,oxidative dehydrogenation coupling have become a hot area in organic synthesis chemistry.Many scientists have reported the C-N bond formation of heterocycle aromatic hydrocarbons via a radical oxidative coupling reaction.In the meantime,research of oxidative dehydrogenation coupling provides a brand new route for purine nucleosides synthesis.In this paper,we developed a transition-metal-free approach of 7-alkyl-9 alkoxy/alkothio purine-8-ones compounds with purine derivatives and alkyl ether/thioether compounds via an oxidative functionalization.We carried out the optimization studies useing6-chloro-purine?0.1 mmol,22.4 mg?and tetrahydrofuran?4 mmol,0.36 ml?as model substrates and then found out that 0.2 equivalent of I₂,3.0 equivalents of tert-Butyl hydroperoxide and 2.0 equivalents of K₂CO₃ at 90?for 12 hours in the air were the most suitable conditions,giving the objective product in 89%yield.This method has a favourable substrates applicability,working successfully with a diverse range of substituted purines and?cyclo?alkyl ether/thioether compounds.In addition,all of the structure of purine-8-ones compounds are vertified by ¹H NMR spectra,¹³C NMR spectra,long range ¹H-¹³C HMBC spectra,HR-MS and IR analysis methods.Combining a series of controlled experimental results and previous research,a possible mechanism of this directly functional reaction containing a free radical intermediate and quaternary ammonium salt is depicted below.We have developed a metal free catalyzed highly regioselective functionalization reaction of purine skeleton with mild reaction conditions and inexpensive reagents.This reaction can tolerate some certain active hydrogen and radical groups,opening a simple and efficient way to achieve purine nucleosieds analogues derivatization.