Iodine-catalyzed Synthesis Of 9-benzylpurin-8-one Analogues With Methylarenes

Nitrogen heterocyclic compounds are a key active structure of many natural products.Among them,purine nucleosides and their derivatives have significant biological activity with excellent therapeutic effects as cancer treatments,and antiviral agents.Thus they occupy an important position in the field of medicine.In recent years,the construction of heterocyclic ketones has rapidily developed in both organic chemistry and pharmaceutical synthesis.Purin-8-ones,typical heterocyclic ketones,are usually synthesized via a purine C₈-H halogenation-hydrolysis reaction,via the use of a transition metal catalyst or via a cyclization reaction.Other heterocyclic ketones are constructed by the functionalization of the C（sp²）-H oxidation which is mediated by a metal or a non-metal catalyst,or through the cyclization of multiple components.Methylarenes often participate in the formation of new C-N,C-C bonds as good alkylating reagents and acylating reagents.The direct C-H activation functionalization method has been rapidly developed with excellent atom economy,and simple reaction conditions.This method abandons the traditional synthesis that require cumbersome halogenation or pre-activation steps.C-H activation provides an efficient channel for purine structural modification and synthesis of its derivatives,providing more choices for drug researchers to screen valuable bioactive molecules.This work uses methylarenes as alkylating reagents,and a metal-free catalyst system.The C=O and N-C bonds are efficiently constructed based on the purine structure via a one-pot difunctionalization to provide a series of 9-benzylpurin-8-one analogues.Using 6-chloro-7-benzylpurine and toluene as substrates,the best reaction conditions for the purine C₈=O and N₉-benzylation reaction were determined as:20 mol%iodine（I₂）,3.0 equiv of tert-butyl hydroperoxide（TBHP）,toluene as both the alkylating reagent and solvent,while reacting for 12h in air at 90℃.Under these conditions,the desired product was obtained with a 70%yield.Various substituted purine or benzimidazole derivatives reacted well with different methylarenes in this reaction system.The products were characterized by NMR,HR-MS,MP,IR and SC-XRD analysis.The single crystal data indicated that a new N₉-benzylation,C₈-carbonylation structure was formed from the N₇-protected purine ring.Control experiments were carried out to explore the reaction mechanism.Using these results combined with previous reports,a plausible reaction mechanism is proposed.Initially,t-Bu O-I and HO-I are generated by I₂ and TBHP.The benzylic C（sp³）is iodinat via t-Bu O-I or HO-I to generate benzyl iodide（Bn I）.A nucleophilic substitution between Bn I and the purine generates the quaternary ammonium salt intermediate.Subsequently,TBHP reacting with the ammonium salt intermediate gives the purine C8 peroxide along with HI.The peroxide subsequently undergoes O-O bond cleavage to afford the purin-8-one product.The iodine catalyst is then regenerated by HI and TBHP.The reaction conditions are simple,mild and metal free,providing an effective method to synthesize purin-8-one analogues.