Copper-mediated Direct Sulfenylation Of The Purines C₈-H Bond With Thiols

The purine derivatives are an important class of pharmaceutical active intermediates that participate in life processes such as metabolism,energy conversion,and genetics in the organism.And sulfur-containing organic compounds are ubiquitous in natural products,drugs and biologically active molecules and organic materials.In recent years,the 6/8-sulfenylpurine derivatives synthesized by modification at the C6 and C8 positions have anti-tumor,anti-cancer and anti-viral activities,and their synthesis methods have become one of the key research directions in the field of organic synthesis.The traditional methods of the direct sulfenylation on the purine ring are:heterocyclic reaction,addition reaction and substitution reaction,but these methods usually require preactivation of purine substrates and face problems such as harsh reaction conditions,poor tolerance of substituents,low product yield,limited substrate adaptability and low atom economy.In recent years,the methods of directly functionalizing heterocyclic aromatic compounds C-H to construct C-C,C-N,C-O,and C-S bonds have developed rapidly,and have attracted much attention in the field of organic synthesis.These methods don't require preactivation of reaction substrates,and have the characteristics of simplicity,high efficiency,high atom economy and environmental friendliness.In our work,we developed the one-step air-oxidized copper-mediated C₈-H thiolation protocol for the coupling of purine derivatives with thiophenols in the presence of base.The coupling of 6-methylthio-9-ethylpurine?1a?with p-toluenethiol?2a?was chosen as the model to determine the optimal reaction conditions:1equivalent of Cu Cl,1,10-Phenanthroline as a ligand,Na₂CO₃ as a base,DMF as a solvent,purine derivatives reacted with thiols in an air atmosphere at 140°C for 18 h to obtain a series of 8-sulfenylpurine derivatives.The reaction is selective for C8 over C2 and C6;It also tolerates a free amine on the purine;The failure of the sulfenylation of the purines C₈-H bond with alkylthiols may be that alkylthiols have a lower reactive than thiophenols;DMSO can be used as a methylthiolation reagent and solvent to participate in the reaction;The reaction can be scaled up to the gram scale,and the target product can be obtained in good yield.To determine the product structure,we used ¹H NMR,¹³C NMR,HR-MS,IR,melting point and single crystal analysis methods.The single crystal data confirmed that the C₈-S cross-coupling reaction occurred on the C8 position of the purine derivatives,indicating excellent regioselectivity.To acquire insights into the mechanism of the reaction,control experiments were carried out,In accordance with some previous reports,a plausible mechanism is proposed.The Cu^II-superoxo intermediate extracts the H-atom of the thiophenol in the presence of air,then complexes with Ar S?to form an Ar S-Cu^II-OOH complex.Subsequently,the purine-coordinated intermediate formed by the coordination of the Ar S-Cu^II-OOH complex with the N-atom on the five-membered ring of the purine skeleton undergoes migration of the phenylthiolate group to the electrophilic sp² C8 of the purine ring to create a HOO-Cu-mercaptopurine complex.Finally,the complex undergoes the base-assisted deprotonation and dissociation of the N-Cu coordination bond to give the desired product and Cu^I-hydropero complex.However,the Cu^I-hydropero complex is subsequently oxidized to the Cu^II species and can't be recycled to participate in the reaction.