【作者】 江伟；

【导师】 林东恩；

【作者基本信息】 华南理工大学 ， 应用化学， 2020， 硕士

【摘要】 嘌呤类衍生物是一类重要的药物活性中间体,参与生物体内的新陈代谢、能量转换和遗传等生命过程。而含硫有机化合物普遍存在于天然产物、药物和生物活性分子以及有机材料中。近些年来,在C6和C8位经修饰而合成的6/8-烃硫基嘌呤衍生物由于具有抗肿瘤、抗癌和抗病毒等活性,其合成方法成为有机合成领域的重点研究方向之一。嘌呤环上进行烃硫基化反应的传统方法主要有:杂环化反应、加成反应和取代反应,但这些方法通常需要对嘌呤底物进行预活化,且面临着反应条件恶劣、取代基耐受性较差、产物收率较低、底物适应性有限且原子经济性低等问题。近年来,杂环芳香化合物C-H直接官能团化构建C-C、C-N、C-O、C-S键的方法发展迅猛,在有机合成领域备受瞩目。这些方法无需对反应底物进行预活化,具有简捷高效、原子经济性高和绿色环保等特点。本课题以硫醇为烃硫化试剂,在碱性条件下使用便宜易得的铜试剂介导而活化C₈-H键,一步合成一系列8-烃硫基嘌呤衍生物。以6-甲硫基-9-乙基嘌呤和对甲苯硫酚为模型,探索嘌呤衍生物C₈-H键与硫醇直接烃硫基化反应的最优条件:氯化亚铜（Cu Cl）1当量,1,10-菲罗啉为配体,Na₂CO₃为碱,空气中的氧气为氧化剂,DMF为溶剂,于140°C下反应18 h以较高产率获得目标产物。铜介导嘌呤衍生物直接烃硫基化反应只发生在C₈-H键,不会发生于C₂-H和C₆-H键上;嘌呤C6和C2位为氨基基团在反应体系中耐受;芳基硫醇比烷基硫醇的反应性强,且烷基硫醇与6-甲硫基/氯-9-烷基-嘌呤发生亲核取代反应后,存在强空间位阻效应,阻碍嘌呤环C₈-H键的偶联反应;DMSO可同时作甲硫醇化试剂和溶剂参与该反应;该反应可以扩大到克级。为确定产物结构,我们对其进行了¹H NMR、¹³C NMR、HR-MS、IR、熔点和单晶数据等表征。通过单晶数据确定该反应高选择性地发生在嘌呤的C8位。我们为探索该反应机理,进行一系列控制实验,结合前人报道的文献,提出了一个可能的机理:在氧气存在下,Cu Cl与配体的络合物和硫酚形成Ar S-Cu ^II-OOH复合物,再与嘌呤咪唑环的N7原子络合,苯硫基团转移到嘌呤环的亲电sp² C8上后,生成HOO-Cu-烃硫基嘌呤复合物,经过碱辅助去质子化和N-Cu配位键的解离,得到8-烃硫基嘌呤衍生物。更多还原

【Abstract】 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 Sˉto 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.更多还原