【作者】 葛军英；

【导师】 丁秋平；

【作者基本信息】 江西师范大学 ， 有机化学， 2021， 博士

【摘要】 N-杂环化合物在有机化学中占有非常重要的地位,广泛存在于天然产物和医药中间体中。因N-杂环化合物独特的结构特征和潜在的生物活性,在医药、农药、材料等领域具有重要的应用价值。吡咯是含氮杂环化合物之一,因其毒性比较低、生物活性比较独特,所以在香料和染料中应用广泛,在许多天然化合物和临床药物中也大量存在,是医药、农药和材料等领域中常见的结构单元。如抗炎药、抗肿瘤药、木糖酯类香料、叶绿素和生物碱都等含有吡咯结构单元。异噁唑也是一类重要的N-杂环化合物,是许多药物分子中常见的结构单元。许多含异噁唑骨架的分子具有广谱的生物学活性,例如抗癌、抗病毒、抗微生物、抗炎、抗真菌和其他药理活性。1,3-烯炔是合成杂环化合物的重要原料,被广泛应用于有机合成中。目前基于烯炔串联环化来合成杂环化合物是较普遍的方法之一。近年来,不少化学家对烯炔串联环化合成杂环化合物进行了大量的科学研究,并取得了显著成效。本论文主要研究了2-硝基-1,3-烯炔的串联环化官能化反应,提供了3类吡咯衍生物和1种异噁唑衍生物的合成方法。本论文的研究工作主要有以下4个部分内容:（1）三氟甲基取代的含氮杂环化合物是目前研究比较热门的有机化合物之一,本文第一部分发展了一种含三氟甲基的全取代吡咯衍生物的有效方法。该方法是在Cu（OAc）₂·H₂O和[Cp^*Rh Cl₂]₂的催化作用下,Togni’s试剂（II）被用作CF₃自由基的前驱体,2-硝基-1,3-烯炔通过串联氮杂迈克尔加成、三氟甲基环化、氧化反应生成全取代的三氟甲基吡咯。（2）有机叠氮类化合物是一类重要化工原料和合成中间体,在医学,生物学和材料科学领域有广泛应用。本文第二部分内容发展了一种由2-硝基-1,3-烯炔、胺和TMSN₃三组分之间的串联环化反应合成叠氮基取代的吡咯衍生物的方法。该反应的可能机制涉及串联氮杂-迈克尔加成、铜催化的分子内环化,以及锰催化的自由基叠氮化和氧化芳构化历程。该反应显示出了高区域选择性,广泛的底物范围和温和的反应条件。同时对叠氮基多取代吡咯化合物进行了衍生化反应,以较好收率得到胺基取代的吡咯产物。（3）磺酰基杂环是众多药物分子中的关键组成部分,因其有独特的生物学活性,以及物理和化学性质,已广泛用于药物化学中。本文第三部分通过铜（Ⅱ）催化2-硝基-1,3-烯炔、胺和苯亚磺酸钠的三组分串联环化反应,制备了一系列含有苯磺酰基的异噁唑衍生物。该方法显示出良好反应效率、化学选择性,以及广泛的底物适应性。其机理可能涉及氮杂-迈克尔加成,分子内环化,磺酰化和氧化芳构化。（4）亚硝基杂环化合物是一类非常重要的有机化合物,是有机合成的重要中间体。本文第四部分内容研究了钯催化下,2-硝基-1,3-烯炔与芳香胺通过迈克尔加成、分子内环化、质子转移、脱水和芳构化生成亚硝基吡咯的反应,为亚硝基吡咯衍生物的合成提供了有效的新方法。更多还原

【Abstract】 N-Heterocyclic compounds occupy a very important position in organic chemistry,which are also commonly used in natural products and pharmaceutical intermediates.Because of their unique structural characteristics and potential biological activity,N-heterocyclic compounds have an important application value in the fields of medicine,pesticides,and materials and so on.Pyrrole is one of the important N-heterocyclic compounds.It’s widely used in perfumes,dyes,natural compounds,clinical drugs,medicines,pesticides,and materials due to its low toxicity and unique biological activity.For examples,many anti-inflammatory drugs,anti-tumor drugs,xylose ester flavors,chlorophyll and alkaloids contain pyrrole structural units.Isoxazole is also an important N-heterocyclic compound,which is a common structural unit in many drug molecules and pesticides.Many Isoxazole derivatives show broad-spectrum biological activities,such as anti-cancer,anti-viral,anti-microbial,anti-inflammatory,anti-fungal,and some other pharmacological activities.1,3-Enyne is an important raw material for the synthesis of heterocyclic compounds,widely used in organic synthesis.Synthesis of heterocycles via tandem cyclization of enynes is a common efficient method.Recently,great progresses have been made on the synthesis of heterocycles via tandem cyclization of enynes.Herein,we study the tandem cyclization/functionalization of 2-nitro-1,3-enynes to provide 3kinds of functionalized pyrrole derivatives and a new route to isoxazole derivatives.This thesis mainly covers the following four parts:（1）Trifluoromethyl substituted N-containing heterocycles are one of the most popular organic compounds.The first part describes an effective method for the synthesis of fully substituted trifluoromethylpyrroles.This method covers the catalytic system of Cu（OAc）₂·2H₂O and[Cp^*Rh Cl₂]₂,using Togni’s reagent（II）as the precursor of trifluoromethyl free radical.The mechanism involves the cascade aza-Michael addition/trifluoromethylation cyclization/oxidation reaction of 2-nitro-1,3-enynes.（2）Organic azides are important chemical raw materials and intermediates,which are widely used in medicine,biology,and material science.The second part of this paper provides a method for the synthesis of fully substituted azido pyrrole derivatives from 2-nitro-1,3-enynes,amines,and TMSN₃.The possible reaction mechanism involves the continuous tandem aza-Michael addition,copper-mediated intramolecular cyclization,Mn-catalyzed free radical azide and oxidative aromatization process.The reaction showed high regioselectivity,wide substrate scope,and mild reaction conditions.In addition,the synthetic application of fully substituted azido pyrrole was examined.The azido pyrrole could be easily converted to the corresponding free amine via reduction reaction in good yield.（3）Sulfonyl heterocycles are a key component of drug molecules and have been widely used in medicinal chemistry.They have unique biological activities and physical and chemical properties.In the third part of this paper,a series of benzenesulfonyl substituted isoxazole derivatives were prepared by copper（II）catalyzed three-component tandem cyclization reaction of 2-nitro-1,3-enynes,amines,and sodium benzenesulfinates.This method shows good reaction efficiency,chemical selectivity,as well as a broad substrate scope.The mechanism may involve tandem aza-Michael addition,intramolecular cyclization,sulfonylation,and oxidative aromatization.（4）Nitroso heterocyclic compounds are a very important class of organic compounds and intermediates,which are widely used in organic synthesis.The fourth part of this paper studies the Pd-catalyzed tandem cyclization reaction of 2-nitro-1,3-enynes and aromatic amines through Michael addition,intramolecular cyclization,proton transformation,dehydration,and aromatization.It provides an effective new method for the synthesis of nitrosopyrroles.更多还原