【作者】 宋霞；

【导师】 范学森；

【作者基本信息】 河南师范大学 ， 环境科学与工程， 2023， 博士

【摘要】 传统化学工业在为人类社会发展做出巨大贡献的同时,也对环境造成了严重污染。为实现零污染的化学工业,人们提出了一种从根本上消除化学污染的新思维、新方法、新战略—绿色化学,以期实现经济、环境和社会的和谐发展。绿色化学是一门从源头上减少或消除污染的化学,符合“碳达峰碳中和”的国家战略。绿色化学的主旋律是绿色合成。在诸多绿色合成策略中,惰性碳氢键活化因具有优异的原子经济性和步骤经济性等特点,降低了合成过程中对环境造成的危害,受到了人们的广泛关注并被发展成为快速构筑碳碳键和碳杂原子键的有效手段。目前,惰性碳氢键活化反应已经取得了丰硕的研究成果,但是螯合辅助的过渡金属催化C-H键活化反应大多局限于单一或对称的多重C-H键官能团化,而有关非对称多重C-H键官能团化的报道还很有限。另一方面,稠环类化合物在医药、能源、材料等领域具有非常广泛的应用,但是多数合成方法存在原料难以制备、合成路线长和效率差等不足之处,因此,发展简单、高效且绿色的合成方法制备稠环类化合物仍然具有较大的挑战。针对以上问题,本论文在绿色化学思想指导下,成功设计并开发了一些非对称多重C-H键活化的反应新模式,利用非对称多重C-H键活化以及C-H键活化-环化策略,设计并发展了一些具有重要应用价值的稠环类化合物的绿色合成新方法,从而有效减少了碳排放,在一定程度上提高了相关化学品制备的经济效益和环境效益。论文的主要研究成果如下:(1)论文研究并发现了以易得的N-芳氧基乙酰胺和重氮吡唑酮为原料,经由非对称双重C(sp~2)-H键活化及相应的卡宾插入等串联反应合成吡唑酮[螺]吲唑类化合物的新方法。初步的机理研究表明,N-芳氧基乙酰胺首先在三价铑的催化作用下发生C-H/N-H键活化-金属化,生成含有金属铑的五元环中间体,再与重氮吡唑酮配位生成卡宾中间体,随后经过卡宾迁移插入和质子化等过程,实现吡唑酮结构单元的引入;而新引入的芳基吡唑酮结构单元在该反应条件下可进而与第二分子重氮吡唑酮发生非对称的碳氢键活化-环化,生成相应的吡唑酮[螺]吲唑类化合物。该反应丰富了非对称多重碳氢键官能团化的研究内容,也为复杂螺环化合物的合成提供了简便、绿色的新策略。(2)在前一部分工作的基础上,进一步研究了N-芳氧基乙酰胺与重氮吲哚酮之间的串联反应,并通过该反应建立了双吲哚酮[螺]苯并二氢呋喃类化合物的高效合成新方法。初步的机理实验及密度泛函数(DFT)计算表明,N-苯氧基乙酰胺在三价铑的催化作用下先发生C-H活化并与一分子重氮吲哚酮反应生成卡宾中间体,该中间体可被第二分子重氮吲哚酮捕获,生成新的卡宾中间体并通过卡宾迁移插入等过程,最终生成双吲哚酮[螺]苯并二氢呋喃类化合物。简而言之,产物的生成经历了未见报道的碳氢键活化以及连续非对称卡宾迁移插入反应,从而为螺环/稠环化合物的合成提供了新途径,同时也揭示了N-芳氧基乙酰胺和重氮吲哚酮的反应新模式。另外,上述研究所得产物还可被方便地转化具有更高附加值的产物,从而进一步彰显了该合成策略的实用价值。(3)研究并发现了以易得的N-芳基斯德酮和联烯醇酯为原料,经由三价铑催化下的双重非对称C(sp~2)–H键活化-环化策略合成喹啉并环丁烷类化合物的新方法。初步的机理研究表明,N-芳基斯德酮在三价铑的催化下首先发生碳氢键金属化并生成相应的含有铑环中间体,该中间体与联烯醇酯配位,然后经过烯基迁移插入和β-氧消除等过程,生成N-芳基斯德酮上C4位烯丙基化中间体。该中间体在三价铑的作用下,进而与另一分子联烯醇酯配位并经过上述类似过程,完成N-芳基邻位的烯丙基化。最后经过分子内[2+2]环加成反应,生成喹啉并环丁烷类化合物。该工作不仅为非对称多重碳氢键官能团化提供了另一成功应用,而且为难以制备的喹啉并环丁烷类化合物提供了一种简便、绿色的合成方法。此外,所得到的喹啉并环丁烷产物可以进行多种结构转化,生成具有更高附加值的多环化合物。(4)研究并发展了经由N-芳基脒与炔丙基碳酸酯的串联反应高效合成1,3-苯二氮卓类化合物的新方法。值得强调的是,在产物的生成过程中,三价铑起到了催化C(sp~2)-H键活化和促进β-氧消除的双重作用。另一方面,空气则扮演了绿色辅助氧化剂的角色。这一串联反应首次实现了以N-芳基脒作为C5合成子和炔丙基碳酸酯作为C2合成子来构筑七元杂环。另外,部分产物对多种癌细胞具有显著的细胞毒性,显示出一定的开发利用价值。最后,采用多项绿色评价指标对本文方法和文献方法进行了绿色性评价及比较,结果表明本文所发展的合成方法在一定程度上符合绿色化学的要求。(5)研究并发展了N-酰基苯并咪唑类化合物的高效合成新方法。以N-芳基脒和二噁唑酮类化合物为原料,合成一系列N-酰基苯并咪唑类化合物。该方法首次实现了在一锅反应中同时完成苯并咪唑骨架的构建和N-酰基的引入。最后,利用多项绿色评价指标对本文方法和文献方法进行绿色性评价及比较,发现本文方法具有较高的原子经济性、较低的质量强度和环境因子,更加符合绿色化学的要求。(6)设计并研究了三价铑催化下苯甲酰乙腈与丙炔醇之间的串联反应,并基于该反应建立了合成苯并富烯类化合物的新方法。通过氢氘交换实验、分子间动力学同位素效应实验和密度泛函理论计算等手段,对反应机理进行了初步研究,并据此提出了产物生成的可能机理。进一步的研究还发现,所得产物可方便地转化为具有更高附加值的化合物,且该方法适用于较大规模的制备应用,这也进一步彰显了其实用价值。与文献方法相比,本文所建立的合成方法具有更高的原子经济性和反应质量效率及较低的质量强度和环境因子,因而更能满足绿色化学的需求。本论文在绿色化学思想指导下,利用三价铑催化碳氢键活化策略,通过碳碳键及碳杂原子键的构筑,建立了一系列简便、绿色的合成新方法,并利用这些方法制备了多种具有潜在生物活性的稠环类化合物。这些研究结果的取得,不仅拓展了碳氢键活化策略在有机合成中的应用范围,而且为相关天然产物及药物分子的绿色合成提供了新手段。更多还原

【Abstract】 To date,although great achievements have been made in the study of single C-H bond functionalization or symmetrical multiple C-H bond functionalization catalyzed by transition metals,the successful applications of unsymmetrical multiple C-H bond functionalization are rather limited.On the other hand,fused cycliccompounds have a wide range of applications in the fields of medicine,energy,and material sciences,but most synthesis methods have some shortcomings,such as difficult preparation of raw materials,long synthesis route and low efficiency.Therefore,developing simple,efficient,and green synthesis methods to prepare polycyclic compounds still poses significant challenges.In order to solve the above problems,under the guidance of green chemistry,thisthesis successfully designed and developed some new reaction models of asymmetric multiple C-H bond activation,using asymmetric multiple C-H bond activation and C-H bond activation-cyclization strategy,designed and developed some new green synthesis methods of fused cycliccompounds with important application valueto effectively reduce carbon emissions and improve the economic and social benefits of the related chemical industry.The main research contents of this thesis are as follows:1.In the first part of this thesis,a novel and efficient synthesis of spiropyrazolonylindazoles from readily available N-aryloxyacetamides and diazopyrazolones by double unsymmetrical C(sp~2)-H bond activation and sequential carbene insertion is presented.Preliminary mechanism studies show that under the catalysis of Rh(III),N-aryloxyacetamide initially undergoes C-H/N-H bond metalation to form a five-membered rhodacycle intermediate,and then coordinates with diazopyrazolone to form a carbene intermediate,followed by carbene insertion and protonation to realize the introduction of the first pyrazolone unit.The newly introduced N-arylpyrazolone unit then undergoes unsymmetrical C-H bond activation-cyclization with the second molecule diazopyrazolone under thereaction condition to form the spiropyrazolonylindazole product.Notably,this work not only enriches the research content of multiple unsymmetrical C-H bond functionalization,but also provides a simple and green new strategy for the synthesis of the otherwise difficult-to-obtain spiroheterocyclic skeleton.2.As a continuation of the study described in previous section,the cascade reaction between N-aryloxyacetamide and diazooxindolewas investigated.From this reaction,a novel and efficient synthesis of bispirooxindoyldihydrobenzofurans was developed.Preliminary mechanism studies and density functional theory(DFT)calculation reveal that under the catalysis of Rh(III),N-phenoxyacetamide initially undergoes C-H bond metalation and then coordinates with diazooxindoleto form a carbene intermediate,which is then captured by the second diazooxindole to form a new carbene intermediate,and eventually generates bispirooxindoyldihydrobenzofuran through the processes of migratory insertion,oxidative insertion,and reductive elimination.In short,the formation of product involves the unprecedented C-H bond activation and sequential unsymmetrical carbene insertion.This unique reaction provides a new way for the synthesis of spiro/fused cyclic compounds,and also discloses novel reaction mode of N-aryloxyacetamides with cyclic diazo compounds.In addition,the products obtained herein can be easily transformed into products with high added value,which further demonstrates the practical value of this synthetic protocol.3.A novel and efficient synthesis of quinoline fused cyclobutane derivatives has been developed via rhodium-catalyzed double unsymmetrical C(sp~2)-H bond functionalization of N-arylsydnones with allenyl acetates.Preliminary mechanism studies how that under the catalysis of Rh(III),N-arylsydnoneinitially undergoes C-H bond metallization and then coordinates with allenyl acetate to initiate the followingalkenyl group migratory insertion andβ-oxygen elimination to afford the C4 mono-allylation product of N-arylsydnone.Under the promotion of Rh(III),this mono-allyation product then coordinates with the second allenyl acetate and goes through similar process as described above to complete the unsymmetrical allylationontheortho-position of the N-phenyl moiety.Finally,quinoline fused cyclobutane is formed through intramolecular[2+2]cycloaddition reaction of the in situ formed diallylation intermediate.This work not only provides another successful example for the unsymmetrical multiple C-H bond functionalization,but also provides a simple and green new strategy for the synthesis of quinoline fused cyclobutane derivatives.In addition,diverse structural elaborations of the products obtained herein furnish some valuable polycyclic compounds.4.An efficient and efficient synthesis of 1,3-benzodiazepines through the tandem reaction of N-aryl amidines with propargylic esters was developed.It is worth emphasizing that in the formation of the title product,Rh(III)plays a dual role in catalyzing the activation of the C(sp~2)-H bond and promoting theβ-oxygen elimination.Meanwhile,air acts as a green co-oxidant.This is the first example in which N-aryl amidines served as a C5 synthon to undergo a regioselective[5+2]annulation with propargyl esters acting as a C2 synthon to afford the valuable seven-membered heterocyclic system.In addition,some of the products showed significant cytotoxicity to a variety of cancer cells,which demonstrated their good potential for pharmaceutical applications.Finally,several green evaluation indicators are used to evaluate and compare the greenness of the method developed herein with literature methods.The results thus obtained show that the synthetic methods developed herein meet the requirements of green chemistry better.5.An efficient and efficient synthesis of N-acylbenzimidazoles through the reaction of N-arylamidines with dioxazolones was developed.To our knowledge,this is the first example in which N-acylbenzimidazoles were synthesized through the simultaneous formation of the imidazoyl moiety and introduction of the N-acyl group.Finally,several green evaluation indicators are used to evaluate and compare the greenness of the method developed herein with literature methods.It is thus found that the method developed herein has higher atom-economy,lower mass intensity,and environmental factors,and is thus more in line with the requirements of green chemistry.6.A novel and efficient synthesis of functionalized benzofulvenes via Rh(III)-catalyzed cascade reactions of benzoyl acetonitriles with propargyl alcohols was developed.The reaction mechanism was studied by hydrogen-deuterium exchange experiment,intermolecular kinetic isotope effect experiment,and density functional theory calculation.Based on these studies,a plausible reaction pathway accounting for the selective formation of the title product was proposed.Further study also found that the obtained products can be easily converted into compounds with higher added value,and this method is suitable for large-scale preparation applications,which further showcases its practical value.Compared with the literature methods,the synthetic method established herein has higher atom-economy and reaction quality efficiency,lower mass intensity and environmental factors.Therefore,it meets the needs of green chemistry better.A series of novel synthetic methods with simple and green have been established under the guidance of green chemistry by taking advantages of Rh(III)-catalyzed C-H bond activation strategy.With these methods,a wide variety of fused cyclic compounds with potential biological activity were prepared.The results presented in this thesis not only expand the application scope of C-H bond activation strategy in organic synthesis,but also provide new means for the green synthesis of related natural products and drug molecules.更多还原