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机械研磨条件下卤化、酰胺化和环加成反应的研究
Studies on Halogenation, Amidation, and Cyclization Reactions under Mechanical Milling Conditions
【作者】 高杰;
【导师】 王官武;
【作者基本信息】 中国科学技术大学 , 有机化学, 2009, 博士
【摘要】 时至今日,有机合成化学的发展已经日渐深入到人们生活中的各个方面,其中最具代表性的便是药物的合成和应用。不管是一些传统化合物的合成,还是新化合物的合成,化学家们总是以使这些合成路径越来越简便为目标。随着人们对生命科学和环境科学的深入了解,环保意识普遍得到提高,在此背景下,“绿色化学”的概念应运而生。如何减少对有毒试剂的使用,减少有害废物的排放,就成为绿色合成化学的主要研究目标。在诸多的绿色合成方法中,机械研磨便是近年来发展起来的一种非常具有潜力的新颖的方法。本论文就是针对在机械研磨条件下对有机小分子的绿色合成研究,主要内容包括以下几个方面:1.在机械研磨条件下,用Oxone/NaBr体系实现对1,3-二羰基化合物、酚类和查尔酮类化合物的溴化反应。利用Oxone作氧化剂,在固相无溶剂条件下,成功实现了1,3-二羰基化合物、酚类以及(氮杂)查尔酮类化合物的溴化反应,大多都定量生成了相应的溴化产物。与传统方法相比,反应中不需要任何有毒有害的有机溶剂,充分体现了绿色化学的理念;不需添加碱、Lewis acid或其它催化剂;所用氧化剂Oxone无毒无害,廉价易得;反应时间短,产率高,适用性广,选择性好。2.在机械研磨条件下,CeCl3·7H2O/Znx2作用下由环氧化物卤化开环合成卤乙醇类化合物halohydrins。在固相无溶剂条件下,在CeCl3·7H2O作用下,首次用卤化锌作为卤源,对一系列环氧化物进行开环反应,生成卤代乙醇类衍生物。分别用氯化锌、溴化锌和碘化锌参与反应,得到相应的卤代乙醇衍生物,效果非常好。对于氯化开环,反应得到了单一的反式产物,碘化开环反应得到了单一的顺式产物,而溴化开环产物则是顺、反式的混合物。反应条件温和,所用试剂无毒无害、廉价易得,后处理简便,为这一类的反应提供了一种新的合成选择途径。3.在机械研磨条件下,芳香醛和芳香胺经由氧化过程的直接酰胺化反应。采用Oxone作为氧化剂,首次在机械研磨条件下由芳醛和芳胺“一锅法”直接经氧化过程转化为酰胺,产率良好。与以往的报道相比,该方法在反应中不用有机溶剂,不用催化剂,对环境友好,充分体现了绿色化学的理念。4.1,3-二羰基化合物和醛在I2/DMAP作用下发生环加成反应,生成二氢呋喃和环丙烷类衍生物。在机械研磨条件下,用达米酮和醛在I2/DMAP作用下发生反应,得到了二氢呋喃结构的环化加成物。当将1,3-二羰基化合物换成1,3-茚二酮时,在完全相同的条件下发生反应,却得到了不同于前者结构的环丙烷结构加成物。最后,我们对反应机理进行了探讨,并提出了一个可行的假设性机理。该反应不使用昂贵的催化剂;反应过程中不使用有毒有害的有机溶剂,对环境友好;反应时间短,收率高;在相同条件下得到不同结构的产物,这提供了一种新型的合成二氢呋喃和环丙烷结构的环化反应。
【Abstract】 Today,the development of organic synthetic chemistry has been growing into people’s lives in all aspects,in which the synthesis and application of drugs is the most representative one.For some traditional synthesis,or synthesis of new compounds,chemists have always been making them more and more convenient for the synthesis of the target path.With a better understanding of life science and environmental science,the public’s awareness of environmental protection has been generally improved.In this context, the "green chemistry" concept came into being.How to reduce the use of toxic reagents and reduce the emission of hazardous waste has become a major research goal for green synthetic chemistry.Among a good many green synthesis methods, mechanical milling has developed in recent years as a novel and promising method. This thesis is a research of green synthetic chemistry of small organic molecules under mechanical milling conditions.The main contents include the following four aspects.1.Bromination of 1,3-Diearbonyl Compounds,Substituted Phenols,Chaleones, and Azachalcones using Oxone/NaBr under Mechanical Milling Conditions.A series of 1,3-dicarbonyl compounds,substituted phenols,chalcones,and azachalcones,were brominated successfully using NaBr as bromine source and Oxone as the oxidant under mechanical milling conditions.Most substrates were converted into corresponding monobromides or dibromides quantitatively.Compared with traditional bromination methods,the reaction did not require any toxic organic solvents,base,Lewis acid,or other catalyst.The oxidant Oxone was non-toxic, harmless,cheap and easy to get.Also,short reaction time,high yields and selectivity and wide generality all make this method fully embodied the concept of green chemistry.2.CeCl3·7H2O/ZnX2:A novel Reagent System for the Synthesis of Halohydrins from EpoxidesRing-opening reaction ofα,β-epoxy aryl ketones to halohydrins was achieved in good to excellent yields using zinc halides,including ZnCl2,ZnBr2,and ZnI2,as halogen sources for the first time and mediated by CeCl3·7H2O under mechanical milling conditions.For the synthesis of chlorohydrins and iodohydrins,the reactions afforded anti-and syn-halohydrins exclusively in high yields,respectively,while the reaction of epoxides with ZnBr2 afforded a mixture of syn/anti isomers.The advantages of mild reaction conditions,non-toxiticity and low cost of reagents,and simple isolation of the products make these ring-opening reactions more appealing and useful in organic synthesis.3.Direct Oxidative Amidation of Aldehydes with Anilines under Mechanical Milling Conditions.A simple and novel one-pot protocol to oxidize aryl aldehydes and anilines directly to amides was proposed in synthetic useful yields under mechanical milling conditions for the first time.Compared with the traditional liquid-phase reaction,this novel solvent-and metal catalyst-free procedure makes the synthesis of amides more efficient,low cost and eco-friendly.To the best of our knowledge,this is unprecedented.4.Selective Formation of Spiro Dihydrofurans and Cyclopropanes through Unexpected Reaction of Aldehydes with 1,3-Dicarbonyl CompoundsThe reactions of aldehydes with dimedone were performed mediated by DMAP/I2 under mechanical milling conditions afforded unexpected products of dihydrofurans. When another 1,3-dicarbonyl compound,i.e.,1,3-indandione,was explored,a cyclopropane ring structure instead of dihydrofuran was formed under similar conditions.We also discussed this unusual reaction process and proposed a reasonable "one method,two paths" mechanism.These novel iodine-mediated oxidative cycloadditions provide a rapid and efficient route to the preparation of a variety of spiro dihydrofuran and cyclopropane derivatives.The non-use of expensive catalyst and toxic organic solvent,short reaction time and high yields,and surpring results make this protocol more charming.
【Key words】 Mechanical Milling; Solvent-free; Bromination; 1,3-Dicarbonyl Compounds; Chalcones; Zinc Halides; Halohydrins; Amidation; Dimedone; 1,3-Indanedione; Dihydrofurans; Cyclopropanes;