Dissertation > Industrial Technology > Chemical Industry > Basic Organic Chemistry Industry > The production of heterocyclic compounds

Studies on the Novel Synthetic Methods of Complicated Indole Derivatives

Author WangZhiJing
Tutor BaoWeiLiang
School Zhejiang University
Course Organic Chemistry
Keywords Indole Organocatalysis Friedel-Crafts alkylation Cascade reaction N-arylation C-H activation
Type PhD thesis
Year 2010
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The indole framework represents a privileged structural motif of established value in biologically active natural products and pharmaceutical compounds. In this regards, the synthesis and applications of indole derivatives is one of the most extensive areas of research. New synthetic methods have been developed to provide these compounds. Comparing to tranditional protocols, such as Fischer Indole synthesis, these methods have significant advantages. For example, they are more efficient and milder, tolerate more functional groups, and offer the opportunity to access highly functionalized indole derivatives.The Friedel-Crafts reaction of aromatic compounds is one of the most important reactions for the formation of C-C bonds in organic synthesis. Indoles are common substrates in Friedel-Crafts alkylation reactions. Chiral 3-substituted indole derivatives could be obtained efficiently through enantioselective Friedel-Crafts alkylation reactions of indoles and prochiral electrophiles.Recently, the synthesis of various heterocyclic compounds via cascade reactions has drawn considerable attention. Compared to tranditional stepwise synthesis, cascade reactions enable multiple bond-forming and bond-cleaving events to occur in a single synthetic operation, circumvent the waste, and offer the opportunity to access highly functionalized final products from simple starting materials. Therefore, most of the recently reported methods for the synthesis of indoles are based on the use of cascade reactions.The dissertation includes three parts. In the first chapter, the research development and current progress of indole derivatives were briefly summarized. In the second chapter, we studied on the enantioselective Friedel-Crafts alkylation reactions of indoles and aromaticα,β-unsaturated aldehydes under organocatalysis. In the last chapter, the application of Cu-catalyzed N-arylation/Pd-catalyzed C-H activation sequential process into the one-pot synthesis of tetracyclic and pentacyclic indole derivatives was investigated.The second chapter contains two sections. Section one:the enantioselective Friedel-Crafts alkylation reactions catalyzed by diphenylprolinol silyl ether. A novel and efficient method for the synthesis of chiral 3-indolyl-3-phenyl-propanols through the enantioselective Friedel-Crafts alkylation reactions of indoles with aromaticα,β-unsaturated aldehyde has been developed. The protocol is applicable to a variety of substituted indoles and aromaticα,β-unsaturated aldehydes. Section two: some unsuccessful attempts on organocatalysisThe third chapter consists of two parts. Part one:A one-pot nucleophilic addition/Cu-catalyzed N-arylation/Pd-catalyzed C-H activation sequential process has been developed for the synthesis of Pyrimido[1,6-a]indol-1(2H)-ones, using ortho-gem-dibromovinyl isocyanates and N-alkyl-anilines as the starting materials. This method involves the use of easilily prepared substrates, more simple work up in contrast to literature synthesis, and the procedure allows the use of a variety of substituted ortho-gem-dibromovinyl isocyanates and N-alkyl-anilines. Part two:the synthesis of 1,1’-carbonyl-2,2’-biindolyl derivatives by a intramolecular Cu-catalyzed N-arylation/Pd-catalyzed C-H activation sequential process. The method involes readily available ortho-gem-dibromovinyl substrates. It is worth mentioning that unsymmetrical 2,2’-biindolyls, which could not be obtained easily using previous methods, could be attained efficiently.

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