Synthesis and applications of 1,2- and 4,5-annulated indoles

The indolic structure is one of the most important heterocyclic motifs with a plethora of applications in our daily lives, which are discussed in chapter 1. This includes essential building blocks of proteins and biological regulators as well as medical applications and in dyes and pigments. Fused indolic structure can be found in Nature and often have biological activities or can be used in the synthesis of dyes. However, the variation on synthesized fused indoles in literature is limited and are often prepared in multistep procedures. This implicates that the biological application of many fused indoles is underexplored, partly due to a lack of convenient synthetic methodologies. In this research, the synthesis of multiple fused indoles and derivatives thereof have been explored. This thesis has been devided into two parts. The first part discusses the synthesis and applications of 1,2-fused indolic structures starting from non-indolic precursors. In chapter 3, we discuss the reported methods where 1,2-fused indoles have been prepared with the formation of the indole core in the final step. In chapter 4, we aimed to prepare piperazinone fused indoles using a Nenitzescu reaction using various quinones and piperazinone enaminones. Surprisingly, a 2-imidazolidinone benzofuran structure was obtained. The viability of this reaction was explored. Furthermore, a one-pot two-steps procedure was disclosed starting from commercially available building blocks. Interestingly, in many cases, traces of the primarily envisioned piperazinone-fused indoles were present in the reaction mixture. This demonstrates that the Nenitzescu reaction can be used for the preparation of these fused indoles and further research therefore will focus onto the variation of the reaction conditions to selectively obtain piperazinone fused indoles. Furthermore, the biological activities of these benzofurans and fused indoles will be explored in future research. The second part of this thesis discusses the synthesis and application of 4,5-fused indoles starting from 4,5,6,7-tetrahydroindol-4-one analogues. An extensive overview of the literature is given in chapter 5. We aimed to prepare 1,2,3-triazole fused indoles with potential biological activities in chapter 6. Furthermore, these fused indoles are interesting building blocks for the preparation of boron-centered fluorophores. Therefore, we explored our 1,2,3-triazole-fused (dihydro)indoles as well as triazole-linked pyrroles in the synthesis of 1,2,3-triazole BOPAHY fluorophores. Furthermore, alkylation of the 1,2,3-triazole affords water-soluble 1,2,3-triazolium BOPAHY salts. The spectroscopic properties of these dyes have been examined. High fluorescence quantum yields were observed for triazole-bridged BOPAHY dyes in DCM and moderate fluorescence quantum yields for 1,2,3-triazolium-bridged BOPAHY chromophores in DCM and water. The fluorescence of the freely rotatable 1,2,3-triazolium-linked BOPAHYs is partially quenched in water. As appendix, chapter 8 discusses the radical C-H arylation of quinones using (hetero)aryl diazonium salts. These arylated quinones are of great importance for the synthesis of arylated indoles as was discussed in chapter 3. Furthermore, arylated quinones are interesting precursors for the synthesis of polyheterocyclic structures. An optimization study was explored with various reducing agents as well as a photocatalytic procedure with in situ diazotization of readily available anilines. Some examples of postmodifications of arylated quinones toward polyhetereocyclic structures have been disclosed.

Publication year:2021

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