Synthesis of heterapillar[m]arenes[n]quinones

Pillar[n]arenes, methylene bridged paracyclophanes, are the latest in several generations of macrocycles. Because of their inherent structural advantages over older generations this unique class of cylindrical scaffolds quickly rose to prominence. Following this popularity, a vast amount of work was performed on the classical carbon linked pillar[n]arenes in the last decade. While replacing these methylene bridges with heteroatoms would allow for fine tuning of the structure and allow for different supramolecular interactions, few reports describe the synthesis of the so called heterapillar[n]arenes. To fill this gap in the literature, we envisioned a simple and straightforward method towards these elusive scaffolds. Other than existing methods, that mostly rely on nucleophilic aromatic substitution of electron deficient arenes requiring a multi-step synthesis, we opted to capitalize on the inherent electrophilic nature of readily available benzoquinones to create cyclic structures. Following this idea, a novel type of macrocycle was developed in a first part of the thesis. By functionalizing chloranil (tetrachloro-1,4-benzoquinone) with a series of well-chosen cyclic amines, monomers were formed suitable for post-functionalization towards aqueous solubility. Reacting these monomers with a bisthiophenol resulted in the formation of a novel type of macrocycle we baptized thiapillar[m]arene[n]quinones. Analysis of the reaction indicated the presence of two different ring sizes which were identified as corresponding to the [2+2] and the [3+3] adduct. After optimization and the successful preparation of a small library of macrocycles, the goal was to examine post-functionalization as a strategy towards achieving aqueous solubility of the ring. During this process, a general instability of the scaffolds was identified. This problem was most pronounced in acidic medium, and was believed to be directly related to the nitrogen-based substituents. x To mitigate this instability, a different type of quinone based monomer was required. We hypothesized arylated quinones to be a suitable kind of substrate, as substituents that would transform into good leaving groups could easily be avoided. Since there were no known efficient routes towards bis-arylated quinones, we developed a straightforward, visible light induced Meerwein type arylation towards these versatile structures. While eosin Y was initially used as a photocatalyst, research indicated that, when performed in methanol as a solvent, the reaction proceeded smoothly in absence of the catalyst. In a first instance the products were prepared by irradiating a mixture of the chlorinated quinone and an appropriate diazonium salt. Later, the reaction was proven to successfully yield bis-arylated quinones when the diazonium salt was prepared in situ. In the same chapter, the versatility of the scaffolds was demonstrated by converting them to different natural products and isoquinoline fused products through a condensation reaction with a series of primary amines. With a series of bis-arylated quinones at our disposal, a first attempt at macrocyclization involved combination of these scaffolds with the sulfurbased nucleophile used earlier in this work. This reaction yielded an inseparable mixture of the [2+2] and [3+3] adduct (similar to earlier work) and was therefore not pursued. Contrarily to this failed attempt, employing the oxygen-based bisphenol A did result in the straightforward isolation of oxapillar[6]arene[3]quinones and a series of scaffolds were prepared. In the last part of the thesis, described in appendix I, we explored the synthesis of a series of novel fused heterocycles with a pyridazine core. Starting from readily available products, we developed a straightforward multi-step procedure towards dihydropyrido[3,4-c]pyridazines. Furthermore, the same starting material was used in a condensation reaction with ammonium acetate and primary amines towards novel pyrido[3,4-c]pyridazines.

Jaar van publicatie:2022

Toegankelijkheid:Closed