The preparation of heterocycles by [2+2+2] cyclization and inverse electron demand Dels-Alder reactions of arynes with 1,2,4-triazines

Transition metal mediated [2 + 2 + 2] cyclizations have been well researched over the past several years. As a well-developed methodology, [2 + 2 + 2] chemistry has been employed as a major pathway to various carbo- and heterocyclic synthetic targets. Numerous transition metals have been applied as catalysts for these cyclizations. Previous work in our group developed cobalt(I) catalyzed inter- and intramolecular [2 + 2 + 2] cyclizations of two alkynes and a nitrile, leading to the preparation of tetrahydro-naphthyridines. Pyridazines could be generated if the cyclization could be accomplished with two nitriles and an alkyne, which would be a novel way to synthesize 1,2-diazines through the formation of the N-N bond. To this end, metal-catalyzed intramolecular [2 + 2 + 2] cyclizations between an alkyne and two nitriles were investigated. The intramolecular nature of the reaction provided the entropic advantage to successfully assist the formation of the critical N-N bond. Optimal conditions were achieved with cobalt(I) catalysts under microwave irradiation in chlorobenzene, producing the desired pyridazines in moderate to good yields. This success led to the preparation of a series of annulated pyridazines. The use of two tethering nitrogens in the preparation of the cyclization precursors incorporated points for further diversification, the next step in the development of this chemistry. This ring closure through N,N-bond formation allowed the construction of annulated pyridazine scaffolds that were utilized further in a small molecule library synthesis. Using this methodology, sixteen new annulated pyridazines were prepared. Inverse electron demand Diels-Alder (IEDDA) reactions of arynes and 1,2,4-triazines were also investigated for the generation of isoquinoline core structures. The results showed that only triazines with electron withdrawing groups participated in the IEDDA reactions with benzyne as a partner after screening of several different arynes, which limited the scope of the reaction. Liebeskind–Srogl reactions of 3-methylthiotriazines and boronic acids were investigated during the diversification of triazines, and microwave irradiation with palladium and copper catalysts were found to be the optimal conditions for the coupling. The chemistry allowed for further triazine diversification.

Author dc:creator

• Cai, Cuifang

• Organic chemistry
• [2+2+2] cyclization
• Cobalt
• Diels-Alder reaction
• Isoquinoline
• Pyridazine

Language dc:language.iso

en_US

Handle dc:identifier.uri

https://hdl.handle.net/2144/27298

OAI identifier oai:identifier

oai:open.bu.edu:2144/27298