Direct and Modular Access to Functionalized Arenes and Cyclohexenes Mediated by Deprotonative C–H Zincation

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2021

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Poly-substituted arenes are valuable skeletons and widespread in pharmaceuticals, agrochemicals, and functional materials. In the design and development of novel functional arenes, the major bottleneck lies in their synthetic access due to the requirement of multi-step syntheses. To tackle such challenges, functionalization directly from abundant C–H bonds offer greater flexibility and efficiency in the synthesis of diverse poly-substituted arenes. In this context, a deprotonative C–H zincation strategy is appealing for two distinct reasons. First, this strategy allows regioselective C–H activation of a variety of arenes and heteroarenes directly. Moreover, generated organozinc intermediates as nucleophiles are capable of performing effective functionalizations. Therefore, we developed several synthetic transformations toward efficient access to poly-substituted arenes using deprotonative C–H zincation. (1) The regioselective azidation of diversely substituted arenes and heteroarenes was achieved through deprotonative C–H zincation and subsequent copper-catalyzed azidation. (2) To achieve multi-bond formation in a single step, we envisioned arene 1,2-difunctionalization methods using aryne intermediates generated from aryl triflates mediated by deprotonative zincation. Both intra- and intermolecular difunctionalization of arenes were developed, providing numerous difunctionalized arenes with diverse functionalities such as carbon, nitrogen, oxygen, sulfur, and halogens. (3) The difunctionalization strategy was extended to cyclohexenes, which are prevalent fundamental structure motifs. Through generation of cyclohexynes via deprotonative zincation of cyclohexenyl triflates, three-component cyclohexyne 1,2-difunctionalization was accomplished with formation of structurally complex and diversely functionalized cyclohexenes.

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Cho, Seoyoung (2021). Direct and Modular Access to Functionalized Arenes and Cyclohexenes Mediated by Deprotonative C–H Zincation. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23091.

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