Nitrogen–Heteroatom Bond Enabled Synthesis of Pharmacologically Valuable Aminoarenes via Aryne and Aryl-Zinc Intermediates

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2017

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Hendrick, Charles Edward

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Wang, Qiu

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Abstract

Aminoarenes are common structural features in pharmaceuticals and biologically relevant scaffolds, motivating continued development of strategies to facilitate their synthesis. Canonical approaches to aryl amination rely upon nucleophilic N–H bond precursors. Nitrogen–heteroatom bonds possess versatile reactivity and can enable synthetically attractive approaches to functionalized aminoarenes. Towards this, we proposed the use of nitrogen–heteroatom bonds in both bond insertion by reactive aryne intermediates and as electrophilic amination reagents in the net C–H amination of arenes via zinc-amide mediated H–Zn exchange.

Herein, we describe the development of nitrogen–heteroatom bond enabled strategies to access functionally diverse aminoarene products. Aryne insertion of N-chloro, -bromo, and even -iodoamines was achieved in moderate yields and excellent regioselectivity to provide direct access to ortho-haloaminoarene motifs. This approach employs ortho-trimethylsilyl aryltriflates and simple fluoride salts as a mild platform for in situ formation of reactive arynes, affording functionally complex aminoarene products in a single transformation. Access to aminoarenes from ubiquitous heteroaryl and aryl C–H bonds was also achieved via copper-catalyzed electrophilic amination with O-benzoylhydroxylamines, mediated by initial H–Zn exchange from highly hindered amide-zinc complexes. In addition to well-established Zn(TMP)2 and Zn(TMP)Cl•LiCl, we developed LiTMP0.1Li[ZnEt2(TMP)] as part of a general ortho-directed C–H zincation/amination strategy. Using O-benzoylhydroxylamines and a copper catalyst to affect electrophilic amination, this zincate base permitted access to a broad scope of heteroarene and arene substrates with varied ortho-directing group functionalities. The improved access to aminoarene products enabled by these methods was then demonstrated through the study of functionally selective dopamine receptor ligands, which yielded valuable information on the complex SAR and SFSR of D2 and D3 receptors and their signaling pathways.

The successful development of strategies to access highly functionalized aminoarene scaffolds provides valuable tools for drug discovery. The methods presented here expand access to diverse aryl amine motifs and will contribute to the development of novel small molecule biochemical tools and therapeutics.

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Hendrick, Charles Edward (2017). Nitrogen–Heteroatom Bond Enabled Synthesis of Pharmacologically Valuable Aminoarenes via Aryne and Aryl-Zinc Intermediates. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/14499.

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