Nitrogen - Heteroatom Bond Enabled Synthesis of Pharmacologically Valuable Aminoarenes via Aryne and Aryl-Zinc Intermediates
Charles Hendrick, Ph.D. candidate
Qiu Wang, advisor
Wednesday, March 29, 2017 - 1:00pm to 2:00pm
Location: French Family Science Center 1243
Avery, Meg

Abstract: Methods to generate complex aminoarene motifs from simple precursors provide valuable access to well-represented scaffolds in pharmaceuticals. Amines bearing nitrogen–heteroatom bonds provide improved versatility over classic N–H nucleophiles, enabling alternative reactivity towards forming functionalized aminoarene products. Direct formation of ortho-haloaminoarenes was achieved by insertion of nitrogen–halide bonds by arynes, formed in situ from mild fluoride salts and ortho-trimethylsilyl aryltriflates, with N-chloro-, -bromo, and -iodoamines in generally moderate to good yields and good to excellent regioselectivity. Additionally, a net C–H amination of arenes and heteroarenes was investigated via initial H–Zn zincation followed by copper catalyzed electrophilic amination with O-benzoylhydroxylamines. Strong, hindered, zinc bases Zn(TMP)Cl•LiCl and Zn(TMP)2 permit C–H zincation/electrophilic amination of activated heteroarenes and arenes. Broader access to functionalized aminoarenes was achieved under this paradigm through an ortho-directed C–H zincation/copper-catalyzed amination strategy, enabled by development of Li(TMP)0.1Li[ZnEt2(TMP)] as a general and efficient base for C–H zincation. A range of general ortho-directing groups facilitated this reaction, including amides, esters, nitriles, heteroarenes, and even aryl halides, to afford aminoarenes in moderate to excellent yields and excellent regioselectivity. The diversity of aminoarenes accessible through both aryne and aryl-zinc mediated strategies was employed towards development of novel pharmacophores for functionally selective dopamine receptor ligands. Derivatives of D2R-selective aripiprazole and D3R-selective cariprazine were thus generated with previously unexplored arylpiperazine pharmacophores to reveal influences on subtype and functional selectivity.