Synthesis of Arynes via Formal Dehydrogenation of Arenes
National Institutes of Health Common Fund and Office of Scientific Workforce Diversity under three linked awards, RL5GM118963, TL4GM118965, and UL1GM118964, administered by the National Institute of General Medical Sciences. The work is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. BEM acknowledges the El-Mansy Family for a summer research fellowship at PSU. The NSF provided instrument funding for the BioAnalytical Mass Spectrometry Facility (MRI #1828753).
Journal of the American Chemical Society
Arynes offer immense potential for diversification of benzenoid rings, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires synthetic precursors, which involve either harsh conditions or multistep syntheses. The development of alternative methods to access arynes using simpler substrates and milder conditions is necessary for a more streamlined approach. Here, we describe a two-step formal dehydrogenation of simple arenes to generate arynes at a remote position relative to traditionally reactive groups, e.g., halides. This approach is enabled by regioselective installation and ejection of an "onium" leaving group, and we demonstrate the compatibility of simple arenes (20 examples) and arynophiles (8 examples). Moreover, through direct comparison, we show that our formal dehydrogenation method is both more functional group tolerant and efficient in generating arynes than the current state-of-the-art aryne precursors. Finally, we show that aryne intermediates offer opportunities for regioselective C-H amination that are distinct from other methods.
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Riley A. Roberts, Bryan E. Metze, Aleksandra Nilova, and David R. Stuart Journal of the American Chemical Society 2023 145 (6), 3306-3311 DOI: 10.1021/jacs.2c13007