Synthesis of Arynes via Formal Dehydrogenation of Arenes

Abstract

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.

Modular Photochemical Flow Synthesis of Structurally Diverse Benzyne and Triazine Precursors

“…[2] Alternatives are anthranilic acid derivatives, halobenzenes, and the newly presented formal dehydrogenation using a thianthrenium group. [3] The generation and use of arynes has been widely explored in recent years with many examples in both batch [2b,4] and continuous flow mode. [5] The use of continuous flow technology for the effective generation and use of benzynes, and for synthetic chemistry in general in both academia and industry, can be explained by its numerous advantages over batch processing.…”

“…In this context, the most common precursor is based on ortho‐TMS aryl triflates (Kobayashi's precursor) [2] . Alternatives are anthranilic acid derivatives, halobenzenes, and the newly presented formal dehydrogenation using a thianthrenium group [3] . The generation and use of arynes has been widely explored in recent years with many examples in both batch [2b,4] and continuous flow mode [5] .…”

[3 + 2] Cycloaddition of azides with arynes formedviaC–H deprotonation of aryl sulfonium salts

“…Recently, Stuart's group have reported their pioneering discovery of using aryl sulfonium salts as aryne precursors, in which aryl sulfonium salts could be easily synthesized from inexpensive and readily available arenes. 13,14 Inspired by those results, we considered whether the synthesis of benzotriazoles could be achieved by using aryl sulfonium salts as aryne precursors. In this manner, the newly developed procedure can have improved functional group tolerance and also synthetic efficiency.…”

Oxidative Cycloaddition Reactions of Arylboron Reagents via a One-pot Formal Dehydroboration Sequence

“…11 (2) The boron group fills a strategic role to activate the arene for regiospecific installation of the nucleofugal iodine leaving group and, therefore, generates arynes at positions that would not be possible from the corresponding simple arene. 16 For instance, electron-deficient arenes with substituents found in 1b−e are not nucleophilic enough for C−H thianthrenation and aryne formation. 16 Likewise, although bromobenzene is a compatible arene nucleophile for thianthrenation, the resulting aryne is formed at the 3,4-position relative to the bromine substituent.…”

“…(1) This is the shortest route that we are aware of to convert arylboron reagents, which lack an ortho -nucleofugal leaving group, into arynes, as the total reaction time is approximately 2 hours . (2) The boron group fills a strategic role to activate the arene for regiospecific installation of the nucleofugal iodine leaving group and, therefore, generates arynes at positions that would not be possible from the corresponding simple arene . For instance, electron-deficient arenes with substituents found in 1b – e are not nucleophilic enough for C–H thianthrenation and aryne formation .…”