Strategies toward Aryne Multifunctionalization via 1,2-Benzdiyne and Benzyne.

Polysubstituted arenes are prevalent in numerous natural products, medicines, agrochemicals, and organic functional materials. Among methods to prepare polysubstituted arenes, pathways involving benzyne intermediates are particularly attractive given they can readily assemble highly diverse vicinal difunctionalized benzenes in a step-economical manner under transition-metal-free conditions. In order to incorporate more than two substituents on a benzene ring via a benzyne intermediate, methodologies involving benzdiyne and benztriyne have been developed, which significantly expand the current difunctionalization strategies in benzyne chemistry. In the past years, our group has been focusing on pushing the frontier of traditional benzyne chemistry and exploring new applications. In an aim to efficiently and conveniently construct polysubstituted arenes, we developed several aryne multifunctionalization strategies. The first strategy is through the 1,2-benzdiyne processes, which can be divided into a domino aryne approach and stepwise 1,2-benzdiyne approach. In our domino aryne study, we developed three domino aryne reagents as "sesquibenzyne" synthons, which are complementary in terms of reactivity and could adapt different modes of cascade transformations. By employing these domino aryne precursors, we were able to accomplish several cascade transformations, including double nucleophilic reactions, i.e., the reaction with carbonyl protected benzothioamides, 1,2-diamination, and 1,3-diamination. In addition, two cascade processes involving nucleophilic and pericyclic reactions, namely, domino aryne annulation via nucleophilic-ene cascade and domino aryne nucleophilic, Diels-Alder process, were successfully achieved as well. Meanwhile, with our desire to expand the scope of 1,2-benzdiyne transformations, we employed stepwise 1,2-benzdiyne tactics to access polysubstituted arenes. Depending on the property of the substituent on the C3-position of a benzyne intermediate, either an electron-withdrawing or electron-donating group, the incoming ortho groups were chosen accordingly. Consequently, we realized a [2 + 2] cycloaddition-Grob fragmentation process using 3-triflyloxybenzyne and a 1,2-benzdiyne process using 3-(trimethylsilyl)benzyne. Our second research strategy is to use single benzyne to access trisubstituted arenes, which represents a more atom- and step-economical protocol. With our deliberate design, we discovered a tandem benzyne S═O bond insertion/C-H functionalization process using single benzyne and aryl allyl sulfoxides, furnishing three chemical bonds of different types in a single process. This transformation is the first 1,2,3-trisubstitution example using single benzyne intermediate. At last, we developed an oxidative dearomatization strategy on Kobayashi benzyne precursors, which led to the preparation of various cyclohexenynone precursors with diverse substituents in highly efficient manner. In this study, we also demonstrated a new reaction mode of these cyclohexenynones with allyl sulfoxides, which involves a deeper utilization of the cyclohexyne triple bond. This work is the first example of successful connection of precursors of benzyne with cyclohexyne together, revealing a new research direction in the field of cyclohexyne.