Triftosylhydrazone in Single-Atom Skeletal Editing

ConspectusIn the past decade, single-atom skeletal editing, which involves the precise insertion, deletion, or exchange of single atoms in the core skeleton of a molecule, has emerged as a promising synthetic strategy for the rapid construction or diversification of complex molecules without laborious de novo synthetic processes. Among them, carbene-initiated skeletal editing is particularly appealing due to the ready availability and diverse reactivities of carbene species. The initial endeavors to modify the core skeleton of heteroarenes through carbon-atom insertion could date back to 1881, when Ciamician and Denstedt described the conversion of pyrroles to pyridines by trapping haloform-derived free carbene. Despite its potential synthetic value, the general applicability of this one-carbon insertion has seen limited progress due to poor yields and harsh reaction conditions. Significant advances in skeletal editing via carbene insertion were achieved only in the past 3 years by Levin, Ball, Xu, Song, Glorius, and others. The hallmark of these approaches is facile halocyclopropanation followed by regioselective ring opening facilitated by the expulsion of the halide ion. Consequently, only specially designed α-halocarbene precursors, such as haloform derivatives, α-halodiazoacetates, chlorodiazirines, and α-chlorodiazo oxime esters, can be employed to achieve Ciamician–Denstedt-type skeletal editing. This not only limits the types of functional groups installed on the ring expansion products but also prevents their widespread adoption, especially in late-stage contexts. The enduring quest to develop environmentally friendly and versatile carbene precursors, superior functional group compatibility, and potential application in late-stage diversifications and the investigation of mechanistic insights into carbon insertion reactions remain a fundamental objective.In our endeavors over the past 5 years, we have developed o-trifluoromethylbenzenesulfonylhydrazones (named Triftosylhydrazones) as operationally safe and easily decomposable diazo surrogates and explored their application in various challenging catalytic carbene transfer reactions. Recently, our group has put great efforts into expanding the application scope and unlocking the potential of triftosylhydrazones as carbene precursors in single-atom skeletal editing reactions. Since 2018, we have realized a range of skeletal editing of acyclic 1,3-dicarbonyls with silver carbenes to access 1,4-dicarbonyls, proceeding through a cyclopropanation/ring-opening process. Inspired by these results, we recently demonstrated a series of transition-metal-catalyzed highly selective single-atom skeletal editing of medicinally interesting heteroarenes like pyrroles, indoles, and 1,2-diazoles via carbenic carbon insertion. We then achieved the skeletal editing of strained three-membered nitrogen- and oxygen-containing heterocycles through the insertion or exchange of single-carbon atoms. In this Account, we present an overview of our achievements in the single-atom skeletal editing of heterocycles, organized based on three types of in situ-generated key intermediates, such as cyclopropane, N-ylide, and O-ylide from triftosylhydrazones and heterocycles, with a focus on reaction scopes, mechanistic features, and synthetic applications. We hope that this Account will provide valuable insights and contribute to the development of new methodologies in both the skeletal editing and carbene chemistry fields.