Triftosylhydrazone in Single-Atom Skeletal Editing

Abstract

In 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.