Monobenzone

Intercepting reactions have recently emerged as an innovative approach in organic synthesis, allowing chemists to harness reactive intermediates to access structures and functionalities that conventional methods cannot easily achieve. By deliberately manipulating reaction pathways, this strategy provides a unique avenue to explore unusual reactivities and complex molecular architectures. In this work, we have developed a new protocol for the nucleophile‐intercepted Beckmann fragmentation reaction (NuBFr). Employing tropone oxime tosylate – a simple and readily accessible precursor – and a diverse set of nucleophiles generated in situ from alcohols, phenols, thiols and alkynes with strong bases, we successfully synthesized a library of novel conjugated Z,Z,Z‐trienecarbonitrile derivatives. This method facilitates rapid access to the conjugated Z,Z,Z‐triene motif, a structural feature rarely encountered in synthetic chemistry. Our computational studies indicate that the NuBFr reaction likely proceeds through the formation of a bicylic azirine intermediate. The resulting Z,Z,Z‐trienecarbonitriles could undergo an unprecedented thermally induced 8π/6π/4π electrocyclization cascade sequence to produce trisubstituted olefins. This sequence underscores the fundamental value of these motifs in pushing the boundaries of unusual reactivities in organic synthesis.

The synthesis of complex mols. by palladium-catalyzed cross-coupling has been pivotal in all stages of drug discovery research.However, this approach has been generally restricted to classical aryl halide electrophiles, requiring the use of a limited pool of precursors.Herein, we report the first highly chemoselective approach to the cross-coupling of bench-stable C-O electrophiles in which abundant phenols can be systematically used as electrophilic cross-coupling partners.Using this approach, we have achieved late-stage functionalization of >20 pharmaceuticals covering various architectures and drug targets.Wingtip-flexible N-heterocyclic carbenes as ancillary ligands enable us to address the major challenges to this mode of catalysis, such as fast oxidative addition to prevent the hydrolysis of C-O electrophiles and facile reductive elimination to establish C-C bond formation in complex settings.The design of wingtip-flexible N-heterocyclic carbene ligands will enable the cross-coupling of a broad range of electrophiles for the development of important medicines.