Dihalomucononitriles as Multifunctional Linchpins for Complex Molecule Synthesis

I. Programmed Sequential Additions to Halogenated Mucononitriles The synthesis and systematic reactivity evaluation of two dihalomucononitrile reagents was achieved. These compounds represent a new class of linchpin diene reagents, efficiently coupling together amine nucleophiles and carbon nucleophiles in a predictable and programmable manner. Difunctionalization at the termini with a secondary amine and a malonate nucleophile followed by a first-in-class internal functionalization of the linchpin diene via conjugate addition cyclization reaction affords complex polycyclic scaffolds in two synthetic steps. II. Programmed Heterocycle Synthesis Using Halomucononitriles as Zincke Nitrile Precursors Halogenated mucononitriles react readily with a diverse array of primary amine nucleophiles, furnishing pyridinimines. These reactions proceed through “zincke nitrile” intermediates, and enable the late-stage functionalization of active pharmaceutical ingredient derivatives. Furthermore, pyridinimines are smoothly converted to two classes of privileged heterocycles – 7-azaindole scaffolds through Sonogashira coupling reactions, or to imidazo[1,2-a]pyridines through a C–H Functionalization approach. III. Synthesis of Heterodimeric Scaffolds through Iterative Halomucononitrile Cycloaddition Reactions Mucononitrile reagents enable the efficient assembly of heterodimeric scaffolds through iterative cycloaddition reactions. The mucononitrile core behaves as a dienophile in cross Diels-Alder cycloaddition reactions with various dienes, selectively furnishing monocycloadducts. These products are then planarized through elimination reactions, setting the stage for subsequent complexity-building cycloaddition reactions that lend access to heterodimeric compounds that are difficult to synthesize using reported methods. III. Divergent Reactivity of α,α-Disubstituted Alkenyl Hydrazones: Bench Stable Cyclopropylcarbinyl Equivalents We report a bioinspired use of α,α-disubstituted hydrazone reagents as cyclopropylcarbinyl palladium precursors. These reagents participate efficiently in cross-coupling reactions with aryl bromides, affording 1,4-dienes and vinylcyclopropane products. The ratio of skipped diene to vinylcyclopropane is dependent on both the structure of the α,α-disubstituted hydrazones and the aryl halide partner. Using sterically encumbered hydrazone reagents provided the trans-cyclopropane products selectively in up to 48% yield. The reaction is stereospecific and stereoselective and occurs alongside a competing 1,2-alkenyl group migration pathway.