Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors.

Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2]pyridines or 7-alkyl azaindoles in two steps from known compounds. Using halomucononitrile reagents, we can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25-93% yield) through the cyclization of transient aminomucononitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (13 examples, up to 91% yield).

Divergent Reactivity of α,α-Disubstituted Alkenyl Hydrazones: Bench Stable Cyclopropylcarbinyl Equivalents.

Herein we report the divergent reactivity of 2,2-dialkyl-3-()-alkenyl -tosylhydrazones using Pd-catalyzed cross-coupling conditions, which enable the -selective synthesis of 3-aryl-1,4-dienes and -dialkyl vinylcyclopropanes. We found that the dialkylbiaryl phosphine ligand SPhos was the optimal ligand for this transformation producing skipped dienes in up to 83% isolated yield. The ratio of skipped diene to vinylcyclopropane is dependent on both the structure of the α,α-disubstituted hydrazones and the aryl halide partner.

Programmed Sequential Additions to Halogenated Mucononitriles.

Dihalomucononitriles were synthesized and their reactivity evaluated to assess their ability to function as linchpin reagents. Bis(2-chloroacrylonitrile) and bis(2-bromoacrylonitrile) were synthesized from 2,1,3-benzothiadiazole and undergo conjugate addition/elimination reactions with both nitrogen (40-95% yield) and carbon nucleophiles (72-93% yield). Secondary amines undergo monosubstitutions, while carbon nucleophiles are added twice.