Herein we report the divergent reactivity of 2,2-dialkyl-3-(E)-alkenyl N-tosylhydrazones using Pd-catalyzed crosscoupling conditions, which enable the Z-selective synthesis of 3-aryl-1,4-dienes and gem-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. Using sterically encumbered aryl bromides provided the trans-cyclopropane products selectively in up to 69% yield. The reaction is stereospecific and stereoselective and occurs alongside a competing 1,2-alkenyl group migration pathway.
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 2,13-benzothiadiazole and shown to undergo conjugate addition reactions with both nitrogen (40-95% yield) and carbon nucleophiles (72-93% yield). Secondary amines were found to undergo monoadditions while carbon nucleophiles added twice. The sequence of addition of the nucleophiles could be controlled giving mixed addition products. The multicomponent coupling products could then be converted to natural product-like motifs using intramolecular cyclization reactions. File list (3) download file view on ChemRxiv Zahara_Hinds_ChemRXIV_2020-FINAL.pdf (743.83 KiB) download file view on ChemRxiv Zahara Hinds SI FINAL_ ChemRXIV.pdf (1.39 MiB) download file view on ChemRxiv Zahara Hinds SI FINAL_ SPECTRA.pdf (8.63 MiB) COMMUNICATION
The isomeric imidazo[1,2-a]pyridines and pyrrolo[2,3-b]-pyridine (7-azaindole) heterocyclic cores are “privileged structures” due in part to their ability to interact with a multitude of different receptors, making them essential to the drug discovery process. Imidazo[1,2,-a]pyridine and 7-azaindole, though structurally related, are typically independently synthesized from 2-aminopyridine starting materials. Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2-a]pyridines or 7-alkyl azaindoles in two steps. 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 (25–95% yield) through a cyclization of transient Zincke nitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (14 examples, up to 91% yield). Under oxidative conditions, the pyridinimines serve as directing groups for C–H functionalization reactions to afford imidazo[1,2-a]pyridines. We have studied the mechanism of the cyclization event using DFT calculations and propose this takes place via ketenimine intermediates.
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 2,13-benzothiadiazole and shown to undergo conjugate addition reactions with both nitrogen (40–95% yield) and carbon nucleophiles (72–93% yield). Secondary amines were found to undergo monoadditions while carbon nucleophiles added twice. The sequence of addition of the nucleophiles could be controlled giving mixed addition products. The multicomponent coupling products could then be converted to natural product-like motifs using intramolecular cyclization reactions.
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 2,13-benzothiadiazole and shown to undergo conjugate addition reactions with both nitrogen (40–95% yield) and carbon nucleophiles (72–93% yield). Secondary amines were found to undergo monoadditions while carbon nucleophiles added twice. The sequence of addition of the nucleophiles could be controlled giving mixed addition products. The multicomponent coupling products could then be converted to natural product-like motifs using intramolecular cyclization reactions.
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