Suppression of oncogenic Wnt-mediated signaling holds promise as an anti-cancer therapeutic strategy. We previously reported a novel class of small molecules (IWR-1/2, Inhibitors of Wnt Response) that antagonize Wnt signaling by stabilizing the Axin destruction complex. Herein, we present the results of structure/activity relationship studies of these compounds.

o-Dihaloarenes acting as aryne precursors react with acetylenes and nitriles catalyzed by the NiBr(2)(dppe)/dppe/Zn system to give substituted naphthalene, phenanthridine or triphenylene derivatives depending on the reaction conditions in moderate to excellent yields with good tolerance of functional groups.

A novel procedure for the NiCl(2)(DME)/dppp/Zn system catalyzed intermolecular insertion of aryl iodides to nitriles was developed, which afforded variously substituted arylketone derivatives in moderate to good yields with tolerance of a wide variety of functional groups.

Novel procedures for the [Pd]/[Ag]/TFA system catalyzed cascade reactions of nitrile directed remote C-H and dual C-H bond activation with insertion of nitrile were developed, which afforded variously polysubstituted fluorenones in moderate to good yields with tolerance of a wide variety of substrates.

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A novel procedure for hydride-induced anionic cyclization has been developed. It includes the reduction of a biaryl bromo-nitrile with a nucleophilic aromatic substitution (S(N)Ar). A range of polysubstituted 6-H-phenanthridines were so obtained in moderate to good yield with good substrate tolerance. This method involves a concise transition-metal-free process and was applied to synthesize natural alkaloids.

Substituted imide and amide derivatives were conveniently prepared from the reaction of isocyanates with o-iodobenzoates and haloarenes catalyzed by the NiBr2(dppe)/dppe/Zn system in moderate to good yields with excellent tolerance of functional groups.

An efficient and concise procedure for the ligand-free copper-catalyzed cascade reaction of C–O and C–N bond coupling was developed to afford various (NH)-phenanthridinones.