Gold-Catalyzed Hydroamination-Hydroarylation Route to Fused Indoles

Significance

Reported is a gold-catalyzed 5-endo-dig hydroamination followed by a 6-endo-trig hydroarylation of aniline diynes, leading to the synthesis of fused indoles. Initially the reaction was effected in good yields using Ph₃PAuCl/­AgOTf as catalyst system, but this approach gave only low yields of products for electron-rich systems. Since increasing catalyst loading did not ­improve yields, it was reasoned that bulky biaryl­phosphine ligands would promote the dissociation of the gold catalyst from the substrate, improving chances of alkyne activation for the hydroamination. The approach was successful, and these conditions were applied in the studies on substrate scope. For R^³ = 2-NCC₆H₄, the reaction essentially fails (10% yield); otherwise, all the yields are above 70%. The scope was well studied and the reaction was extended to azepino- and oxepinoindoles. The synthesized indoles were evaluated for antifungal activity, which ranged from nonexistent to very potent.