Titanocene Lewis Acid Complexes with Diversified N,O-Ligands: Selectivity toward Three-Component Friedel–Crafts Reactions of Indoles

Titanocene complexes by N,O-ligands were rationally designed and tuned for selective three-component aza-Friedel–Crafts reactions of indoles, aldehydes, and unmodified aniline. The combination of Cp2TiCl2 and 8-hydroxyquinoline favored the synthesis of the mono aza-Friedel–Crafts adducts, whereas Cp2TiCl2 combined with anthranilic acid overwhelmingly formed bis-indoles. 1H NMR titration experiments, mass spectroscopy, X-ray crystal structure analyses, and control experiments showed that the reaction of Cp2TiCl2 with 8-hydroxyquinoline resulted in a half-sandwich complex [CpTiCl(C9H6NO)2] (I), in which the Lewis acidity was enhanced via fine-tuning steric and electronic properties of the Ti (IV) center, facilitating mono aza-Friedel–Crafts reaction of indoles, aldehydes, and aniline; in contrast, when anthranilic acid reacted with the same Ti(IV) precursor, a bis-ligand sandwich complex Cp2Ti[(o-NH2)PhCOO]2 (II) was obtained, in which both Lewis acidity of titanium and cooperation with amino groups promoted further transformation of indoles into bis-indole adducts.