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

Abstract

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.

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

“…Since then, various alternative acids have been applied including protic acids, such as silica-bonded S-sulfonic acid [ 13 ], polyvinylsulfonic acid (PVSA) [ 14 ], kaolin-supported H 2 SO 4 [ 15 ], polyvinylpolypyrrolidone-supported triflic acid (PVPP . OTf) [ 16 ], ascorbic acid [ 17 ], phosphoric acid [ 18 ], benzenesulfonic acid [ 19 ], chitosan–SO 3 H (CTSA) [ 20 ], phthalimide- N -sulfonic acid (PISA) [ 21 ] and SiO 2 -KHSO 4 [ 22 ] as well as Lewis acids, such as FeCl 3 [ 23 – 24 ], RuCl 3 ·3H 2 O [ 25 ], AgNO 3 [ 26 ], glycerol and [Fe(III)-(salen)]Cl [ 27 ], Fe(DS) 3 · n H 2 O [ 28 ], Sc(OTf) 3 [ 29 ], B(C 6 F 5 ) 3 or PhSiCl 3 [ 30 ] and Cp 2 TiCl 2 [ 31 ]. However, most of these reactions face some serious drawbacks, such as the requirement of large quantities of the catalyst due to present moisture or formation of adducts with the substrate, long reaction times, lower yields, and production of large amounts of toxic waste during work-up.…”

“…[99]. After repeated studies and experiments on the reaction between indole (11) and benzaldehyde (31), methanol emerged as the optimum solvent with the isolated product yield approaching 98%, after 1 hour, when 69 mg of the nanocomposite were added to the reaction mixture [99]. The recovery of the nanocatalyst was feasible by simple filtration and it was found that its catalytic efficiency would not diminish even after 3 cycles [99].…”