Tunable Titanocene Lewis Acid Catalysts for Selective Friedel–Crafts Reaction of Indoles and <i>N</i>‐Sulfonyl­aldimines

<jats:title>Abstract</jats:title><jats:p>A new strategy to control the selective Friedel–Crafts reaction of indoles and imines under mild conditions was developed. Phenol derivatives were established as efficient ligands to finely tune the activity of titanocene dichloride. Cp<jats:sub>2</jats:sub>TiCl<jats:sub>2</jats:sub> and phenol catalyzed the mono‐Friedel–Crafts reaction of indoles and <jats:italic>N</jats:italic>‐sulfonyl aldimines with good yields (91 %), whereas <jats:italic>o</jats:italic>‐aminophenol significantly enhanced the activity of the titanocene catalyst and promoted the synthesis of bisindole with excellent yields (98 %). The new organometallic Lewis acid catalysts are air‐tolerant, can be used with low catalyst loading (3 mmol‐%) and are compatible with –NO<jats:sub>2</jats:sub>, –F, –Cl, –Br, and –OMe (30 examples with yields from good to excellent). The titanocene catalysts were fully characterized by NMR and HRMS analysis. The results suggest that Cp<jats:sub>2</jats:sub>TiCl(OC<jats:sub>6</jats:sub>H<jats:sub>5</jats:sub>) (<jats:bold>I</jats:bold>) and Cp<jats:sub>2</jats:sub>TiCl(OC<jats:sub>6</jats:sub>H<jats:sub>4</jats:sub>NH<jats:sub>3</jats:sub><jats:sup>+</jats:sup>Cl<jats:sup>–</jats:sup>) (<jats:bold>II</jats:bold>) were catalytic species for the mono‐ and double‐Friedel–Crafts reactions, respectively. Distinguished from single functional acid catalysts <jats:bold>I</jats:bold>, catalyst <jats:bold>II</jats:bold> showed a catalytic cooperative effect of two acid components, which led to a fine tuning of the reactivity as well as to the selectivity of the desired reaction pathways.</jats:p>