C3-Selective Arylation of Indoles Using Palladium-Hydroxyterphenylphosphine Catalysts and Its Application to Syntheses of Nitrogen-containing Polycyclic Compounds

Indole and related skeletons are ubiquitous structural motifs often found in pharmaceuticals and natural compounds, and their arylated species have attracted attention because of their diverse biological activities. Among them, much synthetic effort has been made to obtain 3-arylindoles. Palladium-catalyzed direct arylation of N-unsubstituted indole is a powerful tool for 3-arylated indole synthesis, though achieving high C3-selectivity over C2- and N1-selectivity is still challenging. A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-arylation of N-nonsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity, whereas catalysts with other structurally related phosphine ligands exhibited N1-selectivity. Complex formation between the lithium salts of the ligand and the indole is assumed to promote the selective arylation at the C3-position of the indole ring. In the case of 3-alkylindoles, dearomative C3-arylation proceeded to afford 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives. This methodology was further applied to tryptamine derivatives, and the dearomative C3-arylation followed by intramolecular cyclization of the resulting 3,3-disubstituted indolenines afforded C3a-arylated pyrroloindolines in one-pot. Furthermore, reactions using homotryptamine derivatives successfully provided C4a-arylated pyridoindolines.