Synthesis of Multisubstituted Heterocyclic and Aromatic Compounds Using Catalyst-Controlled Site-Selective Reactions

Abstract

Site-selective reactions are important tools in the synthesis of useful multisubstituted compounds, including pharmaceuticals and functional molecules. Such reactions convert functional groups in a selective manner, thereby enabling the synthesis of various compounds with different substitution patterns from a single starting compound. Although a number of transition metal-catalyzed site-selective reactions have been developed, site-selectivity is usually controlled by the substrate, limiting the scope of the reaction. In contrast, catalyst-controlled site-selective reactions of single substrates have been reported, wherein ligand-controlled reactions are of particular interest. Previously, our group developed hydroxyterphenylphosphine ligands to achieve the palladium-catalyzed ortho-selective cross-coupling reactions of dihalogenated phenols/anilines. In this system, the hydroxy groups of the ligand bind to the substrate via the metal, and the proximity of palladium to the halogen at the ortho-position accelerates the reaction at this less reactive position. These reactions have been employed to synthesize multisubstituted benzofurans and indoles from dichlorophenols/anilines using a one-pot ortho-selective Sonogashira coupling/cyclization/Suzuki–Miyaura coupling protocol. The developed catalyst also has enabled the direct C3-selective arylation of N-nonsubstituted indoles, and both tricyclic pyrroloindolines and pyridoindolines have been obtained from tryptamine derivatives via a C3-dearomative arylation/cyclization strategy. Furthermore, the site-selective arylation of N-nonsubstituted 1H-pyrroles has been achieved by changing the ligand, and the reaction proceeded selectively at the C2 or C3 position, yielding 2,2,5-trisubstituted 2H-pyrroles and other compounds whose preparation is challenging via conventional approaches. Finally, the regioselective synthesis of polycyclic aromatic compounds using appropriate palladium catalysts has been performed using the site-selective approach.