Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts

Abstract

Nucleophilic dearomatization of azaarenium salts is a powerful strategy to access 3D scaffolds of interest from easily accessible planar aromatic azaarene compounds. Moreover, this approach yields complex dihydroazaarenes by allowing the functionalization of the scaffold simultaneously to the dearomatization step. On the other side, organocatalysis is nowadays recognized as one of the pillars of the asymmetric catalysis field of research and is well-known to afford a high level of enantioselectivity for a myriad of transformations thanks to well-organized transition states resulting from low-energy interactions (electrostatic and/or H-bonding interactions…). Consequently, in the last fifteen years, organocatalysis has met great success in nucleophilic dearomatization of azaarenium salts. This review summarizes the work achieved up to date in the field of organocatalyzed nucleophilic dearomatization of azaarenium salts (mainly pyridinium, quinolinium, quinolinium and acridinium salts). A classification by organocatalytic mode of activation will be disclosed by shedding light on their related advantages and drawbacks. The versatility of the dearomatization approach will also be demonstrated by discussing several chemical transformations of the resulting dihydroazaarenes towards the synthesis of structurally complex compounds.

Recent Advances in Catalytic and Technology-Driven Radical Addition to N,N-Disubstituted Iminium Species

“…Thus, several nucleophiles, such as organometallic species (stoichiometric addition of Grignard reagents, metal-catalyzed additions of various reagent, etc.) [ 64 ] or acidic pro-nucleophiles under organocatalytic conditions (including asymmetric versions) to cite a few [ 65 ], were added to azaarenium salts providing access to 3D heterocycles from flat heteroaromatic structures. Although this field of research was intensively explored, some challenges remain: (1) generally speaking, azaarenium salts exhibit different electron-deficient sites (namely C2 or C4 positions for pyridines and quinolines), rendering the regioselective addition very challenging; (2) the addition of the nucleophilic species generally results in a transient dearomatized intermediate (namely dihydroazaarene derivatives), thus requiring high energy cost for the dearomatization step, especially if one considers pyridine ring, which requires a complete loss of aromaticity compared to quinolines or isoquinolines for which only a partial dearomatization occurs.…”

Multicomponent Dearomative Difluoroalkylation of Isoquinolines with Difluorinated Silyl Enol Ethers: Divergent Synthesis of gem-Difluorinated Heterocycles

“…Transformative functionalization of electron-deficient N -heteroarenes represents a unique strategy in the organic synthesis arsenal due to the abundance of readily available N -heteroaromatic systems and the rapid access to valuable molecules both with core N -heterocyclic substructure and with various featured functionalities that are in high demand in medicinal chemistry and drug discovery . Despite significant advances, such as directed metalations, Minisci-type radical reactions, and photoredox transformations, dearomatization strategies especially with a multicomponent fashion through a nucleophilic addition process on N -activation mode have attracted extensive interest owing to the easy achievement of structurally complex and functionally diverse sets of dihydroazaarenes with high atom and step economy (Scheme a). In addition to the practical advantages of the dearomatization strategy, the sequential oxidative rearomatization process provides a formal direct C–H functionalization method of N -heteroarenes , (Scheme a).…”

“…In these contexts, the appropriate N -activation system becomes essential to realize multicomponent dearomative difluoroalkylation with difluorinated silyl enol ethers. Inspired by the widely developed Reissert type multicomponent dearomatization protocols, , we herein report a Reissert type multicomponent dearomative difluoroalkylation of isoquinolines with difluorinated silyl enol ethers to construct bioactively and medicinally important difluoroalkylated dihydroisoquinolines (Scheme c). The sequential oxidative rearomatization with different bases provides a divergent synthesis of difluoroalkylated isoquinolines and difluoromethylated isoquinolines (Scheme c).…”

Synthesis of Stereoselective Multifused Cyclic Compounds via Palladium-Catalyzed C3-Allylative Dearomatization

“…One promising strategy for constructing intricate cyclic compounds involves dearomative functionalization using N -heteroarenes . This approach is particularly attractive for synthesizing complex fused-ring compounds and has demonstrated its practical utility across applications in various fields.…”