Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines

Abstract

Dearomatization reactions have become fundamental chemical transformations in organic synthesis since they allow for the generation of three-dimensional complexity from two-dimensional precursors, bridging arene feedstocks with alicyclic structures. When those processes are applied to pyridines, quinolines, and isoquinolines, partially or fully saturated nitrogen heterocycles are formed, which are among the most significant structural components of pharmaceuticals and natural products. The inherent challenge of those transformations lies in the low reactivity of heteroaromatic substrates, which makes the dearomatization process thermodynamically unfavorable. Usually, connecting the dearomatization event to the irreversible formation of a strong C−C, C− H, or C−heteroatom bond compensates the energy required to disrupt the aromaticity. This aromaticity breakup normally results in a 1,2-or 1,4-functionalization of the heterocycle. Moreover, the combination of these dearomatization processes with subsequent transformations in tandem or stepwise protocols allows for multiple heterocycle functionalizations, giving access to complex molecular skeletons. The aim of this review, which covers the period from 2016 to 2022, is to update the state of the art of nucleophilic dearomatizations of pyridines, quinolines, and isoquinolines, showing the extraordinary ability of the dearomative methodology in organic synthesis and indicating their limitations and future trends.

Synthesis of Phenol–Pyridinium Salts Enabled by Tandem Electron Donor–Acceptor Complexation and Iridium Photocatalysis

“…Dearomatization of heterocyclic compounds has propelled the field of total synthesis into new horizons, granting synthetic chemists an unprecedented gateway to access a variety of saturated and partially unsaturated ring systems. , Pyridines, in their free base form, do not readily undergo dearomatization and must be activated first by substitution on the nitrogen. From there, dearomatization reactions can be affected to access piperidines, which stand out as a particularly pertinent cyclic backbone in medicinal chemistry .…”

Skeletal Editing: Ring Insertion for Direct Access to Heterocycles

“…Organic cyclic compounds are crucial in pharmaceutical science, natural product chemistry, and materials science [1,2]. Cyclic structures significantly impact molecular properties, including lipophilicity, three-dimensional configuration, and rigid scaffolds [3].…”

“…However, despite these Such reactions are unique and belong to the category of ring expansion reactions. When consulting the relevant literature, we referred to some review articles [2,7,15,24,25] and further searched for relevant papers based on these publications while fully utilizing our daily accumulation. While our literature collection may not be exhaustive, it still provides insights into the overall characteristics of this reaction type.…”

Photochemical dearomative skeletal modifications of heteroaromatics

“…22–28 A recent review by Sánchez-Roselló and Carlos del Pozo summarizes nucleophilic dearomatization of pyridines, quinolines, and isoquinolines. 29…”