Nucleophilic Dearomatization of Activated Pyridines

Abstract

Amongst nitrogen heterocycles of different ring sizes and oxidation statuses, dihydropyridines (DHP) occupy a prominent role due to their synthetic versatility and occurrence in medicinally relevant compounds. One of the most straightforward synthetic approaches to polysubstituted DHP derivatives is provided by nucleophilic dearomatization of readily assembled pyridines. In this article, we collect and summarize nucleophilic dearomatization reactions of - pyridines reported in the literature between 2010 and mid-2018, complementing and updating previous reviews published in the early 2010s dedicated to various aspects of pyridine chemistry. Since functionalization of the pyridine nitrogen, rendering a (transient) pyridinium ion, is usually required to render the pyridine nucleus sufficiently electrophilic to suffer the attack of a nucleophile, the material is organized according to the type of N-functionalization. A variety of nucleophilic species (organometallic reagents, enolates, heteroaromatics, umpoled aldehydes) can be productively engaged in pyridine dearomatization reactions, including catalytic asymmetric implementations, providing useful and efficient synthetic platforms to (enantioenriched) DHPs. Conversely, pyridine nitrogen functionalization can also lead to pyridinium ylides. These dipolar species can undergo a variety of dipolar cycloaddition reactions with electron-poor dipolarophiles, affording polycyclic frameworks and embedding a DHP moiety in their structures.

Microbial Degradation of Pyridine: a Complete Pathway inArthrobactersp. Strain 68b Deciphered

“…Hence, on protonating or quaternizing pyridine (as in the case of N-methylnicotinate) (19) to a pyridinium salt, the above chemical features of -electron deficiency become more marked. In addition, a new reaction becomes possible, namely, ring opening, due to the higher electronegativity of the heteroatom, especially when the electron-withdrawing group is connected to the heteroatom (43,45,46). Moreover, pyridinium salt can be effectively oxidized by the milder oxidants such as potassium permanganate and active manganese dioxide instead of Fremy's salt, lead(II) and mercuric acetates, chromic acid, and peracids (47).…”

Electrochemical Dearomatization: Evolution from Chemicals to Traceless Electrons

“…Other types of aromatic systems deserve to be explored, although there are differences in resonance stabilization energies . In principle, every aromatic compound can undergo dearomatization, and especially heteroaromatics such as pyrroles, thiophenes and pyridines can be employed in the ensuing study. Apparently, developments in this field are still in their infancy.…”

“…The fascinating simplicity‐to‐complexity synthetic logic is straightforward and capable of converting simple planar aromatics into three‐dimensionally (3D) preferred cyclic architectures via disturbing the aromatic π‐system. Currently, dearomatization protocols can be classified into several categories, including transition metal‐mediated or transition metal‐catalyzed dearomatizations, dearomative hydrogenations, dearomative cycloadditions, nucleophilic dearomatizing reactions, radical dearomatizations, oxidative dearomatizations, asymmetric dearomatizations and so on . In terms of the feedstock, electron‐rich compounds, for instance, indoles, pyrroles, phenols, naphthols, and arenes as well as electron‐deficient heteroarenes, such as pyridines and pyrazines, can be employed directly.…”

Recent Advances in the Catalytic Dearomatization of Naphthols

“…phenol, naphthol) have been extensively investigated in dearomative procedures enabling energetically favorable reaction profiles to be exploited. On the contrary, electronically‐deactivated arenes (with the exception of pyridine‐type compounds) are still suffering from limited applicability in dearomatization methodologies.…”