meta‐Selective C−H Functionalization of Pyridines

Abstract

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization of C−H bonds in pyridines is a straightforward approach to access valuable substituted pyridines. Compared to the direct ortho‐ and para‐functionalization, meta‐selective pyridine C−H functionalization is far more challenging due to the inherent electronic properties of the pyridine entity. This review summarizes currently available methods for pyridine meta‐C−H functionalization using a directing group, non‐directed metalation, and temporary dearomatization strategies. Recent advances in ligand control and temporary dearomatization are highlighted. We analyze the advantages as well as limitations of current techniques and hope to inspire further developments in this important area.

C–H Functionalization of Pyridines via Oxazino Pyridine Intermediates: Switching to para-Selectivity under Acidic Conditions

“…The chemo-selective and siteselective functionalization of polyheteroarene compounds is of practical value. 47 We found that the developed paraalkylation reaction exhibits excellent chemo-selectivity for more electron-rich pyridine rings in the presence of other Nheteroarenes including pyridines (26−28), pyrimidines (29), thiazoles (30), pyrazoles (31), and xanthines (32). In the first step, the more nucleophilic pyridines in these substrates underwent selective dearomative cycloaddition with DMAD and MP.…”

“…25 Switchable functionalization of meta-and para-C−H bonds of pyridines, however, is very challenging due to their distinct reactivities. 31 Ir-catalyzed meta-and para-C−H borylation as well as Ni- catalyzed meta-and para-C−H alkenylation relied on tailormade catalysts and ligands. 9,12,32,33 A more practical example was recently disclosed by Yu, Lin, and co-workers, who reported electrochemical meta-and para-C−H carboxylation of pyridines using different types of cell setups (Scheme 1C).…”

“…This is particularly relevant for the study of structure–activity relationship (SAR) to expedite drug discovery. , Switchable functionalization of the ortho- and para -C–H bonds of pyridines has been developed through steric control. ,− For instance, Knochel and co-workers reported that the metalation of 3-fluoropyridine was switched from the ortho to the para position in the presence of a Lewis acid (Scheme C) . Switchable functionalization of meta- and para -C–H bonds of pyridines, however, is very challenging due to their distinct reactivities . Ir-catalyzed meta- and para -C–H borylation as well as Ni-catalyzed meta- and para -C–H alkenylation relied on tailor-made catalysts and ligands. ,,, A more practical example was recently disclosed by Yu, Lin, and co-workers, who reported electrochemical meta- and para -C–H carboxylation of pyridines using different types of cell setups (Scheme C) …”

Regiodivergent Arylation of Pyridines via Zincke Intermediates

“…A classical approach to pyridine functionalization is in situ N-activation followed by addition of a nucleophile, creating a de-aromatized electron rich intermediate such as a dihydropyridine or a Zincke imine which offer a more versatile choice of bond formation and options to subsequently re-aromatize. [6][7] The original Zincke pyridinium reaction is illustrated in Scheme 1B, whereby aryl pyridinium 3 reacts with secondary amines to give the ring-opened azahexatriene 4. [8] Exchange with an alkylamine and ring closure gives the alkylpyridinium product 5.…”

Regiodivergent Arylation of Pyridines via Zincke Intermediates

“…A classical approach to pyridine functionalization is in situ N-activation followed by addition of a nucleophile, creating a de-aromatized electron rich intermediate such as a dihydropyridine or a Zincke imine which offer a more versatile choice of bond formation and options to subsequently re-aromatize. [6][7] The original Zincke pyridinium reaction is illustrated in Scheme 1B, whereby aryl pyridinium 3 reacts with secondary amines to give the ring-opened azahexatriene 4. [8] Exchange with an alkylamine and ring closure gives the alkylpyridinium product 5.…”