Directing Group‐Free Regioselective meta‐C−H Functionalization of Pyridines

Abstract

The pyridine core is among the most common motifs found in pharmaceuticals and agrochemicals. Consequently, the CÀ H functionalization of pyridine is a prized reaction, as it can help access a broad spectrum of valuable chemicals. However, the intrinsic electronic properties of pyridines hinder their meta-CÀ H functionalization, requiring drastic conditions affecting functional group compatibility. A synthetic manoeuvre to overcome this challenge involves the temporary conversion of pyridines into electron-rich intermediates and subsequent regioselective electrophilic functionalization. This was recently accomplished by a ring-opening ringclosing sequence via Zincke imine intermediates by McNally and co-workers, and a dearomatization-rearomatization sequence via oxazino-pyridine intermediates by the Studer group. The mildness and simplicity of these protocols enable them to work with complex molecular setups for synthesizing natural products and bioactive molecules.

meta‐Selective C−H Functionalization of Pyridines

“…Two recent breakthroughs along these lines are discussed herein. [78] meta-Halogenation of pyridines could serve as a platform for various subsequent bond-forming reactions. In addition, the halopyridines themselves are of high importance as the halo substituents can facilitate intermolecular interactions with biological targets such as proteins.…”

“…Therefore, dearomatization methods that allow generation of dearomatized pyridine intermediates with enhanced redox stability are highly demanded. Two recent breakthroughs along these lines are discussed herein [78] …”

meta‐Selektive C−H‐Funktionalisierung von Pyridinen

“…Zwei aktuelle Durchbrüche auf diesem Gebiet werden nachfolgend diskutiert. [78] Die meta-Halogenierung von Pyridinen kann als Ausgangspunkt für verschiedene nachfolgende chemische Transformationen dienen. Zusätzlich sind Halopyridine selbst von großer Bedeutung, da der Halo-Substituent intermolekulare Wechselwirkungen mit biologischen Zielstrukturen wie Proteinen eingehen kann.…”

“…Daher sind Dearomatisierungsmethoden, welche dearomatisierte Pyridinintermediate mit verbesserter Redoxstabilität hervorbringen, sehr gefragt. Zwei aktuelle Durchbrüche auf diesem Gebiet werden nachfolgend diskutiert [78] …”

Dearomatization of Pyridines: Stereoselective Synthesis of Functionalized [1,2,4]Triazolo[4,3-a]pyridines

“…Multisubstituted nitrogen-containing heterocycles, especially pyridine and its derivatives, are frequent motifs found in bioactive natural products, small molecule drugs, and functional materials . The effiecient preparation of these important motifs has received considerable attention in the past decades . Among the numerous advances, dearomatization of pyridines to functional six-membered N -heterocycles has served as one of the most direct and reliable approaches …”