4-Selective Pyridine Functionalization Reactions via Heterocyclic Phosphonium Salts

Abstract

Pyridines are widely used across the chemical sciences in applications ranging from pharmaceuticals, ligands for metal complex and battery technologies. Direct functionalization of pyridine C–H bonds is an important strategy to make useful pyridine derivatives, but there are few ways to selectively transform the 4-position of the scaffold. We recently reported that pyridines can be converted into heterocyclic phosphonium salts that can serve as generic handles for multiple subsequent bond-forming processes. Reactions with nucleophiles and transition-metal cross-couplings will be described to make C–O, C–S, C–N, and C–C bonds in a diverse range of pyridines including those embedded in complex pharmaceuticals.1 Introduction2 Direct, Regioselective Functionalization of Pyridines3 4-Position Selectivity via Metal Catalysis4 Versatile Functional Groups versus Specific Bond Constructions5 Phosphonium Salts as Reagents for Pyridine Functionalization6 Conclusions

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

“…Current strategies for direct functionalization of pyridines include directed metalation, [4] Minisci‐type radical reactions, [5] and nucleophilic addition to N ‐activated pyridines [6] . The regiocontrolled direct C3 functionalization of unbiased pyridines was nonetheless a challenging problem, with very few documented examples.…”

“…Current strategies for direct functionalization of pyridines include directed metalation, [4] Minisci-type radical reactions, [5] and nucleophilic addition to N-activated pyridines. [6] The regiocontrolled direct C3 functionalization of unbiased pyridines was nonetheless a challenging problem, with very few documented examples. The harsh acidic conditions, use of elemental halides and high temperatures required for meta-selective halogenation and nitration (Scheme 1C) limit their use and frequently lead to regioisomeric products.…”

Late‐Stage Functionalisation of Pyridine‐Containing Bioactive Molecules: Recent Strategies and Perspectives

“…[79][80][81][82][83] Notably, this chemistry can be extended to a variety of heteroatomic nucleophiles, including sulphur-and selenium-based ones. [84] Carbon-cen-tered nucleophiles, from carbocycles to fluoromethyl groups, as well as halides, can also be employed, although requiring adjustments to the reaction conditions (e.g. the additional use of transition metals or designed phosphines such as 154).…”

Transition Metal-Free Regioselective Phosphonation of Pyridines: Scope and Mechanism

“…Pyridines are key motifs in agrochemicals, functional materials, transition metal catalysis, and organocatalysis. − Thus, the development of practical methods for the selective functionalization of these heterocycles remains an important challenge for both academia and pharmaceutical industry. Apart from the selective activation of C–H bonds of pyridine to forge C–C, C–N, and C–O bonds, the introduction of C–P bonds is of high importance as its enables access to phosphonates, phosphine oxides, and phosphines, which are highly important scaffolds in materials science, biochemistry, and catalysis . More importantly, the development of site-selective phosphonation has attracted much attention during the last decades, given the capability of those approaches to furnish organophosphorus compounds in straightforward and step-economical fashions. , …”