Functionalization Of Pyridines Research Articles

Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch

Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C−H-difluoromethylation of pyridines represents a highly efficient economic way to access these azines. However, the direct meta-difluoromethylation of pyridines has remained elusive and methods for site-switchable regioselective meta- and para-difluoromethylation are unknown. Here, we demonstrate the meta-C−H-difluoromethylation of pyridines through a radical process by using oxazino pyridine intermediates, which are easily accessed from pyridines. The selectivity can be readily switched to para by in situ transformation of the oxazino pyridines to pyridinium salts upon acid treatment. The preparation of various meta- and para-difluoromethylated pyridines through this approach is presented. The mild conditions used also allow for the late-stage meta- or para-difluoromethylation of pyridine containing drugs. Sequential double functionalization of pyridines is presented, which further underlines the value of this work.

Reaction strategies for the meta-selective functionalization of pyridine through dearomatization.

The pyridine moiety is a crucial structural component in various pharmaceuticals. While the direct ortho- and para-functionalization of pyridines is relatively straightforward, the meta-selective C-H functionalization remains a significant challenge. This review highlights dearomatization strategies as a key area of interest in expanding the application of meta-C-H functionalization of pyridines. Dearomatization enables the meta-functionalization through various catalytic methods that directly generate dearomatization products, and some products can be rearomatized back to pyridine derivatives. Furthermore, this article also covers the dearomatization of multiple positions of pyridine in the synthesis of polycyclic compounds. It offers a comprehensive overview of the latest advancements in dearomatization at different positions of pyridine, aiming to provide a valuable resource for researchers in this field. It also highlights the advantages and limitations of existing technologies, aiming to inform a broader audience about this important field and foster its future development.

Photoresponse of new azo pyridine functionalized poly(2-hydroxyethyl methacrylate-co-methyl methacrylate)

A new azo polymer containing photoisomerizable azo pyridine functionalities was synthesized via Mitsunobu reaction of 4-(4-hydroxyphenylazo)pyridine with poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (p(HEMA-co-MMA)) for creating new photochromic materials. The resulting polymer with azo pyridine side groups was characterized for structural, thermal, and optical properties. UV–vis, 1H NMR and IR spectroscopies confirmed that all hydroxyl groups in p(HEMA-co-MMA) were substituted with azo dye. The obtained azo copolymer exhibited high thermal stability (around 240 °C) and a glass transition temperature (113 °C), promising for applications. The trans-to-cis isomerization upon UV irradiation and the thermal back reaction of the azo chromophore in the copolymer in the solid state was studied. A photostationary state with 50% content of cis-isomers upon 6 min of UV irradiation was reached, and during 48 h dark relaxation at ambient temperature, all cis-isomers converted to the trans form. Additionally, the possibility of efficient photogeneration of surface relief gratings with high amplitude of azo copolymer surface modulation was demonstrated.

Recent Progress in Functionalization of the Pyridine Ring through C−S Bond Formation under Transition Metal Catalyst Free Conditions

AbstractPyridines and quinolines substituted with sulfur‐containing functional groups are widely used as drugs, drug candidates, organic materials, N,S‐ligands and others. Traditional synthetic routes to produce these compounds are based on nucleophilic aromatic substitution reactions and transition metal‐catalyzed cross‐coupling reactions of (pseudo)halopyridines. While effective in many cases, both approaches are limited due to using forcing conditions and expensive, specifically designed catalytic systems. In the last decade, a number of innovative methods for the functionalization of the pyridine ring via the formation of a C−S bond have been developed. Most of these methods proceed through the direct or indirect C−H functionalization of unfunctionalized pyridines, thus avoiding the use of oftentimes not readily available halopyridines as the starting materials. Deoxygenative C−H functionalization of pyridine‐N‐oxides and deaminative transformation of aminopyridines have been also employed for the introduction of diverse organosulfur functionality into the pyridine ring. All these processes can be easily performed under mild conditions, typically affording value pyridines and quinolines in good to high yields. Usually being highly chemo‐ and regioselective, these methods allow the late‐stage functionalization of complex molecules including drugs and natural products. In this Review, we summarize the most recent synthetic methods for functionalization of pyridines and fused pyridines with sulfur‐containing functional groups reported mostly since 2018. For a better understanding of the processes, the mechanisms of the described reactions are briefly discussed.

Copper-Catalyzed C4-selective Carboxylation of Pyridines with CO2 via Pyridylphosphonium Salts.

Pyridine motifs are widespread pharmacophores in many drugs. Installing various substituents through pyridine C-H bond functionalization is significant for new drug design and discovery. Developments of late-stage functionalization reactions enrich the strategies for selective functionalization of pyridines. However, late-stage C-H carboxylation of pyridines is a long-standing challenge, especially selectively carboxylation with CO2 on pyridine motifs. Herein, we describe a practical method for C4-H carboxylation of pyridines via one-pot C-H phosphination and copper-catalyzed carboxylation of the resulted phosphonium salts with CO2 . The reaction is conducted under mild conditions and compatible with multiple active groups and several pyridine drugs, providing diverse valuable isonicotinic acid compounds, demonstrating the application potential of this strategy.

Copper‐Catalyzed C4‐selective Carboxylation of Pyridines with CO2 via Pyridylphosphonium Salts

AbstractPyridine motifs are widespread pharmacophores in many drugs. Installing various substituents through pyridine C−H bond functionalization is significant for new drug design and discovery. Developments of late‐stage functionalization reactions enrich the strategies for selective functionalization of pyridines. However, late‐stage C−H carboxylation of pyridines is a long‐standing challenge, especially selectively carboxylation with CO2 on pyridine motifs. Herein, we describe a practical method for C4−H carboxylation of pyridines via one‐pot C−H phosphination and copper‐catalyzed carboxylation of the resulted phosphonium salts with CO2. The reaction is conducted under mild conditions and compatible with multiple active groups and several pyridine drugs, providing diverse valuable isonicotinic acid compounds, demonstrating the application potential of this strategy.

Microwave-Mediated, Catalyst-Free Synthesis of 1,2,4-Triazolo[1,5-a]pyridines from Enaminonitriles.

A catalyst-free, additive-free, and eco-friendly method for synthesizing 1,2,4-triazolo[1,5-a]pyridines under microwave conditions has been established. This tandem reaction involves the use of enaminonitriles and benzohydrazides, a transamidation mechanism followed by nucleophilic addition with nitrile, and subsequent condensation to yield the target compound in a short reaction time. The methodology demonstrates a broad substrate scope and good functional group tolerance, resulting in the formation of products in good-to-excellent yields. Furthermore, the scale-up reaction and late-stage functionalization of triazolo pyridine further demonstrate its synthetic utility. A plausible reaction pathway, based on our findings, has been proposed.

Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Para-Selective radical alkylation of pyridines with diacyl peroxides and peresters

A regioselective para-alkylation of pyridines using alkyl carboxylic acid-derived diacyl peroxides or peresters is reported. This reaction proceeds under mild conditions, and late-stage functionalization of complex pyridines can be realized.

A dearomatization–rearomatization strategy for construction of 4H-quinolizin-4-ones via C–H bond functionalization of pyridines

Herein, the synthesis of 4H-quinolizin-4-ones from N-(2-methoxy-2-oxoethyl) pyridinium salts and alkenes through dearomative cycloaddition and rearomative ring expansion has been developed.

4-Selective Functionalization of Pyridines via Pyridylphosphonium Salts

4-Selective Functionalization of Pyridines via Pyridylphosphonium Salts

Copper(I)‐Catalyzed [4+2] Oxidative Annulation of α,β‐Unsaturated Ketoxime Acetates with Cyclopropanols toward Functional Pyridines

AbstractA Cu(I)‐catalyzed [4+2] oxidative annulation of α,β‐unsaturated ketoxime acetates with cyclopropanols has been developed for the synthesis of 2,4,5‐trisubstituted pyridines in 28–76% yields. This method employs cyclopropanols as C2 synthons and features various functional group compatibility and gram‐scale synthesis. In addition, a plausible reaction pathway was proposed based on the mechanism studies.

Direct Carbon for Nitrogen Replacement Reaction to Access Functionalized Pyridines

Direct Carbon for Nitrogen Replacement Reaction to Access Functionalized Pyridines

Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa.

Due to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due to their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, primary amines, imidazolines, and imidazoles, promote antibiotic and adjuvant activity in Gram-negative bacteria, but few of these have been targeted towards Pseudomonas aeruginosa specifically despite this pathogen being deemed a critical threat by the United States Centers for Disease Control and Prevention. Herein, we examined a small series of known and unknown nitrogenous dimers, with guanidine, amidine, dimethyl amine, and pyridine functionality, for antibacterial activity against multidrug resistant Pseudomonas aeruginosa. We found that two, with bisbenzguanidine and bisbenzamidine functionality, are potent against clinical isolates of multidrug resistant and biofilm forming Pseudomonas aeruginosa.

Para-Selective Functionalization of Pyridines

para-Selective Functionalization of Pyridines

Tributyl(1-((dimethylamino)(dimethyliminio)methyl)-1,4-dihydropyridin-4-yl)phosphonium Ditrifluoromethanesulfonate

Site-selective functionalization of pyridines is a crucial tool for the synthesis of diverse pharmaceuticals and materials. We introduced diiminium pyridine adducts as highly convenient and potent Lewis acids. We report that tributylphosphine selectively adds to the 4-position of pyridine in tetramethyldiiminium pyridine ditrifluoromethanesulfonate, resulting in the formation of the title compound. This finding represents an advancement towards the utilization of diiminium units as organic reagents or catalysts for pyridine functionalization. We also employ computational models to determine fluoride and hydride ion affinities, Fukui function f+(r), molecular electrostatic potential, and pKa values, providing valuable insights for future investigations in this area.

Recent Advances in Direct Pyridine C-H Activation Strategies

Background: Pyridine is one of the most ubiquitous hetero-aromatic moieties in pharmaceutical chemistry and it has enormous importance in a plethora of fields. From a synthetic chemistry standpoint, pyridine moiety has been used as a directing group in C-H activation strategies to functionalize various rings. However, this unique feature to participate as a directing group hinders developing methodologies to carry out C-H activation on the pyridine ring itself. One of the simplest solutions is to block the activity of ring nitrogen at the cost of two extra steps. Here, in this review, along with the blocking, we will briefly mention some interesting ways to get around this problem and the remaining challenges ahead. Objective: The coordinating ability of pyridine N poses a big challenge toward C-H functionalization on the pyridine ring. This review summarizes some of the recent methods towards this challenge. Method: Some key ideas towards that goal have been described. Here, the C-H activation strategies are categorised as follows: (1) Pyridine N-oxide mediated C-H activation, (2) Dimerization of C-H activation of pyridine, (3) Direct Pyridine C2-H activation, (4) Direct Pyridine C3-H activation and (5) Direct Pyridine C4-H activation. Results: Several methods have been highlighted that can be utilised to prepare C-H functionalized products with regiospecificity that subsequently may be manipulated into interesting products which are difficult to attain easily. Conclusion: This review explores various new direct C-H activation methods on pyridine which attempts to fill the void of traditional synthetic protocols in regard to regioselective pyridine functionalization. This review also explores the limitations of current methodologies which must be wiped off to attain a mature state in need of the pharmaceutical industry.

One-pot transformations of tetracyanocyclopropanes into highly functionalized pyridines

One-pot transformations of tetracyanocyclopropanes into highly functionalized pyridines

Meta-Selective C-H Functionalization of Pyridines.

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.

para-Selective C-H functionalization of pyridines holds a significant value but remains underdeveloped. Site-switchable C-H functionalization of pyridines under easily tunable conditions expedites drug development. We recently reported a redox-neutral dearomatization-rearomatization strategy for meta-C-H functionalization of pyridines via oxazino pyridine intermediates. Here, we demonstrate that these oxazino pyridine intermediates undergo highly para-selective functionalization simply by switching to acidic conditions. A broad scope of para-alkylated and arylated pyridines is prepared through radical as well as ionic pathways. These mild and catalyst-free methods are applied to the late-stage para-functionalization of drugs using pyridines as the limiting reagents. Consecutive meta,para-difunctionalization of pyridines is also achieved with complete regiocontrol relying on the pH-dependent reactivity of oxazino pyridines.