Synthesis of five-membered N-heterocycles using Rh based metal catalysts

Abstract

One of the highly emerging and an important aspect of organic chemistry is the metal catalyzed synthesis of heterocycles. The methodologies used earlier for their synthesis were less approachable to the organic chemist because of their high cost, highly specified instrumentation, and inconvenient methods. For both the stereoselective and regioselective synthesis of five-membered nitrogen containing heterocycles, cyclic reactions that are Rh-catalyzed have known to be very efficient. The present review covers the varied applications of Rh as a catalyst and its importance in the formation of five-membered nitrogen containing heterocycles. The fascinating research that has been done in this area is enclosed in this review.     

Ag-mediated synthesis of six-membered N-heterocycles

Abstract

One of the highly emerging and an important aspect of organic chemistry is the metal catalyzed synthesis of heterocycles. The methods used earlier for the synthesis of heterocycles were significant in the organic synthesis and developing cost-effective, improved and facial methods were beneficial to construct the complex architectures. For the both stereoselective and regioselective synthesis of six-membered nitrogen containing heterocycles, cyclic reactions that are Ag-mediated have known to be very efficient. The present review covers the applications of Ag in the formation of six-membered nitrogen containing heterocycles.     

卤素盐参与下有机电合成含氮杂环化合物的研究进展

含氮杂环化合物广泛存在于医药、农药及天然产物中,是许多具有生理活性的化合物和药物的基本骨架.开发高效、绿色的含氮杂环化合物的构建方法具有重要意义.近年来,卤素盐参与下有机电合成含氮杂环化合物取得了诸多进展.该类反应具有操作简单、绿色环保等特点.综述了有机电化学合成反应中,卤素盐作媒介,含氮杂环化合物的合成研究新进展.     

Synthesis of seven and higher-membered heterocycles using ruthenium catalysts

A wide variety of biological activities are possessed by nitrogen, oxygen, and sulfur containing heterocycles and many methods are explored for the preparation of these heterocyclic compounds. Metal catalysts are used in organic reactions with high activity. The synthesis of heterocycles with the help of metal catalysts became very important in organic synthesis. New protocols have been investigated for the synthesis of heterocycles in the last decades. In present review article I have concentrated on the synthesis of seven and higher-membered heterocylces in the presence of ruthenium catalyst.     

Heteroelement Analogues of Benzoxaborole and Related Ring Expanded Systems

The review covers the chemistry of organoboron heterocycles structurally related to benzoxaboroles where one of the carbon atoms in a boracycle or a fused benzene ring is replaced by a heteroelement such as boron, silicon, tin, nitrogen, phosphorus, or iodine. Related ring expanded systems including those based on naphthalene and biphenyl cores are also described. The information on synthetic methodology as well as the basic structural and physicochemical characteristics of these emerging heterocycles is complemented by a presentation of their potential applications in organic synthesis and medicinal chemistry, the latter aspect being mostly focused on the promising antimicrobial activity of selected compounds.     

Nitrogen-Containing Six-Membered Heterocycles: Solid-Phase Synthesis

Solid-phase organic synthesis is a rapidly expanding area of synthetic chemistry that is being widely exploited in the search for new medicinally important compounds using combinatorial techniques. In recent decades, a large number of reports related to solid-phase synthesis of heterocycles have appeared because of the wide variety of their biological activity. In this review, we report the important role of solid-phase synthesis in the synthesis of nitrogen containing six-membered ring heterocycles.     

Monoamine Oxidase Inhibitor Screening by Proteoliposome Capillary Electrophoresis

In this study, a new strategy for screening of enzyme inhibitors based on the interaction between enzyme and substrate was established. The bioactive proteoliposome reconstituted by monoamine oxidase (MAO) and liposome was added in the running buffers of capillary electrophoresis (CE) as pseudostationary phase to simulate the interaction between MAO and its substrate kynuramine (Kyn). The results showed that the relative migration time ratio (RMTR) of Kyn decreased obviously with increase of the proteoliposome, indicating strong interaction between proteoliposome and Kyn. After adding MAO inhibitors into the running buffers containing proteoliposome, the decline of the RMTR value of Kyn became slower. This occurred because MAO was inhibited to some degree by the inhibitors, weakening the interaction between MAO and Kyn. However, adding compounds which do not inhibit MAO activity into the running buffers did not affect the RMTR of Kyn obviously. The results obtained demonstrate that the method developed could characterize the inhibition of MAO inhibitors. Compared with traditional inhibitor screening methods, it does not need incubation outside the column to complete the enzyme catalytic reaction, so analysis is faster and less sample is consumed. With further development, the method might be chosen as a useful tool for screening of membrane protein inhibitors and identification of proteins associated with various diseases.     

Synthesis of heterocyclic compounds via Michael and Hantzsch reactions

Heterocycles represent the largest diversity of organic compounds with signifcant chemical, biomedical, and industrial applications. They exist in numerous natural products, dyes, and as scaffolds in diverse drugs and related pharmaceutically active substances. Substantial attention has been paid to develop various elegant methods to synthesize heterocycles. Among different strategies, Michael and Hantzsch reactions are considered as effective approaches for construction of heterocycles and their corresponding fused derivatives. This review covers this area especially in the last 10 years. The heterocyclic systems reported in this review are classified according to the kind of the heterocyclic systems.     

Palladium acetate and phosphine assisted synthesis of five-membered N-heterocycles

A wide variety of biological activities are possessed by oxygen, nitrogen, and sulfur heterocyclic compounds and much research has been performed for the synthesis of these heterocycles. The synthesis of heterocycles with the help of metal became highly rewarding and important method in organic synthesis. This review article concentrated on the synthesis of nitrogen containing five-membered heterocylces in the presence of palladium acetate and phosphine as a catalyst.     

Applications of palladium dibenzylideneacetone as catalyst in the synthesis of five-membered N-heterocycles

A wide variety of biological activities are possessed by N, O, and S containing heterocycles and recently many reports appeared for the synthesis of these heterocycles. The synthesis of heterocycles with the help of metal became highly rewarding and important method in organic synthesis. This review article concentrated on the synthesis of nitrogen containing five-membered heterocylces in the presence of palladium dibenzylideneacetone as a catalyst.     

Direct sp3 C-H bond activation adjacent to nitrogen in heterocycles

Activation of sp(3) C-H bonds adjacent to nitrogen in heterocycles is an attractive transformation that is emerging as a practical method in organic synthesis. This tutorial review aims to summarize the key examples of direct functionalization of nitrogen-containing heterocycles via metal-mediated and metal-catalyzed processes, which is meant to serve as a foundation for future investigations into this rapidly developing area of research. The review covers functionalization of N-heterocycles via alpha-lithiation with alkyllithium/diamine complexes, alpha-amino radical formation, metal-catalyzed direct C-H activation, C-H oxidations and oxidative couplings, and metal-catalyzed carbene insertions.     

Enantioselective Reactions of N‐Acyliminium Ions Using Chiral Organocatalysts

N‐acyliminium ions are reactive intermediates that can act as electron‐deficient electrophiles toward weak or soft nucleophiles, thereby providing useful methods for both intermolecular‐ and intramolecular carbon–carbon and carbon–heteroatom bond formation. Nucleophilic additions to N‐acyliminium ions constitute an important method for providing α‐functionalized amino compounds and many other biologically active nitrogen‐containing heterocycles. The development of efficient catalytic asymmetric reactions is a key objective in modern organic chemistry and is very important for the synthesis of natural products, pharmaceuticals, and agrochemicals. Various methods are available for this purpose and mostly rely on the use of chiral catalysts for enantioselective synthesis. This review deals with one aspect of such catalysis, which has emerged only in the past few years, and its applications in enantioselective reactions of N‐acyliminium ions to provide various nitrogen‐containing heterocycles.     

Azides in the Synthesis of Various Heterocycles

In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal, catalyzed, or noncatalyzed reaction conditions. The aforementioned reactions in the aim to prepare basic five-, six-, organometallic heterocyclic-membered systems and/or their fused analogs. This review article also provides a report on the developed methods describing the synthesis of various heterocycles from organic azides, especially those reported in recent papers (till 2020). At the outset, this review groups the synthetic methods of organic azides into different categories. Secondly, the review deals with the functionality of the azido group in chemical reactions. This is followed by a major section on the following: (1) the synthetic tools of various heterocycles from the corresponding organic azides by one-pot domino reaction; (2) the utility of the chosen catalysts in the chemoselectivity favoring C−H and C-N bonds; (3) one-pot procedures (i.e., Ugi four-component reaction); (4) nucleophilic addition, such as Aza-Michael addition; (5) cycloaddition reactions, such as [3+2] cycloaddition; (6) mixed addition/cyclization/oxygen; and (7) insertion reaction of C-H amination. The review also includes the synthetic procedures of fused heterocycles, such as quinazoline derivatives and organometal heterocycles (i.e., phosphorus-, boron- and aluminum-containing heterocycles). Due to many references that have dealt with the reactions of azides in heterocyclic synthesis (currently more than 32,000), we selected according to generality and timeliness. This is considered a recent review that focuses on selected interesting examples of various heterocycles from the mechanistic aspects of organic azides.     

Recent developments in the combinatorial synthesis of nitrogen heterocycles using solid phase technology

Recognizing the potential of combinatorial chemistry to accelerate drug discovery and development, most pharmaceutical and related industries are seriously looking toward combinatorial synthesis of compounds in order to facilitate the identification of 'lead' molecules. In particular, solid phase synthesis is the core technology for combinatorial chemistry and is widely used for generating libraries of structurally related compounds. Since many drugs contain the nitrogen heterocyclic component and since heterocycles possess a high order of structural diversity, a precise overview of recent progress in the combinatorial synthesis of nitrogen heterocycles using solid phase methodology would be useful. Since the progress in solid phase synthesis of organic molecules has been reviewed regularly from 1992 to 1998, only the development of solid phase combinatorial synthetic approaches of small nitrogen heterocycles since 1999 will be reviewed here. This review describes the solid phase synthesis of azepanes, benzodiazepines, benzimidazoles, benzothiazepines, cinnolines, indolizines, beta lactams, oxazepins, oxazoles including benzisooxazoles, hydantoins, piperidines, pyrimidines, pyrazolones, quinolones, trizolopyridazines and thiazoles.     

Aldo‐X Bifunctional Building Blocks for the Synthesis of Heterocycles

Compounds containing oxygen, nitrogen, or sulfur atoms inside the rings are attracting much attention and interest due to their biological importance. In recent years, several methods for the synthesis of such molecules have been reported by using aldo‐X bifunctional building blocks (AXB3 s) as substrates; these are a wide class of organic molecules that contain at least two reactive sites, among them, one aldehyde, acetal, or semiacetal group was involved. Because of the multiple reactivities, AXB3 s are widely used in the one‐pot synthesis of biologically important heterocycles. This review summarizes the synthesis of important heterocycles by using AXB3 s as pivotal components in establishing multicomponent reactions, tandem reactions, and so forth. In many cases, the established reaction systems with AXB3 s were characterized by some green properties, such as easy access to the substrate, mild and environmentally benign conditions, and wide scope of the substrate.     

Assembly of nitrogen-containing heterocycles initiated by the aza-Michael reaction

The aza-Michael reaction is considered as the most popular method for the carbon–nitrogen bond formation and the shortest way to β-aminocarbonyl compounds, including β-amino acids and their derivatives. In many cases, conjugate addition of nitrogen-centered nucleophiles to the activated multiple bond triggers a series of cascade transformations being completed by the formation of heterocycles and analogs of natural compounds. The review summarizes the most important advances in the aza-Michael reaction-initiated synthesis of nitrogen-containing heterocycles from unsaturated ketones and enoates.     

Six-Membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications

Cancer stands as a serious malady, posing substantial risks to human well-being and survival. This underscores the paramount necessity to explore and investigate novel antitumor medications. Nitrogen-containing compounds, especially those derived from natural sources, form a highly significant category of antitumor agents. Among these, antitumor agents with six-membered aromatic nitrogen heterocycles have consistently attracted the attention of chemists and pharmacologists. Accordingly, we present a comprehensive summary of synthetic strategies and clinical implications of these compounds in this review. This entails an in-depth analysis of synthesis pathways for pyridine, quinoline, pyrimidine, and quinazoline. Additionally, we explore the historical progression, targets, mechanisms of action, and clinical effectiveness of small molecule inhibitors possessing these structural features.     

Recent advances in asymmetric synthesis of 2-substituted indoline derivatives

Recent advances in asymmetric synthesis of 2-substituted indoline derivatives are discussed.     

Quantum chemical study of the structure and thermochemistry of the five-membered nitrogen-containing heterocycles and their anions and radicals

The nitrogen-containing heterocycles are of interest as high-energy-density materials for use as propellants and explosives, while the pyrolysis of these compounds is also important in understanding the evolution of unwanted NO and NO2 (NOx) from organic fuels such as coal and biomass. We have used ab initio and density functional methods to study the molecular structures and thermochemical properties of the five-membered nitrogen-containing heterocycles and their anions and radicals corresponding to respective heterolytic and homolytic loss of a hydrogen atom from either a nitrogen or carbon site. Many of these thermochemical properties have not previously been measured, especially for the heterocycles containing three and four nitrogen atoms. Using the theoretical methods CBS-APNO, G3, and G3B3, we calculate enthalpies of formation of 26.5, 42.4, 31.9, 63.7, 46.8, 81.0, and 79.0 kcal mol-1 for pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1H-tetrazole, and 2H-tetrazole. A correlation is developed between the number of nitrogen atoms in a heterocycle and its enthalpy, and we extrapolate this relationship to predict the enthalpy of formation of pentazole. N-H BDEs in the heterocycles typically increase with the number of nitrogen atoms in the molecule, while C-H BDEs are similar in all of the studied heterocycles, at around 120 kcal mol-1. In all cases the N-H BDEs are weaker than the C-H BDEs, suggesting abstraction of the N-H hydrogen atom is more likely. Deprotonation enthalpies and free energies reveal that the N-H protons become more acidic with increasing number of nitrogen atoms in the heterocycle. C-H protons are less acidic than N-H protons by ca. 49 kcal mol-1, or ca. 35 kcal mol-1 when adjacent to the NH group. Trends in N-H and C-H acidities can be qualitatively explained by electrostatic effects and electron affinities. From its use as a reference species in our calculations, we identify that the experimental enthalpy of pyrimidine (1,3-diazine) may be in error by ca. 1-3 kcal mol-1, and we recommend an enthalpy of formation of 44.8 +/- 1.0 kcal mol-1.     

Metal catalysts: applications in higher-membered <Emphasis Type="Italic">N</Emphasis>-heterocycles synthesis

In recent decades, a large number of reports related to synthesis of N-, O- and S-containing heterocycles have appeared owing to a wide variety of their biological activity. The metal-catalyzed synthesis of heterocycles is becoming an important and highly rewarding protocol in organic synthesis. This review focuses on the use of metal as a catalyst for the synthesis of nitrogen-containing heterocycles. It describes the formation of higher-membered heterocyclic rings.