Synthesis Of Heterocycles Research Articles

Microwave-Assisted Synthesis of Heterocyclic Scaffolds

AbstractIn recent years, there has been a notable surge in the utilization of microwave energy, leading to the emergence of innovative and groundbreaking methods across various branches of chemistry, including organic synthesis, materials science, heterocyclic chemistry, and medicinal chemistry. This comprehensive literature review delves into the microwave-assisted organic synthesis of specific heterocycles, illuminating its effectiveness in producing diverse molecules with heightened efficiency and selectivity. The review highlights the significant role of microwave irradiation as a potent method for constructing a wide range of compounds. Particular emphasis is placed on the impact of the technique on synthesizing various hybrids such as 1,2,3-triazole hybrids, coumarin hybrids, imidazopyridine hybrids, phenanthridines hybrids, carbene hybrids, and oxazole hybrids. This article is valuable as it offers insights into current synthetic procedures and trends in developing innovative medications utilizing heterocyclic compounds.1 Introduction2 Synthesis of 1,2,3-Triazole Hybrids3 Coumarin Hybrids4 Imidazo Pyridine Hybrids5 Phenanthridine Hybrids6 Carbene Hybrids7 Oxazole Hybrids8 Conclusion

Synthesis, crystal structure, spectroscopic and theoretical studies of a new fluorescent heterocyclic compound containing diketopyrrolopyrrole (DPP) moiety

A new diketopyrrolopyrrole (DPP) derived fluorescent heterocyclic compound, DPP-BA, has been synthesized and characterized by SXRD, FL spectroscopy and computational methods. SXRD studies indicate that hydrogen bonding and π-π stacking interactions are crucial for the assembly of its 3D supramolecular structure. The weak interactions within the compound were studied using IRI and NCI methods, while the planarity of DPP-BA in the DPP-BA-DMSO was quantified using MPP and SDP descriptors. The MEP map highlighted the nucleophilic and electrostatic regions in DPP-BA. In addition, Hirshfeld surface analysis and RESP atomic charges were used to visualize the interactions and to delineate the charge distribution within DPP-BA. The interaction energy and 3D energy frameworks facilitated an intuitive examination and understanding of the molecular arrangement and stability within the crystal. A comparison between the experimental and computational FL spectra was made using a range of DFT functionals, with the PBE0 functional providing the most accurate results. Analyses of the HOMO-LUMO and hole-electron distributions have shed light on the molecular electronic structure, thereby deepening our understanding of the electronic excitation processes within the molecule.

A Study on Synthesis and Biological Activities of Novel Heterocyclic Compounds

A Study on Synthesis and Biological Activities of Novel Heterocyclic Compounds

Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals.

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.

Hexafluoroisopropanol-assisted selective intramolecular synthesis of heterocycles by single-electron transfer

Intramolecular amination of remote aliphatic C–H bonds via hydrogen-atom transfer reactions has become a powerful tool for accessing saturated nitrogen-containing heterocycles. However, the formation of six-membered rings or oxa-heterocycles remains a formidable challenge for Hofmann–Löffler–Freytag reactions. Here we show how by simply combining bench-stable (bis(trifluoroacetoxy)iodo)benzene and hexafluoroisopropanol (HFIP) we can switch from the well-established Hofmann–Löffler–Freytag mechanism to a different versatile reaction pathway that enables selective C(sp3)–H bond functionalization. We have exploited the facile formation of radical cations via single-electron transfer, in the presence or absence of light, to synthesize pyrrolidines and piperidines, including drug-type molecules, along with O-heterocycles. Experimental and computational mechanistic studies support two distinct mechanistic pathways, depending on the electron density of the substrate, in which the HFIP plays a multifunctional role.

Metal Nanoparticle‐Catalyzed Alkyne Cyclization for the Synthesis of Heterocycles

AbstractHeterocycles are important compounds existed in diverse advanced chemicals, functional materials, bioactive molecules and natural products. Different strategies through transition metal‐catalyzed alkyne cyclization have been developed to synthesize various heterocycles. The merger of alkyne cyclization and metal nanoparticle catalysis has emerged as an important approach to diverse heterocycles. By using different kinds of metal nanoparticle catalysts, such as gold, silver, copper and palladium nanoparticles, a number of heterocycles are prepared with high yield and selectivity in a green, sustainable and highly efficient manner. This review summarizes and discusses recent achievements in metal nanoparticle‐catalyzed alkyne cyclization for the synthesis of heterocycles.

Ferrocenyl aniline modified electrode for the electrochemical synthesis of 2-(4-methoxyphenyl)-1H-benzo[d]imidazole

Ferrocenyl aniline is an excellent catalyst used conventionally for heterocyclic syntheses. The use of ferrocenyl aniline, in the presence of electropolymerized thiophene-3-acetic acid (TAA) on carbon fibre paper is novel and found to be an exceptional electrocatalyst, for the synthesis of a proven anti-fungal, anti-proliferative and anti-bacterial, 2-(4-methoxyphenyl)-1H-benzo[d]imidazole. The electrode performance was examined with activity studies and EIS, along with surface characterizations including optical profilometry, FE-SEM, FT-IR and XPS. The synthesis was performed in a single-cell three electrode system, using platinum as counter and saturated calomel electrode (SCE) as the reference, with ethanol as the electrolyte and lithium perchlorate supporting electrolyte. The reaction was performed with o-phenylenediamine and anisaldehyde as starting materials at ambient temperature and pressure, at 1.35 V constant potential for 3 h, and product was isolated and purified using column chromatography to obtain 91% yield and characterized with GC–MS and NMR. This synthesis method is noteworthy, due to its environmentally friendly performance, and high yield for a benzimidazole derivative that is pharmacologically vital.

Synthesis, characterization of isoxazole derivatives and evaluation of their antibacterial, antioxidant and anticancer activity

Introduction and aim. The synthesis of heterocyclic compounds containing oxygen and nitrogen is profoundly intriguing due to their mechanistic implications in both research and development within organic chemistry and drug discovery. The primary aim of this study is to fabricate a range of pharmacologically active drugs containing the isoxazole moiety. Material and methods. The synthesis of new derivatives of isoxazole was achieved through a one-pot condensation reaction of 2-[(Substituted phenyl)hydrazono]malononitrile (1) and 3-[(Substituted phenyl)azo]-2,4-Pentanedione (2) with sodium acetate and hydroxylamine hydrochloride (1:1) in ethanol. All the compounds were screened for their in vitro antibacterial activity, in vitro antioxidant and anticancer activity. The synthesized compounds underwent characterization through FTIR, 1 H NMR, and 13C NMR analyses, supported by mass spectral data and elemental analysis. Results. A set of novel isoxazole derivatives was synthesized with a favorable yield. Among compounds 1d, 1e, 2c, 2d, and 2e exhibited notable antioxidant activities. Compounds 1a, 1b, and 1c demonstrated significant anticancer potential against prostate cancer [PC3] cell lines compared to normal HEK cell lines, while 2a displayed the highest inhibitory zone against Escherichia coli. Conclusion. Novel compounds with multifaceted biological activities have been successfully designed, and a synthetic route to create isoxazole derivatives has been devised and verified.

تحضير، تشخيص و دراسة الفعالية البيولوجية لمركبات حلقية غير متجانسة جديدة حاوية على الكرياتينين

This work included the synthesis of new heterocyclic compounds containing creatinine moiety (A4-A9). These compounds were synthesized from reaction of Schiff bases (A2, A3) with glycine, thioglycolic acid, and glycolic acid to produce imidazolidine-4-one (A4, A5), thiazolidine-4-one A6, A7, and oxazolidine-4-one (A8, A9) respectively. FTIR and 1HNMR were used to identify these compounds. In vitro experiments, the antimicrobial properties of compounds (A1, A2, and A4) were evaluated and showed good results.

TBA(FeCl3Br) Complex as a Photocatalyst in the Csp3–H Bond Activation in Alcohols for the Synthesis of N-Based Heterocycles

TBA(FeCl₃Br) Complex as a Photocatalyst in the C_sp3–H Bond Activation in Alcohols for the Synthesis of N-Based Heterocycles

An Efficient and Magnetically Retrievable Mixed Metal Oxide Nanocatalyst for the Aqueous Media Three-Component Synthesis of Naphtho [1,2-e] [1,3] Oxazine Derivatives Under Green Conditions

Background: In recent years, the use of nanomaterials as heterogeneous catalysts has attracted much attention in organic reactions. Methods: A magnetically separable mixed metal oxide, Manganese Zinc Iron Oxide (Mn2O3/Fe3O4/ZnO) nanoparticles as nanocatalyst (Mmo@NCt) were synthesized using ultrasonic wave methods in the presence of polyethylene glycol as surfactant. In the second part of the present study, a practical procedure for the one-pot ternary condensation of aromatic aldehydes, β- naphthol, and urea in short reaction time for the synthesis of pharmaceutically interesting naphtho[ 1,2-e][1,3]oxazine derivatives using Mmo@NCt as an efficient, cost-effective and recyclable nanocatalyst under green conditions has been developed. Results: The analysis of phase purity, magnetic structure, size, and morphology of the as-synthesized nanocatalyst was characterized by X-ray diffraction, VSM, SEM, and EDX techniques. The results of SEM imaging showed that all compounds have a spherical morphological structure with a mean diameter of 16.50 ± 3.94 nm. The structure of the products was confirmed by FT-IR, 1HNMR spectroscopy, and melting point. Conclusion: This project was designed and performed with the use of magnetic nanocatalysts as a suitable method with high efficiency a shorter time for the synthesis of naphthoxazinones heterocyclic compounds due to the medicinal importance of water as a green solvent.

Chemoenzymatic Synthesis of 2‐Aryl Thiazolines from 4‐Hydroxybenzaldehydes Using Vanillyl Alcohol Oxidases

AbstractNitrogen heterocycles are commonly found in bioactive natural products and drugs. However, the biocatalytic tools for nitrogen heterocycle synthesis are limited. Herein, we report the discovery of vanillyl alcohol oxidases (VAOs) as efficient biocatalysts for the one‐pot synthesis of 2‐aryl thiazolines from various 4‐hydroxybenzaldehydes and aminothiols. The wild‐type biocatalyst features a broad scope of 4‐hydroxybenzaldehydes. Though the scope of aminothiols is limited, it could be improved via semi‐rational protein engineering, generating a variant to produce previously inaccessible cysteine‐derived bioactive 2‐aryl thiazolines using the wild‐type VAO. Benefiting from the derivatizable functional groups in the enzymatic products, we further chemically modified these products to expand the chemical space, offering a new chemoenzymatic strategy for the green and efficient synthesis of structurally diverse 2‐aryl‐thiazoline derivatives to prompt their use in drug discovery and catalysis.

Chemoenzymatic Synthesis of 2-Aryl Thiazolines from 4-Hydroxybenzaldehydes Using Vanillyl Alcohol Oxidases.

Nitrogen heterocycles are commonly found in bioactive natural products and drugs. However, the biocatalytic tools for nitrogen heterocycle synthesis are limited. Herein, we report the discovery of vanillyl alcohol oxidases (VAOs) as efficient biocatalysts for the one-pot synthesis of 2-aryl thiazolines from various 4-hydroxybenzaldehydes and aminothiols. The wild-type biocatalyst features a broad scope of 4-hydroxybenzaldehydes. Though the scope of aminothiols is limited, it could be improved via semi-rational protein engineering, generating a variant to produce previously inaccessible cysteine-derived bioactive 2-aryl thiazolines using the wild-type VAO. Benefiting from the derivatizable functional groups in the enzymatic products, we further chemically modified these products to expand the chemical space, offering a new chemoenzymatic strategy for the green and efficient synthesis of structurally diverse 2-aryl-thiazoline derivatives to prompt their use in drug discovery and catalysis.

Catalysed Aryl Amine Syntheses via Azides: From Azidation of Aryl Halides to Azide Reduction and Direct Amination

AbstractThis review summarises and discusses aryl amine and azide syntheses from aryl halides employing azides. The majority of the reported reactions proceed with copper catalysis or mediation. Often, an aryl azide is formed in the first step, which is then reduced in situ to an aryl amine in a second step. The occurrence of the second step, the reduction, depends on the chosen reaction conditions and the substrates. The formation of only aryl azides through Cu‐mediated C−N bond formations is discussed, followed by mediated and catalytic aryl azide reduction employing different catalytic systems, and azidation with in situ azide reduction to amines, viz. azidation‐amination strategies. The azidation‐amination allows for the synthesis of complex heterocycles in multi‐step one‐pot procedures, of which several are summarised here. Examples of the application of azidation‐amination for synthesising important aryl amines employed in or as biologically active compounds, catalysis and materials science are also summarised. Finally, conducted control reactions have been collected and discussed in combination with mechanistic proposals. This literature survey allows us to pinpoint design criteria for the azide reduction to valuable amines, which includes the choice of reaction conditions such as solvent system and additives, involved metal and promising substrates.

Revolutionizing Indole Synthesis: A Microwave‐Powered Approach

AbstractTempted by the unique medicinal and biological potential of indole‐containing heterocycles, chemists, especially those specializing in heterocycle synthesis and drug discovery, are actively pursuing their efficient construction. This review spotlights the latest advancements in microwave‐assisted (M. W.) synthesis of diverse indole‐based heterocyclic compounds. We systematically categorize the reported methods based on the specific indole substitution patterns. This review concise the microwave assisted synthesis of indole based‐pyridine derivatives, indole based‐pyrimidine, indole based‐oxindole, spiro‐oxindole, Fischer indole Heck‐isomerization derivatives, functionalized indole, substituted indoles, indolyl quinoline, indole triazole and indolylnicotinonitriles derivatives. Ultimately, this review aims to provide organic and medicinal chemists with a concise yet informative guide to recent methodologies employing indole derivatives in the microwave‐powered synthesis of heterocycles.

Switching between the [2π+2σ] and Hetero‐[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles

AbstractThe exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S‐BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3‐benzylideneindoline‐2‐thione derivatives have been established. The first hetero‐(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3‐catalyzed [2π+2σ] reaction with 1,1,2‐trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E‐1,1,2‐trisubstituted alkenes. Additionally, the hetero‐(4+3) cycloaddition may involve a concerted nucleophilic ring‐opening mechanism.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Recent Advances in the Use of α‐Azidochalcones in Heterocycle Synthesis

Abstractα‐Azidochalcones have emerged as remarkably versatile precursors within organic azides, showcasing a broad spectrum of reactivity as a cornerstone for synthesizing diverse molecular scaffolds. The ongoing progress in this field has opened new opportunities for constructing complex organic molecules through diverse chemical transformations due to the versatile reactivity of α‐azidochalcones for further functionalization. The comprehensive review presented herein provides a concise yet detailed examination of the synthesis, reactivity, and potential applications of α‐azidochalcones. Focusing on both thermal and photochemical pathways, this review highlights the versatility of α‐azidochalcones as pivotal precursors in the synthesis of various heterocyclic frameworks.

Advances in the Synthesis of Heterocycles with Two and Three Heteroatoms using Hydrazonoyl Halides

AbstractThe review covers the results of studies published in the literature on the use of hydrazonoyl halides in the synthesis of five‐ (pyrazoles, thiazoles, triazoles, oxa‐ and thiadiazoles), six‐ (oxa‐ and thiadiazines, indazoles, pyridazines, pyrazines, tetrazines) or seven‐membered (benzotriazepine) heterocycles. In the formation of these heterocycles, the main intermediate stage of the reaction is the in situ generation of nitrilimine, which enters into a cycloaddition reaction with substituted acetylenes (including in situ generated benzynes, naphthynes), allenes, activated olefins, anthranilic acid derivatives, organosulfur compounds (mercaptoaldehydes, mercaptocarboxylic acids) or with fused heterocycles. Examples are given of the formation of heterocycles by replacing the halogen atom from a hydrazonoyl halide molecule with a nucleophilic group, followed by exhaustive intramolecular cyclization into the target compound. There are discussions of reactions in which the cycloaddition of the nitrilimine to the in situ synthesized Knoevenagel condensation product (from CH‐acid compounds, such as di‐ and monocarbonyl compounds, dinitrile malonic acid) occurs, leading to spiro‐linked or conventional pyrazoles. Some syntheses of biologically active representatives are shown.

Photochemical Synthesis of Chiral Heterocycles via Asymmetric Carbon‐Heteroatom Bond Formation

AbstractChiral heterocyclic compounds play a crucial role in the pharmaceutical science, materials science, and agrochemical industries. The critical step for synthesizing chiral heterocycles is the formation of asymmetric carbon‐heteroatom bonds, which can be achieved in a chiral environment under thermal or photochemical conditions. However, photochemical asymmetric transformation has become an area of immense growth in the past 15 years. In the drug discovery and development era, chiral photochemical transformations have drawn the attention of researchers to develop new synthetic strategies for chiral heterocycles via asymmetric carbon‐heteroatom bond formation. Chiral photochemistry in the pathway of asymmetric synthesis requires a chirality source which is transferred to the products. A catalytic chiral metal complexing agent or a chiral photosensitizer that generally follows a single electron transfer (SET) or oxidative and reductive quenching cycle has been widely exploited to achieve this goal. In this review, we have demonstrated the recent development of photochemical synthesis of chiral heterocycles via asymmetric carbon‐heteroatom bond formation by using a chiral metal catalyst, asymmetric organocatalyst, or dual catalytic system based on their plausible mechanism.