Synthesis Of Heterocycles Research Articles

Thiadiazole/Thiadiazine Derivatives as Insecticidal Agent: Design, Synthesis, and Biological Assessment of 1,3,4-(Thiadiazine/Thiadiazole)-Benzenesulfonamide Derivatives as IGRs Analogues against Spodoptera littoralis.

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.

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.

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.

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

This 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.

Cobalt(II)-Catalyzed Synthesis of γ-Diketones from Aryl Alkenes and Its Utilization in the Synthesis of Various Heterocyclic Compounds.

An earth-abundant Co(II) salt-catalyzed mild and affordable synthetic route has been developed for the synthesis of industrially relevant 1,4-dicarbonyl compounds (or γ-diketones) via oxidative coupling between aryl alkenes and ketones (both cyclic and acyclic) using TBHP and DBU as the oxidant and base, respectively. 1,4-Dicarbonyl compounds are known to be synthesized using expensive metal catalysts, dual catalysts, or low-cost metal complexes combined with an additive or ligand template, which further needs to be synthesized. Herein, we report the synthesis of 1,4-dicarbonyl compounds using cobalt(II) acetate as a catalyst without any expensive co-catalyst or ligand templates. This methodology has a broad substrate scope with significant yields and good functional group tolerance. Generation of unsymmetrical 1,4-dicarbonyls at room temperature and its versatile synthetic expansion to produce synthetically and biologically valuable heterocyclic compounds are salient features of this novel methodology. In addition, various controlled experiments such as primary kinetic isotope effect study, Hammett analysis with variation of the nature of the substituents on the styrene ring, and theoretical calculations (density functional theory) unravel the mechanistic intricacies involved in this new, simple, and atom-economic methodology.

Deciphering the Origin of Regioselectivity in Ru(II)-Catalyzed C-H Annulation of N-Chlorobenzamides with 1,3-Diynes.

Understanding the reaction mechanism and origin of regioselectivity in transition metal-catalyzed C-H activation/annulation reactions with 1,3-diynes has remained an intriguing challenge. In this article, to establish the mechanism and decipher the origin of regioselectivity, we report a detailed computational density functional theory-based mechanistic investigation on the recently developed Ru(II)-catalyzed [4 + 2] annulation of N-chlorobenzamides with 1,3-diynes for the synthesis of 3-alkynylated isoquinolone derivatives. Our calculations reveal a redox-neutral pathway for the annulation reaction. The stepwise analysis of the reaction channels indicates the migratory insertion step and the concerted reductive elimination/oxidative addition of the Ru(p-cymene) moiety to form the N-C bond leading to the 3-alkynylated product to be the selectivity- and rate-determining steps, respectively. Finally, the distortion/interaction analysis using the activation-strain model suggests the steric effect as the determining factor for the observed regioselectivity for the formation of the 3-alkynylated product. Overall, the computationally obtained key insights into the catalytic mechanism and the origin of regioselectivity in the C-H activation/annulation reaction can be used as a guide to rationally design and develop novel transformation strategies for heterocycle synthesis.

Synthesis of Indolines via Base-Mediated C-H Activation and Defluorinative C-N Coupling, with no Need for Transition-Metals.

Syntheses of (partially) aromatic nitrogen heterocycles increasingly rely on transition-metal catalyzed C-C- and C-N-cross-coupling reactions. Here we describe a different approach to the synthesis of indolines by a domino C(sp3)-H activation, 1,2-addition, and defluorinative SNAr-cyclization sequence to provide the target 1,2-diarylindolines (1,2-diaryl-2,3-dihydroindoles) from ortho-fluorinated methyl-arenes and N-aryl imines (benzylidene anilines) in a cyclocondensation that is mediated by potassium hexa-methyl-di-silazide (KHMDS) as base exclusively. This transition-metal-free process via C-H and C-F bond activation provides a one-step entry into a wide array of indoline scaffolds (43 examples, up to 96% yield). This privileged substructure is common in natural products and pharmaceuticals alike, and cannot be accessed by traditional condensation reactions.

Synthesis, characterization, and antimicrobial activity of novel ferrocene-containing 1-(thio)acetyl pyrazolines

The pyrazoline pharmacophore is the source of numerous biological activities. The synthesis and biological evaluation of new pyrazoline heterocycles is the first step in the development of new potential drugs. Therefore, ferrocene-containing 1-(thio)acetyl pyrazolines were synthesized to test their in vitro antimicrobial activity. All new heterocycles were characterized by standard spectroscopy methods due to confirmation of the structures. In addition, single-crystal X-ray analyses were performed for three representative pyrazole derivatives. Their electrochemical properties were investigated by cyclic voltammetry indicating a reversible one-electron redox couple originating from the ferrocene/ferrocenium pair. All obtained products were evaluated for their antibacterial and antifungal activity. It has been shown that pyrazolines have slightly better antifungal activity compared with their antibacterial activity.

Advances in the synthesis of heterocycles with two and three heteroatoms using hydrazonoyl halides.

The 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.

Synthesis of bioactive heterocyclic compounds using camphor

The aim of the work was to synthesize novel heterocyclic compounds derived from camphor with antibacterial activity. The pyridazine, xanthene, pyranothiazole, pyridinothiazole, thiophene and pyrazole derivatives were produced from 4,11,11-trimethyl-9-phenyl-7-(2-phenylhydrazono)-3,4,5,6,7,9-hexahydro-1H-1,4-methanoxanthen-8(2H)-one (1). Thiophene derivatives 6a,b were produced according to the Gewald’s reaction for  thiophene synthesis. On the other hand, pyranothiazol derivatives 8a,b were synthesized by the multicomponent reactions between xanthene derivative 5, benzaldehyde and ethylcyanoacetate or malononitrile in ethanol/triethylamine. Whereas, pyridinothiazole derivative 9 was produced in ethanol/ammonium acetate by the multicomponent reaction between xanthene derivative 5, benzaldehyde and malononitrile. The antibacterial activity of the synthesized compounds was evaluated against E. coli bacteria. All synthesized compounds showed moderate activity against E. coli bacteria.    KEY WORDS: Anti-microbial, Camphor, Heterocyclic, Pyrazol-3(2H)-one, Thiazol-4(5H)-one, Thieno[3,2-d]thiazole, Xanthenes Bull. Chem. Soc. Ethiop. 2024, 38(4), 1069-1076.                                                          DOI: https://dx.doi.org/10.4314/bcse.v38i4.20

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

Chiral 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.

The use of methanol as a C1 building block.

Methanol is a key building block in the chemical industry. In recent years, it has been used as a C1 source in various organic transformations in the presence of a transition-metal catalyst. This protocol describes the ruthenium- and cobalt-catalyzed utilization of methanol in different types of methylation reactions and heterocycle synthesis. Initially, we describe the synthesis of tridentate ligands (L1-L3) and their corresponding Ru(II) complexes (Ru-1, -2 and -3) and then detail how to apply these Ru(II) complexes and Co/PP3 (PP3 = P(CH2CH2PPh2)3) in various methanol dehydrogenative coupling reactions. We discuss six types of transformations by using methanol or a methanol/water mixture. The experimental setup for all the catalytic reactions is similar and involves adding all the respective reagents and solvents to an argon-filled pressure tube, which is sealed (by screw cap) and refluxed at the indicated temperature before the desired products are isolated and characterized. The catalytic systems described in this protocol work well for both small-scale and preparative-scale synthesis of various N-methylated amines/amides, C-methylated products and quinazolinones. These catalytic reactions are greener and more sustainable than conventional synthesis methods, with only H2 and/or H2O as by-products, and we evaluate the 'green chemistry metrics' for a typical substrate. The total time required for the catalytic experiments described in this protocol is 16-28 h, and the operation time is 4 h. An average level of expertise in organic synthesis is required to carry out these protocols.

Catalytic Asymmetric Cyclizative Rearrangement of Anilines and Vicinal Diketones to Access 2,2-Disubstituted Indolin-3-ones.

The efficient synthesis of chiral 2,2-disubstituted indolin-3-ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one-step construction of enantioenriched 2,2-disubstituted indolin-3-ones is presented. The reaction proceeds through a self-sorted [3+2] heteroannulation/regioselective dehydration/1,2-ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3-binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine-directed regio- and enantioselective ortho-Csp2-H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well.

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

α‐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.

Synthesis and characterization of new heterocycles containing the 1,2,3-triazole ring system

The unexpected (E)-1,4-bis(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)but‑2-ene-1,4‑dione was produced in 89 % yield from the reaction of 2‑bromo-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one and sodium benzenesulfinate dihydrate in boiling ethanol. The reaction of the synthesized symmetrical 2-butene-1,4‑dione and 1,2-phenylenediamine in acetic acid afforded 2-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole in 68 % yield. 2,3-Dibromopropan-1-one was synthesized in 82 % from bromination of the corresponding chalcone under acidic conditions. Treatment of dibromoketone and benzylamine or phosphonic dihydrazide in ethanol in the presence of a basic catalyst unexpectedly afforded 2‑bromo-3-ethoxyketone in reasonable yield. The reactivity of hydrazonoyl chloride towards 5-methyl- and 5‑chloro-1,2,3-triazol-4-carbohydrazides was also investigated to afford the corresponding bis-hydrazone and the unanticipated tris-hydrazone.

Multifunctional Glucose Dehydrogenase Enabled Synthesis of Chiral-Bridged Bicyclic Nitrogen Heterocycles

Multifunctional Glucose Dehydrogenase Enabled Synthesis of Chiral-Bridged Bicyclic Nitrogen Heterocycles

The untold story of starch as a catalyst for organic reactions.

Starch is one of the members of the polysaccharide family. This biopolymer has shown many potential applications in different fields such as catalytic reactions, water treatment, packaging, and food industries. In recent years, using starch as a catalyst has attracted much attention. From a catalytic point of view, starch can be used in organic chemistry reactions as a catalyst or catalyst support. Reports show that as a catalyst, simple starch can promote many heterocyclic compound reactions. On the other hand, functionalized starch is not only capable of advancing the synthesis of heterocycles but also is a good candidate catalyst for other reactions including oxidation and coupling reactions. This review tries to provide a fair survey of published organic reactions which include using starch as a catalyst or a part of the main catalyst. Therefore, the other types of starch applications are not the subject of this review.

Molecular hybrids based on 1,2,3-triazole and 1,3,4-thiadiazole cores: Synthesis, characterization, anticancer activity and in silico study

One sets of 1,3,4-thiadiazole analogs 14a-c and 15a-c were synthesized by the incorporation of two heterocyclic nuclei (1,2,3-triazole & 1,3,4-thiadiazoles) in objective of developing multifunctional molecules for anticancer disease. (R)-Carvone was used as precursors for the synthesis of new heterocycles. The 1,2,3-triazole-1,3,4-thiadiazoles 14a-c and 15a-c were synthesized in good yields from the precursors using simple procedures. The chemical structures of all the newly synthesized hybrids were established using (1H and 13C) NMR and HRMS analysis. The in vitro assessment of the activity of the resultant 1,2,3-triazole-1,3,4-thiadiazoles against human cancer cells, namely fibrosarcoma (HT-1080), lung carcinoma (A-549) and breast carcinoma (MCF-7 and MDA-MB-231) was performed using viability testing (MTT). Compound 14a was the most active heterocycle, and its cytotoxic activity was three times less actives comparable to that obtained for Doxorubicin (6 µM) as a reference. The 1,3,4-thiadiazoles 15a-c showed moderate cytotoxic activities with IC50 values ranging from 25.56 ± 1.13 to 61.81 ± 2.21 μM. Molecular docking studies were conducted against two antiapoptotic proteins namely Bcl-2, and Bcl-XL to elucidate the potential mechanisms of action. The results indicate that compounds interact favorably (binding energy = −7.6 to −9.8 kcal/mol) with the target proteins through hydrophobic, electrostatic interactions, and hydrogen bonding. The negative binding energy indicate the spontaneous nature of the interaction. Further, molecular dynamics simulation parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, and solvent accessible surface area provided insights into the stability and dynamics of the protein-ligand complexes.

Solvent-Free Synthesis of Bioactive Heterocycles

Abstract: The main emphasis of green chemistry is to reduce environmental pollution. Its main goal is to adopt a cost-effective and harmless strategy for human health and the environment. The green synthetic routes have succeeded in adopting solvent-free conditions as an effective tool for sustainability. Heterocycles are organic compounds that are widely distributed by nature. Many of them possess medicinal and pharmacological properties, as this heterocyclic moiety is found in many drugs. The solvent-free strategies for the Synthesis of bioactive heterocycles are, now-adays, regarded as an important objective. Solvent-free reactions are eco-friendly, cost-effective, and an environmentally benign route in organic transformation methods because of their effi-ciency, reduced reaction time, and high yields, thereby saving energy. This mini-review focuses on the environmentally benign solvent-free Synthesis of heterocycles and their potential pharma-cological applications.

NBS-Promoted Synthesis of Thiocyanated Aminomaleimides and Site-Selective Intramolecular Cyclization Access to 1,4-Benzothiazepines via S-CN Bond Cleavage.

A transition metal-free concise and efficient protocol for the synthesis of thiocyanated aminomaleimides and benzo[e][1,4]thiazepine derivatives has been developed. The method involves an initial α-C-H thiocyanation of aminomaleimides with KSCN and TEMPO-mediated tandem S-CN bond cleavage/intramolecular cyclization substitution processes, which enables the formation of seven-membered S/N-heterocycles. This synthetic strategy provides a reliable method for the synthesis of biologically interesting benzo[e][1,4]thiazepine derivatives by using KSCN as sulfur sources as well as expands the application of enaminones thiocyanation reactions in heterocycles synthesis.