ABSTRACT The Sonogashira cross‐coupling reaction remains one of the most powerful and versatile methodologies for the construction of carbon–carbon bonds in modern organic synthesis. Owing to its exceptional functional group tolerance, mild reaction conditions, and broad substrate scope, this transformation has emerged as a key synthetic tool for the preparation of structurally diverse heterocyclic and fused heterocyclic compounds of significant importance in medicinal chemistry, natural product synthesis, materials science, and pharmaceutical research. In recent years, substantial progress has been achieved in Sonogashira coupling‐enabled heterocycle synthesis through the development of tandem, domino, cascade, and one‐pot protocols that integrate cross‐coupling with cyclization, annulation, carbonylation, hydroamination, electrophilic cyclization, and related transformations. This review summarizes the major advances reported between 2020 and 2025 in the application of Sonogashira coupling reactions toward the synthesis of heterocyclic and fused heterocyclic frameworks. Particular emphasis is placed on the construction of nitrogen‐, oxygen‐, and sulfur‐containing heterocycles, including isoquinolines, pyrimidines, pyrazoles, triazoles, indoles, benzofurans, chromones, coumarins, thiophenes, quinolines, fused polyheterocycles, and other structurally complex scaffolds. Recent developments involving palladium‐free methodologies, copper‐catalyzed systems, recyclable catalysts, microwave‐assisted protocols, carbonylative Sonogashira reactions, and sequential coupling–cyclization strategies are also highlighted. Mechanistic aspects of representative transformations, including regioselective 5‐ exo ‐dig and 6‐ endo ‐dig cyclizations, hydroamination, lactonization, electrophile‐promoted cyclization, and Nicholas‐type reactions, are discussed to illustrate the synthetic versatility of Sonogashira‐derived intermediates. By compiling and critically analyzing recent literature, this review demonstrates the continuing evolution of Sonogashira coupling from a classical cross‐coupling reaction into a multifunctional platform for the rapid assembly of complex heterocyclic architectures. The survey is expected to provide valuable insights for researchers engaged in heterocyclic synthesis, catalyst development, and the design of biologically relevant molecular frameworks.
In the present work, we describe the first example of constructing the 3‐hydroxypyridin‐2(1H)‐one core based on the interaction of heterocyclic enamines with ethyl bromopyruvate. Utilizing a wide range of substituted 5‐aminopyrazoles as an enamine component we have shown that the considered condensation leads to the formation of pyrazolo[3,4‐b]pyridin‐6‐one derivatives containing a hydroxyl group. Relying on the investigated reaction a general approach to the synthesis of the target bicyclic system was developed. The application of elaborated protocol to a set of diverse 5‐aminopyrazoles allowed us to obtain an array of 5‐hydroxy‐1,7‐dihydro‐6H‐pyrazolo[3,4‐b]pyridin‐6‐ones with yields up to 82%. The undoubted advantages of the presented method are easily available starting materials, atom economy and facile isolation of the final products without chromatographic purification. The structure of the prepared compounds was confirmed employing 1H and 13C NMR spectroscopy, high‐resolution mass spectrometry as well as data of X‐ray analysis.
A new strategy is described for the first time to synthesize a heterocyclic hybrid system of 1,5‐disubstituted‐1H‐tetrazole‐bis‐1,2,3‐triazoles through a double one‐pot sequence. The approach involves (i) a one‐pot five‐component process to obtain the key 1,5‐DS‐T‐bis‐propargyl compounds 11a–n, using propargylamine as an orthogonal reagent, followed by (ii) a pseudo‐three‐component reaction consisting of a double CuAAC process with aromatic azides to afford the target hybrids 6a–n in moderate yields. The protocol is operationally simple, proceeds under mild reaction conditions, and some products were purified by recrystallization from methanol. Notably, this is the first example of a higher‐order multicomponent sequence combined with a classical pseudo‐multicomponent reaction, underscoring the synthetic utility of this approach for the rapid assembly of structurally complex hybrid scaffolds relevant to medicinal chemistry. Finally, the feasibility of accessing the target hybrids in a truly one‐pot manner was demonstrated starting from propargylamine, with the overall process forming six C–N bonds, one C–C bond, and one N–N bond within a single operation.
Investigation of the microwave‐assisted condensation of anthranilic acid derivatives with ethylpiperidine isothiocyanates into 2‐thioxoquinazolin‐4‐ones revealed an intramolecular cyclization into 2,3‐dihydro‐5H‐thiazolo[2,3‐b]quinazolinones. The study of reaction parameters demonstrated that temperature is a key factor controlling this transformation, while anthranilic acid substituents further modulate the reaction outcome. Here we report the promotion of the intramolecular cyclization to thiazoloquinazoline at high temperatures (200°C), whereas lower temperature (125°C) selectively favors the formation of 2‐thioxoquinazolin‐4‐one in good yield. These findings provide refined conditions for the synthesis of 2‐thioxoquinazolin‐4‐one derivatives and expand the way to synthesize 2,3‐dihydro‐5H‐thiazolo[2,3‐b]quinazolinone derivatives of potential medicinal interest.
Benzoxaboroles are cyclic hemiester versatile scaffolds of boronic acid that demonstrate various pharmacological activities including anti‐fungal, anti‐inflammatory, anti‐malarial, anti‐trypanosomal, anti‐cancer, anti‐pneumococcal and gained significant attention in medicinal chemistry in recent years due to their stable structure. Conventional synthesis methodologies heavily depend on the use of toxic reagents, harsh reaction conditions, harmful by‐products, and higher consumption of energy, which raise environmental issues and economic loss. Green chemistry provides sustainable and efficient routes that use non‐toxic catalysts, eco‐friendly solvents, and less energy‐demanding processes and techniques (catalyst‐free synthesis, green solvents, photocatalysis, microwave‐assisted synthesis, solvent‐free reactions). This review outlines major developments in the green synthesis of benzoxaboroles, providing potential efficient synthetic routes to upgrading conventional practices, thereby contributing to sustainable development goals and their pharmacological importance. While available literature addresses either the conventional or the green synthesis of benzoxaboroles and their derivatives, nonetheless, a notable gap remains regarding reports that combine both methodologies. The current review presents both approaches in a comparative framework. This helps researchers to develop more effective, environmentally friendly synthetic routes and progress in medicinal chemistry.
A novel three‐series of selenium‐containing heterocycles (SeCHet) incorporating tertiary amine functionalities, namely N‐alkyl selenopyridines (5a–e and 6a–c) and N‐alkyl selenopheno[2,3‐b]pyridines 7a–d, were successfully synthesized through the reaction of selenium‐chloroacetamide scaffold derivatives 3a and 3b with various secondary amines. These compounds were designed based on the well‐established biological importance of both selenium‐based heterocyclic compounds and amine‐containing molecules in biological activities, particularly their antioxidant and antibacterial properties against selected Gram‐positive and Gram‐negative bacterial strains. Several compounds exhibited promising biological activity, with derivatives containing the diethylamino and piperidine moieties showing enhanced antibacterial effects, particularly against Bacillus cereus, with an inhibition percentage more than the standard drug (ciprofloxacin). In addition, notable antioxidant activity was observed for selected compounds; the activity of compound 5b was comparable to vitamin C, with an inhibition percentage similar to vitamin C, 74%. Derivatives 6a and 7a showed the highest antioxidant performance, with inhibition rates of 72% and 67%, respectively, indicating the potential of these structures as biologically active agents. Overall, the obtained results highlight the significance of incorporating tertiary amine and selenopyridine functionalities in the development of new compounds with potential pharmaceutical applications.
N‐Bromosuccinimide (NBS) is a versatile and widely employed reagent in organic synthesis, valued for its mild reactivity, operational simplicity, and high selectivity. Since its introduction, NBS has been a cornerstone in bromination reactions, particularly allylic and benzylic bromination via radical pathways. Beyond classical halogenation, NBS has found extensive applications in oxidation, cyclization, functional group transformations, and the synthesis of diverse heterocycles. Its broad substrate compatibility, ability to operate under both radical and ionic conditions, and adaptability to solvent‐free and green chemistry protocols have further enhanced its synthetic utility. This review (2015–present) comprehensively highlights the major applications of NBS in modern organic synthesis, emphasizing mechanistic insights, reaction scope, and recent advancements. Special attention is given to NBS‐mediated heterocyclic construction, including monocyclic rings, five‐ and six‐membered mixed‐atom heterocycles, bicyclic fused systems (saturated, benzofused, and polycyclic), spiro‐heterocycles (monocyclic, heterocycle‐heterocycle, and spiro‐fused hybrids), and miscellaneous heterocyclic frameworks. The review underscores NBS's continuing relevance in both academic and industrial settings as a versatile and sustainable tool for the construction of complex molecular architectures.
TCT: DMF adduct is a unique, versatile, and emerging solid green reagent prepared by the combination of 2,4,6‐trichloro‐1,3,5‐triazine and N,N‐dimethylformamide. A key advantage of using TCT: DMF adduct as a catalyst is its ability to markedly shorten reaction time while achieving higher yields and selectivity. This review presents the first comprehensive literature highlighting the applications of TCT: DMF adduct as a catalyst under mild reaction conditions for various functional group transformations and heterocyclic syntheses. It is a Vilsmeier‐like iminium electrophilic complex efficiently works as chlorinating, dehydrating, and formylating agent. The electron‐deficient character of TCT: DMF adduct activates substrate in a short duration of time and substitution or nucleophilic attack of Cl− make it a valuable auxiliary for various synthetic reactions. It facilitates facile conversion of poor leaving groups like OH, and SO3H to their corresponding chlorides. The dehydrating property of this adduct enables the room temperature conversion of ketones to ketoximes and primary amines to nitriles. TCT: DMF actively participates in formylation and transesterification reactions. It has been established as best alternative of harsh and expensive reagents like SOCl2 and POCl3/DMF. In heterocyclic synthesis, it serves as a key reagent for the synthesis of 2‐azetidinones, quinolones, 3,4‐dihydropyrimidinones/thiones, chromones, flavones, and isoflavones. Moreover, this review covers all catalytic activities of TCT: DMF adduct along with their reaction conditions and mechanisms that may be beneficial for various researchers.
The quest for green synthetic techniques has emerged as a prominent subject, notably in the synthesis of heterocycles that are biologically significant. Imidazole scaffolds are an important class of nitrogen‐containing compounds that have a wide range of applications. The conventional synthetic protocols for imidazole derivatives rely on potentially harmful solvents, homogeneous catalysts, and harsh conditions. Iron‐based nanoparticles have been introduced as efficient, low‐cost, and green catalytic systems as a result of recent advancements in nanocatalysis; their application in solvent‐free conditions is still relatively underexplored. Solvent‐free iron‐based nanocatalytic systems have emerged as a promising green option because they offer high efficiency, operational simplicity, and reduced environmental impact. The purpose of this study is to provide a comprehensive summary of recent advances in the field of iron‐based nanoparticle‐catalyzed synthesis of imidazole scaffolds, with a particular focus on solvent‐free reaction methods. There is a critical discussion and comparison with existing approaches about the mechanistic elements, catalyst design, substrate scope, reaction efficiency, and recyclability of the material.
Isatin (1H‐indole‐2,3‐dione) is a naturally occurring indole scaffold that has attracted considerable attention owing to its broad spectrum of biological activities, including antitumor, antiviral, antimicrobial, anti‐inflammatory, anticonvulsant, and analgesic effects. The molecule possesses several reactive centres: the N‐1 atom, the amidic carbonyl at C‐2, and the ketonic carbonyl at C‐3. These functionalities enable a variety of key transformations such as N‐alkylation, oxidation, ring expansion, Friedel‐Crafts alkylation, and condensation reactions. Among them, the C‐3 carbonyl is the most electrophilic site and can be readily converted into imines, oxindoles, hydrazones, thiosemicarbazones, and spiro‐cyclized derivatives, having significant biological activities. Although numerous reviews have addressed the synthesis of isatin itself or its Schiff‐base derivatives, comprehensive coverage of C‐3‐substituted isatins remains limited. This work presents the first dedicated and an exhaustive review of C‐3‐substituted isatin derivatives, surveying the literature from 2000 to the present. By consolidating synthetic strategies, structural diversity, and pharmacological profiles, the review underscores the chemical and therapeutic relevance of these compounds and highlights their potential as versatile scaffolds in medicinal chemistry. The analysis aims to guide future investigations by highlighting promising structural motifs, identifying gaps in current knowledge, and suggesting directions for the continued development of C‐3‐functionalized isatin derivatives.
In the present communication a novel method for the synthesis of thieno[2,3‐b]pyrrole derivatives was developed. The considered approach is based on a previously undescribed recyclization of thieno[2,3‐b]pyridin‐6(5H)‐ones bearing aroyl fragment under the action of p‐toluenesulfonic acid in alcoholic media. The elaborated general protocol allowed us to obtain a set of 22 target esters of (thieno[2,3‐b]pyrrol‐4‐yl)acetic acids with yields up to 84%. Readily accessible starting materials, mild reaction conditions, atom economy, and convenient isolation of the final products without chromatographic purification are the advantages of the presented procedure. The structure of one of the prepared thieno[2,3‐b]pyrroles was proved by X‐ray diffraction.
The rise of drug or multidrug resistance in Plasmodia strains has made malaria the most important tropical parasitic disease. To address this issue, new antimalarial drugs must be developed. As a fundamental building block in organic synthesis, materials science, and pharmaceutical chemistry, the triazole scaffold is an essential part of heterocyclic chemistry. Because of their broad chemical properties and potential biological applications, including antimalarial, the synthesis of triazoles has gained significant attention in the field of organic chemistry. This review primarily focuses on the synthesis, the wide range of antimalarial activities of several hybridized 1,2,3‐triazoles and 1,2,4‐triazoles, and the structure–activity relationships (SAR) reported since 2022, which target various stages of the Plasmodium life cycle. Because of their adaptability, they are extremely efficient against both drug‐sensitive and drug‐resistant strains of P. falciparum, making them indispensable resources in areas where resistance is common. Even higher antimalarial effectiveness has been achieved by the synergistic effects of mixing the triazole moiety with additional pharmacophores. This strategy may be able to surpass current resistance mechanisms and offer a more long‐lasting way to treat malaria. Triazole hybrid compounds continue to play a significant role in malarial chemotherapy despite the development of numerous antimalarial leads. Researchers can further investigate and innovate in the synthesis, antimalarial evaluation, and structure–activity relationship (SAR) studies of triazoles as pharmaceuticals by including them as crucial components in drug discovery, thereby examining their potential therapeutic importance.
A novel tertiary amine-catalyzed Michael addition strategy was developed to synthesize oxindoles bearing vicinal quaternary-tertiary stereocenters. 3-(Acetylpyrazolyl) oxindoles derivatives were designed as highly reactive C3 synthons for base-catalyzed reactions. These derivatives undergo Michael addition with N-substituted maleimides to construct oxindole skeletons with vicinal stereocenters. Under mild conditions, the reaction affords a broad range of products in up to 98% yield with dr up to 20:1. The broad substrate scope and gram-scale reaction highlight the synthetic utility and practicality of this method.
A novel two-step approach to previously unexplored allomaltol-containing pyrazolo[1,5-a][1,3,5]triazine-2,4-diones has been developed. The method involves the use of fused 1,3-oxazepin-2-one derivatives as precursors, which undergo C-O bond cleavage of the carbamate fragment upon treatment with amines, leading to the formation of substituted ureas. Subsequent condensation of these intermediates with 1,1 '-carbonyldiimidazole provides access to the target bicyclic systems. This methodology employs readily available starting materials and proceeds under mild conditions, offering a straightforward protocol with simple product isolation that does not require chromatographic purification. The generality of this approach was demonstrated by the synthesis of 13 urea intermediates and 11 target heterocycles in yields of up to 78%. The structure of one representative product was confirmed by X-ray analysis.
The first total synthesis and unambiguous structural elucidation of microcystbiopterin C, a pterin glycoside isolated from a Microcystis bloom, has been achieved. Two candidate biopterin glycosides (5a and 5b) corresponding to the proposed structures of microcystbiopterin C were synthesized by glycosylation of a suitably protected biopterin derivative 10 with 2,4-di-O-benzoyl-6-deoxy-3-O-methyl-alpha-L-mannopyranosyl bromide (9) and the corresponding alpha-D-mannopyranosyl bromide (22), respectively, followed by stepwise deprotection. Detailed comparison of the NMR data and the specific rotation of compounds 5a and 5b with those of the natural product established that microcystbiopterin C possesses the structure of 2 '-O-(6-deoxy-3-O-methyl-alpha-D-mannopyranosyl)biopterin (5b).
A series of novel 1,3-thiazole derivatives (5a-5j) was synthesized and fully characterized by FT-IR, NMR, and HR-MS. The compounds were evaluated for antifungal activity and alpha-glucosidase inhibition. Compounds 5e and 5j showed notable antifungal effects against Trichophyton rubrum and T. mentagrophytes. Among the series, compound 5g exhibited the most potent alpha-glucosidase inhibitory activity (IC50 = 8.25 +/- 0.12 mu M), significantly stronger than acarbose. Molecular docking and molecular dynamics simulations supported its stable binding within the enzyme active site, while DFT calculations suggested favorable electronic features associated with enhanced activity. In vivo evaluation further confirmed its glucose-lowering effect in a zebrafish model. Overall, these findings identify compound 5g as a promising lead and highlight the 1,3-thiazole scaffold as a valuable platform for the development of new alpha-glucosidase inhibitors.
In this study, we present an efficient and regioselective synthetic approach for the preparation of novel pyrimido[1,6-a]selenopheno[3,2-d]pyrimidine derivatives. The sequence involves the initial condensation of 3-amino-2,4-dicyano-5-(pyrrolidin-1-yl)selenophene (1) with 5-bromo-2,4-dichloro-6-methylpyrimidine (2), followed by nucleophilic substitution with selected secondary amines. Subsequently, a base-induced intramolecular cyclization occurring on the nitrile group using NaNH2 afforded the fused products (6a-f). Although only a limited number of derivatives were obtained, this sequence offers a straightforward and modular route to fused heterocyclic systems. The structural features, including the disappearance of one nitrile group and the formation of the fused ring system, were characterized by FT-IR, 1H NMR, 13C NMR, HMBC, and 2D NOESY analyses. The obtained data were consistent with the proposed structures and supported the formation of the fused pyrimidine-selenophene framework. This catalyst-free and operationally simple procedure highlights a practical synthetic pathway to selenium-containing fused pyrimidines, which have been previously difficult to access. Furthermore, preliminary antibacterial evaluation indicates promising biological potential for the obtained compounds.
Imidazo[1,5-a]pyridines are intriguing molecules known for their unique biological and photophysical properties, making them valuable in medicinal chemistry. This study reports a solvent-free approach for synthesizing 3-arylimidazo[1,5-a]pyridines 1a-q using carbon tetrachloride as an oxidant reagent and DBU as a base, affording good to high product yields. Based on control experiments, kinetic analysis conducted by 13C NMR and DFT calculations, we propose a plausible reaction pathway to elucidate this transformation. Moreover, we demonstrate that CCl4 is a chloride donor and oxidant by observing the formation of CHCl3 as a byproduct.
A metal-free, efficient method for the simple and convenient synthesis of aryl group-substituted thiocarbonates under ambient conditions has been developed. The described strategy enabled the practical approach to access diaryl-substituted cyclic thiocarbonates from hydrobenzoin using di(1H-imidazol-1-yl)methanethione (Im2CS) in toluene at reflux. N-Heterocyclic carbene (NHCs) have been used as organocatalysts to convert functionalized aromatic aldehydes to substituted benzoin, which is then rapidly reduced with commercially available sodium borohydride (NaBH4) in one-pot conditions, producing functionalized hydrobenzoin derivatives in good yields. The present method offers a greener approach featuring readily accessible catalysts and reagents, broad substrate scope, operational simplicity, high yields, shorter reaction times, and mild conditions.
