Pub Date : 2025-12-23DOI: 10.1016/j.tet.2025.135122
Ting Shao , Botao Wang , Jinhui Yang , Zheng Li
A concise method for the construction of 1-aroyl-2-methylbenzimidazoles using solid calcium carbide as a C2 source, N-(2-aminophenyl)benzamides as substrates, tosyl azides as a mediator, through a one-step procedure is described. The target products were effectively obtained through cascade annulations, involving the one-step formation of two C–N bonds. The salient features for this protocol are the use of inexpensive, abundant, and easy-to-handle solid C2 source, easily synthesized reactants, low-cost catalyst, wide functional tolerance, satisfactory yield, and simple workup procedure. The reactions can also be carried out on a gram scale.
{"title":"One-step construction of 1-aroyl-2-methylbenzimidazoles using solid calcium carbide as a C2 source","authors":"Ting Shao , Botao Wang , Jinhui Yang , Zheng Li","doi":"10.1016/j.tet.2025.135122","DOIUrl":"10.1016/j.tet.2025.135122","url":null,"abstract":"<div><div>A concise method for the construction of 1-aroyl-2-methylbenzimidazoles using solid calcium carbide as a C2 source, <em>N</em>-(2-aminophenyl)benzamides as substrates, tosyl azides as a mediator, through a one-step procedure is described. The target products were effectively obtained through cascade annulations, involving the one-step formation of two C–N bonds. The salient features for this protocol are the use of inexpensive, abundant, and easy-to-handle solid C2 source, easily synthesized reactants, low-cost catalyst, wide functional tolerance, satisfactory yield, and simple workup procedure. The reactions can also be carried out on a gram scale.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135122"},"PeriodicalIF":2.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1016/j.tet.2025.135123
Katsuki Akiyama, Kenshu Fujiwara
The total synthesis of colisporifungin, ophiotine and verruculin, possessing a common cyclic lipohexadepsipeptide framework including three d-amino acids and β-alanine, was successfully achieved by a unified, convergent route based on solution-phase peptide synthesis. The framework was assembled from a tripeptide fragment and a lipotridepsipeptide segment by a connection/cyclization process at the final stage, where a ring-forming condensation between the less-hindered β-alanine and the l-threonine residues effectively occurred. Initial introduction of the fatty acid moiety to d-glutamine to avoid unnecessary protecting group manipulations was also helpful for making the synthesis concise.
{"title":"Unified total synthesis of colisporifungin, ophiotine and verruculin","authors":"Katsuki Akiyama, Kenshu Fujiwara","doi":"10.1016/j.tet.2025.135123","DOIUrl":"10.1016/j.tet.2025.135123","url":null,"abstract":"<div><div>The total synthesis of colisporifungin, ophiotine and verruculin, possessing a common cyclic lipohexadepsipeptide framework including three <span>d</span>-amino acids and β-alanine, was successfully achieved by a unified, convergent route based on solution-phase peptide synthesis. The framework was assembled from a tripeptide fragment and a lipotridepsipeptide segment by a connection/cyclization process at the final stage, where a ring-forming condensation between the less-hindered β-alanine and the <span>l</span>-threonine residues effectively occurred. Initial introduction of the fatty acid moiety to <span>d</span>-glutamine to avoid unnecessary protecting group manipulations was also helpful for making the synthesis concise.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135123"},"PeriodicalIF":2.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.tet.2025.135112
Guoliang Xu , Yixuan Zhao , Hui Wang , Linshu Wang , Junlin Wen , Hui Mei , Xin Ming
Fluorescent nucleoside analogs (FNAs) serve as powerful tools for investigating the structural and dynamic properties of nucleic acids. However, the development of red-emitting molecular rotor-type fluorescent nucleosides has been relatively limited. Here, we present a red-emitting fluorescent nucleoside analog, HBCdU, which is based on a trans-stilbene-linked uracil derivative. This analog exhibits a significant red-shifted emission peak at 625 nm in aqueous solution and demonstrates high sensitivity to changes in polarity, pH, and viscosity. Remarkably, when incorporated into single-stranded oligonucleotides, HBCdU shows an enhancement in brightness by nearly ten times as opposed to the free nucleoside, independent of the surrounding flanking bases. These characteristics position HBCdU as a promising probe for studying nucleic acid microenvironments and protein-nucleic acid interactions.
{"title":"A red-emitting molecular rotor fluorescent nucleoside for microenvironment sensing","authors":"Guoliang Xu , Yixuan Zhao , Hui Wang , Linshu Wang , Junlin Wen , Hui Mei , Xin Ming","doi":"10.1016/j.tet.2025.135112","DOIUrl":"10.1016/j.tet.2025.135112","url":null,"abstract":"<div><div>Fluorescent nucleoside analogs (FNAs) serve as powerful tools for investigating the structural and dynamic properties of nucleic acids. However, the development of red-emitting molecular rotor-type fluorescent nucleosides has been relatively limited. Here, we present a red-emitting fluorescent nucleoside analog, <sup>HBC</sup>dU, which is based on a <em>trans</em>-stilbene-linked uracil derivative. This analog exhibits a significant red-shifted emission peak at 625 nm in aqueous solution and demonstrates high sensitivity to changes in polarity, pH, and viscosity. Remarkably, when incorporated into single-stranded oligonucleotides, <sup>HBC</sup>dU shows an enhancement in brightness by nearly ten times as opposed to the free nucleoside, independent of the surrounding flanking bases. These characteristics position <sup>HBC</sup>dU as a promising probe for studying nucleic acid microenvironments and protein-nucleic acid interactions.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135112"},"PeriodicalIF":2.2,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.tet.2025.135095
Fengyan Lu , Xuyang Li , Qi Zhu , Lifeng Chu , Jianwei Han , Limin Wang
The high performance copper electrodeposition in high-aspect-ratio through-holes for printed circuit board (PCB) is a challenge in the electronics industry. In this text, a family of pyromellitic diimide (PMD) derived quaternary ammonium salts were synthesized in good yields, which exhibited strong suppression of copper deposition. Among these, PMD-bipyridinium (Bpy) salt demonstrates the most pronounced effect, showing excellent adsorption behavior on copper surfaces, as confirmed by electrochemical analyses, theoretical calculations, and molecular dynamics simulations. Practical plating evaluations further verified the superior filling and leveling performance of the PMD-Bpy salt, achieving uniform and defect-free copper electrodeposition.
{"title":"Pyromellitic diimide-derived quaternary ammonium salts: Synthesis and application as efficient copper electroplating levelers","authors":"Fengyan Lu , Xuyang Li , Qi Zhu , Lifeng Chu , Jianwei Han , Limin Wang","doi":"10.1016/j.tet.2025.135095","DOIUrl":"10.1016/j.tet.2025.135095","url":null,"abstract":"<div><div>The high performance copper electrodeposition in high-aspect-ratio through-holes for printed circuit board (PCB) is a challenge in the electronics industry. In this text, a family of pyromellitic diimide (PMD) derived quaternary ammonium salts were synthesized in good yields, which exhibited strong suppression of copper deposition. Among these, PMD-bipyridinium (Bpy) salt demonstrates the most pronounced effect, showing excellent adsorption behavior on copper surfaces, as confirmed by electrochemical analyses, theoretical calculations, and molecular dynamics simulations. Practical plating evaluations further verified the superior filling and leveling performance of the PMD-Bpy salt, achieving uniform and defect-free copper electrodeposition.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135095"},"PeriodicalIF":2.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.tet.2025.135113
Riham M. Bokhtia , Tejas Srinivasan , Mandy Green , Rajeev Shakuja , Siva S. Panda
We report a green, metal-free, and efficient synthetic protocol for the preparation of bis-benzothiazoles via benzotriazole-mediated activation of dicarboxylic acids. This methodology employs N-acylbenzotriazole intermediates, which react with 2-aminothiophenol under mild conditions in acetic acid to afford the target bis-benzothiazoles in excellent yields. The process avoids the use of toxic reagents, metal catalysts, and harsh conditions, offering a sustainable alternative to conventional methods. Density functional theory (DFT) calculations provide mechanistic insights and thermodynamic profiles, highlighting the role of substituent effects and noncovalent interactions in product stability. The protocol demonstrates broad substrate scope, operational simplicity, and high atom economy, making it a valuable contribution to green heterocyclic synthesis.
{"title":"Efficient one-pot synthesis of bis-benzothiazoles from dicarboxylic acids: A metal-free benzotriazole strategy","authors":"Riham M. Bokhtia , Tejas Srinivasan , Mandy Green , Rajeev Shakuja , Siva S. Panda","doi":"10.1016/j.tet.2025.135113","DOIUrl":"10.1016/j.tet.2025.135113","url":null,"abstract":"<div><div>We report a green, metal-free, and efficient synthetic protocol for the preparation of bis-benzothiazoles via benzotriazole-mediated activation of dicarboxylic acids. This methodology employs N-acylbenzotriazole intermediates, which react with 2-aminothiophenol under mild conditions in acetic acid to afford the target bis-benzothiazoles in excellent yields. The process avoids the use of toxic reagents, metal catalysts, and harsh conditions, offering a sustainable alternative to conventional methods. Density functional theory (DFT) calculations provide mechanistic insights and thermodynamic profiles, highlighting the role of substituent effects and noncovalent interactions in product stability. The protocol demonstrates broad substrate scope, operational simplicity, and high atom economy, making it a valuable contribution to green heterocyclic synthesis.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135113"},"PeriodicalIF":2.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.tet.2025.135097
Li-Qin Huang , Mei-Fen Bao , Ping Zhang , Xin Yue , Yang Yu
Chemical investigation of the supercritical CO2 extract from the fruits of Schisandra chinensis resulted in the isolation of four sesquiterpenoids, including a new compound schisandrins A (1). The structures of the compounds were fully elucidated through comprehensive NMR and HRESIMS analyses, supported by X-ray crystallography and ECD. The above isolated compounds are classified as cuparane (1 and 2) and chamigrane (3 and 4) sesquiterpenoids, both derived biosynthetically from bisabolane. Notably, the structure of compound 3, which had been erroneously reported in the literature as a widdarane-type sesquiterpene, was revised to a chamigrane-type spirocyclic skeleton. This study not only expands the structural diversity of sesquiterpenoids from S. chinensis, but also highlights the essential role of X-ray diffraction in correcting misassignments based solely on NMR data.
{"title":"Sesquiterpenes from Schisandra chinensis: Structural characterization and revision","authors":"Li-Qin Huang , Mei-Fen Bao , Ping Zhang , Xin Yue , Yang Yu","doi":"10.1016/j.tet.2025.135097","DOIUrl":"10.1016/j.tet.2025.135097","url":null,"abstract":"<div><div>Chemical investigation of the supercritical CO<sub>2</sub> extract from the fruits of <em>Schisandra chinensis</em> resulted in the isolation of four sesquiterpenoids, including a new compound schisandrins A (<strong>1</strong>). The structures of the compounds were fully elucidated through comprehensive NMR and HRESIMS analyses, supported by X-ray crystallography and ECD. The above isolated compounds are classified as cuparane (<strong>1</strong> and <strong>2</strong>) and chamigrane (<strong>3</strong> and <strong>4</strong>) sesquiterpenoids, both derived biosynthetically from bisabolane. Notably, the structure of compound <strong>3</strong>, which had been erroneously reported in the literature as a widdarane-type sesquiterpene, was revised to a chamigrane-type spirocyclic skeleton. This study not only expands the structural diversity of sesquiterpenoids from <em>S. chinensis</em>, but also highlights the essential role of X-ray diffraction in correcting misassignments based solely on NMR data.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135097"},"PeriodicalIF":2.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.tet.2025.135108
Antony E. Fernandes , Olivier Riant , Alain M. Jonas
The immobilization of homogeneous catalysts has become a central strategy in the design of efficient and sustainable catalytic systems. By anchoring well-defined molecular catalysts onto soluble or insoluble supports, it is possible to combine the high activity and selectivity of homogeneous catalysis with the operational benefits of heterogeneous systems, including ease of recovery, recyclability, and implementation within continuous flow processes. Among the various approaches to covalent immobilization, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) stands out as a particularly versatile and reliable method. This “click” reaction offers exceptional robustness, functional group tolerance, and modularity, allowing for the immobilization of a broad range of catalytic species — organic and organometallic — under mild conditions. In this article, we update our review published in 2014 and highlight recent advances in the use of CuAAC for catalyst immobilization, from simple single-site catalysts to elaborate multicatalytic systems, including organometallic, organic and multifunctional catalysts, and photocatalysts. We also discuss how the triazole linkage itself can serve not only as a passive tether but also as a functional component, influencing the microenvironment and coordination behavior of the resulting materials. Despite its many strengths, CuAAC is not without limitations, such as the requirement for copper catalyst and potential interference of the triazole unit. These drawbacks are considered in the context of emerging complementary “click” immobilization strategies. Overall, CuAAC remains a cornerstone technology in the immobilization toolbox, offering a powerful platform for building next-generation supported catalysts that approach the performance of their homogeneous counterparts while enabling scalable and sustainable chemical processes.
{"title":"Recent advances in the application of CuAAC for the covalent immobilization of homogeneous catalysts, a decade of progress","authors":"Antony E. Fernandes , Olivier Riant , Alain M. Jonas","doi":"10.1016/j.tet.2025.135108","DOIUrl":"10.1016/j.tet.2025.135108","url":null,"abstract":"<div><div>The immobilization of homogeneous catalysts has become a central strategy in the design of efficient and sustainable catalytic systems. By anchoring well-defined molecular catalysts onto soluble or insoluble supports, it is possible to combine the high activity and selectivity of homogeneous catalysis with the operational benefits of heterogeneous systems, including ease of recovery, recyclability, and implementation within continuous flow processes. Among the various approaches to covalent immobilization, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) stands out as a particularly versatile and reliable method. This “click” reaction offers exceptional robustness, functional group tolerance, and modularity, allowing for the immobilization of a broad range of catalytic species — organic and organometallic — under mild conditions. In this article, we update our review published in 2014 and highlight recent advances in the use of CuAAC for catalyst immobilization, from simple single-site catalysts to elaborate multicatalytic systems, including organometallic, organic and multifunctional catalysts, and photocatalysts. We also discuss how the triazole linkage itself can serve not only as a passive tether but also as a functional component, influencing the microenvironment and coordination behavior of the resulting materials. Despite its many strengths, CuAAC is not without limitations, such as the requirement for copper catalyst and potential interference of the triazole unit. These drawbacks are considered in the context of emerging complementary “click” immobilization strategies. Overall, CuAAC remains a cornerstone technology in the immobilization toolbox, offering a powerful platform for building next-generation supported catalysts that approach the performance of their homogeneous counterparts while enabling scalable and sustainable chemical processes.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135108"},"PeriodicalIF":2.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.tet.2025.135111
Yu Zhang , Yu-Chen Zhang , Chen-Sen Xu , Yu-Chen Fan , Jing Zhang , Chao Wang , Hao-Lin Yu , Jin-Zhong Hu , Zhi-Xin Liao
Three previously undescribed steroidal saponins, polypharycosides A–C (1–3), along with eight known analogues (4–11), were isolated from the rhizomes of Paris polyphylla var. yunnanensis. The structures of the previously undescribed compounds were elucidated through comprehensive analysis using 1D/2D NMR spectroscopy, HR-ESI-MS, as well as GC analysis after acid hydrolysis and ECD calculations. the crude steroidal saponin extract showed potent activity against Salmonella typhimurium (MIC = 1 μg/mL, MBC = 8 μg/mL). In vitro antibacterial assays revealed that the extract formed distinct inhibition zones, significantly reduced bacterial ATP levels, and induced protein and nucleic acid leakage from cells, suggesting its antimicrobial mechanism may involve disruption of cell membrane integrity. Furthermore, in a lettuce infection model, the crude steroidal saponin extract effectively inhibited bacterial colonization, with its bactericidal effects exhibiting both dose- and time-dependent dynamics. This study provides a crucial theoretical foundation for the development of novel plant-derived antibacterial agents targeting S. typhimurium.
从云南多叶的根状茎中分离得到3种甾体皂苷，即多药苷A-C（1-3）和8种已知的类似物（4-11）。通过1D/2D NMR谱、HR-ESI-MS以及酸水解和ECD计算后的GC分析，对上述化合物的结构进行了综合分析。甾体皂苷粗提物对鼠伤寒沙门菌具有较强的抗鼠伤寒沙门菌活性（MIC = 1 μg/mL, MBC = 8 μg/mL）。体外抗菌实验显示，该提取物形成明显的抑菌带，显著降低细菌ATP水平，诱导蛋白质和核酸从细胞中泄漏，提示其抗菌机制可能与破坏细胞膜完整性有关。此外，在生菜感染模型中，粗甾体皂苷提取物有效抑制细菌定植，其杀菌效果表现出剂量和时间依赖的动态。该研究为开发针对鼠伤寒沙门氏菌的新型植物源抗菌药物提供了重要的理论基础。
{"title":"Steroidal saponins from Paris polyphylla var. yunnanensis and their application in antibacterial preservation","authors":"Yu Zhang , Yu-Chen Zhang , Chen-Sen Xu , Yu-Chen Fan , Jing Zhang , Chao Wang , Hao-Lin Yu , Jin-Zhong Hu , Zhi-Xin Liao","doi":"10.1016/j.tet.2025.135111","DOIUrl":"10.1016/j.tet.2025.135111","url":null,"abstract":"<div><div>Three previously undescribed steroidal saponins, polypharycosides A–C (<strong>1</strong>–<strong>3</strong>), along with eight known analogues (<strong>4</strong>–<strong>11</strong>), were isolated from the rhizomes of <em>Paris polyphylla</em> var. <em>yunnanensis</em>. The structures of the previously undescribed compounds were elucidated through comprehensive analysis using 1D/2D NMR spectroscopy, HR-ESI-MS, as well as GC analysis after acid hydrolysis and ECD calculations. the crude steroidal saponin extract showed potent activity against <em>Salmonella typhimurium</em> (MIC = 1 μg/mL, MBC = 8 μg/mL). In vitro antibacterial assays revealed that the extract formed distinct inhibition zones, significantly reduced bacterial ATP levels, and induced protein and nucleic acid leakage from cells, suggesting its antimicrobial mechanism may involve disruption of cell membrane integrity. Furthermore, in a lettuce infection model, the crude steroidal saponin extract effectively inhibited bacterial colonization, with its bactericidal effects exhibiting both dose- and time-dependent dynamics. This study provides a crucial theoretical foundation for the development of novel plant-derived antibacterial agents targeting <em>S. typhimurium.</em></div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135111"},"PeriodicalIF":2.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.tet.2025.135094
Timofey N. Chmovzh , Rinat R. Aysin , Egor D. Kotov , Karim S. Gaisin , Darina I. Nasyrova , Oleg A. Rakitin
A study of nucleophilic substitution in 4,7-dichloro[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide 4 showed that the nature of the nucleophile has a significant effect on the position and number of substituted chlorine atoms. Treatment of the dichloride 4 with amines resulted in the selective substitution of the chlorine atom at position 4 or of two chlorine atoms, depending on the amount of amine used. The reaction with thiols does not stop at the formation of a mono-substitution product and leads to bis-substitution products regardless of the structure of the thiol, its amount and reaction conditions. The reaction of 4 with alcohols and sodium alcoholates is not regioselective and afforded a mixture of mono-substitution products at positions 4 and 7, while hydrolysis of 4 gave 4-chloro-7-oxo-6,7-dihydro-[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide only. The results of DFT calculations of the first and second stages of SNAr substitution reactions showed that the reactivity of the chlorine atoms in positions 4 and 7 does not differ significantly, and the reason for the differences in reactivity is the presence of kinetic control for N-nucleophiles, thermodynamic control for reactions with O-nucleophiles, and muted effects for S-nucleophiles. The position of the oxygen atom of the N-oxide in furoxanopyridazines was rigorously proven by X-ray structural analysis data.
{"title":"Striking difference in nucleophilic substitution in 4,7-dichloro-[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide by S-, N- and O-nucleophiles","authors":"Timofey N. Chmovzh , Rinat R. Aysin , Egor D. Kotov , Karim S. Gaisin , Darina I. Nasyrova , Oleg A. Rakitin","doi":"10.1016/j.tet.2025.135094","DOIUrl":"10.1016/j.tet.2025.135094","url":null,"abstract":"<div><div>A study of nucleophilic substitution in 4,7-dichloro[1,2,5]oxadiazolo[3,4-<em>d</em>]pyridazine 1-oxide <strong>4</strong> showed that the nature of the nucleophile has a significant effect on the position and number of substituted chlorine atoms. Treatment of the dichloride <strong>4</strong> with amines resulted in the selective substitution of the chlorine atom at position 4 or of two chlorine atoms, depending on the amount of amine used. The reaction with thiols does not stop at the formation of a mono-substitution product and leads to bis-substitution products regardless of the structure of the thiol, its amount and reaction conditions. The reaction of <strong>4</strong> with alcohols and sodium alcoholates is not regioselective and afforded a mixture of mono-substitution products at positions 4 and 7, while hydrolysis of <strong>4</strong> gave 4-chloro-7-oxo-6,7-dihydro-[1,2,5]oxadiazolo[3,4-<em>d</em>]pyridazine 1-oxide only. The results of DFT calculations of the first and second stages of S<sub>N</sub>Ar substitution reactions showed that the reactivity of the chlorine atoms in positions 4 and 7 does not differ significantly, and the reason for the differences in reactivity is the presence of kinetic control for <em>N</em>-nucleophiles, thermodynamic control for reactions with <em>O</em>-nucleophiles, and muted effects for <em>S</em>-nucleophiles. The position of the oxygen atom of the <em>N</em>-oxide in furoxanopyridazines was rigorously proven by X-ray structural analysis data.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135094"},"PeriodicalIF":2.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.tet.2025.135106
Shi-Jiao Zhang , Yu Teng , Hong-Shuang Li
Small-molecule heterocycles play a critical role in FDA-approved drugs. Remarkably, the introduction of selenium motifs into heterocyclic compounds imparts unique physicochemical properties and enhanced pharmacological activities. Direct C(sp2)–H selenylation of heterocycles represents one of the most atom-economical and effective approaches for accessing heterocyclic selenides. Herein, we review recent advances in transition-metal-catalyzed or mediated C(sp2)–H selenylation of heteroaromatic compounds and uracils over the past five years. Specifically, we highlight representative selenylation examples, including substrate scope and limitations, along with comprehensive mechanistic interpretations. This review will help facilitate the development of chalcogenation of heterocycles and inspire further application of selenylated heterocyclic compounds in pharmaceutical chemistry.
{"title":"Transition-metal-catalyzed/mediated direct C(sp2)–H selenylation of heterocycles","authors":"Shi-Jiao Zhang , Yu Teng , Hong-Shuang Li","doi":"10.1016/j.tet.2025.135106","DOIUrl":"10.1016/j.tet.2025.135106","url":null,"abstract":"<div><div>Small-molecule heterocycles play a critical role in FDA-approved drugs. Remarkably, the introduction of selenium motifs into heterocyclic compounds imparts unique physicochemical properties and enhanced pharmacological activities. Direct C(sp<sup>2</sup>)–H selenylation of heterocycles represents one of the most atom-economical and effective approaches for accessing heterocyclic selenides. Herein, we review recent advances in transition-metal-catalyzed or mediated C(sp<sup>2</sup>)–H selenylation of heteroaromatic compounds and uracils over the past five years. Specifically, we highlight representative selenylation examples, including substrate scope and limitations, along with comprehensive mechanistic interpretations. This review will help facilitate the development of chalcogenation of heterocycles and inspire further application of selenylated heterocyclic compounds in pharmaceutical chemistry.</div></div>","PeriodicalId":437,"journal":{"name":"Tetrahedron","volume":"192 ","pages":"Article 135106"},"PeriodicalIF":2.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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