Vicinal diamine motifs are found in a wide variety of bioactive molecules and act as valuable ligands for transition‐metal catalysts. Aminolysis of aziridines is a direct and atom‐economical synthesis approach to these structural units; however, controlling the regioselectivity of the intermolecular ring opening of nonactivated aziridines remains challenging. Herein, we report a Pr(OTf) 3 ‐catalyzed regioselective intermolecular aminolysis of N ‐alkyl‐2,3‐aziridinyl alcohols. In benzotrifluoride, various aliphatic and aromatic amines undergo selective nucleophilic attack at the C3 position to afford the corresponding vicinal diamines. Investigation of O ‐protected and N ‐protected substrates suggests that bidentate coordination of the lanthanide catalyst to the free hydroxy group and alkylated aziridine nitrogen plays a key role in achieving the observed regioselectivity.
{"title":"Regioselective Synthesis of Vicinal Diamines by Pr(OTf) 3 ‐Catalyzed Intermolecular Aminolysis of N ‐Alkyl‐2,3‐Aziridinyl Alcohols","authors":"Yuse Kuriyama, Atsushi Tahara, Yusuke Sasano, Yoshiharu Iwabuchi","doi":"10.1002/ejoc.70876","DOIUrl":"https://doi.org/10.1002/ejoc.70876","url":null,"abstract":"Vicinal diamine motifs are found in a wide variety of bioactive molecules and act as valuable ligands for transition‐metal catalysts. Aminolysis of aziridines is a direct and atom‐economical synthesis approach to these structural units; however, controlling the regioselectivity of the intermolecular ring opening of nonactivated aziridines remains challenging. Herein, we report a Pr(OTf) <jats:sub>3</jats:sub> ‐catalyzed regioselective intermolecular aminolysis of <jats:italic>N</jats:italic> ‐alkyl‐2,3‐aziridinyl alcohols. In benzotrifluoride, various aliphatic and aromatic amines undergo selective nucleophilic attack at the C3 position to afford the corresponding vicinal diamines. Investigation of <jats:italic>O</jats:italic> ‐protected and <jats:italic>N</jats:italic> ‐protected substrates suggests that bidentate coordination of the lanthanide catalyst to the free hydroxy group and alkylated aziridine nitrogen plays a key role in achieving the observed regioselectivity.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"11 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218744","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}
Samuel A. Fisher, Patrick L. DeRoy, Mark Stradiotto
Reported herein is the first nickel‐catalyzed N ‐arylation of sulfonimidamides at the imine position employing (hetero)aryl chloride reaction partners with useful substrate scope. Such otherwise challenging transformations are enabled under mild conditions and in synthetically useful isolated yields by use of a PAd‐DalPhos/Ni catalyst system, including N ‐arylation of the active pharmaceutical ingredient chlorpromazine.
{"title":"Thermal Nickel‐Catalyzed N ‐Arylation of Sulfonimidamides With (Hetero)aryl Chlorides Enabled by PAd‐DalPhos Ligation","authors":"Samuel A. Fisher, Patrick L. DeRoy, Mark Stradiotto","doi":"10.1002/ejoc.70880","DOIUrl":"https://doi.org/10.1002/ejoc.70880","url":null,"abstract":"Reported herein is the first nickel‐catalyzed <jats:italic>N</jats:italic> ‐arylation of sulfonimidamides at the imine position employing (hetero)aryl chloride reaction partners with useful substrate scope. Such otherwise challenging transformations are enabled under mild conditions and in synthetically useful isolated yields by use of a PAd‐DalPhos/Ni catalyst system, including <jats:italic>N</jats:italic> ‐arylation of the active pharmaceutical ingredient chlorpromazine.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"44 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218743","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}
Chemical post‐modification of peptides is a powerful approach for enabling structural diversification and rapid derivatization during the development of peptide therapeutics. In particular, tyrosine phosphorylation is a key regulatory mechanism in many cellular functions. Furthermore, phosphorylated tyrosine is a fundamental structural unit present in bioactive peptides and their lead compounds. Herein, we report a highly efficient DBU–CHCl 3 ‐mediated umpolung phosphorylation of tyrosine in short peptides using H‐phosphine oxides as electrophilic phosphoryl donors in both solution and solid phases. The method shows base‐controlled selectivity and is applicable to cysteine, and tryptophan using Cs 2 CO 3 as base. The reaction involves base‐promoted carbene generation from CHCl 3 under phosphonium salt catalysis to form an electrophilic phosphorus species that underwent nucleophilic attack by amino acids, enabling umpolung phosphorylation through O─P, S─P, and N─P bond formation. Furthermore, the strategy has been successfully applied to biomolecule‐amino acid conjugates, yielding phosphorylated conjugates in good efficiency.
{"title":"Base‐Controlled Switchable Umpolung Phosphorylation of Tyrosine, Cysteine, and Tryptophan by CHCl 3 ‐Assisted Phosphonium Salt Catalysis","authors":"Haripriya Bhumannagari, Shravani Battula, Kiranmai Nayani","doi":"10.1002/ejoc.70903","DOIUrl":"https://doi.org/10.1002/ejoc.70903","url":null,"abstract":"Chemical post‐modification of peptides is a powerful approach for enabling structural diversification and rapid derivatization during the development of peptide therapeutics. In particular, tyrosine phosphorylation is a key regulatory mechanism in many cellular functions. Furthermore, phosphorylated tyrosine is a fundamental structural unit present in bioactive peptides and their lead compounds. Herein, we report a highly efficient DBU–CHCl <jats:sub>3</jats:sub> ‐mediated umpolung phosphorylation of tyrosine in short peptides using H‐phosphine oxides as electrophilic phosphoryl donors in both solution and solid phases. The method shows base‐controlled selectivity and is applicable to cysteine, and tryptophan using Cs <jats:sub>2</jats:sub> CO <jats:sub>3</jats:sub> as base. The reaction involves base‐promoted carbene generation from CHCl <jats:sub>3</jats:sub> under phosphonium salt catalysis to form an electrophilic phosphorus species that underwent nucleophilic attack by amino acids, enabling umpolung phosphorylation through O─P, S─P, and N─P bond formation. Furthermore, the strategy has been successfully applied to biomolecule‐amino acid conjugates, yielding phosphorylated conjugates in good efficiency.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"239 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198943","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}
An economical and regioselective electrochemical oxidative C─H selenocyanation or thiocyanation of N ‐rich heteroarenes, such as azaindole and deazapurine, is reported utilizing graphite electrodes. The reaction proceeds without the need for any catalyst or oxidant under a constant electric current in an undivided electrolytic cell. The commercially available reagents KSCN or KSeCN were used for the chalcogenocyanation reactions. A variety of selenocyanated and thiocyanated derivatives were synthesized in yields of 70%–90%, and the reactions also tolerated different electron‐rich or electron‐deficient substituents on the heterocyclic core.
{"title":"Electrochemical Selenocyanation and Thiocyanation of Azaindoles and Deazapurines","authors":"Esraphil Hossain, Rajib Bera, Arup Bairagi, Somnath Yadav","doi":"10.1002/ejoc.70869","DOIUrl":"https://doi.org/10.1002/ejoc.70869","url":null,"abstract":"An economical and regioselective electrochemical oxidative C─H selenocyanation or thiocyanation of <jats:italic>N</jats:italic> ‐rich heteroarenes, such as azaindole and deazapurine, is reported utilizing graphite electrodes. The reaction proceeds without the need for any catalyst or oxidant under a constant electric current in an undivided electrolytic cell. The commercially available reagents KSCN or KSeCN were used for the chalcogenocyanation reactions. A variety of selenocyanated and thiocyanated derivatives were synthesized in yields of 70%–90%, and the reactions also tolerated different electron‐rich or electron‐deficient substituents on the heterocyclic core.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"11 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198948","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}
Ana M. Martínez‐Rueda, Leyre Gutiérrez‐Portillo, Laura Erviti‐Marticorena, Alba Millán
Thiomethyl groups (─SMe) are highly relevant in molecular electronics, particularly in studies exploring single‐molecule electron transport using the scanning tunneling microscope‐break junction (STM‐BJ) technique. These groups play a crucial role by acting as anchoring groups for gold electrodes. However, general synthetic methodologies for installing this functional group are scarce. Herein, we present a palladium‐catalyzed reaction for the thiomethylation of aryl iodides, bromides, and triflates using NaSMe as the nucleophilic reagent. This methodology is robust, scalable, and exhibits broad functional group compatibility and structural diversity.
{"title":"Palladium‐Catalyzed Thiomethylation of Arenes: A Convenient Method for Molecular Electronics Applications","authors":"Ana M. Martínez‐Rueda, Leyre Gutiérrez‐Portillo, Laura Erviti‐Marticorena, Alba Millán","doi":"10.1002/ejoc.70894","DOIUrl":"https://doi.org/10.1002/ejoc.70894","url":null,"abstract":"Thiomethyl groups (─SMe) are highly relevant in molecular electronics, particularly in studies exploring single‐molecule electron transport using the scanning tunneling microscope‐break junction (STM‐BJ) technique. These groups play a crucial role by acting as anchoring groups for gold electrodes. However, general synthetic methodologies for installing this functional group are scarce. Herein, we present a palladium‐catalyzed reaction for the thiomethylation of aryl iodides, bromides, and triflates using NaSMe as the nucleophilic reagent. This methodology is robust, scalable, and exhibits broad functional group compatibility and structural diversity.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"53 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172839","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}
An efficient TFA ‐catalyzed cascade transformation of α‐(3‐isoindolinonyl)propargylic alcohols with 3‐aminoindoles has been developed for the de novo synthesis of multisubstituted δ‐carbolines. This one‐pot protocol integrates a series of sequential steps, including dehydration, 1,4‐addition, isomerization, Claisen rearrangement, aromatization, and ring‐opening, to deliver δ‐carbolines derivatives in a highly efficient manner. Notably, this work not only provides a powerful strategy for the de novo construction of these complex polycyclic scaffolds but also significantly expands the synthetic utility of α‐(3‐isoindolinonyl)propargylic alcohols.
{"title":"Organocatalytic Reaction of α‐(3‐Isoindolinonyl) propargylic Alcohols With 3‐Aminoindoles for Construction of δ‐Carbolines","authors":"Yuqing Zhang, Lunfeng Chen, Pengfei Li","doi":"10.1002/ejoc.70918","DOIUrl":"https://doi.org/10.1002/ejoc.70918","url":null,"abstract":"An efficient TFA ‐catalyzed cascade transformation of α‐(3‐isoindolinonyl)propargylic alcohols with 3‐aminoindoles has been developed for the de novo synthesis of multisubstituted δ‐carbolines. This one‐pot protocol integrates a series of sequential steps, including dehydration, 1,4‐addition, isomerization, Claisen rearrangement, aromatization, and ring‐opening, to deliver δ‐carbolines derivatives in a highly efficient manner. Notably, this work not only provides a powerful strategy for the de novo construction of these complex polycyclic scaffolds but also significantly expands the synthetic utility of α‐(3‐isoindolinonyl)propargylic alcohols.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"11 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172840","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}
Copper(II) triflate is found to be an effective catalyst for the regioselective C–H insertion of heteroaromatic compounds into diazo arylidene succinimide‐based carbene precursors. Preferential C3–H insertion occurs in N ‐substituted and unsubstituted indoles, while selective C2–H insertion occurs when the C3 site is blocked. This technique was extended to other heteroaromatic compounds, such as carbazoles, phenothiazines and pyrrole, and all of them yielded the respective C–H insertion products in good yields.
{"title":"Copper‐Catalyzed C–H Insertion of N ‐Heterocycles Into Diazo Arylidene Succinimides","authors":"Arputharaj Francisgracia, Kannupal Srinivasan","doi":"10.1002/ejoc.70890","DOIUrl":"https://doi.org/10.1002/ejoc.70890","url":null,"abstract":"Copper(II) triflate is found to be an effective catalyst for the regioselective C–H insertion of heteroaromatic compounds into diazo arylidene succinimide‐based carbene precursors. Preferential C3–H insertion occurs in <jats:italic>N</jats:italic> ‐substituted and unsubstituted indoles, while selective C2–H insertion occurs when the C3 site is blocked. This technique was extended to other heteroaromatic compounds, such as carbazoles, phenothiazines and pyrrole, and all of them yielded the respective C–H insertion products in good yields.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"33 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198944","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}
Joaquín Marchán‐García, Valeria Cavallaro, A. Paula Murray, Marcos J. Lo Fiego, Yanina Moglie
A practical and efficient method for the synthesis of glycosyl‐1,2,3‐triazole hybrids has been developed using copper nanoparticles supported on activated carbon as a catalyst. The methodology is based on a tandem process combining Cu‐catalyzed azide–alkyne cycloaddition with in situ deacetylation of carbohydrate derivatives under mild conditions. To the best of our knowledge, tandem CuAAC–deacetylation strategies enabling direct access to unprotected glycosyl triazoles have not been previously reported. The reaction proceeds in methanol at 65 °C using a low metal loading (1.0 mol% Cu), affording a series of glucosyl‐, galactosyl‐, and lactosyl‐triazole derivatives in good to excellent yields. The protocol was successfully performed on a larger scale (1 mmol), maintaining comparable efficiency. This approach eliminates the need for a separate deprotection step typically required for carbohydrate‐derived azides, providing a step‐economical and operationally simple route to unprotected glycosyl triazoles. A total of thirteen glycosyl‐1,2,3‐triazole derivatives were synthesized, including 12 new compounds, which were fully characterized by NMR spectroscopy and HRMS. Preliminary biological evaluation revealed promising α‐glucosidase inhibitory activity for selected disaccharide derivatives, which outperformed the reference compound. In silico ADME analysis revealed physicochemical profiles consistent with known α‐glucosidase inhibitors, supporting their suitability for localized intestinal activity.
{"title":"Copper Nanoparticle‐Catalyzed Tandem Cycloaddition–Deacetylation for the Synthesis of Glycosyl Triazoles","authors":"Joaquín Marchán‐García, Valeria Cavallaro, A. Paula Murray, Marcos J. Lo Fiego, Yanina Moglie","doi":"10.1002/ejoc.70828","DOIUrl":"https://doi.org/10.1002/ejoc.70828","url":null,"abstract":"A practical and efficient method for the synthesis of glycosyl‐1,2,3‐triazole hybrids has been developed using copper nanoparticles supported on activated carbon as a catalyst. The methodology is based on a tandem process combining Cu‐catalyzed azide–alkyne cycloaddition with in situ deacetylation of carbohydrate derivatives under mild conditions. To the best of our knowledge, tandem CuAAC–deacetylation strategies enabling direct access to unprotected glycosyl triazoles have not been previously reported. The reaction proceeds in methanol at 65 °C using a low metal loading (1.0 mol% Cu), affording a series of glucosyl‐, galactosyl‐, and lactosyl‐triazole derivatives in good to excellent yields. The protocol was successfully performed on a larger scale (1 mmol), maintaining comparable efficiency. This approach eliminates the need for a separate deprotection step typically required for carbohydrate‐derived azides, providing a step‐economical and operationally simple route to unprotected glycosyl triazoles. A total of thirteen glycosyl‐1,2,3‐triazole derivatives were synthesized, including 12 new compounds, which were fully characterized by NMR spectroscopy and HRMS. Preliminary biological evaluation revealed promising α‐glucosidase inhibitory activity for selected disaccharide derivatives, which outperformed the reference compound. In silico ADME analysis revealed physicochemical profiles consistent with known α‐glucosidase inhibitors, supporting their suitability for localized intestinal activity.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"10 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149199023","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}
A phenalenyl–pyrene hybrid system is presented here as an effective photocatalyst for the direct C(sp 2 )─H arylation of p ‐benzoquinone under visible light. This process yields a range of biologically and optically relevant redox‐active tetra‐arylated‐ p ‐benzoquinones, utilizing aryl diazonium salts as radical sources. Additionally, the catalyst facilitates the conversion of tetra‐arylated‐ p ‐benzoquinones into dibenzofuran‐type molecules through intramolecular O─C coupling when aryl groups contain powerful inductive withdrawing groups. This study also provides mechanistic insights into the catalytic reaction and the structural characteristics of the synthesized tetra‐arylated products.
{"title":"Electronic Effect‐Controlled Visible‐Light‐Driven Tetra‐Arylation of p ‐Benzoquinone Using a Phenalenyl–Pyrene Hybrid Photocatalyst","authors":"Sabnam Azmi, Asik Ikbal, Sourabh Pal, Sandip Sarkar, Rituparna Dutta, Suraj Kumar Agrawalla, Chandra Shekhar Purohit, Bhaskar Biswas, Hari Sankar Das","doi":"10.1002/ejoc.70915","DOIUrl":"https://doi.org/10.1002/ejoc.70915","url":null,"abstract":"A phenalenyl–pyrene hybrid system is presented here as an effective photocatalyst for the direct C(sp <jats:sup>2</jats:sup> )─H arylation of <jats:italic>p</jats:italic> ‐benzoquinone under visible light. This process yields a range of biologically and optically relevant redox‐active tetra‐arylated‐ <jats:italic>p</jats:italic> ‐benzoquinones, utilizing aryl diazonium salts as radical sources. Additionally, the catalyst facilitates the conversion of tetra‐arylated‐ <jats:italic>p</jats:italic> ‐benzoquinones into dibenzofuran‐type molecules through intramolecular O─C coupling when aryl groups contain powerful inductive withdrawing groups. This study also provides mechanistic insights into the catalytic reaction and the structural characteristics of the synthesized tetra‐arylated products.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"31 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172837","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}
Herein, we disclose a Brønsted acid‐catalyzed tandem aldol condensation/1,4‐aza‐Michael addition strategy to achieve highly N 2 ‐selective alkylation of tetrazoles (N 2 /N 1 > 25:1), and the N 2 ‐selectivity was unambiguously confirmed by single‐crystal X‐ray diffraction. Control experiments verify that in situ generated α,β‐unsaturated ketones act as key intermediates, and acid catalysis is indispensable for the condensation and conjugate addition steps. With p‐toluenesulfonic acid (TsOH) as the optimal catalyst, this transformation tolerates a broad spectrum of tetrazole derivatives with aryl, aliphatic, hydroxyl, pyridyl, and thioether substituents, and the reaction is scalable to gram scale. This straightforward method employs readily available ketones and aldehydes without the need for presynthesized α,β‐unsaturated ketones, offering an efficient and regioselective route to N 2 ‐alkyl tetrazoles.
{"title":"Brønsted Acid‐Catalyzed Tandem Aldol Condensation/1,4‐Aza‐Michael Addition: N 2 ‐Selective Alkylation of Tetrazoles","authors":"Hui Zhang, Lifang Tian, Jiawei Li, Guanglu Liu, Li‐Li Zhu, Yahui Wang","doi":"10.1002/ejoc.70917","DOIUrl":"https://doi.org/10.1002/ejoc.70917","url":null,"abstract":"Herein, we disclose a Brønsted acid‐catalyzed tandem aldol condensation/1,4‐aza‐Michael addition strategy to achieve highly N <jats:sup>2</jats:sup> ‐selective alkylation of tetrazoles (N <jats:sup>2</jats:sup> /N <jats:sup>1</jats:sup> > 25:1), and the N <jats:sup>2</jats:sup> ‐selectivity was unambiguously confirmed by single‐crystal X‐ray diffraction. Control experiments verify that in situ generated α,β‐unsaturated ketones act as key intermediates, and acid catalysis is indispensable for the condensation and conjugate addition steps. With p‐toluenesulfonic acid (TsOH) as the optimal catalyst, this transformation tolerates a broad spectrum of tetrazole derivatives with aryl, aliphatic, hydroxyl, pyridyl, and thioether substituents, and the reaction is scalable to gram scale. This straightforward method employs readily available ketones and aldehydes without the need for presynthesized α,β‐unsaturated ketones, offering an efficient and regioselective route to N <jats:sup>2</jats:sup> ‐alkyl tetrazoles.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"53 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172838","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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