Davide Castiglione, Sara Amata, Federica Lauria, Andrea Maranzana, Salvatore Baldino, Alexander Roller, Laura Castoldi, Antonio Palumbo Piccionello, Vittorio Pace, Eisuke Ignacio Comas Iwasita
The constitutive low aromaticity of easily accessible 5-trifluoromethyl-1,2,4-oxadiazoles is explored for the editing modification to the corresponding unprecedented gem-disubstituted 1,2,4-oxadiazolines. The operation consiting in the nucleophilic addition of diverse carbon-centered nucleophiles occurs with excellent regiocontrol (in almost all cases), thus furnishing selectively 2,5-dihydro or 4,5-dihydro isomers. The process - documenting also high chemocontrol – enables the further derivatization of the intermediate anion with externally added electrophilic platforms. Calculations supporting the experimental evidences, attribute a key role in controlling the regioselectivity to intrinsic steric factors of the nucleophiles thus, rationalizing the non optimal outcome observed in particular circumstances (i.e. with LiCH 2 Br).
{"title":"One-pot Dearomatizative C-Nucleophiles Telescoped Addition to Fluorinated 1,2,4-Oxadiazoles - Regioselective N-Functionalization","authors":"Davide Castiglione, Sara Amata, Federica Lauria, Andrea Maranzana, Salvatore Baldino, Alexander Roller, Laura Castoldi, Antonio Palumbo Piccionello, Vittorio Pace, Eisuke Ignacio Comas Iwasita","doi":"10.1039/d5qo01707f","DOIUrl":"https://doi.org/10.1039/d5qo01707f","url":null,"abstract":"The constitutive low aromaticity of easily accessible 5-trifluoromethyl-1,2,4-oxadiazoles is explored for the editing modification to the corresponding unprecedented gem-disubstituted 1,2,4-oxadiazolines. The operation consiting in the nucleophilic addition of diverse carbon-centered nucleophiles occurs with excellent regiocontrol (in almost all cases), thus furnishing selectively 2,5-dihydro or 4,5-dihydro isomers. The process - documenting also high chemocontrol – enables the further derivatization of the intermediate anion with externally added electrophilic platforms. Calculations supporting the experimental evidences, attribute a key role in controlling the regioselectivity to intrinsic steric factors of the nucleophiles thus, rationalizing the non optimal outcome observed in particular circumstances (i.e. with LiCH 2 Br).","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"24 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A novel multicomponent reaction has been developed for the divergent synthesis of semi-saturated fused pyrimidines. Readily available cycloalkylamines, aldehydes and ammonium iodide were directly assembled through oxidative annulation and β-C(sp3)-H functionalization of primary aliphatic amines under metal-free conditions. Moreover, employing an I₂/DMSO/O₂ oxidative system enabled the same multicomponent process to directly afford quinazoline derivatives via oxidative dehydrogenation without requiring intermediate isolation. This approach establishes a new pathway for constructing structurally diverse azaarenes through an oxidative annulation strategy that involves C(sp3)-H functionalization of primary aliphatic amines.
{"title":"Divergent oxidative annulation of primary aliphatic amines to access semi-saturated fused pyrimidines or quinazolines","authors":"Kang Liu, Jiaoling Li, Fanqian Li, Xinyi Tang, Xue Peng, Yao-Fu Zeng, Xinping Liu, Guo-Jun Deng, Zhen Wang, Jinjin Chen","doi":"10.1039/d5qo01676b","DOIUrl":"https://doi.org/10.1039/d5qo01676b","url":null,"abstract":"A novel multicomponent reaction has been developed for the divergent synthesis of semi-saturated fused pyrimidines. Readily available cycloalkylamines, aldehydes and ammonium iodide were directly assembled through oxidative annulation and β-C(sp3)-H functionalization of primary aliphatic amines under metal-free conditions. Moreover, employing an I₂/DMSO/O₂ oxidative system enabled the same multicomponent process to directly afford quinazoline derivatives via oxidative dehydrogenation without requiring intermediate isolation. This approach establishes a new pathway for constructing structurally diverse azaarenes through an oxidative annulation strategy that involves C(sp3)-H functionalization of primary aliphatic amines.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"21 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuyi Li, Yunzhe Du, Ligang Yan, Siliu Cheng, Shuang Cao, Ruijun Xie, Limin Han, Ning Zhu
An efficient multicomponent methodology has been developed for the synthesis of quinazolinones and dihydroquinazolinones through the reaction of o-aminobenzamides or o-aminobenzonitriles with CaC₂ mediated by K₂S. The process begins with the formation of thioacetaldehyde, which results from the direct nucleophilic attack of sulfur anions on the acetylene generated from CaC₂. Subsequently, the thioacetaldehyde reacts with o-aminobenzamides to produce an imine intermediate, which then undergoes cyclization to generate the target compound in moderate to excellent yields. Moreover, this methodology has been extended to a one-pot synthesis of dihydroquinazolinone using 2-aminobenzonitrile and CaC₂. In this approach, the nitrile group is hydrolyzed to form an amide, and then reacts with CaC₂ to yield the target product. Notably, this protocol exhibits excellent scalability and has been successfully applied to synthesize pharmaceutical compounds or drug intermediates. By using cost-effective and eco-friendly reagents such as CaC₂ and inorganic sulfides, this strategy provides a valuable and sustainable alternative to existing methods for the synthesis of quinazolinones.
{"title":"Synthesis of quinazolinone scaffolds from the cascade reaction of o-aminobenzamides/o-aminobenzonitrile and calcium carbide mediated by K2S","authors":"Shuyi Li, Yunzhe Du, Ligang Yan, Siliu Cheng, Shuang Cao, Ruijun Xie, Limin Han, Ning Zhu","doi":"10.1039/d5qo01490e","DOIUrl":"https://doi.org/10.1039/d5qo01490e","url":null,"abstract":"An efficient multicomponent methodology has been developed for the synthesis of quinazolinones and dihydroquinazolinones through the reaction of o-aminobenzamides or o-aminobenzonitriles with CaC₂ mediated by K₂S. The process begins with the formation of thioacetaldehyde, which results from the direct nucleophilic attack of sulfur anions on the acetylene generated from CaC₂. Subsequently, the thioacetaldehyde reacts with o-aminobenzamides to produce an imine intermediate, which then undergoes cyclization to generate the target compound in moderate to excellent yields. Moreover, this methodology has been extended to a one-pot synthesis of dihydroquinazolinone using 2-aminobenzonitrile and CaC₂. In this approach, the nitrile group is hydrolyzed to form an amide, and then reacts with CaC₂ to yield the target product. Notably, this protocol exhibits excellent scalability and has been successfully applied to synthesize pharmaceutical compounds or drug intermediates. By using cost-effective and eco-friendly reagents such as CaC₂ and inorganic sulfides, this strategy provides a valuable and sustainable alternative to existing methods for the synthesis of quinazolinones.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"83 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jianwei Wang, Chunxue Pu, Jianfeng Xu, Yan Cao, Wei Chen, Jun Ying
A novel palladium-catalyzed four-component cascade cyclization and carbonylation of bicyclobutyl (BCB) amides has been developed for the rapid construction of functionalized spiroquinolinone scaffolds. The reaction of bicyclobutyl (BCB) amides with perfluorobutyl iodide and phenols using formic acid as the CO source proceeded smoothly to afford a wide range of ester- and perfluoroalkyl-containing spiroquinolinone derivatives in high yields.
{"title":"Palladium-Catalyzed Four-Component Cascade Cyclization and Carbonylation of Bicyclobutyl (BCB) Amides","authors":"Jianwei Wang, Chunxue Pu, Jianfeng Xu, Yan Cao, Wei Chen, Jun Ying","doi":"10.1039/d5qo01673h","DOIUrl":"https://doi.org/10.1039/d5qo01673h","url":null,"abstract":"A novel palladium-catalyzed four-component cascade cyclization and carbonylation of bicyclobutyl (BCB) amides has been developed for the rapid construction of functionalized spiroquinolinone scaffolds. The reaction of bicyclobutyl (BCB) amides with perfluorobutyl iodide and phenols using formic acid as the CO source proceeded smoothly to afford a wide range of ester- and perfluoroalkyl-containing spiroquinolinone derivatives in high yields.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"39 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We report a palladium(II)-catalyzed (3 + 3) allylic annulations between 2-(1-alkynyl)-2-alken-1-ones and 2- or 3-substituted (Z)-4-hydroxy-but-2-en-1-yl acetates. This substrate-controlled formation of constitutional isomers method efficiently delivers a diversity of 7-vinyl-6,7-dihydro-4H-furo[3,4-c]pyran derivatives containing a quaternary or tertiary carbon center with precise regio- and diastereocontrol (dr > 20:1).
{"title":"Palladium(II)-Catalyzed Substrate-Controlled Diastereoselective Formal (3 + 3) Allylic Annulation of 2- or 3-Substituted 4-Hydroxy-but-2-en-1-yl acetates","authors":"Tuanli Yao, Nan Yang, Jun-E She, Xiangyang Qin","doi":"10.1039/d5qo01637a","DOIUrl":"https://doi.org/10.1039/d5qo01637a","url":null,"abstract":"We report a palladium(II)-catalyzed (3 + 3) allylic annulations between 2-(1-alkynyl)-2-alken-1-ones and 2- or 3-substituted (Z)-4-hydroxy-but-2-en-1-yl acetates. This substrate-controlled formation of constitutional isomers method efficiently delivers a diversity of 7-vinyl-6,7-dihydro-4H-furo[3,4-c]pyran derivatives containing a quaternary or tertiary carbon center with precise regio- and diastereocontrol (dr > 20:1).","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"3 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoying Cao, Pingde Tao, Saisai Yu, Shengwen Yang, Shi-Wu Li
An efficient, reliable and atom-economic strategy employing azomethine ylides with isatin-derived trifluoromethyl acrylates via michael-mannich cascade reaction to afford spirooxindole-pyrrolidine products featuring vicinal quaternary carbon centers at C3 and C4 positions has been developed. The corresponding products with a broad substrate scope, good functional group tolerance and high stereoselectivity. In addition, subsequent amplification experiment and derivations further demonstrated the applicability of the synthetic methodology. Density functional theory calculation shed light on the reaction mechanism, demonstrating that it proceeded via a Michael-Mannich cascade reaction rather than a concerted [3+2] cycloaddition.
{"title":"Asymmetric Michael-Mannich Cascade Reaction of Azomethine Ylides with Isatin-derived Trifluoromethyl Acrylates Catalyzed by a Cu(I) Catalyst","authors":"Xiaoying Cao, Pingde Tao, Saisai Yu, Shengwen Yang, Shi-Wu Li","doi":"10.1039/d5qo01423a","DOIUrl":"https://doi.org/10.1039/d5qo01423a","url":null,"abstract":"An efficient, reliable and atom-economic strategy employing azomethine ylides with isatin-derived trifluoromethyl acrylates via michael-mannich cascade reaction to afford spirooxindole-pyrrolidine products featuring vicinal quaternary carbon centers at C3 and C4 positions has been developed. The corresponding products with a broad substrate scope, good functional group tolerance and high stereoselectivity. In addition, subsequent amplification experiment and derivations further demonstrated the applicability of the synthetic methodology. Density functional theory calculation shed light on the reaction mechanism, demonstrating that it proceeded via a Michael-Mannich cascade reaction rather than a concerted [3+2] cycloaddition.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"34 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The three-dimensional (3D) transformation of readily accessible planar molecules is of significant importance in drug synthesis. We herein report a photocatalytic strategy for the three-dimensional skeleton editing of carboxylic acids via sequential deoxygenation, precisely modulated by acid-base conditions. This approach efficiently constructs 3D lactam frameworks in a single step from a carboxylic acid center. It synergistically integrates radical decarboxylative acylation under basic conditions, acid-promoted intramolecular nucleophilic cyclization, and double bond isomerization. This strategy directly converts structurally diverse and stable carboxylic acids into biologically relevant unsaturated γ-lactams. It provides a concise route for drug synthesis, significantly shortening the synthesis of an endothelin receptor antagonist from eight steps (17% yield) to three steps (35% yield)
{"title":"Photocatalytic 3D Skeletal Editing of Carboxylic Acids via [4+1] Cyclization to Streamlined Synthesis of Unsaturated γ-Lactams","authors":"Jiahui Yu, Xiaohong Li, Liangbin Huang","doi":"10.1039/d5qo01548k","DOIUrl":"https://doi.org/10.1039/d5qo01548k","url":null,"abstract":"The three-dimensional (3D) transformation of readily accessible planar molecules is of significant importance in drug synthesis. We herein report a photocatalytic strategy for the three-dimensional skeleton editing of carboxylic acids via sequential deoxygenation, precisely modulated by acid-base conditions. This approach efficiently constructs 3D lactam frameworks in a single step from a carboxylic acid center. It synergistically integrates radical decarboxylative acylation under basic conditions, acid-promoted intramolecular nucleophilic cyclization, and double bond isomerization. This strategy directly converts structurally diverse and stable carboxylic acids into biologically relevant unsaturated γ-lactams. It provides a concise route for drug synthesis, significantly shortening the synthesis of an endothelin receptor antagonist from eight steps (17% yield) to three steps (35% yield)","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"82 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An efficient scandium catalyzed regio-and enantioselective 1,2-homopropargylic addition of β,γ-unsaturated α-ketoesters with 1-substituted allenylsilanes has been developed. This protocol enables the synthesis of a broad range of enantioenriched tertiary homopropargylic allylic alcohols in good yields with excellent enantioselectivities. The practicality of the method was further demonstrated through gram-scale reactions and versatile synthetic transformations of the product.
{"title":"Scandium-Catalyzed Asymmetric Addition of Allenylsilanes to β,γ-Unsaturated α-Ketoesters: Enantioselective Synthesis of Tertiary Homopropargylic Allylic Alcohols","authors":"Linxuan Wang, Xiangqing Jia, Chen-Ho Tung, Zhenghu Xu","doi":"10.1039/d5qo01584g","DOIUrl":"https://doi.org/10.1039/d5qo01584g","url":null,"abstract":"An efficient scandium catalyzed regio-and enantioselective 1,2-homopropargylic addition of β,γ-unsaturated α-ketoesters with 1-substituted allenylsilanes has been developed. This protocol enables the synthesis of a broad range of enantioenriched tertiary homopropargylic allylic alcohols in good yields with excellent enantioselectivities. The practicality of the method was further demonstrated through gram-scale reactions and versatile synthetic transformations of the product.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"42 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A Pd-catalyzed late-stage C–H olefination of [n]naphthalenophanes has been developed. This method enables the synthesis of a series of enantiomerically enriched [n]naphthalenophanes with high chemoselectivity. The origin of atropisomerism was investigated through thermal stability studies and reductive cleavage experiments. Moreover, a bifunctional thiourea organocatalyst derived from naphthalenophanes demonstrates promising potential in promoting Michael addition reactions, underscoring the versatility of cyclophanes in asymmetric synthesis. The synthesized [14]naphthalenophane 10 exhibited a dissymmetry factor (|glum|) of 1.0 × 10⁻³ and an absolute fluorescence quantum yield of 20.2%.
{"title":"Pd(II)-Catalyzed Atroposelective C−H Olefination to Access [n]Naphthalenophanes","authors":"Xiaoyu Wang, Jia Li, Quan Tang, Changgui Zhao","doi":"10.1039/d5qo01614b","DOIUrl":"https://doi.org/10.1039/d5qo01614b","url":null,"abstract":"A Pd-catalyzed late-stage C–H olefination of [n]naphthalenophanes has been developed. This method enables the synthesis of a series of enantiomerically enriched [n]naphthalenophanes with high chemoselectivity. The origin of atropisomerism was investigated through thermal stability studies and reductive cleavage experiments. Moreover, a bifunctional thiourea organocatalyst derived from naphthalenophanes demonstrates promising potential in promoting Michael addition reactions, underscoring the versatility of cyclophanes in asymmetric synthesis. The synthesized [14]naphthalenophane 10 exhibited a dissymmetry factor (|glum|) of 1.0 × 10⁻³ and an absolute fluorescence quantum yield of 20.2%.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"20 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Enantioselective hydroamination of acyclic conjugated dienes represents a straightforward approach to the synthesis of chiral allylic amines. While recent advances have demonstrated remarkable regio- and enantioselectivity for a range of N-nucleophiles, the development of methodologies for the less reactive aniline derivatives remains underexplored. Here, we report an enantiodivergent strategy for intermolecular hydroamination of acyclic 1,3-dienes using aniline nucleophiles. This Pd-catalyzed protocol employs an anthracene photodimer-derived monophosphine ligand and achiral acids as the essential additive, producing highly regioselective and enantio-enriched products with good substrate scope. Notably, variation of acid additives induces controlled inversion of the products’ absolute configuration.
{"title":"Enantiodivergent Intermolecular Hydroamination of Acyclic 1,3-Dienes Using Aniline Nucleophiles","authors":"Tianlei Ren, Huan Cong","doi":"10.1039/d5qo01645b","DOIUrl":"https://doi.org/10.1039/d5qo01645b","url":null,"abstract":"Enantioselective hydroamination of acyclic conjugated dienes represents a straightforward approach to the synthesis of chiral allylic amines. While recent advances have demonstrated remarkable regio- and enantioselectivity for a range of N-nucleophiles, the development of methodologies for the less reactive aniline derivatives remains underexplored. Here, we report an enantiodivergent strategy for intermolecular hydroamination of acyclic 1,3-dienes using aniline nucleophiles. This Pd-catalyzed protocol employs an anthracene photodimer-derived monophosphine ligand and achiral acids as the essential additive, producing highly regioselective and enantio-enriched products with good substrate scope. Notably, variation of acid additives induces controlled inversion of the products’ absolute configuration.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"53 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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