A copper-catalyzed domino reaction of arylidene isoxazolones with 2-(pyridin-2-yl)acetate derivatives under ball-milling conditions has been developed. This protocol provides a rapid and economic approach to constructing a vast variety of biologically important 3-acylindolizines with remarkable functional group tolerance.
{"title":"Copper-Catalyzed Domino Reaction of Arylidene Isoxazolones with 2-(Pyridin-2-yl)acetate Derivatives under Ball Milling: A Rapid and Economical Synthesis of 3-Acylindolizines","authors":"Xing-Wang Hu, Luan-Ting Wu, Zeng-Yang He, Jiang-Tao Hu, Shi-Zhu Fan, Ze Zhang, Hui Xu","doi":"10.1021/acs.orglett.5c04683","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04683","url":null,"abstract":"A copper-catalyzed domino reaction of arylidene isoxazolones with 2-(pyridin-2-yl)acetate derivatives under ball-milling conditions has been developed. This protocol provides a rapid and economic approach to constructing a vast variety of biologically important 3-acylindolizines with remarkable functional group tolerance.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"6 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704744","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}
Pub Date : 2025-12-08DOI: 10.1021/acs.orglett.5c04507
Sina Rezazadeh, Raphael S. Kim, Donald A. Watson
A stereoselective method for alkylating nitroalkanes with α-bromoketones using nickel/photoredox dual catalysis is described. The mild and functional-group-tolerant conditions allow the formation of complex and highly enantioenriched β-nitroketone products that hold promising utility as precursors for the formation of biologically relevant compounds.
{"title":"Photoredox/Nickel Dual-Catalyzed Asymmetric C-Alkylation of Nitroalkanes with α-Bromoketones","authors":"Sina Rezazadeh, Raphael S. Kim, Donald A. Watson","doi":"10.1021/acs.orglett.5c04507","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04507","url":null,"abstract":"A stereoselective method for alkylating nitroalkanes with α-bromoketones using nickel/photoredox dual catalysis is described. The mild and functional-group-tolerant conditions allow the formation of complex and highly enantioenriched β-nitroketone products that hold promising utility as precursors for the formation of biologically relevant compounds.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"6 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704834","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 unprecedented visible-light-induced strain-release-driven aminopyridylation of bicyclo[1.1.0]butanes with bench-stable and easily accessible N-aminopyridinium ylides was developed. The photoredox-catalyzed transformation proceeds through amidyl-radical-mediated scission of the central C-C bond of bicyclo[1.1.0]butanes followed by intramolecular annulation and homolytic N-N bond cleavage. This cascade reaction delivers biologically and pharmaceutically prominent pyridine-containing polysubstituted cyclobutanecarboxamides in a regio- and diastereoseletive manner. The cyclobutanecarboxamides have a high fraction of sp3-hybridized carbon atoms. This reaction features mild metal-free conditions, excellent functional group compatibility, high atom economy, and potential for downstream late-stage functionalization.
{"title":"Photoredox-Catalyzed Strain-Release-Driven Aminopyridylation of Bicyclo[1.1.0]butanes with N-Aminopyridinium Ylides.","authors":"Hai-Xiang Gao,Yuanhang Li,Mengyu Wu,Xiaoyu Zhu,Chi Zhang,Yu Zhang,Kai Zhao,Patrick J Walsh,Chao Feng","doi":"10.1021/acs.orglett.5c04578","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04578","url":null,"abstract":"An unprecedented visible-light-induced strain-release-driven aminopyridylation of bicyclo[1.1.0]butanes with bench-stable and easily accessible N-aminopyridinium ylides was developed. The photoredox-catalyzed transformation proceeds through amidyl-radical-mediated scission of the central C-C bond of bicyclo[1.1.0]butanes followed by intramolecular annulation and homolytic N-N bond cleavage. This cascade reaction delivers biologically and pharmaceutically prominent pyridine-containing polysubstituted cyclobutanecarboxamides in a regio- and diastereoseletive manner. The cyclobutanecarboxamides have a high fraction of sp3-hybridized carbon atoms. This reaction features mild metal-free conditions, excellent functional group compatibility, high atom economy, and potential for downstream late-stage functionalization.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"133 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696677","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 thia-Paternò-Büchi reactions represent a valuable yet underexploited transformation compared to analogous [2+2] photocycloadditions involving olefins, carbonyls, and imines. Herein, we present visible light thia-Paternò-Büchi reactions of xanthates derived from tryptophol and tryptamine, enabling the synthesis of various tetracyclic indolines contiguously fused with thietane and additional O/N heterocycles. Mechanistic studies indicate that energy transfer activation of the thiocarbonyl chromophore is instrumental in promoting reactivity, which differs from the established cycloadditions utilizing triplet indoles.
{"title":"Visible Light-Mediated Thia-Paternò-Büchi Reaction of Indoles through Energy Transfer: Synthesis of Thietane-Fused Polycyclic Indolines.","authors":"Xixiang Yu,Jianjian Huang,Tengfei Pang,Weijun Yao,Guojiao Wu,Fangrui Zhong","doi":"10.1021/acs.orglett.5c04721","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04721","url":null,"abstract":"The thia-Paternò-Büchi reactions represent a valuable yet underexploited transformation compared to analogous [2+2] photocycloadditions involving olefins, carbonyls, and imines. Herein, we present visible light thia-Paternò-Büchi reactions of xanthates derived from tryptophol and tryptamine, enabling the synthesis of various tetracyclic indolines contiguously fused with thietane and additional O/N heterocycles. Mechanistic studies indicate that energy transfer activation of the thiocarbonyl chromophore is instrumental in promoting reactivity, which differs from the established cycloadditions utilizing triplet indoles.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"4 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696901","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}
Pub Date : 2025-12-08DOI: 10.1021/acs.orglett.5c04405
Xian-Liang Zeng, Wencong Yang, Yi-Fan Du, Hang Li
Comparative genomics identified a nonribosomal peptide synthetase gene cluster (wpa), spanning two genomic scaffolds, responsible for waspergillamide A (1) in Aspergillus sp. CMB-W031. Pathway reconstitution revealed the cytochrome P450 WpaD as a gatekeeper: its presence directs biosynthesis toward the depsi-tetrapeptide diketopiperazine 2, which spontaneously dehydrates to 1 under weak acid condition, whereas its absence yields linear tetrapeptide 4. Pathway characterization further enabled structural revision of 1 and confirmed the conservation of p-nitrobenzoic acid biosynthesis in fungi.
{"title":"Biosynthesis of Waspergillamide A Involves Unclustered Genes and a depsi-Tetrapeptide Diketopiperazine-Forming NRPS","authors":"Xian-Liang Zeng, Wencong Yang, Yi-Fan Du, Hang Li","doi":"10.1021/acs.orglett.5c04405","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04405","url":null,"abstract":"Comparative genomics identified a nonribosomal peptide synthetase gene cluster (<i>wpa</i>), spanning two genomic scaffolds, responsible for waspergillamide A (<b>1</b>) in <i>Aspergillus</i> sp. CMB-W031. Pathway reconstitution revealed the cytochrome P450 WpaD as a gatekeeper: its presence directs biosynthesis toward the <i>depsi</i>-tetrapeptide diketopiperazine <b>2</b>, which spontaneously dehydrates to <b>1</b> under weak acid condition, whereas its absence yields linear tetrapeptide <b>4</b>. Pathway characterization further enabled structural revision of <b>1</b> and confirmed the conservation of <i>p</i>-nitrobenzoic acid biosynthesis in fungi.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"93 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145697085","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}
Methanol is a prominent basic C1 synthon in organic synthesis. Methods for direct coupling of methanol through C-N bond formation have limited precedents, despite their wide potential applications in organic and medicinal chemistry. Herein, we report a bisbenzoxazoline-Cu/nitroxyl-catalyzed method for aerobic oxidative coupling of methanol and amines for the direct synthesis of formamides. Secondary and primary amines were explored in this reaction, providing broad access to tertiary and secondary formamides, respectively. This easily available catalyst system is not sensitive to water and shows high functional group tolerance and broad synthetic utility for late-stage modification of various bioactive complex drugs.
甲醇是有机合成中重要的碱性C1合成物。通过C-N键形成直接偶联甲醇的方法尽管在有机化学和药物化学中有广泛的潜在应用，但其先例有限。在此，我们报道了一种双苯并恶唑- cu /硝基催化甲醇和胺的有氧氧化偶联直接合成甲酰胺的方法。该反应探索了仲胺和伯胺，分别为叔甲酰胺和仲甲酰胺提供了广泛的途径。该催化剂体系对水不敏感，具有较高的官能团耐受性，在各种生物活性复合物药物的后期修饰方面具有广泛的合成用途。
{"title":"Copper/Nitroxyl-Catalyzed Oxidative Coupling of Methanol and Amines to Formamides.","authors":"Hong-Yu Li,Hu-Cheng Yang,Hao-Xiang Hu,Jun Shi,Biaobiao Jiang,Wei Wu,Hai Ren","doi":"10.1021/acs.orglett.5c04401","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04401","url":null,"abstract":"Methanol is a prominent basic C1 synthon in organic synthesis. Methods for direct coupling of methanol through C-N bond formation have limited precedents, despite their wide potential applications in organic and medicinal chemistry. Herein, we report a bisbenzoxazoline-Cu/nitroxyl-catalyzed method for aerobic oxidative coupling of methanol and amines for the direct synthesis of formamides. Secondary and primary amines were explored in this reaction, providing broad access to tertiary and secondary formamides, respectively. This easily available catalyst system is not sensitive to water and shows high functional group tolerance and broad synthetic utility for late-stage modification of various bioactive complex drugs.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"29 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704581","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}
Pub Date : 2025-12-08DOI: 10.1021/acs.orglett.5c04159
Debasish Jana,Geetanjali S Sontakke,Chandra M R Volla
Herein, we report Ru(II)-catalyzed divergent annulations of propargyl cyclic carbonates with arylpyrazolidinones via C-H bond activation. The combination of base and solvent was pivotal in dictating the reaction pathway, enabling selective access to either (4+3) or (3+2) annulated nitrogen-containing heterocycles with high regioselectivity. While AgOAc in DCM promoted the three-center reactivity of propargyl carbonate, NaOAc in toluene induced two-center reactivity. Both protocols exhibited broad substrate scope and excellent functional group tolerance. The synthetic utility was demonstrated through late-stage modification of biologically active derivatives, gram-scale synthesis, and postfunctionalizations of the products to other valuable motifs.
{"title":"Ru(II)-Catalyzed Divergent C-H Annulations of Propargyl Cyclic Carbonates.","authors":"Debasish Jana,Geetanjali S Sontakke,Chandra M R Volla","doi":"10.1021/acs.orglett.5c04159","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04159","url":null,"abstract":"Herein, we report Ru(II)-catalyzed divergent annulations of propargyl cyclic carbonates with arylpyrazolidinones via C-H bond activation. The combination of base and solvent was pivotal in dictating the reaction pathway, enabling selective access to either (4+3) or (3+2) annulated nitrogen-containing heterocycles with high regioselectivity. While AgOAc in DCM promoted the three-center reactivity of propargyl carbonate, NaOAc in toluene induced two-center reactivity. Both protocols exhibited broad substrate scope and excellent functional group tolerance. The synthetic utility was demonstrated through late-stage modification of biologically active derivatives, gram-scale synthesis, and postfunctionalizations of the products to other valuable motifs.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"11 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704586","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}
Pub Date : 2025-12-08DOI: 10.1021/acs.orglett.5c04713
Xianmao Liu,Qian Ni,Yaqi Chen,Xueyu Liu,Yuanhong Ma
Herein, nickel-catalyzed decyanative reductive cross-coupling of benzyl nitriles with aryl chlorides has been developed. The current protocol features a wide scope, good functional group compatibility, and excellent chemoselectivity, thus providing a powerful alternative to the known methods for the synthesis of diarylmethanes. Mechanistic studies demonstrate the formation of benzyl-nickel species as the key intermediate in the catalytic cycle.
{"title":"Nickel-Catalyzed Decyanative Reductive Coupling of Benzyl Nitriles with Aryl Chlorides toward the Synthesis of Diarylmethanes.","authors":"Xianmao Liu,Qian Ni,Yaqi Chen,Xueyu Liu,Yuanhong Ma","doi":"10.1021/acs.orglett.5c04713","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04713","url":null,"abstract":"Herein, nickel-catalyzed decyanative reductive cross-coupling of benzyl nitriles with aryl chlorides has been developed. The current protocol features a wide scope, good functional group compatibility, and excellent chemoselectivity, thus providing a powerful alternative to the known methods for the synthesis of diarylmethanes. Mechanistic studies demonstrate the formation of benzyl-nickel species as the key intermediate in the catalytic cycle.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"4 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696680","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}
Pub Date : 2025-12-08DOI: 10.1021/acs.orglett.5c04436
Devin T Mickles,Courtney Westlund,Justin S Marcum,Simon J Meek
A catalytic multicomponent coupling method for the site-selective and diastereoselective preparation of secondary amines containing tertiary and quaternary carbon centers is disclosed. Reactions employ simple reagents (imines, 1,3-dienes, and organoborons) and are promoted by a readily available nickel-catalyst supported by a pyridyl-phosphine ligand. The influence of diene substitution is shown to be a key factor in controlling the selectivity between quaternary and tertiary carbon center formation.
{"title":"Diastereo- and Site-Selective Synthesis of Bishomoallyl Amines by Nickel-Catalyzed Multicomponent Couplings with Imines and Dienes Enabled by a Pyridyl-Phosphine Ligand.","authors":"Devin T Mickles,Courtney Westlund,Justin S Marcum,Simon J Meek","doi":"10.1021/acs.orglett.5c04436","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04436","url":null,"abstract":"A catalytic multicomponent coupling method for the site-selective and diastereoselective preparation of secondary amines containing tertiary and quaternary carbon centers is disclosed. Reactions employ simple reagents (imines, 1,3-dienes, and organoborons) and are promoted by a readily available nickel-catalyst supported by a pyridyl-phosphine ligand. The influence of diene substitution is shown to be a key factor in controlling the selectivity between quaternary and tertiary carbon center formation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"47 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696672","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}
Pub Date : 2025-12-08DOI: 10.1021/acs.orglett.5c04625
Clara Uriel,Alberto Hernández,Natalia Casado,Jorge Bañuelos,Eduardo Duque-Redondo,Lourdes Infantes,Inmaculada García-Moreno,Ana M Gómez,J Cristóbal López
We report the synthesis of the novel 2,6-di(hydroxymethyl)-1,3,5,7-tetramethyl-8-phenyl BODIPY and its utility in efficient Lewis-acid-catalyzed dehydrative nucleophilic substitution reactions. This diol, readily prepared via a formylation/reduction sequence from the corresponding tetramethyl BODIPY, undergoes bisfunctionalization with a variety of nucleophiles to yield 2,6-substituted BODIPY fluorophores. Notably, the use of trimethylsilyl azide as a nucleophile provides a "clickable" BODIPY, suited for bioconjugation. Furthermore, employing BODIPY or BOPHY as a nucleophile successfully led to a BODIPY trimer and the first example of bis(BOPHY)-BODIPY, respectively, with the latter showcasing its potential as a novel light-harvesting fluorophore.
{"title":"Acid-Catalyzed Dehydrative Nucleophilic Substitutions of 2,6-Di(hydroxymethyl) BODIPYs: A Platform for BODIPY Functionalization.","authors":"Clara Uriel,Alberto Hernández,Natalia Casado,Jorge Bañuelos,Eduardo Duque-Redondo,Lourdes Infantes,Inmaculada García-Moreno,Ana M Gómez,J Cristóbal López","doi":"10.1021/acs.orglett.5c04625","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04625","url":null,"abstract":"We report the synthesis of the novel 2,6-di(hydroxymethyl)-1,3,5,7-tetramethyl-8-phenyl BODIPY and its utility in efficient Lewis-acid-catalyzed dehydrative nucleophilic substitution reactions. This diol, readily prepared via a formylation/reduction sequence from the corresponding tetramethyl BODIPY, undergoes bisfunctionalization with a variety of nucleophiles to yield 2,6-substituted BODIPY fluorophores. Notably, the use of trimethylsilyl azide as a nucleophile provides a \"clickable\" BODIPY, suited for bioconjugation. Furthermore, employing BODIPY or BOPHY as a nucleophile successfully led to a BODIPY trimer and the first example of bis(BOPHY)-BODIPY, respectively, with the latter showcasing its potential as a novel light-harvesting fluorophore.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"4 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696685","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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