Pub Date : 2026-02-05DOI: 10.1021/acs.orglett.5c05370
Bingwei Hu, Xiao Zheng
N-Benzyl amides are important structural motifs in pharmaceuticals and natural products. The nucleophilic substitution reactions between aromatic nucleophiles and N-acyliminium ion precursors (N-acyl hemiaminal derivatives) represent one of the most common and powerful approaches. However, these protocols are typically limited by the scope of aromatic substrates or the requirement for air-sensitive reagents. Herein, we report a nickel-catalyzed reductive arylation reaction between N-acyl hemiaminals and readily available aryl halides, which enables the synthesis of a series of structurally diverse N-benzyl amide derivatives under mild conditions through simple operations. Mechanistic studies support a nickel-catalyzed cross-coupling pathway mediated by an N-acyliminium ion intermediate and exclude the participation of an N-acyl α-aminoalkyl radical.
n -苄基酰胺是药物和天然产物中重要的结构基序。芳香族亲核试剂与n -酰基半胺衍生物之间的亲核取代反应是最常见和最有效的方法之一。然而，这些方案通常受到芳香底物的范围或对空气敏感试剂的要求的限制。本文报道了一种镍催化的n -酰基半胺与芳烃卤化物之间的还原性芳基化反应，该反应可以在温和的条件下通过简单的操作合成一系列结构多样的n -苄基酰胺衍生物。机制研究支持镍催化的交叉偶联途径由n -酰基离子中间体介导，排除了n -酰基α-氨基烷基自由基的参与。
{"title":"Nickel-Catalyzed Reductive Arylation of N-Acyl Hemiaminals","authors":"Bingwei Hu, Xiao Zheng","doi":"10.1021/acs.orglett.5c05370","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c05370","url":null,"abstract":"<i>N</i>-Benzyl amides are important structural motifs in pharmaceuticals and natural products. The nucleophilic substitution reactions between aromatic nucleophiles and <i>N</i>-acyliminium ion precursors (<i>N</i>-acyl hemiaminal derivatives) represent one of the most common and powerful approaches. However, these protocols are typically limited by the scope of aromatic substrates or the requirement for air-sensitive reagents. Herein, we report a nickel-catalyzed reductive arylation reaction between <i>N</i>-acyl hemiaminals and readily available aryl halides, which enables the synthesis of a series of structurally diverse <i>N-</i>benzyl amide derivatives under mild conditions through simple operations. Mechanistic studies support a nickel-catalyzed cross-coupling pathway mediated by an <i>N</i>-acyliminium ion intermediate and exclude the participation of an <i>N</i>-acyl α-aminoalkyl radical.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"89 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122459","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 micellar palladium-catalyzed aqueous Buchwald–Hartwig amination has been developed, enabled by the self-assembly of amphiphilic copolymer polyethylene glycol–polyvinylethylene glycol (PEG–PVEG). Using 0.5 mol % BrettPhos-Pd-G3 as a catalyst, the aqueous amination showed broad a substrate scope, including aryl bromides, aryl chlorides, sterically hindered reaction partners, and amides. The practical utility of this micellar system was demonstrated by the gram-scale synthesis of a key pharmaceutical API intermediate and catalyst recycling.
{"title":"Pd-Catalyzed Aqueous Buchwald–Hartwig Amination with Amphiphilic Polymer PEG–PVEG","authors":"Qiong Chai, Fengming Zhang, Minghang Wang, Meiqi Li, Yong Jian Zhang","doi":"10.1021/acs.orglett.6c00030","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c00030","url":null,"abstract":"An efficient micellar palladium-catalyzed aqueous Buchwald–Hartwig amination has been developed, enabled by the self-assembly of amphiphilic copolymer polyethylene glycol–polyvinylethylene glycol (PEG–PVEG). Using 0.5 mol % BrettPhos-Pd-G3 as a catalyst, the aqueous amination showed broad a substrate scope, including aryl bromides, aryl chlorides, sterically hindered reaction partners, and amides. The practical utility of this micellar system was demonstrated by the gram-scale synthesis of a key pharmaceutical API intermediate and catalyst recycling.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"47 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122460","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 : 2026-02-05DOI: 10.1021/acs.orglett.6c00198
Sofaya Joshi, Arijit Sahoo, Ponneri C. Ravikumar
The controlled synthesis of both E- and Z-stereoisomers remains a long-standing challenge in organic synthesis, yet it is important for accessing structurally and functionally diverse enamides. This study demonstrates the synthesis of E- and Z-hydrophenoxylated enamides using a nickel(II)-catalyst alongside phenols. The stereochemical outcome is controlled by the ligand environment and temperature. Ligands promote syn-addition via a keteniminium intermediate to afford the E-isomer, and elevated temperatures enable efficient E→Z isomerization to deliver the Z-isomer with excellent selectivity. This efficient and versatile strategy exhibits a broad substrate scope and functional group tolerance, including acids, bioactive estrone derivatives, sesamol, and related compounds.
{"title":"Ligand- and Temperature-Controlled Stereodivergent Nickel-Catalyzed Hydrophenoxylation of Ynamides","authors":"Sofaya Joshi, Arijit Sahoo, Ponneri C. Ravikumar","doi":"10.1021/acs.orglett.6c00198","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c00198","url":null,"abstract":"The controlled synthesis of both <i>E</i>- and <i>Z</i>-stereoisomers remains a long-standing challenge in organic synthesis, yet it is important for accessing structurally and functionally diverse enamides. This study demonstrates the synthesis of <i>E</i>- and <i>Z</i>-hydrophenoxylated enamides using a nickel(II)-catalyst alongside phenols. The stereochemical outcome is controlled by the ligand environment and temperature. Ligands promote <i>syn</i>-addition via a keteniminium intermediate to afford the <i>E</i>-isomer, and elevated temperatures enable efficient <i>E→Z</i> isomerization to deliver the <i>Z</i>-isomer with excellent selectivity. This efficient and versatile strategy exhibits a broad substrate scope and functional group tolerance, including acids, bioactive estrone derivatives, sesamol, and related compounds.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"25 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122463","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 : 2026-02-05DOI: 10.1021/acs.orglett.6c00194
Yunlong Qin, Yuanyuan Zeng, Weihan Wang, Congcong Zhang, Jianing Zhang, Zerong Guo, Yang Zhao, Qilin Wang
A visible-light-driven skeletal editing strategy that converts readily available isoquinolinium salts into phenylnaphthyl sulfones via a formal CN-to-CC atom-pair swap is presented. The process is triggered by an isoquinolinium–carbonate electron donor–acceptor (EDA) complex that, upon blue-light excitation, undergoes single-electron transfer to initiate a polarity-mismatched (4 + 2) radical annulation with alkynyl sulfones. The reaction proceeds at room temperature without external photocatalysts, tolerates diverse functional groups (including halides), and furnishes the targeted diarylsulfones with high efficiency.
{"title":"Light Illuminates Polarity-Mismatched Cycloaddition to Convert Isoquinoliniums into Phenylnaphthyl Sulfones","authors":"Yunlong Qin, Yuanyuan Zeng, Weihan Wang, Congcong Zhang, Jianing Zhang, Zerong Guo, Yang Zhao, Qilin Wang","doi":"10.1021/acs.orglett.6c00194","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c00194","url":null,"abstract":"A visible-light-driven skeletal editing strategy that converts readily available isoquinolinium salts into phenylnaphthyl sulfones via a formal CN-to-CC atom-pair swap is presented. The process is triggered by an isoquinolinium–carbonate electron donor–acceptor (EDA) complex that, upon blue-light excitation, undergoes single-electron transfer to initiate a polarity-mismatched (4 + 2) radical annulation with alkynyl sulfones. The reaction proceeds at room temperature without external photocatalysts, tolerates diverse functional groups (including halides), and furnishes the targeted diarylsulfones with high efficiency.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"68 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122462","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}
Electrochemical peptide synthesis using triaryl phosphines has been shown to be a promising approach for reducing the amount of waste in peptide synthesis. However, there is room for improvement from the viewpoint of the substrate scope. In this research, we succeeded in improving the reaction efficiency by utilizing a halide mediator. This method is applicable to highly sterically hindered amino acids, such as N-methyl phenylalanine. We also achieved the synthesis of icatibant, consisting of 10 amino acid residues.
{"title":"Halide-Mediated Electrochemical Peptide Synthesis Applicable to Highly Sterically Hindered Amino Acids","authors":"Shingo Shinjo-Nagahara, Goki Hiratsuka, Yohei Okada, Yoshikazu Kitano, Kazuhiro Chiba","doi":"10.1021/acs.orglett.5c05139","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c05139","url":null,"abstract":"Electrochemical peptide synthesis using triaryl phosphines has been shown to be a promising approach for reducing the amount of waste in peptide synthesis. However, there is room for improvement from the viewpoint of the substrate scope. In this research, we succeeded in improving the reaction efficiency by utilizing a halide mediator. This method is applicable to highly sterically hindered amino acids, such as <i>N</i>-methyl phenylalanine. We also achieved the synthesis of icatibant, consisting of 10 amino acid residues.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"8 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115603","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 : 2026-02-05DOI: 10.1021/acs.orglett.5c05278
Anukriti Singhal, Partha Pratim Sen, Sudipta Raha Roy
A visible-light-mediated metallomimetic charge transfer strategy for the amination of the inert C(sp3)–H bond of ethers has been demonstrated. This organocatalytic strategy utilizes a polyaromatic odd alternant hydrocarbon-based photocatalyst exhibiting a Lewis acidic property and, thereby, mimics the transition-metal-like charge transfer process that drives the single-electron transfer process, enabling the C–H bond functionalization under mild and sustainable conditions. The method offers a mechanistically distinct platform for light-driven C–N bond formation, expanding the scope of photoinduced organic transformations.
{"title":"Organocatalytic Visible-Light-Driven Metallomimetic Charge Transfer Process: Application in C(sp3)–N Bond Formation","authors":"Anukriti Singhal, Partha Pratim Sen, Sudipta Raha Roy","doi":"10.1021/acs.orglett.5c05278","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c05278","url":null,"abstract":"A visible-light-mediated metallomimetic charge transfer strategy for the amination of the inert C(sp<sup>3</sup>)–H bond of ethers has been demonstrated. This organocatalytic strategy utilizes a polyaromatic odd alternant hydrocarbon-based photocatalyst exhibiting a Lewis acidic property and, thereby, mimics the transition-metal-like charge transfer process that drives the single-electron transfer process, enabling the C–H bond functionalization under mild and sustainable conditions. The method offers a mechanistically distinct platform for light-driven C–N bond formation, expanding the scope of photoinduced organic transformations.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"276 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115606","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 : 2026-02-05DOI: 10.1021/acs.orglett.5c05336
Natalia Cano-Sampaio, Juan R. Del Valle
Cyclization of serine and threonine-containing N-hydroxy dipeptides under Mitsunobu conditions affords 1,3-oxazinanes via N-acylimine intermediates. Synthesis of the heterocyclic core of the threoglucin family of antibiotics proceeds in high yield to afford the α-quaternary amidoketal dipeptide. The described method provides convenient entry into a new class of constrained peptides featuring Cα-heteroatom substitution.
{"title":"Synthesis of the Threoglucin 1,3-Oxazinane Core via Cyclothreonine Rearrangement","authors":"Natalia Cano-Sampaio, Juan R. Del Valle","doi":"10.1021/acs.orglett.5c05336","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c05336","url":null,"abstract":"Cyclization of serine and threonine-containing <i>N</i>-hydroxy dipeptides under Mitsunobu conditions affords 1,3-oxazinanes via N-acylimine intermediates. Synthesis of the heterocyclic core of the threoglucin family of antibiotics proceeds in high yield to afford the α-quaternary amidoketal dipeptide. The described method provides convenient entry into a new class of constrained peptides featuring Cα-heteroatom substitution.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"91 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115611","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 photocatalyzed decarboxylative hydroalkylation approach has been developed, providing efficient and stereoselective access to synthetically challenging Z-configured allylamine derivatives from carboxylic acids and alkynes. The reaction is mediated by an iron catalyst, offering a green, environmentally benign, and highly atom-economical process. Moreover, this protocol can be extended to the reaction with alkenes to furnish arylamines and aryl ethers. Overall, this strategy establishes a versatile synthetic platform for the functionalization of unsaturated hydrocarbons.
{"title":"Iron-Catalyzed Photoredox Decarboxylative Hydroalkylation with Alkynes and Alkenes","authors":"Zhenzhu Hu, Haoran Yuan, Yuxin Lin, Jing Peng, Xiaoxiao Ma, Rongqiang Li","doi":"10.1021/acs.orglett.5c05310","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c05310","url":null,"abstract":"A photocatalyzed decarboxylative hydroalkylation approach has been developed, providing efficient and stereoselective access to synthetically challenging <i>Z</i>-configured allylamine derivatives from carboxylic acids and alkynes. The reaction is mediated by an iron catalyst, offering a green, environmentally benign, and highly atom-economical process. Moreover, this protocol can be extended to the reaction with alkenes to furnish arylamines and aryl ethers. Overall, this strategy establishes a versatile synthetic platform for the functionalization of unsaturated hydrocarbons.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"83 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122458","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}
Herein, we report a strategy for the methylalkylation of unactivated alkenes via synergistic photoredox/nickel catalysis. This mild transformation employs di-tert-butyl peroxide (DTBP) as a bifunctional reagent, which serves simultaneously as a hydrogen atom transfer (HAT) reagent and a source of methyl radical, thereby facilitating the coupling of malonate-derived radicals with alkenes. By integrating HAT with radical selectivity control, the method enables the formation of two C(sp3)–C(sp3) bonds in a single synthetic operation, offering a streamlined route to valuable three-dimensional scaffolds.
{"title":"Methylalkylation of Unactivated Alkenes by Photoredox/Nickel Catalytic HAT and Radical Selectivity Control","authors":"Hui Zhang, Ying-Jie Wang, Hao-Wen Jiang, Peng-Fei Xu","doi":"10.1021/acs.orglett.5c05168","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c05168","url":null,"abstract":"Herein, we report a strategy for the methylalkylation of unactivated alkenes via synergistic photoredox/nickel catalysis. This mild transformation employs di-<i>tert</i>-butyl peroxide (DTBP) as a bifunctional reagent, which serves simultaneously as a hydrogen atom transfer (HAT) reagent and a source of methyl radical, thereby facilitating the coupling of malonate-derived radicals with alkenes. By integrating HAT with radical selectivity control, the method enables the formation of two C(sp<sup>3</sup>)–C(sp<sup>3</sup>) bonds in a single synthetic operation, offering a streamlined route to valuable three-dimensional scaffolds.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"1 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115604","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 : 2026-02-05DOI: 10.1021/acs.orglett.6c00021
Xuling Chen, Changzhen Zhai, Yan Guo, Lilei Cheng, Tianli Wang, Pengfei Li
The catalytic construction of medium-sized rings, particularly in an enantioselective manner, remains a significant challenge due to inherent entropic penalties and stereocontrol issues, yet it is an area of great interest. Herein, we disclose the development of a general (6 + n) annulation strategy leveraging 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates as versatile precursors for the efficient assembly of medium-sized rings. Through palladium-catalyzed formal (6 + 5) and (6 + 3) cycloadditions with vinylethylene carbonates (VECs) or trimethylenemethanes (TMMs), we have successfully achieved the regioselective construction of 11- and 9-membered heterocycles, respectively. Of particular note, the enantioselective (6 + 3) annulation, facilitated by rational chiral ligand design, afforded enantioenriched 9-membered heterocycles (up to 75% yield and 93% ee). Featuring readily available starting materials, structural modularity, and mild reaction conditions, this methodology represents a robust platform for accessing synthetically valuable medium-sized ring systems, including their enantioselective variants, thereby addressing a long-standing limitation in organic synthesis.
{"title":"Enantioselective Synthesis of Medium-Sized Rings via a General Palladium-Catalyzed (6 + n) Annulation Platform","authors":"Xuling Chen, Changzhen Zhai, Yan Guo, Lilei Cheng, Tianli Wang, Pengfei Li","doi":"10.1021/acs.orglett.6c00021","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c00021","url":null,"abstract":"The catalytic construction of medium-sized rings, particularly in an enantioselective manner, remains a significant challenge due to inherent entropic penalties and stereocontrol issues, yet it is an area of great interest. Herein, we disclose the development of a general (6 + <i>n</i>) annulation strategy leveraging 2-(4<i>H</i>-benzo[<i>d</i>][1,3]oxazin-4-yl)acrylates as versatile precursors for the efficient assembly of medium-sized rings. Through palladium-catalyzed formal (6 + 5) and (6 + 3) cycloadditions with vinylethylene carbonates (VECs) or trimethylenemethanes (TMMs), we have successfully achieved the regioselective construction of 11- and 9-membered heterocycles, respectively. Of particular note, the enantioselective (6 + 3) annulation, facilitated by rational chiral ligand design, afforded enantioenriched 9-membered heterocycles (up to 75% yield and 93% ee). Featuring readily available starting materials, structural modularity, and mild reaction conditions, this methodology represents a robust platform for accessing synthetically valuable medium-sized ring systems, including their enantioselective variants, thereby addressing a long-standing limitation in organic synthesis.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"177 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122310","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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