The β-fluoroalkylamine motif holds great value in drug development due to the unique properties imparted by fluorine incorporation. Currently, the most promising way for accessing this motif involves alkene aminofluorination, which heavily relies on transition-metal (TM) catalysts. Inspired by a control experiment reported in a related previous study, we herein rationally design a novel metal-free strategy for alkene aminofluorinations. Quantum chemical calculations revealed that the desired aminofluorination pathway (ΔΔG‡ = 38.5 kcal/mol) is inherently less favorable than the competing alkene polymerization side reaction (ΔΔG‡ = 18.7 kcal/mol). To overcome this challenge, we utilized the Energy Decomposition Analysis with Natural Orbitals for Chemical Valence (EDA-NOCV) method to gain insight into various electrophilic amination reagents and found that N-halogeno-amines with weakened N-X bonds (X = F, Cl, Br, I) could be promising candidates for system optimization. Among these, N-I-amines proved most effective, steering the reaction toward aminofluorination. Further reaction kinetics simulations confirmed that the optimized system can achieve an 80% yield of β-fluoroalkylamines within 3 h at 343 K, which is comparable to experimentally reported transition metal-catalyzed system. Therefore, this study introduces a sustainable, metal-free approach for alkene aminofluorination via a radical chain mechanism, offering a greener alternative to the traditional TM-catalyzed process.
{"title":"Mechanistic Insights into Copper-Catalyzed Alkene Aminofluorination and Rational Design of a Metal-Free Strategy.","authors":"Yihao Zhang,Shuqi Zhang,Jiying Xu,Shuhao Ge,Shipeng Sun,Gernot Frenking,Lili Zhao","doi":"10.1021/acs.joc.5c00672","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00672","url":null,"abstract":"The β-fluoroalkylamine motif holds great value in drug development due to the unique properties imparted by fluorine incorporation. Currently, the most promising way for accessing this motif involves alkene aminofluorination, which heavily relies on transition-metal (TM) catalysts. Inspired by a control experiment reported in a related previous study, we herein rationally design a novel metal-free strategy for alkene aminofluorinations. Quantum chemical calculations revealed that the desired aminofluorination pathway (ΔΔG‡ = 38.5 kcal/mol) is inherently less favorable than the competing alkene polymerization side reaction (ΔΔG‡ = 18.7 kcal/mol). To overcome this challenge, we utilized the Energy Decomposition Analysis with Natural Orbitals for Chemical Valence (EDA-NOCV) method to gain insight into various electrophilic amination reagents and found that N-halogeno-amines with weakened N-X bonds (X = F, Cl, Br, I) could be promising candidates for system optimization. Among these, N-I-amines proved most effective, steering the reaction toward aminofluorination. Further reaction kinetics simulations confirmed that the optimized system can achieve an 80% yield of β-fluoroalkylamines within 3 h at 343 K, which is comparable to experimentally reported transition metal-catalyzed system. Therefore, this study introduces a sustainable, metal-free approach for alkene aminofluorination via a radical chain mechanism, offering a greener alternative to the traditional TM-catalyzed process.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"91 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Herein, we developed a cascade alkylarylation reaction of N-arylacrylamides with carboxylic acids to construct 3,3-disubstituted oxindole derivatives. The transformation employs inexpensive iron photocatalysis under visible light irradiation. A broad scope of carboxylic acids and N-arylacrylamides could be well tolerated. Additionally, several synthesized oxindole compounds showed the suppression of nitric oxide generation in LPS-induced RAW 264.7 macrophage cells.
{"title":"Synthesis of 3,3-Disubstituted Oxindoles through Cascade Alkylarylation of N-Arylacrylamides with Carboxylic Acids Enabled by Iron Photocatalysis.","authors":"Xinran Zhang,Shuxin Yang,Jiaxing Lv,Wanpeng Lu,Yi Bi,Xianhe Fang","doi":"10.1021/acs.joc.5c00970","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00970","url":null,"abstract":"Herein, we developed a cascade alkylarylation reaction of N-arylacrylamides with carboxylic acids to construct 3,3-disubstituted oxindole derivatives. The transformation employs inexpensive iron photocatalysis under visible light irradiation. A broad scope of carboxylic acids and N-arylacrylamides could be well tolerated. Additionally, several synthesized oxindole compounds showed the suppression of nitric oxide generation in LPS-induced RAW 264.7 macrophage cells.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"103 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenlong Ren,Yang Liu,Jintao Ou,Jinzi Huang,Xujian Sheng,Yian Shi
Efficient Pd- or Rh-catalyzed regioselective hydroformylation processes with HCO2Na/Ac2O or HCO2H/Ac2O are described. The linear aldehydes can be obtained in good yields with high l/b ratios. These two systems (HCO2Na/Ac2O vs HCO2H/Ac2O) give generally comparable results with their own advantages for certain substrates. In general, the Pd-catalyzed formylation reaction gives higher regioselectivities for vinyl arenes, while the Rh-catalyzed process gives higher regioselectivities for certain alkyl terminal olefins. All of these formylation processes are simple to operate and provide complementary methods for the synthesis of aldehydes from olefins.
描述了高效Pd或rh催化的HCO2Na/Ac2O或HCO2H/Ac2O区域选择性氢甲酰化过程。线性醛的产率高，l/b比高。这两种体系（HCO2Na/Ac2O vs HCO2H/Ac2O）对某些底物具有各自的优势，结果大致相当。一般来说，pd催化的甲酰化反应对乙烯基芳烃具有较高的区域选择性，而rh催化的甲酰化反应对某些烷基末端烯烃具有较高的区域选择性。所有这些甲酰化过程操作简单，并为从烯烃合成醛提供了补充方法。
{"title":"Pd, Rh-Catalyzed Regioselective Hydroformylation of Olefins with Formic Acid and Its Salts.","authors":"Wenlong Ren,Yang Liu,Jintao Ou,Jinzi Huang,Xujian Sheng,Yian Shi","doi":"10.1021/acs.joc.5c00597","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00597","url":null,"abstract":"Efficient Pd- or Rh-catalyzed regioselective hydroformylation processes with HCO2Na/Ac2O or HCO2H/Ac2O are described. The linear aldehydes can be obtained in good yields with high l/b ratios. These two systems (HCO2Na/Ac2O vs HCO2H/Ac2O) give generally comparable results with their own advantages for certain substrates. In general, the Pd-catalyzed formylation reaction gives higher regioselectivities for vinyl arenes, while the Rh-catalyzed process gives higher regioselectivities for certain alkyl terminal olefins. All of these formylation processes are simple to operate and provide complementary methods for the synthesis of aldehydes from olefins.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"5 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bingru Song,Jiangtao Cai,Dazhong Yuan,Fengjiao Xiang,Jinming Zhou,Xiaoli Han
A cost-effective method for directly halogenating isoquinolines at the C4 position has been developed through a one-pot sequence involving Boc2O-mediated dearomatization, electrophilic halogenation (X = Cl, Br, I), and acid-promoted rearomatization. This reaction exhibited high C4 site selectivity, efficiently affording 4-halogenated isoquinolines, and demonstrated good functional group tolerance at C5-C8. In addition, the C-X bond-containing products could serve as versatile synthetic intermediates for further modification of isoquinolines, including Suzuki coupling, Sonogashira coupling, and Stille coupling.
{"title":"Direct C4 Halogenation of Isoquinolines via a Boc2O-Mediated Dearomatization Strategy.","authors":"Bingru Song,Jiangtao Cai,Dazhong Yuan,Fengjiao Xiang,Jinming Zhou,Xiaoli Han","doi":"10.1021/acs.joc.5c00535","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00535","url":null,"abstract":"A cost-effective method for directly halogenating isoquinolines at the C4 position has been developed through a one-pot sequence involving Boc2O-mediated dearomatization, electrophilic halogenation (X = Cl, Br, I), and acid-promoted rearomatization. This reaction exhibited high C4 site selectivity, efficiently affording 4-halogenated isoquinolines, and demonstrated good functional group tolerance at C5-C8. In addition, the C-X bond-containing products could serve as versatile synthetic intermediates for further modification of isoquinolines, including Suzuki coupling, Sonogashira coupling, and Stille coupling.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xianming Wang, Chenggang Zao, Zhuang Tang, Tao Hu, Jianbin Xu, Sifeng Li, Baomin Fan
A visible-light-driven, iron-catalyzed decarboxylative radical alkylation/cyclization strategy for synthesizing alkyl-substituted ring-fused quinazolin-4(3H)-ones has been developed. This method employs secondary and tertiary aliphatic carboxylic acids as alkyl radical precursors under mild conditions achieving moderate to excellent yields (up to 95%) across 35 diverse substrates.This protocol offers a practical and versatile route to access polycyclic quinazolinones with high atom economy and operational simplicity.
{"title":"Photoinduced Iron-Catalyzed Decarboxylative Radical Alkylation/Cyclization of N-Alkenyl Quinazolin-4(3H)-ones","authors":"Xianming Wang, Chenggang Zao, Zhuang Tang, Tao Hu, Jianbin Xu, Sifeng Li, Baomin Fan","doi":"10.1021/acs.joc.5c00765","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00765","url":null,"abstract":"A visible-light-driven, iron-catalyzed decarboxylative radical alkylation/cyclization strategy for synthesizing alkyl-substituted ring-fused quinazolin-4(3<i>H</i>)-ones has been developed. This method employs secondary and tertiary aliphatic carboxylic acids as alkyl radical precursors under mild conditions achieving moderate to excellent yields (up to 95%) across 35 diverse substrates.This protocol offers a practical and versatile route to access polycyclic quinazolinones with high atom economy and operational simplicity.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"227 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The palladium-catalyzed [3 + 2] cycloaddition of vinylethylene carbonates (VECs) with ketones presents significant challenges with only sporadic examples reported. Herein, we have developed an in situ generation strategy enabling the engagement of polycarbonyl-based ketones in [3 + 2] cycloaddition with VECs. This approach utilizes diazo compounds as latent carbonyl precursors and employs DMSO as both the solvent and oxidant, bypassing issues associated with the isolation of easily hydrated polycarbonyl compounds. By this protocol, various 1,3-dioxolanes bearing two quaternary stereocenters were readily constructed.
{"title":"Palladium-Catalyzed [3 + 2] Cycloaddition of Vinylethylene Carbonates with In Situ Generated Ketones from Diazo Compounds and DMSO","authors":"Zemin Pan, Liying Fu, Zhilun Zhou, Chuan Zhu, Chi Zhang, Chao Feng","doi":"10.1021/acs.joc.5c00718","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00718","url":null,"abstract":"The palladium-catalyzed [3 + 2] cycloaddition of vinylethylene carbonates (VECs) with ketones presents significant challenges with only sporadic examples reported. Herein, we have developed an in situ generation strategy enabling the engagement of polycarbonyl-based ketones in [3 + 2] cycloaddition with VECs. This approach utilizes diazo compounds as latent carbonyl precursors and employs DMSO as both the solvent and oxidant, bypassing issues associated with the isolation of easily hydrated polycarbonyl compounds. By this protocol, various 1,3-dioxolanes bearing two quaternary stereocenters were readily constructed.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"26 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A concise synthesis of (−)-lepadiformine A was achieved using a readily available (S)-pyroglutaminol derivative. This approach involves a Brønsted acid-catalyzed cyclization of N-acyliminium ions using diene and acetic acid for the construction of the azaspiro ring system and a stereoconvergent Tsuji–Trost cyclization to generate a substituted piperidine scaffold with excellent diastereoselectivity.
{"title":"Total Synthesis of (−)-Lepadiformine A via Stereo-convergent Tsuji–Trost Cyclization","authors":"Raju Sen, Janakiram Vaitla","doi":"10.1021/acs.joc.5c00921","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00921","url":null,"abstract":"A concise synthesis of (−)-lepadiformine A was achieved using a readily available (<i>S</i>)-pyroglutaminol derivative. This approach involves a Brønsted acid-catalyzed cyclization of <i>N</i>-acyliminium ions using diene and acetic acid for the construction of the azaspiro ring system and a stereoconvergent Tsuji–Trost cyclization to generate a substituted piperidine scaffold with excellent diastereoselectivity.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"12 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A facile base-mediated cyclization and rearrangement of enamine thianthrenium salts for the construction of indole compounds is disclosed. In this reaction, sequential cleavage of two C-S bonds and subsequent formation of C-N and C-C bonds furnish a series of substituted indoles in moderate to good yields. Furthermore, an efficient late-stage functionalization of enamine compounds is established. The method features a wide substrate scope, good functional group tolerance, and low-cost starting materials.
{"title":"Rearrangement and Cyclization of Enamine Thianthrenium Salts: Effective Access to Substituted Indoles.","authors":"Zhixin Ren, Chengli Deng, Zi-Jing Bai, Wei Shi, Peng Gao","doi":"10.1021/acs.joc.5c00299","DOIUrl":"10.1021/acs.joc.5c00299","url":null,"abstract":"<p><p>A facile base-mediated cyclization and rearrangement of enamine thianthrenium salts for the construction of indole compounds is disclosed. In this reaction, sequential cleavage of two C-S bonds and subsequent formation of C-N and C-C bonds furnish a series of substituted indoles in moderate to good yields. Furthermore, an efficient late-stage functionalization of enamine compounds is established. The method features a wide substrate scope, good functional group tolerance, and low-cost starting materials.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":"7661-7672"},"PeriodicalIF":3.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-13Epub Date: 2025-06-04DOI: 10.1021/acs.joc.5c00537
Kelly Lee, Xsingyi Lee, Ci-Yi Zhou, Yung-Lan Chu, Cheng-Kun Lin
We report an efficient and scalable synthesis of 5-(hydroxymethyl)oxazolidin-2-ones using tert-butyl carbonate as a nucleophile in a Boc2O-mediated epoxide ring-opening cascade. Optimization identified Et3N as key to high yields, with electron-withdrawing aryl groups further enhancing efficiency (up to 91%). Mechanistic studies support the nucleophilic role of tert-butyl carbonate. This versatile method enables access to pharmaceutically relevant compounds, including intermediates for Linezolid, highlighting its value in medicinal chemistry.
{"title":"<i>tert</i>-Butyl Carbonate as a Nucleophile in Epoxide Ring Opening: A Cascade Synthesis of 5-(Hydroxymethyl)oxazolidin-2-one.","authors":"Kelly Lee, Xsingyi Lee, Ci-Yi Zhou, Yung-Lan Chu, Cheng-Kun Lin","doi":"10.1021/acs.joc.5c00537","DOIUrl":"10.1021/acs.joc.5c00537","url":null,"abstract":"<p><p>We report an efficient and scalable synthesis of 5-(hydroxymethyl)oxazolidin-2-ones using <i>tert</i>-butyl carbonate as a nucleophile in a Boc<sub>2</sub>O-mediated epoxide ring-opening cascade. Optimization identified Et<sub>3</sub>N as key to high yields, with electron-withdrawing aryl groups further enhancing efficiency (up to 91%). Mechanistic studies support the nucleophilic role of <i>tert</i>-butyl carbonate. This versatile method enables access to pharmaceutically relevant compounds, including intermediates for Linezolid, highlighting its value in medicinal chemistry.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":"7976-7981"},"PeriodicalIF":3.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While ortho-C-H activation has been well explored, meta-C-H functionalization of phenols remains challenging due to regioselectivity constraints. Here, we introduce a site-selective meta-C-H olefination strategy using an aliphatic nitrile template under mild room-temperature conditions. This approach leverages nitrile-metal interactions to enable efficient C-H activation, overcoming the harsh conditions required in traditional methods. With a broad substrate scope and high efficiency, this method has been successfully applied to drug-like and natural product derivatives, delivering high yields and selectivities.
{"title":"The <i>meta</i>-Selective C-H Functionalization of Phenol Derivatives Using a Nitrile-Based Directing Group.","authors":"Kurella Mounika, Dasari Srinivas, Gedu Satyanarayana","doi":"10.1021/acs.joc.5c00812","DOIUrl":"10.1021/acs.joc.5c00812","url":null,"abstract":"<p><p>While <i>ortho</i>-C-H activation has been well explored, <i>meta</i>-C-H functionalization of phenols remains challenging due to regioselectivity constraints. Here, we introduce a site-selective <i>meta</i>-C-H olefination strategy using an aliphatic nitrile template under mild room-temperature conditions. This approach leverages nitrile-metal interactions to enable efficient C-H activation, overcoming the harsh conditions required in traditional methods. With a broad substrate scope and high efficiency, this method has been successfully applied to drug-like and natural product derivatives, delivering high yields and selectivities.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":"7888-7901"},"PeriodicalIF":3.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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