We report an efficient Rh(III)-catalyzed [3 + 3] annulation reaction between cyclopropenones and iodonium ylides. This process proceeds via a ring-opening/ring-closing mechanism to afford a diverse range of 2,5-dihydrochromenedione derivatives. The reaction demonstrates a broad substrate scope and good functional group tolerance, with moderate to excellent yields. The synthetic utility of this methodology is further highlighted by a gram-scale synthesis and successful derivatization of the resulting 2,5-dihydrochromenediones.
{"title":"Rh(III)-Catalyzed [3 + 3] Annulation of Cyclopropenones with Iodonium Ylides for the Synthesis of 2,5-Dihydrochromenediones","authors":"Yu Xu,Zhilai Zhang,Shaolin Yang,Yu Zhang,Menglin Peng,Huimin Hu,Yuanzheng Wei,Li Chen,Fuchao Yu","doi":"10.1021/acs.joc.5c02861","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02861","url":null,"abstract":"We report an efficient Rh(III)-catalyzed [3 + 3] annulation reaction between cyclopropenones and iodonium ylides. This process proceeds via a ring-opening/ring-closing mechanism to afford a diverse range of 2,5-dihydrochromenedione derivatives. The reaction demonstrates a broad substrate scope and good functional group tolerance, with moderate to excellent yields. The synthetic utility of this methodology is further highlighted by a gram-scale synthesis and successful derivatization of the resulting 2,5-dihydrochromenediones.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"398 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111190","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}
Yuta Ito,Ryotaro Yamashita,Yasufumi Fuchi,Yoshiyuki Hari
In solid-phase oligonucleotide (ON) synthesis, a capping step is beneficial for obtaining a pure full-length ON. Acetic anhydride (Ac2O) is widely used as a conventional capping reagent. However, several problems associated with acetyl capping have been reported. In this study, we developed a novel phosphoramidite-type capping reagent, ethano N,N-dicyclohexylphosphoramidite (EDCP), which was obtained as an easy-to-handle crystalline solid. EDCP, with a sterically accessible phosphorus atom, exhibited a higher capping ability than Ac2O and diethyl N,N-diisopropylphosphoramidite, which was previously reported as a phosphoramidite-type capping reagent. Furthermore, capping-derived byproducts were not detected during solid-phase ON synthesis using EDCP. These results indicate that EDCP is a useful capping reagent that can serve as an alternative to Ac2O and has potential applications in ON synthesis.
{"title":"Ethano N,N-Dicyclohexylphosphoramidite: A Capping Reagent for Solid-Phase Oligonucleotide Synthesis","authors":"Yuta Ito,Ryotaro Yamashita,Yasufumi Fuchi,Yoshiyuki Hari","doi":"10.1021/acs.joc.5c02637","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02637","url":null,"abstract":"In solid-phase oligonucleotide (ON) synthesis, a capping step is beneficial for obtaining a pure full-length ON. Acetic anhydride (Ac2O) is widely used as a conventional capping reagent. However, several problems associated with acetyl capping have been reported. In this study, we developed a novel phosphoramidite-type capping reagent, ethano N,N-dicyclohexylphosphoramidite (EDCP), which was obtained as an easy-to-handle crystalline solid. EDCP, with a sterically accessible phosphorus atom, exhibited a higher capping ability than Ac2O and diethyl N,N-diisopropylphosphoramidite, which was previously reported as a phosphoramidite-type capping reagent. Furthermore, capping-derived byproducts were not detected during solid-phase ON synthesis using EDCP. These results indicate that EDCP is a useful capping reagent that can serve as an alternative to Ac2O and has potential applications in ON synthesis.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"31 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111191","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 variety of sterically hindered and functionalized amines were easily constructed by transition-metal-free alkylation under mild conditions. A reactive conjugated anion intermediate was possibly involved.
{"title":"A Mild Protocol for Highly Congested and Functionalized C(sp<sup>3</sup>)-N Bonds Construction.","authors":"Yifei Jiang, Lili Wu, Chengming Wang","doi":"10.1021/acs.joc.5c02608","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02608","url":null,"abstract":"<p><p>A variety of sterically hindered and functionalized amines were easily constructed by transition-metal-free alkylation under mild conditions. A reactive conjugated anion intermediate was possibly involved.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117234","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}
Diazo compounds are hazardous to handle in batch operations due to their toxicity and explosive decomposition to nitrogen gas, often causing exothermic runaway reactions. To address these challenges, a photoflow sulfur alkylation of sulfenamides using diazo compounds was developed, enabling rapid (7.5 min) and safe access to sulfilimines in 76–95% yields with broad functional group tolerance (22 molecules). The method is robust, scalable, and applicable to gram-scale synthesis and late-stage drug modification.
{"title":"Photoflow Sulfur Alkylation of Sulfenamides for Direct Access of S-Methyl Sulfoximines","authors":"Mandeep Purwa,Ajay K. Singh","doi":"10.1021/acs.joc.5c02927","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02927","url":null,"abstract":"Diazo compounds are hazardous to handle in batch operations due to their toxicity and explosive decomposition to nitrogen gas, often causing exothermic runaway reactions. To address these challenges, a photoflow sulfur alkylation of sulfenamides using diazo compounds was developed, enabling rapid (7.5 min) and safe access to sulfilimines in 76–95% yields with broad functional group tolerance (22 molecules). The method is robust, scalable, and applicable to gram-scale synthesis and late-stage drug modification.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"39 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111189","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}
Jongheon Jeong,Solhye Choe,Jun Hee Lee,Eunsung Lee
We report a mild and practical iron-catalyzed protocol for the borylation of aryl fluorides using commercially available FeCl3, a β-diketiminate ligand, and HBpin as a boron source. The method exhibits broad substrate scope with excellent yields (up to 99%), including non-π-extended fluoroarenes, heterocycles, and substrates with unprotected phenolic OH groups, operating efficiently under ambient to elevated temperatures. Comprehensive mechanistic studies reveal that the reaction proceeds via in situ formation of Grignard intermediates and iron nanoparticles, establishing a heterogeneous catalytic pathway distinct from previous homogeneous systems. This protocol offers a cost-effective, atom-economical route to arylboronates using earth-abundant metal catalysis, significantly expanding the synthetic utility of C–F bond functionalization under mild conditions.
{"title":"Heterogeneous Iron-Catalyzed Borylation of Aryl Fluorides","authors":"Jongheon Jeong,Solhye Choe,Jun Hee Lee,Eunsung Lee","doi":"10.1021/acs.joc.5c02752","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02752","url":null,"abstract":"We report a mild and practical iron-catalyzed protocol for the borylation of aryl fluorides using commercially available FeCl3, a β-diketiminate ligand, and HBpin as a boron source. The method exhibits broad substrate scope with excellent yields (up to 99%), including non-π-extended fluoroarenes, heterocycles, and substrates with unprotected phenolic OH groups, operating efficiently under ambient to elevated temperatures. Comprehensive mechanistic studies reveal that the reaction proceeds via in situ formation of Grignard intermediates and iron nanoparticles, establishing a heterogeneous catalytic pathway distinct from previous homogeneous systems. This protocol offers a cost-effective, atom-economical route to arylboronates using earth-abundant metal catalysis, significantly expanding the synthetic utility of C–F bond functionalization under mild conditions.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"23 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111192","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 protocol of C–C direct coupling of the C-2 position of 3-acetylaminofuran, derived from biomass, with quinoxalinone was reported for the first time. This study confirmed that the quinoxalinone free radical, generated by acid protonation and illumination, is used to perform C–C dehydrogenation coupling with 3-acetylaminofuran (3AF), in which oxygen participates in the reaction process. On this basis, acid-catalyzed deacetylation was used to obtain the corresponding aminofuran derivatives. Intramolecular dehydration can be realized to form an imine tetracyclic compound.
{"title":"Synthesis of Aminofuranquinoxalinones from a Two-Step Cascade: Photoinduced TFA-Promoted Coupling of Quinoxalin-2(1H)-ones with 3-Acetamidofuran and Hydrolysis","authors":"Peipei Ma,Guangyu Yang,Yuan Wang,Hongli Wu,Haifeng Gan,Fei Cao,Jianliang Zhu","doi":"10.1021/acs.joc.5c02986","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02986","url":null,"abstract":"A protocol of C–C direct coupling of the C-2 position of 3-acetylaminofuran, derived from biomass, with quinoxalinone was reported for the first time. This study confirmed that the quinoxalinone free radical, generated by acid protonation and illumination, is used to perform C–C dehydrogenation coupling with 3-acetylaminofuran (3AF), in which oxygen participates in the reaction process. On this basis, acid-catalyzed deacetylation was used to obtain the corresponding aminofuran derivatives. Intramolecular dehydration can be realized to form an imine tetracyclic compound.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"108 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111188","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}
RNF4, a RING-type E3 ubiquitin ligase, targets polySUMOylated proteins for ubiquitination and subsequent proteasomal degradation. The ability to chemically synthesize RNF4 will enable future studies of its structure and biological function, particularly its role in degrading the oncoprotein PML-RARα in acute promyelocytic leukemia. To achieve this, we performed a total chemical synthesis of RNF4 using sequential native chemical ligation. The presence of nine cysteine residues enables stepwise ligation of five peptide fragments to assemble the full-length protein. Two synthetic strategies were explored: the first employed a convergent C-to-N ligation, while the second used an N-to-C ligation. In the convergent C-to-N approach, cysteine residues were protected with acetamidomethyl groups to prevent side reactions during ligation, although this required multiple deprotection and purification steps. Conversely, the N-to-C synthesis method proceeded efficiently without cysteine protection, thereby simplifying the workflow and reducing the number of purification steps. This research presents a reliable and accessible method for the complete chemical synthesis of RNF4, addressing significant challenges in synthesizing large proteins and opening up new opportunities for future biological research.
{"title":"Total Chemical Synthesis of RNF4 by Sequential Native Chemical Ligation: C-To-N Versus N-To-C Strategies","authors":"Rajesh Pallava,Saed Bisher,Ashraf Brik","doi":"10.1021/acs.joc.5c03224","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03224","url":null,"abstract":"RNF4, a RING-type E3 ubiquitin ligase, targets polySUMOylated proteins for ubiquitination and subsequent proteasomal degradation. The ability to chemically synthesize RNF4 will enable future studies of its structure and biological function, particularly its role in degrading the oncoprotein PML-RARα in acute promyelocytic leukemia. To achieve this, we performed a total chemical synthesis of RNF4 using sequential native chemical ligation. The presence of nine cysteine residues enables stepwise ligation of five peptide fragments to assemble the full-length protein. Two synthetic strategies were explored: the first employed a convergent C-to-N ligation, while the second used an N-to-C ligation. In the convergent C-to-N approach, cysteine residues were protected with acetamidomethyl groups to prevent side reactions during ligation, although this required multiple deprotection and purification steps. Conversely, the N-to-C synthesis method proceeded efficiently without cysteine protection, thereby simplifying the workflow and reducing the number of purification steps. This research presents a reliable and accessible method for the complete chemical synthesis of RNF4, addressing significant challenges in synthesizing large proteins and opening up new opportunities for future biological research.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"54 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111173","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}
Qifu Deng,Tingting Zhu,Shilin Chen,Lifang Tian,Zixuan Hu,Zhangyi Wang,Hongjun Zhu,Chao Feng,Yufeng Li
A catalyst-free photoaerobic protocol has been developed for the highly selective oxidation of thioethers in the presence of acetic acid. Based on DFT calculations, the thioether-O2 complex is identified as the photosensitizer to trigger the radical cascade. This protocol enables the green synthesis of alkyl-aryl, diaryl, and dialkyl sulfoxides, including pharmaceutical molecules.
{"title":"Photooxidation of Thioethers to Sulfoxides and the Self-Initiating Mechanism Evidenced by DFT Calculations","authors":"Qifu Deng,Tingting Zhu,Shilin Chen,Lifang Tian,Zixuan Hu,Zhangyi Wang,Hongjun Zhu,Chao Feng,Yufeng Li","doi":"10.1021/acs.joc.5c02776","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02776","url":null,"abstract":"A catalyst-free photoaerobic protocol has been developed for the highly selective oxidation of thioethers in the presence of acetic acid. Based on DFT calculations, the thioether-O2 complex is identified as the photosensitizer to trigger the radical cascade. This protocol enables the green synthesis of alkyl-aryl, diaryl, and dialkyl sulfoxides, including pharmaceutical molecules.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"66 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111257","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}
Monday Peter Ajisafe, Idrees Idrees Aliyu, Bright Bassey Oyom, Eman Fayad, Dalal Nasser Binjawhar, Hua-Li Qin
A one-pot protocol for the addition of naturally rich alcohols, carbon disulfide and 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF) for the selective synthesis of a class of novel xanthate-functionalized allylic sulfonyl fluorides has been developed, affording isolated yields up to 99%. Subsequent SuFEx transformations and the modification of natural and pharmaceutical compounds were achieved with remarkable efficiency, offering promising applications in biological and medicinal chemistry.
{"title":"Selective Construction of Xanthate-Functionalized Allylic Sulfonyl Fluorides via a Three-Component Process","authors":"Monday Peter Ajisafe, Idrees Idrees Aliyu, Bright Bassey Oyom, Eman Fayad, Dalal Nasser Binjawhar, Hua-Li Qin","doi":"10.1021/acs.joc.5c03022","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03022","url":null,"abstract":"A one-pot protocol for the addition of naturally rich alcohols, carbon disulfide and 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF) for the selective synthesis of a class of novel xanthate-functionalized allylic sulfonyl fluorides has been developed, affording isolated yields up to 99%. Subsequent SuFEx transformations and the modification of natural and pharmaceutical compounds were achieved with remarkable efficiency, offering promising applications in biological and medicinal chemistry.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"8 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110701","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}
Density functional theory computations were performed to study the reaction mechanism and origins of stereoselectivity of the reaction between β-bromoenals and a pyrazole-dione catalyzed by a chiral N-heterocyclic carbene (NHC). The catalytic cycle for producing spiropyrazolone-butenolide proceeds via six steps: (1) nucleophilic attack of the NHC on β-bromoenal; (2) 1,2-proton transfer; (3) C–C bond formation; (4) C–Br bond cleavage; (5) deprotonation accompanied by cyclization, and (6) elimination of the NHC. Different from previously proposed cyclization through C–O bond formation that determines the stereochemistry, our results demonstrate the C–C bond forming step is the stereoselectivity-determining step, leading preferentially to the S-configuration spiropyrazolone-butenolide. Additionally, the Brønsted acid (DBU·H+) facilitates not only the proton transfer but also the NHC elimination. The calculated barriers for proton transfer without DBU·H+ (45.1 kcal/mol) are significantly higher than that with DBU·H+ (14.3 kcal/mol). Furthermore, the presence of DBU·H+ also decreased the barrier for NHC elimination by 5.8 kcal/mol. NCI and AIM analyses were conducted to reveal the key factors controlling stereoselectivity. These findings provide valuable insights for understanding the mechanism and designing highly selective catalytic reactions in the future.
{"title":"Mechanisms and Origins of Stereoselectivity of the NHC-Catalyzed Reaction between β-Bromoenals and Pyrazole-diones: A DFT Study","authors":"Yan Li,Hecheng Hu,Zhiqiang Zhang","doi":"10.1021/acs.joc.5c02717","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02717","url":null,"abstract":"Density functional theory computations were performed to study the reaction mechanism and origins of stereoselectivity of the reaction between β-bromoenals and a pyrazole-dione catalyzed by a chiral N-heterocyclic carbene (NHC). The catalytic cycle for producing spiropyrazolone-butenolide proceeds via six steps: (1) nucleophilic attack of the NHC on β-bromoenal; (2) 1,2-proton transfer; (3) C–C bond formation; (4) C–Br bond cleavage; (5) deprotonation accompanied by cyclization, and (6) elimination of the NHC. Different from previously proposed cyclization through C–O bond formation that determines the stereochemistry, our results demonstrate the C–C bond forming step is the stereoselectivity-determining step, leading preferentially to the S-configuration spiropyrazolone-butenolide. Additionally, the Brønsted acid (DBU·H+) facilitates not only the proton transfer but also the NHC elimination. The calculated barriers for proton transfer without DBU·H+ (45.1 kcal/mol) are significantly higher than that with DBU·H+ (14.3 kcal/mol). Furthermore, the presence of DBU·H+ also decreased the barrier for NHC elimination by 5.8 kcal/mol. NCI and AIM analyses were conducted to reveal the key factors controlling stereoselectivity. These findings provide valuable insights for understanding the mechanism and designing highly selective catalytic reactions in the future.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"23 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111258","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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