Pub Date : 2025-12-11DOI: 10.1021/acs.orglett.5c04639
Jian-Liang Yu,Ya-Wen Zuo,Yi-Gang Yang,Ruo-Xing Jin,Xi-Sheng Wang
Given the significance of propargyl trifluoromethyl scaffolds in drug discovery, the development of efficient synthetic approaches for their construction remains a pressing challenge. In this work, we present copper-catalyzed Sonogashira-type cross-coupling between trifluoroalkyl bromides and alkynes. This reaction proceeds under mild conditions with excellent regioselectivity, exhibits broad functional group tolerance across both aryl- and alkyl-substituted derivatives, and provides a practical and efficient approach for the synthesis of CF3-incorporated alkynes.
{"title":"Copper-Catalyzed Sonogashira-Type Cross-Coupling of Trifluoroalkyl Bromides with Alkynes.","authors":"Jian-Liang Yu,Ya-Wen Zuo,Yi-Gang Yang,Ruo-Xing Jin,Xi-Sheng Wang","doi":"10.1021/acs.orglett.5c04639","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04639","url":null,"abstract":"Given the significance of propargyl trifluoromethyl scaffolds in drug discovery, the development of efficient synthetic approaches for their construction remains a pressing challenge. In this work, we present copper-catalyzed Sonogashira-type cross-coupling between trifluoroalkyl bromides and alkynes. This reaction proceeds under mild conditions with excellent regioselectivity, exhibits broad functional group tolerance across both aryl- and alkyl-substituted derivatives, and provides a practical and efficient approach for the synthesis of CF3-incorporated alkynes.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"6 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728553","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 : 2025-12-11DOI: 10.1021/acs.orglett.5c04508
Priyambada Prusty, Masilamani Jeganmohan
Herein, we developed a cobalt-catalyzed three-component strategy to synthesize α-quaternary aliphatic nitriles in good yields. This protocol proceeds through the sequential addition of indoles, dienes, and N-cyanosuccinimide. The scope of this method has been extensively explored with various substituted N-pyrimidyl-indoles. Terminally substituted diene and 1,2-disubstituted diene also participated in the reaction. Notably, N-pyridyl-2-pyridones are also compatible with this protocol. The synthesized nitrile product was further converted into a tetrazole derivative. A plausible reaction mechanism is proposed to account for the present transformation.
{"title":"Co(III)-Catalyzed Three-Component Cascade for the Synthesis of α-Quaternary Acyclic Nitriles via C–H Bond Activation","authors":"Priyambada Prusty, Masilamani Jeganmohan","doi":"10.1021/acs.orglett.5c04508","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04508","url":null,"abstract":"Herein, we developed a cobalt-catalyzed three-component strategy to synthesize α-quaternary aliphatic nitriles in good yields. This protocol proceeds through the sequential addition of indoles, dienes, and <i>N</i>-cyanosuccinimide. The scope of this method has been extensively explored with various substituted <i>N</i>-pyrimidyl-indoles. Terminally substituted diene and 1,2-disubstituted diene also participated in the reaction. Notably, <i>N</i>-pyridyl-2-pyridones are also compatible with this protocol. The synthesized nitrile product was further converted into a tetrazole derivative. A plausible reaction mechanism is proposed to account for the present transformation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"38 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718386","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}
Visible light activation enables unprecedented synthetic transformations but typically requires precious metal complexes or elaborate organic dyes to absorb visible light and initiate reactivity. Herein, we report a more general, efficient, and economical catalytic platform for decarboxylative α-amino alkylation of heterocyclic compounds by a catalytic photoactive electron donor–acceptor (EDA) complex through n−π stacking and H-bonding, using readily available 1,4-diazabicyclo[2.2.2]octane (DABCO). Mechanistic studies and DFT calculations indicated that DABCO acts as a highly efficient dual-function catalyst, promoting both EDA complex formation and the intermolecular HAT process. This operationally simple, visible light-mediated platform is efficiently applied in the decarboxylative functionalization of primary, secondary, and tertiary α-amino acid esters with heterocyclic compounds, such as azauracil, coumarin, chromone, and quinoxalin-2(1H)-one, in good to excellent yields.
{"title":"Photoinduced α-Amino Alkylation of Heterocyclic Compounds via Catalytic Electron Donor–Acceptor Complexes","authors":"Zhi-Qiang Zhu, Wen-Yi Zhang, Qian-Qian Xu, Huo-Yu Rao, Zhang-Gao Le, Zhen-Zhen Xu, Zong-Bo Xie","doi":"10.1021/acs.orglett.5c04537","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04537","url":null,"abstract":"Visible light activation enables unprecedented synthetic transformations but typically requires precious metal complexes or elaborate organic dyes to absorb visible light and initiate reactivity. Herein, we report a more general, efficient, and economical catalytic platform for decarboxylative α-amino alkylation of heterocyclic compounds by a catalytic photoactive electron donor–acceptor (EDA) complex through n−π stacking and H-bonding, using readily available 1,4-diazabicyclo[2.2.2]octane (DABCO). Mechanistic studies and DFT calculations indicated that DABCO acts as a highly efficient dual-function catalyst, promoting both EDA complex formation and the intermolecular HAT process. This operationally simple, visible light-mediated platform is efficiently applied in the decarboxylative functionalization of primary, secondary, and tertiary α-amino acid esters with heterocyclic compounds, such as azauracil, coumarin, chromone, and quinoxalin-2(1<i>H</i>)-one, in good to excellent yields.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"49 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718387","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}
This work establishes a chemoselective peptide stapling method via bis-urea bridge formation between native amino groups, using diisocyanates as linchpin reagents. This protocol achieves macrocyclization across 19- to 41-membered rings through either lysine–lysine or N-terminus-lysine cross-linking, while preserving sensitive residues including Arg, His, Trp, Tyr, Ser, Glu and Cys. Evaluation of the resulting stapled peptides revealed improved membrane permeability and increased stability against both chemical and proteolytic degradation. Representative stapled peptides demonstrated potent cytotoxicity in several cancer cell lines and induced dose-dependent apoptotic responses in selected tumor models.
{"title":"Synthesis of Bis-urea-Bridged Cyclopeptides via Stapling of Unprotected Peptides","authors":"Wenfang Xiong, Peiru Chen, Jinyao Liu, Yixin Liao, Meilin Tang, Jinwu Zhao","doi":"10.1021/acs.orglett.5c04412","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04412","url":null,"abstract":"This work establishes a chemoselective peptide stapling method via bis-urea bridge formation between native amino groups, using diisocyanates as linchpin reagents. This protocol achieves macrocyclization across 19- to 41-membered rings through either lysine–lysine or N-terminus-lysine cross-linking, while preserving sensitive residues including Arg, His, Trp, Tyr, Ser, Glu and Cys. Evaluation of the resulting stapled peptides revealed improved membrane permeability and increased stability against both chemical and proteolytic degradation. Representative stapled peptides demonstrated potent cytotoxicity in several cancer cell lines and induced dose-dependent apoptotic responses in selected tumor models.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"224 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718385","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 : 2025-12-11DOI: 10.1021/acs.orglett.5c04653
Xiao-Lin He, Dan Liao, Jun-Hao Huang, Xing-Lei Zhou, Xiao-Wei Zhang
We present a palladium/norbornene-catalyzed ortho-alkoxycarbonylation of aryl iodides utilizing simple chloroformates as efficient alkoxycarbonyl sources, enabling concomitant ipso-functionalization encompassing alkenylation, cyanation, hydrogenation, and arylation. This methodology addresses fundamental limitations of conventional approaches by eliminating the necessity for preactivated reagents, demonstrating improved atom economy, and accommodating a broad spectrum of substrates, including both electron-rich and electron-deficient aryl iodides, diverse olefin terminators, and structurally complex or chiral chloroformates. Notably, the reaction employs a novel indolylphosphine ligand, which has been demonstrated to be essential for achieving enhanced reactivity and selectivity under mild conditions.
{"title":"Palladium/Norbornene-Catalyzed ortho-Alkoxycarbonylation of Aryl Iodides Enabled Directly by Chloroformates","authors":"Xiao-Lin He, Dan Liao, Jun-Hao Huang, Xing-Lei Zhou, Xiao-Wei Zhang","doi":"10.1021/acs.orglett.5c04653","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04653","url":null,"abstract":"We present a palladium/norbornene-catalyzed <i>ortho</i>-alkoxycarbonylation of aryl iodides utilizing simple chloroformates as efficient alkoxycarbonyl sources, enabling concomitant <i>ipso</i>-functionalization encompassing alkenylation, cyanation, hydrogenation, and arylation. This methodology addresses fundamental limitations of conventional approaches by eliminating the necessity for preactivated reagents, demonstrating improved atom economy, and accommodating a broad spectrum of substrates, including both electron-rich and electron-deficient aryl iodides, diverse olefin terminators, and structurally complex or chiral chloroformates. Notably, the reaction employs a novel indolylphosphine ligand, which has been demonstrated to be essential for achieving enhanced reactivity and selectivity under mild conditions.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"144 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718389","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 : 2025-12-11DOI: 10.1021/acs.orglett.5c04775
Kunlong Yang, Menghan Qin, Yurong Tang, Yunfei Cai
A catalytic asymmetric difluoroalkylation/rearrangement of alkenylfurans with difluoroalkyl sulfones and anilines has been developed. This method employs cooperative photoredox/Brønsted acid catalysis, enabling efficient and versatile synthesis of difluoroalkyl-containing 4-aminocyclopentenones with excellent diastereo- and enantioselectivities.
{"title":"Photoredox/Brønsted Acid-Catalyzed Asymmetric Difluoroalkylation/Rearrangement of Alkenylfurans","authors":"Kunlong Yang, Menghan Qin, Yurong Tang, Yunfei Cai","doi":"10.1021/acs.orglett.5c04775","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04775","url":null,"abstract":"A catalytic asymmetric difluoroalkylation/rearrangement of alkenylfurans with difluoroalkyl sulfones and anilines has been developed. This method employs cooperative photoredox/Brønsted acid catalysis, enabling efficient and versatile synthesis of difluoroalkyl-containing 4-aminocyclopentenones with excellent diastereo- and enantioselectivities.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"29 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718390","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 first red-light-driven Minisci reaction of heteroarenes with a readily available BCP-derived redox-active ester (RAE) has been developed, employing mesoporous graphitic carbon nitride (mpg-C3N4) as a recyclable heterogeneous photocatalyst. The heterogeneous nature of mpg-C3N4 allows for easy recovery and reuse, maintaining a high catalytic activity over five consecutive cycles. This approach provides efficient access to heterocycle-functionalized BCP scaffolds, which are of high interest in medicinal chemistry as potential bioisosteres of biaryl scaffolds. Notably, the photoredox reactions proceed smoothly under sunlight irradiation, and a successful scale-up demonstration highlights its promise for industrial applications.
{"title":"Red-Light-Driven Recyclable mpg-C3N4-Catalyzed Minisci Reaction: Access to Heterocycle-Substituted Bicyclo[1.1.1]pentanes","authors":"Chenya Wang,Jianyang Dong,Yajun Sun,Ting Li,Tengfei Kang,Dong Xue","doi":"10.1021/acs.orglett.5c04313","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04313","url":null,"abstract":"The first red-light-driven Minisci reaction of heteroarenes with a readily available BCP-derived redox-active ester (RAE) has been developed, employing mesoporous graphitic carbon nitride (mpg-C3N4) as a recyclable heterogeneous photocatalyst. The heterogeneous nature of mpg-C3N4 allows for easy recovery and reuse, maintaining a high catalytic activity over five consecutive cycles. This approach provides efficient access to heterocycle-functionalized BCP scaffolds, which are of high interest in medicinal chemistry as potential bioisosteres of biaryl scaffolds. Notably, the photoredox reactions proceed smoothly under sunlight irradiation, and a successful scale-up demonstration highlights its promise for industrial applications.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"38 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717370","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}
Site-selective modification of peptides is essential for biomedical research; herein, we develop a versatile strategy for the late-stage functionalization of peptides through copper-catalyzed N-sulfenylation of tryptophan residues. This method is quite compatible with a broad range of functional groups and enables the site-selective formation of a N-S bond at the nitrogen atom of tryptophan without the need for directing groups.
{"title":"Copper-Catalyzed Selective N-Sulfenylation of Tryptophan-Containing Peptides.","authors":"Jian Tang,Qinyu Lu,Han Chu,Hongrui Man,Kun Liu,Caiyue Yuan","doi":"10.1021/acs.orglett.5c04752","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04752","url":null,"abstract":"Site-selective modification of peptides is essential for biomedical research; herein, we develop a versatile strategy for the late-stage functionalization of peptides through copper-catalyzed N-sulfenylation of tryptophan residues. This method is quite compatible with a broad range of functional groups and enables the site-selective formation of a N-S bond at the nitrogen atom of tryptophan without the need for directing groups.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"133 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711013","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}
Halogenated γ-lactams are valuable synthetic targets, but efficient methods for accessing chloro- and bromo-substituted analogues remain elusive. Here we describe a copper-catalyzed radical halocyclization of N-4-pentenamides that enables one-step access to chloro- and bromo-substituted γ-lactams using inexpensive tetrabutylammonium chloride (TBACl) and tetraethylammonium bromide (TEAB) as halogen sources. The reactions proceed under mild conditions to afford desired products in good to excellent yields with a broad substrate scope and functional group tolerance. Preliminary mechanistic studies suggest a radical pathway involving a Cu(I)/Cu(II)/Cu(III) catalytic cycle and 5-exo-trig cyclization.
{"title":"Copper-Catalyzed Radical Halocyclization of N-4-Pentenamides: Synthesis of Chloro- and Bromo-Substituted γ-Lactams","authors":"Xinrong He, Hanyang Zhang, Nawaf Al-Maharik, Qian Zhang, Zeguo Fang, Dong Li","doi":"10.1021/acs.orglett.5c04384","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04384","url":null,"abstract":"Halogenated γ-lactams are valuable synthetic targets, but efficient methods for accessing chloro- and bromo-substituted analogues remain elusive. Here we describe a copper-catalyzed radical halocyclization of <i>N</i>-4-pentenamides that enables one-step access to chloro- and bromo-substituted γ-lactams using inexpensive tetrabutylammonium chloride (TBACl) and tetraethylammonium bromide (TEAB) as halogen sources. The reactions proceed under mild conditions to afford desired products in good to excellent yields with a broad substrate scope and functional group tolerance. Preliminary mechanistic studies suggest a radical pathway involving a Cu(I)/Cu(II)/Cu(III) catalytic cycle and <i>5-exo-trig</i> cyclization.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"144 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711390","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 : 2025-12-10DOI: 10.1021/acs.orglett.5c04407
Anna A. Faizdrakhmanova, Vladimir B. Kharitonov, Yulia V. Nelyubina, Igor A. Ushakov, Aleksandra A. Vidyakina, Natalia A. Danilkina, Dmitry A. Loginov, Andrey G. Lvov
Hybrids of mesoionic sydnone and photoswitchable diarylethene (SyDAEs) exhibited properties uncommon for either class of molecules. Their (photo)chemical reactivity is determined by the size of the central ring, unifying the two functional parts, and the substituents in the fused benzene ring. SyDAEs based on six-membered rings are photochromic yet undergo two novel irreversible photoreactions. A SyDAE with a seven-membered ring is photoinactive but readily undergoes (3+2) cycloaddition with diazacyclononyne provided by the favorable saddle-like conformation.
{"title":"Mutual Enrichment of the (Photo)Chemistry of Sydnones and Diarylethenes in Their Hybrids","authors":"Anna A. Faizdrakhmanova, Vladimir B. Kharitonov, Yulia V. Nelyubina, Igor A. Ushakov, Aleksandra A. Vidyakina, Natalia A. Danilkina, Dmitry A. Loginov, Andrey G. Lvov","doi":"10.1021/acs.orglett.5c04407","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c04407","url":null,"abstract":"Hybrids of mesoionic sydnone and photoswitchable diarylethene (SyDAEs) exhibited properties uncommon for either class of molecules. Their (photo)chemical reactivity is determined by the size of the central ring, unifying the two functional parts, and the substituents in the fused benzene ring. SyDAEs based on six-membered rings are photochromic yet undergo two novel irreversible photoreactions. A SyDAE with a seven-membered ring is photoinactive but readily undergoes (3+2) cycloaddition with diazacyclononyne provided by the favorable saddle-like conformation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"7 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711391","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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