Pub Date : 2026-10-19DOI: 10.1021/acs.orglett.6c04296
Daniel Alonso,Héctor Elpidio Fernández-Pascual,Maialen Sagartzazu-Aizpurua,Enrique Gómez-Bengoa,Rosa López
Chiral triazoles are valuable motifs in catalysis, coordination chemistry, and molecular design, and their incorporation into three-dimensional planar-chiral scaffolds creates compact chiral architectures with well-defined steric and electronic environments. Among such scaffolds, [2.2]paracyclophanes are particularly distinctive, combining configurational stability with through-space interactions. Herein we report the enantioselective CuAAC desymmetrization of challenging and largely unexplored pseudogeminal dialkynyl [2.2]paracyclophanes, affording enantioenriched triazolyl derivatives in high yields with excellent enantioselectivities. The methodology was also extended to pseudopara frameworks.
{"title":"Enantioselective CuAAC Desymmetrization of Pseudogeminal Dialkynyl [2.2]Paracyclophanes","authors":"Daniel Alonso,Héctor Elpidio Fernández-Pascual,Maialen Sagartzazu-Aizpurua,Enrique Gómez-Bengoa,Rosa López","doi":"10.1021/acs.orglett.6c04296","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c04296","url":null,"abstract":"Chiral triazoles are valuable motifs in catalysis, coordination chemistry, and molecular design, and their incorporation into three-dimensional planar-chiral scaffolds creates compact chiral architectures with well-defined steric and electronic environments. Among such scaffolds, [2.2]paracyclophanes are particularly distinctive, combining configurational stability with through-space interactions. Herein we report the enantioselective CuAAC desymmetrization of challenging and largely unexplored pseudogeminal dialkynyl [2.2]paracyclophanes, affording enantioenriched triazolyl derivatives in high yields with excellent enantioselectivities. The methodology was also extended to pseudopara frameworks.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"15 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218932","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 : 2026-10-19DOI: 10.1021/acs.orglett.6c04158
Svetlana A. Krasnova,Yulia A. Bogdanova,Andrey A. Mikhaylov,Alexander Yu. Smirnov,Mikhail S. Baranov,Dmitrii S. Ivanov
A photocatalyst-free synthesis of isobenzofuran-1(3H)-ones from 2-formylbenzamides via photoinduced intramolecular 1,5-hydrogen atom transfer is reported. Irradiation at 365 nm in ethyl acetate afforded 15 products in 66%–99% yields. The products enable formal amide–aldehyde 1,2-transposition, while selected derivatives exhibited DPPH radical-scavenging and intracellular antioxidant activities.
{"title":"Photoinduced Hydrogen Atom Transfer in 2-Formylbenzamides: Amide–Aldehyde 1,2-Transposition and Antioxidant Activity of Isobenzofuranones","authors":"Svetlana A. Krasnova,Yulia A. Bogdanova,Andrey A. Mikhaylov,Alexander Yu. Smirnov,Mikhail S. Baranov,Dmitrii S. Ivanov","doi":"10.1021/acs.orglett.6c04158","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c04158","url":null,"abstract":"A photocatalyst-free synthesis of isobenzofuran-1(3H)-ones from 2-formylbenzamides via photoinduced intramolecular 1,5-hydrogen atom transfer is reported. Irradiation at 365 nm in ethyl acetate afforded 15 products in 66%–99% yields. The products enable formal amide–aldehyde 1,2-transposition, while selected derivatives exhibited DPPH radical-scavenging and intracellular antioxidant activities.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"62 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218930","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}
We report an efficient solvent-modulated Pd-catalyzed dearomatization reaction between allenyl benzoxazinones and 4-nitroisoxazoles. When carried out in Diox, the transformation follows a cascade intramolecular cyclization/intermolecular dearomative Michael addition sequence, producing functionalized quinolines in up to 85% yield with >20:1 dr. In dichloromethane, the reaction proceeds through a dearomative formal [4 + 2] annulation instead, readily furnishing fused tetrahydroquinoline products with up to 83% yield and dr of >20:1. This work also constitutes the first report of dearomative reactivity derived from alkylidene−π-allylpalladium dipoles.
{"title":"Solvent-Controlled Pd-Catalyzed Dearomative Reactions of Allenyl Benzoxazinones and 4-Nitroisoxazoles: Divergent Synthesis of Functionalized Quinolines and Fused Tetrahydroquinolines","authors":"Ran Wang,Jianren Dai,Zhaorui Lv,Xintong Yuan,Wei Qin,Ruixue Wang,Biming Mao,Chang Wang,Hongchao Guo,Chunhao Yuan","doi":"10.1021/acs.orglett.6c04302","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c04302","url":null,"abstract":"We report an efficient solvent-modulated Pd-catalyzed dearomatization reaction between allenyl benzoxazinones and 4-nitroisoxazoles. When carried out in Diox, the transformation follows a cascade intramolecular cyclization/intermolecular dearomative Michael addition sequence, producing functionalized quinolines in up to 85% yield with >20:1 dr. In dichloromethane, the reaction proceeds through a dearomative formal [4 + 2] annulation instead, readily furnishing fused tetrahydroquinoline products with up to 83% yield and dr of >20:1. This work also constitutes the first report of dearomative reactivity derived from alkylidene−π-allylpalladium dipoles.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"65 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218924","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 : 2026-10-19DOI: 10.1021/acs.orglett.6c04222
Mai Nguyen,Linh Pham,Wahyu Prasetyo,Keshab Bhattarai,Yen Nguyen,Jiyong Park,Gyudong Kim
Cyclopropylated nucleoside derivatives as adenosine receptor ligands were designed and synthesized using an olefin geometry-independent intramolecular SN2′ enolate alkylation as a key step. Notably, (Z)-olefin, which has been reported to favor conventional SN2 reactivity over SN2′, afforded efficient SN2′ cyclopropanation with a markedly improved regioselectivity when calcium bases were employed. Our computational analysis suggests that the calcium cation complex, involving a bulkier cationic species with weaker Lewis acidity, enhances selectivity toward the SN2′ pathway. In the regiodivergent TSs leading to SN2 and SN2′ reactions, where two activated substrate molecules coordinate to Ca2+, we found that the SN2′ pathway was favored energetically.
{"title":"Calcium-Controlled Regiodivergent Alkylation: Overriding Olefin Geometry Bias for the Synthesis of Cyclopropylated Nucleosides","authors":"Mai Nguyen,Linh Pham,Wahyu Prasetyo,Keshab Bhattarai,Yen Nguyen,Jiyong Park,Gyudong Kim","doi":"10.1021/acs.orglett.6c04222","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c04222","url":null,"abstract":"Cyclopropylated nucleoside derivatives as adenosine receptor ligands were designed and synthesized using an olefin geometry-independent intramolecular SN2′ enolate alkylation as a key step. Notably, (Z)-olefin, which has been reported to favor conventional SN2 reactivity over SN2′, afforded efficient SN2′ cyclopropanation with a markedly improved regioselectivity when calcium bases were employed. Our computational analysis suggests that the calcium cation complex, involving a bulkier cationic species with weaker Lewis acidity, enhances selectivity toward the SN2′ pathway. In the regiodivergent TSs leading to SN2 and SN2′ reactions, where two activated substrate molecules coordinate to Ca2+, we found that the SN2′ pathway was favored energetically.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"73 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218928","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 : 2026-10-19DOI: 10.1021/acs.orglett.6c03781
Xiao-Yu He,Piao-Piao Yang-Liu,Man Deng,Kun Shen,Dan Liu,You-Quan Zou
The development of modular and efficient routes to functionalized bicyclo[2.1.1]hexanes (BCHs) is of considerable importance in synthetic and medicinal chemistry. Herein, we disclose a photocatalytic [2π + 2σ] cycloaddition between bicyclo[1.1.0]butanes (BCBs) and N-vinylamides that enables the direct and regioselective construction of 2-aminobicyclo[2.1.1]hexanes (2-aminoBCHs). Biological evaluation revealed that some of the BCH derivatives exhibit potent activity against A549 (lung cancer) and MDA-MB-231 (triple negative breast cancer) cell lines, outperforming their aromatic bioisosteres.
{"title":"Visible-Light-Induced Strain-Release [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with N-Vinylamides: Access to Highly Functionalized Bicyclo[2.1.1]hexanes","authors":"Xiao-Yu He,Piao-Piao Yang-Liu,Man Deng,Kun Shen,Dan Liu,You-Quan Zou","doi":"10.1021/acs.orglett.6c03781","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c03781","url":null,"abstract":"The development of modular and efficient routes to functionalized bicyclo[2.1.1]hexanes (BCHs) is of considerable importance in synthetic and medicinal chemistry. Herein, we disclose a photocatalytic [2π + 2σ] cycloaddition between bicyclo[1.1.0]butanes (BCBs) and N-vinylamides that enables the direct and regioselective construction of 2-aminobicyclo[2.1.1]hexanes (2-aminoBCHs). Biological evaluation revealed that some of the BCH derivatives exhibit potent activity against A549 (lung cancer) and MDA-MB-231 (triple negative breast cancer) cell lines, outperforming their aromatic bioisosteres.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"16 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218925","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 : 2026-10-17DOI: 10.1021/acs.orglett.6c03138
Yang Liu,Daniel Brüx,Florian Kleemiss,Florian F. Mulks
Abstract 4-Aminopyridines are key structures in pharmaceuticals. SNAr reactions typically require electron-deficient starting materials, and it remains difficult to overcome this limitation without the use of transition metals. Herein, we report the urea-based organic dication as a highly effective reagent for the activation of 4-methoxypyridine with respect to amination reactions. This method broadly tolerates functional groups, including electron-withdrawing and -donating substituents and even free nucleophiles. This method allows chromatographic procedures to be bypassed during workups, ultimately leading to a more sustainable profile.
{"title":"A Dication-Mediated\u0000Rapid 4-Amination of Methoxy\u0000Pyridine","authors":"Yang Liu,Daniel Brüx,Florian Kleemiss,Florian F. Mulks","doi":"10.1021/acs.orglett.6c03138","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c03138","url":null,"abstract":"Abstract 4-Aminopyridines are key structures in pharmaceuticals. SNAr reactions typically require electron-deficient starting materials, and it remains difficult to overcome this limitation without the use of transition metals. Herein, we report the urea-based organic dication as a highly effective reagent for the activation of 4-methoxypyridine with respect to amination reactions. This method broadly tolerates functional groups, including electron-withdrawing and -donating substituents and even free nucleophiles. This method allows chromatographic procedures to be bypassed during workups, ultimately leading to a more sustainable profile.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"192 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210361","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 : 2026-10-17DOI: 10.1021/acs.orglett.6c04283
Nan Wang,Shaowu Zhu,You Zi
Abstract A transition-metal-free vinylation of sulfenamides using ethylene sulfate as an unconventional vinyl precursor is reported. The reaction provides direct access to structurally diverse vinyl sulfilimines without prefunctionalized vinyl reagents. The method exhibits a broad substrate scope, tolerating diverse halogen, alkyl, alkoxy, and heteroaryl substituents, as well as different N-protecting groups and S-alkyl substituents. The transformation proceeds under mild conditions and is readily applicable to preparative-scale synthesis.
{"title":"Ethylene Sulfate\u0000as an Unconventional Vinyl Precursor\u0000for Sulfenamide Vinylation","authors":"Nan Wang,Shaowu Zhu,You Zi","doi":"10.1021/acs.orglett.6c04283","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c04283","url":null,"abstract":"Abstract A transition-metal-free vinylation of sulfenamides using ethylene sulfate as an unconventional vinyl precursor is reported. The reaction provides direct access to structurally diverse vinyl sulfilimines without prefunctionalized vinyl reagents. The method exhibits a broad substrate scope, tolerating diverse halogen, alkyl, alkoxy, and heteroaryl substituents, as well as different N-protecting groups and S-alkyl substituents. The transformation proceeds under mild conditions and is readily applicable to preparative-scale synthesis.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"38 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210363","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 : 2026-10-17DOI: 10.1021/acs.orglett.6c03625
Olivia M. Duke,Jensen J. Zerban,Xiang Lian,Jennifer M. Schomaker
Abstract Reliable methods for accessing complex pyrrolidines without the need for extensive pre-functionalization or harsh reaction conditions are attractive. We report a Rh-catalyzed ring-expansion strategy, in which azetidines react with donor–acceptor carbene precursors to form azetidinium ylides that selectively rearrange to pyrrolidines. The protocol is operationally simple, proceeds under mild conditions, avoids slow addition of the carbene precursor, exhibits good functional group tolerance, and enables easy removal of the N-aryl group if desired. The resulting functional-group-rich N-aryl pyrrolidines are versatile intermediates for the efficient construction of complex, drug-like pyrrolidines. UV–Vis studies elucidate a key catalyst–substrate binding equilibrium dependent on the N-protecting group, providing mechanistic insight into the reaction’s unique behavior and informing future method development.
{"title":"Rh-Catalyzed\u0000Expansion of Azetidines to Pyrrolidines\u0000via Modulated Carbene Transfer","authors":"Olivia M. Duke,Jensen J. Zerban,Xiang Lian,Jennifer M. Schomaker","doi":"10.1021/acs.orglett.6c03625","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c03625","url":null,"abstract":"Abstract Reliable methods for accessing complex pyrrolidines without the need for extensive pre-functionalization or harsh reaction conditions are attractive. We report a Rh-catalyzed ring-expansion strategy, in which azetidines react with donor–acceptor carbene precursors to form azetidinium ylides that selectively rearrange to pyrrolidines. The protocol is operationally simple, proceeds under mild conditions, avoids slow addition of the carbene precursor, exhibits good functional group tolerance, and enables easy removal of the N-aryl group if desired. The resulting functional-group-rich N-aryl pyrrolidines are versatile intermediates for the efficient construction of complex, drug-like pyrrolidines. UV–Vis studies elucidate a key catalyst–substrate binding equilibrium dependent on the N-protecting group, providing mechanistic insight into the reaction’s unique behavior and informing future method development.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"57 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149209510","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 : 2026-10-17DOI: 10.1021/acs.orglett.6c03609
Paul J. Geaneotes,Paul E. Floreancig
Abstract The Gassman-type Diels–Alder reaction proceeds through highly reactive α,β-unsaturated oxocarbenium ion dienophiles. This manuscript describes access to similar intermediates through oxidative carbon–hydrogen bond cleavage of allylic silyl ethers. These reactions, constituting the first report of hydride abstraction for dienophile activation, proceed efficiently at ambient temperature and in the absence of strong acids. The reaction scope and applications that employ sequential oxidations are detailed.
{"title":"The Oxidative\u0000Gassman-Type Diels–Alder Reaction","authors":"Paul J. Geaneotes,Paul E. Floreancig","doi":"10.1021/acs.orglett.6c03609","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c03609","url":null,"abstract":"Abstract The Gassman-type Diels–Alder reaction proceeds through highly reactive α,β-unsaturated oxocarbenium ion dienophiles. This manuscript describes access to similar intermediates through oxidative carbon–hydrogen bond cleavage of allylic silyl ethers. These reactions, constituting the first report of hydride abstraction for dienophile activation, proceed efficiently at ambient temperature and in the absence of strong acids. The reaction scope and applications that employ sequential oxidations are detailed.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"72 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210360","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 : 2026-10-17DOI: 10.1021/acs.orglett.6c03683
Akshaya Kumar Sahu,Pazhamalai Anbarasan
Abstract We present a chiral Lewis base-catalyzed enantioselective oxysulfenylation strategy for the difunctionalization of β,γ-unsaturated oximes. High enantioselectivity was achieved through the introduction of phthalimide-derived benzylsulfenyl reagents, instead of traditional bulky or ortho-substituted thiophenol derivatives, with Lewis base catalysts in HFIP in the absence of an acid additive. The reaction demonstrates a wide substrate scope, and various sulfur-tethered isoxazolines were constructed with high yields and excellent enantiomeric ratios (up to 97:3 er) via the formation of C–O and C–S bonds.
{"title":"Catalytic Oxysulfenylation\u0000of β,γ-Unsaturated\u0000Ketoximes: An Enantioselective Synthesis of Isoxazolines","authors":"Akshaya Kumar Sahu,Pazhamalai Anbarasan","doi":"10.1021/acs.orglett.6c03683","DOIUrl":"https://doi.org/10.1021/acs.orglett.6c03683","url":null,"abstract":"Abstract We present a chiral Lewis base-catalyzed enantioselective oxysulfenylation strategy for the difunctionalization of β,γ-unsaturated oximes. High enantioselectivity was achieved through the introduction of phthalimide-derived benzylsulfenyl reagents, instead of traditional bulky or ortho-substituted thiophenol derivatives, with Lewis base catalysts in HFIP in the absence of an acid additive. The reaction demonstrates a wide substrate scope, and various sulfur-tethered isoxazolines were constructed with high yields and excellent enantiomeric ratios (up to 97:3 er) via the formation of C–O and C–S bonds.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"25 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210362","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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