Carbohydrates constitute an important class of biologically relevant natural products. Among the synthetic glycomimetics, C-glycosides are particularly interesting due to their chemical and metabolic stability toward acidic and enzymatic hydrolysis at the anomeric position. The stereochemical outcomes of traditional methodologies to access C-glycosides rely heavily on substrate control. Herein, we report a novel synthetic strategy to access diverse C-glycosides with precise stereochemical control at the anomeric position via formal functional group deletion, where both α- and β-anomers of furanoses and pyranoses can be obtained as single stereoisomers. Additionally, the broad scope of heterocyclic C-glycosides obtained via this strategy further illustrates its potential for empowering future application in both chemical biology research and drug discovery.
{"title":"Switchable and Stereospecific C-Glycosylation Strategy via Formal Functional Group Deletion","authors":"Xiaoshen Ma, Stephen J. Sujansky","doi":"10.1021/acs.joc.5c00200","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00200","url":null,"abstract":"Carbohydrates constitute an important class of biologically relevant natural products. Among the synthetic glycomimetics, <i>C-</i>glycosides are particularly interesting due to their chemical and metabolic stability toward acidic and enzymatic hydrolysis at the anomeric position. The stereochemical outcomes of traditional methodologies to access <i>C-</i>glycosides rely heavily on substrate control. Herein, we report a novel synthetic strategy to access diverse <i>C-</i>glycosides with precise stereochemical control at the anomeric position via formal functional group deletion, where both α- and β-anomers of furanoses and pyranoses can be obtained as single stereoisomers. Additionally, the broad scope of heterocyclic <i>C</i>-glycosides obtained via this strategy further illustrates its potential for empowering future application in both chemical biology research and drug discovery.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"25 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806149","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}
An unprecedented approach involving radical-mediated sulfonylation/dearomative ipso-annulation of N-(methyl-2-phenylacetate)propiolamides using arylsulfonyl radical, generated from aryl diazonium salt in the presence of DABSO, is developed. This strategy provides uniquely substituted 3-sulfonyl azaspiro[4.5]decatrienones in good yields. The developed approach has also been extended fruitfully to 3-thiocyano aza-spirocycles through domino thiocyanation/dearomative ipso-annulation.
{"title":"Access to Methylidene-Azaspiro[4.5]decatrienones via Radical-Promoted Domino Thio-Functionalization/Dearomative Ipso-Annulation","authors":"Chada Raji Reddy, Puthiya Purayil Vinaya, Ejjirotu Srinivasu, Muppidi Subbarao","doi":"10.1021/acs.joc.5c00077","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00077","url":null,"abstract":"An unprecedented approach involving radical-mediated sulfonylation/dearomative <i>ipso</i>-annulation of <i>N</i>-(methyl-2-phenylacetate)propiolamides using arylsulfonyl radical, generated from aryl diazonium salt in the presence of DABSO, is developed. This strategy provides uniquely substituted 3-sulfonyl <i>aza</i>spiro[4.5]decatrienones in good yields. The developed approach has also been extended fruitfully to 3-thiocyano <i>aza</i>-spirocycles through domino thiocyanation/dearomative <i>ipso</i>-annulation.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"91 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806382","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}
Sopan Pralhad Khandare, Chloe Xin Ying Peh, Roderick W. Bates
Phochrodines A, B, and C have been synthesized using a CH-activation protocol and palladium-catalyzed carbonylation. To avoid issues of regioselectivity, the inherent symmetry of a common intermediate was exploited.
{"title":"Synthesis of Phochrodines A–C by CH Activation","authors":"Sopan Pralhad Khandare, Chloe Xin Ying Peh, Roderick W. Bates","doi":"10.1021/acs.joc.5c00210","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00210","url":null,"abstract":"Phochrodines A, B, and C have been synthesized using a CH-activation protocol and palladium-catalyzed carbonylation. To avoid issues of regioselectivity, the inherent symmetry of a common intermediate was exploited.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"183 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806383","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}
Guangyu Cui, Zaiqi Han, Xiangqing Feng, Haifeng Du
An enantioselective synthesis of 2-aryl 3,3-disubstituted 3H-indoles has been successfully developed via a deracemization process involving borane-catalyzed hydrogenation and chiral phosphoric-acid-catalyzed asymmetric transfer hydrogenation. A variety of 3H-indoles were effective substrates to afford the desired indolines in 86–95% yields with 45–92% ee’s.
{"title":"Enantioselective Synthesis of 2-Aryl-3,3-Disubstituted Indolines from 3H-Indoles via Deracemization","authors":"Guangyu Cui, Zaiqi Han, Xiangqing Feng, Haifeng Du","doi":"10.1021/acs.joc.5c00100","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00100","url":null,"abstract":"An enantioselective synthesis of 2-aryl 3,3-disubstituted 3<i>H</i>-indoles has been successfully developed via a deracemization process involving borane-catalyzed hydrogenation and chiral phosphoric-acid-catalyzed asymmetric transfer hydrogenation. A variety of 3<i>H</i>-indoles were effective substrates to afford the desired indolines in 86–95% yields with 45–92% ee’s.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"294 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798591","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}
Carlos J. Laglera-Gándara, Rafael Jiménez-Rioboó, Lucía Álvarez-Rodríguez, Riccardo Peloso, Pablo Ríos, Amor Rodríguez
Deuterated silanes are crucial reagents for deuteration, with a diverse range of applications in materials science, pharmaceuticals, and isotopic labeling. While most methods for synthesizing deuterated silanes rely on stoichiometric environmentally harmful processes or noble metal catalysts, research into more sustainable alternatives has received relatively less attention. In this study, we introduce a catalyst based on a nickel PBP-pincer system (PBP = bis(phosphino)boryl), which effectively facilitates catalytic hydrogen/deuterium exchange for primary, secondary, and tertiary silanes, as well as tertiary siloxanes and certain boranes, utilizing a catalyst loading of 2 mol % at 25 °C. DFT calculations identify two reaction pathways that require overcoming similar energy barriers for the H/D exchange step: silane activation assisted by the PBP ligand (ΔG⧧ = 24.1 kcal mol–1) and H/D exchange promoted by nucleophilic Ni-hydride (ΔG⧧ = 22.4 kcal mol–1). These results suggest that both pathways are feasible, with a slight energetic preference for the latter. We also present detailed mechanistic studies, including control experiments, an analysis of catalyst deactivation pathways, and kinetic studies that are in excellent agreement with the outcome of the theoretical calculations.
{"title":"Nickel-Catalyzed Deuteration of Primary, Secondary, and Tertiary Silanes: Scope and Mechanistic Insights","authors":"Carlos J. Laglera-Gándara, Rafael Jiménez-Rioboó, Lucía Álvarez-Rodríguez, Riccardo Peloso, Pablo Ríos, Amor Rodríguez","doi":"10.1021/acs.joc.5c00107","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00107","url":null,"abstract":"Deuterated silanes are crucial reagents for deuteration, with a diverse range of applications in materials science, pharmaceuticals, and isotopic labeling. While most methods for synthesizing deuterated silanes rely on stoichiometric environmentally harmful processes or noble metal catalysts, research into more sustainable alternatives has received relatively less attention. In this study, we introduce a catalyst based on a nickel PBP-pincer system (PBP = bis(phosphino)boryl), which effectively facilitates catalytic hydrogen/deuterium exchange for primary, secondary, and tertiary silanes, as well as tertiary siloxanes and certain boranes, utilizing a catalyst loading of 2 mol % at 25 °C. DFT calculations identify two reaction pathways that require overcoming similar energy barriers for the H/D exchange step: silane activation assisted by the PBP ligand (Δ<i>G</i><sup>⧧</sup> = 24.1 kcal mol<sup>–1</sup>) and H/D exchange promoted by nucleophilic Ni-hydride (Δ<i>G</i><sup>⧧</sup> = 22.4 kcal mol<sup>–1</sup>). These results suggest that both pathways are feasible, with a slight energetic preference for the latter. We also present detailed mechanistic studies, including control experiments, an analysis of catalyst deactivation pathways, and kinetic studies that are in excellent agreement with the outcome of the theoretical calculations.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"20 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798592","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 detailed mechanism of propylene carbonate (PC) formation from propylene oxide (PO) and CO2 is investigated using density functional theory (DFT) methods, catalyzed by amine/MeOH binary systems, in propylene oxide under conditions of room temperature and 1 atm. In these systems, amines (MeNH2, Me2NH, Me3N, and pyrrolidine) serve as nucleophiles, while MeOH acts as a hydrogen bond donor (HBD). The catalyzed reaction pathways for PC formation consistently proceed through two transition states, ts1 and ts2, corresponding to the oxide ring-opening and final ring-closing steps, respectively. The ring-closing step was identified as the rate-determining step in all amine/MeOH binary systems. Notably, the three aliphatic amine/MeOH binary systems significantly lower activation barriers for PC formation by approximately 20 kcal mol–1 compared to the uncatalyzed ring-closing pathway under standard conditions. The Me2NH/MeOH binary system demonstrates slightly higher catalytic efficiency than the MeNH2 and Me3N systems. Furthermore, the pyrrolidine/MeOH binary system exhibits comparable catalytic performance to the Me2NH/MeOH system. Since pyrrolidine is liquid under standard conditions, it can act as a homogeneous catalyst when paired with MeOH, enhancing mixing with PO and improving catalytic activity relative to gaseous Me2NH.
{"title":"Amine–MeOH Binary Systems as Catalysts for Cyclic Carbonate Formation from Epoxides and Carbon Dioxide: A DFT Mechanistic Investigation","authors":"Young Kee Kang, Hae Sook Park","doi":"10.1021/acs.joc.5c00141","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00141","url":null,"abstract":"The detailed mechanism of propylene carbonate (PC) formation from propylene oxide (PO) and CO<sub>2</sub> is investigated using density functional theory (DFT) methods, catalyzed by amine/MeOH binary systems, in propylene oxide under conditions of room temperature and 1 atm. In these systems, amines (MeNH<sub>2</sub>, Me<sub>2</sub>NH, Me<sub>3</sub>N, and pyrrolidine) serve as nucleophiles, while MeOH acts as a hydrogen bond donor (HBD). The catalyzed reaction pathways for PC formation consistently proceed through two transition states, ts1 and ts2, corresponding to the oxide ring-opening and final ring-closing steps, respectively. The ring-closing step was identified as the rate-determining step in all amine/MeOH binary systems. Notably, the three aliphatic amine/MeOH binary systems significantly lower activation barriers for PC formation by approximately 20 kcal mol<sup>–1</sup> compared to the uncatalyzed ring-closing pathway under standard conditions. The Me<sub>2</sub>NH/MeOH binary system demonstrates slightly higher catalytic efficiency than the MeNH<sub>2</sub> and Me<sub>3</sub>N systems. Furthermore, the pyrrolidine/MeOH binary system exhibits comparable catalytic performance to the Me<sub>2</sub>NH/MeOH system. Since pyrrolidine is liquid under standard conditions, it can act as a homogeneous catalyst when paired with MeOH, enhancing mixing with PO and improving catalytic activity relative to gaseous Me<sub>2</sub>NH.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"38 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798587","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}
Point mutations and single base mutations are the dominant mutations found in the KRAS gene. Systematic knockout of the KRAS gene with these point mutations is still challenging. In this study, we developed novel photo-cross-linking oligonucleotides (pU1–ODN and pU2–ODN) that had a diazirine group at the 5-position of the uridine derivatives. Photo-cross-linking studies of the oligonucleotides with wild-type and mutated RNAs revealed that pU2–ODN efficiently and selectively reacts with the mutated RNAs that contain a cytidine, guanosine, or uridine residue at the frontal position of the pU2 nucleoside. These results suggest that pU2–ODN is a promising candidate for use as a photo-cross-linking ODN to selectively inhibit the activity of mRNAs with a point mutation.
{"title":"Point Mutation Selective Photo-Cross-Linking Reactions by Diazirine-Derivatized ODNs","authors":"Kentaro Kobata, Daiki Unita, Kazuya Matsuo, Tomonori Waku, Akio Kobori","doi":"10.1021/acs.joc.4c02493","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02493","url":null,"abstract":"Point mutations and single base mutations are the dominant mutations found in the KRAS gene. Systematic knockout of the KRAS gene with these point mutations is still challenging. In this study, we developed novel photo-cross-linking oligonucleotides (<sup><b>p</b></sup><b>U</b><sub><b>1</b></sub><b>–ODN</b> and <sup><b>p</b></sup><b>U</b><sub><b>2</b></sub><b>–ODN</b>) that had a diazirine group at the 5-position of the uridine derivatives. Photo-cross-linking studies of the oligonucleotides with wild-type and mutated RNAs revealed that <sup><b>p</b></sup><b>U</b><sub><b>2</b></sub><b>–ODN</b> efficiently and selectively reacts with the mutated RNAs that contain a cytidine, guanosine, or uridine residue at the frontal position of the <sup><b>p</b></sup><b>U</b><sub><b>2</b></sub> nucleoside. These results suggest that <sup><b>p</b></sup><b>U</b><sub><b>2</b></sub><b>–ODN</b> is a promising candidate for use as a photo-cross-linking ODN to selectively inhibit the activity of mRNAs with a point mutation.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"14 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798407","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 novel green methodology for the Oxone-mediated oxidative addition of alkenes via intramolecular acyl migration has been developed. This transformation utilizes N-acyl-N-sulfonyl allylamines and diselenides as starting materials, with Oxone serving as the oxidant and water as a partial oxygen source. The protocol enables the synthesis of a series of β-acyloxy-γ-selenyl sulfonamides with high to excellent yields and demonstrates broad substrate scope. Notably, the excellent yield was maintained in gram-scale experiments, highlighting the scalability of this method. Through comprehensive control experiments, we have elucidated the reaction mechanism, which involves rapid radical generation, a predominant cationic pathway, and intramolecular acyl migration. This study presents an efficient and environmentally benign approach to the synthesis of valuable β-acyloxy-γ-selenyl sulfonamides.
{"title":"Intramolecular Acyl-Migration for Acyloxyselenenylation of Alkenes Promoted by Oxone","authors":"Wen Xia, Pei Tian, Xiaohui Zhang, Tongtong Liu, Wenxuan Yu, Yan Xiong, Xiangming Zhu","doi":"10.1021/acs.joc.5c00040","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00040","url":null,"abstract":"A novel green methodology for the Oxone-mediated oxidative addition of alkenes via intramolecular acyl migration has been developed. This transformation utilizes <i>N</i>-acyl-<i>N</i>-sulfonyl allylamines and diselenides as starting materials, with Oxone serving as the oxidant and water as a partial oxygen source. The protocol enables the synthesis of a series of β-acyloxy-γ-selenyl sulfonamides with high to excellent yields and demonstrates broad substrate scope. Notably, the excellent yield was maintained in gram-scale experiments, highlighting the scalability of this method. Through comprehensive control experiments, we have elucidated the reaction mechanism, which involves rapid radical generation, a predominant cationic pathway, and intramolecular acyl migration. This study presents an efficient and environmentally benign approach to the synthesis of valuable β-acyloxy-γ-selenyl sulfonamides.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"55 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798408","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}
Santana Chakraborty, Arijit Singha Mohapatra, Nanda D. Paul
Unprecedented CO–Cα bond cleavage of 1,3-dicarbonyls and enaminone, catalyzed by a well-defined Ru(III)-complex (1) featuring a redox-active triamine ligand (L1) with a free –NH2 arm, opening a new route to accessing substituted pyrroles with broad substrate scope and functional group tolerance in good isolated yields via multicomponent coupling of 1,3-dicarbonyls, amines, and diol, is reported. The hydrogen bonding interaction offered by 1 facilitates the formation of critical reaction intermediates, favoring the formation of pyrroles.
{"title":"Hydrogen-Bond-Assisted Ru(III)-Catalyzed C–C Bond Activation in 1,3-Dicarbonyls: A Direct Route to Multi-Substituted Pyrroles","authors":"Santana Chakraborty, Arijit Singha Mohapatra, Nanda D. Paul","doi":"10.1021/acs.joc.5c00233","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00233","url":null,"abstract":"Unprecedented CO–Cα bond cleavage of 1,3-dicarbonyls and enaminone, catalyzed by a well-defined Ru(III)-complex (<b>1</b>) featuring a redox-active triamine ligand (<b>L</b><sup><b>1</b></sup>) with a free –NH<sub>2</sub> arm, opening a new route to accessing substituted pyrroles with broad substrate scope and functional group tolerance in good isolated yields via multicomponent coupling of 1,3-dicarbonyls, amines, and diol, is reported. The hydrogen bonding interaction offered by <b>1</b> facilitates the formation of critical reaction intermediates, favoring the formation of pyrroles.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"74 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790088","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}
Kinetic and product studies on the reactions of the cumyloxyl (CumO•) and tert-butoxyl (tBuO•) radicals with secondary and tertiary N-methyl and N-benzyl lactams and with cycloalkenes, accompanied by BDE calculations of the substrate C–H bonds involved in these reactions, are reported. Within the lactams, the rate constants for HAT (kH) from the C–H bonds to CumO• decrease by a factor ∼4 going from the 5- and 6-membered derivatives to the 8-membered ones. Product distributions obtained through oxygenation initiated by tBuO• show that HAT preferentially occurs from the most electron-rich α-C–H bonds, with site selectivity that, within the N-methyl and N-benzyl series, progressively shifts from the endocyclic to the exocyclic α-C–H bonds with increasing ring size, indicative of deactivation of the former bonds that, for the 8-membered derivatives, translates into competitive oxygenation at different sites. Similar trends have been observed for the corresponding reactions of the cycloalkenes, with kH values that decrease by a factor of ∼4 together with site selectivity for HAT from the activated allylic C–H bonds, going from cyclopentene to cyclooctene. It is proposed that the greater flexibility of the medium-sized rings decreases the extent of hyperconjugative overlap between the α-C–H bonds and the amide or C═C π-systems, increasing the kinetic barrier for HAT from these sites, with decreases in reactivity that approach factors of 83 and 18, for the endocyclic α-C–H bonds of tertiary N-methyl lactams and the allylic C–H bonds of cycloalkenes, respectively.
{"title":"Hydrogen Atom Transfer-Based C(sp3)–H Bond Oxygenation of Lactams and Cycloalkenes: The Influence of Ring Size on Reactivity and Site Selectivity","authors":"Sergio Sisti, Fabio Ioele, Filippo Scarchilli, Simona Laparelli, Marco Galeotti, Omid Hosseinzadeh, Zhehan Jia, Gino A. DiLabio, Michela Salamone, Massimo Bietti","doi":"10.1021/acs.joc.5c00092","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00092","url":null,"abstract":"Kinetic and product studies on the reactions of the cumyloxyl (CumO<sup>•</sup>) and <i>tert</i>-butoxyl (<i>t</i>BuO<sup>•</sup>) radicals with secondary and tertiary <i>N</i>-methyl and <i>N</i>-benzyl lactams and with cycloalkenes, accompanied by BDE calculations of the substrate C–H bonds involved in these reactions, are reported. Within the lactams, the rate constants for HAT (<i>k</i><sub>H</sub>) from the C–H bonds to CumO<sup>•</sup> decrease by a factor ∼4 going from the 5- and 6-membered derivatives to the 8-membered ones. Product distributions obtained through oxygenation initiated by <i>t</i>BuO<sup>•</sup> show that HAT preferentially occurs from the most electron-rich α-C–H bonds, with site selectivity that, within the <i>N</i>-methyl and <i>N</i>-benzyl series, progressively shifts from the endocyclic to the exocyclic α-C–H bonds with increasing ring size, indicative of deactivation of the former bonds that, for the 8-membered derivatives, translates into competitive oxygenation at different sites. Similar trends have been observed for the corresponding reactions of the cycloalkenes, with <i>k</i><sub>H</sub> values that decrease by a factor of ∼4 together with site selectivity for HAT from the activated allylic C–H bonds, going from cyclopentene to cyclooctene. It is proposed that the greater flexibility of the medium-sized rings decreases the extent of hyperconjugative overlap between the α-C–H bonds and the amide or C═C π-systems, increasing the kinetic barrier for HAT from these sites, with decreases in reactivity that approach factors of 83 and 18, for the endocyclic α-C–H bonds of tertiary <i>N</i>-methyl lactams and the allylic C–H bonds of cycloalkenes, respectively.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"89 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789940","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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