Boron-containing derivatives have numerous applications in medicinal-, industrial- and synthetic chemistry. Considering it, a new mild, catalyst-free, additive-free, base-assisted one-step robust method has been reported for the efficient synthesis of valuable 1,2-oxaborole derivatives via borylation of propynols using only cesium carbonate as a mild base. The reaction proceeds under mild conditions and demonstrates the broad substrate scope and high functional group tolerance, making it suitable for a wide range of propargylic alcohols. Mechanistic investigations reveal that this method proceeds through a non-radical pathway.
{"title":"Synthesis of 1,2-Oxaborole via Base-Mediated Borylation of Propynols","authors":"Sumit Ghosh, Sudip Laru, Mukta Singsardar, Alakananda Hajra","doi":"10.1039/d5qo00709g","DOIUrl":"https://doi.org/10.1039/d5qo00709g","url":null,"abstract":"Boron-containing derivatives have numerous applications in medicinal-, industrial- and synthetic chemistry. Considering it, a new mild, catalyst-free, additive-free, base-assisted one-step robust method has been reported for the efficient synthesis of valuable 1,2-oxaborole derivatives via borylation of propynols using only cesium carbonate as a mild base. The reaction proceeds under mild conditions and demonstrates the broad substrate scope and high functional group tolerance, making it suitable for a wide range of propargylic alcohols. Mechanistic investigations reveal that this method proceeds through a non-radical pathway.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"26 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334889","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}
Two-component alkenes coupling reactions serve as an efficient platform for the synthesis of complex molecular architectures. Herein, leveraging the differences in activation energy barriers among carbon radical precursors and the polarity matching between radicals, this work pioneers the first example of radical 1,4-acylcyanoalkylation to synthesize challenging-to-access ζ-ketonitriles using two identical alkenes. In the metal-free system, 2-(tert-butylperoxy)-2-methylpropane (DTBP) respectively activates α-C−H bonds of aldehydes and alkyl nitriles to generate acyl and cyanoalkyl radicals. The reaction sequence involves selective radical addition of the acyl radical to two identical alkenes, followed by radical-radical coupling with the cyanoalkyl radical, thereby constructing three C−C bonds under simple conditions. Remarkably, when tertiary alkyl aldehydes are employed, decarbonylation preferentially occur to form alkyl radicals, enabling 1,4-alkylcyanoalkylation of alkenes. Mechanistic studies and density functional theory (DFT) calculations reveal that the success of this 1,4-acylcyanoalkylation process is governed by both the preferential addition of acyl radical to alkenes and the thermodynamic stability associated with the two-component alkenes addition cascade.
{"title":"Radical 1,4-acylcyanoalkylation of alkenes for the synthesis of ζ-ketonitriles","authors":"Ying Tong, Jia-Yao Feng, Cuiyan Wu, Shi-Qing Zhang, Ming-Qi Yang, Sheng Du, Dong-Qing Yang, Keqi Tang, Chao Deng, Wenting Wei","doi":"10.1039/d5qo00744e","DOIUrl":"https://doi.org/10.1039/d5qo00744e","url":null,"abstract":"Two-component alkenes coupling reactions serve as an efficient platform for the synthesis of complex molecular architectures. Herein, leveraging the differences in activation energy barriers among carbon radical precursors and the polarity matching between radicals, this work pioneers the first example of radical 1,4-acylcyanoalkylation to synthesize challenging-to-access ζ-ketonitriles using two identical alkenes. In the metal-free system, 2-(tert-butylperoxy)-2-methylpropane (DTBP) respectively activates α-C−H bonds of aldehydes and alkyl nitriles to generate acyl and cyanoalkyl radicals. The reaction sequence involves selective radical addition of the acyl radical to two identical alkenes, followed by radical-radical coupling with the cyanoalkyl radical, thereby constructing three C−C bonds under simple conditions. Remarkably, when tertiary alkyl aldehydes are employed, decarbonylation preferentially occur to form alkyl radicals, enabling 1,4-alkylcyanoalkylation of alkenes. Mechanistic studies and density functional theory (DFT) calculations reveal that the success of this 1,4-acylcyanoalkylation process is governed by both the preferential addition of acyl radical to alkenes and the thermodynamic stability associated with the two-component alkenes addition cascade.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"607 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329487","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}
In recent years, radical-mediated functionalization of olefins has gradually become a research hotspot in the field of organic synthesis due to its high reactivity, excellent regioselectivity, and wide substrate applicability. Compared to traditional ionic pathways, radical strategies effectively avoid compatibility issues with some functional groups through modes such as photocatalysis, electrocatalysis, or chemical initiation, and provide new pathways for the diversified conversion of olefins, such as bifunctional, hydrogen functionalization, and cyclization reactions. Among them, tert-butyl hydroperoxide (TBHP) plays multiple roles in synthetic chemistry as an efficient and inexpensive oxidant and radical precursor: it is not only a classic initiator of radical chain reactions, but also a source of tert-butyl peroxide, tert-butyl oxygen, methyl, oxygen, hydrogen, or hydroxyl groups. The unique capacity to generate controllable radical species establishes TBHP as an indispensable platform for advancing green synthetic methodologies, empowering pharmaceutical innovation, and deciphering fundamental reaction mechanisms. In this review, we summarize the recent progress in TBHP-enabled transformations of alkenes, which are categorized as peroxidation, carbonylation, epoxidation, etherification, hydrogenation, hydroxylation. Within each category, representative studies are presented, and discussed in terms of mechanistic insights and substrate scope expansion.
{"title":"Radical di- and multi-functionalization of alkenes: Recent advances in diverse reaction modes utilizing TBHP as reactants","authors":"Jiantao Zhang, Renhua Su, Weibing Liu","doi":"10.1039/d5qo00785b","DOIUrl":"https://doi.org/10.1039/d5qo00785b","url":null,"abstract":"In recent years, radical-mediated functionalization of olefins has gradually become a research hotspot in the field of organic synthesis due to its high reactivity, excellent regioselectivity, and wide substrate applicability. Compared to traditional ionic pathways, radical strategies effectively avoid compatibility issues with some functional groups through modes such as photocatalysis, electrocatalysis, or chemical initiation, and provide new pathways for the diversified conversion of olefins, such as bifunctional, hydrogen functionalization, and cyclization reactions. Among them, tert-butyl hydroperoxide (TBHP) plays multiple roles in synthetic chemistry as an efficient and inexpensive oxidant and radical precursor: it is not only a classic initiator of radical chain reactions, but also a source of tert-butyl peroxide, tert-butyl oxygen, methyl, oxygen, hydrogen, or hydroxyl groups. The unique capacity to generate controllable radical species establishes TBHP as an indispensable platform for advancing green synthetic methodologies, empowering pharmaceutical innovation, and deciphering fundamental reaction mechanisms. In this review, we summarize the recent progress in TBHP-enabled transformations of alkenes, which are categorized as peroxidation, carbonylation, epoxidation, etherification, hydrogenation, hydroxylation. Within each category, representative studies are presented, and discussed in terms of mechanistic insights and substrate scope expansion.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"38 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329438","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}
Chiral oxazolidines are pivotal structural motifs commonly found in natural products, medicinally important compounds, and chiral ligands. Among various synthetic strategies, the asymmetric formal (3+2) annulation of donor–acceptor (D–A) aziridines with dipolarophiles has emerged as a powerful method for constructing enantioenriched five-membered azaheterocycles with potential bioactivity. Herein, we present a Cu(II)/chiral phosphoric acid (CPA) cooperative catalytic system for the asymmetric intermolecular (3+2) cycloaddition of D–A aziridines with aldehydes via C–C bond cleavage. This approach enables the efficient and highly enantioselective synthesis of cis-(2S,5S)-1,3-oxazolidines with excellent atom-economy, as well as exceptional chemo-, enantio-, and diastereoselectivities. This novel activation model, distinct from existing catalytic methodologies, serves as a complementary approach that significantly broadens the scope of asymmetric (3+2) cycloaddition of D–A aziridines. Moreover, the resulting chiral oxazolidines exhibited significant anti-proliferative activity against various human cancer cell lines, highlighting their potential for further advancement in medicinal chemistry.
{"title":"Cu/chiral phosphoric acid-catalyzed asymmetric (3+2) cycloaddition of donor-acceptor aziridines with aldehydes: synthesis of enantioenriched oxazolidines as potential antitumor agents","authors":"Zhichao Shi, Tingting Fan, Jin-Shun Lin, Weibin Xie, Feng Zhan, Zhe Wang, Qinglu Zuo, Haoran Fu, Xun Zhang, Qiuhua Huang, Yuyang Jiang","doi":"10.1039/d5qo00729a","DOIUrl":"https://doi.org/10.1039/d5qo00729a","url":null,"abstract":"Chiral oxazolidines are pivotal structural motifs commonly found in natural products, medicinally important compounds, and chiral ligands. Among various synthetic strategies, the asymmetric formal (3+2) annulation of donor–acceptor (D–A) aziridines with dipolarophiles has emerged as a powerful method for constructing enantioenriched five-membered azaheterocycles with potential bioactivity. Herein, we present a Cu(II)/chiral phosphoric acid (CPA) cooperative catalytic system for the asymmetric intermolecular (3+2) cycloaddition of D–A aziridines with aldehydes via C–C bond cleavage. This approach enables the efficient and highly enantioselective synthesis of cis-(2S,5S)-1,3-oxazolidines with excellent atom-economy, as well as exceptional chemo-, enantio-, and diastereoselectivities. This novel activation model, distinct from existing catalytic methodologies, serves as a complementary approach that significantly broadens the scope of asymmetric (3+2) cycloaddition of D–A aziridines. Moreover, the resulting chiral oxazolidines exhibited significant anti-proliferative activity against various human cancer cell lines, highlighting their potential for further advancement in medicinal chemistry.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"16 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329439","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}
Shangyong Wu, Binbin Yuan, Yongke Lei, Xiaoli Su, Tristan von Münchow, João C. A. Oliveira, Xuewu Huang, Zhaojun Ding, Rongrong Xu, Lutz Ackermann, Jiayu Mo
In the realm of sustainable molecular synthesis, metallaelectro-catalysis has emerged as a highly potent platform over the past decade. While significant advancements have been achieved in this field, the development of strategies for late-stage C–H functionalization remains a formidable challenge. In this context, we present an electrochemical rhodium-catalyzed C–H activation strategy that facilitates the selective modification of bioactive compounds. The developed electrocatalysis strategy, enabling the efficient C–H/N–H activations and annulations with a variety of diaryl-, dialkyl-, and unsymmetric alkynes, demonstrates broad tolerance towards a range of medicinally relevant functional groups and thus provides expedient access to modification of bioactive compounds.
{"title":"Rhodaelectro-catalyzed C–H activations directed by pharmacophores: enabling modification of bioactive compounds","authors":"Shangyong Wu, Binbin Yuan, Yongke Lei, Xiaoli Su, Tristan von Münchow, João C. A. Oliveira, Xuewu Huang, Zhaojun Ding, Rongrong Xu, Lutz Ackermann, Jiayu Mo","doi":"10.1039/d5qo00808e","DOIUrl":"https://doi.org/10.1039/d5qo00808e","url":null,"abstract":"In the realm of sustainable molecular synthesis, metallaelectro-catalysis has emerged as a highly potent platform over the past decade. While significant advancements have been achieved in this field, the development of strategies for late-stage C–H functionalization remains a formidable challenge. In this context, we present an electrochemical rhodium-catalyzed C–H activation strategy that facilitates the selective modification of bioactive compounds. The developed electrocatalysis strategy, enabling the efficient C–H/N–H activations and annulations with a variety of diaryl-, dialkyl-, and unsymmetric alkynes, demonstrates broad tolerance towards a range of medicinally relevant functional groups and thus provides expedient access to modification of bioactive compounds.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"2 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319460","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}
Xiaoning Yang, Shuyan Wu, Jiayi Wang, Yanqing Peng, Gonghua Song
Benzoxaboroles and benzodiazaborines are pivotal in medicinal chemistry due to their unique biological activities and potential as therapeutic agents. Herein, we present a room-temperature, nickel-catalyzed borylation protocol for the efficient synthesis. Utilizing an inexpensive nickel catalyst system, this method provides a facile synthetic method for a wide range of target compounds. This cost-effective approach offers a sustainable alternative to traditional palladium-based methods, aligning with green chemistry principles by reducing energy input and enhancing reaction efficiency. In addition to expanding the range of boronic acid derivatives, the developed methodology holds significant promise for advancing applications in drug discovery.
{"title":"Room-temperature nickel-catalyzed borylation/cyclization synthesis of benzoxaboroles and benzodiazaborines","authors":"Xiaoning Yang, Shuyan Wu, Jiayi Wang, Yanqing Peng, Gonghua Song","doi":"10.1039/d5qo00728c","DOIUrl":"https://doi.org/10.1039/d5qo00728c","url":null,"abstract":"Benzoxaboroles and benzodiazaborines are pivotal in medicinal chemistry due to their unique biological activities and potential as therapeutic agents. Herein, we present a room-temperature, nickel-catalyzed borylation protocol for the efficient synthesis. Utilizing an inexpensive nickel catalyst system, this method provides a facile synthetic method for a wide range of target compounds. This cost-effective approach offers a sustainable alternative to traditional palladium-based methods, aligning with green chemistry principles by reducing energy input and enhancing reaction efficiency. In addition to expanding the range of boronic acid derivatives, the developed methodology holds significant promise for advancing applications in drug discovery.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"1 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278650","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}
Effectively improving the ability of electron transfer is the cornerstone of designing pure type I photosensitizers (PSs). At present, the bright strategies are to introduce the electron-rich structures to promote electron transfer capacity. Herein, we developed a novel core with fused heterocyclic ring (bicyclic 2-pyridone, BCP) based on which a series of excellent pure type I PSs can subsequently be constructed. BCP, with the fused heterocyclic rings, can act as an “electronic pool” for forming electron-rich environment. Electrochemical experiments and theoretical calculations prove that BCP has a more significant electron transfer phenomenon compared to the non-conjugated one. Based on BCP, the pure type I PSs core, triphenylamine (electron donor, D) was introduced to produce a molecule (BCP-TPA) with near infrared emission and high type I PDT efficiency by the typical D-π-D structure. BCP-TPA showed superior ability to produce pure type I ROS, which effectively inhibited tumor growth in in vivo experiments. This work provides a new core to synthesize pure type I PSs, combining fused heterocyclic rings to form electron-rich environment.
{"title":"Bicyclic 2-Pyridone, with Fused Heterocyclic Rings, a Facile Core for Pure Type I Photosensitizers","authors":"Zhicheng Ban, Ning Ma, Hui Tang, Xiaoyun Ran, Qian Zhou, Yahui Zhang, Zhouyu Wang, Xiao-Qi Yu","doi":"10.1039/d5qo00684h","DOIUrl":"https://doi.org/10.1039/d5qo00684h","url":null,"abstract":"Effectively improving the ability of electron transfer is the cornerstone of designing pure type I photosensitizers (PSs). At present, the bright strategies are to introduce the electron-rich structures to promote electron transfer capacity. Herein, we developed a novel core with fused heterocyclic ring (bicyclic 2-pyridone, BCP) based on which a series of excellent pure type I PSs can subsequently be constructed. BCP, with the fused heterocyclic rings, can act as an “electronic pool” for forming electron-rich environment. Electrochemical experiments and theoretical calculations prove that BCP has a more significant electron transfer phenomenon compared to the non-conjugated one. Based on BCP, the pure type I PSs core, triphenylamine (electron donor, D) was introduced to produce a molecule (BCP-TPA) with near infrared emission and high type I PDT efficiency by the typical D-π-D structure. BCP-TPA showed superior ability to produce pure type I ROS, which effectively inhibited tumor growth in in vivo experiments. This work provides a new core to synthesize pure type I PSs, combining fused heterocyclic rings to form electron-rich environment.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"22 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268961","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}
A highly efficient and straightforward strategy for the synthesis of benzothiadiazine 1-oxides has been developed, involving copper(I)-catalyzed tandem C–N coupling/condensation cyclization of ortho-haloaryl organyl NH-sulfoximines and aromatic/aliphatic amidines. This protocol exhibits several notable advantages, including the absence of the requirement for an additional nitrogen source, a broad substrate scope, mild reaction conditions, and significant potential for application in the industrial production of benzothiadiazine 1-oxides.
{"title":"Copper(I)-Catalyzed Tandem C−N Coupling/Condensation Cyclization for the Synthesis of Benzothiadiazine 1‑Oxides","authors":"Sihan Zhou, Qingle Zeng","doi":"10.1039/d5qo00681c","DOIUrl":"https://doi.org/10.1039/d5qo00681c","url":null,"abstract":"A highly efficient and straightforward strategy for the synthesis of benzothiadiazine 1-oxides has been developed, involving copper(I)-catalyzed tandem C–N coupling/condensation cyclization of ortho-haloaryl organyl NH-sulfoximines and aromatic/aliphatic amidines. This protocol exhibits several notable advantages, including the absence of the requirement for an additional nitrogen source, a broad substrate scope, mild reaction conditions, and significant potential for application in the industrial production of benzothiadiazine 1-oxides.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"6 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260761","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}
Kinetic resolution of benzhydrols via intramolecular C−H silylation is an efficient method for the preparation of chiral benzhydrols. However, the previously reported methods required sterically demanding phenyl rings to achieve group-selective C−H silylation. Herein, we report the kinetic resolution of trifluoromethylated heterobenzhydrols, bearing both phenyl and thiophene rings, via heteroaryl-selective C−H silylation. We conducted computational studies on the factors influencing the enantioselectivity and heteroaryl selectivity.
{"title":"Kinetic resolution of trifluoromethylated heterobenzhydrols via hydrogen-acceptor-free Ir-catalyzed heteroaryl-selective C−H silylation","authors":"Yoshihiko Yamamoto, Takeshi Yasui, Ryu Tadano","doi":"10.1039/d5qo00725a","DOIUrl":"https://doi.org/10.1039/d5qo00725a","url":null,"abstract":"Kinetic resolution of benzhydrols via intramolecular C−H silylation is an efficient method for the preparation of chiral benzhydrols. However, the previously reported methods required sterically demanding phenyl rings to achieve group-selective C−H silylation. Herein, we report the kinetic resolution of trifluoromethylated heterobenzhydrols, bearing both phenyl and thiophene rings, via heteroaryl-selective C−H silylation. We conducted computational studies on the factors influencing the enantioselectivity and heteroaryl selectivity.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"6 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268909","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}
Animesh Das, Siddhartha Kumar Senapati, Tapashi Das
Hexafluoroisopropanol (HFIP)-mediated a one-pot tandem reduction of quinolines to tetrahydroquinolines followed by reductive alkylation by the aldehyde has been demonstrated through H-bonding network-enabled substrate activation. This step-economical synthetic approach is well suited for late-stage functionalization of complex bioactive molecules. The reaction is highly chemoselective and tolerates a wide range of reducible-sensitive functional groups. The current reductive N-alkylation approach was also successfully utilized to synthesize novel tricyclic oxazino-fused-tetrahydroquinoline/ benzoxazine compounds via tandem reductive cyclization of 1-aryl-2-(8-quinolinyloxy) ethanones and synthesis of Lilolidine derivatives through the reductive N-alkylation of quinoline followed by dehydration cyclization sequence. Scope of the reaction has been further extended to C-functionalized N-alkylated THQ derivatives in a one-pot by using para-quinone methides (p-QMs) or nitroolefins as alkylating precursors. The elucidation of the underlying mechanism was achieved through a combination of several control experiments, kinetic studies, and isotopic labelling experiments.
{"title":"Tandem reductive alkylation of quinolines to functionalized tetrahydroquinolines enabled by HFIP","authors":"Animesh Das, Siddhartha Kumar Senapati, Tapashi Das","doi":"10.1039/d5qo00519a","DOIUrl":"https://doi.org/10.1039/d5qo00519a","url":null,"abstract":"Hexafluoroisopropanol (HFIP)-mediated a one-pot tandem reduction of quinolines to tetrahydroquinolines followed by reductive alkylation by the aldehyde has been demonstrated through H-bonding network-enabled substrate activation. This step-economical synthetic approach is well suited for late-stage functionalization of complex bioactive molecules. The reaction is highly chemoselective and tolerates a wide range of reducible-sensitive functional groups. The current reductive N-alkylation approach was also successfully utilized to synthesize novel tricyclic oxazino-fused-tetrahydroquinoline/ benzoxazine compounds via tandem reductive cyclization of 1-aryl-2-(8-quinolinyloxy) ethanones and synthesis of Lilolidine derivatives through the reductive N-alkylation of quinoline followed by dehydration cyclization sequence. Scope of the reaction has been further extended to C-functionalized N-alkylated THQ derivatives in a one-pot by using para-quinone methides (p-QMs) or nitroolefins as alkylating precursors. The elucidation of the underlying mechanism was achieved through a combination of several control experiments, kinetic studies, and isotopic labelling experiments.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"64 2 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260760","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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