Pub Date : 2024-10-22DOI: 10.1021/acs.orglett.4c03680
Subhasish Ray, Nimisha Gupta, Maya Shankar Singh
An operationally simple and highly efficient synthesis of functionalized thiophenes has been developed by LiBr promoted heteroannulation of β-ketodithioesters and thioamides with bench-stable sulfoxonium ylides in open air for the first time. This one-pot strategy involves formal Csp3-H bond insertion/intramolecular cyclization cascade, featuring readily accessible starting materials, TM and additive-free condition, broad substrate scope, high functional group compatibility, and scalability. Moreover, the carbonyl, thiomethyl, and amino groups in the resulting thiophene provide a good handle on downstream transformations.
{"title":"LiBr-Promoted Reaction of β-Ketodithioesters and Thioamides with Sulfoxonium Ylides to Synthesize Functionalized Thiophenes.","authors":"Subhasish Ray, Nimisha Gupta, Maya Shankar Singh","doi":"10.1021/acs.orglett.4c03680","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03680","url":null,"abstract":"<p><p>An operationally simple and highly efficient synthesis of functionalized thiophenes has been developed by LiBr promoted heteroannulation of β-ketodithioesters and thioamides with bench-stable sulfoxonium ylides in open air for the first time. This one-pot strategy involves formal Csp<sup>3</sup>-H bond insertion/intramolecular cyclization cascade, featuring readily accessible starting materials, TM and additive-free condition, broad substrate scope, high functional group compatibility, and scalability. Moreover, the carbonyl, thiomethyl, and amino groups in the resulting thiophene provide a good handle on downstream transformations.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453472","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 two-step procedure, combining a SmI2-mediated transannular pinacol coupling reaction with an acid-catalyzed pinacol rearrangement process, was employed to prepare a diverse range of 1-substituted bicyclo[2.1.1]hexan-5-ones from cyclobutanedione derivatives. To underscore the significance of these bicyclic ketones in drug synthesis, an sp3-rich analog of nitazoxanide, a well-known antiparasitic and antiviral agent, was synthesized.
{"title":"Synthesis of 1-Substituted Bicyclo[2.1.1]hexan-2-ones via a Sequential SmI<sub>2</sub>-Mediated Pinacol Coupling and Acid-Catalyzed Pinacol Rearrangement Reaction.","authors":"Yung-Chi Lee, Yi-Chen Chen, Chun-Fu Wu, Woo-Jin Yoo","doi":"10.1021/acs.orglett.4c03541","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03541","url":null,"abstract":"<p><p>A two-step procedure, combining a SmI<sub>2</sub>-mediated transannular pinacol coupling reaction with an acid-catalyzed pinacol rearrangement process, was employed to prepare a diverse range of 1-substituted bicyclo[2.1.1]hexan-5-ones from cyclobutanedione derivatives. To underscore the significance of these bicyclic ketones in drug synthesis, an sp<sup>3</sup>-rich analog of nitazoxanide, a well-known antiparasitic and antiviral agent, was synthesized.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453475","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 : 2024-10-22DOI: 10.1021/acs.orglett.4c03653
Yu-Lian Zhao, Xuehong Min, Lijing Li, Xiao-Le Han, Yi Wei, Xiao-Qiang Hu
Herein, a direct transformation of aliphatic C-H bonds to oxime ethers has been developed via light-promoted hydrogen atom transfer (HAT) in the absence of a photocatalyst. Singlet oxygen and chlorine radical are complementary C(sp3)-H bond cleaving agents in this reaction, enabling the extraction of hydrogen atoms from a diverse range of compounds, like cycloalkanes, ethers, amines, amides, and cyclic sulfides. This method excels in transforming common aliphatic C-H bonds into valuable oxime ethers featuring abundant chemical feedstocks, good functional group tolerance, and catalyst free conditions.
{"title":"Photocatalyst-Free Transformation of C(sp<sup>3</sup>)-H Bonds to Oxime Ethers via Photoinduced Hydrogen Atom Transfer.","authors":"Yu-Lian Zhao, Xuehong Min, Lijing Li, Xiao-Le Han, Yi Wei, Xiao-Qiang Hu","doi":"10.1021/acs.orglett.4c03653","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03653","url":null,"abstract":"<p><p>Herein, a direct transformation of aliphatic C-H bonds to oxime ethers has been developed via light-promoted hydrogen atom transfer (HAT) in the absence of a photocatalyst. Singlet oxygen and chlorine radical are complementary C(sp<sup>3</sup>)-H bond cleaving agents in this reaction, enabling the extraction of hydrogen atoms from a diverse range of compounds, like cycloalkanes, ethers, amines, amides, and cyclic sulfides. This method excels in transforming common aliphatic C-H bonds into valuable oxime ethers featuring abundant chemical feedstocks, good functional group tolerance, and catalyst free conditions.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453473","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c03372
Giulio Gallorini, Sofia Kiriakidi, Sara Bellini, Carlos Silva López, Giulio Bertuzzi, Marco Bandini
The site-selective alkylation of α-aminotropones is effectively realized via gold(I)-catalyzed electrophilic activation of allenamides and allenyl ethers, yielding up to 85% in 30 examples. A dedicated and combined spectroscopic and computational investigation accounts for both chemo- and regioselective profiles of the protocol. New opportunities in the chemical space of tropone/tropolone derivatives are identified.
{"title":"Site-Selective Gold-Catalyzed Alkylation of α-Aminotropones with Allenes","authors":"Giulio Gallorini, Sofia Kiriakidi, Sara Bellini, Carlos Silva López, Giulio Bertuzzi, Marco Bandini","doi":"10.1021/acs.orglett.4c03372","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03372","url":null,"abstract":"The site-selective alkylation of α-aminotropones is effectively realized via gold(I)-catalyzed electrophilic activation of allenamides and allenyl ethers, yielding up to 85% in 30 examples. A dedicated and combined spectroscopic and computational investigation accounts for both chemo- and regioselective profiles of the protocol. New opportunities in the chemical space of tropone/tropolone derivatives are identified.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452382","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c03187
Mengting Tan, Yunping Zheng, Sen Zhang, Hui Yao, Xin Yan, Xing Zhao, Mingguo Liu, Nianyu Huang, Nengzhong Wang
Controlling the selectivity of reactions is a significantly attractive strategy in synthetic organic chemistry. Herein, an efficient base-controlled chemodivergent domino reaction between o-aminochalcones and γ-bromocrotonates has been developed. A series of cis-2,3-disubstituted indolines and cyclopropane-fused tetrahydroquinolines were obtained via two pathways with a broad substrate scope in moderate to excellent yields under transition-metal-free conditions. It is noteworthy that the γ-bromocrotonates could be used as C1 or C2 synthons by modulating the base; in particular, the γ-bromocrotonates were used as both nucleophiles and electrophiles to generate cyclopropanes for the first time.
{"title":"Base-Controlled Chemodivergent [4 + 1] and [2 + 1]/[4 + 2] Annulations of o-Aminochalcones with γ-Bromocrotonates","authors":"Mengting Tan, Yunping Zheng, Sen Zhang, Hui Yao, Xin Yan, Xing Zhao, Mingguo Liu, Nianyu Huang, Nengzhong Wang","doi":"10.1021/acs.orglett.4c03187","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03187","url":null,"abstract":"Controlling the selectivity of reactions is a significantly attractive strategy in synthetic organic chemistry. Herein, an efficient base-controlled chemodivergent domino reaction between <i>o</i>-aminochalcones and <i>γ-</i>bromocrotonates has been developed. A series of <i>cis</i>-2,3-disubstituted indolines and cyclopropane-fused tetrahydroquinolines were obtained via two pathways with a broad substrate scope in moderate to excellent yields under transition-metal-free conditions. It is noteworthy that the <i>γ-</i>bromocrotonates could be used as C1 or C2 synthons by modulating the base; in particular, the <i>γ-</i>bromocrotonates were used as both nucleophiles and electrophiles to generate cyclopropanes for the first time.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452386","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c03336
Nassim Maarouf Mesli, Pierre Chaurand, William D Lubell
Cholesterol was explored as a support for liquid-phase synthesis. Without the need for chromatography, the cholesterol-supported liquid-phase approach gave access to diverse betaines possessing chiral ammonium, phosphonium, and sulfonium ions. The cholesterol-supported method was further demonstrated by the synthesis of cationic amides and hydrazides.
{"title":"Cholesterol-Supported Liquid-Phase Synthesis of Betaines and Organic Cations without Chromatography.","authors":"Nassim Maarouf Mesli, Pierre Chaurand, William D Lubell","doi":"10.1021/acs.orglett.4c03336","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03336","url":null,"abstract":"<p><p>Cholesterol was explored as a support for liquid-phase synthesis. Without the need for chromatography, the cholesterol-supported liquid-phase approach gave access to diverse betaines possessing chiral ammonium, phosphonium, and sulfonium ions. The cholesterol-supported method was further demonstrated by the synthesis of cationic amides and hydrazides.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453471","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c02221
Olivier Lorthioir, Niall Anderson, Scott Boyd, Luca Carlino, Paul Davey, William Hodds, Megan Howard, Marika Lindhagen, Katie Proctor, Okky Dwichandra Putra, Theo Smith, Oliver Turner, Alfie Woodhouse, Millie Woodward
Saturated isosteres of the ortho-substituted benzene ring remain rare due to the paucity of methods to access complex bridged systems. Using blue-light-mediated [2 + 2] photocycloaddition chemistry, we have developed a quick and practical route to provide novel 2-oxabicyclo[2.1.1]hexanes from simple feedstock materials in only three steps. Matched pair analysis confirmed that this motif could prove useful in the future to the drug discovery community as a scaffold endowed with remarkable properties.
{"title":"Access to 2-Oxabicyclo[2.1.1]hexanes and their use in Scaffold Hopping","authors":"Olivier Lorthioir, Niall Anderson, Scott Boyd, Luca Carlino, Paul Davey, William Hodds, Megan Howard, Marika Lindhagen, Katie Proctor, Okky Dwichandra Putra, Theo Smith, Oliver Turner, Alfie Woodhouse, Millie Woodward","doi":"10.1021/acs.orglett.4c02221","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c02221","url":null,"abstract":"Saturated isosteres of the <i>ortho</i>-substituted benzene ring remain rare due to the paucity of methods to access complex bridged systems. Using blue-light-mediated [2 + 2] photocycloaddition chemistry, we have developed a quick and practical route to provide novel 2-oxabicyclo[2.1.1]hexanes from simple feedstock materials in only three steps. Matched pair analysis confirmed that this motif could prove useful in the future to the drug discovery community as a scaffold endowed with remarkable properties.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452161","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c03429
Fei Li, Jianyang Dong, Chenya Wang, Huijuan Liao, Jiayi Dang, Juan Zhou, Gang Li, Dong Xue
Bicyclo[1.1.1]pentanes (BCPs) play a crucial role in drug discovery research as C(sp3)-rich bioisosteres of benzene rings. However, the preparation of BCPs with strong alkane C(sp3)–H bonds has not been reported to date. In this study, we reported a method for light-induced benzyl alcohol functionalization of [1.1.1]propellane with aliphatic hydrocarbons (which have not previously been explored for this purpose) and aldehydes under metal- and photocatalyst-free conditions. The BCP products could be transformed into various useful derivatives, demonstrating the utility of the method. Notably, we achieved the synthesis of functionalized BCPs with simple alkanes.
{"title":"Benzyl Alcohol Functionalization of [1.1.1]Propellane with Alkanes and Aldehydes","authors":"Fei Li, Jianyang Dong, Chenya Wang, Huijuan Liao, Jiayi Dang, Juan Zhou, Gang Li, Dong Xue","doi":"10.1021/acs.orglett.4c03429","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03429","url":null,"abstract":"Bicyclo[1.1.1]pentanes (BCPs) play a crucial role in drug discovery research as C(sp<sup>3</sup>)-rich bioisosteres of benzene rings. However, the preparation of BCPs with strong alkane C(sp<sup>3</sup>)–H bonds has not been reported to date. In this study, we reported a method for light-induced benzyl alcohol functionalization of [1.1.1]propellane with aliphatic hydrocarbons (which have not previously been explored for this purpose) and aldehydes under metal- and photocatalyst-free conditions. The BCP products could be transformed into various useful derivatives, demonstrating the utility of the method. Notably, we achieved the synthesis of functionalized BCPs with simple alkanes.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452383","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c03453
Lei Xu, Fan Zhang, Yan-En Wang, Congcong Bai, Dan Xiong, Jianyou Mao
A highly regioselective cobalt-catalyzed three-component alkyl arylation of acrylates with alkyl iodides and aryl Grignard reagents has been established. The reaction efficiently provides an alternative strategy for the construction of α-aryl esters with a broad substrate scope and good yields under mild conditions. The practical applicability of this protocol is shown by the scaled-up reaction and further transformations of the products. In addition, the preliminary mechanistic explorations demonstrated that the alkyl radicals generated by the efficient cobalt catalysis are instantaneously added to the acrylates to finally afford the desired products.
{"title":"Cobalt-Catalyzed Three-Component Alkyl Arylation of Acrylates with Alkyl Iodides and Aryl Grignard Reagents","authors":"Lei Xu, Fan Zhang, Yan-En Wang, Congcong Bai, Dan Xiong, Jianyou Mao","doi":"10.1021/acs.orglett.4c03453","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03453","url":null,"abstract":"A highly regioselective cobalt-catalyzed three-component alkyl arylation of acrylates with alkyl iodides and aryl Grignard reagents has been established. The reaction efficiently provides an alternative strategy for the construction of α-aryl esters with a broad substrate scope and good yields under mild conditions. The practical applicability of this protocol is shown by the scaled-up reaction and further transformations of the products. In addition, the preliminary mechanistic explorations demonstrated that the alkyl radicals generated by the efficient cobalt catalysis are instantaneously added to the acrylates to finally afford the desired products.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452388","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 : 2024-10-21DOI: 10.1021/acs.orglett.4c03091
Hussain A. Maashi, Abdulrahman H. Husayni, Kharou M, Michael E. Reid, James Harnedy, Ethan C. Herneman, Marc Pera-Titus, Louis C. Morrill
Herein we report an electrochemical deconstructive functionalization approach for the synthesis of C(sp3)-rich heterocycles. The reaction proceeds via the mesolytic cleavage of anodically generated aromatic radical cations and the trapping of formed carbocation intermediates with internal nucleophiles. The method has been demonstrated across various arylalcohol substrates to access a diverse range of C(sp3)-rich heterocycles including tetrahydrofuran, tetrahydropyran, and pyrrolidine scaffolds (26 examples). The electrochemical method was demonstrated on a 5 mmol scale via single pass continuous flow, which utilized lower supporting electrolyte concentration and exhibited increased productivity in relation to the batch process.
{"title":"Electrochemical Synthesis of C(sp3)-Rich Heterocycles via Mesolytic Cleavage of Anodically Generated Aromatic Radical Cations","authors":"Hussain A. Maashi, Abdulrahman H. Husayni, Kharou M, Michael E. Reid, James Harnedy, Ethan C. Herneman, Marc Pera-Titus, Louis C. Morrill","doi":"10.1021/acs.orglett.4c03091","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03091","url":null,"abstract":"Herein we report an electrochemical deconstructive functionalization approach for the synthesis of C(sp<sup>3</sup>)-rich heterocycles. The reaction proceeds <i>via</i> the mesolytic cleavage of anodically generated aromatic radical cations and the trapping of formed carbocation intermediates with internal nucleophiles. The method has been demonstrated across various arylalcohol substrates to access a diverse range of C(sp<sup>3</sup>)-rich heterocycles including tetrahydrofuran, tetrahydropyran, and pyrrolidine scaffolds (26 examples). The electrochemical method was demonstrated on a 5 mmol scale <i>via</i> single pass continuous flow, which utilized lower supporting electrolyte concentration and exhibited increased productivity in relation to the batch process.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452165","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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