Chenikkayala Siva Sankara, Shweta Prakash Gaikwad, Suman Das Adhikary, Thekke V. Baiju, Rajni Kumari, Irishi N. N. Namboothiri
The Hauser–Kraus annulation of sulfonylphthalide with Morita–Baylis–Hillman (MBH) adducts of nitroalkenes provides access to phenanthrenes and naphthoquinone fused dihydrobenzoxepines. The H–K annulation results in naphthoquinones bearing a key alcohol group in protected form, which leads to naphthoquinone fused tetracyclic oxepines upon reaction with formaldehyde. These alcohols yield functionalized phenanthrenes via oxidation and [3 + 3] annulation with β-ketoesters.
{"title":"Synthesis of Phenanthrenes and Naphthoquinone Fused Benzoxepines via Hauser–Kraus Annulation of Sulfonylphthalide with Morita–Baylis–Hillman Adducts of Nitroalkenes","authors":"Chenikkayala Siva Sankara, Shweta Prakash Gaikwad, Suman Das Adhikary, Thekke V. Baiju, Rajni Kumari, Irishi N. N. Namboothiri","doi":"10.1021/acs.joc.5c00189","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00189","url":null,"abstract":"The Hauser–Kraus annulation of sulfonylphthalide with Morita–Baylis–Hillman (MBH) adducts of nitroalkenes provides access to phenanthrenes and naphthoquinone fused dihydrobenzoxepines. The H–K annulation results in naphthoquinones bearing a key alcohol group in protected form, which leads to naphthoquinone fused tetracyclic oxepines upon reaction with formaldehyde. These alcohols yield functionalized phenanthrenes via oxidation and [3 + 3] annulation with β-ketoesters.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"6 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832538","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}
Spirocyclic motifs are attracting increasing attention owing to their three-dimensional geometries that endow bioactive molecules with superior physical and biological properties. We developed an efficient method for constructing spirocyclic phthalans via the Ru-catalyzed [2 + 2 + 2] cycloaddition of cycloalkanone-derived 1,6-diynes with acetylene gas ex-situ-generated from calcium carbide and H2O.
{"title":"Synthesis of Spirocyclic Phthalans via Ru-Catalyzed [2 + 2 + 2] Cycloaddition of 1,6-Diynes with Ex-Situ Generated Acetylene","authors":"Yoshihiko Yamamoto, Kenichi Yoshimura, Takeshi Yasui","doi":"10.1021/acs.joc.5c00486","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00486","url":null,"abstract":"Spirocyclic motifs are attracting increasing attention owing to their three-dimensional geometries that endow bioactive molecules with superior physical and biological properties. We developed an efficient method for constructing spirocyclic phthalans via the Ru-catalyzed [2 + 2 + 2] cycloaddition of cycloalkanone-derived 1,6-diynes with acetylene gas ex-situ<i>-</i>generated from calcium carbide and H<sub>2</sub>O.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"97 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836891","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}
Huilin Liao, Xianfu Fang, Huihong Wang, Chang Chen, Gong Zhang, Yangfeng Li, Yizhou Li
DNA-encoded libraries (DELs) have emerged as powerful tools in drug discovery. Protected amino acids serve as essential building blocks in the construction of DELs, resulting in the widespread presence of amino groups within these libraries. N-formylation of free amines not only enhances the activity of lead compounds but also functions as an effective amino-protecting strategy. In this study, we introduce trimethyl(bromodifluoromethyl)silane (TMSCF2Br) as a novel N-formylation reagent for DEL synthesis. This approach demonstrates robustness in DEL-compatible synthesis and enables library diversification through functional group transformation (FGT). Additionally, we achieved efficient removal of formyl groups, enabling the formyl group to be strategically used for on-DNA amino protection orthogonal to Fmoc and Boc groups.
{"title":"DNA-Compatible N-Formylation of Amines by Using TMSCF2Br","authors":"Huilin Liao, Xianfu Fang, Huihong Wang, Chang Chen, Gong Zhang, Yangfeng Li, Yizhou Li","doi":"10.1021/acs.joc.5c00055","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00055","url":null,"abstract":"DNA-encoded libraries (DELs) have emerged as powerful tools in drug discovery. Protected amino acids serve as essential building blocks in the construction of DELs, resulting in the widespread presence of amino groups within these libraries. <i>N</i>-formylation of free amines not only enhances the activity of lead compounds but also functions as an effective amino-protecting strategy. In this study, we introduce trimethyl(bromodifluoromethyl)silane (TMSCF<sub>2</sub>Br) as a novel <i>N</i>-formylation reagent for DEL synthesis. This approach demonstrates robustness in DEL-compatible synthesis and enables library diversification through functional group transformation (FGT). Additionally, we achieved efficient removal of formyl groups, enabling the formyl group to be strategically used for on-DNA amino protection orthogonal to Fmoc and Boc groups.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"74 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832537","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}
Kexin Pang, Xin Li, Man Wang, Ran Song, Daoshan Yang, Jian Lv
CF3-substituted tertiary alcohols are valuable as biologically active compounds, but the synthesis of the corresponding cyclopentadiene derivatives remains challenging. The DABCO-catalyzed 1,2-addition reaction of trifluoropyruvates with 2,4-dihydrocyclopenta[b]indoles has been developed, affording CF3-substituted tertiary alcohols in up to 90% yield and with up to >99:1 dr. The catalytic reaction is facilitated by hydrogen bonding (N–H···N) between the cyclic tertiary amine and the indole moiety. Additionally, Et3N (1.0 equiv) can promote the retro-1,2-addition reaction of the CF3-subsituted tertiary alcohols, yielding dihydrocyclopenta[b]indole 1 in up to 72% yield.
{"title":"Hydrogen-Bonding Assisted Catalytic 1,2-Addition Reaction of Trifluoropyruvate with 2,4-Dihydrocylopenta[b]indoles","authors":"Kexin Pang, Xin Li, Man Wang, Ran Song, Daoshan Yang, Jian Lv","doi":"10.1021/acs.joc.5c00418","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00418","url":null,"abstract":"CF<sub>3</sub>-substituted tertiary alcohols are valuable as biologically active compounds, but the synthesis of the corresponding cyclopentadiene derivatives remains challenging. The DABCO-catalyzed 1,2-addition reaction of trifluoropyruvates with 2,4-dihydrocyclopenta[<i>b</i>]indoles has been developed, affording CF<sub>3</sub>-substituted tertiary alcohols in up to 90% yield and with up to >99:1 dr. The catalytic reaction is facilitated by hydrogen bonding (N–H···N) between the cyclic tertiary amine and the indole moiety. Additionally, Et<sub>3</sub>N (1.0 equiv) can promote the retro-1,2-addition reaction of the CF<sub>3</sub>-subsituted tertiary alcohols, yielding dihydrocyclopenta[<i>b</i>]indole <b>1</b> in up to 72% yield.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"42 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832541","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}
We report herein a method of substrate-controlled pentafluorosulfanylation of activated alkenes containing the benzimidazole moiety with SF5Cl, which provides a highly efficient way to access SF5-containing benzo[4,5]imidazole[2,1-a]isoquinolin-6(5H)-ones, as well as SF5-containing N-benzoyl benzimidazoles. Besides the pentafluorosulfanyl group (−SF5), the current method can be applied to the tetrafluorosulfanyl group (−SF4−) incorporation. A radical mechanism involving single electron transfer (SET) or the atom transfer radical addition (ATRA) process is proposed.
{"title":"Substrate-Controlled Pentafluorosulfanylation of Activated Alkenes Containing the Benzimidazole Moiety with SF5Cl","authors":"Xinqiang Tan, Yuezhen Li, Shijie Liu, Ziyou Hao, Yingchang Guo, Ruiping Fan, Yunhui Yan, Jianmei Yuan, Lizhen Fang, Ping-Xin Zhou, Hao Tang, Yingling Wang","doi":"10.1021/acs.joc.5c00103","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00103","url":null,"abstract":"We report herein a method of substrate-controlled pentafluorosulfanylation of activated alkenes containing the benzimidazole moiety with SF<sub>5</sub>Cl, which provides a highly efficient way to access SF<sub>5</sub>-containing benzo[4,5]imidazole[2,1-<i>a</i>]isoquinolin-6(5<i>H</i>)-ones, as well as SF<sub>5</sub>-containing <i>N</i>-benzoyl benzimidazoles. Besides the pentafluorosulfanyl group (−SF<sub>5</sub>), the current method can be applied to the tetrafluorosulfanyl group (−SF<sub>4</sub>−) incorporation. A radical mechanism involving single electron transfer (SET) or the atom transfer radical addition (ATRA) process is proposed.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"6 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827285","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}
Chuantao Huang, Wenlin Zhang, Ying Liu, Zhixin Zhang, Jun Gong, Xiaobo Wang, Ping Xue, Li Feng, Helin Lu
Tetrahydro-γ-carbolines are especially outstanding fused heterocyclic ring systems possessing significant biological activities in the central nervous system. Here, using commercially available NBE derivatives (NBEs), we report an efficient protocol for the one-pot modular synthesis of 4-substituted tetrahydro-γ-carbolines via Catellani/aza-Michael addition cascade from easily available 3-iodo-1-tosyl-1H-indole, aziridines and olefins. This approach exhibits a wide substrate scope, good yields, scalability, and potential extension toward the synthesis of Mebhydroline analogues.
{"title":"Pd/NBE-Catalyzed One-Pot Modular Synthesis of Tetrahydro-γ-carbolines","authors":"Chuantao Huang, Wenlin Zhang, Ying Liu, Zhixin Zhang, Jun Gong, Xiaobo Wang, Ping Xue, Li Feng, Helin Lu","doi":"10.1021/acs.joc.5c00158","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00158","url":null,"abstract":"Tetrahydro-γ-carbolines are especially outstanding fused heterocyclic ring systems possessing significant biological activities in the central nervous system. Here, using commercially available NBE derivatives (NBEs), we report an efficient protocol for the one-pot modular synthesis of 4-substituted tetrahydro-γ-carbolines via Catellani/aza-Michael addition cascade from easily available 3-iodo-1-tosyl-1<i>H</i>-indole, aziridines and olefins. This approach exhibits a wide substrate scope, good yields, scalability, and potential extension toward the synthesis of Mebhydroline analogues.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"218 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832501","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}
Feddro Gilbert Wijaya, Sopan Pralhad Khandare, Dániel Csókás, Raghunath O. Ramabhadran, Roderick W. Bates
A synthesis of (−)-viriditin A and (−)-viriditin B has been completed sequentially using a Suzuki coupling and a Heck reaction of trans-1,2-dichloroethylene. The selectivity for monocoupling of trans-1,2-dichloroethylene is attributed to a lower-energy transition state for the oxidative addition step.
{"title":"Synthesis of Viriditins A and B by Selective Coupling of Trans-1,2-Dichloroethylene","authors":"Feddro Gilbert Wijaya, Sopan Pralhad Khandare, Dániel Csókás, Raghunath O. Ramabhadran, Roderick W. Bates","doi":"10.1021/acs.joc.4c02975","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02975","url":null,"abstract":"A synthesis of (−)-viriditin A and (−)-viriditin B has been completed sequentially using a Suzuki coupling and a Heck reaction of <i>trans</i>-1,2-dichloroethylene. The selectivity for monocoupling of <i>trans</i>-1,2-dichloroethylene is attributed to a lower-energy transition state for the oxidative addition step.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"26 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827282","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}
Azobenzenes are promising materials for energy storage due to their reversible photoisomerization and redox properties. Given the critical role of redox behavior in the latter application, an investigation of their redox processes is essential. We propose a classification of azobenzenes into two categories: benzenoid-type and quinoid-type, based on the mechanism of their oxidation. Benzenoid-type compounds have been extensively studied due to their reversible reduction. Quinoid-type compounds exhibit oxidative and reductive versatility, making them promising for further research in energy storage.
{"title":"Electrochemistry of Azobenzenes and Its Potential for Energy Storage","authors":"Dominic Schatz, Hermann A. Wegner","doi":"10.1021/acs.joc.5c00315","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00315","url":null,"abstract":"Azobenzenes are promising materials for energy storage due to their reversible photoisomerization and redox properties. Given the critical role of redox behavior in the latter application, an investigation of their redox processes is essential. We propose a classification of azobenzenes into two categories: <i>benzenoid</i>-type and <i>quinoid</i>-type, based on the mechanism of their oxidation. <i>Benzenoid</i>-type compounds have been extensively studied due to their reversible reduction. <i>Quinoid</i>-type compounds exhibit oxidative and reductive versatility, making them promising for further research in energy storage.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"40 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832544","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}
Yoshihara, Hiroki, Yagi, and Itami utilized an unusual Friedel–Crafts-like alkylation in the synthesis of an adamantane-annulated arene. The precursor was a 3° carbocation, which they proposed undergoes a Wagner–Meerwein shift to a 2° carbocation, which subsequently alkylates a benzene ring. This mechanism was supported by their DFT calculations. However, their choice of the B3LYP functional often finds false transition structures. A more appropriate functional showed that the alkylation occurs via a concerted reaction.
{"title":"An Unusual Friedel–Crafts Reaction and Violation of the Markovnikov Rule in the Formation of an Adamantyl Arene","authors":"B. Andes Hess, Jr, Lidia Smentek","doi":"10.1021/acs.joc.5c00215","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00215","url":null,"abstract":"Yoshihara, Hiroki, Yagi, and Itami utilized an unusual Friedel–Crafts-like alkylation in the synthesis of an adamantane-annulated arene. The precursor was a 3° carbocation, which they proposed undergoes a Wagner–Meerwein shift to a 2° carbocation, which subsequently alkylates a benzene ring. This mechanism was supported by their DFT calculations. However, their choice of the B3LYP functional often finds false transition structures. A more appropriate functional showed that the alkylation occurs via a concerted reaction.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"1 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832543","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}
Ajal P. Shaji, Nachiketh Sudarshan, Burkhard König, Purushothaman Gopinath
Herein, we describe the photomediated radical cascade addition–cyclization of N-butenoyl tetrahydroquinolines to access various functionalized julolidine-5-one. The scope of the methodology was illustrated with several sulfonyl chlorides and tetrahydroquinolines. Other radical precursors, such as trifluoromethyl, bromoacetonitrile, bromoacetates, etc., also worked efficiently, demonstrating the broad utility of the method. Finally, large-scale synthesis of sulfonyl-substituted julolidine-5-one and downstream conversions of the synthesized julolidine derivatives were carried out to illustrate the synthetic utility of the methodology.
{"title":"Photomediated Radical Cascade Addition–Cyclization of N-Butenoyl Tetrahydroquinolines: Accessing Functionalized Julolidines","authors":"Ajal P. Shaji, Nachiketh Sudarshan, Burkhard König, Purushothaman Gopinath","doi":"10.1021/acs.joc.5c00234","DOIUrl":"https://doi.org/10.1021/acs.joc.5c00234","url":null,"abstract":"Herein, we describe the photomediated radical cascade addition–cyclization of N-butenoyl tetrahydroquinolines to access various functionalized julolidine-5-one. The scope of the methodology was illustrated with several sulfonyl chlorides and tetrahydroquinolines. Other radical precursors, such as trifluoromethyl, bromoacetonitrile, bromoacetates, etc., also worked efficiently, demonstrating the broad utility of the method. Finally, large-scale synthesis of sulfonyl-substituted julolidine-5-one and downstream conversions of the synthesized julolidine derivatives were carried out to illustrate the synthetic utility of the methodology.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"34 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827281","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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