Ting Tang, Ying Han, Chao-Guo Yan, Kun Huang, Jing Sun
A convenient synthetic protocol for diverse functionalized dihydrobenzofuran-fused spirocyclopentane-1,2-diindolin-ones with high diastereoselectivity is developed by base promoted domino annulation reaction of MBH carbonates of isatins and 3-(o-hydroxybenzylidene)indolin-2-ones. The relative configurations of the various polycyclic compounds are clearly elucidated by determination eight single crystal structures.
{"title":"Convenient Synthesis of Dihydrobenzofuran-Fused Spirocyclopentane-1,2-Diindolinone Scaffolds","authors":"Ting Tang, Ying Han, Chao-Guo Yan, Kun Huang, Jing Sun","doi":"10.1002/ejoc.202400777","DOIUrl":"https://doi.org/10.1002/ejoc.202400777","url":null,"abstract":"A convenient synthetic protocol for diverse functionalized dihydrobenzofuran-fused spirocyclopentane-1,2-diindolin-ones with high diastereoselectivity is developed by base promoted domino annulation reaction of MBH carbonates of isatins and 3-(<i>o</i>-hydroxybenzylidene)indolin-2-ones. The relative configurations of the various polycyclic compounds are clearly elucidated by determination eight single crystal structures.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Two cycloaddition modes of isoquinolinium 1,4-zwitterionic thiolates have been established. Upon choosing α-bromo ketones as the counterpart, a range of isoquinoline-fused thiazines can be attained with yields ranging from moderate to excellent through a formal [5 + 1] reaction pathway, exhibiting remarkable substrate adaptability and resilience to diverse functional groups. Additionally, a library of unprecedented thiazepino[5,4-a]isoquinolines, a novel category of seven-membered heterocycles, has been synthesized via a [5 + 2] pathway utilizing acetylenedicarboxylate as the reactive component. Notably, this reaction process stands out for its exceptional 100% atomic utilization efficiency.
{"title":"Assembly of Thiazino[3,4-a]isoquinoline and Thiazepino[5,4-a]isoquinoline Frameworks from Isoquinolinium 1,4-Zwitterionic Thiolates via [5 + 1] and [5 + 2] Cycloaddition Reactions","authors":"Hang-Dong Zuo, Ji-Yun Wang, Yu-Ting Wang, Xiao Zou, Xi Chen, Sheng-Hu Yan, Yue Zhang, Jia-Fa Shen","doi":"10.1002/ejoc.202401020","DOIUrl":"https://doi.org/10.1002/ejoc.202401020","url":null,"abstract":"Two cycloaddition modes of isoquinolinium 1,4-zwitterionic thiolates have been established. Upon choosing α-bromo ketones as the counterpart, a range of isoquinoline-fused thiazines can be attained with yields ranging from moderate to excellent through a formal [5 + 1] reaction pathway, exhibiting remarkable substrate adaptability and resilience to diverse functional groups. Additionally, a library of unprecedented thiazepino[5,4-a]isoquinolines, a novel category of seven-membered heterocycles, has been synthesized via a [5 + 2] pathway utilizing acetylenedicarboxylate as the reactive component. Notably, this reaction process stands out for its exceptional 100% atomic utilization efficiency.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Akshay Kumawat, Sumbul Mansuri, Mary Sravani Galla, Nagula Shankaraiah
A rapid metal-free approach describing one-pot thiocyanation of chromone and coumarin enabling tandem cyclization via potassium thiocyanate as a sulfur surrogate was unveiled. Interestingly, this enaminone-mediated protocol facilitated straightforward access to medicinally significant 2-amino/imino thiazolo fused chromone and coumarin frameworks. This methodology provided good atom-economy, remarkable functional group tolerance, and scalability. Alongside establishing a wide substrate scope, it also provided a feasible scalability up to gram scale.
{"title":"KSCN-mediated one-pot thiocyanation tandem cyclization of enaminones: a facile access to 2-amino/imino thiazolo fused chromone and coumarin frameworks","authors":"Akshay Kumawat, Sumbul Mansuri, Mary Sravani Galla, Nagula Shankaraiah","doi":"10.1002/ejoc.202400690","DOIUrl":"https://doi.org/10.1002/ejoc.202400690","url":null,"abstract":"A rapid metal-free approach describing one-pot thiocyanation of chromone and coumarin enabling tandem cyclization via potassium thiocyanate as a sulfur surrogate was unveiled. Interestingly, this enaminone-mediated protocol facilitated straightforward access to medicinally significant 2-amino/imino thiazolo fused chromone and coumarin frameworks. This methodology provided good atom-economy, remarkable functional group tolerance, and scalability. Alongside establishing a wide substrate scope, it also provided a feasible scalability up to gram scale.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marcio C. S. de Mattos, Carlos Vinícius Pinto dos Santos
A systematic mechanistic study employing kobs kineticsmeasurements, linear free‐energy relationship, hydrogen kinetic isotope effect and rate law, as well as the Density Functional Theory (DFT) approach (M06‐2x/6‐311G(d,p)) for the oxidation of diverse substituted benzyl alcohols with trichloroisocyanuric acid (TCCA) / H2O in 50 % MeCN / CH2Cl2 at 25.0 °C is present. The kinetic results showed an autocatalytic behavior and a primary kinetic isotope effect (4.22). The linear free‐energy relationship (σ, ρ = ‐1.22) indicated a mechanism change for 4‐CF3, 3‐NO2 and 4‐NO2 substituted benzyl alcohols and a fractional rate law (3.25) for benzyl alcohol. The DFT results indicated Cl2, formed in situ from TCCA and the benzyl alcohol, as the actual oxidizing species. Furthermore, calculations support the kinetic results with high agreement through a transition state that performs a hydride abstraction by autocatalytic Cl2 in the induction zone. In the case of substrates bearing strong electron withdrawing groups, the mechanism changes to hydrogen abstraction from the corresponding benzyl hypochlorite as the main pathway.
{"title":"A Mechanistic Study of the Oxidation of Substituted Benzyl Alcohols with Trichloroisocyanuric Acid","authors":"Marcio C. S. de Mattos, Carlos Vinícius Pinto dos Santos","doi":"10.1002/ejoc.202400834","DOIUrl":"https://doi.org/10.1002/ejoc.202400834","url":null,"abstract":"A systematic mechanistic study employing kobs kineticsmeasurements, linear free‐energy relationship, hydrogen kinetic isotope effect and rate law, as well as the Density Functional Theory (DFT) approach (M06‐2x/6‐311G(d,p)) for the oxidation of diverse substituted benzyl alcohols with trichloroisocyanuric acid (TCCA) / H2O in 50 % MeCN / CH2Cl2 at 25.0 °C is present. The kinetic results showed an autocatalytic behavior and a primary kinetic isotope effect (4.22). The linear free‐energy relationship (σ, ρ = ‐1.22) indicated a mechanism change for 4‐CF3, 3‐NO2 and 4‐NO2 substituted benzyl alcohols and a fractional rate law (3.25) for benzyl alcohol. The DFT results indicated Cl2, formed in situ from TCCA and the benzyl alcohol, as the actual oxidizing species. Furthermore, calculations support the kinetic results with high agreement through a transition state that performs a hydride abstraction by autocatalytic Cl2 in the induction zone. In the case of substrates bearing strong electron withdrawing groups, the mechanism changes to hydrogen abstraction from the corresponding benzyl hypochlorite as the main pathway.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An efficient catalytic system employing TMS•OTf for the regioselective thiolation of electron-rich arenes with sulfonyl hydrazides has been developed. The reaction occurs in a solvent mixture of dichloroethane and trifluoroethanol under mild conditions, with the addition of water. This method furnishes a range of para-thio-substituted arenes and 3-sulfenyl-indoles in good to excellent yields, marking a significant advancement in organic synthesis.
{"title":"Lewis acid-promoted C–H Chalcogenation of Arenes and Heteroarenes","authors":"Rahul Vishwakarma, Pragya Sharma, Chinmoy Kumar Hazra","doi":"10.1002/ejoc.202400894","DOIUrl":"https://doi.org/10.1002/ejoc.202400894","url":null,"abstract":"An efficient catalytic system employing TMS•OTf for the regioselective thiolation of electron-rich arenes with sulfonyl hydrazides has been developed. The reaction occurs in a solvent mixture of dichloroethane and trifluoroethanol under mild conditions, with the addition of water. This method furnishes a range of para-thio-substituted arenes and 3-sulfenyl-indoles in good to excellent yields, marking a significant advancement in organic synthesis.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A binary mixture of organic salts, also known as ionic liquids, [C12mim][Br]:[MPIM][HCOO] denoted as BmIL1 has been ex-plored as bifunctional catalyst for the selective synthesis of 2 -phenylquinazolin-4(3H)-ones and 2,3-dihydroquinazolin-(1H)-ones from same precursors under metal, ligand and additive free conditions. The methodology has been extended to the synthesis of 2-phenylquinazolin-4(3H)-ones via another pathway from different precursors under the same catalytic system. Greener synthesis of existing drugs reestablished the multifunctionality of BmIL1. Gram scale synthesis of both the products, DFT calculations and sc-XRD data add significance to the developed protocol. Moreover, high atom economy and eco-scale values justify the sustainability of the methodology.
{"title":"Selective Access to 2-Phenylquinazolin-4(3H)-ones and 2,3-Dihydroquinazolin-4(1H)-ones from Same Precursors in Organic Salts Derived DES","authors":"Bidyutjyoti Dutta, Ramyata Priyam Borah, Lahoucine Bahsis, Apurba Dutta, Bipul Sarma, Kuldeep Singh, Arvind Kumar, Diganta Sarma","doi":"10.1002/ejoc.202400789","DOIUrl":"https://doi.org/10.1002/ejoc.202400789","url":null,"abstract":"A binary mixture of organic salts, also known as ionic liquids, [C12mim][Br]:[MPIM][HCOO] denoted as BmIL1 has been ex-plored as bifunctional catalyst for the selective synthesis of 2 -phenylquinazolin-4(3H)-ones and 2,3-dihydroquinazolin-(1H)-ones from same precursors under metal, ligand and additive free conditions. The methodology has been extended to the synthesis of 2-phenylquinazolin-4(3H)-ones via another pathway from different precursors under the same catalytic system. Greener synthesis of existing drugs reestablished the multifunctionality of BmIL1. Gram scale synthesis of both the products, DFT calculations and sc-XRD data add significance to the developed protocol. Moreover, high atom economy and eco-scale values justify the sustainability of the methodology.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract A family of N,N´-diaryl-N″-(pyridine-2-ylmethyl)guanidines (B) were prepared in 70%−92% yields and subjected to palladium(0) catalyzed aminocarbonylation reactions with aryl iodides using CsOH/CHCl3 mixture as CO surrogate to afford the corresponding N-aroylguanidines (C) in 70%−93% yields. A gram scale synthesis was reported for a representative example. When the aforementioned reaction was carried out with 2-iodoaniline as an electrophile, either a mixture of two distinct 2-aminoquinazolinones (D and E) or one of these 2-aminoquinazolinones are formed. The scope of guanidines and aryl iodides were explored for both of the above-mentioned reactions. The role of directing group in the substrates upon the successful aminocarbonylation of guanidines, B is outlined. When the -C(O)Ar unit in N-aroylguanidines contain 2-aminophenyl unit, a spontaneous cyclisation occurs to afford D or E or a mixture of both. The reactions of a pair of N-aroylguanidines, C with PhI(OAc)2 afforded 2-aminobenzimidazoles, T with unanticipated core. Plausible mechanisms of formation of C, D, E and T are outlined.
摘要 以 70%-92% 的收率制备了一系列 N,N´-二基-N″-(吡啶-2-基甲基)胍 (B)，并使用 CsOH/CHCl3 混合物作为 CO 代用品，在钯（0）催化下与芳基碘化物进行氨基羰基化反应，以 70%-93% 的收率得到相应的 N-芳酰基胍 (C)。报告了一个克级合成的代表性实例。当以 2-iodoaniline 作为亲电子体进行上述反应时，会形成两种不同的 2-氨基喹唑啉酮（D 和 E）的混合物或其中一种 2-氨基喹唑啉酮。在上述两个反应中，都探索了胍类和芳基碘化物的作用范围。本文概述了底物中的指导基团在胍类化合物 B 成功氨基羰基化过程中的作用。当 N-芳酰基胍中的-C(O)Ar 单元含有 2-氨基苯基单元时，会发生自发的环化反应，生成 D 或 E 或两者的混合物。一对 N-芳酰基胍类化合物 C 与 PhI(OAc)2 反应后，得到了具有意外核心的 2-氨基苯并咪唑 T。概述了 C、D、E 和 T 的合理形成机制。
{"title":"Iodoaniline Dependent Formation of N-Aroylguanidines versus 2-Aminoquinazolinones from Palladium(0) Catalysed Aminocarbonylation of N-Arylguanidines","authors":"Natesan Thirupathi, Pooja Nil Yadav","doi":"10.1002/ejoc.202400803","DOIUrl":"https://doi.org/10.1002/ejoc.202400803","url":null,"abstract":"Abstract\u0000A family of N,N´-diaryl-N″-(pyridine-2-ylmethyl)guanidines (B) were prepared in 70%−92% yields and subjected to palladium(0) catalyzed aminocarbonylation reactions with aryl iodides using CsOH/CHCl3 mixture as CO surrogate to afford the corresponding N-aroylguanidines (C) in 70%−93% yields. A gram scale synthesis was reported for a representative example. When the aforementioned reaction was carried out with 2-iodoaniline as an electrophile, either a mixture of two distinct 2-aminoquinazolinones (D and E) or one of these 2-aminoquinazolinones are formed. The scope of guanidines and aryl iodides were explored for both of the above-mentioned reactions. The role of directing group in the substrates upon the successful aminocarbonylation of guanidines, B is outlined. When the -C(O)Ar unit in N-aroylguanidines contain 2-aminophenyl unit, a spontaneous cyclisation occurs to afford D or E or a mixture of both. The reactions of a pair of N-aroylguanidines, C with PhI(OAc)2 afforded 2-aminobenzimidazoles, T with unanticipated core. Plausible mechanisms of formation of C, D, E and T are outlined.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A method for the synthesis of symmetrical and unsymmetrical 3,3'-bis(indolyl)methanes (3,3'-BIMs) has been developed through the direct heteroarylation of indolyl-containing di(hetero)aryl phosphonium salts with indole derivatives in aqueous media. This metal-free reaction proceeds smoothly under mild conditions, eliminating the need for hazardous solvents and expensive additives/catalysts typically used in conventional synthesis routes, thereby highlighting the synthetic practicality and efficiency of the process. The success of this approach is largely attributed to the role of water as a promoter, facilitating the C-P bond functionalization of the phosphonium salts. Furthermore, the reaction demonstrates a broad substrate scope, good functional group tolerance, and excellent scalability. Moreover, the protocol can also be extended to the synthesis of triindolylmethane compound and diarylmethylated indole.
{"title":"Heteroarylation of Organophosphonium Salts with Indoles in Water: Synthesis of Symmetrical and Unsymmetrical 3,3'-Bisindolylmethane Derivatives","authors":"Xin-Long Luo, Wen-Jun Ji, Zi-Lun Yu, Ming-Ming Wang, Chao-Bin Pang, Danhua Ge, Xue-Qiang Chu","doi":"10.1002/ejoc.202400964","DOIUrl":"https://doi.org/10.1002/ejoc.202400964","url":null,"abstract":"A method for the synthesis of symmetrical and unsymmetrical 3,3'-bis(indolyl)methanes (3,3'-BIMs) has been developed through the direct heteroarylation of indolyl-containing di(hetero)aryl phosphonium salts with indole derivatives in aqueous media. This metal-free reaction proceeds smoothly under mild conditions, eliminating the need for hazardous solvents and expensive additives/catalysts typically used in conventional synthesis routes, thereby highlighting the synthetic practicality and efficiency of the process. The success of this approach is largely attributed to the role of water as a promoter, facilitating the C-P bond functionalization of the phosphonium salts. Furthermore, the reaction demonstrates a broad substrate scope, good functional group tolerance, and excellent scalability. Moreover, the protocol can also be extended to the synthesis of triindolylmethane compound and diarylmethylated indole.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A squaramide moiety introduced at the C-4 position of proline produced an organocatalyst that promoted the direct asymmetric aldol addition in the presence of water. A variety of aldol adducts, majorly from the reaction cyclohexanone with aldehydes, were obtained in yields generally in the range of 53-99%, accompanied by 71-97% ee and 82:18 to >99:1 diastereomeric ratios. An asymmetric desymmetrization of 4-alkyl cyclohexanones was also achieved using the transformation.
{"title":"A Squaramide-Tagged Proline-Mediated Direct Asymmetric Aldol Addition in the Presence of Water","authors":"Kiran Kumari, Akram Gulam Hussain Khan, Ajay Kumar Dhiya, Srinivasan Easwar","doi":"10.1002/ejoc.202400992","DOIUrl":"https://doi.org/10.1002/ejoc.202400992","url":null,"abstract":"A squaramide moiety introduced at the C-4 position of proline produced an organocatalyst that promoted the direct asymmetric aldol addition in the presence of water. A variety of aldol adducts, majorly from the reaction cyclohexanone with aldehydes, were obtained in yields generally in the range of 53-99%, accompanied by 71-97% ee and 82:18 to >99:1 diastereomeric ratios. An asymmetric desymmetrization of 4-alkyl cyclohexanones was also achieved using the transformation.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paul Evans, Fahad Alkhathami, Lee Yang Chieng, Yannick Ortin, Marina Rubini
The novel synthesis of racemic cis- and trans-3-fluorofebrifugine and halofuginone is described. This straight-forward seven-step process relies on an electrophilic fluorination-allylation sequence generating a mixture of N-Cbz protected, diastereomeric 2-allyl-3-fluoropiperidines. On separation, a Wacker oxidation-methyl functionalisation sequence enabled introduction of the required quinazolinone portion. Finally, removal of the N-Cbz protecting group lead to isolation of the 3-fluorofebrifugine dihydrobromide analogues that are of potentially pharmacological use. Analysis of the NMR spectra for each stereoisomer provides information concerning the preferred conformers of the different diastereomers. Evidence indicates that the cis-diastereomer favours a conformation where the F-atom occupies an axial orientation. In contrast, for its trans-stereoisomeric counterpart, the 2-substituent overrides any F-atom effect and it preferentially occupies a conformer where both substituents occupy equatorial positions. Finally, interconversion between the cis- and trans-diastereomers was studied. In DMSO-d6 and as their free-bases, isomerisation of each diastereomer gave a common 65:35 ratio of trans- to cis-3-fluorofebrifugine. Determination of the reaction rate constants for the isomerisation process at different temperatures enabled calculation of the activation energy barriers, for each process, using an Arrhenius plot. The activation energy barrier for the isomerisation of the trans-isomer was 94.3 kJ mol-1, whereas for the cis-isomer it was 84.5 kJ mol-1
{"title":"Synthesis of the cis- and trans-3-Fluoro Analogues of Febrifugine and Halofuginone","authors":"Paul Evans, Fahad Alkhathami, Lee Yang Chieng, Yannick Ortin, Marina Rubini","doi":"10.1002/ejoc.202400886","DOIUrl":"https://doi.org/10.1002/ejoc.202400886","url":null,"abstract":"The novel synthesis of racemic cis- and trans-3-fluorofebrifugine and halofuginone is described. This straight-forward seven-step process relies on an electrophilic fluorination-allylation sequence generating a mixture of N-Cbz protected, diastereomeric 2-allyl-3-fluoropiperidines. On separation, a Wacker oxidation-methyl functionalisation sequence enabled introduction of the required quinazolinone portion. Finally, removal of the N-Cbz protecting group lead to isolation of the 3-fluorofebrifugine dihydrobromide analogues that are of potentially pharmacological use. Analysis of the NMR spectra for each stereoisomer provides information concerning the preferred conformers of the different diastereomers. Evidence indicates that the cis-diastereomer favours a conformation where the F-atom occupies an axial orientation. In contrast, for its trans-stereoisomeric counterpart, the 2-substituent overrides any F-atom effect and it preferentially occupies a conformer where both substituents occupy equatorial positions. Finally, interconversion between the cis- and trans-diastereomers was studied. In DMSO-d6 and as their free-bases, isomerisation of each diastereomer gave a common 65:35 ratio of trans- to cis-3-fluorofebrifugine. Determination of the reaction rate constants for the isomerisation process at different temperatures enabled calculation of the activation energy barriers, for each process, using an Arrhenius plot. The activation energy barrier for the isomerisation of the trans-isomer was 94.3 kJ mol-1, whereas for the cis-isomer it was 84.5 kJ mol-1","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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