ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

  • Bohdan A. Chalyk
    Bohdan A. Chalyk
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
  • Kateryna V. Hrebeniuk
    Kateryna V. Hrebeniuk
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
  • Yulia V. Fil
    Yulia V. Fil
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    More by Yulia V. Fil
  • Konstantin S. Gavrilenko
    Konstantin S. Gavrilenko
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
  • Alexander B. Rozhenko
    Alexander B. Rozhenko
    Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
  • Bohdan V. Vashchenko
    Bohdan V. Vashchenko
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
  • Oleksandr V. Borysov
    Oleksandr V. Borysov
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
  • Angelina V. Biitseva
    Angelina V. Biitseva
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
  • Pavlo S. Lebed
    Pavlo S. Lebed
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
  • Iulia Bakanovych
    Iulia Bakanovych
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
  • Yurii S. Moroz
    Yurii S. Moroz
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Chemspace, Ilukstes iela 38-5, Riga LV-1082, Latvia
  • , and 
  • Oleksandr O. Grygorenko*
    Oleksandr O. Grygorenko
    Enamine Ltd, (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
    Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
    *E-mail: [email protected]
Cite this: J. Org. Chem. 2019, 84, 24, 15877–15899
Publication Date (Web):October 18, 2019
https://doi.org/10.1021/acs.joc.9b02264
Copyright © 2019 American Chemical Society

    Article Views

    2259

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (2)»

    Abstract

    Abstract Image

    A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert–Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b02264.

    • 1H, 13C, and 19F NMR spectra, molecular structure of the compound 3h, and computational data (PDF)

    • Crystallographic information file (CIF)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 26 publications.

    1. Weidi Zeng, Hui Li, Duozhi Wang, Lei Zhou. Regioselective Synthesis of 3-Trifluoromethylpyrroles by [3 + 2] Cycloaddition of N-Acyl α-Amino Acids and 2-Bromo-3,3,3-trifluoropropene. The Journal of Organic Chemistry 2023, 88 (19) , 14088-14095. https://doi.org/10.1021/acs.joc.3c01611
    2. Paramita Pattanayak, Tanmay Chatterjee. Synthesis of (4-Trifluoromethyl)isoxazoles through a Tandem Trifluoromethyloximation/Cyclization/Elimination Reaction of α,β-Unsaturated Carbonyls. The Journal of Organic Chemistry 2023, 88 (9) , 5420-5430. https://doi.org/10.1021/acs.joc.2c03053
    3. Ekaterina E. Galenko, Aleksandra M. Puzyk, Mikhail S. Novikov, Alexander F. Khlebnikov. An Isoxazole Strategy for Molybdenum-Mediated Synthesis of 5-Mono- and 4,5-Disubstituted 1H-Pyrrole-2,3-diones. The Journal of Organic Chemistry 2022, 87 (9) , 6459-6470. https://doi.org/10.1021/acs.joc.2c00386
    4. Bohdan A. Chalyk, Andrii V. Khutorianskyi, Bohdan V. Vashchenko, Kyrylo Danyleiko, Anastasiia Grynyova, Anastasiia O. Osipova, Andriy Kozytskiy, Darya Syniuchenko, Anton Tsymbaliuk, Konstantin S. Gavrilenko, Angelina V. Biitseva, Dmitriy M. Volochnyuk, Igor V. Komarov, Oleksandr O. Grygorenko. Reductive Recyclization of sp3-Enriched Functionalized Isoxazolines into α-Hydroxy Lactams. The Journal of Organic Chemistry 2022, 87 (2) , 1001-1018. https://doi.org/10.1021/acs.joc.1c02301
    5. Serhii Trofymchuk, Maksym Bugera, Anton A. Klipkov, Volodymyr Ahunovych, Bohdan Razhyk, Sergey Semenov, Andrii Boretskyi, Karen Tarasenko, Pavel K. Mykhailiuk. Scalable Approach to Fluorinated Heterocycles with Sulfur Tetrafluoride (SF4). The Journal of Organic Chemistry 2021, 86 (17) , 12181-12198. https://doi.org/10.1021/acs.joc.1c01518
    6. Hao Zeng, Xiaojie Fang, Zhiyi Yang, Chuanle Zhu, Huanfeng Jiang. Regioselective Synthesis of 5-Trifluoromethylpyrazoles by [3 + 2] Cycloaddition of Nitrile Imines and 2-Bromo-3,3,3-trifluoropropene. The Journal of Organic Chemistry 2021, 86 (3) , 2810-2819. https://doi.org/10.1021/acs.joc.0c02765
    7. Mary Antony P, Gantala L. Balaji, Pethaperumal Iniyavan, Hiriyakkanavar Ila. Reaction of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via Intramolecular N–O Bond Formation. The Journal of Organic Chemistry 2020, 85 (23) , 15422-15436. https://doi.org/10.1021/acs.joc.0c02216
    8. Alexandra N. Shilova, Nina S. Shatokhina, Evgeniy V. Kondrashov. [3 + 2] Cycloaddition of nitrile oxides to dichloropropenes and 1,3‐dichlorobut‐2‐ene: A regioselectivity issue. Journal of Heterocyclic Chemistry 2024, 61 (4) , 556-567. https://doi.org/10.1002/jhet.4787
    9. Tinghong Tang, Cuiting Chen, Xin Fu, Huilan Xu, Luyong Wu, Wenhao Chen. Copper-Catalyzed Synthesis of 4-CF3-1,2,3-Triazoles: An Efficient and Facile Approach via Click Reaction. Molecules 2024, 29 (6) , 1191. https://doi.org/10.3390/molecules29061191
    10. Garima Sumran, Naman Jain, Prince Kumar, Ranjana Aggarwal. Trifluoromethyl‐β‐dicarbonyls as Versatile Synthons in Synthesis of Heterocycles. Chemistry – A European Journal 2024, 30 (11) https://doi.org/10.1002/chem.202303599
    11. Bohdan A. Chalyk, Vitalii V. Izhyk, Kyrylo Danyleiko, Bohdan Sosunovych, Bohdan V. Vashchenko, Oleksandr Zginnyk, Violetta Olshanska, Peter Teodorovic, Angelina V. Biitseva, Dmitriy M. Volochnyuk, Oleksandr O. Grygorenko. Synthesis of Spirocyclic and Fused Isoxazoline Building Blocks. European Journal of Organic Chemistry 2023, 26 (22) https://doi.org/10.1002/ejoc.202300282
    12. Kamran T. Mahmudov, Armando J. L. Pombeiro. Control of Selectivity in Homogeneous Catalysis through Noncovalent Interactions. Chemistry – A European Journal 2023, 29 (26) https://doi.org/10.1002/chem.202203861
    13. Ekaterina E. Galenko, Timur O. Zanakhov, Mikhail S. Novikov, Alexander F. Khlebnikov. Pd-catalyzed heteroannulation of isoxazoles: Convergent synthesis of isoxazolo[5,4-c]quinolines. Tetrahedron Letters 2023, 114 , 154270. https://doi.org/10.1016/j.tetlet.2022.154270
    14. Vasiliy M. Muzalevskiy, Zoia A. Sizova, Mikhail S. Nechaev, Valentine G. Nenajdenko. Acid-Switchable Synthesis of Trifluoromethylated Triazoles and Isoxazoles via Reaction of CF3-Ynones with NaN3: DFT Study of the Reaction Mechanism. International Journal of Molecular Sciences 2022, 23 (23) , 14522. https://doi.org/10.3390/ijms232314522
    15. Qin Zhou, Yining Bao, Guobing Yan. 2‐Bromo‐3,3,3‐Trifluoropropene: A Versatile Reagent for the Synthesis of Fluorinated Compounds. Advanced Synthesis & Catalysis 2022, 364 (8) , 1371-1387. https://doi.org/10.1002/adsc.202200023
    16. Cai Zhang. Synthesis of trifluoromethyl or trifluoroacetyl substituted heterocyclic compounds from trifluoromethyl‐α,β‐ynones. Journal of the Chinese Chemical Society 2022, 69 (4) , 594-603. https://doi.org/10.1002/jccs.202100544
    17. Yulia O. Edilova, Yulia S. Kudyakova, Mikhail A. Kiskin, Yanina V. Burgart, Victor I. Saloutin, Denis N. Bazhin. Expanding 1,2,4-triketone toolbox for use as fluorinated building blocks in the synthesis of pyrazoles, pyridazinones and β-diketohydrazones. Journal of Fluorine Chemistry 2022, 253 , 109932. https://doi.org/10.1016/j.jfluchem.2021.109932
    18. Timur O Zanakhov, Ekaterina E Galenko, Mikhail S Novikov, Alexander F Khlebnikov. An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates. Beilstein Journal of Organic Chemistry 2022, 18 , 738-745. https://doi.org/10.3762/bjoc.18.74
    19. Roman K. Kostin, Aleksander S. Marshavin. Pyrazoles, isoxazoles, and 1,2,3-triazoles as analogs of the natural cytostatic combretastatin A-4: efficient routes of synthesis, tubulin inhibition, and cytotoxicity. Chemistry of Heterocyclic Compounds 2021, 57 (11) , 1061-1072. https://doi.org/10.1007/s10593-021-03025-y
    20. Girish Chandra Arya, Kamalpreet Kaur, Vikas Jaitak. Isoxazole derivatives as anticancer agent: A review on synthetic strategies, mechanism of action and SAR studies. European Journal of Medicinal Chemistry 2021, 221 , 113511. https://doi.org/10.1016/j.ejmech.2021.113511
    21. Yong Hu, Xiao-Jun Wang, Wen-Shuai Dong, Yu-Fan Bi, Zu-Jia Lu, Wen-Li Cao, Jian-Guo Zhang, Qi Zhang, Dong Chen. Engaging DBFO as a C1N1 “two-atom synthon” in [3 + 2] cycloaddition reaction: synthesis of the energetic material 5-azidotetrazolate 1 N -oxide. Organic Chemistry Frontiers 2021, 8 (11) , 2420-2428. https://doi.org/10.1039/D1QO00123J
    22. Jiawei Lin, Wei Wu, Zhiqiang Weng. A general method for the synthesis of 5-difluoromethyl isoxazoles. Tetrahedron Letters 2020, 61 (52) , 152672. https://doi.org/10.1016/j.tetlet.2020.152672
    23. Wei Wu, Qiaoling Chen, Yishi Tian, Yihui Xu, Yangjie Huang, Yi You, Zhiqiang Weng. Synthesis of polysubstituted 5-trifluoromethyl isoxazoles via denitrogenative cyclization of vinyl azides with trifluoroacetic anhydride. Organic Chemistry Frontiers 2020, 7 (14) , 1878-1883. https://doi.org/10.1039/D0QO00243G
    24. Vasyl Yu. Hys, Oleksandr I. Shevchuk, Bohdan V. Vashchenko, Oleksandr V. Karpenko, Alina O. Gorlova, Oleksandr O. Grygorenko. Functionalization of 2‐Trifluoromethyl‐1 H ‐pyrrole: A Convenient Entry into Advanced Fluorinated Building Blocks Including all Isomeric 2‐(Trifluoromethyl)prolines. European Journal of Organic Chemistry 2020, 2020 (25) , 3896-3905. https://doi.org/10.1002/ejoc.202000519
    25. Mariia M. Efremova, Alexander P. Molchanov, Alexander S. Novikov, Galina L. Starova, Anna A. Muryleva, Alexander V. Slita, Vladimir V. Zarubaev. 1,3-Dipolar cycloaddition of N-allyl substituted polycyclic derivatives of isoindole-1,3-dione with nitrones and nitrile oxides: An experimental and theoretical investigation. Tetrahedron 2020, 76 (15) , 131104. https://doi.org/10.1016/j.tet.2020.131104
    26. Ivan G. Logvinenko, Yevheniia Markushyna, Ivan S. Kondratov, Bohdan V. Vashchenko, Maria Kliachyna, Yuliya Tokaryeva, Valentyna Pivnytska, Oleksandr O. Grygorenko, Günter Haufe. Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group. Journal of Fluorine Chemistry 2020, 231 , 109461. https://doi.org/10.1016/j.jfluchem.2020.109461

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect