From Chemistry Towards Technology Step-By-Step From Chemistry Towards Technology Step-By-Step От химии к технологии шаг за шагом 2782-1900 110687 10.52957/2782-1900-2025-6-4-126-136 Научные статьи Scientific articles Научные статьи Regioselectivity of the SEAr reaction of 8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole Regioselectivity of the SEAr reaction of 8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole Кучеренко Мария Викторовна Kucherenko Maria Viktorovna mariiaku1505@gmail.com Савина Луиза Ильинична Savina Luisa Ilyinichna luizasavina2000@mail.ru Бегунов Роман Сергеевич Begunov Roman Sergeevich begunov@bio.ac.ru

кандидат химических наук;

candidate of chemical sciences;

 Зубишина Алла Александровна Zubishina Alla Alexandrovna

кандидат биологических наук;

candidate of sciences in biology;

 Грачева Екатерина Леонидовна Gracheva Ekaterina Leonidovna Ярославский государственный медицинский университет Yaroslavl State Medical University Ярославский государственный университет им. П.Г. Демидова P.G. Demidov Yaroslavl State University 10 01 2026 10 01 2026 6 4 126 136 14 11 2025 21 12 2025 https://chemintech.ru/en/nauka/article/110687/view

The article investigates the impact of process temperature and electrophilic agent addition time on the regioselectivity of the SEAr reaction. The purpose is an efficient functionalisation of the bifarmacophore molecule 8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole in electrophilic nitration and halogenation reactions. Two isomeric 7- and 9-substituted products were formed during these reactions. A larger amount of 7-R-8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole was formed. Reducing the reaction temperature and the concentration of the electrophilic agent in the reaction mixture increased the selectivity of the process for forming the isomer.

The article investigates the impact of process temperature and electrophilic agent addition time on the regioselectivity of the SEAr reaction. The purpose is an efficient functionalisation of the bifarmacophore molecule 8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole in electrophilic nitration and halogenation reactions. Two isomeric 7- and 9-substituted products were formed during these reactions. A larger amount of 7-R-8-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole was formed. Reducing the reaction temperature and the concentration of the electrophilic agent in the reaction mixture increased the selectivity of the process for forming the isomer.

 bifarmacophore molecules condensed benzimidazole derivatives morpholine ring regioselectivity nitration halogenation The authors would like to acknowledge Valentina Viktorovna Ilyushenkova, junior research scientist at the Laboratory of Metal Complex and Nanoscale Catalysts (No. 30) of the N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, for registering and describing the mass spectra of substances and for her valuable discussions.

Tevyashova A.N., Olsufyeva E.N., Preobrazhenskaya M.N. Design of dual action antibiotics as an approach to search for new promising drugs. Russ. Chem. Rev., 2015, 84(1), 61-97. DOI: doi.org/10.1070/RCR4448. Tevyashova A.N., Olsufyeva E.N., Preobrazhenskaya M.N. Design of dual action antibiotics as an approach to search for new promising drugs. Russ. Chem. Rev., 2015, 84(1), 61-97. DOI: doi.org/10.1070/RCR4448. Tangadanchu V.K.R., Sui Y.F., Zhou C.H. Isatin-derived azoles as new potential antimicrobial agents: Design, synthesis and biological evaluation. Bioorg. Med. Chem. Lett., 2021, 41, 128030. DOI: doi.org/10.1016/j.bmcl.2021.128030. Tangadanchu V.K.R., Sui Y.F., Zhou C.H. Isatin-derived azoles as new potential antimicrobial agents: Design, synthesis and biological evaluation. Bioorg. Med. Chem. Lett., 2021, 41, 128030. DOI: doi.org/10.1016/j.bmcl.2021.128030. Malasala S., Ahmad M.N., Akunuri R., Shukla M., Kaul G., Dasgupta A., Madhavi Y.V., Chopra S., Nanduri S. Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis. Eur. J. Med. Chem., 2021, 212, 112996. https://doi.org/10.1016/j.ejmech.2020.112996. Malasala S., Ahmad M.N., Akunuri R., Shukla M., Kaul G., Dasgupta A., Madhavi Y.V., Chopra S., Nanduri S. Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis. Eur. J. Med. Chem., 2021, 212, 112996. https://doi.org/10.1016/j.ejmech.2020.112996. Karaca Gençer H., Acar Çevik U., Levent S., Sağlık B., Korkut B.N., Özkay Y., Ilgın S., Öztürk Y. New benzimidazole-1,2,4-triazole hybrid compounds: synthesis, anticandidal activity and cytotoxicity evaluation. Molecules, 2017, 22(4), 507. doi: 10.3390/molecules22040507. Karaca Gençer H., Acar Çevik U., Levent S., Sağlık B., Korkut B.N., Özkay Y., Ilgın S., Öztürk Y. New benzimidazole-1,2,4-triazole hybrid compounds: synthesis, anticandidal activity and cytotoxicity evaluation. Molecules, 2017, 22(4), 507. doi: 10.3390/molecules22040507. Aitha S., Thumma V., Ambala S., Matta R., Panga S., Pochampally J. Bis 1, 2, 3‐ triazoles linked deoxybenzoin hybrids as antimicrobial agents: synthesis, in vitro and in silico screening. ChemistrySelect., 2023, 8(13), e202300405. doi: 10.1002/slct.202300405. Aitha S., Thumma V., Ambala S., Matta R., Panga S., Pochampally J. Bis 1, 2, 3‐ triazoles linked deoxybenzoin hybrids as antimicrobial agents: synthesis, in vitro and in silico screening. ChemistrySelect., 2023, 8(13), e202300405. doi: 10.1002/slct.202300405. Aleksandrova Y.R., Nikolaeva N.S., Shagina I.A., Smirnova K.D., Zubishina A.A., Khlopotinin A.I., Fakhrutdinov A.N., Khokhlov A.L., Begunov R.S., Neganova M.E. N-Aryl Benzimidazole and Benzotriazole Derivatives and Their Hybrids as Cytotoxic Agents: Design, Synthesis and Structure–Activity Relationship Studies. Molecules, 2024, 29(22), 5360. https://doi.org/10.3390/molecules29225360 Aleksandrova Y.R., Nikolaeva N.S., Shagina I.A., Smirnova K.D., Zubishina A.A., Khlopotinin A.I., Fakhrutdinov A.N., Khokhlov A.L., Begunov R.S., Neganova M.E. N-Aryl Benzimidazole and Benzotriazole Derivatives and Their Hybrids as Cytotoxic Agents: Design, Synthesis and Structure–Activity Relationship Studies. Molecules, 2024, 29(22), 5360. https://doi.org/10.3390/molecules29225360 Begunov R.S., Egorov D.O., Chetvertakova A.V., Savina L.I., Zubishina A.A. Antibacterial Activity of the Halogen- and Nitro Derivatives of Benzimidazole Against Bacillus Subtilis. Antibiot. Khimioter., 2023, 68(3 4), 19-24. (In Russ.). https://doi.org/10.37489/0235-2990-2023-68-3-4-19-24 Begunov R.S., Egorov D.O., Chetvertakova A.V., Savina L.I., Zubishina A.A. Antibacterial Activity of the Halogen- and Nitro Derivatives of Benzimidazole Against Bacillus Subtilis. Antibiot. Khimioter., 2023, 68(3 4), 19-24. (In Russ.). https://doi.org/10.37489/0235-2990-2023-68-3-4-19-24 Sachs G., Shin J. M., Howden C.W. Review Article: The Clinical Pharmacology of Proton Pump Inhibitors. Aliment. Pharmacol. Ther., 2006, 23, 2−8. https://doi.org/10.1111/j.1365-2036.2006.02943.x Sachs G., Shin J. M., Howden C.W. Review Article: The Clinical Pharmacology of Proton Pump Inhibitors. Aliment. Pharmacol. Ther., 2006, 23, 2−8. https://doi.org/10.1111/j.1365-2036.2006.02943.x Gaba M., Singh S., Mohan C. Benzimidazole: An Emerging Scaffold for Analgesic and Anti Inflammatory Agents. Eur. J. Med. Chem., 2014, 76, 494−505. https://doi.org/10.1016/j.ejmech.2014.01.030 Gaba M., Singh S., Mohan C. Benzimidazole: An Emerging Scaffold for Analgesic and Anti Inflammatory Agents. Eur. J. Med. Chem., 2014, 76, 494−505. https://doi.org/10.1016/j.ejmech.2014.01.030 Michel M.C., Foster C., Brunner H.R., Liu L. A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists. Pharmacol. Rev., 2013, 65(2), 809−848. https://doi.org/10.1124/pr.112.007278 Michel M.C., Foster C., Brunner H.R., Liu L. A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists. Pharmacol. Rev., 2013, 65(2), 809−848. https://doi.org/10.1124/pr.112.007278 Khamitova A.E., Berillo D.A. Overview of Piperidine and Morpholine Derivatives as Promising Sources of Biologically Active Compounds (Review). Drug development & registration, 2023, 12(2), 44-54. (In Russian) https://doi.org/10.33380/2305-2066-2023-12-2-44-54 Khamitova A.E., Berillo D.A. Overview of Piperidine and Morpholine Derivatives as Promising Sources of Biologically Active Compounds (Review). Drug development & registration, 2023, 12(2), 44-54. (In Russian) https://doi.org/10.33380/2305-2066-2023-12-2-44-54 Kourounakis A.P., Xanthopoulos D., Tzara A. Morpholine as a privileged structure: a review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med. Res. Rev., 2020, 40(2), 709–752. DOI:10.1002/med.21634 Kourounakis A.P., Xanthopoulos D., Tzara A. Morpholine as a privileged structure: a review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med. Res. Rev., 2020, 40(2), 709–752. DOI:10.1002/med.21634 Arshad F., Khan M.F., Akhtar W., Alam M.M., Nainwal L.M., Kaushik S. K., Akhter M., Parvez S., Hasan S.M., Shaquiquzzaman M. Revealing quinquennial anticancer journey of morpholine: A SAR based review. Eur. J. Med. Chem., 2019, 167, 324–356. DOI: 10.1016/j.ejmech.2019.02.015 Arshad F., Khan M.F., Akhtar W., Alam M.M., Nainwal L.M., Kaushik S. K., Akhter M., Parvez S., Hasan S.M., Shaquiquzzaman M. Revealing quinquennial anticancer journey of morpholine: A SAR based review. Eur. J. Med. Chem., 2019, 167, 324–356. DOI: 10.1016/j.ejmech.2019.02.015 Han C., Wirianto M., Kim E., Burish M.J., Yoo S. H., Chen Z. Clock-modulating activities of the anti-arrhythmic drug moricizine. Clocks & sleep, 2021, 3(3), 351–365. https://doi.org/10.3390/clockssleep3030022 Han C., Wirianto M., Kim E., Burish M.J., Yoo S. H., Chen Z. Clock-modulating activities of the anti-arrhythmic drug moricizine. Clocks & sleep, 2021, 3(3), 351–365. https://doi.org/10.3390/clockssleep3030022 Aziz M.N., Panda S.S., Shalaby E.M., Fawzy N.G., Girgis A.S. Facile synthetic approach towards vasorelaxant active 4-hydroxyquinazoline-4-carboxamides. RSC Advances, 2019, 9(49), 28534–28540. DOI: 10.1039/C9RA04321G. Aziz M.N., Panda S.S., Shalaby E.M., Fawzy N.G., Girgis A.S. Facile synthetic approach towards vasorelaxant active 4-hydroxyquinazoline-4-carboxamides. RSC Advances, 2019, 9(49), 28534–28540. DOI: 10.1039/C9RA04321G. Pourshojaei Y., Abiri A., Eskandari K., Haghighijoo Z., Edraki N., Asadipour A. Phenoxyethyl piperidine/morpholine Derivatives as pAS and cAS inhibitors of cholinesterases: insights for future Drug Design. Scientific reports, 2019, 9(1), 1–19. DOI:10.1038/s41598-019-56463-2. Pourshojaei Y., Abiri A., Eskandari K., Haghighijoo Z., Edraki N., Asadipour A. Phenoxyethyl piperidine/morpholine Derivatives as pAS and cAS inhibitors of cholinesterases: insights for future Drug Design. Scientific reports, 2019, 9(1), 1–19. DOI:10.1038/s41598-019-56463-2. Begunov R.S., Savina L.I., Astafieva D.A. Intramolecular amination of ortho-nitro-tert-anilines as a method for the synthesis of condensed benzimidazole derivatives with a nodal nitrogen atom. From Chemistry Towards Technology Step-by-Step, 2025, 6(1), 88-98. URL: https://chemintech.ru/ru/nauka/issue/5879/view (accessed 16.10.2025). Begunov R.S., Savina L.I., Astafieva D.A. Intramolecular amination of ortho-nitro-tert-anilines as a method for the synthesis of condensed benzimidazole derivatives with a nodal nitrogen atom. From Chemistry Towards Technology Step-by-Step, 2025, 6(1), 88-98. URL: https://chemintech.ru/ru/nauka/issue/5879/view (accessed 16.10.2025). Li Xin, Zeng Changgen, Dong Huaide, He Feng. Patent CN 116891484, 2023 Li Xin, Zeng Changgen, Dong Huaide, He Feng. Patent CN 116891484, 2023 Dubois L., Evanno Y., Even L., Gille C., Malanda A., Machnik D., Rakotoarisoa N. Patent US 8288376, 2012. Dubois L., Evanno Y., Even L., Gille C., Malanda A., Machnik D., Rakotoarisoa N. Patent US 8288376, 2012. Huo X., Hou D., Wang H., He B., Fang J., Meng Y., Liu L., Wei Z., Wang Z., Liu F.W. Design, synthesis, in vitro and in vivo anti-respiratory syncytial virus (RSV) activity of novel oxizine fused benzimidazole derivatives. Eur. J. Med. Chem., 2021, 224, 113684. doi: 10.1016/j.ejmech.2021.113684. Huo X., Hou D., Wang H., He B., Fang J., Meng Y., Liu L., Wei Z., Wang Z., Liu F.W. Design, synthesis, in vitro and in vivo anti-respiratory syncytial virus (RSV) activity of novel oxizine fused benzimidazole derivatives. Eur. J. Med. Chem., 2021, 224, 113684. doi: 10.1016/j.ejmech.2021.113684. Romero F.A., Kirschberg T.A., Halcomb R., XU Yingzi Patent US 10889571, 2021 Romero F.A., Kirschberg T.A., Halcomb R., XU Yingzi Patent US 10889571, 2021 Begunov R.S., Sokolov A.A., Belova V.O., Fakhrutdinov A.N., Shashkov A.S., Fedyanin I.V. Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents. Tetrahedron Lett., 2015, 56(42), 5701-5704. DOI: 10.1016/j.tetlet.2015.08.014 Begunov R.S., Sokolov A.A., Belova V.O., Fakhrutdinov A.N., Shashkov A.S., Fedyanin I.V. Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents. Tetrahedron Lett., 2015, 56(42), 5701-5704. DOI: 10.1016/j.tetlet.2015.08.014