Synthesis and proof of the structure of bis(4-hydroxy-6H-1,3-oxazine-6-ones) with phenylene bridges between heterocyclic fragments

Introduction. The study of 1,3-oxazine derivatives plays a crucial role in the field of heterocyclic chemistry. However, there is a lack of systematized information in the literature regarding the synthesis methods of bis-derivatives of 1,3-oxazin-6-ones. The development of efficient methods for obtaining these oxazines, as well as the study of their structure, properties, and biological activity, represents a promising direction for both medicinal chemistry and the pharmaceutical industry.

Aim. To develop a laboratory method for the synthesis of bis(4-hydroxy-6H-1,3-oxazin-6-ones) based on the reaction of benzene-1,3-dicarboxamide and benzene-1,4-dicarboxamide with substituted malonyl chlorides, and to confirm their structure using nuclear magnetic resonance (NMR) spectroscopy on ¹H and ¹³C nuclei.

Material and methods. ¹H and ¹³C NMR spectra were recorded on a Bruker AM-600 spectrometer in deuterated dimethyl sulfoxide (DMSO-d6), and their processing was carried out using ACD/Labs software. The progress of the reactions was monitored using thin-layer chromatography on plates coated with silica gel TLC Silicagel 60 F₂₅₄ using ethyl acetate as the eluent and detection in ultraviolet (UV) light. The synthesis procedure included suspending 1 mmol of terephthalic or isophthalic acid diamide in absolute 1,2-dichloroethane, adding 2,4 mmol of substituted malonyl chloride and refluxing the mixture for 15 hours. The end of the reaction was determined by the absence of the initial diamides in the reaction mass by thin-layer chromatography.

Results and discussion. As a result of the study a laboratory method of the synthesis of bis(4-hydroxy-6H-1,3-oxazine-6-ones) with phenylene bridges between heterocyclic fragments was developed. The use of absolute 1,2-dichloroethane as a solvent made it possible to increase the yield of the target compounds by 5–7 % and reduce the synthesis time by 5 hours compared to absolute benzene. The structure of the obtained compounds was proved by nuclear magnetic resonance spectroscopy on ¹H and ¹³C nuclei. The spectra of the obtained compounds contain all the characteristic signals corresponding to bis(4-hydroxy-6H-1,3-oxazine-6-ones).

Conclusion. A laboratory method for the synthesis of bis(4-hydroxy-6H-1,3-oxazin-6-ones) has been developed, implemented, and optimized based on the reaction of benzene-1,3-dicarboxamide and benzene-1,4-dicarboxamide with monosubstituted malonyl chlorides. The target compounds were obtained in absolute 1,2-dichloroethane with yields close to quantitative, confirming the efficiency of the developed approach. The structure of all obtained bis(4-hydroxy-6H-1,3-oxazin-6-ones) was reliably established using nuclear magnetic resonance spectroscopy on ¹H and ¹³C nuclei.

1. Ansari N., Khodagholi F., Amini M. 2-Ethoxy-4,5-diphenyl-1,3-oxazine-6-one activates the Nrf2/HO-1 axis and protects against oxidative stress-induced neuronal death. European Journal of Pharmacology. 2011;658(2–3):84–90. DOI: 10.1016/j.ejphar.2011.02.028.

2. Qamar R., Saeed A., Saeed M., Ashraf Z., Abbas Q., Hassan M., Albericio F. Synthesis, carbonic anhydrase inhibitory activity and antioxidant activity of some 1,3-oxazine derivatives. Drug Development Research. 2018;10:1–10. DOI: 10.1002/ddr.21464.

3. Zinad D. S., Mahal A., Mohapatra R. K., Sarangi A. K., Pratama M. R. F. Medicinal chemistry of oxazines as promising agents in drug discovery. Chemical Biology & Drug Design. 2019;(1):16–47. DOI: 10.1111/cbdd.13633.

4. Mathew B. P., Kumar A., Sharma S., Shukla P. K., Nath M. An eco-friendly synthesis and antimicrobial activities of dihydro-2H-benzo- and naphtho-1,3-oxazine derivatives. European Journal of Medicinal Chemistry. 2010;45(4):1502–1507. DOI: 10.1016/j.ejmech.2009.12.058.

5. Chylińska J. B., Janowiec M., Urbański T. Antibacterial activity of dihydro-1,3-oxazine derivatives condensed with aromatic rings in positions 5, 6. British Journal of Pharmacology. 1971;43(3):649–657. DOI: 10.1111/j.1476-5381.1971.tb07194.x.

6. Zinad D. S., Mahal A., Salman G. A. Synthesis and Antibacterial Activity of Novel 1,3-Oxazine Derivatives. Organic Preparations and Procedures International. 2021;53(6):578–584. DOI: 10.1080/00304948.2021.1975486.

7. Asif M., Imran M. Pharmacological profile of oxazine and its derivatives: a mini review. International Journal of New Chemistry. 2020;7(1):60–73. DOI: 10.22034/IJNC.2020.116058.1061.

8. Kusakabe Y., Nagatsu J., Shibuya M., Kawaguchi O., Hirose C., Shirato S. Minimycin, a new Antibiotic. The Journal of Antibiotics. 1972;25(1):44–47. DOI: 10.7164/antibiotics.25.44.

9. Levshukova P. O., Kolesnik D. A., Dosina M. O., Yakovlev I. P., Tunguskova L. A., Kuvaeva E. V., Semakova T. L., Ksenofontova G. V., Pokhodnya Yu. G. The reaction of 4-hydroxy-6Н-1,3-oxazin-6-ones with amidines – a route to access new 1,3,5-triazine derivatives. Chemistry of Heterocyclic Compounds. 2024;60(1/2):48-51. DOI: 10.1007/s10593-024-03292-5.

10. Dorokhov V. A., Bogdanov V. S., Gordeev M. F. 5-Acyl-4-amino-2-phenyl-1,3-oxazin-6-ones. Russian Chemical Bulletin. 1995;44(7):1276–1277. DOI: 10.1007/BF00700903.

11. Maier G., Schäfer U. Versuche zur Darstellung von Azacyclobutadienen. Liebigs Annalen der Chemie. 1980;13:798–813. DOI: 10.1002/anie.197404251.

12. Boger D. L., Wysocki R. J. A study of the scope of the [4 + 2] cycloaddition reactions of unactivated 1,3-oxazin-6-ones. The Journal of Organic Chemistry. 1989;54(3):714–718. DOI: 10.1021/jo00264a041.

13. Alajarín M., Vidal A., Sánchez-Andrada P., Tovar F., Ochoa G. Conversion of N-Acyl-4-acyloxy-β-lactams into 1,3-Oxazin-6-ones: Two Consecutive Pseudopericyclic Processes. Organic Letters. 2000;2(7):965–968. DOI: 10.1021/ol0056168.

14. Niu B., Jiang B., Yu L.-Z., Shi M. Base-promoted [3 + 3] cyclization of cyclopropenones and cyclopropenethiones with amides for the synthesis of 6H-1,3-oxazin-6-ones and 6H-1,3-thiazin-6-ones. Organic Chemistry Frontiers. 2018;8(5):1267–1271. DOI: 10.1039/C8QO00091C.

15. Zahedifar M., Sheibani H. Unexpected Products from Mesoionic 1,3-Thiazinium and Oxazinium Olates: A Novel Access to 3,5-Diaryl-1,3-thiazine-2,4,6-trione and Alkoxy-3,5-diphenyl-3H-1,3-oxazine-2,6-dione Derivatives. Australian Journal of Chemistry. 2014;67(9):1201–1204. DOI: 10.1071/CH14095.

16. Zakhs V. E., Yakovlev I. P., Ivin B. A. Oxo derivatives of 1,3-oxazines (review). Chemistry of Heterocyclic Compounds. 1987;11:1149-1166. (In Russ.)

17. Komarov A. V., Yakovlev I. P., Novikov D. V., Zakhs V. E. Reactions of 4-hydroxy-5-methyl(phenyl)-2-styryl-6H-1,3-oxazin-6-ones with nucleophiles. Russian Journal of General Chemistry. 2003;73(12):1936–1941. (In Russ.)

18. Ishchenko R. O., Yakovlev I. P., Lalaev B. Yu., Ovsyannikova L. N. Interaction of phthalic acids diamides with malonic acids chlorides – a new way of synthesis of bis(4-hydroxy-6H-1,3-oxazin-6-ones). Butlerov Communications. 2012;29(3):63–65. (In Russ.)