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-6 H -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 1 H and 13 C nuclei. Material and methods. 1 H and 13 C 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 F 254 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-6 H -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 1 H and 13 C nuclei. The spectra of the obtained compounds contain all the characteristic signals corresponding to bis(4-hydroxy-6 H -1,3-oxazine-6-ones). Conclusion. A laboratory method for the synthesis of bis(4-hydroxy-6 H -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-6 H -1,3-oxazin-6-ones) was reliably established using nuclear magnetic resonance spectroscopy on 1 H and 13 C nuclei.