Study of the Interaction of Benzene-1,4-dicarboxamide with Methylmalonyl Dichloride ^†

Abstract

Studies show that compounds such as 1,3-oxazine-6-ones are promising starting reagents that allow us to obtain various acyclic and heteroaromatic systems. These substances demonstrate a wide range of biological activity. Meanwhile, it is known that depending on the 1,3-oxazine cycle number in the molecule, pharmacological activity may vary. Therefore, the purpose of our work was to study the reaction of benzene-1,4-dicarboxamide with methylmalonyl dichloride, as a rational way to obtain new compounds of a given structure. This interaction can potentially lead to both mono- and bis(1,3-oxazine-6-one) derivatives. The reaction between terephthalamide and methylmalonyl dichloride was conducted at an equimolar ratio, with a twofold excess of the latter. Syntheses were carried out in two media—absolute benzene and 1,2-dichloroethane. The reaction of equimolar amounts of reagents resulted in obtaining only one product—4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide (1). In twofold excess of methylmalonyl dichloride, only product 1 was obtained after 24 h of refluxing; after 58 h, only 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) (2) was formed. The determination of the partial negative charge on the nitrogen atoms of the amido groups of terephthalamide and compound 1 allowed us to confirm the sequential formation firstly of the mono- (1) and then the bis(1,3-oxazine-6-one) derivative (2) in the reaction mass. The structure of the obtained compounds was proven using NMR spectroscopy on ¹H and ¹³C nuclei. When studying solvent influence on the synthesis rate, no significant differences were noted between benzene and 1,2-dichloroethane. However, the yield of 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) during synthesis in 1,2-dichloroethane was lower—77% compared with 85% in benzene.

1. Introduction

According to research data [1,2,3], compounds of the 1,3-oxazine-6-one family are promising starting reagents that make it possible to obtain aromatic systems containing various heteroatoms and also systems with acyclic structures [4]. These substances also demonstrate a wide range of biological activity, e.g., antimicrobial, antifungal, or antioxidant [5]. Meanwhile, the structure of the key molecule—specifically the number of 1,3-oxazine cycles included in its composition—has an important effect on the severity of its pharmacological activity [6]. Therefore, the aim of our work was to study the reaction of benzene-1,4-dicarboxamide with methylmalonyl dichloride, which can lead to both mono- and bis(1,3-oxazine-6-one) derivatives. To achieve this goal, it is necessary to solve the following problems:

• Carrying out the reaction of benzene-1,4-dicarboxamide with methylmalonyl dichloride in two media—benzene and 1,2-dichloroethane—and at two ratios of starting reagents, i.e., 1:1 and 1:2, respectively.
• Giving a comparative assessment of the use of benzene and 1,2-dichloroethane as the medium of this reaction, calculating the yields, and setting the time required for the formation of products.
• Proving the structure of the synthesized products in the reactions of benzene-1,4-dicarboxamide: methylmalonyl dichloride at 1:1 and 1:2 using modern physicochemical methods of analysis, namely NMR spectroscopy and elemental analysis.

2. Materials and Methods

The reaction of benzene-1,4-dicarboxamide with methylmalonyl dichloride was carried out in two media (absolute benzene and 1,2-dichloroethane (EDC)) and at two ratios of starting reagents—benzene-1,4-dicarboxamide: methymalonyl dichloride at (1:1) (1.1) and (1:2) (1.2) (Figure 1). The yield of 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide (1) in reaction 1.1 in benzene and 1,2-dichloroethane was 70% and 67%, respectively. The synthesis was carried out for 24 h. The compound 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) (2) was obtained in the reaction 1.2 with a yield of 85% (in benzene) and 77% (in EDC). The final compound 2 was isolated after 58 h of refluxing.

1.1 Synthesis of 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide (1). In total, 6.96 g (0.0424 mol) of benzene-1,4-carboxamide was suspended in benzene (EDC); then, 4.75 mL (0.0424 mol) of methylmalonyl dichloride was added and refluxed for 24 h. The completeness of the reaction was monitored using thin-layer chromatography on TLC Silica gel 60 F254 plates in the methanol: dichloromethane: dimethyl sulfoxide (1:9:0.5) system. After 7 h from the start of the reaction, it was noted that product 1 began to form in the reaction mass. At the end of the synthesis, the resulting 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide was filtered under vacuum. The precipitate was recrystallized from glacial acetic acid.

1.2 Synthesis of 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) (2). A total of 3.48 g (0.0212 mol) of benzene-1,4-carboxamide was suspended in benzene (EDC); then, 4.75 mL (0.0424 mol) of methylmalonyl dichloride was added and refluxed for 58 h. The completeness of the reaction was monitored using thin-layer chromatography on TLC Silica gel 60 F254 plates in the methanol: dichloromethane: dimethyl sulfoxide (1:9:0.5) system. At the end of the synthesis, the resulting 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) was filtered under vacuum. The precipitate was recrystallized from glacial acetic acid.

3. Results

After 7 h of refluxing, the reaction mass (1.1) was analyzed, and its composition was determined using NMR spectroscopy on 1H nuclei (Figure 2). It was established that the end product 1 formed in the reaction mass and the initial compound benzene-1,4-dicarboxamide still remained.

After carrying out reactions 1.1 and 1.2, the following results were obtained. The interaction of equimolar amounts of reagents led to the formation of the only product—4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide—after 24 h of refluxing with a yield of 70% in benzene and 67% in EDC (Figure 3). The solvents (benzene and EDC) used as a synthesis medium did not have a significant effect on the yield of product 1.

When the amount of methylmalonyl dichloride was doubled, after 24 h of reacting, only the mono-1,3-oxazine-6-one derivative (1) was obtained; after 58 h, only 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) formed in the reaction mass, with a yield of 85% in benzene and 77% in 1,2-dichloroethane (Figure 4 and Figure 5).

The structure of the obtained compounds was proven using NMR spectroscopy on ¹H and ¹³C nuclei, which was subsequently confirmed using elemental analysis. The ¹H and ¹³C NMR spectra were obtained using a Bruker AM-500 spectrometer from solutions in DMSO-d6.

4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide. ¹H NMR (DMSO-d6): δ 1.83 (s, 3H, CH₃); δ 7.51 (s, 1H, NH₂); δ 7.94 (s, 2H, C₆H₆); δ 8.09 (s, 1H, NH₂); δ 8.20 (s, 2H, C₆H₆); δ 12.54 (s, 1H, OH). ¹³C NMR spectrum contains a characteristic signal corresponding to a carbon atom of the CH₃ group (9.50 ppm), 91.25 ppm signal belonging to the sp² hybrid carbon atom C₅ of the 1,3-oxazine cycle, and a signal 168.12 ppm belonging to the carbon of the amido group. A number of signals corresponding to the C₄, C₂, and C₆ atoms of the 1,3-oxazine cycle are also observed (160.36, 165.75, 167.74 ppm). The signals of the carbon atoms of the benzene ring are in the range of 128.31–130.70 ppm.

Molecular formula: C₁₂H₁₀N₂O₄. Found %: C—58,25; H—3,92; N—11,34; O—25,36. Calculated %: C—58,54; H—4,09; N—11,38; O—25,99.

2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one). ¹H NMR (DMSO-d6): δ 1.83 (s, 6H, CH₃); δ 8.22 (s, 4H, C₆H₆); δ 12.54 (s, 2H, OH). ¹³C NMR spectrum contains a characteristic signal corresponding to carbon atoms of the CH₃ groups (8.63 ppm) and a signal at 91.23 ppm belonging to the sp² hybrid carbon atoms C₅ of the 1,3-oxazine cycles. A number of signals corresponding to the C₄, C₂, and C₆ atoms of the 1,3-oxazine cycle are also observed (160.35–167.72 ppm).

Molecular formula: C₁₆H₁₂N₂O₆. Found %: C—58,25; H—3,53; N—8,5; O—28,53. Calculated %: C—58,54; H—3,68; N—8,53; O—29,24.

It was found that the solvents used in the synthesis (benzene and 1,2-dichloroethane) do not have a significant effect on the synthesis time; however, the calculation of the yield of the end product bis(1,3-oxazine-6-one) derivative (2) determined that the use of benzene as a reaction medium is more profitable due to an increase in the formation of the target compound—85% compared to 77% in EDC.

4. Discussion

For the nitrogen atoms of the amido groups of the initial compound benzene-1,4-dicarboxamide and 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide, partial negative charges were calculated using the semi-empirical PM6 method (taking into account the solvent benzene); they amounted to −0,576 and −0,569, respectively (Figure 6 and Figure 7). The results obtained make it possible to confirm and justify the sequential formation firstly of the mono- (1) and then the bis(1,3-oxazine-6-one) derivative (2) in the reaction mass. Due to the higher electron density, the nitrogen of the amido group of benzene-1,4-dicarboxamide exhibits a greater nucleophilicity in the reaction with methylmalonyl dichloride compared to with 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide; therefore, the first stage of the reaction ends with the formation of the mono-1,3-oxazine-6-one derivative (1). At the second stage of the reaction, the amido groups of the 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide molecules are attacked, and 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) forms.

5. Conclusions

This paper presents the results of studying of the reaction between benzene-1,4-dicarboxamide and methylmalonyl dichloride. It was shown that in the interaction of equimolar amounts of reagents, the only product was 4-(4-hydroxy-5-methyl-6-oxo-6H-1,3-oxazine-2-yl)benzamide (1). In a twofold excess of methylmalonyl dichloride, only product 1 was obtained after 24 h of refluxing; after 58 h, only 2,2′-(benzene-1,4-diyl)bis(4-hydroxy-5-methyl-6H-1,3-oxazine-6-one) (2) formed. It was found that the choice of solvent affects the yield of product 2 (in benzene—85%; in EDC—77%).