Synthesis of imidazo-1,4-oxazinone derivatives and investigation of reaction mechanism

In this study, nine different C-2 aroyl imidazole derivatives were synthesized in a one pot reaction with two steps, and the reduction reactions of these derivatives with NaBH4 were carried out under mild conditions. Substitution reaction of obtained imidazo methanol derivatives with chloroacetylchloride reagent and ring reaction of substitution products were investigated. It was determined that 1,4-imidazoxazinone derivative was obtained as a result of the cyclization reaction. The intermediate products obtained during the cyclization reaction were isolated, and the path of the reaction under different conditions was discussed.

mode using a Thermo Nicolet iS10. Elemental analysis was carried out using a Thermo Scientific Flash 2000. 1 H-NMR and 13 C-NMR spectra were recorded using a 400 MHz Agilent using TMS (tetramethylsilane) as the internal standard. All experiments were followed by TLC (thin layer chromatography) using DC Alufolien Kieselgel 60 F254 (Merck) and a Camag TLC lamp (254/366 nm). Commercially available chemicals were purchased from Merck, Aldrich, ABCR and Alfa Easer Co.

General procedure 1
Acetophenone (1mmol) 1 derivatives were dissolved in 30 mL of 1,4-dioxane in a 100mL flask. SeO 2 (2.5 mmol) was added and refluxed. The course of the reaction was followed by TLC (thin layer chromatography). The reaction was seen to be finished after 24 h. The reaction was filtered, and 20mL of dissolved ammonium acetate (5 mmol) was added and stirred at room temperature. After determining the completion of the reaction by TLC method, the reaction was filtered with ice water for half an hour and dried. As a result, C-2 aroyl substituted imidazole derivatives 2 were obtained. 2.3. General procedure 2 C-2 aroyl substituted imidazole derivatives 2 (1 mmol) were dissolved in 30 mL of methanol, and NaBH 4 (3 mmol) was added, and it was understood that the reaction was completed after 24 h by TLC method. It was extracted with ethyl acetate and water (30X50). It was dried with MgSO 4 and evaporated. The column chromatography purified the crude product with eluent ethyl acetate / n-hexane 1/5. The C-2 aroyl substituted imidazolo methanol 3a-i derivatives were obtained.    3.70 (s, 3H, OCH 3 ). 13

Results
In this study, for starting compounds, C-2 aroyl substituted imidazolo methanol derivatives 3 shown in Scheme 1 were obtained from C-2 aroyl substituted imidazole derivatives 2, which is not found in the literature. The synthesis of 1,4-imidazoxazinone derivatives of C-2 aroyl substituted imidazolo methanol derivative compounds with chloroacetylchloride 13 under the various base and solvent conditions was investigated.
C-2 aroyl substituted imidazolo methanol 3 derivatives were used as starting compound for obtaining 5 or 6 molecules of heterobicyclic imidazoxazinone derivatives. As shown in Scheme 2, cyclization experiments were carried out on reagents using various bases. Table 1 shows the experiments performed in the presence of various bases, the reagent used, and the starting compound. To abstract the NH and OH protons in the starting compound 3a as in the mechanism given in Scheme 2, when sodium hydride (NaH) is used as a base in DMF, compound 4 formed. However, when compound 13 was added later, neither products 5-6 formation nor starting compound 3a was obtained. No product formation was observed when potassium carbonate (K 2 CO 3 ) was used as a base in dichloromethane (DCM). The starting product 3a was obtained when the starting compound was made directly with acetic acid (AcOH). We know well from previous studies that 4 intermediate products were formed [27]. As a result of the experiments carried out, it is thought that the compound 13 reagent used has two different ends that can react, and the polymeric structures are formed as a result of the reaction of compound 4 formed by the use of inorganic bases.
The experiments were concentrated upon obtaining compound 9 from the reaction of compound 13 with the formation of 8 by breaking off the NH proton present in the phenyl (4-phenyl-1H-imidazol-2-il) methanone 7a with various bases shown in Table 2. Table 2 shows the experiments with various solvents and bases to remove the 7a NH protons of the imidazole compound. Only the starting compound was recovered from the reaction of the molecule 7a with bases such as NaH, K 2 CO 3 , and TEA, with compound 13. In the literature, the NH proton can be easily separated [28][29][30][31] with bases such as NaH, K 2 CO 3 and reacted with the appropriate reagent. In the literature, there are some studies in which removal of one of the NH 2 protons was done using bases such as NaH, K 2 CO 3 and substitutions with chloroacetylchloride [32][33][34].
In the studies performed to obtain imidazoxazinone derivatives in Table 3, no product could be isolated in all other trials except 5a, 8, and 9. It might be due to the presence of more than one reacting group on the imidazole ring, and the presence of two reagent ends in compound 13. At the same time, it may have caused the formation of different polymeric structures. After this observation, crude NMR was obtained without extraction in all our other trials except 8 and 9 in   Table 3. In NMR analysis, the formation of 5a, the molecule we aimed in reactions 1, 2, 5, 6, and 7, was determined. Due to the isolation problems arising from the lactone structure of the molecule 5a, the peaks of compound 13, which is overused with the 5a molecule, were also observed. In the reaction where compound 13 was used at 1/1 stereometric coefficients  (Scheme 3), it was observed that molecule 5a was synthesized purely without using a base, and there was no chemical shift of molecule 13. Using the base molecule 13 with a 1/1 stichiometric coefficient, a mixture of molecules was observed, which was not understood in crude NMR. In the reaction conditions obtained by taking crude NMR, it was determined that when the reaction medium was heated at 45 °C in dry DCM for 2 h without using base, high purity targeted molecule was synthesized without leaving starting compounds 3a and 13.
Various cyclization trials were carried out under the reaction conditions shown in Table 3 to obtain imidazoxazinone derivatives, as shown in Scheme 3. As a result, it was observed that the product formed in the reaction of compound 3a and compound 13 in DCM solvent at a ratio of 1: 1 at 45 °C was imidazoxazinone derivative is compound 5.
In the reaction without the use of a base, it was thought that the OH group would react with the acyl carbonyl [35] and substitute the chloroacetylchloride compound on oxygen, and then the molecule would be cyclized by cleaving the NH proton in the imidazole compound with the appropriate base. As predicted, it was observed that the reaction started when the OH group in the imidazole molecule attacked the electrophilic acyl carbonyl of compound 13, and the compound 5a was formed in the solvent medium without using any base as a result of the attack of the second electrophilic group of compound 13 to the methyl chloride with the unshared electron pair of the NH nitrogen in the imidazole through the resonance that occurred in the molecule. It was determined that the 5a molecule was not degraded by NMR taken at certain intervals within a month. However, introducing a nucleophile such as water, alcohol, etc. causes the molecule to react rapidly.
When the 1 H-NMR spectrum is examined over the 5a compound shown in Figure 3, it is seen that the protons of the C 5 carbon atom are resonant at 4.26 CH 2b and 4.64 CH 2a ppm. It is understood from the spectrum that these protons are diastereotopic, interacting with each other, and are part of an AB system. When the interactions of these protons were examined, the interaction value was measured as J= 15.8 Hz. It is understood from this value that these protons are in the geminal position, and neighboring groups with these protons have π orbitals [36]. It is in harmony with this information in the molecular structure we propose. The proton of the C 8 carbon resonated as a singlet at 7.35 ppm due to its electronic environment. When the HSQC spectrum is examined, it has been confirmed that the protons resonating at 4.26 and 4.64 ppm are geminal protons and are bound to the same carbon. It is seen that protons resonating at 4.26 to 4.64 ppm are C 5 paired with the resonant carbon at 41.1 ppm. On the other hand, it has been confirmed from the HSQC spectrum that the proton resonating in the aromatic field is an aliphatic proton that the C 8 carbon atom protons do not belong to any aromatic system. It was observed that the proton resonant at 7.43 ppm belongs to the resonant carbon C 8 at 70.1 ppm. It is seen that the lactone carbonyl carbon of the imidazoxazinone compound is C 6 resonant at 166 ppm and C 9 , C 2, and C 3 carbon atoms are resonant at 144.9, 134.1, and 114.0 ppm, respectively.

Conclusion
In this work, nine different C-2 aroyl imidazole derivatives were synthesized, and C-2 aroyl substituted imidazolo methanol derivative compounds were obtained as the starting compound in the yield of imidazoxazinone derivatives with suitable reducers. Then, the synthesis of 1,4-imidazoxazinone derivatives with chloroacetylchloride under the various base and solvent conditions was investigated. As a result of the obtained imidazo methanol derivatives and the substitution