SYNTHESIS AND STUDY OF THE METHYLATION REACTION OF 2-METHYLQUINAZOLIN-4-TIONE

ABSTRACT

This research investigates the synthesis of 2-methylquinazolin-4-thione and explores its reactivity in the methylation reaction. The study aims to elucidate the reaction mechanisms involved in the methylation process and characterize the resulting methylated product. The two-stage synthesis and methylation reactions of 2-methylquinazolin-4-thione with "soft" (methyl iodide) and "hard" (dimethyl sulfate, methyl tosylate) methylation agents were studied. It has been established that the methylation reaction, depending on the agent, solvent, and temperature, proceeds with the formation of alkyl products at the N³- and S⁴-reaction centers. This indicates the ambident character of the 2-methylquinazolin-4-thione anion.

АННОТАЦИЯ

В этом исследовании изучается синтез 2-метилхиназолин-4-тиона и исследуется его реакционная способность в реакции метилирования. Целью исследования является выяснение механизмов реакций, участвующих в процессе метилирования, и характеристика образующегося метилированного продукта. Изучены двух стадийный синтез и реакции метилирования 2-метилхиназолин-4-тиона «мягкими» (йодистый метил) и «жесткими» (диметилсульфат, метилтозилат) агентами метилирования. Установлено, что реакция метилирования в зависимости от агента, растворителя и температуры протекает с образованием алкильных продуктов на N³- и S⁴-реакционных центрах. Это свидетельствует об амбидиентном характере аниона 2-метилхиназолин-4-тиона.

Keywords: phosphorus pentasulfide, 2-methylquinazolin-4-thione, ambident anion, methyl iodide, dimethyl sulfate, methyl tosylate, reaction center, solvent, temperature, alkyl product.

Ключевые слова: фосфор пентасульфид, 2-метилхиназолин-4-тион, амбидентный анион, йодистый метил, диметилсульфат, метилтозилат, реакционный центр, растворитель, температура, алкильный продукт.  

Introduction

When alkylation of compounds containing an amide group in most organic substances, the reaction proceeds in two directions. Therefore, in such compounds the reaction occurs either upon bonding with an oxygen atom or with a nitrogen atom [1-3].

Similar systems exist in the form of amide, enol, and imino tautomers. Therefore, when alkylating such compounds, the alkylation reactions are directed towards the oxygen atom. Quinazolin-4-ones, like other heterocyclic compounds, have an amide group, and for the formation of anions in chemical reactions, this negative charge belongs equally to all three atoms [4-7].

Therefore, in chemical processes, the chemical reaction is directed towards O4 or N³ atoms. Determining the reaction direction of these compounds is of great theoretical and practical interest. Analysis of the quinazolin-4-ones and their homologues substituted in the second case shows that the course of the reaction depends on the nature of the solvent and the nature of the substituents on the aromatic ring in the alkylating agents.

In this case, deprotonation of the molecule under the action of a base leads to the formation of an anion. In the second case, the anion formed as a result of deprotonation in quinazolin-4-ones containing a heteroatom is distributed according to its ambient character, i.e., according to its negative charge  or  atoms, or polydentally  character, i.e. fragments.

Methylation of substances of this class, determination of its direction, determination of the resulting ratios O⁴/N³ or O⁴/X² or N¹/X² have been properly studied in the department of organic synthesis of the Institute of Chemistry of Plant Substances. It should be said that these systems are complex, and it is difficult to determine the influence of one or another fragment. Therefore, we decided to take as an object quinazolin-4-ones, which do not contain a heteroatom, but have a methyl group, and study the course of their reactions.

Experimental part

1. N-acetylanthranilic acid.

0.1 mol of anthranilic acid was dissolved in 70 ml of benzene. Benzene was heated to boiling in a water bath, then 0.05 mol of acetic anhydride was added dropwise until white crystals formed. The mixture is cooled, filtered, the residue on the filter is washed 2-3 times with benzene, then dried at 100°C for 1.5 hours. 17.58 g of N-acetylanthranilic acid were obtained with a yield of 92%. Melting temperature:

Тс = 178-181°С. Rf=0.275, system (chloroform:ethanol - 6:4).

2. 2-Methylquinazolin-4-one. Method A.

A 0.1 mol N-acetylanthranilic acid mixture with 0.8 mol NH4Cl was heated and cooled at 210-220°C for 4-5 hours using a reflux condenser. Then it was dissolved in parts with boiling water, the solutions were combined, neutralized with NH4OH to pH 7-8 and cooled. The resulting precipitate was filtered off and dried at room temperature. 2-methylquinazolin-4-one was obtained Ts=238°C Rf=0.134. system (chloroform:ethanol - 6:4).

Method B: A mixture of 0.1 mol anthranilic acid and 0.1 mol acetamide was heated at 210-220°C for 2 hours using a reflux condenser, cooled, filtered and dried. 2-methylquinazolin-4-one was obtained. Ts=238°C Rf=0.134. system (chloroform:ethanol - 6:4).

3. 2-Methylquinazoline-4-thione. 0.005 mol of 2-methylquinazolin-4-one (0.005 mol) was refluxed with P₂S₅ in absolute m-xylene for 4 s. The reaction mixture was filtered, the filter residue was washed with m-xylene and treated with 7 ml of 10% NaOH. The resulting precipitate was filtered off, washed with water and dried. Recrystallize from hexane. 15 g of 2-methylquinazoline-4-thione were obtained with a yield of 90%.

4. Methylation of 2-methylquinazoline-4-thione. 1.6 g (0.01 mol) of 2-methylquinazoline-4-thione (2), 0.56 g (0.01 mol) KOH and 25 ml of ethanol were added to a round-bottom flask and heated in a water bath at 60-65° C for 30 minutes. The reaction mixture was cooled to 25-30°C. Then 1.704 g (0.012 mol, d=2.28 g/ml) of methyl iodide was added and boiled in a water bath at 75-80°C for 6 hours. After completion of the reaction, the mixture was washed with 5% NaOH, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, chloroform was removed in vacuo, and the precipitate was filtered off. The precipitate was recrystallized from methanol to obtain 1.54 g (80%) of product (4), 104-1060°С, R_f=0,65 (chloroform:methanol- 10:1). ¹H ЯМР (CD₃OD, 400 MГц): 8.09 (1H, дд, J=1.5, J=8.0, H-5), 7.71 (1H, дт, J=1.5, J=8.5, H-7), 7.49 (1H, дд, J=1.2, J=8.0, H-8), 7.41 (1H, дт, J=1.1, J=8.1, H-6), 3.54 (3H, с, N-CH₃), 2.56 (3H, с, 2-CH₃).

Results and Research

In the synthesis of 2-methylquinazolin-4-ones, N-acetylanthranilic acid is used as the main raw material. In the literature, this compound was synthesized by various methods with a product yield of 90-96%. Heat to a boil so that all anthranilic acid dissolves, then add 1.75 equivalents of acetic anhydride and the mixture, allow to cool, obtain white N-acetylanthranilic acid:

N-acetylanthranilic acid is formed in high yield (92%)

The synthesis of 2-methylquinazolin-4-one, necessary for research, is carried out in two ways (A and B). According to method A: a mixture of the starting reagents N-acetylanthranilic acid and ammonium chloride in a ratio of 1:7 is heated at 210-220°C for 4 hours. The yield of 2-methylquinazolin-4-one is 73%:

According to method B: anthranilic acid and acetamide were used as starting materials. In this case, a mixture of reagents in a ratio of 1:4 is heated at 210-220ºC for 2 hours. The yield of 2-methylquinazolin-4-one obtained by this method is 92%. That is, the reaction in method B is carried out at a much lower temperature (compared to method A) and in a relatively short time, and obtaining the expected product in almost quantitative yields means that method B is more efficient than method A.

The resulting 2-methylquinazolin-4-one was reacted with P₂S₅. 2-Methylquinazolin-4-one and P₂S₅ were boiled in absolute m-xylene for 3 hours. The reaction mixture was filtered, the residue was washed with xylene on the filter and treated with 7 ml of 10% NaOH. The precipitate was filtered off, washed with water and dried, 2-methylquinazoline-4-thione was obtained in 94% yield, 2-methylquinazoline-4-thione was obtained in 96% yield using Lawesson's reagent.

Reaction of 2-methylquinazoline-4-thione with methylating agents

2-Methylquinazoline-4-thione is dissolved in 50 ml of an absolute solvent (alcohol, DMF, DMSO, acetonitrile), 0.05 mol NaH is added and shaken for 30 minutes, methyl iodide (methyl tosylate, dimethyl sulfate) is added to the resulting mixture. Stir for 24 hours at room temperature and reflux in a water bath. Heated at 80-90°C for 3-4 hours, cooled, added 50 ml of cold water and filtered the precipitate.

Conclusion

When methylating 2-methylquinazoline-4-thiones with methyl iodide, dimethyl sulfate, methyl tosylate, the reaction is carried out with a “soft” alkylating agent (methyl iodide) to a “soft” center (N³ or S-atom), it was found that a “hard” alkylating agent (methyl tosylate ) goes to the “hard” (S⁴ or N³) center. It has been established that the ratio of N³/O⁴ isomers formed depends on the nature of these agents.

References:

1. Giyasov K., Saitkulov F. E., Elmuradov B. Zh. Methylation of 2-methylquinazolin-4-one with “soft” and “hard” methylating agents // Universum: chemistry and biology. – 2022. – No. 11-2 (101). – pp. 49-51
2. Elmuradov B. Zh., Giyasov K., Saitkulov F. E.,  alkylation of quinazolin-4-one with “soft” and “hard” alkylating agents // Universum: chemistry and biology: electron. scientific magazine – 2022. – T. 1. – No. 103. – pp. 53-57.
3. Saitkulov F. E. et al. 2, 3-Dimethylquinazolin-4 (3H)-one //Acta Crystallographica Section E: Structure Reports Online. – 2014. – T. 70. – No. 7. – P. o788-o788.
4. Saitkulov F. et al. alkylation reactions of quinazolin-4-one //Theoretical aspects in the development of pedagogical sciences. – 2023. – T. 2. – No. 1. – pp. 157-163.
5. Ergashevich S. F. et al. Photochemical Processes Photosynthesis Pathway On House Plants Leaves" Black Prince" //Texas Journal of Agriculture and Biological Sciences. – 2022. – Т. 10. – С. 76-78.