CATALYTIC METHYLATION OF QUINAZOLIN-4-ONE

ABSTRACT

Quinazolin-4-one must undergo catalytic methylation in order to produce methylated derivatives, which have different chemical, biological, and physical characteristics. Using methyl donors such methyl iodide (CH₃I) and dimethyl sulfate ((CH₃)₂SO₂), a methyl group (-CH₃) is added to the oxygen atom at position 3 of the quinazolin-4-one molecule in this synthesis. Lewis acids like zinc chloride (ZnCl₂), aluminum chloride (AlCl₃), or ferric chloride (FeCl₃) accelerate the process by activating the oxygen atom, which increases its vulnerability to the methyl donor's nucleophilic assault. To speed up the process, solvents such as dimethylformamide (DMF), acetonitrile, alcohol,  dimethyl sulfoxide (DMSO) are frequently used. The design and synthesis of molecules with improved solubility, bioactivity, and medicinal potential can benefit greatly from this procedure. Quinazolin-4-one's methylation provides a variety of functionalized derivatives for more research and uses in medicinal chemistry.

АННОТАЦИЯ

Для получения метилированных производных киназолин-4-она, обладающих измененными химическими, биологическими и физическими свойствами, необходимо провести каталитическое метилирование. В этом процессе к атомам кислорода на позиции 3 молекулы хиназолин-4-она присоединяется метильная группа (-CH₃) с использованием метильных доноров, таких как йодид метила (CH₃I) или диметилсульфат ((CH₃)₂SO₂). Катализаторы Льюиса, такие как хлорид цинка (ZnCl₂), хлорид алюминия (AlCl₃) или хлорид железа (FeCl₃), ускоряют процесс, активируя атом кислорода, что повышает его восприимчивость к нуклеофильной атаке метильного донора. Для ускорения реакции часто используются растворители, такие как диметилформамид (DMF), ацетонитрил, спирты, диметилсульфоксид (DMSO). Этот процесс имеет большое значение для разработки и синтеза молекул с улучшенной растворимостью, биоактивностью и медицинским потенциалом. Метилирование хиназолин-4-она открывает возможности для получения разнообразных функционализированных производных для дальнейших исследований и применения в медицине.

Keywords: Quinazolin-4-one, catalytic methylation, Lewis acids, methyl iodide, methyl sulfate, dimethylformamide, dimethyl sulfoxide, chemical modification, pharmaceutical synthesis, bioactive compounds.

Ключевые слова: Квинозолин-4-он, каталитическая метилирование, кислоты Льюиса, метилйодид, метилсульфат, диметилформамид, диметилсульфоксид, химическая модификация, фармацевтический синтез, биоактивные соединения.

INTRODUCTION

Quinazolin-4-one and its derivatives are a well-known family of heterocyclic compounds with a wide range of uses in materials science, pharmaceutical chemistry, and chemical synthesis. These substances are crucial scaffolds for drug development because of their diverse biological actions, which include antibacterial, anticancer, anti-inflammatory, and antitubercular qualities. Methylation is one of the most successful chemical changes made to quinazolin-4-one to improve its biological and physicochemical characteristics. A methyl group (-CH₃) is added to the molecule by catalytic methylation, which can drastically change its chemical reactivity, solubility, and bioavailability and increase its use in industrial and therapeutic settings. When quinazolin-4-one is methylated, the oxygen atom at position three is usually the target, resulting in N-methyl derivatives. Methyl donors including methyl iodide (CH₃I) and dimethyl sulfate ((CH₃)₂SO₂) aid in the process. Lewis acid catalysts such as zinc chloride (ZnCl₂), aluminum chloride (AlCl₃), and ferric chloride (FeCl₃) are frequently used in this process to attain excellent efficiency and selectivity. By activating the electrophilic sites, these catalysts improve the interaction between the nucleophilic oxygen atom and the methyl donor. Since they offer a medium for effective catalytic activity and reactant solubility, the use of suitable solvents, such as dimethylformamide (DMF), acetonitrile, ethanol, or dimethyl sulfoxide (DMSO), is equally important. Quinazolin-4-one's physicochemical properties are enhanced by catalytic methylation, which also increases the number of derivatives with distinct biological activity. In pharmacological experiments, for instance, methylation quinazolin-4-ones have demonstrated improved interactions with biological targets, leading to greater potency and selectivity. Because of this, catalytic methylation is a useful approach for creating medicinal substances. These changes can also affect quinazolin-4-one's electrical and thermal stability, making it appropriate for uses outside of medicinal chemistry, such material science and molecular electronics[1, p. 788, 2, p. 258, 3.p.5, 4.p. 256, 5. p, 5].

Notwithstanding its promise, quinazolin-4-one catalytic methylation necessitates meticulous reaction condition optimization, encompassing catalyst selection, solvent selection, temperature, and reaction duration. Changes in these factors can have a big impact on the targeted products' yield, purity, and selectivity.

A logical design and effective synthesis of quinazolin-4-one derivatives depend on an understanding of the mechanistic elements of this reaction.
The purpose of this work is to investigate the catalytic methylation of quinazolin-4-one, with an emphasis on the optimization of reaction conditions through the use of different Lewis acid catalysts and solvents. The investigation's findings will advance knowledge of the reaction process and its usefulness in the production of functionalized quinazolin-4-one derivatives. Future research aiming at creating new quinazolin-4-one-based compounds with enhanced biological and physicochemical features will be built upon the knowledge gathered from this study [6, p. 10, 7, p. 1, 8.p.97, 9.p. 445, 10. p, 61].

Method and results

It is very interesting to perform basic research using heterocyclic compounds that have many active reaction sites. The rationale is that depending on which reaction center is targeted, different isomeric products may be obtained. Furthermore, the synthesis of the desired product might result from reactions aimed at a particular center. In order to do this, it is crucial to carefully choose variables that affect the kind and yield of products during these kinds of reactions, such as temperature, solvent type, and reagent amount.

These substances have complex reactivity, and examining how they respond in various settings can highlight important trends and ideas.

The four solvent types listed below are frequently utilized in catalytic methylation reactions: ethanol (EtOH), dimethylformamide (DMF), acetonitrile (ACN), and dimethyl sulfoxide (DMSO). Because of their unique polarity, solvation characteristics, and molecular structures, each solvent affects the reaction's pace and efficiency. Reaction Mechanism of Acetonitrile (CH₃CN): Acetonitrile is a polar aprotic solvent that aids in the dissociation of methyl iodide, which makes it easier for the CH₃⁺ cation to form. Methylation results from this cation's easy assault on the quinazoline ring's nitrogen atom (N-3). Impact of the Solvent. Because acetonitrile stabilizes the methyl cation's positive charge, its strong polarity and aprotic properties speed up the process. However, protonation procedures could be less effective since it doesn't create hydrogen bonds. Because acetonitrile promotes nucleophilic attack at N-3 and helps create CH₃⁺ cations, the reaction rate is often high.

The interaction of aluminum chloride (AlCl₃) or ferric chloride (FeCl₃) as a catalyst and acetonitrile (CH₃CN) as the solvent affects the reaction mechanism and pace in a catalytic methylation process. A polar aprotic solvent called acetonitrile aids in the dissociation of methyl iodide (CH₃I), producing the very reactive CH₃⁺ cation. The quinazoline ring's nitrogen atom (N-3) is then attacked by this cation, leading to methylation.

Strong Lewis acids like AlCl₃ or FeCl₃ increase the methyl iodide's electrophilicity and dissociation susceptibility. The Lewis acid speeds up the synthesis of CH₃⁺ by coordinating with the iodine atom in CH₃I. This makes CH₃⁺ available for nucleophilic assault on the nitrogen atom in the quinazoline structure. As a result, the quinazoline ring at the N-3 position becomes methylated.

When certain Lewis acids are present, the rate of reaction is greatly enhanced. Being a particularly potent Lewis acid, AlCl₃ has a higher impact on accelerating the pace of reaction by encouraging CH₃I to dissociate and making the methyl cation more accessible. Although FeCl₃ also improves the reaction, it might not be as effective as AlCl₃ in this specific reaction.

Overall, the methylation process is sped up and made more efficient when acetonitrile is used as the solvent and either AlCl₃ or FeCl₃ is used as a catalyst. AlCl₃ is the more efficient catalyst (Table 1).

Table 1.

This updated table includes ZnCl₂ as a catalyst, which acts as a mild Lewis acid

The catalytic methylation reaction using different solvents such as ethanol, DMF, and DMSO proceeds with varying efficiency due to the properties of these solvents.

Ethanol is a polar protic solvent, which can participate in hydrogen bonding. While it may stabilize some intermediates, its nucleophilicity is higher than that of aprotic solvents, which can compete with the nucleophilic attack of the quinazoline ring on the CH₃⁺ cation. In this reaction, ethanol helps protonate CH₃I, facilitating the generation of CH₃⁺, which attacks the nitrogen atom (N-3) of the quinazoline ring, leading to methylation. However, due to its protic nature, ethanol can slow down the reaction by reducing the efficiency of CH₃I dissociation compared to aprotic solvents.

DMF is a polar aprotic solvent that enhances the nucleophilicity of the quinazoline ring by solvating anions rather than cations. It stabilizes the CH₃⁺ cation and increases its electrophilicity, promoting the methylation reaction. In this system, CH₃I dissociates into CH₃⁺ in the presence of DMF, and the highly reactive CH₃⁺ attacks the N-3 position of the quinazoline ring. This results in a high reaction rate, as DMF accelerates the formation of CH₃⁺ and supports the nucleophilic attack.

DMSO is another highly polar aprotic solvent, and its high dielectric constant allows it to efficiently dissociate CH₃I into CH₃⁺. Like DMF, DMSO stabilizes the CH₃⁺ cation, which enhances the methylation reaction. The strong solvation effect of DMSO on CH₃⁺ helps accelerate the reaction. The CH₃⁺ cation attacks the nitrogen atom (N-3) of the quinazoline ring, leading to methylation. Due to its superior ability to stabilize CH₃⁺, DMSO typically results in a very high reaction rate.

Discussion

The catalytic methylation process with several solvents shows how each solvent's characteristics may have a big impact on the reaction's efficiency and pace. DMSO, is the most effective solvent because of its strong polarity and aprotic properties, which encourage a rapid reaction rate. Its capacity to increase the nucleophilic attack on the quinazoline ring by stabilizing the CH₃⁺ cation through solvation is essential. Effective methylation requires the synthesis of the methyl cation, which is ensured by the rapid rate of dissociation of CH₃I in DMSO. DMF, on the other hand, offers a suitable environment for the reaction while being somewhat less effective than DMSO. Although DMF speeds up the reaction and stabilizes CH₃⁺, its solvation impact is less than that of DMSO, resulting in a little slower reaction rate

Another polar aprotic solvent that promotes methylation is acetonitrile; however, the reaction rate is slower due to its reduced capacity to stabilize CH₃⁺ in comparison to DMSO and DMF. It is still a good option in many methylation processes, nevertheless, because of its comparatively high reaction rate. Because it is a protic solvent, ethanol considerably slows down the process. Ethanol molecules' hydrogen bonding interactions with CH₃I hinder the nucleophilic assault and decrease the effectiveness of cation production. Ethanol's protons compete with the nucleophile, making it harder for CH₃I to dissociate and slowing down the process.

Conclusion

Among the solvents used for catalytic methylation reactions, DMSO provides the fastest reaction rate. This is because DMSO is a highly polar aprotic solvent that strongly solvate and stabilizes the CH₃⁺ cation, which is crucial for promoting a nucleophilic attack on the quinazoline ring. The ability of DMSO to efficiently dissociate CH₃I enhances the overall reaction rate, making it the most effective solvent in this case. Following DMSO, DMF also accelerates the reaction due to its polar aprotic nature and ability to stabilize CH₃⁺ cations. DMF is somewhat less effective than DMSO, however. Although it moves a little more slowly than DMSO and DMF in methylation processes, acetonitrile is another polar aprotic solvent that encourages a comparatively high reaction rate. Because of its hydrogen bonding characteristics, ethanol, a polar protic solvent, slows down the reaction, decreasing the effectiveness of CH₃I dissociation and interfering with the methylation process.

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