QUINAZOLIN-4-THIONE SYNTHESIS AND EVALUATION OF ITS EFFECTIVE SYNTHESIS TECHNIQUE

ABSTRACT

The production of quinazolin-4-thione in the presence of quinazolin-4-one using several techniques was carefully examined in the paper. Additionally, the thionation reaction was conducted for the first time with Lavesson's reagent present. Using contemporary physical and chemical research techniques, the structure of the quinazoline-4-thione molecule has been established. Quinazolin-4-one and its equivalent quinazolin-4-thiones are synthesized at comparatively high concentrations. First, the proper quinazolin-4-ones based on anthranilic acid were synthesized, and from these molecules, thiones were produced. The results indicate that the optimized procedure offers a high-yield synthesis of quinazolin-4-thione with potential for further functionalization and biological evaluation. This approach provides an efficient and reproducible route to quinazoline-based compounds, making them accessible for pharmaceutical and agricultural applications.

АННОТАЦИЯ

Производство хиназолин-4-тиона в присутствии хиназолин-4-она с использованием нескольких методов было тщательно изучено в статье. Дополнительно, реакция тионирования была проведена впервые с использованием реагента Лавессона. С помощью современных физических и химических методов исследования была установлена структура молекулы хиназолин-4-тиона. Хиназолин-4-он и его эквиваленты — хиназолин-4-тионы — синтезируются в сравнительно высоких концентрациях. Сначала были синтезированы соответствующие хиназолин-4-оны на основе антраниловой кислоты, из которых затем были получены тионы. Результаты показывают, что оптимизированная методика обеспечивает высокоэффективный синтез хиназолин-4-тиона с потенциалом для дальнейшей функционализации и биологической оценки. Этот подход предоставляет эффективный и воспроизводимый путь к созданию соединений на основе хиназолин-4-она, что делает их доступными для применения в фармацевтической и сельскохозяйственной отраслях.

Keywords: quinazolin-4-thione, quinazolin-4-one, various methods, thionation reaction, Lavesson's reagent, P₂S_5, in an inert atmosphere (argon), cycloreversion (opposite process to cycloaddition!)

Ключевые слова: хиназолин-4-тион, хиназолин-4-он, различные методы, реакция тионирования, реагент Лавессона, P₂S₅, в инертной атмосфере (аргон), циклореверсия (обратный процесс циклоприсоединению!)

Introduction

Organic reactions typically include the target molecule’s individual bonds being formed step-by-step. At later stages of synthesis, it is frequently required to alter the reaction conditions to identify and purify intermediate molecules. There are several benefits to tandem responses. First of all, they make it possible to construct intricate structures in a limited number of steps. Additionally, the method frequently has excellent chemo-, regio-, and stereoselectivity. Additionally, it removes the requirement for purification at every round [1. p.15], [2. p.24], [3. p.36], [4. p.12].

Lastly, the cost and quantity of reagents, solvents, and adsorbents may be reduced by tandem reactions, which also lower waste production, energy expenses, and the number of laboratory procedures [5. p.17], [6. p.28], [7. p.31], [8. p.11].

Quinazolin-4-thione can be made synthetically using a variety of techniques, such as cyclizing 2-aminobenzamides with substances that contain sulfur. However, the catalysts, solvents, and reaction conditions all affect how effective these techniques are. The objective of this study is to assess and enhance quinazolin-4-thione synthesis methods, with an emphasis on reaction optimization to get high yields, fewer byproducts, and improved repeatability. The goal of this research is to develop a more efficient and scalable synthesis technique for use in pharmaceutical and agricultural applications via meticulous testing and analysis [9.p.311], [10.p.120], [11.p.5], [12.p.50].

Materials and methods

Solvents used in the research: hexane, benzene, toluene, chloroform, methyl alcohol, ethyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, and acetonitrile, fully correspond to the information given in the literature. The IR spectra of the synthesized compounds were recorded on a Perkin-Elmer IR-Fure Cistema 2000 spectrometer on KBr tablets, Mass spectrum on MS-30 (Kratos), 1H NMR spectrum on a Unity-400 instrument (operating frequency 400 MHz, internal standard GMDS, d-scale ) was obtained in TFK+CD3COOD, TFK+(CD3)2SO, Py-d5 solutions*, and thin-layer chromatography (TLC) was investigated on Sorbfil (Russia) and Whatman® UV-254 (Germany) plates, with as eluents, benzene: methanol=2:1 (system A), benzene:methanol=3:1 (system B) was used in proportions. Bleaching (proyavitel) UV light (254 and 365 nm Spectroline, USA) and iodine vapor.

Quinazolin-4-thione (2). Method A (in the presence of P₂S₅): A mixture of 1.46 g (0.01 mol) of quinazolin-4-one (1) and 2.22 g (0.01 mol) of P₂S₅ in 50 ml of absolute m-xylene was refluxed for 4 hours, the mixture was cooled and the reaction mixture was filtered, the filter residue was washed with m-xylene and treated with 7 ml (10%) NaOH. The precipitate was filtered, washed with water and dried under normal conditions, and the substance was recrystallized from hexane. As a result, 1.26 g (78%) of quinazolin-4-thione (2) was obtained, melting point 288-289°C.

Method B (with Lesson’s reagent (LR)): A mixture of 1.46 g (0.01 mol) of quinazolin-4-one and 2.02 g (0.005 mol) of LR in 30 ml of absolute toluene was refluxed for 1 hour (inert gas, Ar). It was cooled to 20-25°С, the precipitate was filtered and dried. As a result, 1.57 g (97%) of quinazolin-4-thione (2) was obtained, melting point 288-289°C.

IR (ν, cm⁻¹): 1621 (C=N), 1566 (C=C), 1302 (C=S). ¹H NMR (δ, ppm., Gz): 13.86 (1H,.с., NH), 8.59 (1H, d, J = 8.0, H-5), 8.19 (1H, s, Н-2), 7.90 (1H, t, J = 7.5, Н-7), 7.74 (1H, d, J = 8.0, Н-8), 7.62 (1H, t, J = 7.1, Н-6). LC-MS: m/z = 163 [M + H]⁺.

UV spectrum (nm); ethanol 216, 284, 359; ethanol + acid 205, 357; ethanol + acid + base 216, 274, 357; C₈H₆N₂S.

Results and discussion

From a scientific and practical perspective, heterocyclic molecules having a thione group are acknowledged to be very intriguing. This is because there are many physiologically active compounds in this class and the group has a high synthesis potential. Therefore, for our dissertation study, we believed that quinazolin-4-thione (2) and its several substituted derivatives would be a good way to compare selective methylation processes. Two thionation reactions were performed on quinazolin-4-one (1): one with P₂S₅ and one with Lawesson’s reagent (LR), 2. To conduct reactions with P₂S₅ and LR (2) at the boiling temperature of absolute, the reagents are heated in an equimolar quantity at the boiling temperature of m-xylene for four hours.

The following is an approximate description of the mechanism of the reaction using Lavesson’s reagent (LR):

Its reaction with carbonyl compounds can result in the formation of the intermediate spiro-thioxaphosphetane (A), which due to thermal cycloreversion (reverse process to cycloaddition!) produces the desired thione (2) and (4-methoxyphenyl) (thioxo) phosphine oxide with a stable P=O bond. Normally, RL is in equilibrium with dithiophosphinylide, which when heated in an organic solvent has high reactive activity.

The one-proton singlet of the NH group is at 13.86 ppm in the 1H NMR spectrum, the one-proton doublet signal of the N-2 proton is at 8.59 ppm, and the doublet and triplet signals of the four aromatic protons of the benzene ring are at 7.62 (t), 7.74 (d), 7.90 (t), and 8.59 (d) ppm (fig-1). The IR spectrum of thione (2) shows the absorption frequency corresponding to the C=S bond at 1302 cm^-1.
Its structure was confirmed by identifying the protonated molecular ion m/z = 163 [M ⁺ H] ⁺ in the mass spectrum (M=162).

Quinazolin-4-one (3) and quinazolin-4-thione (2) have aromatic ring chromophores with C=O, C=S, and C=N bonds. As a result, these groupings have particular absorption frequencies in their UV spectrum.

The absorption frequencies of these compounds are 220, 311, and 330 nm. At 311 nm, the n→p* transition is shown by the longest absorption line. It should be mentioned that as quinazolin-4-one (1) and quinazolin-4-thione (2) derivatives are introduced, the primary absorption line positions rise.

Figure 1. ¹H NMR spectra of quinazolin-4-thione

A simple and very effective thionation technique of quinazolin-4-one (1) was created as a consequence of the thiolation reactions with LR occurring at a very low temperature and in a short amount of time, and the product (2) being generated in quantifiable quantities.

CONCLUSION

A chemical reaction was carried out from quinazolin-4-one with the corresponding quinazolin-4-thione phosphorus V-sulfide and Lavesson's reagent. Reaction mechanisms were studied.

Thionation reactions with Lavesson’s reagent occur at very low temperature and in a short time, and the product (2) is generated in quantifiable quantities, resulting in the creation of a quick and highly efficient technique for thionation of quinazolin-4-one (3).

UF After obtaining the spectra in ethanol, 1-2 drops of 0.1 N HCl solution were added, and a shift in the spectral lines was noticed. After that, 0.1 N (NaOH) was added, and it was determined that it was compatible with the original spectrum lines.

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