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Document Type : Original Article

Authors

Department of Chemistry, College of Science, Baghdad University, Baghdad, Iraq

Abstract

The previous effort involved the synthesis of unprecedented Schiff's bases compounds of hydrazine hydrate linked with ethyl 4-hydroxybenzoate, which in turn reacted with carbon disulfide (CS2) and potassium hydroxide (KOH) as catalyst to synthesize 2-marcapto-1,3,4-thiadiazole which reacts with methyl bromoacetate in the presence of triethyl amine N(CH2CH3)3 to form an ester whose methoxy group is converted into a hydrazide, and then reacts with different aromatic aldehydes to form Schiff bases, from which the thiazolidinone and oxazolidinonefive-membered ring heterocyclic compounds' derivatives were formed. All synthetic substances have high yields. The melting points of all compounds and some of their 1H-NMR and FT-IR spectra, were used to authenticate their identities.

Graphical Abstract

Synthesis and Characterization of New Thiazolidinone and Oxazolidinone Heterocyclic Derivatives from 2-Marcapto-1,3,4-Thiadiazole Compounds

Keywords

Main Subjects

Introduction

Heterocyclic compounds are organic compounds that are cyclic in nature containing at least one hetero atom; the most frequent heteroatoms are nitrogen (N), oxygen (O), and sulfur (S) [1]. Due to its activity in various disorders, heterocyclic compounds are regarded one of the most important classes of organic chemicals employed in various biological fields [2]. Anti-cancer, anti-fungal, anti-viral, anti-oxidants, anti-microbial, and anti-bacterial drugs have all been developed by using it [3-7]. Hugo Schiff discovered aldehydes and ketones with a nitrogen analogue which has an imine or azomethine (-CH=N-) group in the place of the carbonyl (CO) group [8]. The N atom of azomethine may interfere with a normal cell function by forming a hydrogen-bond with the active centers of cell constituents [9, 10]. Thiadiazole represent a subclass of bioactive five-membered aromatic heterocycles composed of two nitrogen atoms and one sulfur atom [11, 12]. Many thiadiazole compounds have been studied intensively in recent years, many of which are known to have the interesting biological features such as anti-microbial [13-15], anti-tuberculosis [16], anti-inflammatory [17], anti-convulsants [18], anti-oxidant [19], anti-cancer [20], anti- fungal [21, 22], and anti-viral [23] activities. Many medications have sulfur-containing heterocycles as a structural component. The combinations of condensed sulfur-containing rings with nitrogen heterocycles have frequently played a key role in the discovery of new medications [14]. In the biological system, thiols are compounds with a sulfhydryl group (-SH). Because thiol complexes with shift-reagents are less stable than those of the corresponding alcohols, the induced shifts of the SH group protons are fewer than the similar values for the hydroxy group protons [24]. GSH, for example, is a crucial component of the glutathione conjugation reaction, which is a phase II drug metabolism process in the body that removes harmful reactive electrophiles [25-27]. Thiol levels that are abnormal have been associated to various diseases and biological abnormalities, including cardiovascular disease, cancer, alzheimer's disease, and others [27]. In this study, a number of Schiff bases and thiazolidinone with 1, 3, 4-thiadiazole derivatives rings were synthesized, and verified by FT-IR and 1HNMR.

Materials and Methods

Synthesis of 4-hydroxybenzohydrazide (1)

Ethyl 4-hydroxybenzoate (3 g, 0.018 mole) was dissolved in 20 mL of absolute ethanol, and then 2 mL of hydrazine hydrate (99 %, 0.04 mole) added with stirring. After that, the mixture was stirred for eight hours at room temperature, allowed into a petri dish, and the product has been recrystallized by using ethanol [28].

Synthesis of 4-(5-mercapto-1,3,4-thiodiazol-2-yl) phenol (2)

Compound 1 (2.5 g, 0.016 mole) was placed in absolute ethanol (30 mL) in a round bottom flask, followed by addition of anhydrous sodium carbonate (0.9 g, 0.0083 mole) and carbon disulfide (1.5 mL,0.02 mole) with continued stirring. The interaction mixture has been refluxed for 6 hours. Then, the mixture was filtered after cooling it to room temperature and the resulting solution was allowed to dry at room temperature in a petri dish, after which 50 mL of the cold distilled water was added, and then acidification with HCl (conc.) was carried out dropwise. White-yellowish precipitate was formed, and this precipitate was composed by filtration and distilled water with washed, re-crystallized by using the hot distilled water [29].

Formation of methyl 2-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)thio) acetate (3)

At room temperature, a mixture was stirred containing compound 2 (2 g, 0.01 mole), triethyl amine (1.2 mL, 0.008 mol), and dimethyl formamide (30 mL), for 10 min methyl bromoacetate (0.8 mL, 0.008 mole) was added dropwise to the reaction mixture and stirred for half an hour. Then, for eight hours, the product was heated to 70-80 °C. The reaction mixture was placed into ice water and allowed to cool. After that, by using a separating funnel, the oil product separated, and then washed with water and (5%) sodium bicarbonate before being recrystallized with ethanol [30].

Formation of 2-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)thio) acetohydrazide (4)

Compound 3 (1.7 g, 0.006 mole) was dissolved in 20 mL of absolute ethanol and 2 mL of hydrazine hydrate (99 %, 0.04 mole) was added into that mixture. Then, the mixture has been stirred at room temperature for 8 hours. The resultant solution was put into a petri dish, and the produce was recrystallized by using CH3CH2OH [28].

Synthesis of New Schiff's bases from 2-((5-(4-hydroxyphenyl)-1,3,4-thiodiazol-2-yl)thio) acetohydrazide (compounds 59)

0.008 mole of compound 4 and different aromatic aldehydes was mixed and refluxed for 6 hours in 20 mL of absolute ethanol and five drops from glacial CH3COOH in a water-bath. Under reduced pressure, the excess solvent was evaporated. Drying the crude product and recrystallizing it from ethanol [31]. Table 1 lists the physical characteristics of compounds 59.

Synthesis of 4-thiazolidinone derivatives (compounds 10-14)

Each product of Schiff bases compounds 5-9 (0.001 mole) was mixed in separated round bottom flask and an excess amount of HS-CH2COOH (0.002 mole) was added in EtOH. The reaction mixture has been reflexed 18-20 hours. The solvent was then evaporated (5%) of sodium bicarbonate solution was added to neutralize that thioglycolic acid excess. The produced precipitate has been filtered and washed with water for several times, and then recrystallized by using acetone [32]. Table 1 summarizes the physical property of compounds (10-14).

Synthesis of derivatives of 1,3-oxazolidin-5-one (compounds 15- 19)

mole of compounds 6-9 was dissolved in 20 mL, and then it was added to mono chloro acetic acid (0.001 mole) by using few drops of N(CH3CH2)3 catalyst. The reaction mixture has been refluxed for fifteen hours, and then poured in a petri dish, the solid precipitate and after that it was collected and recrystallized by using ethanol solvent [33]. Table 1 lists the physical properties for compounds 1519.

 

Results and Discussion

New heterocyclic ring derivatives were included in this work, as displayed in Scheme 1.

Synthesis of 4-hydroxybenzohydrazide (1)

In absolute ethanol ethyl 4-hydroxybenzoate was mixed with stirring at room temperature with hydrazine hydrate (99%), as indicated in Scheme 2 to form compound (1). Off-white precipitate, mp 98 °C, and yield 88%. The FT-IR spectrum data for compound (1) demonstrates the existence of the identifiable adsorption band at 3325, 3267 cm-1 belong to NH2 group asymmetric. and symmetric respectively and identifiable adsorption bond at 1676 cm-1 belongs to carbonyl of O=C-NHNH2 group.

Scheme 1: Schematic for the synthesis all reactions

Table 1: Physical property for compound (5-19)

No.

Formula

M.Wt g/mole

mp (°C)

Color

Yield (%)

5

C17H14N4O3S2

386.44

113-114

Dark Yellow

60

6

C17H13N5O4S2

415.44

140-142

Off White

52

7

C18H16N4O3S2

400.47

Oil

Reddish Yellow

92

8

C17H13ClN4O2S2

404.89

136-138

Yellow

88

9

C19H19N5O2S2

413.51

122-124

Yellow

68

10

C19H16N4O4S3

460.54

Oil

Brown

70

11

C19H15N5O5S3

489.54

215-217

Light Brown

44

12

C20H18N4O4S3

474.57

166-167

Light Red

56

13

C19H15ClN4O3S3

478.98

181-184

Dark Yellow

68

14

C21H21N5O3S3

487.61

Oil

Yellow

62

15

C19H16N4O5S2

444.48

182-183

Light Brown

76

16

C19H15N5O6S2

473.48

170-172

Light Red

55

17

C20H18N4O5S2

458.51

150-152

Red

70

18

C19H15ClN4O4S2

462.92

Oil

Yellow

69

19

C21H21N5O4S2

471.55

96-98

Brown

72

Scheme 2: Synthesis of 4-hydroxybenzohydrazide

Synthesis of 4-(5-mercapto-1,3,4-thiodiazol-2-yl) phenol (2)

As depicted in Scheme 2, compound (1) undergoes a reaction with carbon disulfide (CS2) in the presence of anhydrous sodium carbonate as a catalyst, followed by acidification with hydrochloric acid (HCl). Yellow ppt, mp 108-110 °C, and yield 70%. The FT-IR spectrum data for compound (2) showed appearance of the distinctive absorption band at 1672 cm-1 which is belong to C=N and distinctive absorption band at 2530 cm-1belongs to S-H and the demising of adsorption bands 3325, 3267 cm-1 which is belong to NH2 asymmetric and symmetric respectively.

Synthesis of methyl 2-((5-(4-hydroxyphenyl)-1,3,4-thiodiazol-2-yl)thio)acetate (3)

In alkali medium compound (2) reacts with methyl bromoacetate for preparing compound (3), as demonstrated in Scheme 3, which is off white, oily, and with a yield of 66%. The IR spectra data for compound (3) showed the appearance of distinctive adsorption band at 1708 cm-1 belongs to C=O of ester as well as the absorption band 2530 cm-1 have been disappeared which is belongs to S-H.

Scheme 3: Synthesis of 4-(5-mercapto-1,3,4-thiodiazol-2-yl) phenol

Scheme 4: Synthesis of methyl 2-((5-(4-hydroxyphenyl)-1,3,4- thiodiazol-2-yl)thio)acetate

Synthesis of 2-((5-(4-hydroxyphenyl)-1,3,4-thiodiazol-2-yl)thio) acetohydrazide (4)

In absolute ethanol compound (3) and hydrazine hydrate under stirring at room temperature interacted to form the compound (4). mp 70-72 °C, yield 78%. The FT-IR data for compound (4) illustrate the presence of distinctive adsorption bands at 3427, 3309 cm-1 belongs to NH2 asymmetric and symmetric respectively, distinctive adsorption band at 1685 cm-1 that is belongs to carbonyl related to the carbonyl of amide group and demising of the absorption band at 1708 cm-1 that is associated to carbonyl of ester group (Scheme 4).

Synthesis of new Schiff bases from 2-((5-(4-hydroxyphenyl)-1,3,4-thiodiazol-2-yl)thio) acetohydrazide (compounds 59)

The titled compounds were created by reacting compound (4) with various aromatic aldehydes, as indicated in Scheme 5 in absolute ethanol and glacial acetic acid. Table 1 presents the physical properties for compounds (5-9). The FT-IR spectra-data for compounds (5-9) showed the appearance of distinctive adsorption bands at 1627-1642 cm-1 belongs to C=N, distinctive adsorption bonds at 3193-3280 cm-1 belongs to NH, and disappearance of the adsorption bands 3424, 3309 cm-1 belongs to NH2 asymmetric and symmetric. Table 2 summarizes all the details of FT-IR spectra data of compounds (5-9).

Scheme 5: Synthesis of 2-((5-(4-hydroxyphenyl)-1,3,4- thiodiazol-2-yl)thio) acetohydrazide

Scheme 6: Synthesis of new Schiff bases from 2-((5-(4- hydroxyphenyl)-1,3,4-thiodiazol-2-yl)thio) acetohydrazide

Synthesis of 4-thiazolidinone derivatives (compounds 10-14)

As depicted in Scheme 6, the 4-thiazolidinone derivatives (10-14) were synthesized by refluxing the equal moles of compounds (5-9) and mercaptoacetic acid in ethanol. Physical properties for the compounds (10-14) are listed in Table 1. FT-IR spectral data of compounds (10-14) showed the appearance of carbonyl group stretching band at 1680-1735 cm-1 due to thiozolidinone ring. Likewise, disappearance of C=N adsorption bonds at 1627-1642 cm-1. All details of FT-IR and 1H-NMR spectrum are presented in Table 2.

Synthesis of derivatives of 1,3-oxazolidin-5-one compounds (15- 19)

The oxazolidinone derivatives have been prepared by the heating of ClCH2COOH, Schiff bases derivatives, and N(CH2CH3)2, as indicated in Scheme 8. Physical properties of the compounds (15-19) are listed in Table 2. The IR spectral data for compounds (15-19) revealed the appearance of carbonyl group stretching band at 1635-1674 cm-1 and stretching band of carbonyl group at 1699-1760 cm-1 due to oxazolidinone ring and disappearance of C=N absorption bands at 1596-1639 cm-1. All details of FT-IR and 1H-NMR spectrum are presented in Table 2.

Scheme 7: Synthesis of 4-thiazolidinone derivatives (10-14)

Scheme 8. Synthesis of derivatives of 1,3-oxazolidin-5-one (compounds 15-19)

Table 2: FT-IR spectra data of compounds 1-15

Conclusion

The above compounds were prepared and Identified and confirmed for each of them using the solubility degrees, FTIR and 1HNMR for some of them.

Acknowledgments

I extend my thanks and appreciation to everyone who helped me to accomplish this research, especially Prof. Dr. Mohammed R. Ahmed.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.

Conflict of Interest

There are no conflicts of interest in this study.

HOW TO CITE THIS ARTICLE

Bashar S. Salman, Mohammed R. Ahamad. Synthesis and Characterization of New Thiazolidinone and Oxazolidinone Heterocyclic Derivatives from 2-Marcapto-1,3,4-Thiadiazole Compounds. Chem. Methodol., 2022, 6(12) 997-1006

https://doi.org/10.22034/CHEMM.2022.357813.1601

URL: http://www.chemmethod.com/article_156809.html

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