Edelweiss Applied Science and Technology ISSN: 2576-8484 Vol. 9, No. 7, 144-149 2025 Publisher: Learning Gate DOI: 10.55214/25768484.v9i7.8555 © 2025 by the authors; licensee Learning Gate © 2025 by the authors; licensee Learning Gate History: Received: 9 April 2025; Revised: 9 June 2025; Accepted: 12 June 2025; Published: 3 July 2025 * Correspondence: ziad.ibrahim@uodiyala.edu.iq Synthesis of isoxazolidine and isoxazoline rings via 1,3-dipolar cycloaddition reaction tethered to 2-benzothiazolethiol and study their antibacterial activity Ziad T I Alkayar1*, Zena Tariq Ibrahim2, Huda F. Hassan3, Enas Sami Ali3 1Department of Chemistry, College of Education for Pure Science, University of Diyala, Diyala, Iraq; ziad.ibrahim@uodiyala.edu.iq (Z.T.I.A.) 2The General Directorate for Education of Diyala, Diyala, Iraq. 3College of Pharmacy, University of Bilad Alrafidain, Diyala, Iraq. Abstract: New 2-benzothiazolethiol derivatives containing isoxazolidine and isoxazoline rings were made throughout 1,3-dipolar cycloaddition reactions. 4-methyl-o‐phenylenediamine was treated with carbon disulfide to form benzo[d]thiazole-2-thiol 1. The S-alkylation reaction of thiol group using allyl bromide and propargyl bromide gave compounds 2 and 3 in 83% and 90% yields respectively. Then, freshly prepared nitrones which are obtained in stiu by the reaction of N-methylhydroxylamine with deferent substituted aromatic aldehydes; 4-hydroxybenzaldehyde, 4-hydroxy-1-naphthaldehyde, 5- Methyl-2-thiophenecarboxaldehyde, 3-nitrobenzadehyde and 3-bromorobenzaldehyde, then, were reacted with compounds 2 and 3 which gave compounds 4a-e and 5a-e containing isoxazolidine and isoxazoline rings respectively. All the obtained compounds were characterized using infrared (IR) spectroscopy and Nuclear Magnetic Resonance (NMR) spectrophotometer and all were very matched the data of the structure. Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and gram-positive (Bacillus subtilis, Staphylococcus aureus) bacteria were used to evaluate the anti-bacterial activities for the obtained compounds, and the results displayed significant activity towards the selected bacteria by comparison to the standard drug amoxicillin. Keywords: Cycloaddition, Isoxazolidine, Isoxazoline, Nitrone, Ntibacterial activity. 1. Introduction Nitrones is an important reactive intermediate which is useful in organic synthetic reaction [1, 2]. Multifaceted applications of nitrones including 1,3-dipolar cycloaddition to construct the cyclic ring and complex natural products structures [3-5]. Heterocyclic chemistry has attracted interest of many researchers to syntheses and develop new compounds related to the heterocyclic family, which have used extensively in different sectors; medicine, agricultural, pharmaceutical, as well as material sciences [6, 7]. Azoles are crucial family of heterocyclic compounds and it is core structure of enzymes and many receptors that found in various organisms which interact through noncovalent bond and exhibit many biological activities [8] like anti-biotic [9], antimycotic agents [10], anti-viral [11], anti-inflammatory [12], anti-cancer [13], and anti-oxidant agents[14]. 2-Aminobenzenethiol compound containing nitrogen and sulfur atoms is an important fused rings heterocycle. Another types of heterocyclic ring are isoxazolidine and isoxazoline, this structural nature an important intermediate in the synthesis [15, 16] and its derivatives exhibit various bioactivities for their special properties, resulted in wide potential utilization in medicine field [13, 15, 17]. Since there are many strategies that could be used to form isoxazolidine and isoxazoline rings using classical method [18, 19]. The cycloaddition chemistry is a crucial in the synthesis of chemical compounds which can provide quick and control access to a number of natural products [19-21]. 145 Edelweiss Applied Science and Technology ISSN: 2576-8484 Vol. 9, No. 7: 144-149, 2025 DOI: 10.55214/25768484.v9i7.8555 © 2025 by the authors; licensee Learning Gate 2. Material and Methods 2.1. Experimental Section All reagents were brought from the market and were put to use with no more effort to purify; the melting points were detected using stuart smp3 electronic devise. Shimadzu FT-IR 8400S, spectrophotometer was used to obtain the IR spectra. The 1H and 13C Nuclear Magnetic Resonance spectra were obtained using D6-DMSO on Bruker 400 MHz spectrometer and the TMS as reference. The reactions were followed using TLC; the spots were detected using KMnO4 dipping and UV cabinet. 2.2 Synthesis of 2-Benzothiazolethiol 1 Carbon disulfide (1.73 mL, 0.0289 mol) was added to a mixture of 2-aminobenzenethiol (2.5 mL, 0.024 mol) and (1.9 g, 0.048 mol) NaOH in distilled H2O (20 mL) and heated at 80 οC under stirr. After 4 h, neutralization with 3 N HCl solution, followed by extraction with EtOAc, then the organic layers were dried using MgSO4. Solvent evaporation under vacuum gave compound 1 in (85%) yield; IR υmax(film)/cm-1 3124, 3091, 2567, 1618, 1521, 1492. Data consistence with literature [22]. 2.2. The Method for the Synthesis of Compounds 2 and 3 To 2-Benzothiazolethiol 1 (2.0 g, 0.012 mol) in N,N-Dimethylformamide (20 mL) and K2CO3 (0.0015 mol), 3-Bromo-1-propene (1.2 mL, 0.013 mol) or propargyl bromide (1.0 mL, 0.013 mol) was added dropwise at 25 °C, the completion of reaction was monitored using TLC silica plate. After 3 h, water was added and the mixture was extracted with EtOAc (3 x 20 mL). The layers of organic solvent were collected, washed with water, and the obtained organic layer was dried over MgSO4, filtration and solvent evaporation under reduced pressure gave; products 2 (83%) yield in solid phase: m.p 75- 76 °C, IR υmax/cm-1 3421, 3059, 1618, 1525, 1498. Data consistent with literature [23]. Product 3 (90%) yield in solid phase: m.p 197-199 oC, IR υmax/cm-1 3429, 3211, 3059, 2939, 2839, 1622, 1517, 1452, 2117. 2.3. Synthesis of Compounds 4a-e and 5a-e The aldehydes (0.001 mol), N-methylhydroxylamine hydrochloride (0.0011 mol) and triethylamine (0.0012 mol) in PhMe (5.0 mL) were refluxed for 30 min. Compounds 2 or 3 (0.001 mol) was added and the reaction mixture was heated under reflux for 10 h, the completion of the reaction was followed by TLC silica plate. Then, the reaction mixture temperature was reduced to 25 °C and followed by solvent evaporation under vacuum pressure gave; 2.4. Data for Compounds 4a-e Compound 4a (67%) yield as a black in solid phase: m.p 195-197 oC, IR υmax/cm-1 3336, 3280, 3003, 2922, 2810, 1618, 1450, 1583: 1H-NMR (400 MHz, d6-DMSO) δ 8.27-8.24 (8 H, m, Ar CH), 5.82-5.55 (1H, m, O-CH), 4.6 (1H, s, OH), 3.10 (2H, d, SCH2), 2.95 (2H, t, CH2), 2.29 (3H, s, N-CH3), 2.12 (1H, d, N-CH). Compound 4b (70%) yield as a black in solid phase, m.p 257-259 °C, IR υmax/cm-1 3450, 3037, 2980, 2939, 1637, 1473, 1519; 1H NMR (400 MHz, d6-DMSO) δ 7.03-6.57 (10 H, m, Ar CH), 5.81-5.55 (1H, m, CH), 2.87 (1H, t, CH), 2.81 (3H, s, CH3), 2.75 (2H, d, CH2), 1.49 (2H, t, CH2). Compound 4c (77%) yield as a black in solid phase, m.p 215-218 °C, IR υmax/cm-1 3423, 3025, 2937, 2974, 1624, 1469, 1527. 1H NMR (400 MHz, d6-DMSO) δ 8.73-8.31 (6H, m, Ar CH), 5.45-3.39 (1H, m, CH), 2.97 (1H, t, CH), 2.82 (3H, s, CH3), 2.70 (2H, d, CH2), 1.58 (s, 3H, CH3), 1.46 (2H, t, CH2). Compound 4d (70%) yield as a black in solid phase, m.p: 230-228 °C, IR υmax/cm-1 3331, 3013, 2939, 2980, 1625, 1402, 1502, 1348, 1535. 1H NMR (400 MHz, d6-DMSO) δ 7.03-6.18 (8 H, m, CH), 5.67-5.61 (1H, m, CH), 3.86 (2H, d, CH2), 2.86 (3H, s, CH3), 2.76 (1H, d, CH), 1.74 (2H, t, CH2). Compound 4e (75%) yield in solid phase, m.p: 210-212 °C, IR υmax/cm-1 3446, 3035, 2974, 2939, 1638, 1475, 1598, 680; 1H NMR (400 MHz, d6-DMSO) δ 7.03-6.29 (8 H, m, CH), 4.45-4.24 (1H, m, CH), 3.12 (2H, d, CH2), 3.21 (3H, s, NCH3), 2.72 (1H, t, CH), 1.42 (2H, t, CH2). 146 Edelweiss Applied Science and Technology ISSN: 2576-8484 Vol. 9, No. 7: 144-149, 2025 DOI: 10.55214/25768484.v9i7.8555 © 2025 by the authors; licensee Learning Gate 2.5. Data for Compounds 5a-e Compound 5a (85%) yield as a black in solid phase, m.p: 225-227 °C, IR υmax/cm-1 3450, 3215, 3022, 2941, 2976, 1627, 1475, 1581, 1H NMR (400 MHz, d6-DMSO) δ 8.78-7.84 (10 H, m, CH), 4.47 (1H, s, OH). 3.13 (2H, d, CH2), 2.93 (1H, d, CH), 2.29 (3H, s, CH3), 2.19 (1H, d, CH). Compound 5b (87%) yield as a solid, m.p: 170-172 °C, IR υmax/cm-1 3448, 3030, 2974, 2939, 1635, 1475, 1510. 1H NMR (400 MHz, d6-DMSO) δ 7.03-6.20 (10 H, m, CH), 2.89 (3H, s, CH3), 2.89 (1H, d, CH), 2.79 (2H, d, SCH2), 1.49 (1H, d, CH). Compound 5c (84%) yield as a brown in solid phase, m. p: 200-202 °C, IR υmax/cm-1 3446, 3015, 2976, 2939, 1625, 1475, 1530, 1H NMR (400 MHz, d6-DMSO) δ 8.73-8.31 (6H, m, CH), 2.96 (1H, d, NCH), 2.82 (3H, s, CH3), 2.70 (2H, d, CH2), 1.58 (3H, s, CH3), 1.41 (1H, d, CH2). Compound 5d (75%) yield as a brown in solid phase, m.p: 198-200 °C, IR υmax/cm-1, 3269, 3032, 2976, 2939,1627, 1475, 1514, 1367, 1575. 1H NMR (400 MHz, d6-DMSO) δ 8.79-7.47 (10 H, m, Ar CH), 3.89 (2H, d, S-CH2), 2.86 (3H, s, N-CH3), 2.76 (1H, d, N-CH), 1.72 (1H, d, CH). Compound 5e (90%) yield as a grey in solid phase, m.p: 230-232 °C, IR υmax/cm-1 3454, 3022, 2976, 2871, 1635, 1475, 1515, 750. 1H NMR (400 MHz, d6-DMSO) δ 8.67-6.70 (8H, m, CH), 3.57 (2H, d, CH2), 3.17 (3H, s, CH3), 2.89 (1H, d, CH), 1.5 (1H, d, CH). 3. Result and Discussion The aim is to synthesize new compounds contain five membered rings throughout the cycloaddition reaction. The synthetic pathways involve the formation of 2-benzothiazolethiol followed by S- alkylation, then cyclization step to form the isoxazoline and isoxazolidine rings. However, to explore the ability to try the cycloaddition that could lead to five membered rings, compound 1 was needed to obtain compounds 2 and 3. To do so, 2-Mercaptoaniline and CS2 was heated in the presence of NaOH which gave 2-benzothiazolethiol 1 in good yield [22] see (scheme 1). Scheme 1. Synthesis of 2-benzothiazolethiol. The S-alkylation was carried out using allyl bromide which gave compound 2 in good yield and using propargyl bromide gave compounds 3 in excellent yield see (scheme 2) [23]. The completion of reaction was controlled using TLC silica plate. The FT-IR spectra confirmed the presence of the double and triple bonds in products. Scheme 2. S-alkylation step using allyl bromide and propargyl bromide. 147 Edelweiss Applied Science and Technology ISSN: 2576-8484 Vol. 9, No. 7: 144-149, 2025 DOI: 10.55214/25768484.v9i7.8555 © 2025 by the authors; licensee Learning Gate The two compounds 2 and 3 in-hand would allow testing the cycloaddition reactions using oximes in which can be prepared freshly by treating different substituted aldehydes with N- methylhydroxylamine hydrochloride. However, aldehyde 1.0 equivalent was reacted with N- methylhydroxylamine hydrochloride 1.2 equivalents and triethylamine in methyl benzene which was refluxed for 30 min to give nitrones in situ. This was followed by the addition of compound 2 and heating under reflux for 15 hours gave the desired products 4a-e in good yields see (Scheme 3). Based on the FT-IR spectra the double and triple bonds were disappeared. The protons of the isoxazoline ring was assigned on its 1H NMR spectra in which the proton adjacent to nitrogen appeared as triplet at 2.97-2.12 and the proton adjacent oxygen appeared as quintet at 5.81-4.24 ppm. For the formation of isoxazolidine ring, the same nitrones and method with compound 3 were used and gave the desired products 5a-e in good yields see (Scheme 3). 1H NMR spectra for the obtained compounds shows peak at 2.96-219 ppm as doublet belong to proton adjacent to nitrogen. Scheme 3. Cycloaddition reaction to form isoxazoline and isoxazolidine ring. 3. Antibacterial Activity The antibacterial activities for the synthesized compounds 4a-e and 5a-e were investigated against two types of bacteria; gram negative; Esherichia coli and Pseudomonas aeruginosa, and gram positive; Staphylococcus aureus and bacillus subtilis. Uutilizing the disc diffusion method, agar-agar gel [24, 25], two (50 and 100) mg/mL concentrations were used. The inhibition zones were measured in millimetre and were balanced to amoxicillin as a reference. The results clearly indicate that some compounds have good effect against the selected bacteria. 148 Edelweiss Applied Science and Technology ISSN: 2576-8484 Vol. 9, No. 7: 144-149, 2025 DOI: 10.55214/25768484.v9i7.8555 © 2025 by the authors; licensee Learning Gate Table 1. Antibacterial effect of compounds 4a-e and 5a-e. Comp. No. Conc. (mg/mL) Zone of inhibition ( in mm ) Gram negative Gram positive E. Coli P. aeruginosa B. subtilis S. aureus 4a 50 10 5 10 11 100 14 10 15 16 4b 50 14 7 14 10 100 15 9 12 14 4c 50 - 13 - - 100 20 16 15 14 4d 50 9 5 15 - 100 11 11 27 13 4e 50 10 - 10 9 100 15 11 15 14 5a 50 12 10 10 10 100 12 13 17 15 5b 50 11 10 13 12 100 14 12 20 15 5c 50 - 8 9 10 100 14 14 16 15 5d 50 11 8 - 11 100 20 14 15 17 5e 50 - 11 14 12 100 - 17 20 16 Amoxicillin 25 - - 11 8 DMSO - - - - - 4. Conclusion 1,3-dipolar cycloaddition reaction was successfully utilized for the formation of five membered ring isoxazolidine and isoxazoline in good yield which led to obtain new heterocyclic compounds. I have demonstrated the formation of oximes by the condensation of an aldehyde and N-methylhydroxylamine, then cyclization on to prepared compounds having terminal double and triple bonds. The antibacterial study for the synthesized compounds was done against the selected bacteria, the derivatives shows moderate to good activity. Transparency: The authors confirm that the manuscript is an honest, accurate, and transparent account of the study; that no vital features of the study have been omitted; and that any discrepancies from the study as planned have been explained. This study followed all ethical practices during writing. Copyright: © 2025 by the authors. 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