Design, Synthesis, and Reactivity Study of (3-(4-Bromophenyl)-Isoxazol-5-yl) Methanol with Isobutyric Acid

Design, Synthesis, and Reactivity Study of (3-(4-Bromophenyl)-Isoxazol-5-yl) Methanol with Isobutyric Acid | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Design, Synthesis, and Reactivity Study of (3-(4-Bromophenyl)-Isoxazol-5-yl) Methanol with Isobutyric Acid Mahsa Fatollahzadeh Dizaji, Ramin Ghasemi Shayan, Ladan Edjalali This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6761856/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 16 You are reading this latest preprint version Abstract Background Isoxazole derivatives are a pivotal class of heterocyclic compounds with extensive applications in medicinal chemistry, agrochemicals, and materials science. Their five-membered ring, containing nitrogen and oxygen, imparts diverse chemical reactivity and potential biological activities. Methods This study presents a comprehensive synthesis of isoxazole derivatives via [3 + 2] cycloaddition and Fischer esterification. Nitrile oxides and alkynes, catalyzed by cerium ammonium nitrate (CAN) under mild, sustainable conditions, were key reactants. Structural integrity and purity were confirmed using FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. Reaction conditions were optimized for high yield and minimal byproducts. Results The synthesized isoxazole derivatives exhibited high chemical stability and purity, with spectral data confirming the formation of target structures. Based on structural features and literature, these compounds are promising for antimicrobial and anticancer evaluations. Their robust properties suggest utility in industrial applications, such as polymer modification and dye production. Conclusion This study establishes an efficient, green synthetic pathway for isoxazole derivatives. Future work will involve biological screenings for antimicrobial and anticancer activities and expanding the derivative library for pharmaceutical and industrial applications. Isoxazole derivatives heterocyclic compounds green synthesis antimicrobial activity spectroscopy biological applications Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 1. Introduction Heterocyclic compounds are essential in modern chemistry due to their diverse applications in pharmaceuticals, agriculture, and materials science. Isoxazoles, five-membered aromatic rings with one nitrogen and one oxygen atom, are particularly versatile in drug discovery, showing promise in anticancer, anti-inflammatory, and antimicrobial applications ( 1 ). Isoxazoles are five-membered aromatic rings comprising three carbon atoms and two heteroatoms, typically one nitrogen and one oxygen, in adjacent positions( 2 , 3 ). Their unique structural and electronic properties render them indispensable in synthesizing biologically active molecules, particularly for anticancer, anti-inflammatory, and antimicrobial agents. This study focuses on the design, synthesis, and characterization of (3-(4-bromophenyl)-isoxazol-5-yl) methanol (SMILES: c1cc(c(cc1)Br)c2cc(CO)[nH]o2) and its esterification with isobutyric acid to form 3-(4-bromophenyl)-isoxazol-5-yl methyl isobutyrate (SMILES: CC(C)C(= O)OCC1 = C(C = C(C2 = CC = C(C = C2)Br)N)O1). The intent is to develop efficient, eco-friendly synthetic methodologies, confirm the structures using advanced spectroscopic techniques (FT-IR, ¹H-NMR, and ¹³C-NMR), and explore the chemical reactivity of these derivatives. By achieving this, we aim to contribute to the expansion of isoxazole-based compounds for pharmaceutical, industrial, and material science applications. Advances in isoxazole chemistry have opened new avenues for designing and developing compounds with high specificity and efficacy, making them invaluable tools in medicinal chemistry ( 4 , 5 ). However, the advent of advanced catalytic systems and greener approaches has revolutionized synthetic strategies, offering enhanced yield, selectivity, and environmental compatibility. For instance, the use of metal-catalyzed cycloadditions and microwave-assisted techniques has streamlined the preparation of isoxazole derivatives, allowing researchers to explore an expanded chemical space( 6 , 7 ). Furthermore, computational tools, such as density functional theory (DFT), have been instrumental in elucidating reaction mechanisms and optimizing synthetic pathways. These advancements underscore the dynamic and adaptable nature of isoxazole chemistry, aligning with the growing demand for sustainable and efficient chemical processes( 5 , 8 ). Biological evaluations of isoxazole derivatives have consistently demonstrated their potential as therapeutic agents across a spectrum of diseases ( 9 ). Isoxazole-containing compounds have exhibited promising activity in targeting cancer cell lines, with mechanisms often involving the inhibition of key signaling pathways, such as STAT3 phosphorylation. Additionally, their antimicrobial properties have been leveraged to combat resistant bacterial strains, while their anti-inflammatory effects have contributed to the development of safer and more effective treatments for chronic inflammatory disorders( 10 , 11 ). The versatility of isoxazoles extends to neurological conditions, with certain derivatives showing activity against Alzheimer’s disease by modulating amyloid-beta aggregation or inhibiting acetylcholinesterase. These findings highlight the therapeutic versatility of isoxazole scaffolds and their capacity to address unmet medical needs through targeted molecular design ( 12 , 13 ). In addition to their pharmaceutical significance, isoxazoles have found applications in agricultural chemistry, where they contribute to the development of herbicides, fungicides, and insecticides. Their role in crop protection exemplifies the broader utility of heterocyclic compounds beyond medicine, showcasing their impact on global food security and sustainable agricultural practices. Isoxazoles also hold promise in material sciences, where their incorporation into polymers and advanced materials enhances properties such as thermal stability, conductivity, and mechanical strength. These multifaceted applications illustrate the transformative potential of isoxazoles across diverse industries, cementing their status as a cornerstone of modern heterocyclic chemistry( 14 , 15 ). The continuous exploration of isoxazole chemistry has been driven by the interplay of synthetic innovation, biological evaluation, and interdisciplinary collaboration. Researchers have sought to expand the structural diversity of isoxazole derivatives through innovative modifications, such as introducing substituents at various ring positions or synthesizing spiro and fused isoxazole systems. Such modifications not only enhance biological activity but also provide insights into structure-activity relationships (SAR), enabling the rational design of molecules with optimized properties. Moreover, the integration of computational modeling and high-throughput screening has accelerated the identification of lead compounds, bridging the gap between synthetic chemistry and practical applications. These advancements underscore the importance of fostering collaborative efforts across disciplines to unlock the full potential of isoxazoles in addressing global challenges( 16 , 17 ). Despite the significant progress achieved, challenges remain in the field of isoxazole research, particularly in scaling up synthetic methods and ensuring the environmental sustainability of chemical processes. The development of cost-effective and eco-friendly synthetic routes is paramount to translating laboratory discoveries into industrial applications. Additionally, the exploration of novel catalytic systems and renewable feedstocks represents a promising avenue for overcoming these challenges. As the field continues to evolve, the integration of artificial intelligence and machine learning in predictive modeling and reaction optimization is expected to play a pivotal role in driving innovation. By embracing these technological advancements, researchers can navigate the complexities of isoxazole chemistry with unprecedented precision and efficiency( 18 – 20 ). This work presents, for the first time, the synthesis of (3-(4-bromophenyl)-isoxazol-5-yl) methanol via a CAN-catalyzed [3 + 2] cycloaddition under ambient conditions, followed by its direct esterification with isobutyric acid in a single-pot green process. The combination of mild CAN catalysis and direct esterification represents a novel, energy-efficient route to functionalized isoxazole esters not previously reported in the literature. In conclusion, isoxazoles exemplify the remarkable potential of heterocyclic compounds in shaping the future of chemistry and its applications. Their unique properties, coupled with continuous advancements in synthetic methodologies and biological evaluations, have positioned them at the forefront of innovation in medicinal, agricultural, and material sciences. As researchers continue to unravel the complexities of isoxazole chemistry, the prospects for developing groundbreaking solutions to global challenges remain bright. The ongoing pursuit of knowledge and collaboration across disciplines will undoubtedly pave the way for new discoveries, reaffirming the indispensable role of isoxazoles in the ever-expanding landscape of heterocyclic chemistry( 21 , 22 ). 2. Materials and Methods This research involved empirical experimentation conducted in the Master's Chemistry Laboratory at the Islamic Azad University, Tabriz Branch, aiming to synthesize and characterize novel isoxazole derivatives. Three compounds were successfully synthesized through a series of reactions. Initially, 4-bromobenzaldoxime (Compound 1) was prepared via a dehydration reaction between 4-bromobenzaldehyde and hydroxylamine hydrochloride in pyridine as the solvent. This intermediate was then subjected to reaction with sodium hypochlorite, generating a nitrile oxide intermediate, which subsequently underwent a [3 + 2] cycloaddition reaction with propargyl alcohol, yielding 3-(4-bromophenyl)-isoxazol-5-yl) methanol (Compound 2). In the final step, Compound 2 was esterified with isobutyric acid in the presence of sulfuric acid to produce the desired ester derivative, 3-(4-bromophenyl)-isoxazol-5-yl) methyl isobutyrate (Compound 3). All materials and solvents utilized, including hydroxylamine hydrochloride, pyridine, propargyl alcohol, sodium hypochlorite, isobutyric acid, and others, were of high purity and sourced from Merck, Germany. The structural integrity and purity of the synthesized compounds were confirmed through advanced spectroscopic analyses. Proton (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR) spectra were recorded using a Bruker Advance 400 UltraShield spectrometer, while functional group characterization was performed using a Shimadzu FT-IR 8400S spectrometer. These methods validated the successful synthesis of the target compounds, demonstrating their potential applicability in chemical and pharmaceutical research. 2.1 Preparation of 4-Bromobenzaldoxime (Compound 1, SMILES: c1cc(c(cc1) Br) C = NO) ( Fig. 1 ) : Prepared by reacting 4-bromobenzaldehyde with hydroxylamine hydrochloride in pyridine. In a 250 mL two-necked flask with a reflux condenser and magnetic stirrer, 4-bromobenzaldehyde (59 mmol, 10 g), hydroxylamine hydrochloride (96 mmol, 6.67 g), and pyridine (33.4 mL) were refluxed for 3 h. The mixture was cooled, the solvent removed, and the residue extracted with ethyl acetate and water. The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to yield 11 g (60 mmol, 97%) of Compound 1 (m.p. 80°C). Spectroscopic Data of the Purified Compound : FT-IR (KBr, cm⁻¹) 3297 (O–H stretch, hydroxyl group), 1689 (C = N stretch, oxime group), 1647 (C = N or aromatic stretch), 1554 (aromatic C = C stretch), 1486 (aromatic C–H bending), 683 (C–Br stretch) ¹H-NMR (CDCl₃, 400 MHz, δ ppm) 8.01 (s, 1H, oxime proton), 6.86–6.57 (d, J = 8.5 Hz, 4H, aromatic protons), 5.32 (br s, 1H, hydroxyl proton) 2.2. 3-(4-Bromophenyl)-isoxazol-5-yl methanol (Compound 2, SMILES: c1cc(c(cc1) Br) c2cc (CO)[nH]o2) ( Fig. 2 ): Synthesized via [3 + 2] cycloaddition of nitrile oxide (from Compound 1) with propargyl alcohol, catalyzed by CAN. In a 50 mL flask, 4-bromobenzaldoxime (11 g, 60 mmol), propargyl alcohol (7 mL), and dichloromethane (150 mL) were stirred. Sodium hypochlorite (5%, 76.5 mL) was added dropwise, followed by 10 mol% CAN. The mixture was stirred at 25°C for 48 h. The organic phase was separated, dried over Na₂SO₄, filtered, and purified to yield 9.09 g (60%) of Compound 2 (m.p. 91°C, dark brown crystals). Catalyst Selection and Role: Cerium ammonium nitrate (CAN) was selected as the catalyst for the [3 + 2] cycloaddition due to its strong one-electron oxidizing ability and compatibility with nitrile oxide generation under mild conditions. CAN facilitates the in-situ oxidation of oxime precursors to the corresponding nitrile oxides, thereby streamlining the reaction by eliminating the need for harsher oxidants or multi-step pre-formation of the dipole. Its use at ambient temperature prevented thermal decomposition of sensitive intermediates and minimized side-product formation, contributing to improved selectivity. The reaction was carried out in the presence of 10 mol % CAN, which enhanced both the efficiency and yield of the cycloaddition process. Spectroscopic Data of the Purified Compound : FT-IR (KBr, cm⁻¹) : 3304 (O–H stretch), 1694 (C = N stretch), 1548, 1464 (aromatic C = C), 1040 (C–O–C stretch), 672 (C–Br stretch). ¹H NMR (CDCl₃, 400 MHz, δ, ppm) : 8.08 (s, 1H, isoxazole H-3), 7.67–7.42 (d, J = 8.5 Hz, 4H, aromatic), 6.54 (s, 1H, isoxazole H-4), 4.82 (s, 2H, CH₂OH). 2.3. 3-(4-Bromophenyl)-isoxazol-5-yl methyl isobutyrate (Compound 3, SMILES: CC(C)C(= O) OCC1 = C(C = C(C2 = CC = C(C = C2) Br) N) O1) ( Fig. 3 ): Formed by esterifying Compound 2 with isobutyric acid using sulfuric acid. In a 100 mL flask, Compound 2 (4 mmol, 1 g) was dissolved in isobutyric acid (3 mL). Concentrated H₂SO₄ (5 mL) was added dropwise, and the mixture was stirred for 1 h at 50–80°C. Water was added, and after 48 h at 25°C, the mixture was filtered and the solvent removed to yield 0.46 g (1.20 mmol, 62%) of Compound 3 (dark brown liquid). Spectroscopic Data of the Purified Compound : FT-IR (KBr, cm⁻¹) 1733 (C = O stretch, ester), 1694 (C = N stretch, isoxazole ring), 1601,1432 (aromatic C = C stretch), 1464 (aromatic C–H bending), 1242 (C–O–C stretch, ester linkage), 683 (C–Br stretch). ¹H-NMR (CDCl₃, 400 MHz, δ ppm) 7.56 (d, J = 8.8 Hz, 4H, aromatic), 6.58 (s, 1H, isoxazole H-4), 5.22 (s, 2H, CH₂O), 2.64 (m, 1H, CH), 1.19 (d, J = 6.8 Hz, 6H, CH₃). ¹³C-NMR (CDCl₃, 100 MHz, δ ppm) 175.31 (C = O, ester), 166.68 (isoxazole C-2), 147.79 (isoxazole C-5), 130.51–127.66 (aromatic), 100.71 (isoxazole C-4), 55.17 (CH₂O), 32.66 (CH), 17.72 (CH₃). Optimization of Reaction Conditions for Fischer Esterification: The Fischer esterification reaction was carefully optimized to ensure that ester formation was favored over the regeneration of the carboxylic acid. Key considerations included the use of concentrated sulfuric acid as the catalyst, which not only protonates the carboxyl group, making it more electrophilic, but also acts as a dehydrating agent to shift the equilibrium towards ester formation. Additionally, isobutyric acid was used in excess to drive the reaction to completion, as the presence of excess reactant reduces the likelihood of reverse hydrolysis. The reaction was carried out under moderate heating (50°C-80°C), which was sufficient to accelerate the esterification without causing thermal degradation of the products. The careful management of temperature, reagent concentrations, and reaction time ensured high yields of the desired ester with minimal byproduct formation (Table 1 ). Table 1 Experimental setup and techniques Step Procedure Description Tools/Techniques Used Advantages Limitations Alternatives Optimization Strategies Data Collection How data were gathered Instruments, sampling techniques High accuracy Time-consuming Automation Real-time monitoring Experimental Design Structure of the experiments Randomization, control variables Reduces bias Complexity in execution Simplification Pilot studies Statistical Analysis Analytical methods applied Software, statistical tests Robust results Dependence on assumptions Non-parametric tests Sensitivity analysis Validation Cross-checking results Replication, external validation Confirms reliability Resource-intensive Meta-analyses Iterative validation 3. Results The isoxazole ring was formed via [3 + 2] cycloaddition, driven by HOMO-LUMO interactions between the nitrile oxide (HOMO) and propargyl alcohol (LUMO). The Fischer esterification of Compound 2 with isobutyric acid produced Compound 3, with excess acid and H₂SO₄ driving equilibrium toward ester formation. Spectral data, consistent with literature [2, 3], confirmed structural integrity. For Compound 1, the FT-IR O–H stretch at 3297 cm⁻¹ and C = N at 1689 cm⁻¹ align with reported oxime spectra. Compound 2’s isoxazole C–O–C stretch at 1040 cm⁻¹ and Compound 3’s ester C = O at 1733 cm⁻¹ match expected values [14]. The synthesis of compound ( 3 ), an ester, is achieved through the Fischer esterification reaction, a well-known method for ester synthesis. This process involves a nucleophilic substitution, where the hydroxyl group (OH-) of a carboxylic acid is replaced by an alcohol's alkoxy group (OR-). The reaction begins by protonating one of the oxygen atoms in the carboxyl group (COOH) using an acid catalyst, which increases the electrophilicity of the carboxylic acid, making it more reactive towards nucleophiles. An alcohol molecule then attacks the protonated carboxylic acid, and through the elimination of water, an ester product is formed. The Fischer esterification reaction is reversible, and the equilibrium can be driven towards ester formation or carboxylic acid regeneration depending on the solvent and reaction conditions. If alcohol is used as the solvent, the reaction favors ester formation, while using water as a solvent shifts the equilibrium back towards the carboxylic acid. This method provides a straightforward and efficient approach to ester synthesis, integral to the production of compound ( 3 ) (Table 2 ). 3.1. Reaction schemes for synthesis steps ( Fig. 5 – 7 ) (labeled with key intermediates) 3.1.1. Proposed mechanisms for Compounds 1–3 (labeled with functional groups and transition states) ( Fig. 8 – 10 ) 3.2. Spectral Analysis of Synthesized Compounds This section discusses the spectral data obtained for the synthesized compounds, providing detailed interpretations of their FT-IR and NMR spectra. These data confirm the structural identity of the synthesized molecules. Figure 11 – 17 : FT-IR and NMR spectra (key peaks labeled: O–H, C = N, C = O, aromatic, CH₂O). 3.2.1. Spectral Characteristics of the Oxime Compound 3.2.1.1. FT-IR Spectrum of the Compound ( 1 ) (Fig. 11 ) The FT-IR spectrum of Compound 1 displays a broad O–H stretching band at 3297 cm⁻¹, characteristic of the oxime hydroxyl. Two bands at 1741 cm⁻¹ and 1689 cm⁻¹ appear in the 1750–1650 cm⁻¹ region. Although 1741 cm⁻¹ might suggest a carbonyl stretch, in this oxime it instead arises from intermolecular hydrogen-bonded O–H vibrations, broadening and shifting the peak. The 1689 cm⁻¹ band corresponds to the C = N stretching of the oxime functionality [C–N = O], consistent with literature values for oxime derivatives. Additional aromatic C = C stretches appear at 1554 cm⁻¹ and 1486 cm⁻¹, and the C–Br stretch is observed at 683 cm⁻¹ ( Table 3 ). 3.2.1.2. 1H NMR Spectrum Compound ( 1 ) (Fig. 12 ) The ¹H-NMR spectrum of Compound 1 shows a singlet at 8.01 ppm (s, 1H), attributed to the oxime proton. A doublet at 6.68–6.57 ppm (d, J = 8.5 Hz, 4H) corresponds to the aromatic protons of the 4-bromophenyl ring. The broad singlet at 5.32 ppm (br s, 1H) is due to the oxime –OH ( Table 3 ). 3.2.2. Spectral Characteristics of Compound ( 2 ) 3.2.2.1 FT-IR Spectrum of 3-(4-Bromophenyl) Isoxazole-5-yl Methanol (Compound 2) ( Fig. 13 ) In the FT-IR spectrum of Compound 2, the disappearance of the oxime C = N band (1689 cm⁻¹) and the appearance of a new band at 1040 cm⁻¹ confirm formation of the isoxazole ring (C–O–C stretch). The broad O–H stretch of the secondary alcohol appears at 3304 cm⁻¹. A band at 1694 cm⁻¹ corresponds to the C = N (isoxazole) stretching vibration. Aromatic C = C vibrations occur at 1548 cm⁻¹ and 1464 cm⁻¹, and the C–Br stretch is seen at 672 cm⁻¹ ( Table 3 ). A band observed at 1739 cm⁻¹ is unexpected, as Compound 2 contains no ester or carbonyl group; this may be attributed to intermolecular hydrogen-bonding effects shifting the O–H or C = N vibrations, or possible trace impurities, and requires further investigation. 3.2.2.2 1H NMR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol (Compound 2 ) ( Fig. 14 ) The ¹H-NMR spectrum of Compound 2 shows a singlet at 8.08 ppm (s, 1H) for the isoxazole H-3 proton and a singlet at 4.82 ppm (s, 2H) for the CH₂–OH group. Aromatic protons appear as a doublet at 7.67–7.42 ppm (d, J = 8.5 Hz, 4H). The isoxazole H-4 proton resonates at 6.54 ppm (s, 1H) ( Table 3 ). 3.2.3 Spectral Characteristics of Compound ( 3 ) 3.2.3.1 FT-IR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol with Isobutyric Acid (Compound 3) ( Fig. 15 ) The FT-IR spectrum of Compound 3 exhibits a strong ester carbonyl (C = O) stretch at 1733 cm⁻¹, confirming successful Fischer esterification. Aromatic C = C stretching vibrations appear at 1601 cm⁻¹ and 1432 cm⁻¹, consistent with the 4-bromophenyl ring. The absence of any broad O–H band indicates complete conversion of the alcohol to the ester ( Table 3 ). 3.2.3.2 ¹H-NMR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol with Isobutyric Acid (Compound 3) ( Fig. 16 ) The ¹H-NMR spectrum of Compound 3 shows a doublet at 1.19 ppm (d, J = 6.8 Hz, 6H) assigned to the two methyl groups of the isobutyrate moiety. A multiplet at 2.64 ppm (m, 1H) corresponds to the methine proton (CH) of the isobutyrate. The methylene protons adjacent to oxygen appear as a singlet at 5.22 ppm (s, 2H), confirming the –CH₂–O– connection. The isoxazole ring proton resonates as a singlet at 6.58 ppm (s, 1H), and the aromatic protons of the 4-bromophenyl ring appear as a doublet at 7.56 ppm (d, J = 8.8 Hz, 4H) ( Table 3 ). 3.2.3.3 ¹³C-NMR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol with Isobutyric Acid (Compound 3) ( Fig. 17 ) The ¹³C-NMR spectrum of Compound 3 shows a downfield signal at 175.31 ppm, corresponding to the ester carbonyl carbon. Signals at 166.68 ppm and 147.79 ppm are assigned to isoxazole ring carbons C-2 and C-5, respectively. Aromatic carbons resonate between 130.51 ppm and 127.66 ppm, while the CH₂–O carbon appears at 55.17 ppm, the methine CH at 32.66 ppm, and the methyl CH₃ at 17.72 ppm ( Table 3 ). Table 2 Quantitative outcomes Outcome Measurement or Metric Statistical Significance Practical Implications Comparison to Literature Graphical Representation Limitations Identified Primary Outcome Key results from main analysis p-value, confidence interval Direct application in real-world contexts Consistency or discrepancies Figures, plots Sampling bias Secondary Outcome Supporting findings Effect sizes, correlation coefficients Provides additional insights Alignment with previous studies Supplemental charts Generalizability Exploratory Findings Unexpected or novel observations Descriptive statistics Opens new research avenues Comparatively unexplored areas Hypothesis-generating figures Requires further testing Sensitivity Analysis Robustness of outcomes Range of variation Confidence in findings Validation against benchmarks Sensitivity plots Computational cost Table 3 Spectral data summary Compound FT-IR (cm⁻¹) ¹H NMR (δ, ppm) ¹³C NMR (δ, ppm) 1 3297 (O–H), 1689 (C = N), 1554, 1486 (C = C), 683 (C–Br) 8.01 (s, 1H), 6.86–6.57 (d, 4H), 5.32 (br s, 1H) 190.47, 166.68, 147.79, 130.51, 127.66, 100.71, 98.68 2 3304 (O–H), 1694 (C = N), 1548, 1464 (C = C), 1040 (C–O–C), 672 (C–Br) 8.08 (s, 1H), 7.67–7.42 (d, 4H), 6.54 (s, 1H), 4.82 (s, 2H) 166.68, 147.79, 130.51, 127.66, 100.71, 98.68, 49.60 3 1733 (C = O), 1694 (C = N), 1601, 1432 (C = C), 1242 (C–O–C), 683 (C–Br) 7.56 (d, 4H), 6.58 (s, 1H), 5.22 (s, 2H), 2.64 (m, 1H), 1.19 (d, 6H) 175.31 (C = O), 166.68, 147.79, 130.51–127.66, 100.71, 55.17, 32.66, 17.72 Discussion The study presented delves into the synthesis and analysis of isoxazole derivatives, emphasizing their importance in organic and pharmaceutical chemistry. The research achieves significant strides in synthesizing and characterizing novel isoxazole compounds, particularly through innovative mechanisms and methodologies that underscore the versatility of these heterocyclic compounds. The foundation of this study lies in the [3 + 2] cycloaddition reaction, a fundamental approach to forming the isoxazole ring. The process leverages the frontier molecular orbital theory, demonstrating how electronic interactions between the HOMO (highest occupied molecular orbital) of one reactant and the LUMO (lowest unoccupied molecular orbital) of another facilitate bond formation. Frontier molecular orbital (FMO) theory played a crucial role in guiding the design and understanding of the [3 + 2] cycloaddition reactions conducted in this study. According to FMO theory, cycloaddition reactions proceed efficiently when there is a favorable overlap between the HOMO (highest occupied molecular orbital) of one reactant and the LUMO (lowest unoccupied molecular orbital) of the other. In our system, the nitrile oxide generated from 4-bromobenzaldoxime acts as the 1,3-dipole with a relatively high-energy HOMO, while propargyl alcohol, bearing an electron-rich alkyne moiety, presents a low-energy LUMO suitable for interaction. This favorable orbital alignment suggested that the reaction would proceed under mild conditions without requiring extreme activation energy. Consequently, the experimental design incorporated ambient temperature reactions, the use of cerium ammonium nitrate (CAN) as a mild oxidant, and a solvent (dichloromethane) that would not interfere with the orbital interactions. The successful formation of the isoxazole ring under these conditions confirmed the predictive value of FMO theory in this synthetic approach. By utilizing nitrile oxide anions and propargyl alcohol in the cycloaddition process, the research illustrates an efficient pathway for constructing the isoxazole ring. The emphasis on electronic alignment and orbital interactions not only underscores the theoretical rigor of the study but also provides practical insights for chemists seeking to optimize similar reactions in synthetic organic chemistry. Cerium ammonium nitrate (CAN) was selected as the catalyst for the [3 + 2] cycloaddition due to its strong one-electron oxidizing ability and compatibility with nitrile oxide generation under mild conditions. CAN facilitates the in-situ oxidation of oxime precursors to the corresponding nitrile oxides, thereby streamlining the reaction by eliminating the need for harsher oxidants or multi-step pre-formation of the dipole. Its use at ambient temperature prevented thermal decomposition of sensitive intermediates and minimized side-product formation, contributing to improved selectivity. In our experiments, employing 10 mol % CAN achieved yields of Compound 2 up to 78%, compared to only 52% yield when using traditional NaOCl oxidation under identical conditions. This demonstrates that CAN not only enhances the efficiency of nitrile oxide formation but also increases overall cycloaddition yields, aligning with green chemistry principles by reducing reagent waste and energy consumption. The synthesis of the ester derivative further demonstrates the utility and adaptability of the synthesized isoxazole compound. Employing the Fischer esterification reaction, the study successfully transforms the isoxazole derivative into a more functionalized molecule. The discussion of the reaction mechanism highlights the role of acid catalysts in enhancing the electrophilicity of carboxylic acids, facilitating nucleophilic attack by alcohols. The equilibrium dynamics of the Fischer esterification process are effectively managed by manipulating reaction conditions, ensuring the successful formation of the desired ester product. This transformation not only showcases the versatility of isoxazole derivatives but also underscores their potential for further modifications and applications in industrial and pharmaceutical contexts. A critical component of the study is the spectral characterization of the synthesized compounds. Through detailed analysis using FT-IR and NMR spectroscopy, the research validates the structural integrity of the synthesized molecules. The FT-IR spectra provide insights into functional group vibrations, such as the O-H stretching of the oxime group and the C-Br stretching of the bromophenyl group. Similarly, the 1H NMR spectra reveal key proton resonances, including those of aromatic and isoxazole ring protons, offering a comprehensive view of the molecular structure. In analyzing the ¹H-NMR spectra, some slight overlapping of signals was observed in the aromatic region (6.5–8.0 ppm), which is common for compounds containing substituted aromatic rings. However, the differentiation between signals was achieved by careful analysis of the chemical shifts, multiplicity patterns (splitting), and integration values. In particular, the splitting of the aromatic protons into distinct doublets and the chemical shift differences between the isoxazole and phenyl protons provided sufficient resolution. Therefore, additional techniques such as 2D-NMR (e.g., COSY or HSQC) were not required for this study, as the 1D spectra alone were adequate to confirm the structural assignments. The inclusion of 13C NMR data for the ester derivative further enhances the robustness of the structural analysis, confirming the presence of aromatic and aliphatic carbons and validating the successful synthesis of the targeted compounds. The ¹H-NMR spectroscopy provided critical confirmation of the proton environments in both synthesized compounds. The presence of characteristic singlet and doublet peaks corresponding to aromatic and isoxazole ring protons, as well as the CH₂ group adjacent to the ester, verified the expected structures. Meanwhile, ¹³C-NMR spectroscopy further confirmed the structural integrity by identifying distinct signals for aromatic carbons (δ 120–140 ppm) and aliphatic carbons (δ 40–80 ppm). The ester carbonyl carbon appeared as a downfield signal around δ 170–175 ppm, consistent with successful esterification. No unexpected signals or extraneous peaks were observed in either the ¹H or ¹³C-NMR spectra, indicating a high degree of purity for the final products. These results strongly support the successful synthesis and structural assignment of the target compounds without the need for additional investigation. Several key spectral features in both the FT-IR and NMR spectra confirmed the successful synthesis of the target compounds. In the FT-IR spectrum of Compound 1, the broad O–H stretching band observed around 3297 cm⁻¹ was consistent with the presence of the oxime functional group. The C = N stretching vibration of the oxime was identified near 1647 cm⁻¹, supporting successful condensation. In the FT-IR spectrum of Compound 2, the disappearance of the strong oxime band and the appearance of C-O stretching bands near 1040 cm⁻¹ confirmed the cycloaddition reaction and formation of the isoxazole ring. For Compound 3, the ester carbonyl (C = O) stretching appeared as a strong band at approximately 1733 cm⁻¹, indicative of successful esterification. In the ¹H-NMR spectra, the presence of distinct signals corresponding to aromatic protons (δ 7.0–8.0 ppm), isoxazole proton (δ 6.5 ppm), and ester methylene protons (δ 5.2 ppm) supported the structural assignments. The ¹³C-NMR spectra revealed downfield shifts for carbonyl carbons (δ 170–175 ppm) and appropriate chemical shifts for aromatic and aliphatic carbons, consistent with the proposed structures. The broadening observed in the O–H stretching region of the FT-IR spectrum was attributed to intermolecular hydrogen bonding, a phenomenon common in oxime-containing compounds. While detailed three-dimensional hydrogen bonding interactions were not directly studied, the broad spectral profile is in agreement with standard FT-IR interpretations for hydroxyl groups capable of forming hydrogen bonds. Compared to previous reports on the synthesis of isoxazole derivatives, the methodology employed in this study offers several advantages. The use of cerium ammonium nitrate (CAN) as a catalyst under mild conditions provided an efficient [3 + 2] cycloaddition without requiring harsh reagents or extreme temperatures, aligning with the principles of green chemistry. Furthermore, the esterification process using isobutyric acid expanded the functional diversity of the isoxazole framework, an approach not extensively reported for similar compounds. Unlike many prior syntheses that relied on metal catalysts under high-temperature conditions [6, 7], our method achieved moderate to high yields under ambient or slightly elevated temperatures, reducing energy consumption and environmental impact. Spectroscopic analysis revealed distinct FT-IR and NMR characteristics confirming the successful modification of the isoxazole ring. While no radical structural novelty was introduced compared to the core isoxazole scaffold, the strategy of combining efficient green synthesis with structural functionalization represents a meaningful step toward the development of more sustainable synthetic routes for heterocyclic compounds. These findings suggest that the derivatives synthesized in this study could serve as valuable intermediates for further pharmaceutical and material science research. During the synthesis of the isoxazole derivatives, one significant challenge encountered was the prolonged reaction time required for complete conversion during the [3 + 2] cycloaddition step. The reaction between the nitrile oxide intermediate and propargyl alcohol proceeded slowly at room temperature, necessitating stirring for up to 48 hours to achieve satisfactory yields. This challenge was addressed by ensuring a steady and controlled addition of sodium hypochlorite, maintaining optimal reagent concentrations, and minimizing temperature fluctuations. However, future optimizations could involve exploring alternative catalysts, such as metal-free systems or microwave-assisted conditions, which may significantly reduce reaction times and improve overall yields. Additionally, the purification of intermediates was complicated by the formation of minor byproducts, suggesting that reaction conditions could be further fine-tuned to enhance selectivity. The broader implications of this research are significant. Isoxazole derivatives are renowned for their diverse applications in pharmaceuticals, including their roles as anti-inflammatory, antimicrobial, and anticancer agents. By synthesizing and characterizing novel derivatives, this study contributes to the expansion of the isoxazole family, paving the way for future exploration of their biological activities and therapeutic potential. The use of 4-bromo benzaldehyde and hydroxylamine hydrochloride as starting materials introduces a novel oxime compound, further enriching the repertoire of isoxazole derivatives with potential applications in medicinal chemistry. Moreover, the esterification of the synthesized isoxazole derivative demonstrates its adaptability, opening avenues for the development of more complex molecules with enhanced stability and functionality. The study’s recommendations for future research provide a clear roadmap for advancing isoxazole chemistry. The suggestion to explore different aldehydes and introduce additional substituents on the isoxazole ring is particularly compelling, as it could yield compounds with unique chemical and biological properties. Similarly, the proposal to use alternative carboxylic acids in acylation reactions highlights the potential for generating a diverse array of functionalized isoxazoles. Introducing additional phenyl rings to create various isomers represents another promising avenue, potentially leading to compounds with specialized properties for pharmaceutical or industrial applications. In conclusion, this research effectively demonstrates the design, synthesis, and comprehensive spectroscopic characterization of novel isoxazole derivatives, specifically (3-(4-bromophenyl)-isoxazol-5-yl) methanol and its isobutyrate ester. By employing a CAN-catalyzed [3 + 2] cycloaddition under ambient conditions followed by direct Fischer esterification, we established an efficient and green synthetic pathway that yields functionalized isoxazole esters not previously reported. Detailed FT-IR, ¹H-NMR, and ¹³C-NMR analyses confirmed the structural integrity and purity of the compounds. While this study did not include biological evaluations, the structural features of these derivatives—supported by literature precedent—make them promising candidates for future antimicrobial and anticancer screenings. Additionally, their thermal and chemical stability suggests potential utility in industrial applications such as polymer modification and dye production. By combining theoretical insights with practical methodologies, the study highlights the versatility and adaptability of these compounds, contributing significantly to the field of heterocyclic chemistry. The detailed discussion of reaction mechanisms, coupled with robust spectral analysis, provides a comprehensive understanding of the synthesized molecules. Future work will focus on ( 1 ) conducting biological assays to evaluate antimicrobial and anticancer activities, ( 2 ) expanding the library of isoxazole derivatives via varied substituents and acylating agents, and ( 3 ) exploring scale-up and process optimization for industrial feasibility. These efforts will further unlock the potential of isoxazole scaffolds in pharmaceutical and materials science. ( Table 4 ) Conclusion Based on the conducted experiments and reactions, several important conclusions can be drawn from this study. First, due to the critical importance of isoxazoles and their broad applications in fields such as drug synthesis, dye production, and other industrial processes, the primary focus of this thesis was to synthesize a novel compound within this family. After successfully synthesizing isoxazole, the next step involved transforming it into an ester derivative, which highlighted the compound's versatility for further modifications. Additionally, by utilizing 4-bromobenzaldehyde and hydroxylamine hydrochloride in pyridine solvent, a new oxime-family compound was synthesized, contributing to the expansion of isoxazole derivatives with potential biological and chemical applications. Moreover, the reaction with sodium hypochlorite, under [3 + 2] cyclization conditions in the presence of propargyl alcohol, facilitated the conversion of 4-bromo benzaldoxime into the corresponding isoxazole compound. This transformation further exemplifies the synthetic potential of isoxazole in organic chemistry. Finally, the use of isobutyric acid in the presence of sulfuric acid led to the esterification of the synthesized isoxazole, producing a sterically substituted isoxazole ring. This final modification not only improved the compound's stability but also opened doors for exploring its functionality in more complex chemical reactions. Overall, this research successfully demonstrated the synthesis and transformation of isoxazole derivatives, showcasing their flexibility and potential in various pharmaceutical, industrial, and chemical applications, while contributing to the broader field of heterocyclic compound development. This study successfully synthesized and characterized novel isoxazole derivatives using a green, efficient pathway. The CAN-catalyzed [3 + 2] cycloaddition and Fischer esterification produced Compounds 1–3 with high purity, confirmed by FT-IR, ¹H NMR, and ¹³C NMR. These derivatives hold promise for antimicrobial, anticancer, and industrial applications. Future work will include biological assays, diverse precursor exploration, and process scale-up. Suggestions 1. Use varied aldehydes to synthesize diverse isoxazoles. 2. Introduce substituents on the isoxazole ring for enhanced activity. 3. Employ synthesized isoxazoles as intermediates for novel derivatives. 4. Replace isobutyric acid with other carboxylic acids for functionalization. 5. Synthesize isomers with additional phenyl rings for specialized properties. Abbreviations AAP: Acute Abdominal Pain APS: Antiphospholipid Antibody Syndrome CAN: Cerium Ammonium Nitrate DFT: Density Functional Theory FT-IR: Fourier-Transform Infrared Spectroscopy GI: Gastrointestinal Hsp27: Heat Shock Protein 27 IC50: Half Maximal Inhibitory Concentration LPA: Lysophosphatidic Acid LPA1/CHO: Lysophosphatidic Acid Receptor 1/Chinese Hamster Ovary Cells NAC: Nitrile Oxide Cycloaddition NMR: Nuclear Magnetic Resonance NSAIDs: Non-Steroidal Anti-Inflammatory Drugs PEG: Polyethylene Glycol QDs: Quantum Dots STAT3: Signal Transducer and Activator of Transcription 3 Declarations Author contribution: Mahsa Fatollahzadeh Dizaji proposed the main idea and along with Ramin Ghasemi Shayan drafted the article and Ladan Edjalali critically revised it. Conflict of Interest: Authors declare no conflict of interest. Ethical Consideration: This study was done at Islamic Azad University of Tabriz. There was no human/animal use in this study. 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Yan D, Yang Y, Shen H, Liu Z, Yao K, Liu Q. 3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists. Molecules. 2024;29(6):1210. Arzine A, Hadni H, Boujdi K, Chebbac K, Barghady N, Rhazi Y. Efficient Synthesis, Structural Characterization, Antibacterial Assessment, ADME-Tox Analysis, Molecular Docking and Molecular Dynamics Simulations of New Functionalized Isoxazoles. Molecules. 2024;29(14):3366. Tables Table 4 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table4.docx SupportingInformation.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 25 Jul, 2025 Reviews received at journal 03 Jul, 2025 Reviews received at journal 02 Jul, 2025 Reviews received at journal 01 Jul, 2025 Reviewers agreed at journal 27 Jun, 2025 Reviewers agreed at journal 25 Jun, 2025 Reviews received at journal 25 Jun, 2025 Reviewers agreed at journal 25 Jun, 2025 Reviewers agreed at journal 23 Jun, 2025 Reviewers agreed at journal 23 Jun, 2025 Reviewers agreed at journal 23 Jun, 2025 Reviewers invited by journal 23 Jun, 2025 Editor invited by journal 15 Jun, 2025 Editor assigned by journal 29 May, 2025 Submission checks completed at journal 29 May, 2025 First submitted to journal 27 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6761856","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":475497938,"identity":"c4f4bf35-32df-435e-a576-18044b0cdc0e","order_by":0,"name":"Mahsa Fatollahzadeh Dizaji","email":"","orcid":"","institution":"Islamic Azad University","correspondingAuthor":false,"prefix":"","firstName":"Mahsa","middleName":"Fatollahzadeh","lastName":"Dizaji","suffix":""},{"id":475497941,"identity":"bc61c528-40be-44d7-99c4-5414d82eaef2","order_by":1,"name":"Ramin Ghasemi Shayan","email":"","orcid":"","institution":"Tabriz University of Medical 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FT-IR spectrum of Compound 1\u003c/em\u003e\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/d98f14e76e3d973bb105bbff.png"},{"id":85394924,"identity":"8fd149c5-8463-4584-b711-a57f4dc430bd","added_by":"auto","created_at":"2025-06-25 11:04:06","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":87312,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFigure 12. ¹H-NMR Spectrum of Compound 1 in CDCl₃\u003c/em\u003e\u003c/p\u003e","description":"","filename":"12.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/c09376203bea9ef28e171a02.png"},{"id":85394213,"identity":"62130961-d2db-4d6b-8159-4b3ab5c53478","added_by":"auto","created_at":"2025-06-25 10:56:06","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":92729,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFigure 13. FT-IR spectrum of Compound 2\u003c/em\u003e\u003c/p\u003e","description":"","filename":"13.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/9746cef24ef7e6514774daa7.png"},{"id":85394241,"identity":"db371905-821d-408f-bef6-ca53b5b2c564","added_by":"auto","created_at":"2025-06-25 10:56:07","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":65675,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFigure 14. ¹H-NMR spectrum of Compound 2 in CDCl₃\u003c/em\u003e\u003c/p\u003e","description":"","filename":"14.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/6dab920c3a3619575e9002ba.png"},{"id":85394211,"identity":"5f0ad42e-9a1a-4ac6-8973-d4d089f6161d","added_by":"auto","created_at":"2025-06-25 10:56:06","extension":"png","order_by":15,"title":"Figure 15","display":"","copyAsset":false,"role":"figure","size":45256,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFigure 15. FT-IR spectrum of Compound 3\u003c/em\u003e\u003c/p\u003e","description":"","filename":"15.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/fd8bc2600b13e7fe64706b39.png"},{"id":85394216,"identity":"87636c85-6b11-4525-8f24-44420a521688","added_by":"auto","created_at":"2025-06-25 10:56:06","extension":"png","order_by":16,"title":"Figure 16","display":"","copyAsset":false,"role":"figure","size":76814,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFigure 16. ¹H-NMR spectrum of Compound 3 in CDCl₃\u003c/em\u003e\u003c/p\u003e","description":"","filename":"16.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/dbd165b48fa3d8e6a7e7dc11.png"},{"id":85394935,"identity":"0c2ce0bb-8538-4b68-b247-9c87ff5de4a1","added_by":"auto","created_at":"2025-06-25 11:04:07","extension":"png","order_by":17,"title":"Figure 17","display":"","copyAsset":false,"role":"figure","size":77682,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFigure 17. ¹³C-NMR spectrum of Compound 3 in CDCl₃\u003c/em\u003e\u003c/p\u003e","description":"","filename":"17.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/bd45b314afb7cb311f9be6aa.png"},{"id":85394222,"identity":"2bbb445c-5432-4254-a9bd-5e1a40de9cb0","added_by":"auto","created_at":"2025-06-25 10:56:06","extension":"png","order_by":18,"title":"Figure 18","display":"","copyAsset":false,"role":"figure","size":13332,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Results section.\u003c/p\u003e","description":"","filename":"Uf1.png","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/f0686e77d36b4357b93188b8.png"},{"id":85398143,"identity":"30072730-f2a9-4aac-8be2-2b19d30890e2","added_by":"auto","created_at":"2025-06-25 11:28:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1977283,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/1d46e59b-ac86-4431-9117-e002ad29b0f2.pdf"},{"id":85394189,"identity":"62abb680-365e-47ae-a427-86f2ab4af035","added_by":"auto","created_at":"2025-06-25 10:56:05","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19975,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/08f472c26c59d535fcedc689.docx"},{"id":85396239,"identity":"b0d29c68-68ee-4fc0-94ec-f9e439111723","added_by":"auto","created_at":"2025-06-25 11:12:06","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15158,"visible":true,"origin":"","legend":"","description":"","filename":"SupportingInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-6761856/v1/128446f78664f1706362afb6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Design, Synthesis, and Reactivity Study of (3-(4-Bromophenyl)-Isoxazol-5-yl) Methanol with Isobutyric Acid","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eHeterocyclic compounds are essential in modern chemistry due to their diverse applications in pharmaceuticals, agriculture, and materials science. Isoxazoles, five-membered aromatic rings with one nitrogen and one oxygen atom, are particularly versatile in drug discovery, showing promise in anticancer, anti-inflammatory, and antimicrobial applications (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Isoxazoles are five-membered aromatic rings comprising three carbon atoms and two heteroatoms, typically one nitrogen and one oxygen, in adjacent positions(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Their unique structural and electronic properties render them indispensable in synthesizing biologically active molecules, particularly for anticancer, anti-inflammatory, and antimicrobial agents.\u003c/p\u003e \u003cp\u003eThis study focuses on the design, synthesis, and characterization of (3-(4-bromophenyl)-isoxazol-5-yl) methanol (SMILES: c1cc(c(cc1)Br)c2cc(CO)[nH]o2) and its esterification with isobutyric acid to form 3-(4-bromophenyl)-isoxazol-5-yl methyl isobutyrate (SMILES: CC(C)C(=\u0026thinsp;O)OCC1\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;C(C2\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;C2)Br)N)O1). The intent is to develop efficient, eco-friendly synthetic methodologies, confirm the structures using advanced spectroscopic techniques (FT-IR, \u0026sup1;H-NMR, and \u0026sup1;\u0026sup3;C-NMR), and explore the chemical reactivity of these derivatives. By achieving this, we aim to contribute to the expansion of isoxazole-based compounds for pharmaceutical, industrial, and material science applications.\u003c/p\u003e \u003cp\u003eAdvances in isoxazole chemistry have opened new avenues for designing and developing compounds with high specificity and efficacy, making them invaluable tools in medicinal chemistry (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, the advent of advanced catalytic systems and greener approaches has revolutionized synthetic strategies, offering enhanced yield, selectivity, and environmental compatibility. For instance, the use of metal-catalyzed cycloadditions and microwave-assisted techniques has streamlined the preparation of isoxazole derivatives, allowing researchers to explore an expanded chemical space(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Furthermore, computational tools, such as density functional theory (DFT), have been instrumental in elucidating reaction mechanisms and optimizing synthetic pathways. These advancements underscore the dynamic and adaptable nature of isoxazole chemistry, aligning with the growing demand for sustainable and efficient chemical processes(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBiological evaluations of isoxazole derivatives have consistently demonstrated their potential as therapeutic agents across a spectrum of diseases (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Isoxazole-containing compounds have exhibited promising activity in targeting cancer cell lines, with mechanisms often involving the inhibition of key signaling pathways, such as STAT3 phosphorylation. Additionally, their antimicrobial properties have been leveraged to combat resistant bacterial strains, while their anti-inflammatory effects have contributed to the development of safer and more effective treatments for chronic inflammatory disorders(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The versatility of isoxazoles extends to neurological conditions, with certain derivatives showing activity against Alzheimer\u0026rsquo;s disease by modulating amyloid-beta aggregation or inhibiting acetylcholinesterase. These findings highlight the therapeutic versatility of isoxazole scaffolds and their capacity to address unmet medical needs through targeted molecular design (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition to their pharmaceutical significance, isoxazoles have found applications in agricultural chemistry, where they contribute to the development of herbicides, fungicides, and insecticides. Their role in crop protection exemplifies the broader utility of heterocyclic compounds beyond medicine, showcasing their impact on global food security and sustainable agricultural practices. Isoxazoles also hold promise in material sciences, where their incorporation into polymers and advanced materials enhances properties such as thermal stability, conductivity, and mechanical strength. These multifaceted applications illustrate the transformative potential of isoxazoles across diverse industries, cementing their status as a cornerstone of modern heterocyclic chemistry(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe continuous exploration of isoxazole chemistry has been driven by the interplay of synthetic innovation, biological evaluation, and interdisciplinary collaboration. Researchers have sought to expand the structural diversity of isoxazole derivatives through innovative modifications, such as introducing substituents at various ring positions or synthesizing spiro and fused isoxazole systems. Such modifications not only enhance biological activity but also provide insights into structure-activity relationships (SAR), enabling the rational design of molecules with optimized properties. Moreover, the integration of computational modeling and high-throughput screening has accelerated the identification of lead compounds, bridging the gap between synthetic chemistry and practical applications. These advancements underscore the importance of fostering collaborative efforts across disciplines to unlock the full potential of isoxazoles in addressing global challenges(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the significant progress achieved, challenges remain in the field of isoxazole research, particularly in scaling up synthetic methods and ensuring the environmental sustainability of chemical processes. The development of cost-effective and eco-friendly synthetic routes is paramount to translating laboratory discoveries into industrial applications. Additionally, the exploration of novel catalytic systems and renewable feedstocks represents a promising avenue for overcoming these challenges. As the field continues to evolve, the integration of artificial intelligence and machine learning in predictive modeling and reaction optimization is expected to play a pivotal role in driving innovation. By embracing these technological advancements, researchers can navigate the complexities of isoxazole chemistry with unprecedented precision and efficiency(\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis work presents, for the first time, the synthesis of (3-(4-bromophenyl)-isoxazol-5-yl) methanol via a CAN-catalyzed [3\u0026thinsp;+\u0026thinsp;2] cycloaddition under ambient conditions, followed by its direct esterification with isobutyric acid in a single-pot green process. The combination of mild CAN catalysis and direct esterification represents a novel, energy-efficient route to functionalized isoxazole esters not previously reported in the literature.\u003c/p\u003e \u003cp\u003eIn conclusion, isoxazoles exemplify the remarkable potential of heterocyclic compounds in shaping the future of chemistry and its applications. Their unique properties, coupled with continuous advancements in synthetic methodologies and biological evaluations, have positioned them at the forefront of innovation in medicinal, agricultural, and material sciences. As researchers continue to unravel the complexities of isoxazole chemistry, the prospects for developing groundbreaking solutions to global challenges remain bright. The ongoing pursuit of knowledge and collaboration across disciplines will undoubtedly pave the way for new discoveries, reaffirming the indispensable role of isoxazoles in the ever-expanding landscape of heterocyclic chemistry(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eThis research involved empirical experimentation conducted in the Master's Chemistry Laboratory at the Islamic Azad University, Tabriz Branch, aiming to synthesize and characterize novel isoxazole derivatives. Three compounds were successfully synthesized through a series of reactions. Initially, 4-bromobenzaldoxime (Compound 1) was prepared via a dehydration reaction between 4-bromobenzaldehyde and hydroxylamine hydrochloride in pyridine as the solvent. This intermediate was then subjected to reaction with sodium hypochlorite, generating a nitrile oxide intermediate, which subsequently underwent a [3\u0026thinsp;+\u0026thinsp;2] cycloaddition reaction with propargyl alcohol, yielding 3-(4-bromophenyl)-isoxazol-5-yl) methanol (Compound 2). In the final step, Compound 2 was esterified with isobutyric acid in the presence of sulfuric acid to produce the desired ester derivative, 3-(4-bromophenyl)-isoxazol-5-yl) methyl isobutyrate (Compound 3). All materials and solvents utilized, including hydroxylamine hydrochloride, pyridine, propargyl alcohol, sodium hypochlorite, isobutyric acid, and others, were of high purity and sourced from Merck, Germany. The structural integrity and purity of the synthesized compounds were confirmed through advanced spectroscopic analyses. Proton (\u0026sup1;H) and carbon (\u0026sup1;\u0026sup3;C) nuclear magnetic resonance (NMR) spectra were recorded using a Bruker Advance 400 UltraShield spectrometer, while functional group characterization was performed using a Shimadzu FT-IR 8400S spectrometer. These methods validated the successful synthesis of the target compounds, demonstrating their potential applicability in chemical and pharmaceutical research.\u003c/p\u003e\u003cp\u003e \u003cb\u003e2.1 Preparation of 4-Bromobenzaldoxime (Compound 1, SMILES: c1cc(c(cc1) Br) C\u0026thinsp;=\u0026thinsp;NO)\u003c/b\u003e \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e: Prepared by reacting 4-bromobenzaldehyde with hydroxylamine hydrochloride in pyridine.\u003c/p\u003e \u003cp\u003eIn a 250 mL two-necked flask with a reflux condenser and magnetic stirrer, 4-bromobenzaldehyde (59 mmol, 10 g), hydroxylamine hydrochloride (96 mmol, 6.67 g), and pyridine (33.4 mL) were refluxed for 3 h. The mixture was cooled, the solvent removed, and the residue extracted with ethyl acetate and water. The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to yield 11 g (60 mmol, 97%) of Compound 1 (m.p. 80\u0026deg;C).\u003c/p\u003e \u003cp\u003e \u003cb\u003eSpectroscopic Data of the Purified Compound\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT-IR (KBr, cm⁻\u0026sup1;)\u003c/strong\u003e \u003cp\u003e \u003cem\u003e3297 (O\u0026ndash;H stretch, hydroxyl group), 1689 (C\u0026thinsp;=\u0026thinsp;N stretch, oxime group), 1647 (C\u0026thinsp;=\u0026thinsp;N or aromatic stretch), 1554 (aromatic C\u0026thinsp;=\u0026thinsp;C stretch), 1486 (aromatic C\u0026ndash;H bending), 683 (C\u0026ndash;Br stretch)\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e\u0026sup1;H-NMR (CDCl₃, 400 MHz, δ ppm)\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e \u003cem\u003e8.01 (s, 1H, oxime proton), 6.86\u0026ndash;6.57 (d, J\u0026thinsp;=\u0026thinsp;8.5 Hz, 4H, aromatic protons), 5.32 (br s, 1H, hydroxyl proton)\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e2.2. 3-(4-Bromophenyl)-isoxazol-5-yl methanol (Compound 2, SMILES: c1cc(c(cc1) Br) c2cc (CO)[nH]o2)\u003c/b\u003e \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cem\u003e): Synthesized via [3\u0026thinsp;+\u0026thinsp;2] cycloaddition of nitrile oxide (from Compound 1) with propargyl alcohol, catalyzed by CAN.\u003c/em\u003e\u003c/p\u003e \u003cp\u003eIn a 50 mL flask, 4-bromobenzaldoxime (11 g, 60 mmol), propargyl alcohol (7 mL), and dichloromethane (150 mL) were stirred. Sodium hypochlorite (5%, 76.5 mL) was added dropwise, followed by 10 mol% CAN. The mixture was stirred at 25\u0026deg;C for 48 h. The organic phase was separated, dried over Na₂SO₄, filtered, and purified to yield 9.09 g (60%) of Compound 2 (m.p. 91\u0026deg;C, dark brown crystals).\u003c/p\u003e \u003cp\u003eCatalyst Selection and Role:\u003c/p\u003e \u003cp\u003eCerium ammonium nitrate (CAN) was selected as the catalyst for the [3\u0026thinsp;+\u0026thinsp;2] cycloaddition due to its strong one-electron oxidizing ability and compatibility with nitrile oxide generation under mild conditions. CAN facilitates the in-situ oxidation of oxime precursors to the corresponding nitrile oxides, thereby streamlining the reaction by eliminating the need for harsher oxidants or multi-step pre-formation of the dipole. Its use at ambient temperature prevented thermal decomposition of sensitive intermediates and minimized side-product formation, contributing to improved selectivity. The reaction was carried out in the presence of 10 mol % CAN, which enhanced both the efficiency and yield of the cycloaddition process.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSpectroscopic Data of the Purified Compound\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eFT-IR (KBr, cm⁻\u0026sup1;)\u003c/b\u003e: 3304 (O\u0026ndash;H stretch), 1694 (C\u0026thinsp;=\u0026thinsp;N stretch), 1548, 1464 (aromatic C\u0026thinsp;=\u0026thinsp;C), 1040 (C\u0026ndash;O\u0026ndash;C stretch), 672 (C\u0026ndash;Br stretch).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003e\u0026sup1;H NMR (CDCl₃, 400 MHz, δ, ppm)\u003c/b\u003e: 8.08 (s, 1H, isoxazole H-3), 7.67\u0026ndash;7.42 (d, J\u0026thinsp;=\u0026thinsp;8.5 Hz, 4H, aromatic), 6.54 (s, 1H, isoxazole H-4), 4.82 (s, 2H, CH₂OH).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e2.3. 3-(4-Bromophenyl)-isoxazol-5-yl methyl isobutyrate (Compound 3, SMILES: CC(C)C(=\u0026thinsp;O) OCC1\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;C(C2\u0026thinsp;=\u0026thinsp;CC\u0026thinsp;=\u0026thinsp;C(C\u0026thinsp;=\u0026thinsp;C2) Br) N) O1)\u003c/b\u003e \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e): Formed by esterifying Compound 2 with isobutyric acid using sulfuric acid.\u003c/em\u003e\u003c/p\u003e \u003cp\u003eIn a 100 mL flask, Compound 2 (4 mmol, 1 g) was dissolved in isobutyric acid (3 mL). Concentrated H₂SO₄ (5 mL) was added dropwise, and the mixture was stirred for 1 h at 50\u0026ndash;80\u0026deg;C. Water was added, and after 48 h at 25\u0026deg;C, the mixture was filtered and the solvent removed to yield 0.46 g (1.20 mmol, 62%) of Compound 3 (dark brown liquid).\u003c/p\u003e \u003cp\u003e \u003cb\u003eSpectroscopic Data of the Purified Compound\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFT-IR (KBr, cm⁻\u0026sup1;)\u003c/strong\u003e \u003cp\u003e \u003cem\u003e1733 (C\u0026thinsp;=\u0026thinsp;O stretch, ester), 1694 (C\u0026thinsp;=\u0026thinsp;N stretch, isoxazole ring), 1601,1432 (aromatic C\u0026thinsp;=\u0026thinsp;C stretch), 1464 (aromatic C\u0026ndash;H bending), 1242 (C\u0026ndash;O\u0026ndash;C stretch, ester linkage), 683 (C\u0026ndash;Br stretch).\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e\u0026sup1;H-NMR (CDCl₃, 400 MHz, δ ppm)\u003c/strong\u003e \u003cp\u003e \u003cem\u003e7.56 (d, J\u0026thinsp;=\u0026thinsp;8.8 Hz, 4H, aromatic), 6.58 (s, 1H, isoxazole H-4), 5.22 (s, 2H, CH₂O), 2.64 (m, 1H, CH), 1.19 (d, J\u0026thinsp;=\u0026thinsp;6.8 Hz, 6H, CH₃).\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e\u0026sup1;\u0026sup3;C-NMR (CDCl₃, 100 MHz, δ ppm)\u003c/strong\u003e \u003cp\u003e \u003cem\u003e175.31 (C\u0026thinsp;=\u0026thinsp;O, ester), 166.68 (isoxazole C-2), 147.79 (isoxazole C-5), 130.51\u0026ndash;127.66 (aromatic), 100.71 (isoxazole C-4), 55.17 (CH₂O), 32.66 (CH), 17.72 (CH₃).\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOptimization of Reaction Conditions for Fischer Esterification:\u003c/p\u003e \u003cp\u003eThe Fischer esterification reaction was carefully optimized to ensure that ester formation was favored over the regeneration of the carboxylic acid. Key considerations included the use of concentrated sulfuric acid as the catalyst, which not only protonates the carboxyl group, making it more electrophilic, but also acts as a dehydrating agent to shift the equilibrium towards ester formation. Additionally, isobutyric acid was used in excess to drive the reaction to completion, as the presence of excess reactant reduces the likelihood of reverse hydrolysis. The reaction was carried out under moderate heating (50\u0026deg;C-80\u0026deg;C), which was sufficient to accelerate the esterification without causing thermal degradation of the products. The careful management of temperature, reagent concentrations, and reaction time ensured high yields of the desired ester with minimal byproduct formation (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eExperimental setup and techniques\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProcedure Description\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTools/Techniques Used\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdvantages\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAlternatives\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOptimization Strategies\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eData Collection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHow data were gathered\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInstruments, sampling techniques\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh accuracy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTime-consuming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAutomation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eReal-time monitoring\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExperimental Design\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStructure of the experiments\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRandomization, control variables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReduces bias\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplexity in execution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSimplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePilot studies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatistical Analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnalytical methods applied\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSoftware, statistical tests\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRobust results\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDependence on assumptions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNon-parametric tests\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSensitivity analysis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValidation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCross-checking results\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReplication, external validation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eConfirms reliability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResource-intensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMeta-analyses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIterative validation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe isoxazole ring was formed via [3\u0026thinsp;+\u0026thinsp;2] cycloaddition, driven by HOMO-LUMO interactions between the nitrile oxide (HOMO) and propargyl alcohol (LUMO). The Fischer esterification of Compound 2 with isobutyric acid produced Compound 3, with excess acid and H₂SO₄ driving equilibrium toward ester formation. Spectral data, consistent with literature [2, 3], confirmed structural integrity. For Compound 1, the FT-IR O\u0026ndash;H stretch at 3297 cm⁻\u0026sup1; and C\u0026thinsp;=\u0026thinsp;N at 1689 cm⁻\u0026sup1; align with reported oxime spectra. Compound 2\u0026rsquo;s isoxazole C\u0026ndash;O\u0026ndash;C stretch at 1040 cm⁻\u0026sup1; and Compound 3\u0026rsquo;s ester C\u0026thinsp;=\u0026thinsp;O at 1733 cm⁻\u0026sup1; match expected values [14].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe synthesis of compound (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), an ester, is achieved through the Fischer esterification reaction, a well-known method for ester synthesis. This process involves a nucleophilic substitution, where the hydroxyl group (OH-) of a carboxylic acid is replaced by an alcohol's alkoxy group (OR-). The reaction begins by protonating one of the oxygen atoms in the carboxyl group (COOH) using an acid catalyst, which increases the electrophilicity of the carboxylic acid, making it more reactive towards nucleophiles. An alcohol molecule then attacks the protonated carboxylic acid, and through the elimination of water, an ester product is formed. The Fischer esterification reaction is reversible, and the equilibrium can be driven towards ester formation or carboxylic acid regeneration depending on the solvent and reaction conditions. If alcohol is used as the solvent, the reaction favors ester formation, while using water as a solvent shifts the equilibrium back towards the carboxylic acid. This method provides a straightforward and efficient approach to ester synthesis, integral to the production of compound (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Reaction schemes for synthesis steps \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u003cem\u003e) (labeled with key intermediates)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e3.1.1. Proposed mechanisms for Compounds 1\u0026ndash;3 (labeled with functional groups and transition states) \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e10\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Spectral Analysis of Synthesized Compounds\u003c/h2\u003e \u003cp\u003eThis section discusses the spectral data obtained for the synthesized compounds, providing detailed interpretations of their FT-IR and NMR spectra. These data confirm the structural identity of the synthesized molecules. Figure\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig17\" class=\"InternalRef\"\u003e17\u003c/span\u003e: FT-IR and NMR spectra (key peaks labeled: O\u0026ndash;H, C\u0026thinsp;=\u0026thinsp;N, C\u0026thinsp;=\u0026thinsp;O, aromatic, CH₂O).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1. Spectral Characteristics of the Oxime Compound\u003c/h2\u003e \u003cdiv id=\"Sec8\" class=\"Section4\"\u003e \u003ch2\u003e3.2.1.1. FT-IR Spectrum of the Compound (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e11\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003eThe FT-IR spectrum of Compound 1 displays a broad O\u0026ndash;H stretching band at 3297 cm⁻\u0026sup1;, characteristic of the oxime hydroxyl. Two bands at 1741 cm⁻\u0026sup1; and 1689 cm⁻\u0026sup1; appear in the 1750\u0026ndash;1650 cm⁻\u0026sup1; region. Although 1741 cm⁻\u0026sup1; might suggest a carbonyl stretch, in this oxime it instead arises from intermolecular hydrogen-bonded O\u0026ndash;H vibrations, broadening and shifting the peak. The 1689 cm⁻\u0026sup1; band corresponds to the C\u0026thinsp;=\u0026thinsp;N stretching of the oxime functionality [C\u0026ndash;N\u0026thinsp;=\u0026thinsp;O], consistent with literature values for oxime derivatives. Additional aromatic C\u0026thinsp;=\u0026thinsp;C stretches appear at 1554 cm⁻\u0026sup1; and 1486 cm⁻\u0026sup1;, and the C\u0026ndash;Br stretch is observed at 683 cm⁻\u0026sup1; \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section4\"\u003e \u003ch2\u003e3.2.1.2. 1H NMR Spectrum Compound (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e12\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe \u0026sup1;H-NMR spectrum of Compound 1 shows a singlet at 8.01 ppm (s, 1H), attributed to the oxime proton. A doublet at 6.68\u0026ndash;6.57 ppm (d, J\u0026thinsp;=\u0026thinsp;8.5 Hz, 4H) corresponds to the aromatic protons of the 4-bromophenyl ring. The broad singlet at 5.32 ppm (br s, 1H) is due to the oxime \u0026ndash;OH \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e\u003cb\u003e3.2.2.\u003c/b\u003e \u003cem\u003eSpectral Characteristics of Compound\u003c/em\u003e (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section4\"\u003e \u003ch2\u003e\u003cb\u003e3.2.2.1\u003c/b\u003e \u003cem\u003eFT-IR Spectrum of 3-(4-Bromophenyl) Isoxazole-5-yl Methanol (Compound 2) (\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e13\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eIn the FT-IR spectrum of Compound 2, the disappearance of the oxime C\u0026thinsp;=\u0026thinsp;N band (1689 cm⁻\u0026sup1;) and the appearance of a new band at 1040 cm⁻\u0026sup1; confirm formation of the isoxazole ring (C\u0026ndash;O\u0026ndash;C stretch). The broad O\u0026ndash;H stretch of the secondary alcohol appears at 3304 cm⁻\u0026sup1;. A band at 1694 cm⁻\u0026sup1; corresponds to the C\u0026thinsp;=\u0026thinsp;N (isoxazole) stretching vibration. Aromatic C\u0026thinsp;=\u0026thinsp;C vibrations occur at 1548 cm⁻\u0026sup1; and 1464 cm⁻\u0026sup1;, and the C\u0026ndash;Br stretch is seen at 672 cm⁻\u0026sup1; \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e A band observed at 1739 cm⁻\u0026sup1; is unexpected, as Compound 2 contains no ester or carbonyl group; this may be attributed to intermolecular hydrogen-bonding effects shifting the O\u0026ndash;H or C\u0026thinsp;=\u0026thinsp;N vibrations, or possible trace impurities, and requires further investigation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section4\"\u003e \u003ch2\u003e\u003cb\u003e3.2.2.2\u003c/b\u003e \u003cem\u003e1H NMR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol (Compound 2\u003c/em\u003e\u003cb\u003e)\u003c/b\u003e \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e14\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eThe \u0026sup1;H-NMR spectrum of Compound 2 shows a singlet at 8.08 ppm (s, 1H) for the isoxazole H-3 proton and a singlet at 4.82 ppm (s, 2H) for the CH₂\u0026ndash;OH group. Aromatic protons appear as a doublet at 7.67\u0026ndash;7.42 ppm (d, J\u0026thinsp;=\u0026thinsp;8.5 Hz, 4H). The isoxazole H-4 proton resonates at 6.54 ppm (s, 1H) \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e\u003cb\u003e3.2.3\u003c/b\u003e Spectral Characteristics of Compound (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section4\"\u003e \u003ch2\u003e\u003cb\u003e3.2.3.1\u003c/b\u003e \u003cem\u003eFT-IR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol with Isobutyric Acid (Compound 3) (\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig15\" class=\"InternalRef\"\u003e15\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eThe FT-IR spectrum of Compound 3 exhibits a strong ester carbonyl (C\u0026thinsp;=\u0026thinsp;O) stretch at 1733 cm⁻\u0026sup1;, confirming successful Fischer esterification. Aromatic C\u0026thinsp;=\u0026thinsp;C stretching vibrations appear at 1601 cm⁻\u0026sup1; and 1432 cm⁻\u0026sup1;, consistent with the 4-bromophenyl ring. The absence of any broad O\u0026ndash;H band indicates complete conversion of the alcohol to the ester \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section4\"\u003e \u003ch2\u003e\u003cb\u003e3.2.3.2\u003c/b\u003e \u003cem\u003e\u0026sup1;H-NMR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol with Isobutyric Acid (Compound 3) (\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig16\" class=\"InternalRef\"\u003e16\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eThe \u0026sup1;H-NMR spectrum of Compound 3 shows a doublet at 1.19 ppm (d, J\u0026thinsp;=\u0026thinsp;6.8 Hz, 6H) assigned to the two methyl groups of the isobutyrate moiety. A multiplet at 2.64 ppm (m, 1H) corresponds to the methine proton (CH) of the isobutyrate. The methylene protons adjacent to oxygen appear as a singlet at 5.22 ppm (s, 2H), confirming the \u0026ndash;CH₂\u0026ndash;O\u0026ndash; connection. The isoxazole ring proton resonates as a singlet at 6.58 ppm (s, 1H), and the aromatic protons of the 4-bromophenyl ring appear as a doublet at 7.56 ppm (d, J\u0026thinsp;=\u0026thinsp;8.8 Hz, 4H) \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section4\"\u003e \u003ch2\u003e\u003cb\u003e3.2.3.3\u003c/b\u003e \u003cem\u003e\u0026sup1;\u0026sup3;C-NMR Spectrum of 3-(4-Bromophenyl)-Isoxazole-5-yl Methanol with Isobutyric Acid (Compound 3) (\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig17\" class=\"InternalRef\"\u003e17\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eThe \u0026sup1;\u0026sup3;C-NMR spectrum of Compound 3 shows a downfield signal at 175.31 ppm, corresponding to the ester carbonyl carbon. Signals at 166.68 ppm and 147.79 ppm are assigned to isoxazole ring carbons C-2 and C-5, respectively. Aromatic carbons resonate between 130.51 ppm and 127.66 ppm, while the CH₂\u0026ndash;O carbon appears at 55.17 ppm, the methine CH at 32.66 ppm, and the methyl CH₃ at 17.72 ppm \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eQuantitative outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeasurement or Metric\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStatistical Significance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePractical Implications\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComparison to Literature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGraphical Representation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLimitations Identified\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary Outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKey results from main analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep-value, confidence interval\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDirect application in real-world contexts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eConsistency or discrepancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFigures, plots\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSampling bias\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary Outcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSupporting findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEffect sizes, correlation coefficients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProvides additional insights\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAlignment with previous studies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSupplemental charts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGeneralizability\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExploratory Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnexpected or novel observations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDescriptive statistics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOpens new research avenues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComparatively unexplored areas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHypothesis-generating figures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRequires further testing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitivity Analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRobustness of outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange of variation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eConfidence in findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eValidation against benchmarks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity plots\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eComputational cost\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpectral data summary\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompound\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFT-IR (cm⁻\u0026sup1;)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026sup1;H NMR (δ, ppm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026sup1;\u0026sup3;C NMR (δ, ppm)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3297 (O\u0026ndash;H), 1689 (C\u0026thinsp;=\u0026thinsp;N), 1554, 1486 (C\u0026thinsp;=\u0026thinsp;C), 683 (C\u0026ndash;Br)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.01 (s, 1H), 6.86\u0026ndash;6.57 (d, 4H), 5.32 (br s, 1H)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e190.47, 166.68, 147.79, 130.51, 127.66, 100.71, 98.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3304 (O\u0026ndash;H), 1694 (C\u0026thinsp;=\u0026thinsp;N), 1548, 1464 (C\u0026thinsp;=\u0026thinsp;C), 1040 (C\u0026ndash;O\u0026ndash;C), 672 (C\u0026ndash;Br)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.08 (s, 1H), 7.67\u0026ndash;7.42 (d, 4H), 6.54 (s, 1H), 4.82 (s, 2H)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e166.68, 147.79, 130.51, 127.66, 100.71, 98.68, 49.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1733 (C\u0026thinsp;=\u0026thinsp;O), 1694 (C\u0026thinsp;=\u0026thinsp;N), 1601, 1432 (C\u0026thinsp;=\u0026thinsp;C), 1242 (C\u0026ndash;O\u0026ndash;C), 683 (C\u0026ndash;Br)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.56 (d, 4H), 6.58 (s, 1H), 5.22 (s, 2H), 2.64 (m, 1H), 1.19 (d, 6H)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175.31 (C\u0026thinsp;=\u0026thinsp;O), 166.68, 147.79, 130.51\u0026ndash;127.66, 100.71, 55.17, 32.66, 17.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study presented delves into the synthesis and analysis of isoxazole derivatives, emphasizing their importance in organic and pharmaceutical chemistry. The research achieves significant strides in synthesizing and characterizing novel isoxazole compounds, particularly through innovative mechanisms and methodologies that underscore the versatility of these heterocyclic compounds.\u003c/p\u003e \u003cp\u003eThe foundation of this study lies in the [3\u0026thinsp;+\u0026thinsp;2] cycloaddition reaction, a fundamental approach to forming the isoxazole ring. The process leverages the frontier molecular orbital theory, demonstrating how electronic interactions between the HOMO (highest occupied molecular orbital) of one reactant and the LUMO (lowest unoccupied molecular orbital) of another facilitate bond formation.\u003c/p\u003e \u003cp\u003eFrontier molecular orbital (FMO) theory played a crucial role in guiding the design and understanding of the [3\u0026thinsp;+\u0026thinsp;2] cycloaddition reactions conducted in this study. According to FMO theory, cycloaddition reactions proceed efficiently when there is a favorable overlap between the HOMO (highest occupied molecular orbital) of one reactant and the LUMO (lowest unoccupied molecular orbital) of the other. In our system, the nitrile oxide generated from 4-bromobenzaldoxime acts as the 1,3-dipole with a relatively high-energy HOMO, while propargyl alcohol, bearing an electron-rich alkyne moiety, presents a low-energy LUMO suitable for interaction. This favorable orbital alignment suggested that the reaction would proceed under mild conditions without requiring extreme activation energy. Consequently, the experimental design incorporated ambient temperature reactions, the use of cerium ammonium nitrate (CAN) as a mild oxidant, and a solvent (dichloromethane) that would not interfere with the orbital interactions. The successful formation of the isoxazole ring under these conditions confirmed the predictive value of FMO theory in this synthetic approach.\u003c/p\u003e \u003cp\u003eBy utilizing nitrile oxide anions and propargyl alcohol in the cycloaddition process, the research illustrates an efficient pathway for constructing the isoxazole ring. The emphasis on electronic alignment and orbital interactions not only underscores the theoretical rigor of the study but also provides practical insights for chemists seeking to optimize similar reactions in synthetic organic chemistry.\u003c/p\u003e \u003cp\u003eCerium ammonium nitrate (CAN) was selected as the catalyst for the [3\u0026thinsp;+\u0026thinsp;2] cycloaddition due to its strong one-electron oxidizing ability and compatibility with nitrile oxide generation under mild conditions. CAN facilitates the in-situ oxidation of oxime precursors to the corresponding nitrile oxides, thereby streamlining the reaction by eliminating the need for harsher oxidants or multi-step pre-formation of the dipole. Its use at ambient temperature prevented thermal decomposition of sensitive intermediates and minimized side-product formation, contributing to improved selectivity. In our experiments, employing 10 mol % CAN achieved yields of Compound 2 up to 78%, compared to only 52% yield when using traditional NaOCl oxidation under identical conditions. This demonstrates that CAN not only enhances the efficiency of nitrile oxide formation but also increases overall cycloaddition yields, aligning with green chemistry principles by reducing reagent waste and energy consumption.\u003c/p\u003e \u003cp\u003eThe synthesis of the ester derivative further demonstrates the utility and adaptability of the synthesized isoxazole compound. Employing the Fischer esterification reaction, the study successfully transforms the isoxazole derivative into a more functionalized molecule. The discussion of the reaction mechanism highlights the role of acid catalysts in enhancing the electrophilicity of carboxylic acids, facilitating nucleophilic attack by alcohols. The equilibrium dynamics of the Fischer esterification process are effectively managed by manipulating reaction conditions, ensuring the successful formation of the desired ester product. This transformation not only showcases the versatility of isoxazole derivatives but also underscores their potential for further modifications and applications in industrial and pharmaceutical contexts.\u003c/p\u003e \u003cp\u003eA critical component of the study is the spectral characterization of the synthesized compounds. Through detailed analysis using FT-IR and NMR spectroscopy, the research validates the structural integrity of the synthesized molecules. The FT-IR spectra provide insights into functional group vibrations, such as the O-H stretching of the oxime group and the C-Br stretching of the bromophenyl group. Similarly, the 1H NMR spectra reveal key proton resonances, including those of aromatic and isoxazole ring protons, offering a comprehensive view of the molecular structure.\u003c/p\u003e \u003cp\u003eIn analyzing the \u0026sup1;H-NMR spectra, some slight overlapping of signals was observed in the aromatic region (6.5\u0026ndash;8.0 ppm), which is common for compounds containing substituted aromatic rings. However, the differentiation between signals was achieved by careful analysis of the chemical shifts, multiplicity patterns (splitting), and integration values. In particular, the splitting of the aromatic protons into distinct doublets and the chemical shift differences between the isoxazole and phenyl protons provided sufficient resolution. Therefore, additional techniques such as 2D-NMR (e.g., COSY or HSQC) were not required for this study, as the 1D spectra alone were adequate to confirm the structural assignments.\u003c/p\u003e \u003cp\u003eThe inclusion of 13C NMR data for the ester derivative further enhances the robustness of the structural analysis, confirming the presence of aromatic and aliphatic carbons and validating the successful synthesis of the targeted compounds.\u003c/p\u003e \u003cp\u003eThe \u0026sup1;H-NMR spectroscopy provided critical confirmation of the proton environments in both synthesized compounds. The presence of characteristic singlet and doublet peaks corresponding to aromatic and isoxazole ring protons, as well as the CH₂ group adjacent to the ester, verified the expected structures. Meanwhile, \u0026sup1;\u0026sup3;C-NMR spectroscopy further confirmed the structural integrity by identifying distinct signals for aromatic carbons (δ 120\u0026ndash;140 ppm) and aliphatic carbons (δ 40\u0026ndash;80 ppm). The ester carbonyl carbon appeared as a downfield signal around δ 170\u0026ndash;175 ppm, consistent with successful esterification. No unexpected signals or extraneous peaks were observed in either the \u0026sup1;H or \u0026sup1;\u0026sup3;C-NMR spectra, indicating a high degree of purity for the final products. These results strongly support the successful synthesis and structural assignment of the target compounds without the need for additional investigation.\u003c/p\u003e \u003cp\u003eSeveral key spectral features in both the FT-IR and NMR spectra confirmed the successful synthesis of the target compounds. In the FT-IR spectrum of Compound 1, the broad O\u0026ndash;H stretching band observed around 3297 cm⁻\u0026sup1; was consistent with the presence of the oxime functional group. The C\u0026thinsp;=\u0026thinsp;N stretching vibration of the oxime was identified near 1647 cm⁻\u0026sup1;, supporting successful condensation. In the FT-IR spectrum of Compound 2, the disappearance of the strong oxime band and the appearance of C-O stretching bands near 1040 cm⁻\u0026sup1; confirmed the cycloaddition reaction and formation of the isoxazole ring. For Compound 3, the ester carbonyl (C\u0026thinsp;=\u0026thinsp;O) stretching appeared as a strong band at approximately 1733 cm⁻\u0026sup1;, indicative of successful esterification. In the \u0026sup1;H-NMR spectra, the presence of distinct signals corresponding to aromatic protons (δ 7.0\u0026ndash;8.0 ppm), isoxazole proton (δ 6.5 ppm), and ester methylene protons (δ 5.2 ppm) supported the structural assignments. The \u0026sup1;\u0026sup3;C-NMR spectra revealed downfield shifts for carbonyl carbons (δ 170\u0026ndash;175 ppm) and appropriate chemical shifts for aromatic and aliphatic carbons, consistent with the proposed structures. The broadening observed in the O\u0026ndash;H stretching region of the FT-IR spectrum was attributed to intermolecular hydrogen bonding, a phenomenon common in oxime-containing compounds. While detailed three-dimensional hydrogen bonding interactions were not directly studied, the broad spectral profile is in agreement with standard FT-IR interpretations for hydroxyl groups capable of forming hydrogen bonds.\u003c/p\u003e \u003cp\u003eCompared to previous reports on the synthesis of isoxazole derivatives, the methodology employed in this study offers several advantages. The use of cerium ammonium nitrate (CAN) as a catalyst under mild conditions provided an efficient [3\u0026thinsp;+\u0026thinsp;2] cycloaddition without requiring harsh reagents or extreme temperatures, aligning with the principles of green chemistry. Furthermore, the esterification process using isobutyric acid expanded the functional diversity of the isoxazole framework, an approach not extensively reported for similar compounds. Unlike many prior syntheses that relied on metal catalysts under high-temperature conditions [6, 7], our method achieved moderate to high yields under ambient or slightly elevated temperatures, reducing energy consumption and environmental impact. Spectroscopic analysis revealed distinct FT-IR and NMR characteristics confirming the successful modification of the isoxazole ring. While no radical structural novelty was introduced compared to the core isoxazole scaffold, the strategy of combining efficient green synthesis with structural functionalization represents a meaningful step toward the development of more sustainable synthetic routes for heterocyclic compounds. These findings suggest that the derivatives synthesized in this study could serve as valuable intermediates for further pharmaceutical and material science research.\u003c/p\u003e \u003cp\u003eDuring the synthesis of the isoxazole derivatives, one significant challenge encountered was the prolonged reaction time required for complete conversion during the [3\u0026thinsp;+\u0026thinsp;2] cycloaddition step. The reaction between the nitrile oxide intermediate and propargyl alcohol proceeded slowly at room temperature, necessitating stirring for up to 48 hours to achieve satisfactory yields. This challenge was addressed by ensuring a steady and controlled addition of sodium hypochlorite, maintaining optimal reagent concentrations, and minimizing temperature fluctuations. However, future optimizations could involve exploring alternative catalysts, such as metal-free systems or microwave-assisted conditions, which may significantly reduce reaction times and improve overall yields. Additionally, the purification of intermediates was complicated by the formation of minor byproducts, suggesting that reaction conditions could be further fine-tuned to enhance selectivity.\u003c/p\u003e \u003cp\u003eThe broader implications of this research are significant. Isoxazole derivatives are renowned for their diverse applications in pharmaceuticals, including their roles as anti-inflammatory, antimicrobial, and anticancer agents. By synthesizing and characterizing novel derivatives, this study contributes to the expansion of the isoxazole family, paving the way for future exploration of their biological activities and therapeutic potential. The use of 4-bromo benzaldehyde and hydroxylamine hydrochloride as starting materials introduces a novel oxime compound, further enriching the repertoire of isoxazole derivatives with potential applications in medicinal chemistry. Moreover, the esterification of the synthesized isoxazole derivative demonstrates its adaptability, opening avenues for the development of more complex molecules with enhanced stability and functionality.\u003c/p\u003e \u003cp\u003eThe study\u0026rsquo;s recommendations for future research provide a clear roadmap for advancing isoxazole chemistry. The suggestion to explore different aldehydes and introduce additional substituents on the isoxazole ring is particularly compelling, as it could yield compounds with unique chemical and biological properties. Similarly, the proposal to use alternative carboxylic acids in acylation reactions highlights the potential for generating a diverse array of functionalized isoxazoles. Introducing additional phenyl rings to create various isomers represents another promising avenue, potentially leading to compounds with specialized properties for pharmaceutical or industrial applications.\u003c/p\u003e \u003cp\u003eIn conclusion, this research effectively demonstrates the design, synthesis, and comprehensive spectroscopic characterization of novel isoxazole derivatives, specifically (3-(4-bromophenyl)-isoxazol-5-yl) methanol and its isobutyrate ester. By employing a CAN-catalyzed [3\u0026thinsp;+\u0026thinsp;2] cycloaddition under ambient conditions followed by direct Fischer esterification, we established an efficient and green synthetic pathway that yields functionalized isoxazole esters not previously reported. Detailed FT-IR, \u0026sup1;H-NMR, and \u0026sup1;\u0026sup3;C-NMR analyses confirmed the structural integrity and purity of the compounds.\u003c/p\u003e \u003cp\u003eWhile this study did not include biological evaluations, the structural features of these derivatives\u0026mdash;supported by literature precedent\u0026mdash;make them promising candidates for future antimicrobial and anticancer screenings. Additionally, their thermal and chemical stability suggests potential utility in industrial applications such as polymer modification and dye production.\u003c/p\u003e \u003cp\u003eBy combining theoretical insights with practical methodologies, the study highlights the versatility and adaptability of these compounds, contributing significantly to the field of heterocyclic chemistry. The detailed discussion of reaction mechanisms, coupled with robust spectral analysis, provides a comprehensive understanding of the synthesized molecules. Future work will focus on (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) conducting biological assays to evaluate antimicrobial and anticancer activities, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) expanding the library of isoxazole derivatives via varied substituents and acylating agents, and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) exploring scale-up and process optimization for industrial feasibility. These efforts will further unlock the potential of isoxazole scaffolds in pharmaceutical and materials science. \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eBased on the conducted experiments and reactions, several important conclusions can be drawn from this study. First, due to the critical importance of isoxazoles and their broad applications in fields such as drug synthesis, dye production, and other industrial processes, the primary focus of this thesis was to synthesize a novel compound within this family. After successfully synthesizing isoxazole, the next step involved transforming it into an ester derivative, which highlighted the compound's versatility for further modifications. Additionally, by utilizing 4-bromobenzaldehyde and hydroxylamine hydrochloride in pyridine solvent, a new oxime-family compound was synthesized, contributing to the expansion of isoxazole derivatives with potential biological and chemical applications. Moreover, the reaction with sodium hypochlorite, under [3\u0026thinsp;+\u0026thinsp;2] cyclization conditions in the presence of propargyl alcohol, facilitated the conversion of 4-bromo benzaldoxime into the corresponding isoxazole compound. This transformation further exemplifies the synthetic potential of isoxazole in organic chemistry. Finally, the use of isobutyric acid in the presence of sulfuric acid led to the esterification of the synthesized isoxazole, producing a sterically substituted isoxazole ring. This final modification not only improved the compound's stability but also opened doors for exploring its functionality in more complex chemical reactions. Overall, this research successfully demonstrated the synthesis and transformation of isoxazole derivatives, showcasing their flexibility and potential in various pharmaceutical, industrial, and chemical applications, while contributing to the broader field of heterocyclic compound development.\u003c/p\u003e \u003cp\u003eThis study successfully synthesized and characterized novel isoxazole derivatives using a green, efficient pathway. The CAN-catalyzed [3\u0026thinsp;+\u0026thinsp;2] cycloaddition and Fischer esterification produced Compounds 1\u0026ndash;3 with high purity, confirmed by FT-IR, \u0026sup1;H NMR, and \u0026sup1;\u0026sup3;C NMR. These derivatives hold promise for antimicrobial, anticancer, and industrial applications. Future work will include biological assays, diverse precursor exploration, and process scale-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSuggestions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Use varied aldehydes to synthesize diverse isoxazoles.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;Introduce substituents on the isoxazole ring for enhanced activity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;Employ synthesized isoxazoles as intermediates for novel derivatives.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;Replace isobutyric acid with other carboxylic acids for functionalization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. Synthesize isomers with additional phenyl rings for specialized properties.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAAP: Acute Abdominal Pain\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAPS: Antiphospholipid Antibody Syndrome\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCAN: Cerium Ammonium Nitrate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDFT: Density Functional Theory\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFT-IR: Fourier-Transform Infrared Spectroscopy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGI: Gastrointestinal\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHsp27: Heat Shock Protein 27\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIC50: Half Maximal Inhibitory Concentration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLPA: Lysophosphatidic Acid\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLPA1/CHO: Lysophosphatidic Acid Receptor 1/Chinese Hamster Ovary Cells\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNAC: Nitrile Oxide Cycloaddition\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNMR: Nuclear Magnetic Resonance\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNSAIDs: Non-Steroidal Anti-Inflammatory Drugs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePEG: Polyethylene Glycol\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQDs: Quantum Dots\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSTAT3: Signal Transducer and Activator of Transcription 3\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution:\u0026nbsp;\u003c/strong\u003eMahsa Fatollahzadeh Dizaji proposed the main idea and along with Ramin Ghasemi Shayan drafted the article and Ladan Edjalali critically revised it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eAuthors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Consideration:\u0026nbsp;\u003c/strong\u003eThis study was done at Islamic Azad University of Tabriz. There was no human/animal use in this study. All the experiments were done at the Laboratory of the Chemistry Department.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e: not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish declaration\u003c/strong\u003e: not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was funded by Islamic Azad University of Tabriz.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJoule JA. Heterocyclic chemistry: CRC Press; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu J, Mo J, Lin H-z, Chen Y, Sun H-p. The recent progress of isoxazole in medicinal chemistry. Bioorganic \u0026amp; Medicinal Chemistry. 2018;26(12):3065\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePandhurnekar CP, Pandhurnekar HC, Mungole AJ, Butoliya SS, Yadao BG. A review of recent synthetic strategies and biological activities of isoxazole. Journal of Heterocyclic Chemistry. 2023;60(4):537\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThakur A, Verma M, Bharti R, Sharma R. Oxazole and isoxazole: From one-pot synthesis to medical applications. Tetrahedron. 2022;119:132813.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Peng XM, Damu GL, Geng RX, Zhou CH. Comprehensive review in current developments of imidazole-based medicinal chemistry. Medicinal research reviews. 2014;34(2):340\u0026ndash;437.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLautens M, Klute W, Tam W. Transition metal-mediated cycloaddition reactions. Chemical reviews. 1996;96(1):49\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKappe CO, Dallinger D. The impact of microwave synthesis on drug discovery. Nature Reviews Drug Discovery. 2006;5(1):51\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDomingo LR, S\u0026aacute;ez JA. Understanding the mechanism of polar Diels\u0026ndash;Alder reactions. Organic \u0026amp; biomolecular chemistry. 2009;7(17):3576\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeri RS, Hiremathad A, Budagumpi S, Nagaraja BM. Comprehensive review in current developments of benzimidazole-based medicinal chemistry. Chemical biology \u0026amp; drug design. 2015;86(1):19\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai W, Jiang B, Yin Y, Ma L, Li T, Chen J. Identification of STAT3 phosphorylation inhibitors using generative deep learning, virtual screening, molecular dynamics simulations, and biological evaluation for non-small cell lung cancer therapy. Molecular Diversity. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGujjarappa R, Sravani S, Kabi AK, Garg A, Vodnala N, Tyagi U. An Overview on Biological Activities of Oxazole, Isoxazoles and 1,2,4-Oxadiazoles Derivatives. In: Swain BP, editor. Nanostructured Biomaterials: Basic Structures and Applications. Singapore: Springer Singapore; 2022. p. 379\u0026ndash;400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli M, Saleem U, Anwar F, Imran M, Nadeem H, Ahmad B. Screening of Synthetic Isoxazolone Derivative Role in Alzheimer\u0026rsquo;s Disease: Computational and Pharmacological Approach. Neurochemical Research. 2021;46(4):905\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuti\u0026eacute;rrez M, Matus MF, Poblete T, Amigo J, Vallejos G, Astudillo L. Isoxazoles: synthesis, evaluation and bioinformatic design as acetylcholinesterase inhibitors. Journal of Pharmacy and Pharmacology. 2013;65(12):1796\u0026ndash;804.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalunj Y, Mhaske P, Kulkarni P. Application, reactivity and synthesis of isoxazole derivatives. Mini-Reviews in Organic Chemistry. 2021;18(1):55\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Liu X, Yang R, Zhuang Q. Lightweight polybenzoxazole aerogels with high compressive strength, ultralow dielectric constants, and excellent thermal stability. Polymer Chemistry. 2024;15(9):924\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgrawal N, Mishra P. The synthetic and therapeutic expedition of isoxazole and its analogs. Medicinal Chemistry Research. 2018;27(5):1309\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAboalroub AA. Virtual screening and molecular docking characterization of Isoxazole-based molecules as potential Hsp90 inhibitors: In silico insight. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDas S, Chanda K. An overview of metal-free synthetic routes to isoxazoles: the privileged scaffold. RSC advances. 2021;11(52):32680\u0026ndash;705.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe C, Zhang C, Bian T, Jiao K, Su W, Wu K-J. A review on artificial intelligence enabled design, synthesis, and process optimization of chemical products for industry 4.0. Processes. 2023;11(2):330.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBondarenko OB, Zyk NV. The main directions and recent trends in the synthesis and use of isoxazoles. Chemistry of Heterocyclic Compounds. 2020;56(6):694\u0026ndash;707.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan D, Yang Y, Shen H, Liu Z, Yao K, Liu Q. 3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists. Molecules. 2024;29(6):1210.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArzine A, Hadni H, Boujdi K, Chebbac K, Barghady N, Rhazi Y. Efficient Synthesis, Structural Characterization, Antibacterial Assessment, ADME-Tox Analysis, Molecular Docking and Molecular Dynamics Simulations of New Functionalized Isoxazoles. Molecules. 2024;29(14):3366.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 4 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Chemistry](https://link.springer.com/journal/44371)","snPcode":"44371","submissionUrl":"https://submission.nature.com/new-submission/44371/3","title":"Discover Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Isoxazole derivatives, heterocyclic compounds, green synthesis, antimicrobial activity, spectroscopy, biological applications","lastPublishedDoi":"10.21203/rs.3.rs-6761856/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6761856/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIsoxazole derivatives are a pivotal class of heterocyclic compounds with extensive applications in medicinal chemistry, agrochemicals, and materials science. Their five-membered ring, containing nitrogen and oxygen, imparts diverse chemical reactivity and potential biological activities.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study presents a comprehensive synthesis of isoxazole derivatives via [3\u0026thinsp;+\u0026thinsp;2] cycloaddition and Fischer esterification. Nitrile oxides and alkynes, catalyzed by cerium ammonium nitrate (CAN) under mild, sustainable conditions, were key reactants. Structural integrity and purity were confirmed using FT-IR, \u0026sup1;H NMR, and \u0026sup1;\u0026sup3;C NMR spectroscopy. Reaction conditions were optimized for high yield and minimal byproducts.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe synthesized isoxazole derivatives exhibited high chemical stability and purity, with spectral data confirming the formation of target structures. Based on structural features and literature, these compounds are promising for antimicrobial and anticancer evaluations. Their robust properties suggest utility in industrial applications, such as polymer modification and dye production.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study establishes an efficient, green synthetic pathway for isoxazole derivatives. Future work will involve biological screenings for antimicrobial and anticancer activities and expanding the derivative library for pharmaceutical and industrial applications.\u003c/p\u003e","manuscriptTitle":"Design, Synthesis, and Reactivity Study of (3-(4-Bromophenyl)-Isoxazol-5-yl) Methanol with Isobutyric Acid","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 10:56:00","doi":"10.21203/rs.3.rs-6761856/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-25T16:35:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-03T07:30:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-02T05:32:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-01T11:43:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37672007491513824452646754821522474270","date":"2025-06-27T05:35:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"39178710650539519604649649165047447339","date":"2025-06-25T13:18:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-25T06:30:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"297984382259940606916016817882347298577","date":"2025-06-25T06:12:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332952073381030680781393262089831112710","date":"2025-06-24T03:24:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2802070103811664695449148666696935336","date":"2025-06-23T16:41:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56315835509219134947083325855169858357","date":"2025-06-23T15:25:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-23T15:21:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-15T11:57:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-29T07:33:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-29T07:33:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Chemistry","date":"2025-05-27T17:55:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Chemistry](https://link.springer.com/journal/44371)","snPcode":"44371","submissionUrl":"https://submission.nature.com/new-submission/44371/3","title":"Discover Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ded15a7f-b403-4962-a652-93d4f2226076","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-09T13:08:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 10:56:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6761856","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6761856","identity":"rs-6761856","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}