Modern Approaches to the Synthesis of Triazole Derivatives:
Advances in Catalysis and Green Chemistry
Waghamare Suresh*
NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan - 30312, India.
*Corresponding Author E-mail: waghasuresh@gmail.com
ABSTRACT:
The synthesis of N-heterocycles, particularly triazole derivatives, has become a focal point of modern organic chemistry due to their significant applications in medicinal chemistry, materials science, and agrochemicals. Triazole derivatives are known for their diverse pharmacological properties, including antimicrobial, anticancer, and anti-inflammatory activities. This review focuses on the contemporary methods for synthesizing triazole derivatives, with an emphasis on advanced strategies such as click chemistry, transition-metal-catalyzed reactions, and microwave-assisted synthesis. These modern approaches provide more efficient, selective, and sustainable synthetic routes. The application of triazole derivatives in drug design, including their role in the development of novel therapeutic agents and their incorporation into materials science through metal-organic frameworks (MOFs), are discussed. The review highlights key trends in the synthesis of triazoles and their broader implications across various fields of research.
N-heterocyclic compounds, in which one or more heteroatoms (e.g., nitrogen, oxygen, or sulfur) are incorporated into a ring system, have drawn considerable interest over the past few years.1 Among them, triazoles, particularly 1,2,3-triazoles, are an important subclass as they occupy a prominent place in pharmaceuticals, agrochemicals, and materials science. Triazole derivatives possess a wide spectrum of biological activity, and therefore, they are promising leads for drug design, such as antifungal, anticancer, antiviral, and anti-inflammatory activities. 1 Triazole derivative synthesis has been an area of significant interest, with various synthetic strategies developed to assemble these N-heterocycles.
Among these, the copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) approach, a quintessential instance of "click chemistry," has transformed the process of triazole synthesis. Click chemistry is characterized by high efficiency, regioselectivity, and yields, which are among the most employed methods for the synthesis of triazoles. Also, other transition metal-catalyzed processes, such as palladium and ruthenium-catalyzed reactions, have broadened the synthetic avenues to provide access to a broad array of functionalized triazole derivatives.2 These recent developments also involve green methodologies like microwave-assisted synthesis, which enhances reaction times and solvent consumption, thus enhancing sustainability in the synthesis of triazoles. The combination of these strategies not only enhanced the efficiency of synthesizing triazoles but also allowed for the synthesis of compounds with higher bioactivity.2
Triazoles have deep implications that extend far beyond drug discovery. In materials science, triazole derivatives are used as building blocks for the synthesis of metal-organic frameworks (MOFs) and polymeric materials, reflecting their utility as ligands in coordination chemistry. Their stability and functional diversity render them useful in the development of new materials for use in sensors, catalysis, and energy storage.4 This review will explore the cutting-edge trends in triazole synthesis, focusing on recent developments, challenges, and applications in both medicinal and materials chemistry. By examining the latest synthetic approaches and their implications, we aim to highlight the growing potential of triazole derivatives in a wide range of scientific fields.
SYNTHESIS REACTION OF TRIAZOLE:
2,4,5-triaryl-1,2,3-triazole synthesis with a catalyst made of copper.
A copper(II) acetate-catalyzed oxidative cyclization was used to prepare 2,4,5-triaryl-1,2,3-triazoles from aryl-substituted hydrazones. Compounds 1 and 2 couple in the presence of Cu(OAc)₂·H₂O (20 mol%) in toluene at 60°C under air to give compound 3. The reaction involves copper-mediated activation and subsequent intramolecular cyclization followed by oxidative aromatization. Air is a green oxidant, so the process is environmentally friendly. This process offers a gentle, effective, and scalable pathway to structurally diverse triazole derivatives, with potential uses in pharmaceuticals and materials science owing to their stability and functional versatility.3,4
Using aryl diazonium ions and isocyanide, 1,3, and 1,5-disubstituted 1,2,4-triazoles are synthesized.
The two synthetic pathways (Pathway A and B) for building 1,2,3-triazole derivatives through metal-catalyzed cycloaddition reactions of diazonium salts with nitrile or azodicarboxylate intermediates are shown in the picture.
Pathway A:
It is an approach where a cycloaddition between a nitrile (compound 5) and a diazonium salt (compound 6) is carried out in the presence of a silver (Ag) or copper (Cu) catalyst to give a 1,2,3-triazole intermediate (compound 4). The first reaction (Step ii) produces an intermediate azide-like compound (7), which gets cyclized intramolecularly to produce the triazole ring system. The process offers an effective pathway to 2,4-disubstituted triazoles, with wide applicability for varying alkyl and aryl substituents.5
Pathway B:
A second route (B) involves a diazonium tetrafluoroborate salt (compound 8) that reacts with an azodicarboxylate ester (compound 9) under phase-transfer conditions catalyzed by tetrabutylammonium chloride (n-Bu₄NCl) in acetonitrile (CH₃CN) and in the presence of Na₂SO₄ at room temperature. This yields compound 10, a heavily substituted 1,2,3-triazole derivative. The process involves a copper- or silver-catalyzed cycloaddition to yield a wide range of triazole scaffolds under mild conditions.6 Both routes provide regioselective and modular syntheses of biologically useful triazole structures, which find applications in pharmaceuticals, agrochemicals, and materials science.
1,2,3-triazole synthesised by the organocatalytic enamine azide reaction 1,4,5-trisubstituted.
The reaction shows a metal-free 1,2,3-triazole (compound 13) synthesis through the [3+2] cycloaddition of organic azides (compound 11) with α,β-unsaturated carbonyl compounds (compound 12). It is efficiently catalyzed by 5 mol% of ethylenediamine in DMSO at 70°C under mild conditions. The diamine activates the enone system for nucleophilic attack by the azide, resulting in regioselective triazole formation. This procedure is beneficial owing to its ease of use, minimal catalyst loading, and lack of metals or oxidants, consistent with the tenets of green chemistry. It presents a viable means of preparing biologically interesting triazoles of varying functional groups.3,7
Synthesis of n1-arylidene-arenecarboxamidrazone and its conversion to 3,5-diaryl-1,2,4-triazoles.
The reaction demonstrates the synthesis of 1,2,4-triazole derivatives (compound 16) from amidrazones (compound 14) through a bromination-cyclization process. The process begins with N-bromosuccinimide (NBS) in CH₂Cl₂ at room temperature to introduce a bromine atom and create an intermediate (compound 15). Cyclization then occurs in ammonium acetate (NH₄OAc) at 110°C to induce ring closure to create the triazole core. Alternatively, amidrazones can be initially treated with NH₄OAc and subsequently with NBS at 110°C to achieve the same conversion. The procedure is efficient and metal-free and provides a practical method for the synthesis of biologically relevant triazole derivatives under relatively mild and green conditions. 8
Synthesis of 1,2,3-triazoles with ultrasound assistance.
This sequence of reactions describes the preparation of a chlorophenyl-1,2,3-triazole derivative (compound 19) from 4-chloroaniline (compound 17). First, compound 17 is diazotized by NaNO₂ and 2M HCl in water at 0°C to give a diazonium salt intermediate. This intermediate is then reacted with an alkyne-substituted hydrazone, giving the triazole intermediate 18 through a [3+2] cycloaddition. In the last step, compound 18 is reduced under hydrogenation conditions by H₂ and Pd/C to give compound 19, a functionalized triazole bearing an amino and chloro substituent on the aromatic ring. This process allows triazole-based pharmacophores to be synthesized under mild conditions. 9
Green synthesis of 1,2,4-triazole 3,4,5-trisubstituted by employing polyethylene glycol and ceric ammonium nitrate.
The reaction is an example of the synthesis of 1,2,4-triazole derivatives (compound 22) through a condensation-cyclization reaction from a phenyl-substituted amidrazone (compound 20) and an aldehyde (compound 21). The reaction is under the catalysis of ceric ammonium nitrate (CAN) acting as an oxidant and under the condition in polyethylene glycol (PEG) at 80°C. First, the aldehyde reacts with the amidrazone to produce a Schiff base-like intermediate, which is then oxidatively cyclized by CAN to create the triazole ring. This green and cost-effective process does not use severe conditions and employs the environmentally friendly solvent PEG, which is highly valuable for the synthesis of bioactive triazole derivatives. 10,11
Amidrazones react with the Mitsunobu reagent to form 1,2,4-triazoles that are 1,3,5-trisubstituted.
This reaction depicts the synthesis of 1,2,4-triazole derivatives (25 and 26) from a substituted hydrazone (compound 23) and an azodicarboxylate ester (compound 24). The reaction is conducted in ethanol (EtOH) using triethylamine (Et₃N) under reflux for 10–15 hours. The nucleophilic nitrogen of the hydrazone attacks the electrophilic azodicarboxylate, triggering a cyclization process that produces triazole products 25 and 26. The by-product 27, an ester derivative, is generated through cleavage of the azodicarboxylate moiety. This multicomponent reaction efficiently constructs heterocyclic scaffolds under mild, metal-free conditions, which is valuable for building pharmacologically relevant molecules.12
Bioactive 1,2,4-triazole synthesized from hydrazides.
This reaction scheme describes the multistep synthesis of triazole-thiol derivatives (compound 31). Initially, compound 28 (a hydrazide) is treated with carbon disulfide (CS₂) and KOH in ethanol for 15–16 hours to form a dithiocarbazate intermediate (compound 29). This intermediate then reacts with hydrazine hydrate (NH₂NH₂·H₂O) to afford compound 30, a 1,2,4-triazole-3-thiol derivative. Subsequently, this compound undergoes condensation with a carbonyl compound (RCHO) in methanol for 3–4 hours, yielding the final product compound 31, a thiol-functionalized triazole Schiff base. This method offers an efficient route to bioactive heterocycles, often explored for antimicrobial and anticancer properties 13
Synthesis of 1, 4- or 2,4-disubstituted 1,2,3-triazoles using Cu-catalyzed cycloaddition:
This reaction represents a one-pot multicomponent synthesis of triazole derivatives involving a terminal alkyne (compound 32), sodium azide, and formaldehyde (compound 33). The reaction is catalyzed by CuSO₄ (5 mol%) and sodium ascorbate (20 mol%), enabling a Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC). This "click" reaction forms the 1,2,3-triazole core (compound 34), which further reacts with formaldehyde in the presence of acetic acid (1.5 eq) in 1,4-dioxane at room temperature (67%) to yield a hydroxymethyl-functionalized triazole (compound 35). The equilibrium between 34 and 35 involves hydroxymethylation at the triazole ring. This mild and efficient reaction provides a green chemistry approach to synthesizing functionalized triazoles, widely applicable in pharmaceutical and materials chemistry due to their biological activity and structural versatility.14
Using sodium azide, chalcone, and halogenated aromatics, n2-substituted-1,2,3-triazole is manufactured.
The reaction showcases the transformation of chalcone derivative (compound 36) into a 1,2,3-triazole-functionalized compound (37) using a copper-mediated azidation-cycloaddition protocol. In the first step, CuO and NaN₃ in DMF at 80°C facilitate in situ azidation of the alkyne moiety. Subsequently, an aryl halide (Ar₃X) undergoes cycloaddition to form the triazole ring. This efficient one-pot strategy combines azidation and cycloaddition in a streamlined process to produce triazole-linked aromatic ketones, which are valuable in medicinal chemistry due to their biological activity and structural complexity.15,16
Green Synthesis of Schiff Base
The reaction shown is a green synthesis of a 1,2,4-triazole derivative (compound 40) using natural reagents. Compound 38 (thiosemicarbazide derivative) reacts with benzaldehyde (compound 39) in lemon juice, which acts as a natural acidic catalyst. The reaction proceeds at 50°C for 30 minutes, forming the triazole ring via cyclization. Lemon juice provides an eco-friendly, sustainable alternative to synthetic acids. This method aligns with green chemistry principles, offering a safer, cost-effective, and efficient approach to synthesizing biologically active heterocycles like 1,2,4-triazoles, which have various pharmaceutical applications. 17
Preparation of triazoles from phosphorus-based Cu(I) complexes:
The reaction depicted is a copper-catalyzed multicomponent one-pot synthesis of 1,2,3-triazoles, followed by the formation of a bis-triazole derivative. In this transformation, benzyl bromide (44), sodium azide (45), and a terminal alkyne (46) are combined in the presence of 5mol% of the copper(I) iodide catalyst complex \([Cu_2(μ-I)_2]\), at 50°C for 3 hours in acetonitrile (MeCN). The reaction leads to the formation of 1,4-disubstituted 1,2,3-triazole (compound 47) through the well-known Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC), also known as the click" reaction. The benzyl bromide first undergoes nucleophilic substitution with sodium azide to form benzyl azide in situ. This azide then reacts with the terminal alkyne (R² group can be alkyl or aryl) to form the triazole core. The product 47, containing a hydrazinyl group, can further undergo dimerization or other coupling to form symmetrical bis-triazole structures such as compound 48, which exhibit interesting biological and material properties.20 This method is highly efficient, regioselective, and environmentally friendly. The use of mild conditions, short reaction time, and readily available starting materials makes it attractive for the synthesis of bioactive triazoles and their derivatives in pharmaceutical and materials chemistry.21,22
Synthesis of triazoles by ultrasound irradiation:
The reaction shown is a green, one-pot multicomponent synthesis of 1,2,3-triazole derivatives (compound 52) using alkyl halides (49), sodium azide (50), and terminal alkynes (51). This process utilizes the well-established copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), a hallmark of click chemistry. In situ formation of the organic azide from alkyl halide and sodium azide simplifies the procedure and enhances atom economy. The reaction proceeds efficiently under various green conditions, such as ultrasound (US) irradiation using either a US bath or homogenizer, significantly reducing reaction time and improving yields. Copper catalysts like CuI or CuSO₄•5H₂O with sodium ascorbate (NaAsc) are employed in aqueous or mixed green solvents such as H₂O/t-BuOH, H₂O/DMSO, or H₂O/EtOH, avoiding harsh conditions and toxic reagents. These methods deliver excellent yields ranging from 52% to 98% under mild temperatures and short reaction times (5–60 minutes). This environmentally friendly approach provides access to a variety of substituted triazoles, which are important scaffolds in medicinal chemistry, agrochemicals, and materials science due to their chemical stability, bioactivity, and ease of functionalization. The use of ultrasound and green solvents highlights its potential for sustainable and scalable synthesis in modern organic chemistry. 20,23,
CONCLUSION:
The synthesis of triazole derivatives has made significant strides with the incorporation of advanced catalytic procedures and green chemistry principles. Methods like copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), transition metal catalysis, organocatalysis, and microwave or ultrasound-assisted reactions have significantly improved the efficiency, selectivity, and sustainability of triazole formation. These processes enable the rapid and regioselective construction of a wide variety of triazole frameworks under mild and environmentally friendly conditions. Green solvents, natural catalysts, and multicomponent reactions have also contributed to minimizing the ecological footprint of chemical synthesis. Triazole derivatives possess a broad spectrum of bioactivities such as antimicrobial, anticancer, antiviral, and anti-inflammatory activities and hence are of interest in drug discovery. Their use as ligands for coordination chemistry has also provided new opportunities for materials development, including metal-organic frameworks (MOFs), sensors, and energy storage devices. In general, the ongoing development of synthetic methods has not only enhanced access to structurally intricate triazoles but also concurred with the objectives of green and sustainable chemistry. With further research, such strategies will continue to promote more innovative, scalable, and environmentally friendly processes, consolidating triazole derivatives as central molecules in medicinal and materials science.
CONFLICT OF INTEREST:
No conflicts of interest.
ACKNOWLEDGEMENTS:
The author is thankful for the encouragement and support of the administration and faculty members of NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan. Sincere thanks are also extended to colleagues and mentors for their constructive criticism and valuable suggestions that helped in shaping this review. The author also thanks many researchers whose path-breaking work in the area of triazole chemistry has been referenced and extended in this article. Lastly, sincere thanks are expressed to all those who indirectly assisted this research through their ongoing encouragement and scholarly guidance.
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Received on 08.04.2025 Revised on 22.05.2025 Accepted on 30.06.2025 Published on 12.08.2025 Available online from August 18, 2025 Asian J. Research Chem.2025; 18(4):285-290. DOI: 10.52711/0974-4150.2025.00044 ©A and V Publications All Right Reserved
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