Parth Vinod Joshi

English 21003- Writing for the Sciences

Professor Michael Grove

Improved Mechanisms for Synthesis of 1,2,3-Triazoles

 

Heterocycles are an important class of compounds that are prevalent in nature and in our everyday life. For example, they are part of carbohydrates, nucleic acids, some natural amino acids, as well as alkaloids. They have found multitude of applications, such as in pharmaceutical and agrochemical chemistry, electronics, dyes and in polymer chemistry, to name a few. 1,2,3-Triazole is one of a pair of isomeric chemical compounds with molecular formula C₂H₃N₃, called triazoles, which have a five-membered ring of two carbon atoms and three nitrogen atoms. 1,2,3-Triazole is a basic aromatic heterocycle.¹ 1,4 positions-substituted 1,2,3-triazoles is currently produced using the azide alkyne Huisgen cycloaddition process (AAHC) in which an azide and an alkyne undergo additions at the 1,3 positions. Though in this process, a lot of impurities like 1,3- and 1,4-disubstituted triazoles are formed.

It is a very stable structure compared to other organic compounds with three adjacent nitrogen atoms. However, flash vacuum pyrolysis at 500 °C leads to loss of molecular nitrogen (N₂) leaving a three-member C₂H₅N ring. 1,2,3-Triazole finds use in research in medicinal chemistry as a building block for more complex chemical compounds, including pharmaceutical drugs such as mubritinib and tazobactam.¹

The most common method used to prepare 1,2,3-substituted triazoles is the Huisgen ligation. The Huisgen ligation of azides and alkynes is an exceptionally atom-economical reaction leading to the formation of 1,2,3- triazoles. However, the thermal process is not region-selective, resulting in the formation of 1,4- and 1,5-disubstituted 1,2,3- triazoles.^[1]

The 1,2,3-triazole ring has been used as a heteroaryl ring in medicinal chemistry, and its well-known click chemistry (Huisgen reactions) has expanded the many pharmacological applications of N-1-substituted 1,2,3-triazoles. In chemical synthesis, “click” chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. As synthesis reactants, broom- and iodo-1,2,3-triazoles are useful building blocks for metal-catalyzed coupling reactions, such as Suzuki-Miyaura coupling. There are few known synthetic routes to prepare Bromo- and iodo-1,2,3-triazoles. 4-Bromo-1,2,3-triazole, for example is commercially available but expensive.^[2]

The classic click reaction is the copper-catalyzed reaction of an azide with an alkyne to form a 5-membered heteroatom ring. Click chemistry is not a single specific reaction but describes a way of generating products that follow examples in nature, which also generates substances by joining small modular units. In general, click reactions usually join a biomolecule and a reporter molecule. Click chemistry is not limited to biological conditions: the concept of a “click” reaction has been used in pharmacological and various biomimetic applications. However, they have been made notably useful in the detection, localization and qualification of biomolecules

One of the methods that are used for the synthesis of such chemicals is using Copper-catalyzed azide-alkyne cycloaddition (CuAAC). In such a method, the production of the 1,3- and 1,4-disubstituted impurities are significantly reduced to ensure higher yield per mole of the reactants using deuterated carriers of hydrogen to proceed with the reaction. This gives a reduced chance of early protonation and subsequent formation of the impurities.²

However, in CuAAC, the reaction cannot reach equilibrium or completion in an aqueous medium as the deuterium atom reacts with the hydronium ions and for a protio-triazole without any radioactive ‘tags’ or a purer yield of the product, rendering is less useful for medicinal purposes.

While the reaction can be performed using commercial sources of copper(I) such as cuprous bromide or iodide, the reaction works much better using a mixture of copper(II) (e.g. copper(II) sulfate) and a reducing agent (e.g. sodium ascorbate) to produce Cu(I) in situ. As Cu(I) is unstable in aqueous solvents, stabilizing ligands are effective for improving the reaction outcome, especially if tris-(benzyltriazolylmethyl)amine (TBTA) is used. The reaction can be run in a variety of solvents, and mixtures of water and a variety of (partially) miscible organic solvents including alcohols, DMSO, DMF, trans-BuOH and acetone. Owing to the powerful coordinating ability of nitriles towards Cu(I), it is best to avoid acetonitrile as the solvent. The starting reagents need not be completely soluble for the reaction to be successful. In many cases, the product can simply be filtered from the solution as the only purification step required.²

Souza et. Al. developed a mild and versatile one-pot three-component protocol for the synthesis of novel imine 1,2,3- triazole compounds involving a-thio aldehyde, propargylamine, and organoazides by the [3+2]-cycloaddition methodology. They performed other functionalizations on the products through different methodologies, which show the versatility of the molecule for synthesis of more complex molecules.^[3]

The reaction to form the azide was successful and the product was obtained with a good yield after purification. The product was used to form bis-1,2,3-triazole, which did not show the same good performance as for the formation of the first triazole, but still retained an acceptable yield due be a complex molecule.

Next, the conditions to prepare bromo- and iodo-1,2,3-triazoles had to be explored. Because the halogenation of 1,2,3-triazole using one equivalent of bromine or NIS generated dihalo-1,2,3-triazole as a major product, the direct preparation of monohalo-1,2,3- triazoles from 1,2,3-triazole was believed to be difficult.³ Therefore, the team investigated the removal of one halogen atom from the dihalo-1,2,3-triazoles. 4,5-Dibromo-1,2,3-triazole was treated with sodium sulfite in water at 110 C, and the reaction interestingly gave 4-bromo-1,2,3-triazole without notable over-reaction. In addition, basic and acidic conditions were examined. In the presence of K₃PO₄, no desired product was observed. The addition of acetic acid did not affect the reaction. To minimize the risk of thermal decomposition of the desired product, the hot plate was set to 100 C, at which temperature the reaction took 3 days, which is unreliable for research purposes. For the reduction of 4,5-diiodo-1,2,3-triazole, mild conditions (80 C for 2.5 h) produced the desired product in good yield. With a few modifications to the aforementioned method, introduced by Melda and Sharpless, uses metal catalyst to address the regioisomer problem by giving 1,4-disubstituted 1,2,3-triazole as the only Regio isomer. It is also of advantage because it produces high yields and can be performed under mild reaction conditions.^[4]

The conditions of the di-iodination and reduction reactions used only common reagents and solvents. Using these facile synthetic methods, halo-1,2,3-triazoles become easily accessible, expanding the synthetic strategies to produce 1,2,3-triazole derivatives. Since a lot of publications have been developed on the click reaction by Huisgen, many papers have appeared to construct those compounds.

In a different experiment, various 4-trifluoroacetyl1,2,3-triazoles were attempted to synthesize, as it makes synthesizing tazobactam sodium simpler. The scope of azide substrates was first examined. All benzyl azide compounds were reacted smoothly under mild conditions to give the corresponding triazoles, where electron donating groups or electron withdrawing groups in the para position include methyl, F, Cl substituted benzyl azide provides excellent yield and high regioselectivity.³

To further improve on this mechanism, another modification done to this procedure was the addition of CaC₂ gar in situ in an aqueous medium. In such conditions, the stability of D₂O is increased and thus does not cleave the D—O bond so the proton is not released early in the reaction.^[5]

Recently, the discovery of a general Ag(I)-catalyzed azide–alkyne cycloaddition reaction (Ag-AAC) leading to 1,4-triazoles is reported. Mechanistic features are like the generally accepted mechanism of the copper(I)-catalyzed process. Silver(I)-salts alone are not enough to promote the cycloaddition.^[6] However ligated Ag(I) sources have proven to be exceptional for AgAAC reaction.^[7] However, metallic or solid silver is very hard to obtain and is one of the most expensive of the reactants. Thus the objective of cost-efficient production is compromised.

Though the use of isocyanides has been prevalent in the production of triazoles, primarily the synthesis of 1,2,4-triazoles take place. Though irrelevant to the current discussion of beta-lactams like the 1,2,3-triazoles, its importance is significant in the process of drug-manufacturing.^[8]

As discussed by the authors of the articles indicating the mentioned methods to accurately synthesize triazoles with further influence on the yield and the purity of the final product, the click chemistry process is still used to commercially generate the chemicals. These reactions are so important as to the degree of use of triazole derivatives is rapidly increasing and is soon to become a sub-industry into the chemical engineering of substances with medicinal value. Hence, it is important that most cost efficient way and one with minimal equipment is used to synthesize 1,2,3-triazoles when the need arrives.

 

 

 

Works Cited.

1. Akula, Hari K., and Lakshman, Mahesh K. “Synthesis of Deuterated 1,2,3-Triazoles. (Report).” Journal of Organic Chemistry, vol. 77, no. 20, 2012, pp. 8896–8904.
2. Sakurada, Isao. “Facile Synthesis of Bromo- and Iodo-1,2,3-Triazoles.” Tetrahedron Letters, vol. 58, no. 32, 2017, pp. 3188–3190
3. Souza, et al. “Microwave-Assisted One-Pot Three-Component Synthesis of Imine 1,2,3-Triazoles.” Tetrahedron Letters, vol. 57, no. 14, 2016, pp. 1592–1596.
4. Testa, Kunga., “Julia-Kocienski Approach to 4-Substituted 1- Alkenyl-1H-1,2,3-Triazoles”. CUNY Academic Works, 2016.
5. Gonda, et al. “Efficient Synthesis of Deuterated 1,2,3-Triazoles.” Tetrahedron Letters, vol. 51, no. 48, 2010, pp. 6275–6277
6. McNulty, J.; Keskar, K; Vemula, R. (2011). “The First Well-Defined Silver(I)-Complex-Catalyzed Cycloaddition of Azides onto Terminal Alkynes at Room Temperature”. Chemistry: A European Journal.
7. Proietti Silvestri, et al. “Copper(i)-catalyzed cycloaddition of silver acetylides and azides: Incorporation of volatile acetylenes into the triazole core”. Organic and Biomolecular Chemistry, 2011
8. Sarnpitak, and Krasavin. “Synthesis of 1,2,4-Triazoles Employing Isocyanides.” Tetrahedron, vol. 69, no. 10, 2013, pp. 2289–2295