Role of Click Chemistry in Organic Synthesis

*Ayushi Sethiya, Nusrat Sahiba and Shikha Agarwal*

#### **Abstract**

Click chemistry involves highly efficient organic reactions of two or more highly functionalized chemical entities under eco-benign conditions for the synthesis of different heterocycles. Several organic reactions such as nucleophilic ring-opening reactions, cyclo-additions, nucleophilic addition reactions, thiol-ene reactions, Diels Alder reactions, etc. are included in click reactions. These reactions have very important features *i.e.* high functional group tolerance, formation of a single product, high atom economy, high yielding, no need for column purification, etc. It also possesses several applications in drug discovery, supramolecular chemistry, material science, nanotechnology, etc. Being highly significant and valuable, we have elaborated on several aspects of click reactions in organic synthesis in this chapter. Recent advancements in the field of organic synthesis using click chemistry approach have been deliberated by citing last five years articles.

**Keywords:** click chemistry, organic synthesis, eco-benign synthesis, selectivity, atom economy, cyclo-addition

### **1. Introduction**

Presently, researchers are paying considerable attention to devise eco-friendly approaches for organic transformations. There has been a significant hike in interest among the scientists for more environmentally acceptable processes in the chemical industries. Synthetic chemistry has led us to the development of more potent structural analogs of natural products. The high therapeutic efficiency, bioavailability, and pharmacological characteristics of synthetic molecules have increased their use in medicinal chemistry as compared to natural products. Pharmaceutical chemistry encompasses the design, synthesis, and evaluation of compounds. In designing drugs, there is an upsurge demand for eco-benign pathways to accomplish the green aspects of chemistry. Novel green pathways play a vital role in the synthetic chemistry field by eradication of harmful solvents and chemicals or suitable handling of waste materials. The quest for new and proficient approaches for the synthesis of numerous biologically active scaffolds has made click chemistry a promising approach in chemistry. Click chemistry is a fruitful approach for the fabrication of molecules.

Huisgen and co-workers demonstrated a click reaction, Cu(I)-catalyzed azide– alkyne cycloaddition (CuAAC). The advanced use of this reaction and click chemistry was introduced by K. Barry Sharpless in 2001. The term click chemistry not only refers to the reaction which occurs fast but also to those that involve twelve principles of green chemistry *i.e*. selective, easier product isolation, mild reaction

condition, high yield, good atom economy, avoid toxic catalyst and solvent, and so on. They encompass reactions that are high yielding, fast, modular, and wide in scope. They are practical and tolerant for a variety of functional groups. Finally, the product isolation is expected to be effortless due to lack of by-products. These vast characteristics make click chemistry a powerful tool that paves a path in several fields of research *viz.* designing of drugs and lead structures [1–4]. Therefore the synergy between these disciplines has given rise to an area of intense research activity. The click chemistry has been such an engrossing topic of research that a lot of review articles have been published so far which explained its applicability in various fields of chemistry like manufacturing and alteration of metal–organic frameworks [5], making devices in bio-sensing system for responsive copper identification [6], designing bio-adhesives for hastening wound closure [7], in virusrelated research [8], generation of biosensors [9], proteomics analysis [10], in strategy for indirect 18F-labeling [11], *in vivo* bio-imaging [12], to identify the interaction of curcumin with protein [13], synthesis of polymers and material science [14], for surface modification [15], and so on. In this chapter, the state-ofart modernization with a particular focus on click chemistry assisted synthesis and their uses in various fields of science have been discussed. An attempt has been done to prepare an outline of the importance of click chemistry and its foremost requirement in the research area. It is predicted that this methodical study will pave the way for future opportunities in this direction and design of safer, economical, and eco-friendly pathways.

**3. Role of click reactions in synthetic chemistry**

*Role of Click Chemistry in Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.96146*

chromophores [19, 20].

identified [21, 22].

tion, etc. [23]

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**3.1 Classification of click reaction**

hetero-Diels-Alder cycloadditions.

heterocycles, amides, etc.

efficient conjugation pathway [24].

addition, and certain Michael additions.

Click chemistry includes a cluster of powerful linking chemical reactions that are

There is no specific classification of click reactions. The chief requisite for "Click Chemistry" is well met by reactions that take place in nature and their mimic in the laboratory is the closest and most desirable to the mind and spirit of most synthetic organic chemists. Usually, four main classifications of click reactions have been

• **Cycloadditions**: These refers to 1,3-dipolar cycloadditions reactions and

• **Nucleophilic ring-opening reactions**: This classification belongs to the opening of strained heterocyclic electrophiles, such as epoxides, aziridines,

• **Nucleophilic addition reaction:** It includes the reaction of carbonyl groups like formation of hydrazones, urease, thiourease, oxime ethers, aromatic

Presently, click chemistry inspired synthesis has become the most fascinating approach. Several multi-component reactions have been designed in an ecofriendly manner like aldol condensation followed by Michael addition, Ugi reaction/aldol reaction, Ugi reaction/Huisgen reaction, Ugi Reaction/Diels-Alder reaction, Ugi reaction/Heck reactions, Michael addition/Mannich reac-

The most famous click reaction is the classical reaction between an azide and an

alkyne. Both the substrates do not react under physiological conditions and go through a cycloaddition reaction only at a particular temperature. The uncatalyzed reaction is usually slow and not regio-selective. On the other hand, it was found that the use of electron-deficient terminal alkynes can cause 1,4-regioselectivity to a great extent. These factors limit the use of uncatalyzed Huisgen cycloaddition as an

• **Additions to carbon–carbon multiple bonds:** It involves epoxidation, dihydroxylation, aziridination, nitrosyl halide addition, sulfenyl halide

aziridinium ions, cyclic sulfates episulfonium ions, etc.

easy to perform, have high yields, require no or minimal purification, and are flexible in the unification of different structures without the prerequisite of protection steps. Molecular diversity, modularity, and efficiency are essential in synthetic organic chemistry and expected to be involved in the preparation of several complexes and multi-purpose compounds. In general "Click Chemistry" is a class of biocompatible reactions, to link desired substrates with particular biomolecules. Natural products are produced by joining tiny modular units *via* biosynthesis as well as photosynthesis [18]. Click chemistry provides a route for the synthesis of several heterocyclic scaffolds, amino acids, triazole-fused heterocycles, peptides, and
