**3.1 Classification of click reaction**

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 identified [21, 22].


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 reaction, etc. [23]

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 efficient conjugation pathway [24].

## **3.2 Metal-catalyzed approach for the click synthesis**

### *3.2.1 Synthesis of triazole derivatives*

Metals have been used to catalyze several click reactions. The mechanism of metal catalyzed azide alkyne click reaction involves formation of π-alkynyl complex with metal followed by complexation of azide by metal of the π-coordinated triple bond. After cyclization, metallacycle is formed followed by the reductive elimination to afford the relevant 1,2,3-triazole. Several metal like Cu, Ru, Ag, Au, etc. have been employed to accomplish click reactions [25–28]. This section has been divided in two subsections:

#### *3.2.1.1 Metal-catalyzed synthesis of triazole derivatives*

Transition metals have been used to catalyze several organic reactions as they provide large surface area and they have vacant d-orbitals due to which they can show variable oxidation state that help in generation of intermediate for organic synthesis [29, 30]. The common process for the click reaction is the transition metal catalyzed synthesis of 1,2,3-triazoles. 1,3-dipolar cyclo-addition of an azide and an alkyne catalyzed by Cu is the most extensively used click-chemistry pathway due to its high selectivity and simplicity [31]. In 2014, Guo and co-workers synthesized β-cyclodextrin derivatives (1) using mono-6-azidocyclodextrin and aromatic aldehydes by Cu<sup>I</sup> -catalyzed azide–alkyne cyclo-addition. The mono, di, and tri derivatives were synthesized upto 75% yield under mild reaction conditions [32] **(Figure 2).**

Later on, Kumar *et al.* [33] designed a library of new nucleosides **(2 and 3)** having 1,2,3-triazole scaffold at the 2″-position of the sugar nucleus. It was synthesized by 2″-azidouridine using the copper (I)-catalyzed Huisgen–Sharpless–Meldal 1,3-dipolar cyclo-addition reaction **(Figure 3).** The reaction gave 52–82% yield and 1,4-disubstituted 1,2,3-triazoles were obtained.

Tale and co-workers also synthesized 1,2,3-triazoles in excellent yields using (1-(4-methoxybenzyl)-1-*H*-1,2,3-triazol-4-yl)methanol (MBHTM) ligand (1.1 mol%) and CuSO4 (1 mol%) as a catalyst and sodium ascorbate (5 mol%) in DMSO:H2O(1:3) as a solvent [34]. Shamla and co-workers synthesized coumarin substituted triazole derivatives (4) in good yields using 4-bromomethylcoumarins, terminal alkynes, and sodium azide in the presence of triethylamine and CuI as a catalyst [35] (**Figure 4**).

Yarlagadda *et al*. synthesized N-((l-benzyl-sl*H*-l,2,3-triazol-5-yl) methyl)-4- (6-methoxy benzo[d]thiazol-2-yl)-2-nitrobenzamide derivatives (5) and examined their anti-microbial activity. Among these compounds, compounds **5a, 5 h, 5i** possessed promising activity in comparison to standard drug ciprofloxacin and miconazole (**Figure 5**) [36].

Anand *et al*. designed Cu(I) catalyzed regio-selective synthesis of iso-indoline-1,3-dione linked 1,4 coumarinyl 1,2,3-triazoles (6) and Ru (II) catalyzed pathway of 1,5 coumarinyl 1,2,3-triazoles in high yields with no need for further purification

*Synthesis of N-((l-benzyl-lH-l,2,3-triazol-5-yl) methyl)-4-(6-methoxy benzo[d]thiazol-2-yl)-2-*

Anandhan *et al*. prepared a series of triazole-based macrocyclic amides (7) *via* click chemistry using CuSO4 (5 mol%), sodium ascorbate (10 mol %) in the presence of H2O/THF (1:1), RT. The synthesized compounds showed good antiinflammatory activity although at low concentration (50 μg/mL) in comparison to

Li and co-workers designed triazole derivatives (8 and 9) by click chemistry using CuSO4∙5H2O (0.1 g) and ascorbic acid (0.1 g) in tBuOH/H2O as a solvent and investigated their applications to synthesize self-assembled membrane against copper corrosion. As per the investigation results, it was found that 2-(1-tosyl-1*H*-1,2,3 triazol-4-yl)-ethanol (TTE) (8) and 2-(1-tosyl-1*H*-1,2,3-triazol-4-yl)-propan-2-ol (TTP) (9) coating on film can sturdily decrease the corrosion caused by copper in

the reference drug prednisolone (**Figure 7**) [38].

*Synthesis of coumarin substituted triazole derivatives.*

*Synthesis of library of traizole substituted nucleosides.*

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

(**Figure 6**) [37].

*nitrobenzamide derivatives.*

**Figure 4.**

**Figure 3.**

**Figure 5.**

**69**

**Figure 2.** *Synthesis of β-cyclodextrin derivatives using click chemistry approach.*

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

#### **Figure 3.**

**3.2 Metal-catalyzed approach for the click synthesis**

*Current Topics in Chirality - From Chemistry to Biology*

*3.2.1.1 Metal-catalyzed synthesis of triazole derivatives*

1,4-disubstituted 1,2,3-triazoles were obtained.

*Synthesis of β-cyclodextrin derivatives using click chemistry approach.*

Metals have been used to catalyze several click reactions. The mechanism of metal catalyzed azide alkyne click reaction involves formation of π-alkynyl complex with metal followed by complexation of azide by metal of the π-coordinated triple bond. After cyclization, metallacycle is formed followed by the reductive elimination to afford the relevant 1,2,3-triazole. Several metal like Cu, Ru, Ag, Au, etc. have been employed to accomplish click reactions [25–28]. This section has been divided

Transition metals have been used to catalyze several organic reactions as they provide large surface area and they have vacant d-orbitals due to which they can show variable oxidation state that help in generation of intermediate for organic synthesis [29, 30]. The common process for the click reaction is the transition metal catalyzed synthesis of 1,2,3-triazoles. 1,3-dipolar cyclo-addition of an azide and an alkyne catalyzed by Cu is the most extensively used click-chemistry pathway due to its high selectivity and simplicity [31]. In 2014, Guo and co-workers synthesized β-cyclodextrin derivatives (1) using mono-6-azidocyclodextrin and aromatic

derivatives were synthesized upto 75% yield under mild reaction conditions [32]

Later on, Kumar *et al.* [33] designed a library of new nucleosides **(2 and 3)** having 1,2,3-triazole scaffold at the 2″-position of the sugar nucleus. It was synthesized by 2″-azidouridine using the copper (I)-catalyzed Huisgen–Sharpless–Meldal 1,3-dipolar cyclo-addition reaction **(Figure 3).** The reaction gave 52–82% yield and

Tale and co-workers also synthesized 1,2,3-triazoles in excellent yields using (1-(4-methoxybenzyl)-1-*H*-1,2,3-triazol-4-yl)methanol (MBHTM) ligand (1.1 mol%) and CuSO4 (1 mol%) as a catalyst and sodium ascorbate (5 mol%) in DMSO:H2O(1:3) as a solvent [34]. Shamla and co-workers synthesized coumarin substituted triazole derivatives (4) in good yields using 4-bromomethylcoumarins, terminal alkynes, and sodium azide in the presence of triethylamine and CuI as a catalyst [35] (**Figure 4**). Yarlagadda *et al*. synthesized N-((l-benzyl-sl*H*-l,2,3-triazol-5-yl) methyl)-4- (6-methoxy benzo[d]thiazol-2-yl)-2-nitrobenzamide derivatives (5) and examined their anti-microbial activity. Among these compounds, compounds **5a, 5 h, 5i** possessed promising activity in comparison to standard drug ciprofloxacin and


*3.2.1 Synthesis of triazole derivatives*

in two subsections:

aldehydes by Cu<sup>I</sup>

miconazole (**Figure 5**) [36].

**Figure 2.**

**68**

**(Figure 2).**

*Synthesis of library of traizole substituted nucleosides.*

**Figure 4.** *Synthesis of coumarin substituted triazole derivatives.*

#### **Figure 5.**

*Synthesis of N-((l-benzyl-lH-l,2,3-triazol-5-yl) methyl)-4-(6-methoxy benzo[d]thiazol-2-yl)-2 nitrobenzamide derivatives.*

Anand *et al*. designed Cu(I) catalyzed regio-selective synthesis of iso-indoline-1,3-dione linked 1,4 coumarinyl 1,2,3-triazoles (6) and Ru (II) catalyzed pathway of 1,5 coumarinyl 1,2,3-triazoles in high yields with no need for further purification (**Figure 6**) [37].

Anandhan *et al*. prepared a series of triazole-based macrocyclic amides (7) *via* click chemistry using CuSO4 (5 mol%), sodium ascorbate (10 mol %) in the presence of H2O/THF (1:1), RT. The synthesized compounds showed good antiinflammatory activity although at low concentration (50 μg/mL) in comparison to the reference drug prednisolone (**Figure 7**) [38].

Li and co-workers designed triazole derivatives (8 and 9) by click chemistry using CuSO4∙5H2O (0.1 g) and ascorbic acid (0.1 g) in tBuOH/H2O as a solvent and investigated their applications to synthesize self-assembled membrane against copper corrosion. As per the investigation results, it was found that 2-(1-tosyl-1*H*-1,2,3 triazol-4-yl)-ethanol (TTE) (8) and 2-(1-tosyl-1*H*-1,2,3-triazol-4-yl)-propan-2-ol (TTP) (9) coating on film can sturdily decrease the corrosion caused by copper in

**Figure 6.** *Synthesis of iso-indoline-1,3-dione linked 1,4 coumarinyl 1,2,3-triazoles derivatives.*

**Figure 7.** *Triazole based macrocyclic amides.*

Khanapurmath *et al*. synthesized various derivatives of triazole by click chemistry approach using CuSO4 and ascorbic acid in H2O:DMF solvent and assessed them

Green synthesis is the fundamental requirement of present synthetic protocol and use of nanoparticles (Nps) is one of the key tackle for organic transformations. NPs are microscopic particles with dimension between 1–100 nm. These are used as catalysts because they provide large surface area, high catalytic activity, nontoxic, heterogeneous nature, etc. In lieu of this, Chetia *et al*. designed copper Nps (nano particles) supported over hydrotalcite and used these Nps (15 mg) to catalyze 1,3 dipolar cycloaddition reaction to form 1,4 disubstituted-1,2,3-triazoles (17)

against *Mycobacterium tuberculosis H37Rv*. 6-Methyluracil and theophylline mono-triazole compounds **14(a-d)** and bis-triazole compounds, **15(a-e)** showed reasonable inhibition of *M. tuberculosis H37Rv*, with MIC values in the range of 55.62–115.62 μM. Benzimidazolone bis-triazole derivatives **16(a**-**n**) inhibited

*M. tuberculosis H37Rv* with MIC 2.35–18.34 μM **(Figure 11**) [42].

*Methyluracil and theophylline mono-triazole compounds and Bis-triazole compounds.*

*3.2.1.2 Metal Nano-particle based triazole synthesis*

**Figure 9.**

**Figure 10.**

**Figure 11.**

**71**

*Cytisine conjugated triazole derivative.*

*Triazole ring fused coumarin and quinolinone derivatives.*

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

**Figure 8.** *Derivatives of triazole.*

3 wt.% NaCl solution and the inhibition effectiveness of TTP and TTE were 93.1% and 89.4%, respectively (**Figure 8**) [39].

Savanur and co-workers developed facile click chemistry inspired synthesis of triazole ring fused coumarin and quinolinone derivatives using CuSO4 (10 mol%), sodium ascorbate (10 mol%), H2O:PEG, RT followed by K2CO3/DMF at 50–60 °C and examined their anti-microbial activity. Among the synthesized compounds, compounds **10j, 11 g** and **12f** displayed good anti-bacterial activities. Derivatives **10e** and **10j** were found highly active against yeast strains. Compound **11f** was highly active against filamentous strain *A. niger* and yeast fungi [40] (**Figure 9**).

Yarovaya *et al.* [41] fabricated a conjugate of cytisine with camphor having triazole ring using click chemistry pathway by employing CuSO4∙5H2O, sodium ascorbate, t-BuOH/H2O. The designed molecules were examined for *in vitro* antiviral activity against A/PuertoRico/8/34 influenza virus (H1N1). The compound (13) has highest inhibition activity with IC50 = 8 1 μmol (**Figure 10**).

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

**Figure 9.**

*Triazole ring fused coumarin and quinolinone derivatives.*

#### **Figure 10.**

*Cytisine conjugated triazole derivative.*

**Figure 11.**

3 wt.% NaCl solution and the inhibition effectiveness of TTP and TTE were 93.1%

*Synthesis of iso-indoline-1,3-dione linked 1,4 coumarinyl 1,2,3-triazoles derivatives.*

*Current Topics in Chirality - From Chemistry to Biology*

(13) has highest inhibition activity with IC50 = 8 1 μmol (**Figure 10**).

Savanur and co-workers developed facile click chemistry inspired synthesis of triazole ring fused coumarin and quinolinone derivatives using CuSO4 (10 mol%), sodium ascorbate (10 mol%), H2O:PEG, RT followed by K2CO3/DMF at 50–60 °C and examined their anti-microbial activity. Among the synthesized compounds, compounds **10j, 11 g** and **12f** displayed good anti-bacterial activities. Derivatives **10e** and **10j** were found highly active against yeast strains. Compound **11f** was highly active against filamentous strain *A. niger* and yeast fungi [40] (**Figure 9**). Yarovaya *et al.* [41] fabricated a conjugate of cytisine with camphor having triazole ring using click chemistry pathway by employing CuSO4∙5H2O, sodium ascorbate, t-BuOH/H2O. The designed molecules were examined for *in vitro* antiviral activity against A/PuertoRico/8/34 influenza virus (H1N1). The compound

and 89.4%, respectively (**Figure 8**) [39].

**Figure 6.**

**Figure 7.**

**Figure 8.**

**70**

*Derivatives of triazole.*

*Triazole based macrocyclic amides.*

*Methyluracil and theophylline mono-triazole compounds and Bis-triazole compounds.*

Khanapurmath *et al*. synthesized various derivatives of triazole by click chemistry approach using CuSO4 and ascorbic acid in H2O:DMF solvent and assessed them against *Mycobacterium tuberculosis H37Rv*. 6-Methyluracil and theophylline mono-triazole compounds **14(a-d)** and bis-triazole compounds, **15(a-e)** showed reasonable inhibition of *M. tuberculosis H37Rv*, with MIC values in the range of 55.62–115.62 μM. Benzimidazolone bis-triazole derivatives **16(a**-**n**) inhibited *M. tuberculosis H37Rv* with MIC 2.35–18.34 μM **(Figure 11**) [42].

#### *3.2.1.2 Metal Nano-particle based triazole synthesis*

Green synthesis is the fundamental requirement of present synthetic protocol and use of nanoparticles (Nps) is one of the key tackle for organic transformations. NPs are microscopic particles with dimension between 1–100 nm. These are used as catalysts because they provide large surface area, high catalytic activity, nontoxic, heterogeneous nature, etc. In lieu of this, Chetia *et al*. designed copper Nps (nano particles) supported over hydrotalcite and used these Nps (15 mg) to catalyze 1,3 dipolar cycloaddition reaction to form 1,4 disubstituted-1,2,3-triazoles (17)

**Figure 12.** *Triazole derivatives.*

**Figure 13.** *Spirochromenocarbazole tethered 1,2,3-triazole derivatives.*

of triazole derivatives (22 and 23) using terminal alkyne, azide, epoxide or

lyst and employed them in the synthesis of triazole derivatives using terminal alkynes, α-haloketones or alkyl halides and sodium azide in H2O at RT to give 1,4 disubstitued 1,2,3-triazoles (24) (**Figure 15**). The catalyst being heterogenous and

Thanh *et al*. [50] designed a hybrid structure of chromene and triazole by applying click chemistry approach for the synthesis of 1H-1,2,3-triazole-tethered 4H-chromene-D-glucose analogs (25) using Cu@MOF-5 (2 mol%) as a catalyst to afford 80–97.8% yields. The copper supported over metal organic frame work was found better catalyst in comparison to conventional catalysts *viz*. CuSO4.5H2Osodium ascorbate, CuI, Cu Nps, CuIM2(IM is imidazole) as it afforded high yields of desired products in less reaction time and in the presence of ethanol whereas other required long reaction time and non green solvent. All the derivatives were assessed for *in vitro* anti-microbial activity with MIC values in the range of 1.56–6.25 μM

regioselective gave high yields in short reaction times [49].

Pourmohammad *et al*. synthesized (CuI@[PMMA-CO-MI]) (0.02 g) nano cata-

Click chemistry has been used to synthesize biologically active hybrids of several synthetic organic molecules. In lieu of this, Sharova *et al*. [51] demonstrated click chemistry inspired phosphorylation of anabasine, camphor, and cytisine using Cu assisted 1,3-diploar cycloaddition reaction. Later on, Touj *et al.* [52] synthesized copper N-heterocyclic carbene (Cu-NHC) complexes using benzimidazolium salt as a catalyst. These complexes were further used for the synthesis of triazole deriva-

The reaction involved mild reaction conditions, water as a green solvent with low catalyst loading, no need of further purification which made the protocol ecofriendly. Bernard *et al*. [53] investigated a cost effective, and convenient click chemistry inspired synthesis of cyclooctyne (27) and trans-cyclooctene (28) using

Qui *et al.* [54] synthesized parthenolide–thiazolidinedione (29) hybrids using

click chemistry-mediated coupling. The compounds were screened for antiproliferative activity against prostate (PC3), breast (MDA-MB-231), and human

haloarene (**Figure 14**) [48].

*Synthesis of triazole derivatives.*

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

**Figure 15.** *Triazole derivatives.*

**Figure 16.**

(**Figure 15**).

tives (26) **(Figure 16**).

**73**

*3.2.2 Synthesis of other organic molecules*

inexpensive Cu powder as a catalyst **(Figure 17**).

**Figure 14.**

*Structures of different triazole derivatives.*

(**Figure 12**) at room temperature using ethylene glycol as a solvent. The catalyst is heterogeneous, easily recyclable, and further reusable [43]. In this context, Poshala and co-workers developed copper Nps (0.1 mmol) using rongalite as a reducing agent and examined their catalytic efficiency in synthesizing triazole (18) derivatives in the presence of β-cyclodextrin (0.02 mmol) [44].

Chavan *et al*. [45] designed a click chemistry assisted MCR strategy for the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles (19) using CuINps supported over cellulose (7 mol%) as a catalyst in the presence of DMF:Water (1:2) (**Figure 13**). The synthesized compounds were screened for anti-cancer activity against MCF-7, HeLa, MDA-MB-231, A-549, PANC-1 and THP-1. Compounds **19i** and **19j** were observed to be the most potent against MCF-7 with IC50 = 2.13 μM and 4.80 μM respectively. Compound **19 k** was the most potent one against MDA-MB-231 with (IC50 = 3.78 μM). All the products were found to be safe against the human umbilical vein endothelial cells (HUVECs).

Elavarasan *et al*. prepared nano rod shaped triazine functional hierarchical mesoporous organic polymers (HMOP) containing Cu metal. This catalyst was used to synthesize triazole derivatives (20) *via* stirring at 80 °C in the presence of water as a solvent [46]. In the same year 2019, Gholampour *et al*. synthesized a library of 1,4-naphthoquinone-1,2,3-triazole hybrids (21) using CuSO4 (0.15 mmol) and sodium ascorbate (.05 mmol) catalyzed click chemistry approach from 2-(prop-2 ynylamino)naphthalene-1,4-dione and different azidomethyl-benzene analogs. The anti-cancer activity of synthesized compounds was anticipated against three cancer cell lines (MCF-7, HT-29 and MOLT-4) by MTT assay. The compound **21f** possessed the highest activity [47]. In continuation to this, magnetic CuFe2O4/g-C3N4 hybrids were synthesized and their catalytic activity was examined in the synthesis

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

**Figure 16.** *Synthesis of triazole derivatives.*

of triazole derivatives (22 and 23) using terminal alkyne, azide, epoxide or haloarene (**Figure 14**) [48].

Pourmohammad *et al*. synthesized (CuI@[PMMA-CO-MI]) (0.02 g) nano catalyst and employed them in the synthesis of triazole derivatives using terminal alkynes, α-haloketones or alkyl halides and sodium azide in H2O at RT to give 1,4 disubstitued 1,2,3-triazoles (24) (**Figure 15**). The catalyst being heterogenous and regioselective gave high yields in short reaction times [49].

Thanh *et al*. [50] designed a hybrid structure of chromene and triazole by applying click chemistry approach for the synthesis of 1H-1,2,3-triazole-tethered 4H-chromene-D-glucose analogs (25) using Cu@MOF-5 (2 mol%) as a catalyst to afford 80–97.8% yields. The copper supported over metal organic frame work was found better catalyst in comparison to conventional catalysts *viz*. CuSO4.5H2Osodium ascorbate, CuI, Cu Nps, CuIM2(IM is imidazole) as it afforded high yields of desired products in less reaction time and in the presence of ethanol whereas other required long reaction time and non green solvent. All the derivatives were assessed for *in vitro* anti-microbial activity with MIC values in the range of 1.56–6.25 μM (**Figure 15**).

#### *3.2.2 Synthesis of other organic molecules*

Click chemistry has been used to synthesize biologically active hybrids of several synthetic organic molecules. In lieu of this, Sharova *et al*. [51] demonstrated click chemistry inspired phosphorylation of anabasine, camphor, and cytisine using Cu assisted 1,3-diploar cycloaddition reaction. Later on, Touj *et al.* [52] synthesized copper N-heterocyclic carbene (Cu-NHC) complexes using benzimidazolium salt as a catalyst. These complexes were further used for the synthesis of triazole derivatives (26) **(Figure 16**).

The reaction involved mild reaction conditions, water as a green solvent with low catalyst loading, no need of further purification which made the protocol ecofriendly. Bernard *et al*. [53] investigated a cost effective, and convenient click chemistry inspired synthesis of cyclooctyne (27) and trans-cyclooctene (28) using inexpensive Cu powder as a catalyst **(Figure 17**).

Qui *et al.* [54] synthesized parthenolide–thiazolidinedione (29) hybrids using click chemistry-mediated coupling. The compounds were screened for antiproliferative activity against prostate (PC3), breast (MDA-MB-231), and human

(**Figure 12**) at room temperature using ethylene glycol as a solvent. The catalyst is heterogeneous, easily recyclable, and further reusable [43]. In this context, Poshala and co-workers developed copper Nps (0.1 mmol) using rongalite as a reducing agent and examined their catalytic efficiency in synthesizing triazole (18) deriva-

Chavan *et al*. [45] designed a click chemistry assisted MCR strategy for the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles (19) using CuINps supported over cellulose (7 mol%) as a catalyst in the presence of DMF:Water (1:2) (**Figure 13**). The synthesized compounds were screened for anti-cancer activity against MCF-7, HeLa, MDA-MB-231, A-549, PANC-1 and THP-1. Compounds **19i** and **19j** were observed to be the most potent against MCF-7 with IC50 = 2.13 μM and 4.80 μM respectively. Compound **19 k** was the most potent one against MDA-MB-231 with (IC50 = 3.78 μM). All the products were found to be safe against the human

Elavarasan *et al*. prepared nano rod shaped triazine functional hierarchical mesoporous organic polymers (HMOP) containing Cu metal. This catalyst was used to synthesize triazole derivatives (20) *via* stirring at 80 °C in the presence of water as a solvent [46]. In the same year 2019, Gholampour *et al*. synthesized a library of 1,4-naphthoquinone-1,2,3-triazole hybrids (21) using CuSO4 (0.15 mmol) and sodium ascorbate (.05 mmol) catalyzed click chemistry approach from 2-(prop-2 ynylamino)naphthalene-1,4-dione and different azidomethyl-benzene analogs. The anti-cancer activity of synthesized compounds was anticipated against three cancer cell lines (MCF-7, HT-29 and MOLT-4) by MTT assay. The compound **21f** possessed the highest activity [47]. In continuation to this, magnetic CuFe2O4/g-C3N4 hybrids were synthesized and their catalytic activity was examined in the synthesis

tives in the presence of β-cyclodextrin (0.02 mmol) [44].

umbilical vein endothelial cells (HUVECs).

*Spirochromenocarbazole tethered 1,2,3-triazole derivatives.*

*Current Topics in Chirality - From Chemistry to Biology*

**Figure 12.** *Triazole derivatives.*

**Figure 13.**

**Figure 14.**

**72**

*Structures of different triazole derivatives.*

**Figure 17.** *Synthesis of cyclooctyne and trans-cyclooctene.*

**Figure 18.**

*Synthesis of parthenolide–thiazolidinedione and 3'-O-1,2,3-triazolyl-guanosine-5*<sup>0</sup> *-*o*-monophosphate derivatives.*

erythroleukemia cell line (HEL) by MTT assay. The compound (29f) having 3,5-dimethoxyphenyl group exhibited the highest inhibitory effect against HEL (IC50 = 2.99 � 0.22 μM), MDAMB-231 (IC50 = 2.07 � 0.19 μM), and PC3 (IC50 = 3.09 � 0.20 μM) (**Figure 18**).

Knoevenagel/azide-alkyne cycloaddition reaction between indole, aromatic aldehydes or pyrazole and phenylazide was fruitfully accomplished in the presence of piperidinium acetate in methanol to furnish the desired triazole derivatives (33)

In 2018, Han *et al*. [61] developed a metal-free and solvent-free approach for the synthesis of 4-trifluroacetyl 1,2,3-triazoles in good yields with great selectivity. The synthesized compounds were examined for the anti-cancer activity and compound **34b** possessed superior activity as compared to others against HePG2 (0.0267 μmol/

In the same year, Tan *et al*. [62] used thiol-ene click chemistry for the controlled functionalization of poly vinylidene fluoride in the presence of a base. The mechanism of the reaction suggests that it involves addition reaction followed by both Markonikov and anti-Markonikov mechanism and furnishes the same product. Later on in 2019, Moore and co-workers [63] designed a novel methodology for the synthesis of ionic liquids which were based on fluoroalkynyl imidazolium using thio-ene/yne click chemistry. The pathway has high conversion efficiency and high

Visible-light-assisted organic transformations have received a huge response in chemical synthesis in order to design environmentally friendly approaches. The synthesis using economical, easily available visible-light sources have become vanguard in the synthetic chemistry as a prevailing approach for the activation of small

(**Figure 19 Method 3**) [60].

*4-Trifluroacetyl 1,2,3-triazole derivatives.*

*Metal-free synthetic route of triazole based heterocycles.*

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

yields with no need for further purification.

**3.4 Visible light assisted click chemistry**

molecules to furnish the desired products [64–66].

mL) (**Figure 20**).

**75**

**Figure 19.**

**Figure 20.**

Senthilvelan *et al.* [55] designed synthesis of 3'-O-1,2,3-triazolyl-guanosine-5<sup>0</sup> -*o*monophosphate (30) from in situ generation of azide from the resultant bromide followed by copper and β-cyclodextrin catalyzed cyclo-addition with 30 -O-propargyl guanosine monophosphate in aqueous media. The designed pathway has high regioselectivity and gave good yield of products (**Figure 18**).

#### **3.3 Metal-free approach for click reaction**

Several new metal-free click chemistry assisted syntheses of heterocyclic scaffolds have been designed up to date. These pathways involve a variety of functional group tolerance in the substrate of cyclo-addition reaction. These synthetic pathways can be achieved under mild conditions and give high yields of desired products using organo-catalyst [56, 57]. In 2010, Fokin and co-authors developed the first transition metal-free synthesis of 1,5-diaryl-1,2,3-triazoles (31) employing azide-alkyne cyclo-addition [58] (**Figure 19 Method 1**). In this reaction, tetraalkylammonium hydroxide was used as the catalyst that provided moderate to high yield of products. Later on, in 2013, Ramachary and co-workers [59] achieved a region-selective synthesis of N-arylbenzotriazoles at room temperature using a cyclic enone and an arylazide under pyrrolidine catalysis at room temperature. Additional aromatization by DDQ gave fused heterocyclic scaffolds (32) (**Figure 19 Method 2).** In the subsequent year, a one-pot tandem,

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

**Figure 19.** *Metal-free synthetic route of triazole based heterocycles.*

**Figure 20.** *4-Trifluroacetyl 1,2,3-triazole derivatives.*

Knoevenagel/azide-alkyne cycloaddition reaction between indole, aromatic aldehydes or pyrazole and phenylazide was fruitfully accomplished in the presence of piperidinium acetate in methanol to furnish the desired triazole derivatives (33) (**Figure 19 Method 3**) [60].

In 2018, Han *et al*. [61] developed a metal-free and solvent-free approach for the synthesis of 4-trifluroacetyl 1,2,3-triazoles in good yields with great selectivity. The synthesized compounds were examined for the anti-cancer activity and compound **34b** possessed superior activity as compared to others against HePG2 (0.0267 μmol/ mL) (**Figure 20**).

In the same year, Tan *et al*. [62] used thiol-ene click chemistry for the controlled functionalization of poly vinylidene fluoride in the presence of a base. The mechanism of the reaction suggests that it involves addition reaction followed by both Markonikov and anti-Markonikov mechanism and furnishes the same product. Later on in 2019, Moore and co-workers [63] designed a novel methodology for the synthesis of ionic liquids which were based on fluoroalkynyl imidazolium using thio-ene/yne click chemistry. The pathway has high conversion efficiency and high yields with no need for further purification.

#### **3.4 Visible light assisted click chemistry**

Visible-light-assisted organic transformations have received a huge response in chemical synthesis in order to design environmentally friendly approaches. The synthesis using economical, easily available visible-light sources have become vanguard in the synthetic chemistry as a prevailing approach for the activation of small molecules to furnish the desired products [64–66].

erythroleukemia cell line (HEL) by MTT assay. The compound (29f) having 3,5-dimethoxyphenyl group exhibited the highest inhibitory effect against HEL (IC50 = 2.99 � 0.22 μM), MDAMB-231 (IC50 = 2.07 � 0.19 μM), and PC3

Senthilvelan *et al.* [55] designed synthesis of 3'-O-1,2,3-triazolyl-guanosine-5<sup>0</sup>


Several new metal-free click chemistry assisted syntheses of heterocyclic scaffolds have been designed up to date. These pathways involve a variety of functional group tolerance in the substrate of cyclo-addition reaction. These synthetic pathways can be achieved under mild conditions and give high yields of desired products using organo-catalyst [56, 57]. In 2010, Fokin and co-authors developed

monophosphate (30) from in situ generation of azide from the resultant bromide

followed by copper and β-cyclodextrin catalyzed cyclo-addition with

*Synthesis of parthenolide–thiazolidinedione and 3'-O-1,2,3-triazolyl-guanosine-5*<sup>0</sup>

has high regioselectivity and gave good yield of products (**Figure 18**).

the first transition metal-free synthesis of 1,5-diaryl-1,2,3-triazoles (31)

(**Figure 19 Method 2).** In the subsequent year, a one-pot tandem,

employing azide-alkyne cyclo-addition [58] (**Figure 19 Method 1**). In this reaction, tetraalkylammonium hydroxide was used as the catalyst that provided moderate to high yield of products. Later on, in 2013, Ramachary and co-workers [59] achieved a region-selective synthesis of N-arylbenzotriazoles at room temperature using a cyclic enone and an arylazide under pyrrolidine catalysis at room temperature. Additional aromatization by DDQ gave fused heterocyclic scaffolds (32)


*-*o*-monophosphate*

(IC50 = 3.09 � 0.20 μM) (**Figure 18**).

*Synthesis of cyclooctyne and trans-cyclooctene.*

*Current Topics in Chirality - From Chemistry to Biology*

**3.3 Metal-free approach for click reaction**

30

**74**

**Figure 17.**

**Figure 18.**

*derivatives.*

deprotection of TMS group [74]. In 2020, Kritchenkov *et al*. synthesized triazole chitin derivatives and used them in the synthesis of Pd(II) complexes. Initially, ultrasound-assisted interaction of chitin with 1-azido-3-chloropropan-2-ol gave azido chitin and was further converted to triazole derivatives **(37)** that were used as

The use of microwave irradiation in cyclo-addition reactions for click chemistry has also been comprehensively deliberated. It allows efficient internal heat transfer and therefore decreases the reaction time as well as enhances the reaction rate with high yield [76, 77]. The increased temperature can be used over short periods thus avoiding decomposition or polymerization. Ashok and co-workers demonstrated the synthesis of 1,2,3-triazole analogs using microwave irradiations in 8–10 min and examined their antimicrobial activity [78] (**Figure 23 Method 1**). This method has also been applied in the preparation of 1,2,3-triazole analogs of nucleosides [79] (**Figure 23 Method 2)**. In general, those reactions which require prolonged conventional heating are accomplished in just 10–15 min using microwave irradiation. A chronological one pot Ru catalyzed cycloaddition was also designed from primary

ligands for the complex formation (**Figure 22**) [75].

aryl or aliphatic bromides (**Figure 23 Method 3**) [80].

**Figure 23.**

**77**

*Microwave assisted synthesis of triazole based scaffolds.*

**3.6 Microwave-assisted click chemistry**

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

**Figure 21.** *Visible light assisted synthesis of vinyl sulphide.*

**Figure 22.** *Synthesis of ultrasound assisted 1-azido-3-chloropropan-2-ol azido chitin derivatives.*

Burykina *et al*. [67] synthesized different kinds of vinyl sulphides **(35)** in high yields with good selectivity using thiol-yne click reaction using visible light. The designed pathway is transition-metal-free and gave Markonvikov-type product through a radical photo-redox pathway (**Figure 21 Method 1**).

Recently, Wu *et al*. [68] synthesized triazole analogs **(36)** through photo-redox electron-transfer mechanism. The authors inspected the reaction of benzyl azide with phenylacetylene using diverse photo-catalysts under ambient reaction conditions like room temperature (RT), air, and visible light irradiation. The catalyst (piq)2Ir(acac) or TPPT-Cl catalyzed the formation of triazole derivatives. The designed pathway is high region-selective, high yielding, having a high atom economy, and using solar catalysis **(Figure 21 Method 2).**

#### **3.5 Ultrasound assisted click chemistry**

Ultrasound assisted reactions are milder and faster. The mechanism of ultrasound is based on an acoustic cavitation phenomenon. This technology hastens the reaction in both heterogeneous and homogeneous media, due to amplified energy intake. It shortens the reaction time and augments the competence of the system by triggering the catalyst surface area and removing deposited impurities [69, 70]. A decades ago, Cintas *et al*. [71] depicted the synthesis of 1,4- disubstituted 1,2,3 triazole analogs using Cu under ultrasound irradiation exclusive of a ligand. Later on, a heterogeneous catalytic system, Cu(II) doped clay was used at RT with ultrasonic irradiations [72]. The use of heterogeneous catalyst evaded needless complexity due to copper (I) salt redox protocol that involved the presence of ligands and protecting agents. The reaction is eco-friendly, easy to prepare, and recoverable. One-pot synthesis of 1,4-disubstituted-1,2,3-triazoles was successfully achieved using a benzyl or alkyl halide, sodium azide, and a terminal alkyne under these conditions [73]. The formation of triazole starting from a TMS protected alkynylglycoside was also demonstrated under ultrasound conditions with *in situ*

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

deprotection of TMS group [74]. In 2020, Kritchenkov *et al*. synthesized triazole chitin derivatives and used them in the synthesis of Pd(II) complexes. Initially, ultrasound-assisted interaction of chitin with 1-azido-3-chloropropan-2-ol gave azido chitin and was further converted to triazole derivatives **(37)** that were used as ligands for the complex formation (**Figure 22**) [75].
