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Ratnakar Dutt Shukla, Byanju Rai (2021). Employment of Green and Sustainable Protocols for C(sp3)-H bond Functionalization of 2-Methyl azaarenes and subsequent C-C bond formation. Spectrum of Emerging Sciences, 1(1), pp.21-28.

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Employment of Green and Sustainable Protocols for C(sp3)-H bond Functionalization of 2-Methyl azaarenes and subsequent C-C bond formation

Ratnakar Dutt Shuklaa*, Byanju Raia

a,a*Department of Chemistry, Pt. DDU Govt. Model College, Bahua, Fatehpur, India        



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Original Research Article

Received:   9 November 2021

Accepted: 11 November 2021





C(sp3)-H Functionalization,

2-Methyl azaarenes,

C-C bond construction,

Green and sustainable protocols



Twenty-first century witnessed the importance of C-H bond functionalization which is regarded as a potent, promising and direct tool for the construction of the carbon-carbon bond. The concept of C-H bond functionalization has been highly explored in the field of synthetic organic chemistry. The current scenario of research is shifted towards the development of novel sustainable protocols which should have great environmental impact. It does not need pre‐functionalization of the substrates and thus offers an atom‐economic strategy hence regarded as green and sustainable approach. The applications of C-H functionalization approach, as a potential synthetic tool, have been well exemplified in the formation of C-C bond and carbon-heteroatom bonds (C-O, C-N, C-S and C-X) which have notable applications in the preparation of complex natural products and medicinally potent compounds. The present review covers the employment of numerous novel and innovative sustainable approaches in the field of C(sp3)-H Functionalization reactions.



The C-H functionalization of inactivated C-H bonds has been extensively explored strategies of the twenty-first century in synthetic organic chemistry[1], [2].Because of the ever-presence of C-H bonds, the C-H functionalization has now revolutionized as a potential synthetic strategies for the installation of various functional groups in organic substances (Figure 1). This concept does not need pre‐functionalization of the substrates and thus offers an atom‐economic strategy. The applications of C-H functionalization approach, as a potential synthetic tool, have been well exemplified in the construction of C-C bond [3]  and carbon-heteroatom bonds (C-O, C-N, C-S and C-X) which have notable applications in the synthesis of valuable organic molecules such as complex natural products, and medicinally potent compounds [4]–[6].

Medicinal importance of Azaarenes (Pyridine and Quinoline):  Quinolines and related scaffolds have always been significant candidates for drug development program. Among N-heterocycles, pyridine and quinoline are privileged scaffolds that appear as an important constituent in several FDA approved drugs (Figure 2). Pyridine moiety is an important constituent in several natural products like niacin, vitamin B6, nicotinamide adenine dinucleotide (NAD), and alkaloids such as trigonelline. Pyridine is one of the most extensively used azaarene in pharmaceutical research with numerous biological applications[7].

Figure 1: Common Approach to C-H Functionalization


The quinoline ring system presents in several natural products like Quinine, Chimanine A, B and D, Cusparine, etc. with interesting biological activities[8]–[10]. Quinoline nucleus is endowed with several biological activities; therefore, quinoline and related moieties constitute a significant group of heterocycles for the development of novel drugs. Notably, many biological activities like antibacterial, antimalarial, anticancer, antiviral, anthelmintic, antifungal, anti-inflammatory, central nervous system, analgesic, hypoglycemic and cardiovascular have been observed from quinoline derivatives[11], [12].

C(sp3)-H Functionalization of 2-methylazaarene

Owing to the medicinal importance of quinoline and pyridine, the C(sp3)-H functionalization of 2-methylazaarenes has secured a remarkable position in the area of synthetic organic chemistry. A growing repertoire of C-H functionalization of 2-methyl azaarenes are continuously widening via an array of protocols by using transition metals with ligands,[13] transition metals without ligands[14], [15], Lewis acids[16], Brønsted Acids[17],  etc. Some representative protocols for C(sp3)-H functionalization of 2-methylazaarenes are demonstrated in figure 3. 

Figure 2: Examples of Azaarene (pyridine and quinoline) containing FDA approved drugs


Figure 3: Representative examples of various developed protocols for C(sp3)-H functionalization of 2-methylazaarene

The present review covers some selected publications on the C(sp3)-H Functionalization of 2-methylazaarene.

1. Preparation of Alkyl Azarene Pyridinium (AAP) Zwitterions via C(sp3)-H Bond functionalization using Iodine

In 2011, Atul Kumar et al described a potent as well as conceptually greener strategy for the C-H bond functionalization using iodine for the preparation of alkyl azaarene pyridinium zwitterions. This transition-metal-free approach demonstrates the remarkable importance of being the first preparation of a novel group of alkyl azaarene pyridinium zwitterion (Scheme 1). The designed the scheme for the aforementioned synthesis using the reactions of 2-methyl quinoline, aromatic aldehydes, meldrum acid, pyridine in the presence of iodine as Lewis acid catalyst and triethylamine as base. The salient feature of this report includes that the complete multicomponent reaction is performed in one pot without using transition metal catalyst. This article may be considered as a breakthrough in the field of synthetic chemistry for conducting the C-H functionalization reaction in absence of hazardous transition metal catalysts as well as ligands.

Scheme 1: Iodine catalyzed C(sp3)-H Bond functionalization of 2-methyl azaarenes

The plausible mechanism for the above reaction is well demonstrated in Figure 4. Functionalization of methyl azaarenes by coordination to iodine as Lewis acid enhances the acidity of the benzylic C-H bonds. In presence of Lewis acid breaking of the C-H bond generates a 1-iodo-2-methylene-1, 2- dihydroquinoline species (2). In next step, pyridine attacks 2 as a nucleophile to generate 1-(quinolin-2-ylmethyl) pyridinium iodide (3). Finally, the attack of iodide salt is done on arylidene dione (an adduct of aromatic aldehyde meldrum acid generated through Knoevenagel condensation) to form AAP zwitterions.

The developed protocol is efficiently explored for the synthesis of number of AAP zwitterionic salts in good to excellent yields.



2. Benzylic C-H Bond Functionalization of Azaarenes in presence of Lewis Acid

Motomu Kanai and group (2011) have described a Lewis acid catalyzed C(sp3)-H bond functionalization of 2-methyl azaarenes(Scheme 2)[11].

Scheme 2: Lewis acid catalyzed C(sp3)-H Bond functionalization of 2-methyl pyridine

Here Sc(OTf)3 and Y(OTf)3 have been used as Lewis acid which promotes the direct addition of 2-methyl pyridine to enones and an α, β-unsaturated N-acylpyrrole. This Lewis acid promoted protocol provides the products were in 60-96% yield.

On the basis of literature reports regarding Lewis acid catalyzed intramolecular C(sp3)-H functionalization,[18] Lewis acid promoted C(sp2)-H functionalization of quinolines and/or pyridines[19], as well as acid/base catalyzed proton transfer reactions[20], herein it is suggested that Lewis acid has been employed for the functionalization of 2-methyl azaarenes in the presence proton-transfer conditions[21]. A plausible mechanistic approach for the present reaction is clearly depicted in figure 5



Figure 4: Probable mechanistic strategy for Methyl azaarene Pyridinium (AAP) Zwitterions


Figure 5: Plausible mechanism for Lewis acid catalyzed C-H functionalization of alkyl-substituted azaarenes with enones


3. TBAF (Tetrabutylammonium fluoride)-catalyzed C(sp3)-H functionalization of 2-methyl azaarenes for the synthesis of azarene substituted 3-hydroxy-2-oxindoles

A mild, smooth, efficient and metal-free sustainable protocol for direct addition of 2-alkylazaarenes to isatins via C(sp3)-H functionalization in the presence of controlled microwave radiation using water as reaction medium[22].

This green strategy offers a simple and practical synthetic route for bioactive azaarene-substituted 3-hydroxy-2-oxindoles in good to excellent yields. The present innovative approach will provide a new organocatalytic option for the functionalization of C-H bonds.

Scheme 3: TBAF catalyzed C(sp3)-H functionalization of 2-methyl azaarenes


In view point of green chemistry, synthetic community is trying to replace conventional hazardous catalysts and solvents in order to develop a sustainable protocol. Taking into account the necessity of environmental and economic awareness, the employment of a more general and practical method under mild conditions, preferably using solvent of natural origin for C-H functionalization is need of the day. Water is considered as one of the most important gift from nature. The exploitation of water as a solvent in synthetic chemistry is completely following the green chemistry mandate. The emergence of organocatalysis has attracted the great interest due to its unique advantages. The exploration of organocatalysts in combination to aqueous medium will give the promising practical outcomes in field of green chemistry.


4. β-Cyclodextrin catalysed C(sp3)-H functionalization of 2-methyl azaarenes with diones using water as reaction medium

Atul Kumar and Ratnakar Dutt Shukla have reported first time exploration of β-cyclodextrin as catalyst for the functionalization of C(sp3)-H bonds of 2-alkyl-azaarenes with heterocyclic as well as homocyclic diones water[23].

Scheme 4: β-Cyclodextrin catalysed C(sp3)-H functionalization of 2-methyl azaarenes

This biomimetic catalyst dependent approach gives a green and sustainable methodology for C-H functionalization reactions. This study exploited the easily available, biodegradable, non-toxic and reusable β-cyclodextrin as catalyst and hence breaks the dominancy of hazardous transition metal catalyzed C-H bond functionalization reactions. This β-cyclodextrin catalyzed methodology expands the repertoire of a sustainable and green protocol for C-H bond functionalization reactions, the one of the most important approach in synthetic organic chemistry.

Cyclodextrins as a reusable catalyst

Cyclodextrins (CD) are readily available cyclic oligosaccharides consisting of D (+)-glucose units associated by α-1,4-glycosidic bonds (Figure 6). Cyclodextrins contains a hydrophobic central cavity as well as a hydrophilic outer surface which have attracted great interest as aqueous-based hosts for inclusion complex phenomena with a variety of guest. Cyclodextrins have substrates selective binding potential and catalyze numerous chemical reactions under the concept of supramolecular catalysis[24]. The inclusion complex is formed via non-covalent bond interaction between hydrophobic guest molecule and the hydrophobic cavity of CD.

Figure 6: Schematic representation of α-, β-, and ϒ-CD with their equivalent truncated cone structure

With view point of green chemistry, the employment of readily available, cost effective and eco-friendly catalysts and solvents remains highly recommended. From green chemistry prospective, water, the readily available and environmentally benign, is a most suitable replacement for the hazardous organic solvents. Water, the nature’s solvent, has been employed many times as a solvent in numerous organic reactions. β-CD is a well-known green, reusable, biodegradable and environmentally compatible catalyst for organic synthesis.




Scheme 5: Synthesis of azaarene-substituted 3-hydroxy-2-oxindoles

A number of 2-methylazaarenes viz., 2-methyl pyridine, 2-methyl quinoline, 6-fluoro-2-methyl quinoline, 6-chloro-2-methyl quinoline, 8-chloro-2-methyl quinoline, 6-bromo-2-methyl quinoline were smoothly functionalized and prepared to react with various possible substituted isatins, for example, 5-methylisatin, 5-nitroisatin, 7-fluoroisatin, 5-chloroisatin, 5-bromoisatin, 5-iodoisatin, N-methylisatin, N-benzylisatin to generate a variety of 3-substituted-3-hydroxy-2-oxindoles (3a-3p). Isatins having electron-releasing group (-CH3), electron-withdrawing (-NO2) substituents, and halogens, participated successfully in reaction, and the desired products were afforded in good to excellent yields. The observations showed that N-protected isatins provided better yield in comparison to unprotected ones. No side products i.e., bis(quinolin-2-ylmethyl)indolin-2-ones were noticed under the present synthetic protocol (Scheme 5).

To check the broadness of the present greener protocol, next, we conducted the reaction of 2-methylazaarenes with benzo-[b]thiophene-2,3-dione (4a), i.e., thioisatin. Similar to isatin, the thioisatin performed well in reaction. Gratifyingly, the corresponding products (5a-5d) were formed in good to excellent yields, as well depicted in scheme 6.

Scheme 6: Synthesis of azaarene-substituted 3-hydroxy-benzo[b]thiophen-2(3H)-ones

As the heterocyclic diones (isatins and thioisatin) afforded the expected products in excellent yields using present developed protocol (Scheme 5 and Scheme 6), various homocyclic diones were also explored to evaluate the scope and compatibility of this sustainable synthetic approach.

Scheme 7: Synthesis of azaarene-substituted 2-hydroxy acenaphthylene-1(2H)-ones and azaarene-substituted-2-hydroxy aceanthrylene-1(2H)-ones

In this context, we assessed bicyclic as well as tricyclic homocyclic diones like acenaphthylene-1,2-dione (6a) and aceanthrylene-1,2-dione (6b) respectively (Scheme 7). So, we carried out a reaction of 2-methylpyridine and 2-methyl quinoline with acenaphthylene-1,2-dione under the optimized protocol, gratifyingly, the desired products 7a and 7b were obtained respectively. Next, we explored the present methodology for reaction of polycyclic aceanthrylene-1,2-dione with 2-methylazaarenes, the observations showed that the reaction well grown with aceanthrylene-1,2-dione too and expected products (7c and 7d respectively) were delivered with excellent yields.

To evaluate the sustainability of present protocol, the reusability of β-cyclodextrin was examined for five cycles (including the fresh catalyst) for the syntheses of compounds 3l, 3c, 3m, 5b, and 7b, no significant losses in catalytic efficacy were shown during the reusability experiments [Figure 7 (a)].

Figure 7: (a) Reusability data for β-CD; (b) Cross reusability data for β-CD

In addition, cross catalytic reusability experiments were also performed for the synthesis compound 3c and 3m, and negligible loss in catalytic efficacy was reported. The fresh batch of β-cyclodextrin as a catalyst was employed for the synthesis of compound 3c, then the recovered catalyst was employed for the synthesis of compound 3m, and vice versa [Figure 7 (b)].

This environmentally benign protocol is applicable to C(sp3)-H functionalization of several 2-methylazaarenes with a broad category of heterocyclic as well as homocyclic diones. This quest confers a greener option for establishing a new horizon for C-H functionalized reactions.


Initially, the C(sp3)-H functionalization of 2-methyl pyridines/quinolines was performed with the employment of strong bases like nBuLi, NaNH2, KNH2, LDA, etc. Subsequently efficient and practical functionalization reactions have been emerged, such as at the starting of this decade, it was regarded as C-H activation reaction. Then it was thought that C-H activation is not suitable to use as the 2-methyl quinoline is a preactivated molecule because of the imine-enamine tautomerism. Latter on many Lewis and Brønsted acid and transition metal-catalyzed reactions were evolved. With the emergence of concept of green chemistry, numerous sustainable protocols have been developed for C-H functionalization reactions and many of them have been well covered in this review. Recently, many catalyst-free, aqueous medium and very recently catalyst and solvent-free approaches for C-H functionalization were also developed. Considering the medicinal importance of pyridine/quinoline, the application of developed C-H functionalization approaches will generate of a wide range of pyridine/quinoline derivatives.

 Conflict of interest:

Authors declares no conflicts of interest.

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