Citric acid Mediated One-pot Regioselective Synthesis of N-Alkylated Indazoles: An Efficient Green Strategy

Citric acid mediated green synthetic route has been demonstrated for the regioselective synthesis of N-alkylated indazoles in good to excellent isolated yields ( ~ 78-96%) from readily available starting materials 2-methylanilines (1), NaNO2 (2) and ethyl chloroacetate (3) via diazotization, intra molecular cyclization and followed by N-alkylation in the presence of 1:1 ratio of ethanol and water in one-pot. Notably, if the substrate (1) contains – NO2 group and is reduced to – NH2 in the presence of Fe, CaCl2 in the same pot at 60-65°C for 30-40 min. The remarkable advantages of this method include cleaner reaction profile, easy to perform, high yields of products and simple work-up procedure. Besides, the reaction is step-and atom-economic and is carried out in green catalytic medium.


Introduction
Heterocyclic ring systems are frequently found in numerous naturally occurring compounds and they compose the core structures of many biologically active motifs as well as some industrial compounds [1]. Among them, indazoles represent an important class of nitrogen containing heterocycles and this nucleus ( Figure 1) [2,3] is of great current interest as partial structure in many synthetic drugs or drug candidates with a broad range of pharmacological activities including anti-HIV [4], anti-inflammatory [5], anti-tumor [6,7], anti-depressant [8], analgesic and antipyretic [9], anti-leukemia [10], anti-convulsant activity [11], anti-cancer [12], anti-arthritic [13], anthelmintic [14] and anti-diabetes [15]. Indazole moiety is present only in three natural products such as Nigellicine, Nigeglanine and Nigellidine indicates their rare presence in nature [16,17].
However, all the above methods are highly promising, but, most of them suffer from one or more disadvantages including the use of i) acids or reagents that are not environmentally compatible and corrosive, ii) hazardous starting materials, iii) metal catalysts

Trends in Green Chemistry ISSN 2471-9889
and solvent(s), iv) long reaction time, v) cumbersome workup procedures and vi) production of a large amount of waste. In view of the importance of indazoles and the limitations of previous methods, the development of one-pot synthesis of indazoles from readily available starting materials in green catalytic medium would be of prime synthetic value. On the path of finding suitable one-pot green approach, our attention is directed towards classical diazotization and intramolecular cyclization in the presence of AcOH [37]. Prompted by this idea, biodegradable citric acid medium has been identified for the synthesis of N-alkylated 1H-indazoles in a single step operation. Citric acid is the non-toxic, low-cost, biodegradable and environmentally benign catalyst which is also employed in many organic transformations [38][39][40][41].
In this work, we demonstrated a biodegradable citric acid mediated green synthetic route for the regioselective synthesis of N-alkylated indazoles in good to excellent isolated yields ( ~ 78-96%) from readily available starting materials 2-methylanilines (1), NaNO 2 (2) and ethyl chloroacetate (3) via diazotization, intra molecular cyclization and followed by N-alkylation in the presence of 1:1 ratio of ethanol and water in a single step operation. If the substrate (1) contains -NO 2 group and is reduced to -NH 2 in the presence of Fe, CaCl 2 at 60-65°C (Chandrappa, Vinaya, Ramakrishnappa, & Rangappa, 2010) in the same step as shown in Figure 2.     After completion of the reaction as per TLC, reaction mixture is filtered to remove the iron residue and washed with EtOAc (2 × 10 mL). The organic layer is washed with water, dried over MgSO 4 and concentrated. The obtained crude product (4f) is purified by silica gel using n-hexane and EtOAc (3:1 ratio). The same procedure is followed for the preparation of compounds 4g-j. The synthesized compounds (4f-j) gave satisfactory spectroscopic data in accordance with their proposed structures.

Results and Discussion
In the present study, our initial efforts are focused on identifying the catalyst, solvent(s) for the construction of 1H-indazole followed by N-alkylation in a single step operation. For this purpose, the reaction of 2-methyl anilines (1a) with NaNO 2 (2) and followed by treatment with ethyl chloroacetate (3) in onepot was chosen as a model reaction to optimize the reaction conditions and the obtained results are presented in Table 1. The construction of 1H-indazole followed by N-alkylation involved in the present process which is carried out in the presence of various biodegradable α-hydroxy acidic catalysts such as malic acid, mandelic acid, tartaric acid and citric acid (1.0 equivalent) in water for about 150 min. Low yields of product 4a, 5%, 5%, 8% and 15%, are obtained respectively. To improve the yield, the same reaction is repeated by employing various solvents, like methanol, isopropanol, EtOH, EtOH:H 2 O (1:1 ratio), EtOH:H 2 O (2:1 ratio) and EtOH:H 2 O (3:1 ratio) and the results are presented in Table 1. After the examination of various α-hydroxy acid catalysts and solvents, it is found that citric acid (1.0 eq) and 1:1 ratio of EtOH:H 2 O medium is the best option to obtain good yield (75%) of the product (4a) and other α-hydroxy acid catalysts and solvents give low yields of product (4a).

Effect of mode of addition of NaNO 2
It is interesting to mention the effect of mode of NaNO 2 addition. It is investigated and found that the portion wise addition and one time addition of NaNO 2 had a significant effect on the isolated yield of the desired product (4a). For example, the isolated yield of the product (4a) is increased on addition of NaNO 2 in portion wise (entries 2-4, Table 2) when compared to one-time addition of NaNO 2 (entry 1, Table 2). The review concluded that addition of NaNO 2 in 4 portions provided improved yield of product 4a (entry 4).
Further, it is noteworthy to mention that the substrate (1) contains -NO 2 group and is reduced to -NH 2 in the presence of Fe, CaCl 2 at 60-65°C for 30-40 min in the same pot. This functional group transformation is useful for the development of indazole based new chemical entities of potential pharmacological interest.

Scope of the method
With the help of the above optimized reaction conditions, the scope of the present method is studied using different types of substituted 2-methyl anilines (1a-j) and the obtained results are presented in Table 3. The 2-methyl aniline (1a) provided excellent yields of desired product (4a) i.e. 96% (entry 1, Table  3). The substrates (1d) and (1c) bearing chloro group at 4-and 5-positions, afforded excellent yield of products 4c (94%) and 4d (94%) when compared to the same substituent at 2-and 6positions of the substrates (1b) and (1e) (entries 2-5, Table 3). This may be due to the ortho effect. Substrate (1 g) with -NO 2 group at 5-position, afforded good yields of product (4 g) when compared to the same substituent at 4-and 6-positions of the substrates (1f) and (1h) (entries 6-8, Table 3). The main reason is that the -NO 2 group in (1f) and (1h) is suitably located for withdrawing of electrons strongly from NH 2 group whereas this type of situation is not observed in the case of (1 g). Substrates (1i) and (1j) containing both nitro (-NO 2 ) and chloro (-Cl) groups provided lower yields of products 4i (80%) and 4j (78%) compared to the mono substituted substrates (entries 9 and 10, Table 3). This may be attributed to the steric effects. From the above study, it is found that the substrates bearing weak electron-withdrawing substituents (i.e. chloro) (1b-e) provided excellent isolated yields of desired products in the range of 90-94% (entries 2-5, Table 3) when compared to the substrates with strong electron-withdrawing substituents (i.e. nitro) (1f-h) (84-92% yields) (entries 6-8, Table 3).

Physical and spectral data of the synthesized compounds
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Conclusion
A practical and green synthetic route has been developed for the regioselective synthesis of N-alkylated indazoles in onepot from readily available starting materials 2-methylanilines (1), NaNO 2 (2) and ethyl chloroacetate (3) via diazotization, intra molecular cyclization and followed by N-alkylation in the presence of citric acid in a mixture of ethanol and water (1:1 ratio). Notably, if the substrate (1) contains -NO 2 group and is reduced to -NH 2 in the presence of Fe, CaCl 2 in the same pot at 65°C. The superior features of the present method comprise of broad substrate scope, cleaner reaction profile, easy to perform, high yields of products and simple work-up procedure. Besides, the reaction is step-and atom-economic