अनुसंधान एवं विकास जर्नल
खुला एक्सेस
आईएसएसएन: 2311-3278
आईएसएसएन: 2311-3278
Trivikram Reddy
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. Keywords: Citric acid; o-Toluidines; Ethyl chloroacetate; Regioselectivity; N-Alkylated Indazoles.
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.
Materials and Methods :
1H NMR spectra are recorded on a Varian 300 MHz. Chemical shifts are expressed in parts per million (ppm), coupling constants are expressed in Hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Mass spectra (MS) are acquired on a Waters LCT premier XE TOF with electron spray ionization (ESI) source. Thin-layer chromatography is performed on 0.25 mm Merck silica gel plates and visualized with UV light. Column chromatography is performed on silica gel. Chemicals are purchased from Sigma Aldrich and Acros organics. Solvents are purchased from Merck. Millipore deionized water is used. Isolated compounds are identified on the basis of spectroscopic data and Mass spectrometry.
General experimental procedure for (substrates without – NO2 functional group) the regioselective synthesis of ethyl 2-(1H-indazol-1-yl)acetate (4a): In a 100 mL three necked round bottom flask, 2-methylaniline (1a) (10 mmol) and citric acid (20 mmol) are dissolved in a mixture of ethanol (8 mL) and water (4 mL). The clear solution was cooled at 0-5°C and stirred well. To this added ice-cold solution of NaNO2 (2) (12 mmol) in 4 mL of water in 4 portions for 5-10 minutes. The formation of 1H-indazole was monitored by TLC. After the completion of the reaction as per TLC, ethyl chloroacetate (3) (12 mmol) is added to the reaction mixture and is stirred under reflux conditions for 60 min. The progress of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is quenched in ice and the crude product is extracted twice with ethyl acetate (2 × 10 mL). The organic layer is washed with brine, dried over MgSO4 and concentrated. The obtained crude product (4a) is purified by silica gel using n-hexane and EtOAc (3:1 ratio). The same procedure is followed for the preparation of compounds 4b-e. The synthesized compounds (4a-e) gave satisfactory spectroscopic data in accordance with their proposed structures. General experimental procedure for the (substrates with – NO2 functional group) regioselective synthesis of ethyl 2-(5-amino-1H indazol-1-yl)acetate (4f): In a 100 mL three necked round bottom flask, 2-methyl-4-nitroaniline (1f) (10 mmol) and citric acid (20 mmol) are dissolved in a mixture of ethanol (8 mL) and water (4 mL). The clear solution is cooled at 0-5°C and stirred well. To this added ice-cold solution of NaNO2 (2) (12 mmol) in 4 mL of water in 4 portions for 5-10 minutes. The formation of 1H-indazole is monitored by TLC. After the completion of the reaction as per TLC, ethyl chloroacetate (3) (12.0 mmol) is added to the reaction mixture and is stirred under reflux conditions for 60 min. The progress of the reaction is monitored by TLC. After completion of the reaction as per TLC, iron powder (30 mmol) and CaCl2 (10 mmol) are added to the reaction mixture and stirred at 60-65°C for 60 min. The progress of the reaction is monitored by TLC. 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 MgSO4 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.