Green and Efficient Synthesis of 3-Pyrazolyl Indoles in Water
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doi: 10.1007/s40242-019-0011-8
Green and Efficient Synthesis of 3-Pyrazolyl Indoles in Water ZHAO Yanhui1, YU Haifeng1*, LIAO Peiqiu2 and WANG Wenju1* 1. College of Chemistry, Baicheng Normal University, Baicheng 137000, P. R. China; 2. Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China Abstract A green and efficient synthesis of 3-pyrazolyl indoles was developed by the cyclocondensation reaction of β-ethylthio-β-indolyl-α,β-unsaturated ketones with semicarbazide hydrochloride as hydrazine equivalent in the presence of 3 equiv. of PEG-400(1a/PEG mole ratio of 1:3) in reflux water. This procedure did not require toxic hydrazine and product purification, eliminating the use of toxic liquid chemicals. Keywords 3-Pyrazolyl indole; Green synthesis; Semicarbazide hydrochloride; Polyethylene glycol; Hydrazine equivalent
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Introduction
3-Pyrazolyl indoles as an important subset of indole derivatives have exhibited their versatile synthetic values[1—4] and a broad spectrum of biological activities[5—7], such as antimicrobial[8], anti-inflammatory[9] and antioxidant[10,11]. As a result, much effort has focused on the synthesis of 3-pyrazolyl indoles, mainly including the cyclocondensation of 1,3-diketones and related derivatives with hydrazines[12—19], the direct coupling of indole derivatives and pyrazole derivatives[20,21], acid-catalyzed intramolecular cyclization reaction of N-propargylation of N-acetyl-N-tosylhydrazine[22], and other procedures[23—25]. However, all the reported reactions are performed in organic medium and extremely toxic hydrazines as a main nitrogen source for most of reactions, which can lead to serious environmental and safety problems. Therefore, from the green chemistry point of view, the development of environmentally compliance synthesis of 3-pyrazolyl indoles is of great importance and necessity. During the last two decades, organic reaction in water had received more and more attention in green chemistry because the use of water can remarkably reduce the discharge of harmful organic solvents[26—31]. Recently, in our research on the organic reaction in water[32—35], we reported the thioacetalization[32] and synthesis of dithiines[33] using ketene dithioacetals as odorless thiol equivalent in water, DBSAcatalyzed Friedel-Crafts alkylation of ketene dithioacetals with alcohols[34] and hydrolysis of chain α-oxo ketene dithioacetals in water[35]. As part of our continuing research in the context, we more recently have developed a green protocol for the synthesis of 3-pyrazolyl indoles by the cyclocondensation of β-ethylthio-β- indolyl-α,β-unsaturated ketones and semicarbazide hydrochloride as nitrogen source in water. β-Ethylthioβ-indolyl-α,β-unsaturated ketones, which are easily prepared in good yields via acid mediated selective desulfitative
carbon-carbon coupling reaction between indoles and α-oxo ketene dithioacetals[36,37], are emerging as versatile intermediates in
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