Original article Efficient synthesis of functionalized hydroindoles via catalyst-free multicomponent reactions of ninhydrin in water Faramarz Rostami-Charati Department of Chemistry, Facualty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran 1. Introduction One of the powerful tools used to connect economic features with the green concerns is performing organic reactions in water; this strategy consists of two or more synthetic steps, which are carried out in water as a cheap, nontoxic, environmentally friendly solvent, in a one-step reaction, without isolation of any interme- diate thus reducing time, saving money, energy and raw materials [1–7]. Indole moiety has been found in a wide variety of pharmacologically and biologically active compounds [8,9]. For example, melatonin and indole-3-propionic acid (IPA) reduce reactive oxygen species that cause cellular damage and prevent death of neurons exposed to amyloid b-proteins, the agent responsible for Alzhimer’s disease [10]. Some indole derivatives function as dopamine agonists and/or selective serotonin reuptake inhibitors (SSRIs), the latter being a class of anti-depressants [11]. Acemetacin [12] and indometacin [13] are clinically used as anti- inflammatory drugs and fluvastatin sodium [14] is a well-known HMG-CoA reductase inhibitor. Hence, we describe herein the reaction of cyclic-1,3-dione 1 and ninhydrin 3 in the presence of primary amines 2 in water as the green solvent. 2. Experimental All chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN–O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 spectrometer operating at an ionization potential of 70 eV. IR spectra were measured on a Shimadzu IR-460 spectrometer. 1 H NMR and 13 C NMR spectra were measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz, respectively. 1 H NMR and 13 C NMR, spectra were obtained for solutions in CDCl 3 using TMS as the internal standard or 85% H 3 PO 4 as the external standard. 2.1. General procedure for preparation of compounds 4a–k To a magnetically stirred solution of 1,3-activated dicarbonyl compound 1 (2 mmol) and primary amine 2 (2 mmol) in water (10 mL) as the solvent was added ninhydrin 3 (2 mmol). The reaction mixture was stirred for 4 h at 70 8C. After completion of reaction (monitored by TLC), the mixture of reaction was purified in the room temperature by column chromatography (silica gel (230–400 mesh, Merck) using n-hexane-EtOAc as eluent to give compound 4. 3. Results and discussion The starting point for our experiments was to optimize the reaction conditions such as solvent and reactions time for the production of indol derivatives which are usable in a wide variety of pharmacologically and biologically active compounds (Table 1). Chinese Chemical Letters 25 (2014) 169–171 A R T I C L E I N F O Article history: Received 20 July 2013 Received in revised form 26 August 2013 Accepted 6 September 2013 Available online 5 November 2013 Keywords: Ninhydrin Primary amine Indole Three-component reaction 1,3-Dicarbonyls A B S T R A C T An efficient synthesis of hydroindeno[1,2-b]indoles is described via three-component reaction of ninhydrin and cycloalkan-1,3-dione in the presence of primary amines in water as the green solvent in excellent yield. ß 2013 Faramarz Rostami-Charatif. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. E-mail address: f_rostami_ch@yahoo.com. Contents lists available at ScienceDirect Chinese Chemical Letters jo u rn al h om epag e: ww w.els evier.c o m/lo cat e/cc let 1001-8417/$ – see front matter ß 2013 Faramarz Rostami-Charatif. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. http://dx.doi.org/10.1016/j.cclet.2013.09.016