An Efficient One-Pot Multicomponent Synthesis of 4-Aza-Podophyllotoxin Derivatives in Ionic Liquid

Hindawi Publishing Corporation Journal of Chemistry Volume 2013, Article ID 169695, 9 pages http://dx.doi.org/10.1155/2013/169695 Research Article An Efficient One-Pot Multicomponent Synthesis of 4-Aza-Podophyllotoxin Derivatives in Ionic Liquid Hossein Naeimi,1 Zahra Rashid,1 Amir Hassan Zarnani,2 and Ramin Ghahremanzadeh3 1 Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan 87317, Iran Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran 1936773493, Iran 3 Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran 1936773493, Iran 2 Correspondence should be addressed to Ramin Ghahremanzadeh; Received 6 May 2013; Accepted 2 September 2013 Academic Editor: Andrea Penoni Copyright © 2013 Hossein Naeimi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A simple, green, and efficient procedure for the synthesis of 4-aza-podophyllotoxin derivatives by using a one-pot three-component reaction of benzaldehydes, 1,3-cyclohexanediones, and anilinolactones in the presence of catalytic amount of alum in 1-butyl3-methylimidazolium triflate as green media is described. This reaction proceeded under mild conditions with the use of an inexpensive and readily available catalyst, high to excellent yields, and simple workup procedure. 1. Introduction Multicomponent reactions (MCRs) are one-pot processes in which three or more reactants come together in a single reaction vessel to give a final product containing substantial elements of all the reactants [1–4], and in recent year much attention has been directed toward the one-pot multicomponent reactions, because of their wide range of applications in pharmaceutical chemistry for the production of structural scaffolds and combinatorial libraries for drug discovery [5– 8]. The strategies of MCRs offer significant advantages over conventional linear-type syntheses because of high degree of atom economy, high selectivity, and procedural simplicity due to formation of carbon-carbon and carbon-heteroatom bonds in one-pot procedure [9–11]. MCRs, particularly those performed in green and eco-friendly media, have become increasingly useful tools for the synthesis of chemically and biologically important compounds because of their environmentally friendly atom economy and green characteristics, and the “greening” of global chemical processes has became a major issue in the chemical industry [12, 13]. Organic reactions in ionic liquid (IL) media have received the considerable attention of synthetic organic chemists in recent years; IL is an environmentally friendly solvent with unique properties such as high ionic conductivity, nonvolatility, high thermal stability, nonflammability, and miscibility with organic compounds, especially with the heterocyclic compounds [14–17]. Because of these useful properties numerous works have been published in the last decades reporting the possibility to perform several organic reactions and catalyzed processes in these green media [18–20]. 1,4-Dihydropyridine compounds are molecules based upon pyridine and this nucleus is one of the significant core structures among the most extensively natural and unnatural heterocyclic compounds, have been recognized as vital drugs for the treatment of cardiovascular diseases, and are well known as calcium channel modulators [21, 22]. 1,4-Dihydropyridine derivatives exhibit a variety of biological properties such as antihypertensive, antianginal [23–25], antitumor [26], anti-inflammatory [27, 28], antitubercular [29], analgesic [30], and antithrombotic [31, 32]. The biological activity of 1,4-dihydropyridine derivatives has led to extensive structural modifications resulting in several clinically useful compounds as a source of valuable drug candidates. Extensive structural modifications have been performed to obtain more potent and less toxic anticancer agents [33–35]. Among these compounds, furo[3,4-b]quinoline1,8(3H,4H)-dione (podophyllotoxin) derivatives, which were reported as powerful DNA topoisomerase inhibitors and inhibit microtubule assembly as an antitumor ligand [36–38], have attracted attention in the recent decade [39–42]. 2 Journal of Chemistry O H2 N O O O Dioxane r.t. + H O N R2 R2 Scheme 1: Synthesis of anilinolactones. With the aim to develop efficient synthetic processes using green and eco-friendly methods and to reduce laborious multistep techniques and minimize by-products, we report herein a novel and clean synthesis of some 4-azapodophyllotoxin derivatives in ionic liquid through a threecomponent condensation reaction of benzaldehydes 1, 1,3cyclohexanediones 2, and anilinolactones 3 in the presence of catalytic amount of alum as catalyst. Table 1: Different polar and nonpolar used solvents, for the synthesis of 4ia under reflux conditions. Entry 1 2 3 4 5 6 7 8 9 10 Solvent MeOH EtOH 1,4-Dioxane DMF Toluene [bmim][triflate] [bmim]OH [bmim]PF6 [bmim]BF4 [bmim]Br Time (min) 120 120 120 120 120 30 30 30 30 30 Yield (%)b 72 75 60 70 65 90 75 88 83 80 a Reaction conditions: 4-bromobenzaldehyde 1d (1 mmol), dimedone 2b (1 mmol), and 4-(4-methylphenylamino)furan-2(3H)-one 3d (1 mmol), pTSA (20 mol%). b Isolated yields. 2. Results and Discussion Table 2: Diverse used catalyst in a model reaction for the synthesis of 4ia in [bmim][triflate]. In this study, firstly, the anilinolactones were prepared from the condensation reaction of tetronic acid with various anilines. As shown in Scheme 1, when tetronic acid reacted with an equimolar amount of various anilines in dioxane solution at room temperature, the corresponding products were obtained in excellent yields, appropriate reaction times, and high purity [43]. In continuation of this research, investigation on the preparation of 4-aza-podophyllotoxin derivatives 4 by using a one-pot three-component condensation reaction of benzaldehydes 1, 1,3-cyclohexanediones 2, and anilinolactones 3 was surveyed (Scheme 2). To achieve suitable conditions for the synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives, the reaction of 4-bromobenzaldehyde 1d, dimedone 2b, and 4(4-methylphenylamino)furan-2(3H)-one 3d was chosen as a model reaction (Scheme 3). This reaction was first performed in various solvents in the presence of a catalytic amount of ptoluene sulfonic acid (p-TSA) as an inexpensive and readily available catalyst at 90∘ C. The results are summarized in Table 1. It was observed that, among all solvents and media, the best result was obtained when 1-butyl-3-methylimidazolium triflate was chosen in the presence of catalytic amount of pTSA at 90∘ C. The desired product was obtained in excellent yield and high purity The catalyst plays a crucial role in the success of the reaction in terms of rate of the reaction and yi (...truncated)