Green Chemistry COMMUNICATION Cite this: DOI: 10.1039/c3gc42130a Received 14th October 2013, Accepted 5th December 2013 DOI: 10.1039/c3gc42130a www.rsc.org/greenchem A facile protocol for the synthesis of 3-aminoimidazo-fused heterocycles via the Groebke–Blackburn–Bienayme reaction under catalyst-free and solvent-free conditions† Shinde Vidyacharan, Anand H. Shinde, Bishnupada Satpathi and Duddu S. Sharada* A one-pot catalyst, solvent, work-up and column free synthesis of 3-aminoimidazo-fused heterocycles by a three-component reaction of a 2-aminoheterocycle, aldehyde, and isocyanide is presented. This efficient and green protocol has the advantages of environmental friendliness, high yields and operational simplicity. Introduction Synthetic organic chemistry has a vast scope in various areas like pharmaceuticals, industry and academia. Sustainability has become one of the greatest scientific challenges nowadays, due to environmental, health and societal concerns. Thus, there is a need for developing facile, efficient, and non-pollut- ing synthetic procedures that reduce the use of organic sol- vents and toxic reagents. One such approach, which involves green and sustainable chemistry, 1 drives towards pollution pre- vention and environmental protection, and is now gaining importance. It mainly involves designing chemical products and processes that reduce or eliminate the use of hazardous substances, volatile organic compounds, generation of waste materials, by-product formation and unnecessary derivatiza- tion (like blocking, protecting/deprotecting) etc. 2 Multicomponent reactions (MCRs) 3 provide diverse and highly functionalized molecules via the formation of multiple bonds 4 in a one-pot operation, without isolating the intermedi- ates or changing the reaction conditions. It involves the use of three or more different starting materials to get a complex product 5 which has incorporated in it most, if not all, of the starting materials. MCRs comply with the principles of green chemistry and as a consequence of which, they have emerged as a significant tool in organic synthesis. 6 One of the strategies widely implemented is the development of alternative sustainable routes, among which catalyst-free and solvent-free reactions (CFR & SFR) 7 have gained importance recently. These approaches have several advantages over the conventional organic synthetic methods, like (a) reduced pollutant production, (b) reduced use or elimination of toxic and hazardous chemicals, (c) operational simplicity, (d) reduced reaction time (under SFR), (e) formation of pure products which avoids tedious purifi- cations, (f ) high yields, (g) reduced cost and many more. 7a,8 Among the nitrogen derivatives, imidazo-fused heterocycles are becoming more important in medicinal and organic chem- istry, as they exhibit a broad spectrum of pharmacological and biological activities, such as antiviral, antibacterial, fungicidal, and anti-inflammatory properties. 9 The significance of imidazopyridine scaffolds in the drug discovery sector is well appreciated because of the appealing benefits they offer. Many commercially available drugs featuring this scaffold have been developed, for example an anxiolytic drug (alpidem), 10 a hyp- notic drug (zolapidem), 11 an anti-ulcer drug (zolimidine), 12 a PDE 3 inhibitor (olprinone), 13 sedative agents (saripidem & necopidem), 14 and an optically active drug (GSK812397) which is a prospect for the treatment of HIV infection 9 (Fig. 1). Due to the high biological activity of 3-aminoimidazo-fused heterocyclic derivatives, several isocyanide based three com- ponent reactions have been reported in past decades, such as the condensation of 2-aminoazine, aldehydes and isocyanides in the presence of Bronsted acids like AcOH, 15 HClO 4 , 16 cellu- lose sulfuric acid, 17 p-toluene sulfonic acid, 18 and Lewis acids like Sc(OTf) 3 , 19 MgCl 2 , 20 SnCl 2 , 21 ZrCl 4 , 22 ZnCl 2 23 and recently reported RuCl 3 . 24 Nevertheless, many of these methods suffer from drawbacks such as long reaction time, requirement for an inert atmosphere, low yield, tedious work-up leading to the generation of large amounts of toxic metal-containing waste, and the use of stoichiometric or relatively expensive reagents. In order to overcome some of these drawbacks a few mild catalytic and solid supported protocols such as the use of γ-Fe 2 O 3 @SiO 2 -OSO 3 H nanoparticles, 25 montmorillonite K10 (microwave) 26 and resin supported reactions have been reported. They too have certain disadvantages, and even though several methods are available for making † Electronic supplementary information (ESI) available. See DOI: 10.1039/c3gc42130a Department of Chemistry, Indian Institute of Technology, Ordinance Factory Estate, Yeddumailaram-502205, Medak District, Hyderabad, Andhra Pradesh, India. E-mail: sharada@iith.ac.in This journal is © The Royal Society of Chemistry 2014 Green Chem. Published on 05 December 2013. Downloaded by Indian Institute of Technology Hyderabad on 24/02/2014 06:27:53. View Article Online View Journal