Synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the one-pot reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate Maryam Sadat Hosseini-Zare a , Mohammad Mahdavi b , Mina Saeedi b , Mehdi Asadi b , Shahrzad Javanshir a , Abbas Shafiee b , Alireza Foroumadi b,⇑ a Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran b Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences, Tehran 14176, Iran article info Article history: Received 3 March 2012 Revised 30 March 2012 Accepted 19 April 2012 Available online 26 April 2012 Keywords: Imidazo[2,1-a]isoindol-5-one 1,2-Diketones Ammonium acetate abstract We describe a new one-pot synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate in acetic acid under reflux conditions and in the absence of a catalyst. Ó 2012 Elsevier Ltd. All rights reserved. The synthesis of benzimidazole-based heterocycles has attracted growing interest owing to their important biological activities. 1–3 2- Substituted 4,5-diaryl-1H-imidazoles have been identified as COX-2 inhibitors 4 and as human cannabinoid-1 (CB1) receptor inverse ago- nists. 5 Moreover, fused imidazoles have exhibited interesting bio- logical properties. 6 5H-Imidazo[2,1-a]isoindol-5-one derivatives have also been applied as biologically active agents. For example, 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones (Fig. 1) pos- sess anti-inflammatory, analgesic, antihypertensive, spasmolytic, tranquilizing, and antitussive properties, 7 and are also useful seda- tive and hypotensive agents. 8 Thus improvements in the synthesis of imidazoles, including the preparation of new 5H-imidazo[2,1-a]isoindol-5-one derivatives are very important in the context of medicinal chemistry. There are a number of useful routes for the synthesis of imidazo[2,1-a]iso- indol-5-one derivatives. Katritzky et al. 9 reported the synthesis of chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5- ones via condensation of 2-formylbenzoic acids or 2-acetylbenzoic acid with chiral diamines. The synthesis of 5H-imidazo[2,1-a] isoindol-5-ones by reaction of o-benzoylbenzoic acids and ethylenediamine has also been reported. 10,11 Focusing on the imidazo[2,1-a]isoindolone skeleton, Gomes et al. 12 synthesized various 1H-imidazo[2,1-a]isoindol-2,5(3H,9bH)-diones by the reac- tion of N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-2-amin- oalkylamide derivatives and formylbenzoic acid. Their products were found to exhibit anti-malarial activity. In continuation of our research on the synthesis of biologically active heterocycles, 13–16 and due to the fact that reports on the syn- thesis of 5H-imidazo[2,1-a]isoindol-5-ones are infrequent, herein, we present a new, reliable, and efficient synthetic route for the syn- thesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-one derivatives 4 in the absence of a catalyst (Scheme 1). The products were obtained by the condensation reaction between 1,2-diketones 1, 2-formyl- benzoic acids 2, and ammonium acetate (NH 4 OAc) (3) in acetic acid under reflux conditions. It is worthwhile to mention that there are reports on the synthesis of 2,4,5-triaryl-1H-imidazoles 6 using 1,2-diketones 1, aromatic aldehydes 5, and ammonium acetate 3 under various conditions (Scheme 2). 17–20 Our results revealed that replacing the aldehyde with a 2-formyl- benzoic acid can lead directly to the formation of the imidazo[2,1-a] isoindol-5-one nucleus which undergoes further cyclization to give 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-one derivatives 4. N N O R 1 R 2 R 3 R 4 Figure 1. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-one derivatives. 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.04.088 ⇑ Corresponding author. Tel.: +98 21 66954708; fax: +98 21 66461178. E-mail address: aforoumadi@yahoo.com (A. Foroumadi). Tetrahedron Letters 53 (2012) 3448–3451 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet