Facile synthesis of diverse isoindolinone derivatives via Ugi-4CR followed by Cu-catalyzed deamidative C(sp 2 )–C(sp 3 ) coupling Vikas Tyagi, Shahnawaz Khan, Prem M. S. Chauhan ⇑ Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, India article info Article history: Received 9 November 2012 Revised 18 December 2012 Accepted 22 December 2012 Available online 29 December 2012 Keywords: Multicomponent reactions Copper catalysis Isoindolenone Ugi reaction C–C coupling abstract The present work highlights a synthetic approach to the diverse isoindolinone derivatives using Ugi-4CR followed by a Cu-catalyzed deamidative C–C coupling reaction. This two-step sequence tolerates a broad range of amines, aldehydes, and isocyanides as starting mate- rials for Ugi-4CR products to provide medicinally relevant isoindolinone derivatives in moderate to good yields. Ó 2013 Elsevier Ltd. All rights reserved. Isoindolinone derivatives are valuable building blocks for the synthesis of various drugs and natural products and are of signifi- cant interest due to their broad range of biological activities such as antihypertensive, antipsychotic, antiinflammatory, anesthetic, and antiulcer activities. 1 Additionally, the substituted isoindoli- none scaffold is also found in a great variety of natural products and biologically active compounds such as isoindolobenzazepine alkaloid lennoxamine (1), antiproliferative agent (2), anxiolytic drug pagoclone (3), and a potent dopamine D4 ligand (S)- PD172938 (4)(Fig. 1). 2 In fact, several common methods are available for the synthesis of isoindolinone derivatives, but most of these traditional ap- proaches suffer from low yields and/or poorly accessible precur- sors and take place under harsh reaction conditions. 3 In view of their broad range of biological activities, isoindolinone derivatives are an attractive synthetic target and a concise method involving commercially available and cheap starting materials is still re- quired for their practical synthesis. In this context, numerous transition metal catalyzed protocols for the synthesis of substituted isoindolinone derivatives have re- ceived considerable attention. 4 Thus, Zhu et al. reported the syn- thesis of isoindolinone via Rh catalyzed C–H olefination of N- benzoylsulfonamides with internal alkenes, Massa and co-workers reported the first organocatalytic asymmetric synthesis of 3- substituted isoindolinone and Gu and co-workers reported the synthesis of N-substituted isoindolinone using Pt nanowires as catalyst. 5 In the recent past, isocyanide-based multicomponent reactions (IMCRs) followed by other synthetic transformations have emerged as an approach to introduce a large degree of diversity into final heterocyclic scaffolds in an atom economical fashion. 6 For example, Andreana and co-workers reported the synthesis of spiro-2,5-diketopiperazines via a cascade Ugi/6-exo-trig Aza-Mi- chael reaction, Riva et al. described the synthesis of tricyclic N-het- erocycles using an Ugi reaction with a tandem S N 2-Heck double cyclization reaction and Hulme’s group developed a strategy for 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.12.091 ⇑ Corresponding author. Tel.: +91 522 2262411x4470; fax: +91 522 2623405. E-mail addresses: premsc58@hotmail.com, prem_chauhan_2000@yahoo.com (P.M.S. Chauhan). N O O Me Me N N Cl NH O N N Me Me N O MeO OMe O O N HN N Cl O 1 2 3 4 Figure 1. Biologically active compounds containing the isoindolinone scaffold. Tetrahedron Letters 54 (2013) 1279–1284 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet