Facile ligand-free Pd-catalyzed tandem C–C/C–N coupling reaction: a novel access to highly diverse tetrazole tag isoindoline derivatives Moni Sharma a , Irfan Khan a , Shahnawaz Khan a , Rohit Mahar b , Sanjeev K. Shukla b , Ruchir Kant c , Prem M. S. Chauhan a,⇑ a Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, U.P., India b Sophisticated Analytical Instrumentation Facility, CSIR-Central Drug Research Institute, Lucknow 226031, India c Molecular and Structural Biology, Central Drug Research Institute, CSIR, Lucknow 226031, India article info Article history: Received 26 May 2015 Revised 4 August 2015 Accepted 5 August 2015 Available online 8 August 2015 Keywords: Isoindolines Tetrazole Pd-catalyzed Isocyanide insertion Ligand-free abstract A novel and robust route for the synthesis of diversely substituted isoindoline skeletons through a ligand- free Pd-catalyzed cascade consisting of isocyanide insertion into Ugi-tetrazole has been developed. The tetrazole precursor is prepared in one step by the Ugi-four component reaction. The reaction proceeds smoothly under mild conditions with high efficiency. This chemistry is simple, economical, and is believed to be the key step during the synthesis of significant pharmaceuticals. Ó 2015 Elsevier Ltd. All rights reserved. Introduction The isoindolines and 1-substituted isoindolin-3-ones nuclei are substructures present in many natural products such as fumaridine and lennoxamine. 1–3 and the core skeleton of some biologically active compounds (Fig. 1). 4 These heterocyclic frameworks have attracted considerable attention in synthetic organic and medicinal chemistry due to their broad structural diversity and broad-spec- trum biological activities, including: Endothelin-A Receptor Antagonists, 5 inhibition of prolyl dipeptidase DPP8, 6 PPARd agonists, 7 histone deacetylase inhibitors, 8 inhibitors of selective serotonin reuptake, 9 diuretic, NMDA receptor antagonists, herbici- dal, 10 anti-inflammatory, and antileukemic agents. 11 Furthermore, isoindolines inhibit the amyloid protein aggregation which demonstrate a potency in the treatment of Alzheimer’s disease, the ligand affinity for the melanocortin subtype-4 receptor (MC4R) (D), act as multidrug resistance reversal agents, and fib- rinogen receptor antagonists. 12,13 On the other side, tetrazole is an extremely valuable scaffolds due to their diverse biological activity. 14 A variety of synthetic procedures have been reported for the preparation of isoindoline core structural skeletons. 15 However, most of them usually require the use of expensive starting materi- als/catalysts or high catalyst loadings, suffer from long reaction time, difficulty in workup, high temperature, and with fewer points of diversity. 16 Hence, the fascinating biological profiles of this group of compounds has spurred organic chemists to devise new, efficient, and straightforward methods for their viable preparation with increased molecular diversity and complexity. Transition metal catalyzed synthesis of substituted isoindoline analogues has received noteworthy attention. 17 In this perspective, palladium catalysis is of undisputed importance in organic synthe- sis for the formation of carbon–carbon and carbon–heteroatom bonds. In the recent past, synthesis of biologically important hete- rocycles by isocyanide insertion under palladium catalysis is an efficient but relatively unexplored method. 18 Due to the presence of a formally divalent carbon atom, iso- cyanides have been recognized as powerful building blocks for constructing functional molecules with increased molecular diver- sity for drug discovery and natural product synthesis. 19 On the other hand, isocyanides serve not simply as a carbon monoxide equivalent but also as a unique C1 source to substitute the well- known CO insertions, such as more practical handling and an extra diversity point for scaffold embellishment. 20 http://dx.doi.org/10.1016/j.tetlet.2015.08.008 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +91 522 2771940, +91 522 2771942; fax: +91 522 2771941. E-mail addresses: prem_chauhan_2000@yahoo.com, premsc58@hotmail.com (P.M.S. Chauhan). Tetrahedron Letters 56 (2015) 5401–5408 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet