Microwave-assisted iridium-catalyzed [2+2+2] cycloaddition of resin-bound dipropargylamine with alkynes Muthian Shanmugasundaram, Ana Luisa Aguirre, Melissa Leyva, Beili Quan and Luis E. Martinez * Department of Chemistry, University of Texas at El Paso, 500 West University Ave., El Paso, TX 79968, United States Received 12 January 2007; revised 10 August 2007; accepted 20 August 2007 Available online 24 August 2007 Abstract—The [Ir(COD)Cl] 2 /dppe system effectively catalyzes the solid-phase [2+2+2] cycloaddition of resin-bound dipropargyl- amine with alkynes under microwave conditions. The reaction results in high purity of isoindoline derivatives with moderate yields. Ó 2007 Elsevier Ltd. All rights reserved. Transition metal-mediated [2+2+2] alkyne cyclotrimer- ization is a powerful and atom efficient strategy for the convergent synthesis of polysubstituted benzene deriva- tives. 1 In most cases however, it has been difficult to control the regioselectivity of the intermolecular [2+2+2] cycloaddition and as well as eliminate unwanted oligomeric or self-trimerized products through competing alkyne cycloadditions. A partially intermolecular [2+2+2] alkyne cyclotrimerization is usually utilized to control the selectivity pattern around the arene ring, 2 however; control of both the dimeriz- ation and trimerization of diynes and the trimerization of alkynes remains a challenging issue in this chemistry. As an approach for eliminating the formation of self- dimerization and trimerization of diynes, we envisaged that the immobilization of diynes could potentially sup- press these side reactions due to the partial site isolation imposed by covalent attachment to the polymer- support. 3 As part of our continuous interest in microwave-assisted carbocyclizations on solid-support, 4 we were prompted to explore the solid-phase combinatorial synthesis of iso- indolines through transition metal-catalyzed [2+2+2] cycloaddition where these competitive pathways could be suppressed by immobilization on solid-support. The isoindoline ring system forms a fundamental part of numerous natural products 5 and represents an under- developed area of validated chemical diversity space in which to explore their chemical biology. Structures incorporating this moiety show a wide range of biolo- gical properties including platelet aggregation inhibitors and antitumor agents. 6 While the solution-phase synthe- sis of isoindolines have been described, 7 only a couple of examples using solid-phase synthesis via a rhodium-cat- alyzed [2+2+2] cycloaddition have been reported. 8 Both of these recently reported solid-supported synthesis suffer from long reaction times (12–48 h) and in particular, isolation of the HCl salt of isoindolines. 8b The salt form of isoindolines may be a disadvantage when considering compound stability in the long term storage of screening collections 9 or potentially undesirable for biological screening when salts can cause problems with an assay. Herein, we report the first example of the microwave- assisted iridium-catalyzed solid-phase [2+2+2] cyclo- addition of resin-bound dipropargylamine with various alkynes, providing an efficient method for the synthesis of salt free isoindoline derivatives in moderate yields. The required resin-bound dipropargylamine 3 for the cycloaddition was prepared by the reaction of trityl chloride resin 1 (Advanced Chem. Tech, 1% cross linked 1.5 mmol/g) with dipropargyl amine (2) using DIEA as the base (Scheme 1). The loading of the reaction was found to be quantitative as evidenced by the nitrogen content present in 3. 10 The IR spectrum of 3 shows characteristic signal at 3301 and 2120 cm À1 due to the presence of alkyne moiety. Treatment of 3 with 4a in the presence of [Ir(COD)Cl] 2 catalyst and THF as the solvent under microwave 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.08.073 Keywords: Solid-phase synthesis; Microwave; Cycloaddition; Isoindolines. * Corresponding author. Tel.: +1 915 747 5944; fax: +1 915 747 5748; e-mail: luisem@utep.edu Tetrahedron Letters 48 (2007) 7698–7701