An efficient synthesis of polymer-supported silyl linkers using a di-Grignard reagent Takayuki Doi, Masahito Yoshida, Ichiro Hijikuro and Takashi Takahashi * Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro, Tokyo 152-8552, Japan Received 31 March 2004; revised 13 May 2004; accepted 17 May 2004 Abstract—Various trialkylsilyl linked polymer supports have been prepared by reacting benzyl chloride resin and a di-Grignard reagent with CuBr®Me 2 S, followed by dialkylchlorosilanes. 4-Alkoxybenzyl type resin, Wang-Cl 2c and Argogel Wang-Cl 2d provided 4c and 4d at ambient temperature, whereas nonactivated resin, Merrifield 2a and Argogel-Cl 2b afforded 4a and 4b at 60 °C. Primary and secondary alcohols 6–10 were attached to the alkyldiisopropyl-linked Wang type resin 4cA by a novel dehydrosilation with B(C 6 F 5 ) 3 as well as by conventional methods. Ó 2004 Elsevier Ltd. All rights reserved. Solid-phase synthesis has recently been studied not only in the field of peptides and nucleotides but also for the combinatorial synthesis of small organic molecules. 1 Linkers that join synthetic compounds to the polymer support are particularly important for solid-phase syn- thesis 2 and their stability should be well tuned, as the linker has to be fully stable during all the reaction processes but should be removed without decomposition of the final products. Trialkylsilyl linkers are very useful in solid-phase synthesis. They can support alcohols, enolates, and aryl functionality, and their cleavage conditions are tunable by different alkyl substituents. 3–12 We have already reported on polymer-supported gly- cosylation 13 and the efficient solid-phase synthesis of libraries of enediyne–oligosaccharide hybrid com- pounds 14 and activated vitamin D 3 analogues 15 utilizing an alkyldiethylsilyl linker. 3 Depending on the sensitivi- ties of polymer-supported compounds, the best combi- nation should be selected between the linkers and the reaction conditions, that is, attachment of starting compound, diversity of the solid-phase reactions, and cleavage from the polymer support. To make this strategy successful, we require a range of silyl linkers on the appropriate polymer support. Here we wish to report an efficient synthesis of a variety of trialkylsilyl linkers on various polymer supports using sequential coupling of a di-Grignard reagent. In order to introduce a variety of silyl linkers onto solid supports, we planned to utilize the di-Grignard reagent 1 as an alkyl spacer to connect the linkers to the polymer support as illustrated in Scheme 1. Since the X Si X = CH 2 or O R = i-Pr or Ph H R R X Cl step 1 Cu I -catalyzed alkylation BrMg MgBr step 2 Nucleophilic substitution 1 2a X = CH 2 , Merrifield resin 2b X = CH 2 , Argogel -Cl 2c X = O, Wang-Cl 2d X = O, Argogel Wang-Cl 3A R = i-Pr 3B R = Ph 4 Si R R Cl H Table 1 Scheme 1. Sequential coupling of di-Grignard reagent 1 to polymer-supported benzyl chlorides 2 and dialkylchlorosilanes 3. * Corresponding author. Tel.: +81-3-5734-2120; fax: +81-3-5734-2884; e-mail: ttak@apc.tiitech.ac.jp 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.05.100 Tetrahedron Letters 45 (2004) 5723–5726 Tetrahedron Letters