TETRAHEDRON LETTERS Tetrahedron Letters 43 (2002) 7201–7203 Pergamon Solid phase-mediated synthesis of isonitriles Delphine Launay, a Susan Booth, b Ian Clemens, c Andrew Merritt d and Mark Bradley a, * a Combinatorial Centre of Excellence, Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK b Organon, Newhouse, Lanarkshire, Scotland, UK c Eli Lilly & Co., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK d GSK, Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage SG12NY, UK Received 12 February 2002; revised 2 August 2002; accepted 9 August 2002 Abstract—Supported sulfonyl chlorides and microwave irradiation are an efficient combination for isonitrile synthesis. © 2002 Elsevier Science Ltd. All rights reserved. Multi-component reactions (MCRs) have become an important constituent of the combinatorial chemist’s arsenal, allowing large numbers of compounds to be produced in a rapid parallel synthesis programme. Thus, the Passerini 1 and Ugi 2 reactions, to name but two, have become well established in library synthesis programmes (Scheme 1). 3 One of the most important components of these reac- tions, and one that is very limited in accessibility, is the isonitrile. Isonitriles are especially important due to their unusual bifunctional reactivity, acting as both a nucleophile and an electrophile during the reaction. There are numerous methods reported for isonitrile synthesis, 4 however, during the synthesis of a series of isonitrile tags we became aware of the limited utility and applicability of many current methods. Eventually the synthetically most useful conditions, the treatment of formamides with p -toluene sulfonyl chloride, were identified 5 and this led to the synthesis of a number of isonitriles in reasonable yield and purity (Scheme 2). Scheme 2. Solution synthesis of isonitiriles. Work-up and purification of this reaction was problem- atic due to the reactivity of the isonitriles. The use of a polymer supported sulfonyl chloride therefore appeared to offer a fast and efficient method of isonitrile genera- tion, with just a simple filtration and acidic work-up (to remove the pyridine) being involved. A number of reactions were therefore investigated using a range of formamides, as shown in Table 1 and Scheme 3. Scheme 1. (a) Passerini and (b) Ugi reaction. * Corresponding author. 0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(02)01672-6