Sequential Ugi/Strecker reactions via microwave assisted organic synthesis: novel 3-center-4-component and 3-center-5-component multi-component reactions Thierry Masquelin, a Hai Bui, b Bob Brickley, b Gregory Stephenson, c John Schwerkoske d and Christopher Hulme a, * a High-Throughput Medicinal Chemistry, Eli Lilly and Company, Indianapolis, IN 46285, USA b Analytical Technologies, Discovery Chemistry and Research Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA c X-ray Crystallography, Eli Lilly and Company, Indianapolis, IN 46285, USA d The Lilly Summer Intern Program Received 19 December 2005; revised 31 January 2006; accepted 31 January 2006 Available online 10 March 2006 Abstract—Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[1,2-a]pyridines and imidazo[1,2- a]pyridyn-3-ylamino-2-acetonitriles are reported. Reactions are performed under microwave condition in methanol by simply mixing a-amino-pyridines, aldehydes, and trimethylsilylcyanide (TMSCN) with distinct reagent stoichiometries, catalyzed by poly- mer-bound scandium triflate, to afford either product. Furthermore, functionally different aldehydes were shown to proceed to different end-points, adding an extra caveat to the studies. The new methodology represents examples of both formal 3-center-4- component and 3-center-5-component multi-component reactions. Ó 2006 Elsevier Ltd. All rights reserved. The Strecker reaction was initially reported in 1850 and enables the oldest known synthesis of a-amino acids. 1 In its classical form the reaction consists of a condensation of an aldehyde, cyanide source, and ammonia. Hydro- lysis of the newly formed a-amino nitrile then gives the desired a-amino acid. 2 As such, considerable effort has been applied into developing asymmetric processes for the production of both natural and unnatural amino acids for use as key building blocks in the pharmaceuti- cal industry. 3 Today, 150 years after the discovery of this early multi-component reaction (MCR), interest in the field is high, having been re-invigorated with the emergence of high-speed parallel synthesis, high- throughput screening, and the need for novel highly tractable chemical starting points in drug discovery. In fact, a plethora of multi-component reactions (MCR) are now widely employed for the rapid assembly of ar- rays with high-molecular diversity. 4 Digging deeper into this field of study, IMCRs (I = isonitrile) are a powerful subset of these reactions. One example, reported by three independent groups, involves the production of widely available 3-imidazo[1,2-a]pyridines in an acid catalyzed condensation involving a-aminopyridines, 1, aldehydes, and isonitriles. 5 Interestingly, this laboratory has recently reported that the isonitrile can be replaced by a traditional cyanide source, namely TMSCN, to afford 3-aminoimidazo[1,2-a]pyridines, 2, in only one step. 6 The new procedure has the benefit of avoiding established protocols, where pungent isonitriles with removable side chains are required to access this chemo- type in two steps. 7 The mechanism of the condensation is highly analogous to the classical Strecker and Ugi reactions and represents a novel 3-center 3-component MCR. Further studies with TMSCN as a classical iso- nitrile replacement gave rise to the results described herein. Thus, this letter reports two novel one-pot microwave mediated extensions of this reaction, enabling both the selective formation of 3-iminoaryl- imidazo[1,2-a]pyridines 3 and imidazo[1,2-a]pyridyn-3- ylamino-2-acetonitriles 4, in good yield. Both conver- sions represent non-isocyanide based MCRs, mediated by careful adjustment of reagent stoichiometry. The reaction pathway detailing the formation of the three sequential products, 2, 3, 4, is shown in Scheme 1 and 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.01.160 * Corresponding author. E-mail: hulme_christopher@lilly.com Tetrahedron Letters 47 (2006) 2989–2991