Synthesis of functionalized heterocycles via a tandem Staudinger/aza-Wittig/Ugi multicomponent reaction Mattie S. M. Timmer, Martijn D. P. Risseeuw, Martijn Verdoes, Dmitri V. Filippov, Jasper R. Plaisier, Gijsbert A. van der Marel, Herman S. Overkleeft * and Jacques H. van Boom * ,z Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands Received 28 October 2004; accepted 29 November 2004 Available online 5 January 2005 With deep sadness the authors inform the reader that our colleague, Jacques van Boom, died on July 31st, at the age of 67 Abstract—By combining a Staudinger/aza-Wittig and an Ugi three-component reaction in a one-pot process (SAWU-3CR), a new and efficient multicomponent reaction was developed. The application of this reaction on readily available azido-aldehydes gave easy access to highly functionalized, enantiomerically pure pipecolic acid amides and bridged morpholine amide derivatives. The versatility of this methodology is demonstrated by the construction of a molecular library. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Multicomponent reactions (MCRs), processes in which three or more reactants are combined in one reaction vessel resulting in the formation of products featuring characteristicsofallreactants,havefoundwideapplica- tion in the synthesis of many structurally diverse mole- cules. 1 In 1959, Ugi et al. reported 2 the one-pot condensationofanaldehyde I,anamine II,acarboxylic acid IV and an isocyanide V (Scheme 1). This reaction, now referred to as the Ugi 4-component reaction (Ugi- 4CR), provides an efficient entry to the construction of functionalized acylamidoacetamides VI.Inthefirststep of the Ugi-4CR, aldehyde I is condensed with amine II to produce an intermediate imine III that further reacts with the isocyanide and carboxylic acid entities to the bisamide end product. It occurred to us that the generation of the bis-substi- tuted imine III, which plays a pivotal role in the Ugi-4CR process, could be accomplished by executing a tandem Staudinger/aza-Wittig event. 3 Thus, reaction oftheazide VII with trialkyl(aryl)phosphine would lead to the formation of the intermediate phosphazene VIII which, in turn, undergoes an aza-Wittig reaction with the aldehyde I toproducetheimine III andtheinerttri- alkyl(aryl)phosphineoxide.Anattractiveandimportant aspect of performing a tandem Staudinger/aza-Wittig sequence is depicted in Scheme 2. It can be seen that a substrate containing both an azide and an aldehyde, as well as functional groups (R) will give access to a substituted cyclic imine, thus opening the way to the 0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2004.11.079 * Corresponding authors. Tel.: +31 71 5274342; fax: +31 71 5274307; e-mail: h.s.overkleeft@chem.leidenuniv.nl z Deceased. N R 1 P R R R N 3 R 1 R 2 O H 2 N R 1 N R 2 R 1 IV R 3 OH O R 4 NC O R 2 R 3 P I II III V VIII VII I R 3 P=O VI N R 2 R 1 R 3 O H N O R 4 + Ugi Staudinger Aza-Wittig Scheme 1. Ugi four component and Staudinger/aza-Wittig reactions. Tetrahedron: Asymmetry 16 (2005) 177–185 Tetrahedron: Asymmetry