Multicomponent reactions - Zhu.pdf - Index of

2
Post-condensation Modifications
of the Passerini and Ugi Reactions
Stefano Marcaccini and Tomás Torroba
Multicomponent reactions of isocyanides (I-MCRs) are extremely powerful synthetic
tools for the preparation of structurally diverse complex molecules [1] as
well as combinatorial libraries of compounds [2]. The enormous synthetic possibilities
of I-MCRs can be further increased by post-condensation transformations.
These modifications are usually accomplished by employing suitable functionalized
and/or protected reagents and take place spontaneously or upon treatment
with additional reagents. The design of cleavable reagents is therefore an important
goal for I-MCR post-condensation reactions. The use of protected reagents
such as acetals, N-Boc, N-Fmoc amino derivatives, etc. is well known [3]. A survey
of cleavable reagents in I-MCRs has been published [4]. In this chapter the use of
cleavable reagents will be discussed, convertible isocyanides will be introduced in a
special section and a general approach to post-condensation reactions of the classical
Passerini and Ugi reactions in syntheses of open-chain and heterocyclic products
will be summarized.
2.1
Convertible Isocyanides
1-Cyclohexen-1-yl isocyanide 1 known as ‘‘Armstrong convertible isocyanide’’ has
also been called ‘‘universal isocyanide’’. It was prepared in 1963 by Ugi and Rosendahl
[5] to be used as a synthetic equivalent of the unknown ‘‘hydrogen isocyanide’’.
The Ugi-4CR between 1, cyclohexanone N-benzylimine 2, and formic acid
afforded N-cyclohexen-1-yl amide 3, which was cleaved in acidic medium to afford
the primary a-acylamino amide 4 rather than the N-substituted amides usually obtained
by the Ugi-4CR (Scheme 2.1).
After the first report this isocyanide was not followed up until the studies of
Armstrong and co-workers, which signaled the renaissance of 1-cyclohexen-1-yl
isocyanide for synthetic purposes. Effectively, the Ugi-4CR adducts 5 obtained
from 1 can be cleaved into the corresponding acids, esters, and thioesters 6 upon
treatment with acids, alcoholic HCl, and thiols, respectively (Scheme 2.2) [6].
Multicomponent Reactions. Edited by Jieping Zhu, Hugues Bienaymé
Copyright 8 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30806-7
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