SCHEME 1. Different Mechanisms of the Ugi Reaction with
a Secondary Amine
Synthesis of Passerini-Ugi Hybrids by a
Four-Component Reaction Using the
Glycolaldehyde Dimer
Riccardo Mossetti, Tracey Pirali, and Gian Cesare Tron*
Dipartimento di Scienze Chimiche, Alimentari,
Farmaceutiche e Farmacologiche and Drug and Food
Biotechnology Center, UniVersita` degli Studi del Piemonte
Orientale “A. AVogadro”, Via BoVio 6, 28100 NoVara, Italy
ReceiVed March 20, 2009
molecule is effective in generating a new multicomponent
reaction where the classical Ugi scaffold was split,7 as the use
of a secondary amine in the Ugi reaction can give origin to a
different mechanisms of reaction. Indeed, after the formation
of the iminium ion and the isocyanide and carboxylic acid attack,
the imino anhydride intermediate generated (1) can no longer
undergo the Mumm rearrangement, as meanwhile the nitrogen
atom has become a tertiary amine.8 The intermediate can now
undergo different synthetic fates: (a) being attacked by acyl
acceptors in the presence of nucleophilic solvents (e.g., metha-
nol)9 to give an R-amino amide, (b) being attacked by the
isocyanide nitrogen atom in presence of non-nucleopilic solvents
to give the acylating agent R-amino imide,9,10 or (c) being
intramolecularly intercepted by another secondary nitrogen atom
to give the new scaffold 27a (Scheme 1).
Searching for new MCRs using this strategy, we planned to
generate a novel skeleton that could formally be viewed as a
hybrid between Ugi and Passerini products.11 To achieve this
task, we thought that the imino anhydride intermediate could
also be intercepted by nucleophiles other than the nitrogen atom
and reasoned that the incorporation of a hydroxyl group in the
aldehyde component, using the commercially available glyco-
laldehyde dimer and the presence of a secondary amine, could
give rise to an O-acyl Mumm rearrangement, typical of the
Passerini reaction, with the formation of a new molecular
Passerini-Ugi hybrid adducts can be obtained through a
four-component reaction by using glycolaldehyde dimer.
Over the past decades, multicomponent reactions (MCRs)
have demonstrated their ability and efficiency in the generation
of chemical diversity.1 For this reason, MCRs are featured in
many diversity-oriented projects, whose biological relevance has
been validated by the discovery of novel biological probes and
drug leads.2 The Ugi four-component reaction3 and the Passerini
three-component reaction4 are the two most important and used
isocyanide-mediated MCRs.5
To broaden their potentiality, both intramolecular variations,
where two of the four functional groups belong to the same
molecule, and post-transformation strategies have been per-
formed, giving easy access to a vast array of heterocycles.6
However, a limitation of these reactions lies in the fact that in
all of the final adducts the obtainable molecular skeletons always
follow the same connectivity, namely, NCCNC and NCCOC
for Ugi and Passerini products, respectively. Recently, we tried
to modify the scaffold extension of the Ugi reaction and reported
that the combination of two secondary amines in the same
(7) (a) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I. G.; Pirali,
T. Angew. Chem., Int. Ed. 2006, 45, 1099–1102. For recent applications of the
N-split Ugi reaction see:(b) Pirali, T.; Callipari, G.; Ercolano, E.; Genazzani,
A. A.; Giovenzana, G. B.; Tron, G. C. Org. Lett. 2008, 10, 4199–4202. (c)
Piersanti, G.; Remi, F.; Fusi, V.; Formica, M.; Giorgi, L.; Zappia, G. Org. Lett.
2009, 11, 417–420.
(1) Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH:
Weinheim, 2005 and references therein.
(8) McFarland, J. W. J. Org. Chem. 1963, 28, 2179–2181.
(2) (a) Weber, L. Curr. Med. Chem. 2002, 9, 1241–1253. (b) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51–80. (c) Akritopoulou-Zanze, I. Curr.
Opin. Chem. Biol. 2008, 12, 324–331.
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbru¨ckner, C. Angew. Chem. 1959,
71, 386–388. (b) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632–639.
(4) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126–129. (b) Riva, R.; Banfi,
L. Org. React. 2005, 65, 1–140.
(5) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(6) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(b) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–147.
(9) Ugi, I.; Steinbru¨ckner, C. Ber. Dtsch. Chem. Ges. 1961, 94, 2802–2814.
(10) (a) Mumm, O. Ber. Dtsch. Chem. Ges. 1910, 43, 886–893. A similar
mechanism has been proposed by Danishefsky et al. in the reaction between
isocyanides and carboxylic acids: (b) Li, X.; Danishefsky, S. J. Am. Chem. Soc.
2008, 130, 5446–5448. (c) Jones, G. O.; Li, X.; Hayden, A. E.; Houk, K. N.;
Danishefsky, S. J Org. Lett. 2008, 10, 4093–4096.
(11) For the synthesis of N-acyloxyethylamino acid amides obtained by
reacting N-alkyloxazolidines, isocyanides, and carboxylic acids, see: Diorazio,
L. J.; Motherwell, W. B.; Sheppard, T. D.; Waller, R. W. Synlett 2006, 14, 2281–
2283.
4890 J. Org. Chem. 2009, 74, 4890–4892
10.1021/jo9005969 CCC: $40.75 2009 American Chemical Society
Published on Web 05/18/2009