Communications
DOI: 10.1002/anie.200902683
Multicomponent Reactions
The Efficient One-Pot Reaction of up to Eight Components by the
Union of Multicomponent Reactions**
Niels Elders, Dion van der Born, Loes J. D. Hendrickx, Brian J. J. Timmer, Alrik Krause,
Elwin Janssen, Frans J. J. de Kanter, Eelco Ruijter, and Romano V. A. Orru*
The development of synthetic methods has advanced enor-
mously in the past decades. At present, chemists can design
and prepare almost any type of molecule. The typical
approach for the synthesis of (complex) molecules with pre-
defined properties is, however, still characterized by rather
inefficient step-by-step reaction sequences. The greatest
challenge for synthetic chemists is therefore the improvement
of overall efficiency by using atom-, step-, and energy-
economic procedures that proceed with high yield and
selectivity.[1,2] This goal can be achieved by focusing on
bond construction and functional-group compatibility in the
development of new reaction types. Multicomponent reac-
tions (MCRs)[3] are important tools for the accomplishment of
this goal as they inherently involve the formation of several
bonds in one operation. As such, MCRs are convergent step-
efficient procedures that can take place with remarkably high
atom economy[1a] and E factors,[2] by reducing the number of
functional-group manipulations and thus avoiding the use of
protecting groups.
Synthetic efficiency can be further improved by combin-
ing more than one MCR. Central to this concept of the union
of MCRs[4,5] is the orthogonal reactivity of functional groups,
which can be combined in one molecule to allow the union of
different reactions if their reactivity is fully independent
(orthogonal). Such strategies avoid the use of protective
groups and increase efficiency in organic synthesis.
The most straightforward approach to such combinations
is the incorporation of a functional group in one of the inputs
of the primary MCR that does not participate in the reaction,
but does react as one of the components in a secondary MCR
(Figure 1). In an ideal case, both reactions are combined in
one pot to create a higher-order MCR. Although there are
several reports of combinations of MCRs in the literature, the
true one-pot combination (union of MCRs[4] first introduced
by the research group of Ugi[5]) is generally not possible
Figure 1. Combination (or union) of MCRs.
because: 1) the experimental procedure limits the scope in
substrate inputs, 2) additional (de)protection steps are
required, and 3) solvent incompatibilities mean that the
solvent must be changed between subsequent reaction steps.
Consequently, one-pot sequences of MCRs have remained
limited to isolated examples by Ugi and co-workers,[5,6]
Portlock and co-workers,[7] and our research group.[8]
We report herein a novel approach that combines two or
more MCRs in one pot to achieve higher-order MCRs with
unprecedented possibilities for complexity generation and
diversification. Our strategy is based on two recently reported
MCRs that display extraordinary functional-group and sol-
vent compatibilities and lead to 2H-2-imidazolines[9] and N-
(cyanomethyl)amides,[10] respectively.
In an initial approach, we focused on the introduction of a
carboxylic acid function in the 2H-2-imidazoline produced by
the primary MCR using an amino acid as one of the starting
materials. Thus, reaction of isocyanide 1, acetone, and sodium
glycinate (2)[11] led to a clean conversion to form intermediate
A (Scheme 1). After protonation of the intermediate carbox-
ylate A (methanolic HCl, one equivalent), a one-pot combi-
nation with iPrCHO, n-propylamine, and tBuNC in an Ugi
4CR[3g] led to the isolation of 3a in 38% yield. The yield could
be improved to 62% by using benzylamine instead of n-
propylamine, which is excellent when considering the number
[*] N. Elders, D. van der Born, L. J. D. Hendrickx, B. J. J. Timmer,
A. Krause, E. Janssen, Dr. F. J. J. de Kanter, Dr. E. Ruijter,
Prof. Dr. R. V. A. Orru
Department of Chemistry and Pharmaceutical Sciences
Vrije Universiteit Amsterdam
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
Fax: (+31)20-598-7488
E-mail: orru@few.vu.nl
[**] This work was financially supported by the Dutch Science Founda-
tion (NWO, VICI grant). Dr. M. T. Smoluch (Vrije Universiteit
Amsterdam) and J. W. H. Peeters (University of Amsterdam) are
kindly acknowledged for conducting HRMS measurements.
Supporting information for this article is available on the WWW
Scheme 1. Union of the MCR for 2H-2-imidazolines and the Ugi 4CR
with sodium glycinate. M.S.=molecular sieves.
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Angew. Chem. Int. Ed. 2009, 48, 5856 –5859