1

Introduction
T. J. J. Mller

The science of synthesis has reached a tremendous level of highly sophisticated complex-
ity and almost any kind of conceivable molecule can nowadays be synthesized. Conceptu-
ally, the art of synthesis is predominantly practiced in the sense of the transformation of a
substrate and a reactant, i.e. in a two-component fashion, for accessing natural and non-
natural target molecules in a series of many individual two-component reactions. These
reaction steps represent an ongoing economic and practical challenge for organic synthe-
sis, and the past half-century has witnessed an enormous rise in powerful novel method-
ologies that enable synthetic chemists to create complex molecules more elegantly, more
efficiently, and more rapidly.
In all fields of chemistry, there is a steadily increasing demand for new chemical en-
tities; innovative synthetic solutions are required to meet societal needs for new function-
al materials and active pharmaceutical ingredients, and for molecular probes to tackle
problems in the neighboring sciences. All of this poses important questions to the chem-
ist: How should these molecules be synthesized? And, Is there an ideal synthesis?[1,2]
There are many good reasons for trying to square this circle. An ideal synthesis should
be simple, safe, concise, selective, efficient, and ultimately green, it should start from
simple reactants, and, of course, it should be highly diverse, because nobody, after opti-
mizing the desired properties, wants to start the synthetic design all over again. From a
technical viewpoint, this ideal synthesis will be performed in a single reaction vessel. Fac-
ing the issues of atom- and step-economy, these one-pot multistep reaction sequences are
a major challenge in terms of fine-tuning organic reactivity. Ostensively, this endeavor
has to be a recent invention of our time. In contrast, multicomponent reactions
(MCRs),[39] which can be regarded as masterpieces of synthetic efficiency and reaction de-
sign, have been around since the very early days of organic chemistry; indeed, the first
examples date back to the middle of the 19th century. Many of these early multicompo-
nent reactions were associated with heterocycle synthesis. Conceptually, one-pot process-
es are concatenated sequences of elementary organic reactions under similar conditions.
However, it was not until 1959 that this fundamental principle was recognized by Ugis
groundbreaking extension of the Passerini reaction and his conclusions.[10,11]
Furthermore, this unique one-pot strategy has also found industrial applications,
such as in the technical one-step Hantzsch synthesis of the calcium antagonist nifedipine
(Adalat)[12] or in the Ugi four-component reaction (Ugi-4CR) synthesis of piperazine-2-car-
boxamide,[13] which is the core structure of the HIV protease inhibitor indinivir (Crixivan).
Most advantageously and practically, multicomponent reactions can often be extended
into combinatorial, solid-phase, or flow syntheses, promising manifold opportunities
for developing novel lead structures of active agents and catalysts, and even novel small-
molecule-based materials.
Today, the field of multicomponent reactions is emerging systematically and, togeth-
er with new concepts in chemical reactivity that range from radical reactions through or-
ganometallic chemistry and catalysis to organo- and enzyme-catalyzed reactions, unpre-
cedented sequences are being invented. And there is no end in sight so far, because a mul-
ticomponent reaction is a reactivity-based concept, which relies on the gradual transfor-
mation and generation of reactive functionalities or intermediates.

Introduction, Mller, T. J. J.
Science of Synthesis 4.8, Section 1.0 for references see p 4
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 2 Multicomponent Reactions Introduction

The generation and transformation of reactive functionalities is the leitmotif of this

two-volume set for the Science of Synthesis Reference Library on Multicomponent Reactions.
Based upon the fundamental concept of Science of Synthesis to summarize critically the
major experimentally relevant synthetic processes, it was decided to create an overall
structure that reflects the general idea of multicomponent reactions, i.e. the perpetual
transformation of reactive functionalities. This concept is outlined and illustrated in an
introductory chapter (Section 1.1) by T. J. J. Mller. In principle, the carbonyl group plays
a central role as the starting point for many multicomponent reactions in the realm of
polar reactivity (Section 1.2); all of the major multicomponent name reactions fall into
this classification. Often amines or their analogues are the second nucleophilic compo-
nents and iminium intermediates are being formed within the sequence. This increase
in electrophilicity sets the stage for many veritable multicomponent processes: Biginelli
reactions, introduced by V. A. Chebanov, N. Yu. Gorobets, and Yu. V. Sedash, lead off this
survey (Section 1.2.1.1), before J. J. Vanden Eynde and A. Mayence present the related
Hantzsch pyridine synthesis (Section 1.2.1.2), which is followed by a discussion of the
Strecker reaction by M. Ayaz, F. De Moliner, G. A. Morales, and C. Hulme (Section
1.2.1.3). L. Bernardi and A. Ricci then address the Mannich reaction (Section 1.2.1.4),
which is followed by E. Le Galls treatment of multicomponent reactions where metal al-
kyls or aryls are the third nucleophilic component (Section 1.2.1.5). Due to their relative
acidity, alkynes can be activated by deprotonation or by transition metals in the sense of a
CH activation. W.-J. Yoo, L. Zhao, and C.-J. Li take care of this interesting functionality in
the context of multicomponent reaction methodology (Section 1.2.1.6). The Petasis reac-
tion (Section 1.2.1.7), covered by B. Carboni and F. Berre, can be considered as a Mannich-
type reaction where boronates have taken the role of the nucleophile attacking the imini-
um intermediate. Mechanistically still debatable but synthetically very useful is the Will-
gerodtKindler reaction presented by Y. Huang and A. Dmling (Section 1.2.1.8). The Ka-
bachnikFields reaction is also a Mannich-type process and is reviewed by N. S. Zefirov, E.
D. Matveeva, and M. V. Shuvalov (Section 1.2.1.9). The carbonyl-group-based first volume
concludes with a series of chapters addressing alternative nucleophilic components, such
as in the Povarov reaction involving enamines, as covered by M. J. Arvalo and R. Lavilla
(Section 1.2.2). The vast and important class of isocyanide-based multicomponent reac-
tions then follows: the Passerini reaction is presented by R. Riva, L. Banfi, and A. Basso
(Section 1.2.3.1), the Ugi reaction is reviewed by L. A. Wessjohann, G. N. Kaluderovic, R.
A. W. Neves Filho, M. C. Morejon, G. Lemanski, and T. Ziegler (Section 1.2.3.2), and modi-
fications of the Ugi reaction are discussed by R. S. Menon and V. Nair (Section 1.2.3.3). Fi-
nally, a chapter by Y. Huang and A. Dmling on the Gewald aminothiophene synthesis
reports on the use of a CH-acid nitrile and sulfur as polyfunctional components (Section
1.2.4).
Volume 2 opens with the special role of ,-unsaturated carbonyl compounds (Sec-
tion 2.1), which are generally referred to as Michael systems. Indeed, such substrates are
pivotal points in many multicomponent reactions, simultaneously bridging the gap to cy-
cloadditions, where they serve as electron-deficient reaction partners. J. Rodriguez, D.
Bonne, Y. Coquerel, and T. Constantieux address reactions involving Michael addition as
the key step (Section 2.1.1). The use of the Wittig reaction as a highly chemoselective
entry to activated double bonds is covered by N. S. Alavijeh, E. Ghabraie, and S. Balalaie
(Section 2.1.2). A. Shaabani, A. Sarvary, and S. Shaabani discuss the participation of isocy-
anides (Section 2.1.3), and the special role adopted by electron-deficient alkynes as elec-
trophiles is then covered by the same authors (Section 2.1.4). The involvement of cycload-
ditions as the key step is addressed by K. Takasu {[2 + 2] cycloadditions (Section 2.1.5)}, by
R. Raghunathan and S. Purushothaman {[3 + 2] cycloadditions (Section 2.1.6)}, and by M. C.
Elliott and D. H. Jones {[4 + 2] cycloadditions (Section 2.1.7)}.
Patterns of nonpolar reactivity are introduced with cycloadditions (Section 2.2). Here,
the most prominent examples that do not use ,-unsaturated carbonyl compounds as
Introduction, Mller, T. J. J.
Science of Synthesis 4.8, Section 1.0
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 Introduction 3

electrophiles are found for [3 + 2] cycloadditions (Section 2.2.1), which are reviewed by S.
G. Modha and E. V. Van der Eycken, and for [4 + 2] cycloadditions (Section 2.2.2), which are
covered by L. G. Voskressensky and A. A. Festa.
Boron-mediated (Section 2.3) and silicon-mediated (Section 2.4) multicomponent re-
actions are reviewed by K. J. Szab and J.-P. Wan, respectively, and allow for some peculiar
reactivity patterns. Another mode of unipolar reactivity is that of free-radical-mediated
multicomponent reactions, which are discussed by A. Fusano and I. Ryu (Section 2.5). Vol-
ume 2 concludes with metal-mediated multicomponent reactions (Section 2.6). In this
context, stoichiometric metal participation is treated by C. Xi and C. Chen (Section
2.6.1), whereas catalytic metal participation is covered by B. A. Arndtsen and J. Tjutrins
(Section 2.6.2).
The reactivity-based outline of this two-volume set Multicomponent Reactions creates
an additional perspective on state-of-the-art multicomponent syntheses, and encourages
the development of new sequences and even more sophisticated contributions to one-pot
methodologies. The authors hope that this will stimulate an increase in application and
methodological development of multicomponent reactions toward new syntheses of nat-
ural and nonnatural targets, as well as to addressing general scientific needs beyond
chemistry.

Introduction, Mller, T. J. J.
Science of Synthesis 4.8, Section 1.0 for references see p 4
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 4 Multicomponent Reactions Introduction

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[2]
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[3]
Multicomponent Reactions, Zhu, J.; Bienaym, H., Eds.; Wiley-VCH: Weinheim, Germany, (2005).
[4]
Ramn, D. J.; Yus, M., Angew. Chem. Int. Ed., (2005) 44, 1602.
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Ruijter, E.; Scheffelaar, R.; Orru, R. V. A., Angew. Chem. Int. Ed., (2011) 50, 6234.
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Introduction, Mller, T. J. J.
Science of Synthesis 4.8, Section 1.0
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