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DOI: 10.1055/sos-SD-210-00001

Müller, T. J. J.Science of Synthesis: Multicomponent Reactions, (201411.

The science of synthesis has reached a tremendous level of highly sophisticated complexity and almost any kind of conceivable molecule can nowadays be synthesized. Conceptually, 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 nonnatural target molecules in a series of many individual two-component reactions. These reaction steps represent an ongoing economic and practical challenge for organic synthesis, and the past half-century has witnessed an enormous rise in powerful novel methodologies 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 entities; innovative synthetic solutions are required to meet societal needs for new functional materials and active pharmaceutical ingredients, and for molecular probes to tackle problems in the neighboring sciences. All of this poses important questions to the chemist: “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 optimizing 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. Facing 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 design, 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 multicomponent reactions were associated with heterocycle synthesis. Conceptually, one-pot processes are concatenated sequences of elementary organic reactions under similar conditions. However, it was not until 1959 that this fundamental principle was recognized by Ugiʼs 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-carboxamide,[‌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, together with new concepts in chemical reactivity that range from radical reactions through organometallic chemistry and catalysis to organo- and enzyme-catalyzed reactions, unprecedented sequences are being invented. And there is no end in sight so far, because a multicomponent reaction is a reactivity-based concept, which relies on the gradual transformation and generation of reactive functionalities or intermediates.

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. Müller. 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 components 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, before J. J. Vanden Eynde and A. Mayence present the related Hantzsch pyridine synthesis (Section, which is followed by a discussion of the Strecker reaction by M. Ayaz, F. De Moliner, G. A. Morales, and C. Hulme (Section L. Bernardi and A. Ricci then address the Mannich reaction (Section, which is followed by E. Le Gallʼs treatment of multicomponent reactions where metal alkyls or aryls are the third nucleophilic component (Section Due to their relative acidity, alkynes can be activated by deprotonation or by transition metals in the sense of a C—H activation. W.-J. Yoo, L. Zhao, and C.-J. Li take care of this interesting functionality in the context of multicomponent reaction methodology (Section The Petasis reaction (Section, covered by B. Carboni and F. Berrée, can be considered as a Mannich-type reaction where boronates have taken the role of the nucleophile attacking the iminium intermediate. Mechanistically still debatable but synthetically very useful is the Willgerodt–Kindler reaction presented by Y. Huang and A. Dömling (Section The Kabachnik–Fields reaction is also a Mannich-type process and is reviewed by N. S. Zefirov, E. D. Matveeva, and M. V. Shuvalov (Section 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. Arévalo and R. Lavilla (Section 1.2.2). The vast and important class of isocyanide-based multicomponent reactions then follows: the Passerini reaction is presented by R. Riva, L. Banfi, and A. Basso (Section, the Ugi reaction is reviewed by L. A. Wessjohann, G. N. Kaluđerović, R. A. W. Neves Filho, M. C. Morejon, G. Lemanski, and T. Ziegler (Section, and modifications of the Ugi reaction are discussed by R. S. Menon and V. Nair (Section Finally, a chapter by Y. Huang and A. Dömling 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 α,β-unsaturated carbonyl compounds (Section 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 cycloadditions, 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 isocyanides (Section 2.1.3), and the special role adopted by electron-deficient alkynes as electrophiles is then covered by the same authors (Section 2.1.4). The involvement of cycloadditions 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 α,β-unsaturated carbonyl compounds as 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 reactions are reviewed by K. J. Szabó 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). Volume 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 natural and nonnatural targets, as well as to addressing general scientific needs beyond chemistry.