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Multicomponent Reactions

Multicomponent Reactions (MCRs) are convergent reactions, in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product. In an MCR, a product is assembled according to a cascade of elementary chemical reactions. Thus, there is a network of reaction equilibria, which all finally flow into an irreversible step yielding the product. The challenge is to conduct an MCR in such a way that the network of pre-equilibrated reactions channel into the main product and do not yield side products. The result is clearly dependent on the reaction conditions: solvent, temperature, catalyst, concentration, the kind of starting materials and functional groups. Such considerations are of particular importance in connection with the design and discovery of novel MCRs. (A. Dömling, Org. Chem. Highlights 2004, April 5. Link)

A. Dömling, Org. Chem. Highlights 2004, April 5.

Multicomponent Reactions with Carbonyl Compounds

Some of the first multicomponent reactions to be reported function through derivatization of carbonyl compounds into more reactive intermediates, which can react further with a nucleophile. One example is the Mannich Reaction:

Mannich Reaction

Obviously, this reaction only proceeds if one carbonyl compound reacts faster with the amine to give an imine, and the other carbonyl compound plays the role of a nucleophile. In cases where both carbonyl compounds can react as the nucleophile or lead to imines with the same reaction rate, preforming the intermediates is an alternative, giving rise to a standard multistep synthesis.

Carbonyl compounds played a crucial role in the early discovery of multicomponent reactions, as displayed by a number of name reactions:

Biginelli Reaction

Bucherer-Bergs Reaction

Gewald Reaction

Hantzsch Dihydropyridine (Pyridine) Synthesis

Kabachnik-Fields Reaction

Mannich Reaction

Strecker Synthesis

Kindler Thioamide Synthesis

Isocyanide-based Multicomponent Reactions

Isocyanides play a dual role as both a nucleophile and electrophile, allowing interesting multicomponent reactions to be carried out. One of the first multicomponent reactions to use isocyanides was the Passerini Reaction. The mechanism shows how the isocyanide displays ambident reactivity. The driving force is the oxidation of CII to CIV, leading to more stable compounds.

Passerini Reaction

This interesting isocyanide chemistry has been rediscovered, leading to an overwhelming number of useful transformations. One of these is the Ugi Reaction:

Ugi Reaction

Both the Passerini and Ugi Reactions lead to interesting peptidomimetic compounds, which are potentially bioactive. The products of these reactions can constitute interesting lead compounds for further development into more active compounds. Both reactions offer an inexpensive and rapid way to generate compound libraries. Since a wide variety of isocyanides are commercially available, an equivalently diverse spectrum of products may be obtained.

Variations in the starting compounds may also lead to totally new scaffolds, such as in the following reaction, in which levulinic acid simultaneously plays the role of a carboxylic acid and a carbonyl compound:

H. Tye, M. Whittaker, Org. Biomol. Chem., 2004, 2, 813-815.

But how can multicomponent reactions be discovered? It's sometimes a simple matter of trial and error. Some very interesting MCRs have even been discovered by preparing libraries from 10 different starting materials. By analyzing the products of each combination (three-, four-, up to ten-component reactions), one is able to select those reactions that show a single main product. HPLC and MS are useful analytical methods, because the purity and mass of the new compounds help to decide rapidly whether a reaction might be interesting to investigate further. (L. Weber, K. Illgen, M. Almstetter, Synlett, 1999, 366-374. DOI)

Links of Interest

Organic Chemistry Highlights: Multicomponent Reactions

Reviews on Multicomponent Reactions

A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168. DOI
A. Dömling, Org. Chem. Highlights 2004, April 5. Link

Books on Multicomponent Reactions

Multicomponent Reactions

Jieping Zhu, Hugues Bienaymé
Hardcover, 468 Pages
First Edition, 2005
ISBN: 3-527-30806-7 - Wiley-VCH

Recent Literature

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A multicomponent protocol enables the synthesis of highly substituted imidazole derivatives in excellent yield from various α-azido chalcones, aryl aldehydes, and anilines in the presence of erbium triflate as a catalyst.
K. Rajaguru, R. Suresh, A. Mariappan, S. Muthusubramanian, N. Bhuvanesh, Org. Lett., 2014, 16, 744-747

A three-component reaction of alkynes, elemental sulfur, and aliphatic amines allows a general, straightforward, and atom-economical synthesis of thioamides.
T. B. Nguyen, M. Q. Tran, L. Ermolenko, A. Al-Mourabit, Org. Lett., 2014, 16, 310-313.

A highly practical copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes provides a general and straightforward way to synthesize various useful CF3-containing nitriles, which can be used for the preparation of pharmaceutically and agrochemically important compounds.
Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu, Y.-M. Liang, Org. Lett., 2014, 16, 270-273.

A facile formation of C-N, C-O, and C-S bonds from ynals, pyridin-2-amines, and alcohols or thiols enables a transition-metal-free three-component reaction for the construction of imidazo[1,2-a]pyridines.
H. Cao, X. Liu, L. Zhao, J. Cen, J. Lin, Q. Zhu, M. Fu, Org. Lett., 2014, 16, 146-149.

Unusual N-Acyl-N,O-acetals are present in a number of bioactive natural products and  can act as a synthetic precursor to unstable reactive N-acylimines. Various N-acyl-N,O-acetals can be prepared under mild conditions mediated by titanium ethoxide (Ti(OEt)4). The method also offers a new strategy to make other O-alkyl-N,O-acetals.
M. Li, B. Luo, Q. Liu, Y. Hu, A. Ganesan, P. Huang, S. Wen, Org. Lett., 2014, 16, 10-13.

An operationally simple and rapid copper-catalyzed three-component synthesis of trisubstituted N-aryl guanidines involving cyanamides, arylboronic acids, and amines is performed in the presence of K2CO3, a catalytic amount of CuCl2·2H2O, bipyridine, and oxygen (1 atm).
J. Li, L. Neuville, Org. Lett., 2013, 15, 6124-6127.

Heating a solution of an aldehyde, an aromatic amine, and a nitroalkane in 20% water-methanol at 60°C for five hours enables an environmentally benign three-component, one-pot synthesis of 2-nitroamines in the absence of a catalyst.
C. G. Piscopo, G. Sartori, J. A. Mayoral, D. Lanari, L. Vaccaro, R. Maggi, Synlett, 2013, 24, 2596-2600.

A Lewis acid palladium-catalyzed reaction of amides, aryl aldehydes, and arylboronic acids enables a practical and general synthesis of α-substituted amides from simple, readily available building blocks.
T. Beisel, G. Manolikakes, Org. Lett., 2013, 15, 6046-6049.

A simple and straightforward multicomponent reaction of vinyl azide, aldehyde, and tosylhydrazine affords 3,4,5-trisubstituted 1H-pyrazoles regioselectively in good yields in the presence of a base. The reaction tolerates a range of functional groups.
G. Zhang, H. Ni, W. Chen, J. Shao, H. Liu, B. Chen, Y. Yu, Org. Lett., 2013, 15, 5967-5969.

A highly regioselective cyanotrifluoromethylation of electron-deficient styrenes with a trifluoromethylated hypervalent iodine reagent proceeds under mild conditions in the presence of a bulky phosphine and CuCN. The process involves the consecutive formation of two C-C bonds in a single addition reaction. In the presence of a p-methoxy substituent in the styrene, oxytrifluoromethylation occurs instead of the cyanotrifluoromethylation.
N. O. Ilchenko, P. G. Janson, K. J. Szabó, J. Org. Chem., 2013, 78, 11087-11091.

Copper-catalyzed condensation and C-N bond formation of 2-iodoanilenes, arylacetaldehydes, and sodium azide, in a one-pot three-component reaction enables the synthesis of quinoxalines in good yields. Under optimized reaction conditions, starting materials were reacted in the presence of CuI, K2CO3 in DMSO at 80°C for 20 hours.
H. Yuan, K. Li, Y. Chen, Y. Wang, J. Cui, B. Chen, Synlett, 2013, 24, 2315-2319.

π-Stacking can be used to increase the barrier to rotation in chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A3-coupling.
F. S. P. Cardoso, K. Abboud, A. Aponick, J. Am. Chem. Soc., 2013, 135, 14548-14551.

A highly efficient Bi(OTf)3-catalyzed multicomponent synthesis of amidomethylated arenes and heteroarenes from readily available starting materials proceeds under mild conditions and has a broad substrate scope with water as the only side product.
A. E. Schneider, G. Manolikakes, Synlett, 2013, 24, 2057-2060.

A simple multicomponent reaction of aldehydes, diethyl phosphite, and azides gives α-aminophosphonates in the presence of iodine and iron under solvent-free conditions. The reactions were completed at room temperature within 5 minutes to 12 hours and afforded the corresponding products in good yields.
Y.-Q. Yu, Synthesis, 2013, 45, 2545-2550.

A multicomponent domino reaction of readily available isocyanides, primary or secondary amines, and gem-diactivated olefins enables a chemoselective, catalyst-free synthesis of structurally diverse, polysubstituted pyrroles in good yields under mild conditions.
X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou, S.-J. Ji, Org. Lett., 2013, 15, 4246-4249.

A catalytic asymmetric 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides was realized using Cu(I)/pybox and axially chiral dicarboxylic acid cocatalysts.
T. Hashimoto, Y. Takiguchi, K. Maruoka, J. Am. Chem. Soc., 2013, 135, 11473-11476.

In ruthenium-catalyzed three-component reactions, ketones, amines, and vicinal diols are converted into various substituted pyrroles in good isolated yields. Additionally, α-functionalized ketones gave synthetically interesting amido-, alkoxy-, aryloxy-, and phosphate-substituted pyrroles in a straightforward manner. The synthetic protocol proceeds with high atom-efficiency and shows a broad substrate scope and functional group tolerance.
M. Zahng, X. Fang, H. Neumann, M. Beller, J. Am. Chem. Soc., 2013, 135, 11384-11388.

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