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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 Rh(III)-catalyzed cascade arylation and chlorination of α-diazocarbonyl compounds with arylboronic acids and N-chlorosuccinimide exhibits excellent functional group tolerance on the organoboron and the diazo reagents. Functionalized α-aryl-α-chlorocarbonyl compounds were obtained in good yields.
F.-N. Ng, Y.-F. Lau, Z. Zhou, W.-Y. Yu, Org. Lett., 2015, 17, 1676-1679.

A one-step, three-component condensation of allenyl boronic acids or allenyl pinacolboronates with amines and aldehydes affords α-allenyl or α-propargyl α-amino acids and anti-β-amino alcohols. Secondary amines generate exclusively α-allenyl α-amino acids, while primary aliphatic amines lead to α-propargyl α-amino acids.
F. Liepouri, G. Bernasconi, N. A. Petasis, Org. Lett., 2015, 17, 1628-1631.

A practical three-component domino reaction of α-nitroepoxides and cyanamide with a series of amines enables the synthesis of functionalized 2-aminoimidazole derivatives under mild conditions without any additives.
X. Guo, W. Chen, B. Chen, W. Huang, W. Qi, G. Zhang, Y. Yu, Org. Lett., 2015, 17, 1157-1159.

Cu-catalyzed aerobic oxidative three-component coupling of a terminal alkyne, secondary amine, and sulfonamide enables an efficient synthesis of amidines. The use of Cu(OTf)2 as catalyst produces amidines selectively via an initial oxidative coupling of the terminal alkyne with the secondary amine, followed by hydroamidation of the ynamine intermediate with the sulfonamide. Glaser-Hay alkyne homocoupling products are not observed.
J. Kim, S. S. Stahl, J. Org. Chem., 2015, 80, 2448-2454.

In a palladium-catalyzed intermolecular aminocarbonylation of alkenes, the use of hypervalent iodine reagent can accelerate the reaction. The current transformation presents a convenient method to generate β-amino acid derivatives from simple alkenes.
J. Cheng, X. Qi, M. Li, P. Chen, G. Liu, J. Am. Chem. Soc., 2015, 137, 2480-2483.

A decarboxylative redox cyclization strategy enables the synthesis of 2-substituted benzothiazoles from o-chloronitroarenes and arylacetic acids in the presence of elemental sulfur/N-methylmorpholine under metal- and solvent-free conditions.
T. Guntreddi, R. Vanjari, K. N. Singh, Org. Lett., 2015, 17, 976-978.

In the presence of CuCl, a three-component reaction of o-iodoanilines and K2S with TosMIC proceeded smoothly to yield the corresponding benzothiazolethiones in very good yields. Notably, isocyanide served as a carbon source and K2S functioned as a sulfur source.
P. Dang, W. Zeng, Y. Liang, Org. Lett., 2015, 17, 34-37.

A one-pot catalyst-free chemoselective synthesis of N-benzyl propargylamines with good functional group compatibility involves in situ formation of an active amine through Petasis reaction of primary amines, formaldehyde solution, and boronic acids, which reacts in a decarboxylative coupling reaction with propiolic acids to give products in high yields.
H. Feng, H. Jia, Z. Sun, J. Org. Chem., 2014, 79, 11812-11818.

A completely atom-economic reaction of isocyanides with aliphatic amines in the presence of elemental sulfur proceeds efficiently at (nearly) ambient temperature to produce thioureas in excellent yields.
T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Synthesis, 2014, 46, 3172-3179.

Optimized reaction conditions for a Heck-type carbonylation of (hetero)aryl bromides with [Fe(CO)5] enable alkoxycarbonylations in the presence of methanol and butanol and aminocarbonylations in the presence of various amines, including aniline and benzotriazole, with reasonable results.
M. Babjak, O. Caletková, D. Ďurišová, T. Gracza, Synlett, 2014, 25, 2579-2584.

A highly efficient molecular iodine mediated formal [3 + 2 + 1] cycloaddition reaction enables the direct synthesis of substituted quinolines from methyl ketones, arylamines, and styrenes. A self-sequenced iodination/Kornblum oxidation/Povarov/aromatization mechanism has been proposed.
Q. Gao, S. Liu, X. Wu, A. Wu, Org. Lett., 2014, 16, 4582-4585.

A decarboxylative strategy for the synthesis of thioamides involves a three-component reaction of arylacetic or cinnamic acids, amines and elemental sulfur powder, without the need of a transition metal and an external oxidant.
T. Guntreddi, R. Vanjari, K. N. Singh, Org. Lett., 2014, 16, 3624-3625.

Microwave irradiation enables an expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines. This methodology offers high availability of commercial reagents and great efficiency in expanding molecule diversity.
Y. Wang, B. Frett, H.-y. Li, Org. Lett., 2014, 16, 3016-3019.

An operational simple palladium-catalyzed three-component reaction of readily available 2-aminobenzamides, aryl halides, and tert-butyl isocyanide efficiently constructs quinazolin-4(3H)-ones in good yields via a palladium-catalyzed isocyanide insertion/cyclization sequence.
X. Jiang, T. Tang, J.-M. Wang, Z. Chen, Y.-M. Zhu, S.-J. Ji, J. Org. Chem., 2014, 79, 5082-5087.

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