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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 zwitterion-catalyzed intermolecular bromoesterification of alkenes works with acid and olefin in an equimolar ratio. Mechanistic study revealed that the charge pair in the zwitterion works synergistically in activating both NBS and carboxylic acid.
W.-H. Ng, R.-B. Hu, Y.-P. Lam, Y.-Y. Yeung, Org. Lett., 2020, 22, 5567-5571.

Three-component reactions of enaminoesters, fluorodibromoiamides/ester, and sulfur provide thiazoles and isothiazoles via two C-F bond cleavages along with the formation of new C-S, C-N, and N-S bonds. Both methods offer high selectivity for the synthesis of thiazoles/isothiazoles, which have vital applications in drug discovery and development.
X. Ma, X. Yu, H. Huang, Y. Zhou, Q. Song, Org. Lett., 2020, 22, 5284-5288.

Three-component reactions of enaminoesters, fluorodibromoiamides/ester, and sulfur provide thiazoles and isothiazoles via two C-F bond cleavages along with the formation of new C-S, C-N, and N-S bonds. Both methods offer high selectivity for the synthesis of thiazoles/isothiazoles, which have vital applications in drug discovery and development.
X. Ma, X. Yu, H. Huang, Y. Zhou, Q. Song, Org. Lett., 2020, 22, 5284-5288.

A modular, practical, and general palladium-catalyzed, radical three-component coupling enables selective 1,4-difunctionalization of unactivated 1,3-dienes, such as butadiene, by employing different commercially available nitrogen-, oxygen-, sulfur-, or carbon-based nucleophiles and unactivated alkyl bromides.
H.-M. Huang, P. Bellotti, P. M. Pfüger, J. L. Schwarz, B. Heidrich, F. Glorius, J. Am. Chem. Soc., 2020, 142, 10173-10183.

A three-component reaction of o-iodoanilines or electron-rich aromatic amines with K2S and DMSO provides 2-unsubstituted benzothiazoles in good isolated yields with good functional group tolerance. A similar reaction of o-phenylenediamines provided 2-unsubstituted benzimidazoles without K2S. DMSO plays three vital roles: carbon source, solvent, and oxidant.
X. Zhu, F. Zhang, D. Kuang, G. Deng, Y. Yang, J. Yu, Y. Liang, Org. Lett., 2020, 22, 3789-3793.

A nucleophilic activation of elemental sulfur by thiols enables a mild and chemoselective thioacylation of amines with α-keto acids and elemental sulfur. The reaction tolerates a broad range of functional groups, including unprotected hydroxyl, carboxyl, amide, sulfide, and tertiary amine moieties.
M. Saito, S. Murakami, T. Nanjo, Y. Kobayashi, Y. Takemoto, J. Am. Chem. Soc., 2020, 142, 8130-8135.

An iron-catalyzed radical alkylazidation of electron-deficient alkenes with trimethylsilyl azide and alkyl diacyl peroxides as the alkyl source provides a range of α-azido esters, an α-azido ketone, and an α-azido cyanide in high yields. This method features mild reaction conditions, wide substrate scope, and good functional group tolerance.
R. Wei, H. Xiong, C. Ye, Y. Li, H. Bao, Org. Lett., 2020, 22, 3195-3199.

A Cu/Pd-catalyzed borylallenylation of alkynes with propargylic carbonates and bis(pinacolato)diboron enables the synthesis of boryl-substituted ene-allenes. Densely (tetra-, penta-, and hexa-) substituted ene-allenes were synthesized in acceptable yield with high regio- and stereoselectivity. More important molecule structures can be obtained by subsequent modifications.
S.-H. Yu, T.-J. Gong, Y. Fu, Org. Lett., 2020, 22, 2941-2945.

An efficient and convenient, copper-catalyzed decarboxylative cycloaddition of propiolic acids, azides, and arylboronic acids provides fully substituted 1,2,3-triazoles from readily available starting materials. A possible mechanism is proposed.
X.-X. Wang, Y. Xin, Y. Li, W.-J. Xia, B. Zhou, R.-R. Ye, Y.-M. Li, J. Org. Chem., 2020, 85, 3576-3586.

An improved procedure for the aminocarbonylation of benzyl chloride derivatives provides 2-arylacetamides under mild conditions using an inexpensive phosphine ligand, carbon monoxide and either primary or secondary amines.
E. Rilvin-Derrick, N. Oram, J. Richardson, Synlett, 2020, 31, 369-372.

A copper(I)-mediated tandem three-component reaction using alkynes, azides, allyl iodides, CuI and NaNH2 provides 5-allyl-1,2,3-triazoles smoothly at room temperature in good yields. The products can be further converted into 1,2,3-triazole-fused tricyclic scaffolds.
Y. Song, S. Lee, P. Dutta, J.-S. Ryu, Synthesis, 2020, 52, 744-754.

A one-pot three-component reaction involving nitroarenes, (hetero)arylboronic acids, and potassium pyrosulfite provides a broad range of sulfonamides bearing different reactive functional groups in very good yields through sequential C-S and S-N coupling.
K. Chen, W. Chen, B. Han, W. Chen, M. Liu, H. Wu, Org. Lett., 2020, 22, 1841-1845.

A photoinduced, copper-catalyzed, three-component reaction of haloalkane, alkenes, and alkyne under mild reaction conditions helps to introduce privileged functionalities into propargylic systems.
Y. Zhang, D. Zhang, J. Org. Chem., 2020, 85, 3213-3223.

Starting from readily available aryl iodides and allenes, with formic acid as the CO source and reductant, good yields of α-branched enones were isolated. The use of a CO source avoids the manipulation of CO gas.
H.-Q. Geng, L.-C. Wang, C.-Y. Hou, X.-F. Wu, Org. Lett., 2020, 22, 1160-1163.

A highly regioselective three-component reaction of 2-bromo-3,3,3-trifluoropropene (BTP), aldehydes, and sulfonyl hydrazides provides 3-trifluoromethylpyrazoles. This metal-free, catalyst-free, and operationally simple approach offers mild conditions, a broad substrate scope, high yields, and valuable functional group tolerance.
C. Zhu, H. Zeng, C. Liu, Y. Cai, X. Fang, H. Jiang, Org. Lett., 2020, 22, 809-813.

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