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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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In a copper-catalyzed intermolecular aminoalkynylation of alkenes, N-fluoro-N-alkylsulfonamides (NFASs) are used as nitrogen-centered radical precursors and alkynyltrimethoxysilanes as alkynylating reagents. This radical relay process presents an efficient and straightforward approach to various highly enantioenriched 2-alkynyl-2-arylethylamines in good yields.
Z. Hu, L. Fu, P. Chen, W. Cao, G. Liu, Org. Lett., 2021, 23, 107-112.

By using Yb(OTf)3 as a catalyst and under solvent-free reaction conditions, the yields of the one-pot Biginelli reaction can be increased while the reaction time was shortened. In addition, the catalyst can be easily recovered and reused. It not only led to economical automation but also reduces hazardous pollution to achieve environmentally friendly processes.
Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem., 2000, 65, 3864-3868.

A Au(III)-catalyzed isomerization-A3-coupling/cyclization cascade enables an efficient and convenient synthesis of 2,4-disubstituted cyclopentenones.
J. Li, Y. Xu, X. Hu, S. Zhu, L. Liu, Org. Lett., 2020, 22, 9478-9483.

An electrochemical reductive functionalization of alkenes with strategic choice of reagents and reaction conditions enables an addition of two distinct electrophiles in a highly chemo- and regioselective fashion. Intermolecular carboformylation, anti-Markovnikov hydroalkylation, and carbocarboxylation of alkenes can be achieved via electroreductive generation of alkyl radical and carbanion intermediates.
W. Zhang, S. Lin, J. Am. Chem. Soc., 2020, 142, 19844-19849.

A convenient Ni-catalyzed multicomponent coupling reaction of alkyl halides, isocyanides, and H2O provides alkyl amides. Bench-stable NiCl2(dppp) is able to initiate this transformation under mild reaction conditions.
Q. Li, H. Jin, Y. Liu, B. Zhou Synthesis, 2020, 52, 1841-1846.

A nickel-catalyzed three-component reductive alkylacylation of electron-deficient activated alkenes with acid anhydrides and tertiary alkyl bromides  enables the efficient preparation of a variety of ketones with broad substrate scope and high functionality tolerance starting from simple precursors.
L. Wang, C. Wang, Org. Lett., 2020, 22, 8829-8835.

The reaction of an imine with an aryne generated in situ in the presence of a dialkyl phosphite provides α-aminophosphonates in good yields. This transition-metal-free multicomponent phosphonylation shows a broad substrate scope.
T. Lim, B. M. Kim, J. Org. Chem., 2020, 85, 13037-13049.

Commercially available chiral ligands enable a widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of β,γ-unsaturated ketones that contain an α-stereogenic center.
J. del Pozo, S. Zhang, F. Romiti, S. Xu, R. P. Conger, A. H. Hoveyda, J. Am. Chem. Soc., 2020, 142, 18200-18212.

Electrochemical technology enables alkene alkoxyhalogenation and organohalide dehalogenation in one pot. Anodic conversion of the C=C bond to radical cation intermediates and cathodic transformations of organohalides run in parallel.
T.-T. Zhang, M.-J. Luo, Y. Li, R.-J. Song, J.-H. Li, Org. Lett., 2020, 22, 7230-7233.

A synthesis of 2-carboxybenzofurans from 2-gem-dibromovinylphenols is based on Cu-catalyzed intramolecular C-O coupling followed by Mo(CO)6-mediated intermolecular carbonylation. This protocol provides a broad range of functionalized benzofuran-2-carboxylic acids, esters, and amides in very good yields under Pd- and CO gas-free conditions.
Q. Mo, N. Sun, L. Jin, B. Hu, Z. Shen, X. Hu, J. Org. Chem., 2020, 85, 11490-11500.

A convenient Fe-catalyzed A-D-A-T-type radical-dual-difunctionalization and cross-coupling of two different alkenes provides chain elongated and trifluoromethylated aromatic alkenes.
J. Zhao, R.-X. Liu, C.-P. Luo, L. Yang, Org. Lett., 2020, 22, 6776-6779.

A nickel-catalyzed thiocarbonylation of arylboronic acid with sulfonyl chlorides in the presence of Mo(CO)6 as CO source and reductant provides a broad range of thioesters in good yields with good functional group tolerance.
X. Qi, Z.-P. Bao, X.-T. Yao, X.-F. Wu, Org. Lett., 2020, 22, 6671-6676.

A highly efficient asymmetric intermolecular Ni-catalyzed reductive dicarbofunctionalization of vinyl amides, vinyl boranes, or vinyl phosphonates with two distinct readily available electrophiles, namely, Csp2- and Csp3-halides, provides chiral products in a highly regio- and enantioselective manner.
X. Wei, W. Shu, A. García-Domínguez, E. Merino, C. Nevado, J. Am. Chem. Soc., 2020, 142, 13515-13522.

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.

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