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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 simple, efficient, and general one-pot reaction of aldehydes and ketones with amines in the presence of indium(III) chloride as a catalyst provides α-amino phosphonates. Sonication accelerates the reaction.
B. C. Ranu, A. Hajra, U. Jana, Org. Lett., 1999, 1, 1141-1143.

Cu(CH3CN)4BF4 catalyzes a radical bis(trifluoromethylation) of alkynes and 1,3-enynes with Togni reagent II and (bpy)Zn(CF3)2 at room temperature to afford the corresponding 1,2-bis(trifluoromethylated) alkenes and 1,4-bis(trifluoromethylated) allenes in good yields. This protocol exhibits broad substrate scope and excellent functional group compatibility.
H. Shen, H. Xiao, L. Zhu, C. Li, Synlett, 2020, 31, 41-44.

A Cu-catalyzed reductive aminocarbonylation of primary, secondary, and tertiary alkyl iodides using nitroarenes as the nitrogen source provides a diverse range of secondary N-aryl alkylamides. The single copper catalyst synergistically mediates both carbonylation of alkyl iodides and reduction of nitroarenes, to provide acyl iodides and anilines as possible reactive intermediates.
S. Zhao, N. P. Mankad, Org. Lett., 2019, 21, 10106-10110.

The combination of I2 with dimethyl sulfoxide mediates a cross-coupling cyclization of enaminones, tosylhydrazine, and elemental sulfur for the synthesis of 5-acyl-1,2,3-thiadiazoles in very good yields under transition-metal-free conditions. This strategy is operationally simple and compatible with a wide range of functional groups.
Z. Yang, Y. Liang, A. Li, K. Liu, L. Li, T. Yang, C. Zhou, J. Org. Chem., 2019, 84, 16262-16267

A copper-catalyzed [3 + 2] cycloaddition reaction of alkynes with nitrile oxides generated in situ from the coupling reaction of a copper carbene and nitroso radical provides isoxazoles in a highly regioselective manner in a single step.
X.-D. Wang, L.-H. Zhu, P. Liu, X.-Y. Wang, H.-Y. Yuan, Y.-L. Zhao, J. Org. Chem., 2019, 84, 16214-16221.

A metal-free oxidative-amidation strategy enables the synthesis of α-ketothioamides and amides from α-azido ketones. The C-H bond thionation of α-azido ketones with elemental sulfur could form α-ketothioacyl azide, which was then nucleophilically attacked by amines, while amides could be formed with the release of nitrogen gas and cyano anion in the presence of PhI(OAc)2.
P. Yu, Y. Wang, Z. Zeng, Y. Chen, J. Org. Chem., 2019, 84, 14883-14891.

A metal bis(trimethylsilyl)amide/Cs2CO3 co-catalyzed benzylation of in situ generated N-(trimethylsilyl) aldimines with toluene derivatives provides a diverse array of bioactive 1,2-diarylethylamines with excellent efficiency and broad functional group tolerance. The catalyst exhibits high chemoselectivity for deprotonation of toluenes at the benzylic position.
G. Liu, P. J. Walsh, J. Mao, Org. Lett., 2019, 21, 8514-8518.

The use of inorganic sodium metabisulfite as the sulfur dioxide surrogate and di-tert-butyl peroxide as source of the methyl radical enables a direct C-H methylsulfonylation of alkenes. This method provides convenient access to (E)-2-methyl styrenyl sulfones in good yields.
F.-S. He, Y. Gong, P. Rojsitthisak, J. Wu, J. Org. Chem., 2019, 84, 13159-13163.

A selective, TBHP/KI-promoted C-O bond cleavage of ethers followed by annulation with anilines and elemental sulfur provides a wide range of 2-aryl-, 2-heteroaryl-, and 2-alkyl-substituted benzothiazoles with satisfactory yields and good functional group compatibility under transition-metal-free conditions.
J. Zhang, X. Zhao, P. Liu, P. Sun, J. Org. Chem., 2019, 84, 12596-12605.

A green and efficient multicomponent reaction provides S-aryl dithiocarbamates without adding any transition-metal catalysts, ligands, or photocatalysts under visible light. This method provides a straightforward way to create valuable S-aryl dithiocarbamates while minimizing chemical wastes and metal residues in the end products.
G. Li, Q. Yan, Z. Gan, Q. Li, X. Dou, D. Yang, Org. Lett., 2019, 21, 7851-7856.

A one-pot three-component cascade cyclization of enaminones, cyanamide, and elemental sulfur provides 2-amino-5-acylthiazoles in good yields with good functional group tolerance. This method offers an effective way for accessing valuable and potentially bioactive 2-amino-5-acylthiazole derivatives.
R.-G. Fu, Y. Wang, F. Xia, H.-L. Zhang, Y. Sun, D.-W. Yang, Y.-W. Wang, P. Yin, J. Org. Chem., 2019, 84, 12237-12245.

The combination of potassium sulfide and chloroform provides an efficient and practical thiocarbonyl surrogate. A variety of dithiocarbamates can be synthesized in one-pot reactions in which the thiocarbonyl motif was generated in situ.
W. Tan, N. Jänsch, T. Öhlmann, F.-J. Meyer-Almes, X. Jiang, Org. Lett., 2019, 21, 7484-7488.

A N-heterocyclic carbene-catalyzed radical relay enables the vicinal alkylacylation of styrenes, acrylates and acrylonitrile with complete regioselectivity using aldehydes and tertiary alkyl carboxylic acid-derived redox-active esters  to produce functionalized ketone derivatives.
T. Ishii, K. Ota, K. Nagao, H. Ohmiya, J. Am. Chem. Soc., 2019, 141, 14073-14077.

The combination of a Ni catalyst with TDAE as sacrificial reductant enables a dicarbofunctionalization of a broad range of olefins with two electrophilic carbon sources under reductive conditions via simultaneous formation of one C(sp3)-C(sp3) and one C(sp3)-C(sp2) bond with exquisite selectivity.
W. Shu, A. García-Domínguez, M. T. Quirós, R. Mondal, D. J. Cárdenas, C. Nevado, J. Am. Chem. Soc., 2019, 141, 13812-13821.

A cobalt-catalyzed allylation of amides with styrenes, in which DMSO was used as both the solvent and the α-methylene source, provides privileged allylic amines in high yields, and selectivity for the (E)-isomer of the linear product.
X. Zhang, Z. Zhou, H. Xu, X. Xu, X. Yu, W. Yi, Org. Lett., 2019, 21, 7248-7253.

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