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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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Iodine catalyzes a cascade reaction between enaminones, hydrazines, and DMSO in the presence of Selectfluor to provide 1,4-disubstituted pyrazoles. DMSO plays a dual role as the C1 source and the reaction medium. In addition, the synthesis of 1,3,4-trisubstituted pyrazoles using aldehydes as alternative C1 building blocks has also been achieved.
H. Guo, L. Tian, Y. Liu, J.-P. Wan, Org. Lett., 2022, 24, 228-233.

A metal- and oxidant-free three-component desulfurization and deamination condensation of amidines, isothiocyanates, and hydrazines provides structurally diverse fully substituted 1H-1,2,4-triazol-3-amines. This [2 + 1 + 2] cyclization strategy offers mild reaction conditions, environmental friendliness, and easy gram-scale applications.
W. Guo, G. Liu, L. Deng, W. Mei, X. Zou, Y. Zhong, X. Zhuo, J. Org. Chem., 2021, 86, 17244-17248.

A three-component assembly of α-CF3 carbonyls, NaN3, and amines provides a variety of 5-amino NH-1,2,3-triazoles under transition-metal-free and open-air conditions. The method provides a general and operationally simple route to functionalized biologically important molecules. The NH-1,2,3-triazoles can be smoothly converted to N-2 alkylated 1,2,3-triazole products.
L. Lv, G. Gao, Y. Luo, K. Mao, Z. Li, J. Org. Chem., 2021, 86, 17197-17212.

A three-component coupling reaction of alcohols or thiols with N,N-dibromoarylsulfonamides and isonitrile and in the presence of K2CO3 provides both isoureas and isothioureas in very good yields. This metal-free process proceeds via carbodiimide intermediate at room temperature within a very short reaction time.
D. Mishra, P. Phukan, J. Org. Chem., 2021, 86, 17581-17593.

A three-component coupling involving arynes, CS2, and aliphatic amines enables a facile synthesis of biologically important S-aryl dithiocarbamates. This transition-metal-free and mild reaction is scalable and operates with good functional group compatibility. With 3-triflyloxybenzyne, a unique four-component coupling incorporating tetrahydrofuran was observed.
S. Bhattarcharjee, S. Deswal, N. Manoj, G. Jindal, A. T. Biju, Org. Lett., 2021, 23, 9083-9088.

A three component coupling of amines, carbon dioxide, and halides enables an efficient synthesis of carbamates in the presence of cesium carbonate and TBAI. The method offers mild reaction conditions and short reaction times and avoids N-alkylation of the amine and overalkylation of the carbamate. In addition, chiral substrates were resistant to racemization.
R. N. Salvatore, S. Il Shin, A. S. Nagle, K. W. Jung, J. Org. Chem., 2001, 66, 1035-1037.

An annulation between 2-aminobenzyl alcohols, benzaldehydes, and DMSO provides quinolines. Interestingly, introducing substituent groups to the α-position of sulfoxides resulted in the interchange of the positions between benzaldehydes and sulfoxides in the product quinolines.
T. Yang, Z.-w. Nie, M.-d. Su, H. Li, W.-p. Luo, Q. Liu, C.-C. Guo, J. Org. Chem., 2021, 86, 15232-15241.

A chiral sulfinamide phosphine ligand enables a Pd-catalyzed enantioselective three-component coupling of N-tosylhydrazones, aryl halides, and terminal alkynes under mild conditions utilizing  (GF-Phos) to provide chiral diarylmethyl alkynes. This reaction features readily available starting materials, general substrate scope, high enantioselectivity, and ease of scale-up.
G. Zhao, Y. Wu, H.-H. Wu, J. Yang, J. Zhang, J. Am. Chem. Soc., 2021, 143, 17983-17988.

The photoexcitation of Hantzsch ester can directly activate chromium reagents through a single-electron transfer process. The synthetic application was demonstrated through a photoredox decarboxylative allylation of aldehydes with feedstock butadiene without exogenous photocatalysts, metallic reductants, or additives.
S. Lin, Y. Chen, H. Yan, Y. Liu, Y. Sun, E. Hao, C. Shi, D. Zhang, N. Zhu, L. Shi, Org. Lett., 2021, 23, 8077-8081.

A highly efficient microwave-assisted Cu(I)-catalyzed cross-A3-coupling/decarboxylative coupling of two different amines, formaldehyde, and propiolic acid provides unsymmetric 1,4-diamino-2-butynes through a domino process in good yields with high chemoselectivity.
X. Xu, H. Feng, E. V. Van der Eycken, J. Org. Chem., 2021, 86, 14036-14043.

An oxidative carbonylation of aryl boronic acids with inert tertiary amines provides tertiary amides via C(sp3)-N bond activation. This efficient protocol significantly restricts the formation of the homocoupling biarylketone product.
Y. A. Kolekar, B. M. Bhanage, J. Org. Chem., 2021, 86, 14028-14035.

A palladium-catalyzed synthesis of 3-arylquinolin-2(1H)-ones proceeds through a reductive aminocarbonylation of benzylic ammonium triflates with o-nitrobenzaldehydes. The reaction provides a wide range of 3-arylquinolin-2(1H)-ones in good yields with very good functional group compatibility.
Y. Liu, X. Qi, X.-F. Wu, J. Org. Chem., 2021, 86, 13824-13832.

The photocatalytic activation of elemental sulfur enables a mild, rapid, and chemoselective three-component thioesterification in the presence of olefins and α-ketoacids. This novel reaction is characterized by high yields and a broad substrate scope.
S. Murakami, T. Nanjo, Y. Takemoto, Org. Lett., 2021, 23, 7650-7655.

An efficient, facile, and eco-friendly synthesis of pyrimidine derivatives involves an oxidative [3 + 2 + 1] three-component annulation of amidines, ketones, and N,N-dimethylaminoethanol as the one carbon source. The reaction tolerates many important functional groups.
Z. Qin, Y. Ma, F. Li, J. Org. Chem., 2021, 86, 13734-13743.

An iodine-mediated formal [2 + 2 + 1] cyclization of methyl ketones, p-toluenesulfonyl hydrazines, and 1-aminopyridinium iodide provides 4-aryl-NH-1,2,3-triazoles under metal- and azide-free conditions. This is achieved using p-toluenesulfonyl hydrazines and 1-aminopyridinium iodide as azide surrogates.
C. Huang, X. Geng, P. Zhao, Y. Zhou, X.-X. Yu, L.-S. Wang, Y.-D. Wu, A.-X. Wu, J. Org. Chem., 2021, 86, 13664-13672.

An easy to prepare, tridentate arylazo pincer iron complex catalyzes an eco-friendly construction of trisubstituted pyrimidines under mild aerobic conditions via dehydrogenative functionalization of alcohols with alkynes and amidines.
R. Mondal, G. Chakraborty, A. K. Guin, S. Sarkar, N. D. Paul, J. Org. Chem., 2021, 86, 13186-13197.

Palladium catalyzes a domino Heck arylation and alkylation of nonconjugated cyclohexadienes to produce trans isomers of disubstituted cyclohexenes in exceptionally high enantiomeric ratios.
D. Zhu, W. Xu, M. Pu, Y.-D. Wu, Y. R. Chi, J. S. Zhou, Org. Lett., 2021, 23, 7064-7068

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