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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 Cu(I)-catalyzed three-component reaction of terminal alkynes, trifluoromethyl diazo compounds, and nitrosoarenes provides a series of trifluoromethyl-substituted dihydroisoxazoles in high yields under mild reaction conditions.
X. Lv, Z. Kang, D. Xing, W. Hu, Org. Lett., 2018, 20, 4843-4847.

A palladium-catalyzed oxidative three-component coupling of easily accessible N-substituted anthranilamides with isocyanides and arylboronic acids provides 2,3-disubstituted quinazolinones with a wide substrate scope and good functional group tolerance.
C. Qian, K. Liu, S.-W. Tao, F.-L. Zhang, Y.-M. Zhu, S.-L. Yang, J. Org. Chem., 2018, 83, 9201-9209.

The use of K2S2O8 and DMSO enables an efficient and transition-metal-free synthesis of 4-arylquinolines from readily available aryl alkynes and anilines with a diverse range of substitution patterns. DMSO acts as one carbon source, thus providing a highly atom-economical and environmentally benign approach for the synthesis of 4-arylquinolines.
M. Phanindrudu, S. B. Wakade, D. K. Tiwari, P. R. Likhar, D. K. Tiwari, J. Org. Chem., 2018, 83, 9137-9143.

In a highly regioselective, direct visible-light-mediated aminofluorination of styrenes, a shelf-stable N-Ts-protected 1-aminopyridine salt serves as the nitrogen-radical precursor, and the commercially available hydrogen fluoride-pyridine was used as the nucleophilic fluoride source.
J.-N. Mo, W.-L. Yu, J.-Q. Chen, X.-Q. Hu, P.-F. Xu, Org. Lett., 2018, 20, 4471-4474.

A Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents  provides 1,1-diarylalkanes. The reaction proceeds well with primary, secondary and tertiary alkyl halides, and electronically diverse arylzinc reagents.
S. KC, R. K. Dhungana, B. Shrestha, S. Thapa, N. Khanal, P. Basnet, R. W. Lebrun, R. Giri, J. Am. Chem. Soc., 2018, 140, 9801-9805.

A light-induced, Ru-catalyzed three-component alkyl-fluorination of olefins under mild reaction conditions provides a wide range of fluorinated products with good functional group tolerance. A key advantage of this photoredox reaction is the use of generic alkyl groups and nucleophilic fluoride.
W. Deng, W. Feng, Y. Li, H. Bao, Org. Lett., 2018, 20, 4245-4249.

A mild and metal-free multi-component reaction enables the synthesis of 4,5-disubstituted 1H-1,2,3-triazoles from phosphonium salts, aldehydes, and sodium azide. An organocatalyzed coupling of the formyl group with the phosphonium group provides an olefinic phosphonium salt as key intermediate, that undergoes [3+2] cycloaddition with the azide.
G.-L. Wu, Q.-P. Wu, Synthesis, 2018, 50, 2768-2774.

A N-heterocyclic carbene (NHC)-catalyzed trifluoromethylation of α-chloro aldehydes provides valuable α-trifluoromethyl ester derivatives in good yields. The unique combination of an electrophilic trifluoromethylation reagent with NHC catalysis was the key for the functionalization of a broad range of substrate. An enantioselective version of this reaction afforded products in moderate yields with good ee values.
F. Gelat, A. Patra, X. Pannecoucke, A. T. Biju, T. Poisson, T. Besset, Org. Lett., 2018, 20, 3897-3901.

A three-component reaction of potassium alkyltrifluoroborates, DABCO·(SO2)2 as sulfur dioxide surrogate, and alkenes under photocatalysis provides diverse sulfones in very good yields at room temperature. This reaction works efficiently under mild conditions via generation of alkyl and alkylsulfonyl radicals as key intermediates, and a reductive single-electron transfer.
T. Liu, Y. Li, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett., 2018, 20, 3605-3608.

A zinc salt promotes cyclization as well as provides a counteranion in a redox-neutral synthesis of isoquinolinium salts via C-H activation of presynthesized or in situ formed imines and coupling with α-diazo ketoesters. Under three-component conditions, both ketone and aldehydes are viable substrates. The coupling of imines with diazo malonates under similar conditions afforded isoquinolin-3-ones as the coupling product.
M. Tian, G. Zheng, X. Fan, X. Li, J. Org. Chem., 2018, 83, 6477-6488.

A palladium-catalyzed, three-component tandem reaction of 2-aminobenzonitriles, aldehydes, and arylboronic acids provides diverse quinazolines good yields. The reaction tolerates bromo and iodo groups.
K. Hu, Q. Zhen, J. Gong, T. Cheng, L. Qi, Y. Shao, J. Chen, Org. Lett., 2018, 20, 3061-3064.

A thiol-promoted site-specific addition of 1,3-dioxolane to imines through a radical chain process enables a metal-free and redox-neutral conversion of inexpensive materials to a broad range of protected α-amino aldehydes in very good yields using only a catalytic amount of radical precursor. Both the thiol and a small amount of oxygen from air are indispensable to the success of this reaction.
H. Zeng, S. Yang, H. Li, D. Lu, Y. Gong, J.-T. Zhu, J. Org. Chem., 2018, 83, 5256-5266.

An efficient copper-catalyzed aerobic oxidative dehydrogenative annulation of amines, alkynes, and O2 provides trisubstituted oxazoles via dioxygen activation and oxidative C-H bond functionalization.
J. Pan, X. Li, X. Qiu, X. Luo, N. Jiao, Org. Lett., 2018, 20, 2762-2765.

Practical Cu-catalyzed oxidative, multiple Csp3-H bond cleavage processes achieve a synthesis of thiazoles from simple aldehydes, amines, and element sulfur in the presence of molecular oxygen as a green oxidant.
X. Wang, X. Qiu, J. Wei, J. Liu, S. Song, W. Wang, N. Jiao, Org. Lett., 2018, 20, 2632-2636.

A practical and general microwave-mediated Biginelli cyclocondensation of guanidine with aldehydes and β-dicarbonyl compounds provides functionalized 2-amino-3,4-dihydropyrimidines in good yields, with short reaction times and a simple workup. The scope is considerably wider than that of similar reactions carried out under conventional heating.
F. Felluga, F. Benedetti, F. Berti, S. Drioli, G. Regini, Synlett, 2018, 29, 986-992.

A transition-metal-free cleavage of C-C triple bonds in aromatic alkynes in the presence of S8 and amides furnishes aryl thioamides in good yields. The method offers mild reaction conditions, as well as wide substrate scope that is particularly compatible with some internal aromatic alkynes and acetamides.
K. Xu, Z. Li, F. Cheng, Z. Zuo, T. Wang, M. Wang, L. Liu, Org. Lett., 2018, 20, 2228-2231.

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