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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 silver-catalyzed, one-pot, four-component reaction of terminal alkynes, TMSN3, sodium sulfinate, and sulfonyl azide provides amidines. A possible cascade reaction mechanism consists of alkyne hydroazidation, sulfonyl radical addition, 1,3-dipolar cycloaddition of TMSN3, and retro-1,3-dipolar cycloaddition.
B. Liu, Y. Ning, M. Virelli, G. Zanoni, E. A. Anderson, X. Bi, J. Am. Chem. Soc., 2019, 141, 1593-1598.

The low-melting mixture urea-ZnCl2 as reaction medium efficiently catalyzes the formation of imidazoles from a dicarbonyl compound, ammonium acetate, and an aromatic aldehyde to provide a broad range of triaryl-1H-imidazoles or 2-aryl-1H-phenanthro[9,10-d]imidazoles in very good yields. In addition, the eutectic solvent can be reused five times without loss of catalytic activity.
N. L. Higuera, D. Peña-Solórzano, C. Ochoa-Puentes, Synlett, 2019, 30, 225-229.

A mild, metal-free, multicomponent reaction provides N-acyl amidines from nitroalkene derivatives, dibromo amides, and amines via formation of an initial α,α-dibromonitroalkane intermediate that can undergo C-C bond cleavage. This alternative approach toward N-acyl amidines enables rapid construction of amidine frameworks with high diversity and complexity.
M. Zhou, J. Li, C. Tian, X. Sun, X. Zhu, Y. Cheng, G. An, G. Li, J. Org. Chem., 2019, 84, 1015-1024.

A highly efficient rhodium-catalyzed tandem reaction of isocyanides with azides and various oxygen nucleophiles provides various N-sulfonyl/acylisoureas with broad substrate scope in an atom-economical manner.
X.-B. Bu, Z.-X. Zhang, Q.-Q. Peng, X. Xu, Y.-L. Zhao, J. Org. Chem., 2019, 84, 53-59.

A nickel-catalyzed conjunctive cross-coupling of simple alkenyl amides with aryl iodides and aryl boronic esters delivers the desired 1,2-diarylated products with excellent regiocontrol. The reaction is enabled by an electron-deficient olefin (EDO) ligand. Under optimized conditions, a wide range of amides derived from 3-butenoic acid, 4-pentenoic acid, and allyl amines are compatible substrates.
J. Derosa, R. Kleinmans, V. T. Tran, M. K. Karunananda, S. R. Wisniewski, M. D. Eastgate, K. M. Engle, J. Am. Chem. Soc., 2018, 140, 17878-17883.

Base-controlled three component reactions of styrenes, amines, and sulfur provide thioamides. Depending on the base, 2-phenylethanethioamides and benzothioamides were obtained selectively.
P. Zhang, W. Chen, M. Liu, H. Wu, J. Org. Chem., 2018, 83, 14269-14276

A constant current electrolysis synergizing with a Lewis-acid catalysis protocol enables an external oxidant-free oxytrifluoromethylation and aminotrifluoromethylation of styrene derivatives using sodium trifluoromethanesulfinate as the trifluoromethyl source.
L. Zhang, G. Zhang, P. Wang, Y. Li, A. Lei, Org. Lett., 2018, 20, 7396-7399.

An operationally simple, palladium-catalyzed three-component reaction between terminal alkynes, isonitriles, and sodium carboxylates have provides N-acyl propiolamide derivatives under mild conditions.
Y. He, Y. Wang, X. Liang, B. Huang, H. Wang, Y.-M. Pan, Org. Lett., 2018, 20, 7117-7120.

A rhodium-catalyzed carbonylative annulation methodology with nonactivated aromatic sulfides and terminal alkynes as the substrates provides thiochromenones effectively via [3 + 2+1]-type annulation.
F. Zhu, X.-F. Wu, J. Org. Chem., 2018, 83, 13612-13617.

(NH4)2S2O8 mediates a metal-free three-component alkene oxyalkynylation using H2O or alcohol as oxygenation agent. The reversed regioselectivity should be dictated by an alkene radical cation intermediate.
Y. Li, R. Lu, S. Sun, L. Liu, Org. Lett., 2018, 20, 6836-6839.

A catalyst-free Petasis reaction of sulfonamides as amine components, glyoxylic acid, and aryl- or alkenylboronic acids tolerates a broad range of functional groups and provides a wide array of α-amino acid derivatives.
A. M. Diehl, O. Ouadoudi, E. Andreadou, G. Manolikakes, Synthesis, 2018, 50, 3936-3946.

Chiral task-specific ionic liquids bearing chiral anions as the catalysts enable an enantioselective multicomponent Biginelli reaction. A combined role of asymmetric counteranion-directed catalysis (ACDC) and ionic liquid effect (ILE) for the chiral induction in the Biginelli multicomponent reaction is demonstrated.
H. G. O. Alvim D. L. J. Pinheiro, V. H. Carvalho-Silva, M. Fioramonte, F. C. Gozzo, W. A. da Silva, G. W. Amarante, B. A. D. Neto, J. Org. Chem., 2018, 83, 12143-12153.

An electrochemical multicomponent reaction of aryl hydrazines, paraformaldehyde, NH4OAc, and alcohols provides 1,5-disubstituted and 1-aryl 1,2,4-triazoles. Alcohols act as solvents as well as reactants and NH4OAc is used as the nitrogen source. With the assistance of reactive iodide radical or I2 and NH3 electrogenerated in situ, this process effectively avoids the use of strong oxidants and transition-metal catalysts.
N. Yang, G. Yuan, J. Org. Chem., 2018, 83, 11963-11969.

An efficient two-step Ugi/cyclization reaction sequence provides hydantoins. This microwave-assisted one-pot cyclization strategy, in which an alkyne group acts as a leaving group under basic conditions, could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like hydantoins.
Z.-G. Xu, Y. Ding, J.-P. Meng, D.-Y. Tang, Y. Li, J. Lei, C. Xu, Z.-Z. Chen, Synlett, 2018, 29, 2199-2202.

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.

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