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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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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

A nickel-catalyzed, multicomponent regio- and enantioselective hydroformylation and carbonylation using chloroformate as a safe CO source provides a wide variety of unsymmetrical dialkyl ketones bearing a functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones and α-amino ketones.
J. Chen, S. Zhu, J. Am. Chem. Soc., 2021, 143, 14089-14096.

A copper(I)-catalyzed regio- and stereoselective three-component coupling reactions between gem-dialkylallenes, alkyl halides, and bis(pinacolato)diboron provides sterically congested allylic boronates. A subsequent allylboration of aldehydes diastereoselectively furnished the corresponding homoallylic alcohols that bear a quaternary carbon.
Y. Ozawa, K. Endo, H. Ito, J. Am. Chem. Soc., 2021, 143, 13865-138772.

A 3CR of homophthalic anhydride, amines, and aldehydes provides dihydroisoquinolones in good yields and excellent diastereoselectivity.
S. Y. Howard, M. J. Di Maso, K. Shimabukuro, N. P. Burlow, D. Q. Tan, J. C. Fettinger, T. C. Malig, J. E. Hein, J. T. Shaw, J. Org. Chem., 2021, 86, 11599-11607.

Enantioenriched 1,1-silylboryl alkanes are highly valued building blocks in asymmetric synthesis as well as medicinal chemistry. An enantioselective cobalt-catalyzed hydrosilylation/hydroboration cascade of terminal alkynes offers chemo-, regio-, and stereoselectivity exquisitely controlled by a single set of metal catalyst and ligand.
S. Jin, K. Liu, S. Wang, Q. Song, J. Am. Chem. Soc., 2021, 143, 13124-13134.

An efficient [2 + 1 + 3] cyclization reaction of aryl methyl ketones, arylamines, and 1,3-dicarbonyl compounds provides 2-aryl-4-quinolinecarboxylates in good yields under mild conditions. This metal-free process achieved a C-C bond cleavage of 1,3-dicarbonyl compounds for use as a C1 synthon.
Y. Zhou, P. Zhao, L.-S. Wang, X.-X. Yu, C. Huang, Y. D. Wu, A.-X. Wu, Org. Lett., 2021, 23, 6461-6465.

An efficient transition-metal-free one-pot three-component reaction between diaryliodonium triflates, cyclic and acyclic aliphatic amines, and carbon disulfide provides biologically relevant S-aryl dithiocarbamates in good yields under mild conditions. This methodology is robust, scalable, and exhibits a broad substrate scope.
S. K. Parida, S. Jaiswal, P. Singh, S. Murarka, Org. Lett., 2021, 23, 6401-6406.

Trifluoromethylsulfonyl-pyridinium salt (TFSP) is an efficient, solid trifluoromethylation reagent, which can be readily prepared from cheap and easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis, that can be used for azido- or cyano-trifluoromethylation reactions of alkenes.
M. Zhang, J.-H. Lin, J.-C. Xiao, Org. Lett., 2021, 23, 6079-6083.

The combination of dirhodium(II)/Xantphos catalyzes a three-component reaction of readily accessible amines, diazo compounds, and allylic compounds to afford various architecturally complex and functionally diverse α-quaternary α-amino acid derivatives in good yields with high atom and step economy.
B. Lu, X. Liang, J. Zhang, Z. Wang, Q. Peng, X. Wang, J. Am. Chem. Soc., 2021, 143, 11799-11810.

CuO catalyzes a three-component reaction of α-ketoaldehydes, 1,3-dicarbonyl compounds, and organic boronic acids in water to provide a wide range of products containing 1,3- and 1,4-diketones. The method offers use of readily available starting materials, wide substrate scope, excellent yields, gram-scale synthesis, and mild reaction conditions.
Q. Xia, X. Li, X. Fu, Y. Zhou, Y. Peng, J. Wang, G. Song, J. Org. Chem., 2021, 86, 9914-9923.

A catalyst- and metal-free visible-light-mediated protocol enables the iodoamination of miscellaneous olefins in high yields under environmentally benign reaction conditions using DMC as green and biodegradable solvent. Furthermore, the protocol allows for late-stage functionalization of bioactive molecules and can be scaled to gram quantities of product.
S. Engl, O. Reiser, Org. Lett., 2021, 23, 5581-5586.

A convenient base-catalyzed three-component reaction between chalcones, isothiocyanates, and elemental sulfur provides thiazole-2-thiones in very good yields.
T. B. Nguyen, P. Retailleau, Org. Lett., 2021, 23, 5344-5348.

A multicomponent reaction of primary amines (amino acids), carbon disulfide, and γ-bromocrotonates provides thiazolidine-2-thiones in excellent yields via a domino alkylation/intramolecular Michael addition. The synthetic utility of the adducts was demonstrated by hydrolysis, amidation, and oxidation reactions.
M. K. Foumeshi, A. Z. Halimehjani, A. Alaei, B. Klepetářová, P. Beier, Synthesis, 2021, 53, 2219-2228.

An efficient and modular strategy based on a four-component sequential reaction provides enaminones under mild conditions without a catalyst in one pot. Furthermore, the products could be transformed into thiadiazoles.
J. Zhang, P. Zhou, A. Yin, S. Zhang, W. Liu, J. Org. Chem., 2021, 86, 8980-8986.

Copper iodide catalyzes a sustainable and time economic synthesis of polysubstituted pyrroles in excellent yields with high regioselectivity under mild conditions. The reaction proceedes through imine formation followed by cyclization with an alkyne-Cu intermediate.
M.-H. Hsu, M. Kapoor, T. K. Pradhan, M.-H. Tse, H.-Y. Chen, M.-J. Yan, Y.-T. Cheng, Y.-C. Lin, C.-Y. Hsieh, K.-Y. Liu, C.-C. Han, Synthesis, 2021, 53, 2212-2218.

A facile photocatalyzed strategy for difunctionalization of styrenes in the presence of CS2 and amines provides β-keto dithiocarbamates. However, 4-nitrostyrene and 2-vinylpyridine can only be converted to 2-arylethylthiocarbamates.
R. K. Vishwakarma, S. Kumar, K. N. Singh, Org. Lett., 2021, 23, 4147-4151.

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