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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 facile and efficient multicomponent reaction of arynes, sulfamides, and thiosulfonates provides a broad range of sulfilimines in very good yields. This protocol could be conducted on a gram scale, and the products were easily converted to sulfides and sulfoximines. Mechanism studies revealed that a sulfenamide generated in situ is the key intermediate for the reaction.
P. Xie, Y. Zheng, Y. Luo, J. Luo, L. Wu, Z. Cai, L. He, Org. Lett., 2023, 25, 6133-6138.

An oxidative cyanomethylation of amines using nitromethane as the methylene source in the presence of Me3SiCN provides α-amino nitriles without the addition of an external oxidant. A catalytic amount of AgCN and a stoichiometric amount of LiBF4 cooperatively promoted the transformation. A wide variety of the amines, including both aromatic and aliphatic compounds were converted.
T. Takashima, H. Ece, T. Yurino, T. Ohkuma, Org. Lett., 2023, 25, 6052-6056.

A visible light-induced palladium-catalyzed homologative three-component synthesis of a broad range of allylic amines involves two distinct cycles enabled by the same Pd(0) catalyst: a visible light-induced hybrid radical alkyl Heck reaction between 1,1-dielectrophile and styrene, followed by the "in dark" classical Tsuji-Trost-type allylic substitution reaction.
N. Kvasovs, J. Fang, F. Kliuev, V. Gevorgyan, J. Am. Chem. Soc., 2023, 145, 18497-18505.

A simple, base-catalyzed three-component reaction of ynals, isocyanates, amines and alcohols provides highly decorated pyridine derivatives in good yields with high regioselectivities. This synthesis of 6-amino-5-arylpicolinates is metal-free, environmentally benign, and inexpensive.
B. Zhu, J. He, K. Zou, A. Li, C. Zhang, J. Zhao, H. Cao, J. Org. Chem., 2023, 88, 11450-11459.

A Pd-catalyzed multicomponent cross-coupling of allyl esters with alkyl bromides and K2S2O5 provides allylic sulfones with high linear and exclusive E selectivity. The reaction displays an excellent functional group compatibility.
K.-Y. Zhang, F. Long, C.-C. Peng, J.-H. Liu, L.-J. Wu, Org. Lett., 2023, 25, 5817-5821.

3-Fluoro-2-iodo-1-methylpyridinium triflate catalyzes a one-pot cascade reaction for 2,3-dihydropyridinone synthesis. The desired [4+2] cycloaddition products, bearing aryl, heteroaryl, alkyl, and alicyclic substituents, were successfully furnished in good yields. A strong halogen-bonding interaction between the iodopyridinium catalyst and imine intermediate was essential.
Y. Li, Y. Ge, R. Sun, X. Yang, S. Huang, H. Dong, Y. Liu, H. Xue, X. Ma, F. Fu, Z. Chen, J. Org. Chem., 2023, 88, 11069-11082.

A Ag-catalyzed three-component annulation of o-alkynylaryl aldehydes, amines, and trifluorodiazoethane or diazoacetonitrile provides trifluoromethyl- and cyano-functionalized benzo[d]azepines. Key steps in this reaction are the transient formation of an isoquinolinium intermediate and a subsequent ring-expansive addition of in situ-formed silver trifluorodiazoethylide.
S. P. Chandrasekharan, A. Dhami, K. Mohanan, Org. Lett., 2023, 25, 5806-5811.

An unprecedented Pd(II)-catalyzed cascade annulation of o-aminobenzoic acids with CO, amines, and aldehydes provides N3-substituted and N1,N3-disubstituted 2,3-dihydroquinazolin-4(1H)-ones in good yields under mild conditions. The reaction offers low cost, high step economy, broad substrate scope, and good product diversity.
X. Zhang, J. Wang, J. Xu, Q. Pang, D. Liu, G. Zhang, J. Org. Chem., 2023, 88, 10266-10276.

A cascade reaction of isonitriles with N,N-dibromoarylsulfonamides and sodium azide provide aminotetrazoles in the presence of K2CO3 at room temperature. This metal-free process proceeds via an isolable carbodiimide intermediate, which could further react with sodium azide and subsequently cyclizes intermolecularly to provide 5-aminotetrazoles within a short reaction time.
D. Mishra, S. Kashyap, P. Phukan, J. Org. Chem., 2023, 88, 9401-9408.

(NaN(SiMe3)2) catalyzes a deprotonation of allylbenzenes. Trapping of the deprotonated allyl anion with in situ generated N-(trimethylsilyl) aldimines provides value-added homoallylic amines with excellent linear selectivity.
Y. Gu, Y.-E. Wang, Y. Yuan, H. Xu, Y. Lu, Y. Zhang, F. Xue, D. Xiong, J. Mao, J. Org. Chem., 2023, 88, 7362-7372.

An asymmetric nickel-catalyzed borylative coupling of terminal alkenes with nonactivated alkyl halides provides a broad range of chiral boronic esters with high regio- and enantioselectivity under mild reaction conditions. The success of this three-component strategy is ascribed to the application of a chiral anionic bisoxazoline ligand.
Z. Li, H. Shi, X. Chen, L. Peng, Y. Li, G. Yin, J. Am. Chem. Soc., 2023, 145, 13603-13614.

An efficient copper-catalyzed intermolecular decarboxylative cascade cyclization of aryl aldehydes, anilines, and acrylic acid permits the direct synthesis of 2-substituted quinolines. This method features promising chemo- and regioselectivity and also tolerates a wide variety of substrates with excellent functional-group tolerance, high yields, a radical reaction pathway, and aerobic reaction conditions.
R. Chatterjee, M. Pothireddy, R. Dandela, Synlett, 2023, 34, 1058-1062.

Multicomponent reactions of CS2, sulfoxonium ylides and secondary amines provide β-keto dithiocarbamates, whereas primary amines afforded thiazolidine-2-thiones or thiazole-2-thiones after dehydration in an acidic environment. These simple, versatile, and catalyst-free synthetic methods have a wide substrate scope and excellent functional group tolerance.
N. Kumar, A. Sharma, U. Kumar, S. K. Panday, J. Org. Chem., 2023, 88, 6120-6125.

A photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst provides chiral α-chlorinated carboxylic acid esters. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.
D. Weinzierl, M. Piringer, P. Zebrowski, L. Stockhammer, M. Waser, Org. Lett., 2023, 25, 3126-3130.

A metal-free, cascade regio- and stereoselective trifluormethyloximation, cyclization, and elimination strategy of readily available α,β-unsaturated carbonyl compounds with CF3SO2Na and tBuONO provides a wide variety of 4-(trifluoromethyl)isoxazoles. Mechanistic studies revealed a radical pathway for the reaction.
P. Pattanayak, T. Chatterjee, J. Org. Chem., 2023, 88, 5420-5430.

A unique Au-allenylidene pathway enables an in situ formation of highly unsaturated alkylidene ketenes from propargyl alcohol derivatives. A subsequent trapping with a broad range of nucleophiles such as alcohols, phenols, water, amines, and sulfoximines in the presence of an N-oxide provides α,β-unsaturated drug and natural product derivatives.
X. Sun, X. Duan, N. Zheng, W. Song, Org. Lett., 2023, 25, 2798-2805.

A chemoselective heterodimerization of weak electrophilic ortho-diisocyanoarenes and common isocyanides generates quinoxaline-based zwitterionic intermediates. This reactive zwitterion could react in situ with various trapping agents to furnish a range of structurally diverse quinoxalines.
L. Bao, M. Li, L. Zhang, Y. Xue, J. Dong, X. Xu, Org. Lett., 2023, 25, 2366-2371.

Pd/Cu-catalyzed coupling and boration of acyl chlorides with alkynes and B2pin2 provide the corresponding saturated β-boryl ketones in the presence of ethyl acetate as the hydrogen source. Various β-boryl ketones were synthesized in very good yields with broad functional group tolerance.
F. Zhu, P. Yin, J. Org. Chem., 2023, 88, 4352-4358.                                              

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