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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 synergistic I2/amine promoted formal [4 + 2] cycloaddition of methyl ketones, arylamines, and aryl(alkyl)acetaldehydes provides various 2-acyl-3-aryl(alkyl)quinolines via an iodination/Kornblum oxidation/Povarov/aromatization sequence. Notably, the arylamine reactants also acted as indispensable catalysts to promote enamine formation.
X. Geng, X. Wu, P. Zhao, J. Zhang, Y.-D. Wu, A.-X. Wu, Org. Lett., 2017, 19, 4179-4182.


A copper-catalyzed regiocontrolled three-component reaction of nitriles, diaryliodoniums, and ynamides provides diversified 4-aminoquinolines. The C7-substituted regioisomers were formed regioselectively when meta-substituted phenyliodonium salts were used. [1,3] N-to-C rearrangement of the products to quinolin-4-ylmethanesulfonamides and simultaneous deprotection of benzyl and sulfonamide group are also reported.
K. H. Oh, J. G. Kim, J. K. Park, Org. Lett., 2017, 19, 3994-3997.


A Cu-catalyzed hydrocarbonylative C-C coupling of unactivated alkyl iodides with terminal alkynes enables a highly chemo- and regioselective synthesis of unsymmetrical dialkyl ketones. A variety of functional groups are tolerated, and both primary and secondary alkyl iodides react well.
L.-J. Cheng, N. P. Mankad, J. Am. Chem. Soc., 2017, 139, 10200-10203.


In a direct and efficient method for the acetamidosulfenylation reaction of alkenes, NaI was used as a catalyst, DMSO as the oxidant, nitriles as both the solvent and nucleophiles and stable, readily available Bunte salts as thiolating reagents. The reactions were carried out under mild conditions to provide β-acetamido sulfides in good yields. Moreover, the reaction can be performed with alcohols as nucleophiles.
R. Zhang, Z. Yan, D. Wang, Y. Wang, S. Lin, Synlett, 2017, 28, 1195-1200.


A highly efficient one-pot synthesis of 4-aminoquinazolines from easily available 2-iodo- or 2-bromobenzimidamides, aldehydes, and sodium azide proceeds via consecutive copper-catalyzed SNAr substitution, reduction, cyclization, oxidation and tautomerization.
L. Yang, H. Luo, Y. Sun, Z. Shi, K. Ni, F. Li, D. Chen, Synthesis, 2017, 49, 2535-2543.


An efficient synthesis of diversified indolizine derivatives in good yields from pyridines, methyl ketones and alkenoic acids under solvent-free conditions involves a copper-catalyzed bromination of the methyl ketone, 1,3-dipolar cycloaddition of the pyridinium ylide with the alkenoic acid, followed by oxidative decarboxylation and dehydrogenative aromatization of the primary cycloadduct in oxygen atmosphere.
W. Wang, J. Han, J. Sun, Y. Liu, J. Org. Chem., 2017, 82, 2835-2842.


A single-step, facile synthesis of 1,8-naphthyridine derivatives in good yields was carried out at room temperature under mild conditions using a three-component condensation reaction of substituted 2-aminopyridines, malononitrile or methyl/ethyl cyanoacetate, and various aldehydes in the presence of a N-bromosulfonamide as Lewis acid.
R. Ghorbani-Vaghei, S. M. Malaekehpoor, Synthesis, 2017, 49, 763-769.


2,4,6-Trimethylpyridine catalyzes a trifluoromethylalkynylation of unactivated alkenes with alkynyl sulfones and Togni's reagent to provide various β-trifluoromethylated alkynes under metal-free conditions with a broad substrate scope and wide functional group compatibility. A mechanism involving catalytic nonchain radical processes is proposed.
S. Zhou, T. Song, H. Chen, Z. Liu, H. Shen, C. Li, Org. Lett., 2017, 19, 698-701.


The use of CHCl3 as a convenient and safe carbonyl source in the presence of KOH enables a modular, palladium catalyzed synthesis of aryl(hetero)aryl benzophenones and aryl benzoates from aryl(hetero)aryl halides via an initial carbonylation to generate an aroyl halide, which undergoes coupling with arylboronic acids, boronates, and phenols. Direct carbonylative coupling of indoles at the third position has also been accomplished.
P. Sharma, S. Rohilla, N. Jain, J. Org. Chem., 2017, 82, 1105-1113.


A three-component cascade annulation of readily available aryl diazonium salts, nitriles, and alkynes enables an efficient, additive-free, and rapid synthesis of multiply substituted quinolines in good yields. Various aryl diazonium salts, nitriles, and alkynes can participate in this transformation.
H. Wang, Q. Xu, S. Shen, S. Yu, J. Org. Chem., 2017, 82, 770-775.


A one-pot, three-component cascade reaction combining photoredox catalyzed radical addition and formal [3 + 2] annulation provides imidazoline and oxazolidine derivatives in very good yields. The advantages of this transformation are mild reaction conditions, operational simplicity, and easy accessibility of raw materials.
J.-Q. Chen, W.-L. Yu, Y.-L. Wei, T.-H. Li, P.-F. Xu, J. Org. Chem., 2017, 82, 243-249.


An efficient copper-mediated three-component coupling reaction of boronic acids, amines, and carbon disulfide provides a wide range of functionalized dithiocarbamates in very good yields. The method offers mild reaction conditions, easily available substrates, wide substrate scope, and high functional-group tolerance.
C. Qi, T. Guo, W. Xiong, Synlett, 2016, 27, 2626-2630.


A copper-catalyzed [3+1+1]-type condensation of oximes, anhydrides and potassiumthiocyanate (KSCN) provides thiazoles in very good yields under mild reaction conditions. The transformation has good functional group tolerance.
X. Tang, J. Yang, Z. Zhu, M. Zheng, W. Wu, H. Jiang, J. Org. Chem., 2016, 81, 11461-11466.


NH4I promotes an efficient indole-to-carbazole strategy under metal-free conditions. The reaction offers high regioselectivity through formal [2 + 2 + 2] annulation of indoles, ketones, and nitroolefins and enables the assembly of a large number of diversified carbazoles with good functional group tolerance.
S. Chen, Y. Li, P. Ni, H. Huang, G.-J. Deng, Org. Lett., 2016, 18, 5384-5387.


An efficient and versatile Pd(II)-catalyzed oxidative three-component cascade reaction of diverse amines, alkyne esters, and alkenes enables the direct synthesis of diverse 2,3,4-trisubstituted pyrroles with broad functional group tolerance and in good to excellent yields.
X. Zhang, X. Xu, G. Chen, W. Yi, Org. Lett., 2016, 18, 4864-4867.


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