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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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Direct reaction of isocyanides with sulfoxides affords thiocarbamic acid S-esters in very good yields. In addition, multicomponent reactions involving isocyanide, sulfoxide, and a suitable nucleophile provide a diverse range of sulfur-containing compounds, including isothioureas, carbonimidothioic acid esters, and carboximidothioic acid esters.
S. Wu, X. Lei, E. Fan, Z. Sun, Org. Lett., 2018, 20, 522-525.

A copper-catalyzed, practical, and straightforward one-pot synthesis of multisubstituted imidazoles in good yields from arylacetic acids, N-arylbenzamidines, and nitroalkanes involves simultaneous activation of C–H and N–H bonds. The use of inexpensive copper sulfate as a catalyst and readily available starting materials makes this protocol economically viable.
S. D. Pardeshi, P. A. Sathe, K. S. Vadagaonkar, L. Melone, A. C. Chaskar, Synthesis, 2018, 50, 361-370.

Photoredox-catalyzed and nitrogen-centered radical-triggered cascade reactions of styrenes (or phenylacetylenes), enol derivatives, and O-acyl hydroxylamines in DMSO provide functionalized β-amino alcohols. Structurally diverse reaction components, including complex molecular scaffolds can be converted.
X.-D. An, Y.-Y. Jiao, H. Zhang, Y. Gao, S. Yu, Org. Lett., 2018, 20, 401-404.

A synthesis of 2-substituted benzothiazoles in good yields from o-iodoanilines, arylacetic acids, and elemental sulfur is catalyzed by cheap copper metal. This S8-mediated directed decarboxylative redox-cyclization strategy is operationally simple, ligand-free, and compatible with a wide range of functional groups.
X. Wang, X. Li, R. Hu, Z. Yang, R. Gu, S. Ding, P. Li, S. Han, Synlett, 2018, 29, 219-224.

An efficient Pd-catalyzed cascade reaction of azides with isonitriles and amines provides N-sulfonyl-, N-phosphoryl-, and N-acyl-functionalized guanidines in excellent yield. In addition, the less reactive intermediate benzoyl carbodiimide could be isolated in moderate yield.
G. Qiao, Z. Zhang, B. Huang, L. Zhu, F. Xiao, Z. Zhang, Synthesis, 2018, 50, 330-340.

Using cheap and eco-friendly iron(III) nitrate as the nitration and cyclization reagent and KI as an additive for the synthesis of isoxazoles from alkynes, both self-coupling and cross-coupling products could be successfully prepared. In the cross-coupling and cyclizing of two different alkynes, the iron-mediated system shows a good chemoselectivity.
Z. Lai, Z. Li, Y. Liu, P. Yang, X. Fang, W. Zhang, B. Liu, H. Chang, H. Xu, Y. Xu, J. Org. Chem., 2018, 84, 145-153.

A transition-metal-free direct carboxylation of the ipso-C(sp2)-H bond of diazo compounds proceeds at ambient temperature under atmospheric pressure of carbon dioxide in the presence of a weak base. A series of unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with good yields and good functional group compatibility.
Q. Liu, M. Li, R. Xiong, F. Mo, Org. Lett., 2017, 19, 6756-6759.

Copper-catalyzed cross-coupling reactions of phenolic esters such as acetates, tosylates, and triflates with arylboronic acids or triphenyltin chlorides as the coupling partners in the presence of sulfur and a base provide unsymmetrical diaryl sulfides. In addition, NaOtBu promotes a synthesis of symmetrical diaryl sulfides from phenolic compounds in the presence of sulfur.
A. Rostami, A. Rostami, A. Ghaderi, M. Gholinejad, S. Gheisarzadeh, Synthesis, 2017, 49, 5025-5038.

An unprecedented cross-coupling reaction between copper carbenes and nitroso radicals provides various isoxazolines via construction of C-C, C-O, and C=N bonds in a one-pot process. The convenient method offers mild reaction conditions and wide substrate scope.
R. Chen, Y. Zhao, S. Fang, W. Long, H. Sun, X. Wan, Org. Lett., 2017, 19, 5896-5899.

A [2 + 1 + 1] radical tandem cycloaddition of styrenes, arylamines, and tert-butyl hydroperoxide enables a regioselective synthesis of polysubstituted 1,2-oxazetidines. TBHP was employed in this conversion not only as the oxidant but also as the oxygen source.
W. Liu, C. Chen, P. Zhou, H. Tan, Org. Lett., 2017, 19, 5830-5832.

Mn(OAc)3-mediated phosphinoyl radical addition followed by CuCN-catalyzed cyanation enables a double-functionalization reaction of alkenes under mild conditions to afford vicinal cyanophosphinoylation products.
P.-Z. Zhang, L. Zhang, J.-A. Li, A. Shoberu, J.-P. Zou, W. Zhang, Org. Lett., 2017, 19, 5537-5540.

A simple and efficient method for the base-mediated synthesis of unsymmetrical 1,3,5-triazin-2-amines uses readily available imidates, guanidines, and amides or aldehydes as the starting materials and cesium carbonate as the base. This three-component reaction provides diverse 1,3,5-triazin-2-amines in good yields with tolerance of a broad range of functional groups.
L. Pan, Z. Li, T. Ding, X. Fang, W. Zhang, H. Xu, Y. Xu, J. Org. Chem., 2017, 82, 10043-10050.

A one-pot reaction cascade reaction enables a transition-metal-free construction of functionalized quinolines from readily available acetophenones and anthranils. The reaction involves in situ generation of α,β-unsaturated ketones from the acetophenone via one-carbon homologation by DMSO followed by the aza-Michael addition of anthranils and subsequent annulation. DMSO acts not only as solvent but also as one carbon source.
S. B. Wakade, D. K. Tiwari, P. S. K. P. Ganesh, M. Phanindrudu, P. R. Likhar, D. K. Tiwari, Org. Lett., 2017, 19, 4948-4951.

A practicable quinoline synthesis from aniline and two amino acids provides a wide range of quinolines with high efficiency and diversity including pharmaceutical derivatives, photochemical active compounds, and challenging scaffolds. Mechanistic studies revealed that I2 promotes decarboxylation, oxidative deamination, and selective formation of new C-N and C-C bonds.
J.-C. Xiang, Z.-X. Wang, Y. Cheng, S.-Q. Xia, M. Wang, B.-C. Tang, Y.-D. Wu, A.-X. Wu, J. Org. Chem., 2017, 82, 9210-9216.

A copper-catalyzed three-component reaction of methyl ketones, organic azides, and DMF as one-carbon (C1) donor provides 4-acyl-1,2,3-triazoles in good yields. The transformation proceeds via an oxidative C-H/C-H cross-dehydrogenative coupling followed by an oxidative 1,3-dipolar cycloaddition.
Y. Liu, G. Nie, Z. Zhou, L. Jia, Y. Chen, J. Org. Chem., 2017, 82, 9198-9203.

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