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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 transition-metal-free cleavage of C-C triple bonds in aromatic alkynes in the presence of S8 and amides furnishes aryl thioamides in good yields. The method offers mild reaction conditions, as well as wide substrate scope that is particularly compatible with some internal aromatic alkynes and acetamides.
K. Xu, Z. Li, F. Cheng, Z. Zuo, T. Wang, M. Wang, L. Liu, Org. Lett., 2018, 20, 2228-2231.

Nickel catalyzes a multicomponent coupling reaction of terminal alkenes, carbon dioxide, and organoaluminum reagents to provide homoallylic alcohols in good yields with excellent regio- and stereoselectivities.
Y. Mori, C. Shigeno, Y. Luo, B. Chan, G. Onodera, M. Kimura, Synlett, 2018, 29, 742-746.

Photoredox catalysis enables a direct oxidative addition of CF3 and H2O to alkynes to provide α-trifluoromethyl ketones via rapid enol-keto tautomerization. The reaction exhibits high functional group tolerance and regioselectivity. In addition, trifluoromethylated heterocycles of various sizes were synthesized from α-CF3-substituted diketones.
Y. R. Malpani, B. K. Biswas, H. S. Han, Y.-S. Jung, S. B. Han, Org. Lett., 2018, 20, 1693-1697.

The use of 1,3-diiodo-5,5,-dimethylhydantoin and HF-based reagents enables a regio- and stereoselective iodofluorination of internal and terminal alkynes. A facile method for a controlled regioselective double iodofluorination of terminal alkynes is also presented.
L. Pfeifer, V. Gouverneur, Org. Lett., 2018, 20, 1576-1579.

A CuI/MNAO [2-((2-methylnaphthalen-1-yl)amino)-2-oxoacetic acid] catalyzed cross-coupling of (hetero)aryl chlorides with potassium cyanate in alcohols provides N-(hetero)aryl carbamates in very good yields at 120-130°C. Moreover, (hetero)aryl bromides and (hetero)aryl iodides were reacted at lower catalyst loadings and lower temperatures.
S. V. Kumar, D. Ma, J. Org. Chem., 2018, 83, 2706-2713.

An enantioselective Cu-catalyzed borylative cross-coupling reaction of alkenes, bis(pinacolato)diboron, and methyl iodide provides the desired methylboration products with excellent diastereoselectivities and enantioselectivities.
B. Chen, P. Cao, Y. Liao, M. Wang, J. Liao, Org. Lett., 2018, 20, 1346-1349.

A copper-promoted [3 + 1 + 1]-type cyclization reaction enables a selective construction of 2-aryl or 2-benzyl substituted benzothiazoles from o-iodoaniline derivatives, S8, and N-tosylhydrazones depending on the reaction system.
Y. Huang, P. Zhou, W. Wu, H. Jiang, J. Org. Chem., 2018, 83, 2460-2466.

A simple copper-catalyzed aminosulfonylation of aryldiazonium tetrafluoroborates, DABCO·(SO2)2, and N-chloroamines  provides a wide range of sulfonamides in good yields under mild conditions. Mechanistic investigation suggests that a radical process and transition-metal catalysis take place.
F. Zhang, D. Zheng, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett., 2018, 20, 1167-1170.

A three-component, Ni-catalyzed reductive coupling enables a convergent synthesis of tertiary benzhydryl amines, which are challenging to access by traditional reductive amination methodologies. The condensation of secondary N-trimethylsilyl amines with benzaldehydes provides iminium ions in situ, which react with several distinct classes of organic electrophiles.
C. Heinz, J. P. Lutz, E. M. Simmons, M. M. Miller, W. R. Ewing, A. G. Doyle, J. Am. Chem. Soc., 2018, 140, 2292-2300.

Copper catalysis enables the synthesis of polysubstituted pyrroles from aldehydes, amines, and β-nitroalkenes. Remarkably, the use of α-methyl-substituted aldehydes provides efficient access to a series of tetra- and pentasubstituted pyrroles via an overwhelming 1,2-phenyl/alkyl migration. Non α-substituted aldehydes provide the corresponding trisubstituted pyrroles.
D. Andreou, M. G. Kallitsakis, E. Loukopoulos, C. Gabries, G. E. Kostakis, J. N. Lykakis, J. Org. Chem., 2018, 83, 2104-2113.

A one-pot protocol for the construction of fluoroalkylated isoxazoles directly from commercially available amines and alkynes is regioselective, scalable, operationally simple, mild, and tolerant of a broad range of functional groups. Preliminary mechanistic investigations reveal that the transformation involves an unprecedented Cu-catalyzed cascade sequence involving RfCHN2.
X.-W. Zhang, W.-L. Hu, S. Chen, X.-G. Hu, Org. Lett., 2018, 20, 860-863.

Pyrrole-2-carbaldehydes can efficiently be prepared from aryl methyl ketones, arylamines, and acetoacetate esters via oxidative annulation and Csp3-H to C=O oxidation in the presence of a copper catalyst, iodine, and oxygen. Mechanistic investigations indicate that the aldehyde oxygen atom originates from oxygen. The reaction avoids the use of stoichiometric quantities of hazardous oxidants.
X. Wu, P. Zhao, X. Geng, C. Wang, Y.-d. Wu, A.-x. Wu, Org. Lett., 2018, 20, 688-691.

A visible light-promoted three-component tandem annulation of α-bromoesters, amines, and aryl/alkyl isothiocyanates provides 2-iminothiazolidin-4-ones at room temperature in the absence of metal and photocatalyst. This [1 + 2 + 2] cyclization strategy offers broad substrate scope, excellent functional group tolerance, mild reaction conditions, step-economy, and simple operation.
W. Guo, M. Zhao, W. Tan, L. Zheng, K. Tao, L. Liu, X. Wang, D. Chen, X. Fan, J. Org. Chem., 2018, 83, 1402-1413.

A highly efficient and regioselective Co(III)-catalyzed C-H activation/cyclization of simple, cheap, and easily available anilines with alkynes enables a direct synthesis of a broad range of privileged quinolines. In this reaction, DMSO serves both as the solvent and a C1 building block.
X. Xu, Y. Yang, X. Zhang, W. Yi, Org. Lett., 2018, 20, 566-569.

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.

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