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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 highly regioselective cyanotrifluoromethylation of electron-deficient styrenes with a trifluoromethylated hypervalent iodine reagent proceeds under mild conditions in the presence of a bulky phosphine and CuCN. The process involves the consecutive formation of two C-C bonds in a single addition reaction. In the presence of a p-methoxy substituent in the styrene, oxytrifluoromethylation occurs instead of the cyanotrifluoromethylation.
N. O. Ilchenko, P. G. Janson, K. J. Szabó, J. Org. Chem., 2013, 78, 11087-11091.

Copper-catalyzed condensation and C-N bond formation of 2-iodoanilenes, arylacetaldehydes, and sodium azide, in a one-pot three-component reaction enables the synthesis of quinoxalines in good yields. Under optimized reaction conditions, starting materials were reacted in the presence of CuI, K2CO3 in DMSO at 80°C for 20 hours.
H. Yuan, K. Li, Y. Chen, Y. Wang, J. Cui, B. Chen, Synlett, 2013, 24, 2315-2319.

π-Stacking can be used to increase the barrier to rotation in chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A3-coupling.
F. S. P. Cardoso, K. Abboud, A. Aponick, J. Am. Chem. Soc., 2013, 135, 14548-14551.

A highly efficient Bi(OTf)3-catalyzed multicomponent synthesis of amidomethylated arenes and heteroarenes from readily available starting materials proceeds under mild conditions and has a broad substrate scope with water as the only side product.
A. E. Schneider, G. Manolikakes, Synlett, 2013, 24, 2057-2060.

A simple multicomponent reaction of aldehydes, diethyl phosphite, and azides gives α-aminophosphonates in the presence of iodine and iron under solvent-free conditions. The reactions were completed at room temperature within 5 minutes to 12 hours and afforded the corresponding products in good yields.
Y.-Q. Yu, Synthesis, 2013, 45, 2545-2550.

A multicomponent domino reaction of readily available isocyanides, primary or secondary amines, and gem-diactivated olefins enables a chemoselective, catalyst-free synthesis of structurally diverse, polysubstituted pyrroles in good yields under mild conditions.
X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou, S.-J. Ji, Org. Lett., 2013, 15, 4246-4249.

A catalytic asymmetric 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides was realized using Cu(I)/pybox and axially chiral dicarboxylic acid cocatalysts.
T. Hashimoto, Y. Takiguchi, K. Maruoka, J. Am. Chem. Soc., 2013, 135, 11473-11476.

In ruthenium-catalyzed three-component reactions, ketones, amines, and vicinal diols are converted into various substituted pyrroles in good isolated yields. Additionally, α-functionalized ketones gave synthetically interesting amido-, alkoxy-, aryloxy-, and phosphate-substituted pyrroles in a straightforward manner. The synthetic protocol proceeds with high atom-efficiency and shows a broad substrate scope and functional group tolerance.
M. Zahng, X. Fang, H. Neumann, M. Beller, J. Am. Chem. Soc., 2013, 135, 11384-11388.

A multicomponent process enables the synthesis of 1-aryl 1,2,4-triazoles directly from anilines, amino pyridines, and pyrimidines. The reaction scope was explored with 21 different substrates.
A. Tam, I. S. Armstrong, T. E. La Cruz, Org. Lett., 2013, 15, 3585-3589.

A metal-free decarboxylative three-component coupling reaction was developed. When alkynyl carboxylic acids, paraformaldehyde, and amines were reacted in CH3CN at 65 °C for 3 h, the desired propargylamines were obtained in good yields. This coupling reaction also showed good yield in water solvent. This reaction showed higher selectivity toward alkynyl carboxylic acids than a terminal alkyne.
K. Park, Y. Heo, S. Lee, Org. Lett., 2013, 15, 3298-3301.

An efficient three-component coupling reaction toward a variety of furan derivatives proceeds via a gold-catalyzed coupling reaction of phenylglyoxal derivatives, secondary amines, and terminal alkynes.
J. Li. L. Liu, D. Ding, J. Sun, Y. Ji, J. Dong, Org. Lett., 2013, 15, 2858-2861.

Pd/C-catalyzed oxidative alkoxycarbonylation of terminal alkynes using alcohols in the presence of tetrabutylammonium iodide under CO/O2 gave α,β-alkynyl esters and unsymmetrical maleate esters in very good yields depending on the reaction conditions. The protocols eliminate the use of phosphine ligands and offer catalyst recovery. The catalyst was recycled up to six times without significant loss of catalytic activity.
S. T. Gadge, B. M. Bhanage, Synlett, 2013, 24, 981-986.

A practical one-pot and regiospecific three-component process gives 2,3-disubstituted indoles from 2-bromoanilides via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.
B. Z. Lu, H.-X. Wei, Y. Zhang, W. Zhao, M. Dufour, G. Li, V. Farina, C. H. Senanayake, J. Org. Chem., 2013, 78, 4558-4562.

A simple, efficient, cost-effective, and metal-free multicomponent one-pot synthesis with amines, dialkyl acetylenedicarboxylates, and propargylic alcohols afforded fully substituted pyrroles in high yields in three hours using iodine as a catalyst.
N. Bhunia, B. Das, Synthesis, 2013, 45, 1045-1050.

A Cu-catalyzed regioselective and stereospecific aminoboration of styrenes with bis(pinacolato)diboron and O-benzoyl-N,N-dialkylhydroxylamines delivers β-aminoalkylboranes in good yields. The Cu catalysis enables introduction of both amine and boron moieties to C-C double bonds simultaneously in a syn fashion. Moreover, the use of a chiral biphosphine ligand, (S,S)-Me-Duphos, provides optically active β-aminoalkylboranes.
N. Matsuda, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc., 2013, 135, 4934-4937.

tert-Butyl isocyanide insertion enables a simple and efficient palladium-catalyzed carbonylative Sonogashira coupling. This methodology demonstrates the utility of isocyanides in intermolecular C-C bond construction and provides a novel pathway for the synthesis of alkynyl imines which can undergo simple silica gel catalyzed hydrolysis to afford alkynones. The approach is tolerant of a wide range of substrates and applicable to library synthesis.
T. Tang, X.-D. Fei, Z.-Y. Ge, Z. Chen, Y.-M. Zhu, S.-J. Ji, J. Org. Chem., 2013, 78, 3170-3175.

An efficient synthesis of aryl carbamates - including major carbamate protecting groups - was achieved by introducing alcohols into the reaction of palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate. This methodology also provides direct access to S-thiocarbamates and diisocyanate precursors to polyurethane materials.
E. V. Vinogradova, N. H. Park, B. P. Fors, S. L. Buchwald, Org. Lett., 2013, 15, 1394-1397.

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