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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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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.

A highly stereoselective three-component direct Mannich reaction between aromatic aldehydes, p-toluenesulfonamide, and unfunctionalized ketones in the presence of a bifunctional quinidine thiourea catalyst gives the corresponding N-tosylated β-aminoketones in high yields and excellent diastereo- and enantioselectivities.
Q. Guo, J. C.-G. Zhao, Org. Lett., 2013, 15, 508-511.

A convenient and practical method for the one-pot, three-component synthesis of terminal vinylphosphonates from aldehydes, nitromethane and trialkylphosphites through a tandem Henry-Michael reaction followed by nitro elimination in the presence of 5-hydroxypentylammonium acetate (5-HPAA) as a task-specific ionic liquid offers good yields of the products under mild reaction conditions.
S. Sobhani, M. Honarmand, Synlett, 2013, 24, 236-240.

An easy and efficient one-pot, three-component reaction of aldehydes, hydroxylamine, and [bmim]N3 enables the synthesis of 5-substituted 1H-tetrazole derivatives.
M. M. Heravi, A. Fazeli, H. A. Oskooie, Y. S. Beheshtiha, H. Valizadeh, Synlett, 2012, 23, 2927-2930.

An efficient base-catalyzed [3 + 3] oxidative aromatization of α,β-unsaturated carbonyl compounds with dimethyl glutaconate under mild, metal-free conditions affords substituted benzenes in high to excellent yields with oxygen as oxidant and water as sole byproduct. In situ generation of the α,β-unsaturated carbonyl compounds from aldehydes and ketones enables a more convenient tandem [3 + 2 + 1] aerobic oxidative aromatization reaction.
A. Diallo, Y.-L. Zhao, H. Wang, S.-S. Li, C.-Q. Ren, Q. Liu, Org. Lett., 2012, 14, 5776-5779.

An intermolecular reductive coupling of ynoates and aldehydes in the presence of a silane using catalytic amounts of Ni(COD)2, an N-heterocyclic carbene ligand, and PPh3 delivers invaluable silyl-protected γ-hydroxy-α,β-enoates. This methodology provides a quick entry to many other 1,4-difunctional compounds and oxygen-containing five-membered rings. The intermediacy of metallacycles in the catalytic process has been established.
S. K. Rodrigo, H. Guan, J. Org. Chem., 2012, 77, 8303-8309.

Utilizing a recyclable tartaric acid-SDS catalyst system help to achieve a green synthesis of 2,3-dihydro/spiroquinazolin-4(1H)-ones via three-component cyclocondensation reaction of isatoic anhydride, amines and aldehydes/ketones. Mechanochemical activation at room temperature lead to significant improvement on previously described methods for the synthesis of such compounds even in large-scale reactions.
R. Sharma, A. K. Pandey, P. M. S. Chauhan, Synlett, 2012, 23, 2209-2214.

An efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines allows the synthesis of thioamides in the presence of elemental sulfur under solvent-free conditions.
T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Org. Lett., 2012, 14, 4274-4277.

The unusual alcohol mediated reaction of 4-hydroxycoumarins and β-nitroalkenes leads to 4-oxo-2-aryl-4H-chromene-3-carboxylate (flavone-3-carboxylate) derivatives. The transformation occurs via the in situ formation of a Michael adduct, followed by the alkoxide ion mediated rearrangement of the intermediate. The effects of different media on the reaction were investigated.
M. R. Zanwar, M. J. Raihan, S. D. Gawande, V. Kavala, D. Janreddy, C.-W. Kuo, R. Ambre, C.-F. Yao, J. Org. Chem., 2012, 77, 6495-6504.

An efficient one-pot synthesis of isoquinolines and heterocycle-fused pyridines by a three-component reaction involves condensation of aryl ketones and hydroxylamine, rhodium(III)-catalyzed C-H bond activation of the in situ generated oxime, and cyclization with an internal alkyne. This protocol enables rapid assembly of multisubstituted isoquinolines as well as fused heterocycles.
L. Zheng, J. Ju, Y. Bin, R. Hua, J. Org. Chem., 2012, 77, 5794-5800.

Self-assembly of copper sulfate and a poly(imidazole-acrylamide) amphiphile provides a highly active, reusable, globular, solid-phase catalyst for click chemistry. The insoluble amphiphilic polymeric imidazole Cu catalyst drove the cycloaddition of various of alkynes and organic azides at very low catalyst loadings and can be readily reused without loss of activity to give the corresponding triazoles quantitatively.
Y. M. A. Yamada, S. M. Sarkar, Y. Uozumi, J. Am. Chem. Soc., 2012, 134, 9285-9286.

With a mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO4 with glucose, an efficient and eco-friendly multicomponent cascade reaction of A3-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded therapeutically important versatile N-fused imidazoles.
S. K. Guchhait, A. L. Chandgude, G. Priyadarshani, J. Org. Chem., 2012, 77, 4438-4444.

A single Cu(II) catalyst couples a diverse range of nitrogen sources with various alkynes and aldehydes without the addition of ligand or base. Copper-catalyzed alkynylation involving p-toluenesulfonamide provides high yields of N-Ts-protected propargylamines. The superior activity of copper(II) triflate also allows this three-component alkynylation to incorporate a ketone.
C. E. Meyet, C. J. Pierce, C. H. Larsen, Org. Lett., 2012, 14, 964-967.

Benzyl halides, that are first oxidized to aldehydes under mild Kornblum conditions, undergo a three-component reaction with isatoic anhydride and primary amines to produce 4(3H)-quinazolinones in excellent yields.
M. Adib, E. Sheikhi, H. R. Bijanzadeh, Synlett, 2012, 23, 85-88.

Efficient and convenient three-component couplings of aryl halides, amino alcohols and tert-butyl isocyanide under palladium catalysis provide a range of oxazolines in excellent yield. The use of 1,2-amino phenols instead of amino alcohols enables the synthesis of benzoxazoles.
P. J. Boissarie, Z. E. Hamilton, S. Lang, J. A. Murphy, C. J. Suckling, Org. Lett., 2011, 13, 6184-6187.

A copper-catalyzed, one-pot, three-component reaction of 2-haloanilines, aldehydes, and NaN3 enabled the synthesis of benzimidazoles in good yields using catalytic amounds of CuCl and TMEDA in DMSO at 120°C for 12 h. The reaction tolarated many functional groups such as ester, nitro, and chloro.
Y. Kim, M. R. Kumar, N. Park, Y. Heo, S. Lee, J. Org. Chem., 2011, 76, 9577-9583.

Polyethylene glycol (PEG) is an inexpensive nontoxic and effective medium for the one-pot synthesis of N-substituted azepines under catalyst-free conditions in excellent yields. Environmental acceptability, low cost, high yields, and recyclability of the PEG are the important features of this protocol.
R. Mallepalli, L. Yeramanchi, R. Bantu, L. Nagarpu, Synlett, 2011, 2730-2732.

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