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)
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:
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:
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.
This interesting isocyanide chemistry has been rediscovered, leading to an overwhelming number of useful transformations. One of these is the 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:
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
Books on Multicomponent Reactions
Jieping Zhu, Hugues Bienaymé
Hardcover, 468 Pages
First Edition, 2005
ISBN: 3-527-30806-7 - Wiley-VCH
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.
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.
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