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:
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:
Hantzsch Dihydropyridine (Pyridine) 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.
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:
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
A MCM-41-immobilized bidentate phosphine palladium complex catalyzes an
efficient carbonylative cyclization of aryl iodides and 2-hydroxyacetophenones
under 3 bar of carbon monoxide in the presence of DBU in DMSO at 120°C to
provide a wide variety of flavones in very good yields. The supported palladium
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A copper-based system enables methylene insertion between an amine and an
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method gives an expedient access to a broad range of propargylic amines in good
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Pd(OAc)2/PCy3HBF4 catalyzes an addition of
aryl halides and alkynes to norbornenes to construct saturated bridged C-C bonds.
This efficient difunctionalization of norbornenes includes C-X/C-H bond cleavage and
highly selective C(sp3)-C(sp2)/C(sp3)-C(sp)
bond formation. The reaction offers broad substrate scope and
excellent functional group tolerance.
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A palladium-catalyzed asymmetric C-C bond activation/carbonylation of
cyclobutanones with CO provides chiral indanones bearing a quaternary carbon
stereocenter in good yields with an excellent enantiomeric ratio and good
functional group tolerance. Transformations of the products to chiral
3,4-dihydroquinolin-2(1H)-ones and 1H-indenes are also reported.
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Visible-light mediates a photocatalytic regioselective [2 + 2 + 1] radical
annulation reaction of alkenes, tert-butyl nitrite, and gem-dihalides
to provide isoxazolines in good yields under mild conditions. Whereas gem-dihalides
serve as C1 synthons, cheap tert-butyl nitrite acts as an ideal "N-O"
synthon.
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A polyaniline-graphitic carbon nitride-titanium dioxide composite catalyzes a
radical cascade reaction of an aryl diazonium salt, DABCO·(SO2)2
and 3-bromoprop-1-ene to provide aryl allyl sulfones under visible light
irradiation. A series of substrates were tolerated, providing the corresponding
products in good yields. Moreover, the photocatalyst could be readily recovered
and reused several times.
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Addition of an allyl copper species to an isocyanate provides access to
α-vinyl β-boryl amides in high yields and enantioselectivities. The
diversification of these products affords highly useful scaffolds.
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A visible-light-induced excited-state copper-catalyzed [4 + 1] annulation
reaction of acrylamides and aroyl chlorides provides a wide range of γ-H, -OH,
and -OR-substituted α,β-unsaturated-γ-lactams . The procedures offer mild
reaction conditions, broad substrate scope, and high functional group tolerance.
S. Sarkar, A. Banerjee, J. A. Shah, U. Mukherjee, N. C. Frederiks, C. J.
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The one-pot reaction of N-(2-formylaryl)sulfonamides, secondary
amines, and calcium carbide as convenient alkyne source enables a switchable
synthesis of 2-methylene-3-aminoindolines and 2-methyl-3-aminoindoles in good
yields.
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The reaction of sulfoxonium ylides with primary or secondary amines afforded
α-ketothioamides in the presence of elemental sulfur, whereas α-ketoamides were
produced when I2 and TBHP were present. This simple, scalable
reaction proceeded well at room temperature, tolerated a range of functional
group, and generated the corresponding products in very good yields.
T. N. Chaubey, P. J. Borpatra, A. Sharma, S. K. Pandey, Org. Lett., 2022, 24,
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Benzoic acid catalyzes an efficient multicomponent reaction of readily
available vinyl azides, aromatic aldehydes, and aromatic amines to provide
1,2,5-trisubstituted imidazoles under metal-free conditions without generating
any toxic waste. This convenient approach offers high functional group
compatibility.
J. Li, X. Jia, J. Qiu, M. Wang, J. Chen, M. Jing, Y. Xu, X. Zheng, H. Dai, J. Org. Chem., 2022, 87,
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An efficient synthesis of 2-substituted 3-thioxoisoindolin-1-one derivatives is
based on the solvent-free reaction of 2-carboxybenzaldehyde with aliphatic
amines and sulfur at 100°C. This reaction enables a facile synthesis of
asymmetric thioxoisoindolin-1-one derivatives with phthalimide backbones.
F. Gholami, A. Moazzam, S. Bahadorikhalili, M. Adib, S. Hosseini, B. Larijani,
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A visible-light-promoted three component reaction of diazo compounds,
nitriles, and carboxylic acids provides a wide range of imide products in very
good yield. The reaction utilizes acceptor-only diazo compounds as carbene
precursors and nitriles as carbene-trapping reagents to form the key nitrile
ylides.
B.-G. Cai, W.-Z. Yao, L. Li, J. Xuan, Org. Lett.,
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A copper(I)-catalyzed tandem reaction of 2-bromoaryl ketones, terminal alkynes,
and CH3CN efficiently produces densely functionalized isoquinolines
via N atom transfer and a three-component [3 + 2 + 1] cyclization in a facile,
highly selective, and general manner.
L. Su, S. Xie, J. Dong, F. Liu, S.-F. Yin, Y. Zhou, Org. Lett.,
2022, 24, 5994-5999.
A Ni-catalyzed three-component cross-electrophile coupling of 1,3-dienes with
aldehydes and aryl bromides using manganese metal as the reducing agent provides
1,4-disubstituted homoallylic alcohols.
Y.-Q. Qi, S. Liu, Y. Xu, Y. Li, T. Su, H.-L. Ni, Y. Gao, W. Yu, P. Cao, P. Hu,
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A Xantphos-containing dinuclear palladium complex catalyzes a geminal
aminoallylation of diazocarbonyl compounds to provide a range of quaternary
α-amino esters. Direct N-H insertion, allylic alkylation of amino nucleophiles,
and diene formation were not observed under standard conditions.
P. Ou, L. Zhu, Y. Yu, L. Ma, X. Huang, Org. Lett.,
2022, 24, 4109-4113.
A general palladium-catalyzed carbonylative synthesis of acyl fluorides from
aryl, heteroaryl, alkyl, and functionalized organic halides proceeds via a
synergistic combination of visible light photoexcitation of Pd(0) to induce
oxidative addition with a ligand-favored reductive elimination. Subsequent
nucleophilic reactions provide highly functionalized carbonyl-containing
products.
Y. Liu, C. Zhou, M. Jiang, B. A. Arndtsen, J. Am. Chem. Soc.,
2022, 144, 9413-9420.
The use of an electrophilic cyanation source enables electrocatalytic
three-component acylcyanations and aminocyanations of a broad range of simple
alkenes. The reaction offers high functional group tolerance and can easily be
scaled up.
X. Kong, X. Chen, Y. Chen, Z.-Y. Cao, J. Org. Chem., 2022, 87,
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