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
A. Dömling, I. Ugi, Angew. Chem. Intl. Ed. 2000, 39, 3168.
DOI
A. Dömling, Org. Chem. Highlights 2004, April 5.
Link
Books
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Multicomponent Reactions Jieping Zhu, Hugues Bienaymé Hardcover, 468
Pages |
Recent Literature
Highly functionalized δ-lactones were produced in the presence of a catalytic
amount of the Cu(OAc)2-DIFLUORPHOS complex through three-component assembly of
dialkylzincs, allenic esters, and unactivated ketones. This CAMCR (catalytic
asymmetric multicomponent reaction) constructs two C-C bonds and one
tetrasubstituted chiral center simultaneously.
K. Oisaki, D. Zhao, M. Kanai, M. Shibasaki, J. Am. Chem. Soc., 2007,
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Exposure of aromatic and aliphatic N-arylsulfonyl aldimines to equal
volumes of acetylene and hydrogen gas at 45°C and ambient pressure in the
presence of chirally modified cationic rhodium catalysts provides (Z)-dienyl
allylic amines in highly optically enriched form and as single geometrical
isomers.
E. Skucas, J. R. Kong, M. J. Krische, J. Am. Chem. Soc., 2007,
129, 7242-7243.
Substituted 2-oxazolines, that are found in several families of bioactive
natural products, can be prepared in an efficient and general one-pot,
four-component condensation.
L. Fan, E. Lobkovsky, B. Ganem, Org. Lett., 2007,
9, 2015-2017.
2-Nitrobenzylamine can be used as an ammonia equivalent in a modified U-4CR
multi-component reaction. A photochemical cleavage of the 2-nitrobenzyl group gives
peptides in good yields, without isolation of the protected intermediates.
K. Sung, F.-L. Chen, P.-C. Huang, Synlett, 2006,
2667-2669.
[bmim]OH, a basic ionic liquid, efficiently promotes a one-pot condensation of
aldehydes, malononitrile, and thiophenols to produce highly substituted
pyridines in high yields. The ionic liquid can be recovered and recycled.
B. C. Ranu, R. Jana, S. Sowmiah, J. Org. Chem., 2007,
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Functionalized 2-(sulfonylimino)-4-(alkylimino)azetidine derivatives were
prepared in good to excellent yields via a copper-catalyzed multicomponent
reaction of readily available terminal alkynes, sulfonyl azides, and
carbodiimides without the assistance of a base under very mild conditions.
X. Xu, D. Cheng, J. Li, H. Guo, J. Yan, Org. Lett., 2007,
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Modified Bucherer-Bergs Reaction for the One-Pot Synthesis of 5,5′-Disubstituted
Hydantoins from Nitriles and Organometallic Reagents
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Iodine efficiently catalyzes the three-component coupling of aromatic aldehydes,
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chloride at room temperature to afford β-acetamido ketones in good yields.
B. Das, K. Ravinder Reddy, R. Ramu, P. Thirupathi, B. Ravikanth, Synlett, 2006,
1756-1758.
α-Acyloxy carboxamides were easily obtained in one step by a Passerini reaction
between carboxylic acids, aldehydes and isocyanides in ionic liquids or
polyethyleneglycol as green reaction media.
C. K. Z. Andrade, S. C. S. Takada, P. A. Z. Suarez, M. B. Alves, Synlett, 2006,
1539-1541.
A versatile and highly efficient Zn(OTf)2-catalyzed one-pot
reaction of alkenes, NBS, nitriles, and TMSN3 gives various 1,5-disubstituted
tetrazoles containing an additional α-bromo functionality of the N1-alkyl
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S. Hajra, D. Sinha, M. Bhowmick, J. Org. Chem., 2007,
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A Pd-catalysed termolecular allenylation cascade followed by a Ru catalysed RCM
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H. A. Dondas, B. Clique, B. Cetinkaya, R. Grigg, C. Kilner, J. Morris, V.
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ureas and thioureas. N1-alkyl-, N1-aryl-, and N1,N3-dialkyl-3,4-dihydropyrimidin-2(1H)-(thi)ones
were readily prepared in excellent yield using chlorotrimethylsilane in N,N-dimethylformamide
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reaction of amines, aldehydes or ketones, and di-/trialkyl phosphites (Kabachnik-Fields
reaction) under solvent-free conditions to afford the corresponding
α-aminophosphonates in high yields. Using Mg(ClO4)2 as
catalyst, no imines or α-hydroxy phosphonates were observed as intermediates.
S. Bhagat, A. K. Chakraborti, J. Org. Chem., 2007,
72, 1263-1270.
A copper(I)-catalyzed three-component reaction of amines, propargyl halides and
azides forms 1-substituted-1H-1,2,3-triazol-4-ylmethyl)-dialkylamines in
water. Synthetic advantages are high atom economy, low environmental impact,
atmospheric oxygen, wide substrate scope, mild reaction condition and good
yields.
Z.-Y. Yan, Y.-B. Zhao, M.-J. Fan, W.-M. Liu, Y.-M. Liang, Tetrahedron, 2005,
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The three-component coupling of aldehyde, dimethyl acetylenedicarboxylate (DMAD)
and cyclohexyl isocyanide proceeds efficiently in [bmim]BF4 ionic
medium under extremely mild conditions to afford 2-aminofurans in high yields.
The recovered ionic liquid was reused for five to six times with consistent
activity.
J. S. Yadav, B. V. S. Reddy, S. Shubashree, K. Sadashiv, J. J. Naidu, Synthesis,
2004, 2376-2380.
A silver(I) triflate-catalyzed one-pot three-component reaction of terminal
alkynes, p-anisidine, and diethyl formylphosphonate hydrate gave good
yields of N-PMP protected α-aminopropargylphosphonates.
R. Dodda, C.-G. Zhao, Org. Lett., 2007,
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Various
ketones as the electrophiles react in a one pot three-component coupling with an aluminum allenoate
intermediate derived from ethyl propiolate and alluminium iodide to yield β-iodo Morita-Baylis-Hillman adducts with high
yield and excellent Z-stereoselectivity.
S. Il Lee, G.-S. Hwang, D. H. Ryu, Synlett, 2007, 59-62.
Homoallylic α-amino esters and amines were prepared via a Pd(II)-catalyzed
coupling of 1,2-nonadiene and boronic acids with ethyl iminoacetate or aliphatic,
aromatic, and heteroaromatic imines.
C. D. Hopkins, H. C. Malinakova, Org. Lett., 2006,
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Please cite and link this page as follows:
Multicomponent Reactions ( URL: http://www.organic-chemistry.org/topics/multicomponent-reactions.shtm )
Friday, 09-May-2008 16:13:23 CEST
