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
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,
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.
A simple, efficient, cost-effective, and metal-free four-component coupling
reaction of aldehydes, amines, dialkyl acetylenedicarboxylates, and nitromethane
furnished the corresponding 1,2,3,4-tetrasubstituted pyrroles under reflux in
the presence of molecular iodine as a catalyst in high yields within 8 hours.
B. Das, N. Bhunia, M. Lingaiah, Synthesis, 2011,
3471-3474.
A novel electrophilic one-pot reaction of an olefin, a cyanimide, an
amine, and N-bromosuccinimide enables the synthesis of a number of
guanidine derivatives with very good yields - including an rTRTVI precursor.
L. Zhou, J. Chen, J. Zhou, Y.-Y. Yeung, Org. Lett., 2011,
13, 5804-5807.
A one-pot reaction of aldehydes, 2-aminopyridines, and terminal alkynes, in
the presence of the copper(I) iodide-CuI-NaHSO4•SiO2 combination catalyst in
refluxing toluene, generates the corresponding imidazo[1,2-a]pyridines in high to excellent yields.
S. Mishra, R. Ghosh, Synthesis, 2011,
3463-3470.
A three-component reaction of nitroarenes, aldehydes, and phenylacetylene in the
presence of indium in dilute hydrochloric acid produces quinoline derivatives
under reflux. The conversion involves reduction of the nitroarenes to anilines
followed by coupling of the anilines, aldehydes, and phenylacetylene, followed
by cyclization of the resulting species and dehydrogenation of the cyclic
intermediates.
B. Das, P. Jangili, J. Kashanna, R. A. Kumar, Synthesis, 2011,
3267-3270.
Ketones, dienes, and B2(pin)2 undergo a stereoselective
multicomponent coupling reaction in the presence of catalytic amounts of Ni(cod)2
and P(t-Bu)3. A subsequent oxidation furnishes 1,3-diols as
the major reaction product.
H. Y. Cho, Z. Yu, J. P. Morken, Org. Lett., 2011,
13, 5267-5269.
An efficient three-component coupling reaction of substituted picolinaldehydes,
amines, and formaldehyde produces imidazo[1,5-a]pyridinium ions in high
yields under mild conditions, allowing the incorporation of diverse
functionality and chiral substituents. Higher order condensations are also
described that provide access to multidentate NHC ligands useful for a variety
of applications.
J. T. Hutt, Z. D. Aron, Org. Lett., 2011,
13, 5256-5259.
A straightforward and efficient Yb(OTf)3 catalyzed three-component
reaction of aldehydes, alkynes, and amines under microwave irradiation in an
ionic liquid provides 2,4-disubstituted quinolines in excellent yield under mild
reaction condition. The catalyst can be recycled up to four times.
A. Kumar, V. K. Rao, Synlett, 2011,
2157-2162.
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