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
Imines generated in situ from aldehydes and p-methoxyaniline, as well
as other azomethines, can be used as radical acceptors for reactions with
carboxylic acids as radical precursors in the presence of acridine and
tetrabutylammonium decatungstate photocatalysts.
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of unactivated alkenes with in situ prepared dithiocarbamic acids provides a
wide array of alkyl dithiocarbamates. A variety of terminal, internal, cyclic,
and acyclic unactivated alkenes were applied successfully in this
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reductive amination, simplifies purification, and improves reaction scope.
Furthermore, this reaction can be used for gram-scale synthesis of
medicinally-relevant compounds, also harnesses redox active esters as alkyl
donors, and facilitates the synthesis of α-trialkyl tertiary amines, which are
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An efficient synthesis of β-lactams is based on carbonylation of diazo
compounds, using [Co2(CO)8], to the corresponding ketenes,
followed by [2 + 2] cycloaddition with imines. Electronically and structurally
diverse substrates produce the corresponding β-lactams under mild reaction
conditions in very good yields.
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A photoinduced iron-catalytic decarboxylation of carboxylic acids enables a
mild, highly efficient, convenient synthesis of sulfones in the presence of
DABSO and carbon electrophiles. A mechanism involving an iron-catalyzed
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aryl halide CO insertion, alkene insertion, and
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utilizing Co2(CO)8 as an abundant solid carbonyl source,
provides 1,4-keto esters and 1,4-diketones in good
yields. The products can easily be subjected to further functionalization in
synthesis. Mechanism studies indicated that this reaction is initiated by the
generation of an aryl
radical.
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A modular and transition-metal-free, aryne-induced three-component coupling
protocol allows the facile synthesis of structurally diverse N-aryl (iso)quinolones
from readily accessible halo-(iso)quinolines in the presence of water. The
method enables scale-up synthesis, downstream derivatization, and flexible
synthesis involving other types of aryne precursors.
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A 1,4-alkylcyanation of enynes with cyclic alcohol derivatives in the
presence of trimethylsilyl cyanide (TMSCN) under copper/photoredox dual
catalysis provides efficient access to functionalized allenes with easily
transformable aldehyde and cyano groups. The reactions proceeded smoothly under
mild conditions with broad functional groups tolerance.
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A practical base-promoted tandem condensation N-alkylation reaction of
aldehydes and hydrazines with alkyl halides provides trisubstituted hydrazones
without chemoselectivity problems in a one-pot manner. Halo- and
heterofunctional groups, as well as free hydroxyl and amino groups, are
tolerated in this transformation to produce a wide range of trisubstituted
hydrazones in very good yields.
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A three-component reaction of a terminal alkyne, a diazo ester, and an
allylic carbonate provides 1,5-enynes with an all-carbon quaternary center via
cooperative Cu/Rh catalysis with Xantphos as the ligand. In reactions using
propargylic alcohols, a Meyer-Schuster rearrangement results in an unprecedented
acylation-allylation of carbenes.
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A convenient and mild iron-catalyzed 1,2-azidoamidation of 1,3-dienes shows
excellent functional group compatibility to furnish versatile precursors to
1,2-diamine products with high levels of site, regio-, and stereoselectivity.
The reaction is proposed to proceed via a single electron transfer/radical
addition/C-N bond formation relay process.
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An electrochemical multicomponent reaction of methanol as green C1 source,
secondary amines, and sulfonamides provides a broad range of N-sulfonyl
amidines in good yields.
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Sodium carbonate promotes a facile synthesis of 5-amino-1,2,4-thiadiazoles
and 5-amino-1,2,4-selenadiazoles in good yields with elemental sulfur and
selenium in the presence of air as the green oxidant. The reaction offers low
cost, low toxicity, and stable sulfur and selenium sources, water as the sole
byproduct, simple operation, and a broad substrate scope.
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A mild one-pot reaction of weakly nucleophilic aromatic amines, highly
nucleophilic secondary aliphatic amines, and carbonyl sulfide (COS) provides a
series of asymmetric ureas under catalyst-free conditions.
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A highly regioselective intermolecular azidoamination of olefins under
metal-free conditions enables an operationally simple synthesis of 2-azidoimines
as versatile precursors to value-added vicinal unsymmetrical diamines. The
approach proceeds through two differentiated N-centered radicals.
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An effective and economical acid-promoted three-component reaction enables
the construction of C-P and C-C bonds for the synthesis of γ-ketophosphine
oxides with water as the only byproduct. The reaction proceeds by phospha-aldol
elimination, in which a benzylic carbocation is generated from the
phosphorylation of aldehydes, which then reacts with ketone enolates under
acidic conditions.
X.-H. Wang, Y.-W. Xue, C.-Y. Bai, Y.-B. Wang, X.-H. Wei, Q. Su, J. Org. Chem., 2023, 88,
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NH4I promotes a facile and practical three-component tandem
reaction of ketones, NH4OAc, and N,N-dimethylformamide
dimethyl acetal to provide a broad range of substituted pyrimidines in
acceptable yields under metal- and solvent-free conditions. The method offers a
broad substrate scope with good functional group tolerance, and gram-scale
synthesis.
F. Fang, J. Xia, S. Quan, S. Chen, G.-J. Deng, J. Org. Chem., 2023, 88,
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In situ generated aryltrifluoromethylnitrones can be trapped with arynes to
access trifluoromethylated benzoxazolines in high yields. This three-component
strategy involves a nitrone formation/[3 + 2] cycloaddition/thermal
rearrangement cascade.
M. F. Jamali, M. Ahmad, S. P. Chandrasekharan, K. Mohanan, Org. Lett., 2023, 25,
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An electrochemical, Pd-catalyzed N-aroylation of NH-sulfoximines
with arylhydrazine hydrochlorides and carbon monoxide in the presence of TBAI
provides a wide range of products in good yield. This oxidant- and ligand-free
method offers mild
reaction conditions that are easy to
scale up to gram scale.
M. Li, M. Peng, W. Huang, L. Zhao, S. Wang, C. Kang, G. Jiang, F. Ji, Org. Lett., 2023, 25,
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A three-component reaction of nitrosoarenes, olefins, as well as iodonium
ylides provides N-aryl isoxazolidines derivatives in good yields. This
reaction includes a 1,3-dipolar cycloaddition of nitrones generated in situ from
iodonium ylides and nitroso compounds, with olefins in the absence of any
catalysts and additives.
Y.-R. Zhao, L. Li, J. Xuan, Synlett, 2023,
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