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 three-component reaction of potassium alkyltrifluoroborates, DABCO·(SO2)2
as sulfur dioxide surrogate, and alkenes under photocatalysis provides diverse
sulfones in very good yields at room temperature. This reaction works
efficiently under mild conditions via generation of alkyl and alkylsulfonyl
radicals as key intermediates, and a reductive single-electron transfer.
T. Liu, Y. Li, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett.,
2018, 20, 3605-3608.
A zinc salt promotes cyclization as well as provides a counteranion in a
redox-neutral synthesis of isoquinolinium salts via C-H activation of
presynthesized or in situ formed imines and coupling with α-diazo ketoesters.
Under three-component conditions, both ketone and aldehydes are viable
substrates. The coupling of imines with diazo malonates under similar conditions
afforded isoquinolin-3-ones as the coupling product.
M. Tian, G. Zheng, X. Fan, X. Li, J. Org. Chem., 2018, 83,
6477-6488.
A palladium-catalyzed, three-component tandem reaction of 2-aminobenzonitriles,
aldehydes, and arylboronic acids provides diverse quinazolines good yields. The
reaction tolerates bromo and iodo groups.
K. Hu, Q. Zhen, J. Gong, T. Cheng, L. Qi, Y. Shao, J. Chen, Org. Lett.,
2018, 20, 3061-3064.
A thiol-promoted site-specific addition of 1,3-dioxolane to imines through a
radical chain process enables a metal-free and redox-neutral conversion of
inexpensive materials to a broad range of protected α-amino aldehydes in very
good yields using only a catalytic amount of radical precursor. Both the thiol
and a small amount of oxygen from air are indispensable to the success of this
reaction.
H. Zeng, S. Yang, H. Li, D. Lu, Y. Gong, J.-T. Zhu, J. Org. Chem., 2018, 83,
5256-5266.
An efficient copper-catalyzed aerobic oxidative dehydrogenative annulation of
amines, alkynes, and O2 provides trisubstituted oxazoles via dioxygen
activation and oxidative C-H bond functionalization.
J. Pan, X. Li, X. Qiu, X. Luo, N. Jiao, Org. Lett.,
2018, 20, 2762-2765.
Practical Cu-catalyzed oxidative, multiple Csp3-H bond cleavage
processes achieve a synthesis of thiazoles from simple aldehydes, amines, and
element sulfur in the presence of molecular oxygen as a green oxidant.
X. Wang, X. Qiu, J. Wei, J. Liu, S. Song, W. Wang, N. Jiao, Org. Lett.,
2018, 20, 2632-2636.
A practical and general microwave-mediated Biginelli cyclocondensation of
guanidine with aldehydes and β-dicarbonyl compounds provides functionalized
2-amino-3,4-dihydropyrimidines in good yields, with short reaction times and a
simple workup. The scope is considerably wider than that of similar reactions
carried out under conventional heating.
F. Felluga, F. Benedetti, F. Berti, S. Drioli, G. Regini,
Synlett, 2018, 29, 986-992.
A transition-metal-free cleavage of C-C triple bonds in aromatic alkynes in the
presence of S8 and amides furnishes aryl thioamides in good yields.
The method offers mild reaction conditions, as well as wide substrate scope that
is particularly compatible with some internal aromatic alkynes and acetamides.
K. Xu, Z. Li, F. Cheng, Z. Zuo, T. Wang, M. Wang, L. Liu, Org. Lett.,
2018, 20, 2228-2231.
Nickel catalyzes a multicomponent coupling reaction of terminal alkenes, carbon
dioxide, and organoaluminum reagents to provide homoallylic alcohols in good
yields with excellent regio- and stereoselectivities.
Y. Mori, C. Shigeno, Y. Luo, B. Chan, G. Onodera, M. Kimura,
Synlett, 2018, 29, 742-746.
Photoredox catalysis enables a direct oxidative addition of CF3 and H2O
to alkynes to provide α-trifluoromethyl ketones via rapid enol-keto
tautomerization. The reaction exhibits high functional group tolerance and
regioselectivity. In addition, trifluoromethylated heterocycles of various sizes
were synthesized from α-CF3-substituted diketones.
Y. R. Malpani, B. K. Biswas, H. S. Han, Y.-S. Jung, S. B. Han, Org. Lett.,
2018, 20, 1693-1697.
The use of 1,3-diiodo-5,5,-dimethylhydantoin and HF-based reagents enables a
regio- and stereoselective iodofluorination of internal and terminal alkynes. A
facile method for a controlled regioselective double iodofluorination of
terminal alkynes is also presented.
L. Pfeifer, V. Gouverneur, Org. Lett.,
2018, 20, 1576-1579.
A CuI/MNAO [2-((2-methylnaphthalen-1-yl)amino)-2-oxoacetic acid] catalyzed
cross-coupling of (hetero)aryl chlorides with potassium cyanate in alcohols
provides N-(hetero)aryl carbamates in very good yields at 120-130°C.
Moreover, (hetero)aryl bromides and (hetero)aryl iodides were reacted at lower
catalyst loadings and lower temperatures.
S. V. Kumar, D. Ma, J. Org. Chem., 2018, 83,
2706-2713.
An enantioselective Cu-catalyzed borylative cross-coupling reaction of alkenes,
bis(pinacolato)diboron, and methyl iodide provides the desired methylboration
products with excellent diastereoselectivities and enantioselectivities.
B. Chen, P. Cao, Y. Liao, M. Wang, J. Liao, Org. Lett.,
2018, 20, 1346-1349.
A copper-promoted [3 + 1 + 1]-type cyclization reaction enables a selective
construction of 2-aryl or 2-benzyl substituted benzothiazoles from o-iodoaniline
derivatives, S8, and N-tosylhydrazones depending on the
reaction system.
Y. Huang, P. Zhou, W. Wu, H. Jiang, J. Org. Chem., 2018, 83,
2460-2466.
A simple copper-catalyzed aminosulfonylation of aryldiazonium tetrafluoroborates,
DABCO·(SO2)2, and N-chloroamines provides a
wide range of sulfonamides in good yields under mild conditions. Mechanistic
investigation suggests that a radical process and transition-metal catalysis
take place.
F. Zhang, D. Zheng, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett.,
2018, 20, 1167-1170.
A three-component, Ni-catalyzed reductive coupling enables a convergent
synthesis of tertiary benzhydryl amines, which are challenging to access by
traditional reductive amination methodologies. The condensation of secondary
N-trimethylsilyl amines with benzaldehydes provides iminium ions in situ,
which react with several distinct classes of organic electrophiles.
C. Heinz, J. P. Lutz, E. M. Simmons, M. M. Miller, W. R. Ewing, A. G. Doyle, J. Am. Chem. Soc., 2018,
140, 2292-2300.
Copper catalysis enables the synthesis of polysubstituted pyrroles from
aldehydes, amines, and β-nitroalkenes. Remarkably, the use of
α-methyl-substituted aldehydes provides efficient access to a series of tetra-
and pentasubstituted pyrroles via an overwhelming 1,2-phenyl/alkyl migration.
Non α-substituted aldehydes provide the corresponding trisubstituted
pyrroles.
D. Andreou, M. G. Kallitsakis, E. Loukopoulos, C. Gabries, G. E. Kostakis, J.
N. Lykakis, J. Org. Chem., 2018, 83,
2104-2113.
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