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 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,
K.-Q. Zhao, B.-Q. Wang, B. Chen, Org. Lett.,
2022, 24, 5023-5028.
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,
7013-7021.
A photoredox-catalyzed sulfonylation of silyl enol ethers with DABCO·(SO2)2
and thianthrenium salts provides diverse β-keto sulfones in moderate yields with
good functional group compatibility. The use of a MeOH-derived methyl
thianthrenium intermediate enables the synthesis of α-methylsulfonated ketones.
F.-S. He, P. Bao, Z. Zang, F. Yu, W.-P. Deng, J. Wu, Org. Lett.,
2022, 24, 2955-2960.
A Ni-catalyzed carbonylation of cyclopropanols with benzyl
bromides provides multisubstituted cyclopentenones in good yields under 1 atm of CO. The
reaction proceeds through cascade carbonylation of benzyl bromides, followed by
generation of nickel homoenolate from cyclopropanols via β-C elimination to
afford 1,4-diketones, which undergoes intramolecular Aldol condensation.
L. Hou, W. Huang, X. Wu, J. Qu, Y. Chen, Org. Lett.,
2022, 24, 2699-2704.
A copper-catalyzed highly anti-selective radical 1,2-alkylarylation of
terminal alkynes with aryl boronic acids and alkyl bromides providesg facile
access to various stereodefined trisubstituted alkenes in high yield under mild
reaction conditions. The reaction exhibits high compatibility with a wide range
of terminal alkynes and diverse aryl boronic acids.
J.-B. Tang, J.-Q. Bian, Y.-S. Zhang, Y.-F. Cheng, H.-T. Wen, Z.-L. Yu, Z.-L.
Yu, Z.-L. Li, Q.-S. Gu, G.-Q. Chen, X.-Y. Liu, Org. Lett.,
2022, 24, 2536-2540.
Dibenziodolium triflate displays high catalytic activity
for the Groebke-Blackburn-Bienaymé Reaction that leads to a series of imidazopyridines.
This salt can play the role of a hybrid hydrogen- and halogen-bond-donating organocatalyst, which electrophilically activates the carbonyl and imine groups.
M. V. Il'in, A. A. Sysoeva, A. S. Novikov, D. S. Bolotin, J. Org. Chem., 2022, 87,
4569-4579.
A [3+1+1+1] annulation of arylamines, arylaldehydes and dimethyl sulfoxide
(DMSO) provides 3-arylquinolines in very good yields. In this
annulation, arylamines provide two carbon atoms and one nitrogen atom,
arylaldehydes furnish one carbon atom, and DMSO provides two nonadjacent
methines (=CH-).
T. Yang, H. Li, Z. Nie, M.-d. Su, W.-p. Luo, Q. Liu, C.-C. Guo, J. Org. Chem., 2022, 87,
2797-2808.
Water mediates a greener and mild synthesis of thioamides with no input
energy, additives, or catalysts. The presented protocol enables the conversion
of readily available starting materials and the use of different array amines,
and can easily be scaled-up.
A. Gupta, J. K. Vankar, J. P. Jadav, G. N. Gururaja, J. Org. Chem., 2022, 87,
2410-2420.
An ultrasound-promoted three-component reaction provides C3-cyanomethylated
imidazo[1,2-a]pyridines under catalyst-free, oxidant-free, and mild
conditions. A series of C3-cyanomethylated imidazo[1,2-a]pyridines were rapidly
prepared with satisfactory yields and good functional group compatibility.
. Zhang, Y. Zhang, J. Zhang, Q. Wu, H. Yang, Synlett, 2022,
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264-268.
A copper-catalyzed three-component reaction of α,β-unsaturated ketoximes,
paraformaldehyde, and amines provides imidazoles and dihydroimidazoles depending
on the reaction conditions in good yields with a broad substrate scope.
G. Xu, C. Jia, X. Wang, H. Yan, S. Zhang, Q. Wu, N. Zhu, J. Duan, K. Guo, Org. Lett.,
2022, 24, 1060-1065.
An N-heterocyclic carbene (NHC) and photo-co-catalyzed alkylacylation of
olefins in the presence of a diazo ester provides 1,5-ketoesters with great atom
economy and N2 as the only byproduct. Particularly, this radical
process employs a traditional carbene precursor as the radical
source.
B. Zhang, J.-Q. Qi, Y. Liu, Z. Li, J. Wang, Org. Lett., 2022, 24,
279-283.
Iodine catalyzes a cascade reaction between enaminones, hydrazines, and DMSO in
the presence of Selectfluor to provide 1,4-disubstituted pyrazoles. DMSO plays a
dual role as the C1 source and the reaction medium. In addition, the
synthesis of 1,3,4-trisubstituted pyrazoles using aldehydes as alternative C1
building blocks has also been achieved.
H. Guo, L. Tian, Y. Liu, J.-P. Wan, Org. Lett., 2022, 24,
228-233.
A metal- and oxidant-free three-component desulfurization and deamination
condensation of amidines, isothiocyanates, and hydrazines provides structurally
diverse fully substituted 1H-1,2,4-triazol-3-amines. This [2 + 1 + 2]
cyclization strategy offers mild reaction conditions, environmental friendliness,
and easy gram-scale applications.
W. Guo, G. Liu, L. Deng, W. Mei, X. Zou, Y. Zhong, X. Zhuo, J. Org. Chem., 2021, 86,
17244-17248.
A three-component assembly of α-CF3 carbonyls, NaN3,
and amines provides a variety of 5-amino NH-1,2,3-triazoles under
transition-metal-free and open-air conditions. The method provides a general and
operationally simple route to functionalized biologically important molecules.
The NH-1,2,3-triazoles can be smoothly converted to N-2 alkylated
1,2,3-triazole products.
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17197-17212.
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