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-catalyzed four-component formal oxyaminalization of alkenes with
Togni's reagent and amines in the presence of molecular oxygen as both the oxidant and oxygen
source efficiently provides a range of structurally diverse
α-oxoketene aminals. This simple procedure offers excellent functional group tolerance, broad substrate scope,
and mild conditions.
L. Wang, C. Qi, T. Guo, H. Jiang,
Org. Lett., 2019, 21, 2223-2226.
Reactions of thiocarbonyl fluoride derived from CF3SiMe3, elemental sulfur, and KF with secondary amines
provides a wide variety of thiocarbamoyl
fluorides in good yields at room temperature in THF, whereas the reaction with primary
amines gives isothiocyanates. The
two reactions show broad substrate scope and good functional group tolerance.
Moreover, AgSCF3 can be used as an alternative.
L. Zhen, H. Fan, X. Wang, L. Jiang,
Org. Lett., 2019, 21, 2106-2110.
A highly efficient reaction of readily available aromatic amines,
benzaldehydes, and NH4SCN as a sulfur source provides
2-arylbenzothiazoles with wide functional group compatibility in good yields via
an iodine-mediated oxidative annulation.
A. Dey, A. Hajra,
Org. Lett., 2019, 21, 1686-1689.
Molecular iodine catalyzes a facile and practical synthesis of thiocarbamates
in good yields from readily available sodium sulfinates, isocyanides, and water.
The present methodology offers favorable functional group tolerance and the use
of odorless sodium sulfinates.
P. Bao, L. Wang, H. Yue, Y. Shao, J. Wen, D. Yang, Y. Zhao, H. Wang, W. Wei, J. Org. Chem., 2019, 84,
2976-2983.
A chiral
iron(II) complex catalyzes a regio- and enantioselective α-halo-β-azido difunctionalization of both
α,β-unsaturated amides and α,β-unsaturated esters under mild reaction conditions
to provide a broad spectrum of valuable functionalized amides and esters.
P. Zhou, X. Liu, W. Wu, C. Xu, X. Feng, Org. Lett., 2019, 21,
1170-1175.
Acenaphthoimidazolylidene gold complexes are effective catalysts for a
chemoselective arylsulfonylation of boronic acids using potassium metabisulfite
(K2S2O5) and diaryliodonium salts to provide
sterically hindered diarylsulfones even in gram scale. Sterically hindered aryl
groups in unsymmetric diaryliodonium salts are preferentially transferred over
less bulky ones.
H. Zhu, Y. Shen, D. Wen, Z.-G. Le, T. Tu, Org. Lett., 2019, 21,
974-979.
A three-component reaction of nitroarenes, alcohols, and sulfur powder
provided 2-substituted benzothiazoles in good yield with a good functional group
tolerance via nitro reduction, C-N condensation, and C-S bond formation.
Q. Xing, Y. Ma, H. Xie, F. Xiao, F. Zhang, G.-J. Deng, J. Org. Chem., 2019, 84,
1238-1246.
A silver-catalyzed, one-pot, four-component reaction of terminal alkynes,
TMSN3, sodium sulfinate, and sulfonyl azide provides amidines. A
possible cascade reaction mechanism consists of alkyne hydroazidation, sulfonyl
radical addition, 1,3-dipolar cycloaddition of TMSN3, and
retro-1,3-dipolar cycloaddition.
B. Liu, Y. Ning, M. Virelli, G. Zanoni, E. A. Anderson, X. Bi, J. Am. Chem. Soc.,
2019,
141, 1593-1598.
The low-melting mixture urea-ZnCl2 as reaction medium efficiently
catalyzes the formation of imidazoles from a dicarbonyl compound, ammonium
acetate, and an aromatic aldehyde to provide a broad range of triaryl-1H-imidazoles
or 2-aryl-1H-phenanthro[9,10-d]imidazoles in very good yields. In
addition, the eutectic solvent can be reused five times without loss of
catalytic activity.
N. L. Higuera, D. Peña-Solórzano, C. Ochoa-Puentes, Synlett, 2019,
30,
225-229.
A mild, metal-free, multicomponent reaction provides N-acyl amidines
from nitroalkene derivatives, dibromo amides, and amines via formation of an
initial α,α-dibromonitroalkane intermediate that can undergo C-C bond cleavage.
This alternative approach toward N-acyl amidines enables rapid
construction of amidine frameworks with high diversity and complexity.
M. Zhou, J. Li, C. Tian, X. Sun, X. Zhu, Y. Cheng, G. An, G. Li, J. Org. Chem., 2019, 84,
1015-1024.
A highly efficient rhodium-catalyzed tandem reaction of isocyanides with azides and
various oxygen nucleophiles provides various N-sulfonyl/acylisoureas
with broad substrate scope in an atom-economical manner.
X.-B. Bu, Z.-X. Zhang, Q.-Q. Peng, X. Xu, Y.-L. Zhao, J. Org. Chem., 2019, 84,
53-59.
A nickel-catalyzed conjunctive cross-coupling of simple alkenyl amides with aryl
iodides and aryl boronic esters delivers the desired 1,2-diarylated products
with excellent regiocontrol. The reaction is enabled by an electron-deficient
olefin (EDO) ligand. Under optimized conditions, a wide range of amides derived
from 3-butenoic acid, 4-pentenoic acid, and allyl amines are compatible
substrates.
J. Derosa, R. Kleinmans, V. T. Tran, M. K. Karunananda, S. R. Wisniewski, M. D.
Eastgate, K. M. Engle, J. Am. Chem. Soc.,
2018,
140, 17878-17883.
Base-controlled three component reactions of styrenes, amines, and sulfur
provide thioamides. Depending on the base, 2-phenylethanethioamides and
benzothioamides were obtained selectively.
P. Zhang, W. Chen, M. Liu, H. Wu, J. Org. Chem., 2018, 83,
14269-14276
A constant current electrolysis synergizing with a Lewis-acid catalysis
protocol enables an external oxidant-free oxytrifluoromethylation and
aminotrifluoromethylation of styrene derivatives using sodium
trifluoromethanesulfinate as the trifluoromethyl source.
L. Zhang, G. Zhang, P. Wang, Y. Li, A. Lei, Org. Lett.,
2018, 20, 7396-7399.
An operationally simple, palladium-catalyzed three-component reaction between
terminal alkynes, isonitriles, and sodium carboxylates have provides N-acyl
propiolamide derivatives under mild conditions.
Y. He, Y. Wang, X. Liang, B. Huang, H. Wang, Y.-M. Pan, Org. Lett.,
2018, 20, 7117-7120.
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