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 unprecedented Pd(II)-catalyzed cascade annulation of o-aminobenzoic
acids with CO, amines, and aldehydes provides N3-substituted and N1,N3-disubstituted
2,3-dihydroquinazolin-4(1H)-ones in good yields under mild conditions. The
reaction offers low cost, high step economy, broad substrate scope, and good
product diversity.
X. Zhang, J. Wang, J. Xu, Q. Pang, D. Liu, G. Zhang, J. Org. Chem., 2023, 88,
10266-10276.
A cascade reaction of isonitriles with N,N-dibromoarylsulfonamides and
sodium azide provide aminotetrazoles in the presence of K2CO3
at room temperature. This metal-free process proceeds via an isolable
carbodiimide intermediate, which could further react with sodium azide and
subsequently cyclizes intermolecularly to provide 5-aminotetrazoles within a
short reaction time.
D. Mishra, S. Kashyap, P. Phukan, J. Org. Chem., 2023, 88,
9401-9408.
(NaN(SiMe3)2) catalyzes a deprotonation of allylbenzenes. Trapping of the deprotonated allyl anion with in situ generated N-(trimethylsilyl) aldimines provides
value-added homoallylic amines with excellent linear
selectivity.
Y. Gu, Y.-E. Wang, Y. Yuan, H. Xu, Y. Lu, Y. Zhang, F. Xue, D. Xiong, J. Mao, J. Org. Chem., 2023, 88,
7362-7372.
An asymmetric nickel-catalyzed borylative coupling of terminal alkenes with
nonactivated alkyl halides provides a broad range of chiral boronic esters with
high regio- and enantioselectivity under mild reaction conditions. The success
of this three-component strategy is ascribed to the application of a chiral
anionic bisoxazoline ligand.
Z. Li, H. Shi, X. Chen, L. Peng, Y. Li, G. Yin, J. Am. Chem. Soc.,
2023, 145, 13603-13614.
An efficient copper-catalyzed intermolecular decarboxylative cascade cyclization
of aryl aldehydes, anilines, and acrylic acid permits the direct synthesis of
2-substituted quinolines. This method features promising chemo- and
regioselectivity and also tolerates a wide variety of substrates with excellent
functional-group tolerance, high yields, a radical reaction pathway, and aerobic
reaction conditions.
R. Chatterjee, M. Pothireddy, R. Dandela, Synlett, 2023,
34,
1058-1062.
Multicomponent reactions of CS2, sulfoxonium ylides and secondary
amines provide β-keto dithiocarbamates, whereas primary amines afforded
thiazolidine-2-thiones or thiazole-2-thiones after dehydration in an acidic
environment. These simple, versatile, and catalyst-free synthetic methods have a
wide substrate scope and excellent functional group tolerance.
N. Kumar, A. Sharma, U. Kumar, S. K. Panday, J. Org. Chem., 2023, 88,
6120-6125.
A photochemical Wolff rearrangement, trapping of the generated ketene with a
chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a
final nucleophilic displacement of the bound catalyst provides chiral
α-chlorinated carboxylic acid esters. The obtained products were successfully
utilized for stereospecific nucleophilic displacement reactions with N-
and S-nucleophiles.
D. Weinzierl, M. Piringer, P. Zebrowski, L. Stockhammer, M. Waser, Org. Lett., 2023, 25,
3126-3130.
A metal-free, cascade regio- and stereoselective trifluormethyloximation,
cyclization, and elimination strategy of readily available α,β-unsaturated
carbonyl compounds with CF3SO2Na and tBuONO
provides a wide variety of 4-(trifluoromethyl)isoxazoles. Mechanistic studies
revealed a radical pathway for the reaction.
P. Pattanayak, T. Chatterjee, J. Org. Chem., 2023, 88,
5420-5430.
A unique Au-allenylidene pathway enables an in situ formation of highly
unsaturated alkylidene ketenes from propargyl alcohol derivatives. A subsequent trapping with a broad
range of nucleophiles such as alcohols, phenols, water, amines, and sulfoximines
in the presence of an N-oxide provides α,β-unsaturated drug and natural
product derivatives.
X. Sun, X. Duan, N. Zheng, W. Song, Org. Lett., 2023, 25,
2798-2805.
A chemoselective heterodimerization of weak electrophilic ortho-diisocyanoarenes
and common isocyanides generates quinoxaline-based zwitterionic intermediates.
This reactive zwitterion could react in situ with various trapping agents to
furnish a range of structurally diverse quinoxalines.
L. Bao, M. Li, L. Zhang, Y. Xue, J. Dong, X. Xu, Org. Lett., 2023, 25,
2366-2371.
Pd/Cu-catalyzed coupling and boration of acyl chlorides with alkynes and B2pin2
provide the corresponding saturated β-boryl ketones in the presence of ethyl
acetate as the hydrogen source. Various β-boryl ketones were synthesized in very
good yields with broad functional group tolerance.
F. Zhu, P. Yin, J. Org. Chem., 2023, 88,
4352-4358.
An acidic I2-DMSO system converts readily available aspartates/phenylalanines
and anilines into alkyl quinoline-3-carboxylates/3-arylquinolines. While DMSO is
activated by HI via a Pummerer reaction, I2 mediates a Strecker
degradation of the the amino acid. A formal [3 + 2 + 1] annulation of these two
concurrently generated C1 and C2 synthons with aniline provides the quinoline
core.
J.-T. Ma, T. Chen, B.-C. Tang, X.-L. Chen, Z.-C. Yu, Y. Zhou, S.-Y. Zhuang,
Y.-D. Wu, J.-C. Xiang, , J. Org. Chem., 2023, 88,
3714-3723.
Direct
photocatalyzed hydrogen atom transfer enables a three-component coupling of aldehydes, alkenes, or alkynes and elemental sulfur. This carbonyl thiyl
radical-based thioester synthesis represents an orthogonal
strategy to the conventional thiol-based nucleophilic substitution and exhibits
a remarkably broad substrate scope.
H. Tang, M. Zhang, Y. Zhang, P. Luo, D. Ravelli, J. Wu, J. Am. Chem. Soc.,
2023, 145, 5846-5854.
A photoredox/nickel dual catalytic protocol enables a regioselective
three-component carboacylation of alkenes with tertiary and secondary
alkyltrifluoroborates as well as acyl chlorides. This redox-neutral
protocol can be applied to the rapid synthesis of ketones with high diversity
and complexity via a radical relay process. Many functional groups are tolerated under the mild conditions.
Z.-K. Wang, Y.-P. Wang, Z.-W. Rao, C.-Y. Liu, X.-H. Pan, L. Guo, Org. Lett., 2023, 25,
1673-1677.
A convenient and metal-free three-component oxychalcogenation reaction of
alkenes, diselenides/thiophenols, and H2O/alcohols provides
β-hydroxyl or β-alkoxy organochalcogenides in very good yields.
Tetrabutylammonium tribromide (TBATB) and dimethylsulfoxide (DMSO) are utilized
as the catalyst and the terminal oxidant, respectively.
J. Huang, X. Li, L. Xu, Y. Wei, J. Org. Chem., 2023, 88,
3054-3067.
A MCM-41-immobilized bidentate phosphine palladium complex catalyzes an
efficient carbonylative cyclization of aryl iodides and 2-hydroxyacetophenones
under 3 bar of carbon monoxide in the presence of DBU in DMSO at 120°C to
provide a wide variety of flavones in very good yields. The supported palladium
catalyst can be easily recovered via centrifugation and recycled more than nine
times.
G. Xie, J. Zhang, M. Cai, B. Huang, Synthesis, 2023,
55,
647-656.
A copper-based system enables methylene insertion between an amine and an
alkyne counterpart, via C-N bond cleavage of N,N-dimethylacetamide. The
method gives an expedient access to a broad range of propargylic amines in good
yields.
A. Rahaman, R. D. Shinde, S. Bhadra, J. Org. Chem., 2023, 88,
1884-1889.
Pd(OAc)2/PCy3HBF4 catalyzes an addition of
aryl halides and alkynes to norbornenes to construct saturated bridged C-C bonds.
This efficient difunctionalization of norbornenes includes C-X/C-H bond cleavage and
highly selective C(sp3)-C(sp2)/C(sp3)-C(sp)
bond formation. The reaction offers broad substrate scope and
excellent functional group tolerance.
Y. Shi, C.-L. Ji, C. Liu, J. Org. Chem., 2023, 88,
261-271.
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