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 iron-catalyzed radical alkylazidation of electron-deficient alkenes with
trimethylsilyl azide and alkyl diacyl peroxides as the alkyl source provides a
range of α-azido esters, an α-azido ketone, and an α-azido cyanide in high
yields. This method features mild reaction conditions, wide substrate scope, and
good functional group tolerance.
R. Wei, H. Xiong, C. Ye, Y. Li, H. Bao,
Org. Lett., 2020, 22, 3195-3199.
A Cu/Pd-catalyzed borylallenylation of alkynes with propargylic carbonates
and bis(pinacolato)diboron enables the synthesis of boryl-substituted
ene-allenes. Densely (tetra-, penta-, and hexa-) substituted ene-allenes were
synthesized in acceptable yield with high regio- and stereoselectivity. More
important molecule structures can be obtained by subsequent modifications.
S.-H. Yu, T.-J. Gong, Y. Fu,
Org. Lett., 2020, 22, 2941-2945.
An efficient and convenient, copper-catalyzed decarboxylative cycloaddition of
propiolic acids, azides, and arylboronic acids provides fully substituted
1,2,3-triazoles from readily available starting materials. A possible mechanism
is proposed.
X.-X. Wang, Y. Xin, Y. Li, W.-J. Xia, B. Zhou, R.-R. Ye, Y.-M. Li, J. Org. Chem., 2020, 85, 3576-3586.
An improved procedure for the aminocarbonylation of benzyl chloride
derivatives provides 2-arylacetamides under mild conditions using an inexpensive
phosphine ligand, carbon monoxide and either primary or secondary amines.
E. Rilvin-Derrick, N. Oram, J. Richardson, Synlett, 2020,
31,
369-372.
A copper(I)-mediated tandem three-component reaction using alkynes, azides,
allyl iodides, CuI and NaNH2 provides 5-allyl-1,2,3-triazoles smoothly at
room temperature in good yields. The products can be further
converted into 1,2,3-triazole-fused tricyclic scaffolds.
Y. Song, S. Lee, P. Dutta, J.-S. Ryu, Synthesis, 2020, 52,
744-754.
A one-pot three-component reaction involving nitroarenes, (hetero)arylboronic
acids, and potassium pyrosulfite provides a broad
range of sulfonamides bearing different reactive functional groups in very good yields through sequential C-S and S-N coupling.
K. Chen, W. Chen, B. Han, W. Chen, M. Liu, H. Wu,
Org. Lett., 2020, 22, 1841-1845.
A photoinduced, copper-catalyzed, three-component reaction of haloalkane,
alkenes, and alkyne under mild reaction conditions helps to introduce privileged
functionalities into propargylic systems.
Y. Zhang, D. Zhang, J. Org. Chem., 2020, 85,
3213-3223.
Starting from readily available aryl iodides and allenes, with formic acid as
the CO source and reductant, good yields of α-branched enones were isolated. The
use of a CO source avoids the manipulation of CO gas.
H.-Q. Geng, L.-C. Wang, C.-Y. Hou, X.-F. Wu,
Org. Lett., 2020, 22, 1160-1163.
A highly regioselective three-component reaction of
2-bromo-3,3,3-trifluoropropene (BTP), aldehydes, and sulfonyl hydrazides
provides 3-trifluoromethylpyrazoles. This metal-free, catalyst-free, and
operationally simple approach offers mild conditions, a broad substrate scope,
high yields, and valuable functional group tolerance.
C. Zhu, H. Zeng, C. Liu, Y. Cai, X. Fang, H. Jiang,
Org. Lett., 2020, 22, 809-813.
Graphitic carbon nitride (p-g-C3N4) photocatalyzes a
hydrosulfonylation of alkynes with the insertion of sulfur dioxide in aerobic
conditions. Whereas the oxygen atom of the products is derviced from water, the
O2 plays an important role by quenching the DABCO radical cation.
Furthermore, this reaction could be carried out under solar light irradiation
and was applicable for large scale.
B. Ni, B. Zhang, J. Han, B. Peng, Y. Shan, T. Niu,
Org. Lett., 2020, 22, 636-641.
A convenient Pd-catalyzed reaction of aryl halides, tert-butyl isocyanide as the CO
source, and organoaluminum reagents provides 1,2-diketones in very good yields
and with good
functional group tolerance.
B. Chen, X.-F. Wu,
Org. Lett., 2020, 22, 636-641.
A carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in
the presence of Togni reagent provides β-trifluoromethyl-α-substituted ketones
with a broad scope and good yields.
B. Zhang, Q. Peng, D. Guo, J. Wang,
Org. Lett., 2020, 22, 443-447.
A simple, efficient, and general one-pot reaction of aldehydes and ketones
with amines in the presence of indium(III) chloride as a catalyst provides
α-amino phosphonates. Sonication accelerates the reaction.
B. C. Ranu, A. Hajra, U. Jana,
Org. Lett., 1999, 1, 1141-1143.
Cu(CH3CN)4BF4 catalyzes a radical
bis(trifluoromethylation) of alkynes and 1,3-enynes with Togni reagent II and
(bpy)Zn(CF3)2 at room temperature to afford the
corresponding 1,2-bis(trifluoromethylated) alkenes and
1,4-bis(trifluoromethylated) allenes in good yields. This protocol exhibits
broad substrate scope and excellent functional group compatibility.
H. Shen, H. Xiao, L. Zhu, C. Li, Synlett, 2020,
31,
41-44.
A Cu-catalyzed reductive aminocarbonylation of primary, secondary, and
tertiary alkyl iodides using nitroarenes as the nitrogen source provides a
diverse range of secondary N-aryl alkylamides. The single copper catalyst
synergistically mediates both carbonylation of alkyl iodides and reduction of
nitroarenes, to provide acyl iodides and anilines as possible reactive
intermediates.
S. Zhao, N. P. Mankad,
Org. Lett., 2019, 21, 10106-10110.
Please cite and link this page as follows:
Multicomponent Reactions ( URL: https://www.organic-chemistry.org/topics/multicomponent-reactions.shtm )
