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
Palladium catalyzes a domino Heck arylation and alkylation of nonconjugated
cyclohexadienes to produce trans isomers of disubstituted cyclohexenes in
exceptionally high enantiomeric ratios.
D. Zhu, W. Xu, M. Pu, Y.-D. Wu, Y. R. Chi, J. S. Zhou, Org. Lett., 2021, 23,
7064-7068
A nickel-catalyzed, multicomponent regio- and enantioselective
hydroformylation and carbonylation using chloroformate as a safe CO source
provides a wide variety of unsymmetrical dialkyl ketones bearing a
functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones
and α-amino ketones.
J. Chen, S. Zhu, J. Am. Chem. Soc.,
2021, 143, 14089-14096.
A copper(I)-catalyzed regio- and stereoselective three-component coupling
reactions between gem-dialkylallenes, alkyl halides, and bis(pinacolato)diboron provides sterically congested allylic
boronates. A subsequent allylboration of
aldehydes diastereoselectively furnished the corresponding homoallylic alcohols
that bear a quaternary carbon.
Y. Ozawa, K. Endo, H. Ito, J. Am. Chem. Soc.,
2021, 143, 13865-138772.
A 3CR of homophthalic anhydride, amines, and aldehydes provides
dihydroisoquinolones in good yields and excellent diastereoselectivity.
S. Y. Howard, M. J. Di Maso, K. Shimabukuro, N. P. Burlow, D. Q. Tan, J. C.
Fettinger, T. C. Malig, J. E. Hein, J. T. Shaw, J. Org. Chem., 2021, 86,
11599-11607.
Enantioenriched 1,1-silylboryl alkanes are highly valued building blocks in asymmetric
synthesis as well as medicinal chemistry. An enantioselective cobalt-catalyzed hydrosilylation/hydroboration
cascade of terminal alkynes offers chemo-, regio-, and stereoselectivity exquisitely controlled by a single
set of metal catalyst and ligand.
S. Jin, K. Liu, S. Wang, Q. Song, J. Am. Chem. Soc.,
2021, 143, 13124-13134.
An efficient [2 + 1 + 3] cyclization reaction of aryl methyl ketones, arylamines, and
1,3-dicarbonyl compounds provides 2-aryl-4-quinolinecarboxylates in good yields
under mild conditions. This metal-free process achieved a C-C bond cleavage of 1,3-dicarbonyl compounds
for use as a C1
synthon.
Y. Zhou, P. Zhao, L.-S. Wang, X.-X. Yu, C. Huang, Y. D. Wu, A.-X. Wu, Org. Lett., 2021, 23, 6461-6465.
An efficient transition-metal-free one-pot three-component reaction between
diaryliodonium triflates, cyclic and acyclic aliphatic amines, and carbon
disulfide provides biologically relevant S-aryl dithiocarbamates in good
yields under mild conditions. This methodology is robust, scalable,
and exhibits a broad substrate scope.
S. K. Parida, S. Jaiswal, P. Singh, S. Murarka, Org. Lett., 2021, 23, 6401-6406.
Trifluoromethylsulfonyl-pyridinium salt (TFSP) is an efficient, solid
trifluoromethylation reagent, which can be readily prepared from cheap and
easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl
radical under photocatalysis, that can be used for azido- or
cyano-trifluoromethylation reactions of alkenes.
M. Zhang, J.-H. Lin, J.-C. Xiao, Org. Lett., 2021, 23,
6079-6083.
The combination of dirhodium(II)/Xantphos catalyzes a three-component
reaction of readily accessible amines, diazo compounds, and allylic compounds to
afford various architecturally complex and functionally diverse α-quaternary
α-amino acid derivatives in good yields with high atom and step economy.
B. Lu, X. Liang, J. Zhang, Z. Wang, Q. Peng, X. Wang, J. Am. Chem. Soc.,
2021, 143, 11799-11810.
CuO catalyzes a three-component reaction of α-ketoaldehydes, 1,3-dicarbonyl
compounds, and organic boronic acids in water to provide a wide range of
products containing 1,3- and 1,4-diketones. The method offers use of readily
available starting materials, wide substrate scope, excellent yields, gram-scale
synthesis, and mild reaction conditions.
Q. Xia, X. Li, X. Fu, Y. Zhou, Y. Peng, J. Wang, G. Song, J. Org. Chem., 2021, 86,
9914-9923.
A catalyst- and metal-free visible-light-mediated protocol enables the
iodoamination of miscellaneous olefins in high yields under environmentally
benign reaction conditions using DMC as green and biodegradable solvent.
Furthermore, the protocol allows for late-stage functionalization of bioactive
molecules and can be scaled to gram quantities of product.
S. Engl, O. Reiser, Org. Lett., 2021, 23,
5581-5586.
A convenient base-catalyzed three-component reaction between chalcones,
isothiocyanates, and elemental sulfur provides thiazole-2-thiones in very good
yields.
T. B. Nguyen, P. Retailleau, Org. Lett., 2021, 23,
5344-5348.
A multicomponent reaction of primary amines (amino acids), carbon
disulfide, and γ-bromocrotonates provides thiazolidine-2-thiones in excellent
yields via a domino alkylation/intramolecular Michael addition. The synthetic
utility of the adducts was demonstrated by hydrolysis, amidation, and oxidation
reactions.
M. K. Foumeshi, A. Z. Halimehjani, A. Alaei, B. Klepetářová, P. Beier, Synthesis, 2021, 53,
2219-2228.
An efficient and modular strategy based on a four-component sequential
reaction provides enaminones under mild conditions without a catalyst
in one pot. Furthermore, the products could be transformed into thiadiazoles.
J. Zhang, P. Zhou, A. Yin, S. Zhang, W. Liu, J. Org. Chem., 2021, 86,
8980-8986.
Copper iodide catalyzes a sustainable and time economic synthesis
of polysubstituted pyrroles in excellent yields with high
regioselectivity under mild conditions. The reaction proceedes through imine
formation followed by cyclization with an alkyne-Cu intermediate.
M.-H. Hsu, M. Kapoor, T. K. Pradhan, M.-H. Tse, H.-Y. Chen, M.-J. Yan, Y.-T.
Cheng, Y.-C. Lin, C.-Y. Hsieh, K.-Y. Liu, C.-C. Han, Synthesis, 2021, 53,
2212-2218.
A facile photocatalyzed strategy for difunctionalization of styrenes in the
presence of CS2 and amines provides β-keto dithiocarbamates. However,
4-nitrostyrene and 2-vinylpyridine can only be converted to
2-arylethylthiocarbamates.
R. K. Vishwakarma, S. Kumar, K. N. Singh, Org. Lett., 2021, 23,
4147-4151.
Please cite and link this page as follows:
Multicomponent Reactions ( URL: https://www.organic-chemistry.org/topics/multicomponent-reactions.shtm )
