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 Cu(I)-catalyzed three-component reaction of terminal alkynes,
trifluoromethyl diazo compounds, and nitrosoarenes provides a series of
trifluoromethyl-substituted dihydroisoxazoles in high yields under mild reaction
conditions.
X. Lv, Z. Kang, D. Xing, W. Hu, Org. Lett.,
2018, 20, 4843-4847.
A palladium-catalyzed oxidative three-component coupling of easily accessible
N-substituted anthranilamides with isocyanides and arylboronic acids
provides 2,3-disubstituted quinazolinones with a wide substrate scope and good
functional group tolerance.
C. Qian, K. Liu, S.-W. Tao, F.-L. Zhang, Y.-M. Zhu, S.-L. Yang, J. Org. Chem., 2018, 83,
9201-9209.
The use of K2S2O8 and DMSO enables an efficient and transition-metal-free synthesis of
4-arylquinolines from readily available aryl alkynes and anilines with a
diverse range of substitution patterns. DMSO acts as one carbon source, thus
providing a highly atom-economical and environmentally benign approach for the
synthesis of 4-arylquinolines.
M. Phanindrudu, S. B. Wakade, D. K. Tiwari,
P. R. Likhar, D. K. Tiwari, J. Org. Chem., 2018, 83,
9137-9143.
In a highly regioselective, direct visible-light-mediated aminofluorination of
styrenes, a shelf-stable N-Ts-protected 1-aminopyridine salt serves as
the nitrogen-radical precursor, and the commercially available hydrogen
fluoride-pyridine was used as the nucleophilic fluoride source.
J.-N. Mo, W.-L. Yu, J.-Q. Chen, X.-Q. Hu, P.-F. Xu, Org. Lett.,
2018, 20, 4471-4474.
A Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides
and arylzinc reagents provides 1,1-diarylalkanes. The reaction proceeds
well with primary, secondary and tertiary alkyl halides, and electronically
diverse arylzinc reagents.
S. KC, R. K. Dhungana, B. Shrestha, S. Thapa, N. Khanal, P. Basnet, R. W. Lebrun,
R. Giri, J. Am. Chem. Soc.,
2018,
140, 9801-9805.
A light-induced, Ru-catalyzed three-component alkyl-fluorination of olefins
under mild reaction conditions provides a wide range of fluorinated products
with good functional group tolerance. A key advantage of this photoredox
reaction is the use of generic alkyl groups and nucleophilic fluoride.
W. Deng, W. Feng, Y. Li, H. Bao, Org. Lett.,
2018, 20, 4245-4249.
A mild and metal-free multi-component reaction enables the synthesis of
4,5-disubstituted 1H-1,2,3-triazoles from phosphonium salts, aldehydes,
and sodium azide. An organocatalyzed coupling of the formyl group with the
phosphonium group provides an olefinic phosphonium salt as key intermediate,
that undergoes [3+2] cycloaddition with the azide.
G.-L. Wu, Q.-P. Wu, Synthesis, 2018, 50,
2768-2774.
A N-heterocyclic carbene (NHC)-catalyzed trifluoromethylation of α-chloro
aldehydes provides valuable α-trifluoromethyl ester derivatives in good yields.
The unique combination of an electrophilic trifluoromethylation reagent with NHC
catalysis was the key for the functionalization of a broad range of substrate.
An enantioselective version of this reaction afforded products in moderate
yields with good ee values.
F. Gelat, A. Patra, X. Pannecoucke, A. T. Biju, T. Poisson, T. Besset, Org. Lett.,
2018, 20, 3897-3901.
A three-component reaction of potassium alkyltrifluoroborates, DABCO·(SO2)2
as sulfur dioxide surrogate, and alkenes under photocatalysis provides diverse
sulfones in very good yields at room temperature. This reaction works
efficiently under mild conditions via generation of alkyl and alkylsulfonyl
radicals as key intermediates, and a reductive single-electron transfer.
T. Liu, Y. Li, L. Lai, J. Cheng, J. Sun, J. Wu, Org. Lett.,
2018, 20, 3605-3608.
A zinc salt promotes cyclization as well as provides a counteranion in a
redox-neutral synthesis of isoquinolinium salts via C-H activation of
presynthesized or in situ formed imines and coupling with α-diazo ketoesters.
Under three-component conditions, both ketone and aldehydes are viable
substrates. The coupling of imines with diazo malonates under similar conditions
afforded isoquinolin-3-ones as the coupling product.
M. Tian, G. Zheng, X. Fan, X. Li, J. Org. Chem., 2018, 83,
6477-6488.
A palladium-catalyzed, three-component tandem reaction of 2-aminobenzonitriles,
aldehydes, and arylboronic acids provides diverse quinazolines good yields. The
reaction tolerates bromo and iodo groups.
K. Hu, Q. Zhen, J. Gong, T. Cheng, L. Qi, Y. Shao, J. Chen, Org. Lett.,
2018, 20, 3061-3064.
A thiol-promoted site-specific addition of 1,3-dioxolane to imines through a
radical chain process enables a metal-free and redox-neutral conversion of
inexpensive materials to a broad range of protected α-amino aldehydes in very
good yields using only a catalytic amount of radical precursor. Both the thiol
and a small amount of oxygen from air are indispensable to the success of this
reaction.
H. Zeng, S. Yang, H. Li, D. Lu, Y. Gong, J.-T. Zhu, J. Org. Chem., 2018, 83,
5256-5266.
An efficient copper-catalyzed aerobic oxidative dehydrogenative annulation of
amines, alkynes, and O2 provides trisubstituted oxazoles via dioxygen
activation and oxidative C-H bond functionalization.
J. Pan, X. Li, X. Qiu, X. Luo, N. Jiao, Org. Lett.,
2018, 20, 2762-2765.
Practical Cu-catalyzed oxidative, multiple Csp3-H bond cleavage
processes achieve a synthesis of thiazoles from simple aldehydes, amines, and
element sulfur in the presence of molecular oxygen as a green oxidant.
X. Wang, X. Qiu, J. Wei, J. Liu, S. Song, W. Wang, N. Jiao, Org. Lett.,
2018, 20, 2632-2636.
A practical and general microwave-mediated Biginelli cyclocondensation of
guanidine with aldehydes and β-dicarbonyl compounds provides functionalized
2-amino-3,4-dihydropyrimidines in good yields, with short reaction times and a
simple workup. The scope is considerably wider than that of similar reactions
carried out under conventional heating.
F. Felluga, F. Benedetti, F. Berti, S. Drioli, G. Regini,
Synlett, 2018, 29, 986-992.
A transition-metal-free cleavage of C-C triple bonds in aromatic alkynes in the
presence of S8 and amides furnishes aryl thioamides in good yields.
The method offers mild reaction conditions, as well as wide substrate scope that
is particularly compatible with some internal aromatic alkynes and acetamides.
K. Xu, Z. Li, F. Cheng, Z. Zuo, T. Wang, M. Wang, L. Liu, Org. Lett.,
2018, 20, 2228-2231.
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