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
Direct reaction of isocyanides with sulfoxides affords thiocarbamic acid S-esters
in very good yields. In addition, multicomponent reactions involving isocyanide,
sulfoxide, and a suitable nucleophile provide a diverse range of
sulfur-containing compounds, including isothioureas, carbonimidothioic acid
esters, and carboximidothioic acid esters.
S. Wu, X. Lei, E. Fan, Z. Sun, Org. Lett.,
2018, 20, 522-525.
A copper-catalyzed, practical, and straightforward one-pot synthesis of
multisubstituted imidazoles in good yields from arylacetic acids, N-arylbenzamidines,
and nitroalkanes involves simultaneous activation of C–H and N–H bonds. The use
of inexpensive copper sulfate as a catalyst and readily available starting
materials makes this protocol economically viable.
S. D. Pardeshi, P. A. Sathe, K. S. Vadagaonkar, L. Melone, A. C. Chaskar, Synthesis, 2018, 50,
361-370.
Photoredox-catalyzed and nitrogen-centered radical-triggered cascade reactions
of styrenes (or phenylacetylenes), enol derivatives, and O-acyl
hydroxylamines in DMSO provide functionalized β-amino alcohols. Structurally
diverse reaction components, including complex molecular scaffolds can be
converted.
X.-D. An, Y.-Y. Jiao, H. Zhang, Y. Gao, S. Yu, Org. Lett.,
2018, 20, 401-404.
A synthesis of 2-substituted benzothiazoles in good yields from o-iodoanilines,
arylacetic acids, and elemental sulfur is catalyzed by cheap copper metal. This
S8-mediated directed decarboxylative redox-cyclization strategy is
operationally simple, ligand-free, and compatible with a wide range of
functional groups.
X. Wang, X. Li, R. Hu, Z. Yang, R. Gu, S. Ding, P. Li, S. Han,
Synlett, 2018, 29, 219-224.
An efficient Pd-catalyzed cascade reaction of azides with isonitriles and amines
provides N-sulfonyl-, N-phosphoryl-, and N-acyl-functionalized
guanidines in excellent yield. In addition, the less reactive intermediate
benzoyl carbodiimide could be isolated in moderate yield.
G. Qiao, Z. Zhang, B. Huang, L. Zhu, F. Xiao, Z. Zhang, Synthesis, 2018, 50,
330-340.
Using cheap and eco-friendly iron(III) nitrate as the nitration and cyclization
reagent and KI as an additive for the synthesis of isoxazoles from alkynes, both
self-coupling and cross-coupling products could be successfully prepared. In the
cross-coupling and cyclizing of two different alkynes, the iron-mediated system
shows a good chemoselectivity.
Z. Lai, Z. Li, Y. Liu, P. Yang, X. Fang, W. Zhang, B. Liu, H. Chang, H. Xu, Y.
Xu, J. Org. Chem.,
2018, 84, 145-153.
A transition-metal-free direct carboxylation of the ipso-C(sp2)-H
bond of diazo compounds proceeds at ambient temperature under atmospheric
pressure of carbon dioxide in the presence of a weak base. A series of
unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with good
yields and good functional group compatibility.
Q. Liu, M. Li, R. Xiong, F. Mo, Org. Lett.,
2017, 19, 6756-6759.
Copper-catalyzed cross-coupling reactions of phenolic esters such as acetates,
tosylates, and triflates with arylboronic acids or triphenyltin chlorides as the
coupling partners in the presence of sulfur and a base provide unsymmetrical
diaryl sulfides. In addition, NaOtBu promotes a synthesis of symmetrical
diaryl sulfides from phenolic compounds in the presence of sulfur.
A. Rostami, A. Rostami, A. Ghaderi, M. Gholinejad, S. Gheisarzadeh, Synthesis, 2017,
49, 5025-5038.
An unprecedented cross-coupling reaction between copper carbenes and nitroso
radicals provides various isoxazolines via construction of C-C, C-O, and C=N
bonds in a one-pot process. The convenient method offers mild reaction
conditions and wide substrate scope.
R. Chen, Y. Zhao, S. Fang, W. Long, H. Sun, X. Wan, Org. Lett.,
2017, 19, 5896-5899.
A [2 + 1 + 1] radical tandem cycloaddition of styrenes, arylamines, and tert-butyl
hydroperoxide enables a regioselective synthesis of polysubstituted
1,2-oxazetidines. TBHP was employed in this conversion not only as the oxidant
but also as the oxygen source.
W. Liu, C. Chen, P. Zhou, H. Tan, Org. Lett.,
2017, 19, 5830-5832.
Mn(OAc)3-mediated phosphinoyl radical addition followed by
CuCN-catalyzed cyanation enables a double-functionalization reaction of alkenes
under mild conditions to afford vicinal cyanophosphinoylation products.
P.-Z. Zhang, L. Zhang, J.-A. Li, A. Shoberu, J.-P. Zou, W. Zhang, Org. Lett.,
2017, 19, 5537-5540.
A simple and efficient method for the base-mediated synthesis of
unsymmetrical 1,3,5-triazin-2-amines uses readily available imidates,
guanidines, and amides or aldehydes as the starting materials and cesium
carbonate as the base. This three-component reaction provides diverse
1,3,5-triazin-2-amines in good yields with tolerance of a broad range of
functional groups.
L. Pan, Z. Li, T. Ding, X. Fang, W. Zhang, H. Xu, Y. Xu, J. Org. Chem.,
2017, 82, 10043-10050.
A one-pot reaction cascade reaction enables a transition-metal-free construction
of functionalized quinolines from readily available acetophenones and anthranils.
The reaction involves in situ generation of α,β-unsaturated ketones from the
acetophenone via one-carbon homologation by DMSO followed by the aza-Michael
addition of anthranils and subsequent annulation. DMSO acts not only as solvent
but also as one carbon source.
S. B. Wakade, D. K. Tiwari, P. S. K. P. Ganesh, M. Phanindrudu, P. R. Likhar, D.
K. Tiwari, Org. Lett.,
2017, 19, 4948-4951.
A practicable quinoline synthesis from aniline and two amino acids provides a
wide range of quinolines with high efficiency and diversity including
pharmaceutical derivatives, photochemical active compounds, and challenging
scaffolds. Mechanistic studies revealed that I2 promotes
decarboxylation, oxidative deamination, and selective formation of new C-N and
C-C bonds.
J.-C. Xiang, Z.-X. Wang, Y. Cheng, S.-Q. Xia, M. Wang, B.-C. Tang, Y.-D. Wu,
A.-X. Wu, J. Org. Chem.,
2017, 82, 9210-9216.
A copper-catalyzed three-component reaction of methyl ketones, organic azides,
and DMF as one-carbon (C1) donor provides 4-acyl-1,2,3-triazoles in good yields.
The transformation proceeds via an oxidative C-H/C-H cross-dehydrogenative
coupling followed by an oxidative 1,3-dipolar cycloaddition.
Y. Liu, G. Nie, Z. Zhou, L. Jia, Y. Chen, J. Org. Chem.,
2017, 82, 9198-9203.
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