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
A. Dömling, I. Ugi, Angew. Chem. Intl. Ed. 2000, 39, 3168.
DOI
A. Dömling, Org. Chem. Highlights 2004, April 5.
Link
Books
Multicomponent Reactions
Jieping Zhu, Hugues Bienaymé
Hardcover, 468 Pages
First Edition, 2005
ISBN: 3-527-30806-7 - Wiley-VCH
Recent Literature
A three-component coupling reaction of alkynylsilanes, aldehydes and amines
produces a variety of propargyl amine derivatives by a cooperative catalytic
system comprised of CuCl and Cu(OTf)2. This catalytic system was
successfully applied to the practical preparation of 1,6-diyne derivatives via
twice-performed, domino-type coupling reactions.
N. Sakai, N. Uchida, T. Konakahara, Synlett, 2008,
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Mannich-rype reactions of secondary amines, aldehydes and ketene silyl acetals
were efficiently promoted by catalytic amounts of diarylborinic acid esters,
affording β-amino esters selectively with no formation of the corresponding
β-hydroxy esters.
Y. Tanaka, T. Hasui, M. Suginome, Synlett, 2008, 1239-1241.
The reaction of aldehydes, amines, and TMSCN in the presence of 2-iodoxybenzoic
acid (IBX) and tetrabutylammonium bromide (TBAB) afforded α-iminonitriles in
good to excellent yields under mild conditions. The presence of TBAB is
essential for this transformation.
P. Fontaine, A. Chiaroni, G. Masson, J. Zhu, Org. Lett., 2008,
10, 1509-1512.
Hantzsch 1,4-dihydropyridine and polyhydroquinoline derivatives were synthesized
in excellent yields in aqueous micelles. The reaction is catalyzed by PTSA and
strongly accelerated by ultrasonic irradiation.
A. Kumar, R. A. Maurya, Synlett, 2008,
883-885.
Uncatalyzed cyanosilylation of ketones with NaCN and various
chlorotrialkylsilanes in DMSO proceeds smoothly to give silyl-protected
cyanohydrins in excellent yields. The role of DMSO consists in rendering naked
cyanide anions that reversibly add to the carbonyl at the rate-determining step
followed by fast sillylation of the transient tertiary alcoholates with
chlorotrialkylsilanes or in situ generated cyanotrialkylsilanes.
F. L Cabirol, A. E. C. Lim, U. Hanefuld, R. A. Sheldon, I. M. Lyapkalo, J. Org. Chem., 2008,
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Various 2-alkyl-5-aryl-(1H)-pyrrole-4-ol derivatives were synthesized via
a multicomponent reaction of β-dicarbonyl compounds with arylglyoxals in the
presence of ammonium acetate in water at room temperature.
B. Khalili, P. Jajarmi, B. Eftekhari-Sis, M. M. Hashemi, J. Org. Chem., 2008,
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One-Pot Synthesis of 1,4-Dihydropyridines via a Phenylboronic Acid Catalyzed
Hantzsch Three-Component Reaction
A. Debache, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, Synlett, 2008,
509-512.
Copper(I) immobilized on 3-aminopropyl-functionalized silica gel catalyzed the
reaction of terminal alkynes with benzyl- or alkyl halides and sodium azide in
ethanol to give 1,4-disubstituted 1,2,3-triazoles in good to excellent yields.
This procedure allows the conversion of unstable low-molecular-weight azides.
Furthermore, the silica-supported copper could be recovered and recycled by
simple filtration.
T. Miaoa, L. Wang, Synthesis, 2008,
363-368.
A one-pot method allows the synthesis of α-siloxy-Weinreb amides from aldehydes
using N,O-dimethylhydroxylamine and a masked acyl cyanide reagent bearing
a tert-butyldimethylsilyl group. The TBS group avoids the competitive
reaction toward N-methoxy-N-methyl-2-amino-1-siloxymalononitrile.
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A mild, convenient, and practical one-pot procedure gives dithiocarbamates in
good to excellent yields by condensation of amines, CS2, and a
Michael acceptor, under solvent-free conditions at room temperature.
N. Azizi, F. Ebrahimi, E. Aakbari, F. Aryanasab, M. R. Saidi, Synlett, 2007,
2797-2800.
Phosphonium bromide ionic liquids are superior media in the carbonylation of
aryl and vinyl halides. Formation of acid bromide intermediates was detected in
control experiments providing an extended view on the overall catalytic cycle
involved. Solvent-free product isolation and recycling of the ionic liquid
containing active Pd-catalyst are also demonstrated.
J. McNulty, J. J. Nair, A. Robertson, A. Lei, Org. Lett., 2007,
9, 4575-4578.
Using an iridium catalyst modified by (R)-Cl,MeO-BIPHEP, the
hydrogenating of alkynes in the presence of N-arylsulfonyl imines
delivers the corresponding allylic amines in highly optically enriched form.
This protocol circumvents the use of preformed vinyl metal reagents and is
applicable to aromatic, heteroaromatic, and aliphatic N-arylsulfonyl
aldimines.
M.-Y. Ngai, A. Barchuk, M. J. Krische, J. Am. Chem. Soc., 2007,
129, 12644-12645.
Acid-Free, Aminoborane-Mediated Ugi-Type Reaction Leading to General
Utilization of Secondary Amines
Y. Tanaka, T. Hasui, M. Suginome, Org. Lett., 2007,
9, 4407-4410.
A gold(III)-catalyzed multicomponent coupling/cycloisomerization reaction of
heteroaryl aldehydes, amines, and alkynes under solvent-free conditions or in
water provides rapid access to substituted aminoindolizines with high atom
economy and high catalytic efficiency.
B. Yan, Y. Liu, Org. Lett., 2007,
9, 4323-4326.
Polysubstituted pyridines are prepared in good yield and with total regiocontrol
by the one-pot reaction of an alkynone, 1,3-dicarbonyl compound and ammonium
acetate in alcoholic solvents. This new three-component heteroannulation
reaction proceeds under mild conditions in the absence of an additional acid
catalyst.
X. Xiong, M. C. Bagley, K. Chapaneri, Tetrahedron Lett., 2004,
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