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 novel cationic Br initiated one-pot synthesis using olefin, nitrile, amine,
and N-bromosuccinimide gives imidazolines in good yields. The olefinic
substrates and the nitrile partners can be flexibly varied to achieve a range of
imidazoline derivatives.
L. Zhou, J. Zhou, C. K. Tan, J. Chen, Y.-Y. Yeung, Org. Lett., 2011,
13, 2448-2451.
A mild three-component reaction of aromatic aldehydes, alkyl bromides, and
aqueous ammonia as the nitrogen source gives imines in very good yields. The
reaction conditions are compatible with a range of functional groups. The
reaction of aldehydes and aqueous ammonia with epoxides leads to imines bearing
a vicinal hydroxyl group regioselectively.
J.-M. Huang, J.-F. Zhang, Y. Dong, W. Gong, J. Org. Chem., 2011,
76, 3511-3514.
A simple one-pot conversion of carboxylic acids to carbamates is achieved in the
presence of propylphosphonic anhydride (T3P) in combination with
azidotrimethylsilane and an alcohol via the Curtius rearrangement. Besides
diverse primary to tertiary alcohols, the reaction tolerated a wide scope of
aromatic, heterocyclic, and aliphatic carboxylic acids which underwent
rearrangement in excellent yields.
J. K. Augustine, A. Bombrun, A. B. Mandal, P. Alagarsamy, R. N. Atta, P. Selvam, Synthesis, 2011,
1477-1483.
A highly chemoselective PPh3-catalyzed three-component reaction of an
imine, alkyl vinyl ketone, and phthalimide or succinimide gives various highly
functional adducts with high diastereoselectivities via
aza-Morita-Baylis-Hillman reactions of aryl-substituted imines and alkyl vinyl
ketones followed by Michael additions of imides and then epimerization.
S.-e. Syu, Y.-T. Lee, Y.-J. Jang, W. Lin, J. Org. Chem., 2011,
76, 2888-2891.
A tandem catalysis protocol based on decarboxylative coupling of alkynoic acids
and 1,3-dipolar cycloaddition of azides avoids usage of gaseous or highly
volatile terminal alkynes, reduces handling of potentially unstable and
explosive azides to a minimum, and furnishes various functionalized
1,2,3-triazoles in excellent yields and a very good purity without the need for
additional purification.
A. Kolarovič, M. Schnürch, M. D. Mihovilovic, J. Org. Chem., 2011,
76, 2613-2618.
A true Click catalytic system is based on commercially available [CuBr(PPh3)3].
This system is active at room temperature, with catalyst loadings of 0.5 mol %
or less, in the absence of any additive, and it does not require any
purification step to isolate pure triazoles.
S. Lal, S. Diez-González, J. Org. Chem., 2011,
76, 2367-2373.
A well-defined copper(I) isonitrile complex is an efficient, heterogeneous
catalyst for azide-alkyne 1,3-dipolar cycloadditions and three-component
reactions of halides, sodium azide and alkynes to form 1,4-disubstituted
1,2,3-triazoles in high yields under mild conditions in water. The complex can
be recycled for at least five runs without significant loss of activity by
simple precipitation and filtration.
M. Liu, O. Reiser, Org. Lett., 2011,
13, 1102-1105.
Using commercially available Ph3PAuCl and readily prepared, benign
arylsilanes, a gold-catalyzed oxyarylation of alkenes proceeds smoothly in air.
The oxidant, Selectfluor, not only facilitates entry to the Au(I/III) manifold
but also provides a fluoride anion for silane activation, thereby avoiding the
need for addition of a stoichiometric base.
L. T. Ball, M. Green G. C. Lloyd-Jones, C. A. Russel, Org. Lett., 2010,
12, 4724-4727.
A new method for a highly effective addition of isocyanides to aldehydes
proceeded smoothly in the presence of a silanol to give the corresponding
α-siloxyamides in high yields. A wide range of aldehydes and isocyanides are
applicable in this reaction.
T. Soeta, Y. Kojima, Y. Ukaji, K. Inomata, Org. Lett., 2010,
12, 4280-4283.
A new silver-catalyzed highly regio- and stereoselective difunctionalization
reaction of simple terminal alkynes gives (Z)-β-haloenol acetate
derivatives in good yields. The resulting products are versatile intermediates
in organic synthesis.
Z. Chen, J. Li, H. Jiang, S. Zhu, Y. Li, C. Qi, Org. Lett., 2010,
12, 3262-3265.
Halofluorination of alkenes in the presence of trihaloisocyanuric acids and HF•pyridine
results in the formation of vicinal halofluoroalkanes in good yields. The
reaction is regioselective leading to Markovnikov-oriented products and the
halofluorinated adducts follow anti-addition in the case of cyclohexene
and 1-methylcyclohexene.
L. T. C. Crespo, R. da S. Ribeiro, M. S. S. de Mattos, P. M. Esteves, Synthesis, 2010,
2379-2382.
Rhodium-catalyzed regioselective arylzincation of terminal allenes affords
synthetically useful functionalized allylzinc reagents, which can be protonated
or react with various electrophiles such as carbonyl compounds and acetonitrile.
Y. Yoshida, K. Murakami, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc., 2010,
132, 8878-8879.
Borono-Mannich reactions can be performed in solvent-free conditions under
microwave irradition with short reaction time. Full conversion of the starting
materials towards the expected product was achieved, starting from
stoichiometric quantities of reactants, avoiding column chromatography. No
purification step other than an aqueous washing was required.
P. Nun, J. Martinez, F. Lamaty, Synthesis, 2010,
2063-2068.
An efficient one-pot procedure allows the synthesis of various functionalized
2-aminothiophene scaffolds catalyzed by L-proline in high yields under mild
conditions. Low catalyst loading, simple procedure, and high yields are the
important attributes of this methodology.
T. Wang, X.-G. Huang, J. Liu, B. Li, J.-J. Wu, K.-X. Chen, W.-L. Zhu, X.-Y. Xu,
B.-B. Zeng, Synlett, 2010,
1351-1354.
A three-component reactions of arylacyl bromides, amines, and dialkyl
acetylenedicarboxylate in the presence of iron(III) chloride as a catalyst at
room temperature afforded polysubstituted pyrroles in high yields.
B. Das, G. C. Reddy, P. Balasubramanyam, B. Veeranjaneyulu, Synthesis, 2010,
1625-1628.
The complementary use of small cyclopropenylidene carbene ligands or highly
hindered N-heterocyclic carbene ligands allows the regiochemical reversal
in aldehyde-alkyne reductive couplings with unbiased internal alkynes, aromatic
internal alkynes, conjugated enynes, or terminal alkynes.
H. A. Malik, G. J. Sormunen, J. Montgomery, J. Am. Chem. Soc., 2010,
132, 6304-6305.
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