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)
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:
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:
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
Books on Multicomponent Reactions
Jieping Zhu, Hugues Bienaymé
Hardcover, 468 Pages
First Edition, 2005
ISBN: 3-527-30806-7 - Wiley-VCH
A highly efficient Fe/Cu relay-catalyzed domino protocol for the synthesis of 2-phenylquinazolin-4-amines from commercially available ortho-halogenated benzonitriles, aldehydes, and sodium azide involves consecutive iron-mediated [3 + 2] cycloaddition, copper-catalyzed SNAr, reduction, cyclization, oxidation, and copper-catalyzed denitrogenation sequences. The formed structure is the privileged core in drugs and bioactive molecules.
F.-C. Jia, Z.-W. Zhou, C. Xu, Q. Cai, D.-K. Li, A.-X. Wu, Org. Lett., 2015, 17, 4236-4239.
A facile gold-catalyzed heterocyclization provides 2-amino-1,3-oxazoles functionalized at the nitrogen atom as well as at the fifth position of the heterocyclic ring in good to moderate yields. The reaction is based on intermolecular trapping of intermediate α-oxo gold carbenes with various cyanamides.
V. A. Rassadin, V. P. Boyarskiy, V. Yu. Kukushkin, Org. Lett., 2015, 17, 3502-3505.
The use of quaternary ammonium salts, which are environmental friendly, inexpensive, and recyclable enables a simple and highly efficient multicomponent reaction of aldehydes or ketones with amines and diethyl or triethyl phosphite to give the corresponding α-aminophosphonates in excellent yields at room temperature.
Y.-Q. Yu, D.-Z. Xu, Synthesis, 2015, 47, 1869-1876.
A palladium-catalyzed, enantioselective three-component reaction of sulfonamides, aldehydes, and arylboronic acids generates a wide array of α-arylamines with high yields and enantioselectivities. Notably, this process tolerates air and moisture and provides an operationally simple approach for the synthesis of chiral α-arylamines.
T. Beisel, G. Manolikakes, Org. Lett., 2015, 17, 3162-3165.
A Cu/Pd transmetalation relay catalysis enables a three-component click reaction of azide, alkyne, and aryl halide to yield 1,4,5-trisubstituted 1,2,3-triazoles in one step in high yields with complete regioselectivity. This reaction offers an alternative to the well-established CuAAC click reactions only working on terminal alkynes.
F. Wei, H. Li, C. Song, Y. Ma, L. Zhou, C.-H. Tung, Z. Xu, Org. Lett., 2015, 17, 2860-2863.
A Pd-catalyzed three-component reaction of 3-(pinacolatoboryl)allyl acetates, aldehydes, and organoboranes provides (Z)-anti-homoallylic alcohols with high levels of diastereoselectivity and alkene stereocontrol.
Y. Horino, A. Aimono, H. Abe, Org. Lett., 2015, 17, 2824-2827.
A copper-catalyzed one-pot multicomponent cascade reaction of 1-bromo-2-(2,2-dibromovinyl)benzenes with aldehydes and aqueous ammonia enables a selective synthetis of various indole derivatives. 3-Cyano-1H-indoles, 9H-pyrimido[4,5-b]indoles, or 9H-pyrido[2,3-b]indoles depending on the concentration of ammonia, the molar ratio of reagents, and the structural features of the aldehyde.
B. Li, S. Guo, J. Zhang, X. Zhang, X. Fan, J. Org. Chem., 2015, 80, 5444-5456.
A wide range of 2-aroylbenzothiazoles can be obtained in high yields by simply heating o-halonitrobenzenes, acetophenones, elemental sulfur, and N-methylmorpholine. This three-component coupling occurs in an excellent atom-, step-, and redox-efficient manner with elemental sulfur as nucleophile building block and redox moderating agent.
T. B. Nguyen, K. Pasturaud, L. Ermolenko, A. Al-Mourabit, Org. Lett., 2015, 17, 2562-2565.
An efficient and practical one-pot Mannich reaction of aromatic ketones with aldehydes and amines at room temperature under solvent-free conditions is catalyzed by (C4H12N2)2[BiCl6]Cl·H2O. The catalyst can be recycled multiple times by simple isolation protocols without compromising the catalytic efficiency.
H. Lu, R. Wu, H. Cheng, S. Nie, Y. Tang, Y. Gao, Z. Luo, Synthesis, 2015, 47, 1280-1290.
A Rh(III)-catalyzed cascade arylation and chlorination of α-diazocarbonyl compounds with arylboronic acids and N-chlorosuccinimide exhibits excellent functional group tolerance on the organoboron and the diazo reagents. Functionalized α-aryl-α-chlorocarbonyl compounds were obtained in good yields.
F.-N. Ng, Y.-F. Lau, Z. Zhou, W.-Y. Yu, Org. Lett., 2015, 17, 1676-1679.
A one-step, three-component condensation of allenyl boronic acids or allenyl pinacolboronates with amines and aldehydes affords α-allenyl or α-propargyl α-amino acids and anti-β-amino alcohols. Secondary amines generate exclusively α-allenyl α-amino acids, while primary aliphatic amines lead to α-propargyl α-amino acids.
F. Liepouri, G. Bernasconi, N. A. Petasis, Org. Lett., 2015, 17, 1628-1631.
A practical three-component domino reaction of α-nitroepoxides and cyanamide with a series of amines enables the synthesis of functionalized 2-aminoimidazole derivatives under mild conditions without any additives.
X. Guo, W. Chen, B. Chen, W. Huang, W. Qi, G. Zhang, Y. Yu, Org. Lett., 2015, 17, 1157-1159.
Cu-catalyzed aerobic oxidative three-component coupling of a terminal alkyne, secondary amine, and sulfonamide enables an efficient synthesis of amidines. The use of Cu(OTf)2 as catalyst produces amidines selectively via an initial oxidative coupling of the terminal alkyne with the secondary amine, followed by hydroamidation of the ynamine intermediate with the sulfonamide. Glaser-Hay alkyne homocoupling products are not observed.
J. Kim, S. S. Stahl, J. Org. Chem., 2015, 80, 2448-2454.
In a palladium-catalyzed intermolecular aminocarbonylation of alkenes, the use of hypervalent iodine reagent can accelerate the reaction. The current transformation presents a convenient method to generate β-amino acid derivatives from simple alkenes.
J. Cheng, X. Qi, M. Li, P. Chen, G. Liu, J. Am. Chem. Soc., 2015, 137, 2480-2483.
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