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 copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines, and sodium azide provides benzimidazoles in the presence of TBHP at moderate temperature via a domino C-H functionalization, transimination, ortho-selective amination, and a cyclization sequence. The reaction offers broad substrate scope and functional group compatibility.
D. Mahesh, P. Sadhu, T. Punniyamurthy, J. Org. Chem., 2016, 81, 3227-3234.
The use of N-Boc-protected hydrazine in the Ugi tetrazole reaction provides a library of highly substituted 5-(hydrazinomethyl)-1-methyl-1H-tetrazoles in good yield.
P. Patil, J. Zhang, K. Kurpiewska, J. Kalinowska-Tłuścik, A. Dömling, Synthesis, 2016, 48, 1122-1130.
A direct difunctionalization protocol of alkenes with nitriles and thiols under metal-free synthesis conditions provides various β-acetamido sulfides with very good yields simply by using inexpensive molecular iodine as a catalyst, DMSO as a mild oxidant, and readily available thiols as thiolating reagents.
H. Cui, X. Liu, W. Wei, D. Yang, C. He, T. Zhang, H. Wang, J. Org. Chem., 2016, 81, 2252-2260.
A multicomponent reaction involving aryl boronic acids, elemental sulfur, and P(O)H compounds provides valuable S-aryl phosphorothioates and S-aryl phosphorodithioates in excellent yields. Moreover, this method can be easily scaled up.
J. Xu, L. Zhang, X. Li, Y. Gao, G. Tang, Y. Zhao, Org. Lett., 2016, 18, 1100-1103.
A palladium-catalyzed three-component synthesis of arylmethylsulfonamide derivatives from sulfonamides, paraformaldehyde, and arylboronic acids is operationally simple and provides a broad range of structurally interesting sulfonamidomethyl compounds.
T. Beisel, G. Manolikakes, Synthesis, 2016, 48, 379-386.
A Schiff’s base complex nickel catalyst (Ni-C) enables a highly efficient one-pot microwave-assisted synthesis of 2,4,5-trisubstituted imidazoles in excellent yields from aldehydes, benzil, and ammonium acetate. The catalyst could be easily recovered by simple filtration and reused.
T. S. Chundawat, N. Sharma, P. Kumari, S. Bhagat, Synlett, 2016, 27, 404-408.
In an efficient aqueous synthesis of thioamides from aldehydes and N-substituted formamides, sodium sulfide serves as the sulfur source in water, which makes this method very practical and efficient. Furthermore, late-stage modifications of bioactive molecules are demonstrated.
J. Wei, Y. Li, X. Jiang, Org. Lett., 2016, 18, 340-343.
The use of a H8-BINOL-based phosphoramidite ligand enables a Pd-catalyzed highly enantioselective three-component coupling of 1,3-dienes with aryl iodines and sodium dialkyl malonates via a Pd-catalyzed cascade arylation and asymmetric allylic alkylation reaction. This reaction provides an efficient strategy for the enantioselective 1,2-difunctionalization of 1,3-dienes.
X. Wu, H.-C. Lin, M.-L. Li, L.-L. Li, Z.-Y. Han, L.-Z. Gong, J. Am. Chem. Soc., 2015, 137, 13467-13479.
A regioselective, iridium-catalyzed multicomponent synthesis of pyrimidines from amidines and up to three (different) alcohols proceeds via a sequence of condensation and dehydrogenation steps. While the condensation steps deoxygenate the alcohol components, the dehydrogenations lead to aromatization. PN5P-Ir-pincer complexes catalyze this sustainable multicomponent process most efficiently.
N. Deibl, K. Ament, R. Kempe, J. Am. Chem. Soc., 2015, 137, 12804-12807.
The use of Mo(CO)6 and an amine enables a regiospecific, Pd-free aminocarbonylation of various terminal alkynes. The Mo(CO)6-amine system played a dual role as complexing agent and as CO donor.
A. Nagarsenkar, S. K. Prajapti, S. D. Guggilapu, B. N. Babu, Org. Lett., 2015, 17, 4592-4595.
The three-component reactions of enaminones, tosylhydrazine and primary amines enabled a regioselective construction of 1,5-disubstituted 1,2,3-triazoles via cascade dual C-N bond formation, N-N bond formation and an acyl migration-based C-C bond formation. This metal- and azide-free method proceeds in the presence of only molecular iodine.
J.-P. Wan, S. Cao, Y. Liu, J. Org. Chem., 2015, 80, 9028-9033.
An operationally simple Pd-catalyzed three component reaction involving terminal alkynes, boronic acids, and perfluoroalkyl iodides gives trisubstituted perfluoroalkenes in a highly regio- and stereocontrolled manner by simultaneous additions across the triple bond in a radical-mediated process. The reaction is broad in scope and tolerates many functional groups.
Z. Li, A. García-Domínguez, C. Nevado, J. Am. Chem. Soc., 2015, 137, 11610-11613.
A concise copper-catalyzed N-O bond cleavage/C-C/C-N bond formation procedure enables the synthesis of multisubstituted pyridines from various oxime acetates, activated methylene compounds, and a wide range of aldehydes. This method features inexpensive catalysts, no need for extra oxidant, and high step-economy.
H. Jiang, J. Yang, X. Tang, J. Li, W. Wu, J. Org. Chem., 2015, 80, 8763-8771.
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.
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