Four-component reaction

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

The synthesis of functionahzed tetrahydrocarbazoles can be promoted by microwave irradiation [84], The organocatalytic four-component reaction of a solution of 2-substituted indole, aromatic aldehyde (2 equiv) and Mel-drum s acid in benzene in the presence of DL-proline proceeds when heated under Dean-Stark conditions for 5 min in a single-mode microwave reactor to give the tetrahydrocarbazole product as a mixture of diastereoisomers (Scheme 24). 

Another kind of combinatorial synthesis can be applied to reactions that assemble the product from several components in a single step, a multicomponent reaction. A particularly interesting four-component reaction is the Ugi reaction, which generates dipeptides from an isocyanide, an aldehyde, an amine, and a carboxylic acid. 

Hantzsch four-component reaction hexafluoroisopropanol human immunodefficiency virus human leukocyte elastase hydroxymethylglutamate hexamethylphosphoric triamide highest occupied molecular orbital histrionicotoxin... 

The application of the one-pot Ugi four-component reaction by stirring a mixture of the aldehyde 486, benzyl amine 487, isocyanide 479, and acrylic acid 385 in methanol at room temperature for 36 h afforded the triene 488 as a 74 26 mixture of amine rotational isomers in 80% combined yield. The triene 488 on heating in DMSO at 120 °C for 12 h underwent cycloaddition to give the tricyclic compound 489 as a single diastereomer in 98% yield (Scheme 111). 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

Other multicomponent reactions are exemplified in the following two schemes. A new highly diastereoselective four-component reaction was developed for the synthesis of dihydropyridones 191 substituted with an isocyanide functionality <06OL5369>, thereby generating a synthetically useful complex isocyanide for use in further reactions. In this strategy, a phosphonate, a nitrile, and an aldehyde are used to generate an azadiene intermediate 192, which is trapped by an isocyanoacetate in the same pot. 

Raja and Perumal reported the synthesis of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones via a four-component reaction consisting of arylthioacetones, 2-substituted aromatic aldehydes and methylamine or ammonium acetate <06CPB795>. Further elaboration of this four component reaction to a novel five component tandem Mannich-enamine-substitution sequence involving the reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, two equivalents of a substituted aromatic aldehyde, and two equivalents of ammonium acetate is shown below <06T4892>. When this five-component tandem reaction involves para-substituted benzaldehydes, the cis (193) and trans (194) diastereomers of thiazones are obtained. Alternatively, orf/zo-substituted benzaldehydes form only the trans (194) diastereomer along with an air-oxidized product 195. 

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R1 = PhCH R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular IV-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

Y. Li, X. Zhang, S. Chu, K. Yu, and H. Guan, Synthesis of cluster mannosides via a Ugi four-component reaction and their inhibition against the binding of yeast mannan to concanavalin A, Carbohydr. Res., 339 (2004) 873-879. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

Several multi-component domino reactions for the preparation of libraries have been developed in the last years.141 One of the first examples in solution is a four-component reaction described by Ugi et al. in which a carbocyclic acid 5, an aldehyde 6 and an isocyanide 7 are condensed in presence of methanol to give amino acids 8 (scheme 2).151... 

THE FOUR-COMPONENT REACTION AND OTHER MULTICOMPONENT REACTIONS OF THE ISOCYANIDES... 

Perhaps the most useful and most widely employed multicomponent reaction in this context is the Ugi four-component reaction (U4CR and variations, Fig. 11), where an isonitrile, an aldehyde, an amine, and a carboxylic acid react to form a single product [65, 66]. The principal product is a dipeptide or dipeptide derivative and a high degree of diversity can be introduced by substituents (each of the four components can be varied), subsequent reactions, or by other reaction paths, which can lead to a vast varia-... 

In the previous cases, the two or four Ugi reactions taking place were either identical or similar, but in this case, the reaction taking place at the oxime side involves other components than the reaction on the carboxylic acid side. In effect, two four-component reactions are combined to give a five-component macrocyclization reaction. 

Lindhorst T, Bock H, Ugi I (1999) A new class of convertible isocyanides in the Ugi four-component reaction. Tetrahedron 55 7411-7420... 

Bonnaterre F, Bois-Choussy M, Zhu JP (2006) Rapid access to oxindoles by the combined use of an Ugi four-component reaction and a microwave-assisted intramolecular Buchwald-Hartwig amidation reaction. Org Lett 8 4351-4354... 

Wu JL, Jiang Y, Dai WM (2009) Assembly of l,3-dihydro-2H-3-henzazepin-2-one conjugates via Ugi four-component reaction and palladium-catalyzed hydroamidation. Synlett 1162-1166... 

Dai WM, Shi JY, Wu JL (2008) Synthesis of 3-arylideneindolin-2-ones from 2-aminophe-nols by Ugi four-component reaction and Heck carbocyclization. Synlett 2716-2720... 

Faggi et al. describes the synthesis of a 1,6-dihydro-6-oxopyrazine-2-carboxylic acid derivative via the Ugi four-component reaction (Scheme 8) [28]. Arylglyoxals 44, an amine 45, benzoylformic acid 46, and an isocyanide 47 afforded the Ugi intermediate 48, which was cyclized in a [5+1] fashion with ammonium acetate to give the final product 49 in good yields. 

Scheme 8 Synthesis of a l,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives via the Ugi four-component reaction and two representative 3D conformation of 49A (cyan) and 49B (blue). Yield shown represents yield over all steps...

Scheme 20 Synthesis of 2,5-DKPs via Ugi three-center four-component reaction with two representative 3D conformations of 123A (blue) and 123B cyan). Yield shown represents yield overall steps...

DKP as opposed to 2,5-DKPs are rather rarely described by isocyanide-based MCRs. Ugi et al. describes the only 2,6-DKP synthesized by isocyanide MCR [48]. This reaction (Scheme 25) uses the well known five-center-four-component reaction (U-5C-4CR) of an a-amino acid, an aldehyde or ketone, an isocyanide,... 

Umkehrer et al. developed the synthesis of tetrazolopiperazine building blocks 178 via Ugi five-center-four-component reaction (U-5C-4CR) of primary amines 179, aldehydes 180, trimethylsilylazide 181, and 2-isocyanoethyltosylate 182 [54]. The in situ generated secondary amine finally gets alkylated by the toluenesulfo-nate, leading to the expected fused tetrazoles 178 (Scheme 31). The primary amines and the aldehydes can be varied broadly, which allows to produce products with two potential diversity points. 

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