Four component condensations

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

Scheme 24 Synthesis of tetrahydrocarbazoles by four-component condensation...

If ammonia or an amine is also added to the mixture (in which case the reaction is known as the Ugi reaction, or the Ugi four-component condensation, abbreviated 4... 

P., Warrington, B., Wong, S., A microreactor device for the Ugi four component condensation (4CC) reaction, in Ramsey,... 

N-Hydro-2/C-(a-AcyloxyallFour component Condensation (4CC)... 

Such a strategy follows the philosophy of resin capture, as introduced by Armstrong and Keating Keating TA, Armstrong RW. Postcondensation modifications of Ugi four-component condensation products 1-isocyano-cyclohexane as a convertible isocyanide. Mechanism of conversion, synthesis of diverse structures, and demonstration of resin capture. J Am Chem Soc 1996 118 2574-2583. See also Brown SD, Armstrong RW. Synthesis of tetrasubstituted ethylenes on solid support via resin capture. J Am Chem Soc 1996 118 6331-6332. 

The l-chloro-2,2-dibromocyclopropanes 164 similarly undergo the nickel-carbonyl-induced ring-opening carbonylation with an amine or an alcohol to give the / ,y-unsaturated carboxylic acid derivatives 165 and the dicarboxylic acid ones 166 [84]. The mechanism described above appears to be operating this is supported by the four-component condensation to 167. (Scheme 61 and 62)... 

The first solid-phase application of the Ugi four-component condensation, generating an 18-member acylamino amide library, was presented in 1999 by Nielsen and Hoel [53]. The authors described a library generation utilizing amino-functionalized PEG-polystyrene (Tentagel S RAM) as the solid support (Scheme 7.36). A set of three aldehydes, three carboxylic acids, and two isonitriles was used for the generation of the 18-member library. 

Multicomponent reactions (MCR), in which three or more reactions combine to give a single product, have lately received much attention. The Ugi four-component condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an isocyanide combine to yield an ot-acylamino amide, is particularly interesting, because... 

K. Paulvannan, Preparation of Tricyclic Nitrogen Heterocycles via Tandem Four-Component Condensation/ Intramolecular Diels-Alder Reaction , Tetrahedron Lett. 1999, 40,1851-1854. 

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. 

Keating TA, Armstrong RW (1995) Molecular diversity via a convertible isocyanide in the Ugi four-component condensation. J Am Chem Soc 117 7842-7843... 

Rikimaru K, Yanagisawa A, Kan T, Fukuyama T (2004) A versatile synthesis of a-amino acid derivatives via the ugi four-component condensation with a novel convertible isonitrile. Synlett 1 41-44... 

Mjalli AMM, Sarshar S, Baiga TJ (1996) Solid phase synthesis of pyrroles derived from a four component condensation. Tetrahedron Lett 37 2943-2946... 

Trifilenkov AS, Ilyin AP, Kysil VM, Sandulenko YB, Ivachtchenko AV (2007) One-pot tandem complexity-generating reaction based on Ugi four component condensation and intramolecular cyclization. Tetrahedron Lett 48 2563-2567... 

Faggi C, Marcaccini S, Pepino R, Pozo MC (2002) Studies on isocyanides and related compounds synthesis of l,4-benzodiazepine-2,5-diones via Ugi four-component condensation. Synthesis 18 2756-2760... 

Marcaccini S, Miliciani M, Pepino R (2005) A facile synthesis of 1, 4-benzodiazepine derivatives via Ugi four-component condensation. Tetrahedron Lett 46 711-713... 

Paulvannan K (1999) Preparation of tricyclic nitrogen heterocycles via tandem four-component condensation/intramolecular Diels-Alder reaction. Tetrahedron Lett 40 1851-1854... 

However, attempts from the authors of [125] to synthesize fused imidazoles involving isoxazols, pyrazols, or 1,3,5-triazols as primary amines in the presence of catalytic amounts of glacial acetic acid were unsuccessful and led either to the formation of complex product mixtures or even to the formation of Ugi-type four-component condensation compounds in low yields. 

A general strategy towards praziquantel derivatives 217 was developed by Liu et al. based on an Ugi four-component condensation (Ugi-4CR) followed by a Pictet-Spengler cyclization (PS-2CR) [66]. The variations of the groups and sub-stitutents in these scaffolds arise from the four starting materials isocyanide 218, aldehyde 219, amine 214, and carboxylic acid 220 (Scheme 39). This process produces ketopiperazine fused ring systems that mimic the scaffold of praziquantel. 

Keating, T. A. Armstrong, R. W. Postcondensation Modifications of Ugi Four-Component Condensation Products 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture, J. Am. Chem. Soc. 1996, 118, 257. 

Imidazoles have been synthesised by a four-component condensation of benzoin, an aromatic aldehyde, a primary amine and ammonium acetate on silica or Zeolite HY13. The reactions were complete in 6 min using a domestic instrument, in contrast to the many hours required for the conventionally thermal heated condensation reaction. In addition, it was found that it is possible to replace the aromatic aldehyde/ammonium acetate combination with a benzonitrile (Scheme 3.10)14. 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

I loci, A.M.L.and Nielsen, J., Microwave assisted solid phase Ugi four-component condensations, Tetrahedron Lett., 1999, 40, 3941-3944. 

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