Ugi 5-component condensation

Keating, T. A. Armstrong, R. W. Postcondensation Modifications of Ugi 4-Component Condensation Products—1-Isocyanocyclohexane as a Convertible lsocyanide—Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture, J. Am. Chem. Soc. 1996, 118, 2574-2583. 

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... 

Keating TA, Armstrong RW (1996) A remarkable two-step synthesis of diverse 1, 4-benzodiazepine-2, 5-diones using the Ugi four-component condensation. J Org Qiem... 

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... 

Saturated 1,4-dicarbonyl compounds give 1,4-dihydro-pyridazines or -pyridazinones, etc., which are easily oxidized. 1,2-Diketone monohydrazones 124 and esters 125 containing a reactive CH2 group give 3-pyridazinones 126 (Scheme 64) . A popular modification of this approach is the Ugi four-component condensation of diarylethane-l,2-dione monohydrazones 127 with isocyanides, aldehydes, and methylene active acids leading to the corresponding substituted pyridazin-3(2//)-ones 128 (Scheme 65) The intermediate Ugi condensation products have never been observed because of their tendency to cyclize <2003S691>. 

Isonitriles can otherwise attain tetravalent respectability by participating in cyclization reactions, - and in multicomponent condensations such as the Passerini (3-component) and Ugi (4-component) re-actions. Nitrilium-type intermediates are implicated in many of Aese processes. These isonitrile reactions of major synthetic importance are discussed in detail elsewhere in this compendium. 

Further general syntheses are shown in Scheme 6.5 (animation of halogenoalka-noic acid derivatives (Equation 6.4), carboxylation or carbonylation of alkylamines (Equation 6.5) and the Ugi four-component condensation (Equation 6.6)). These are useful methods capable of development in certain cases for large-scale syntheses of simple amino acids. 

A very versatile application of the Ugi reaction has been reported by Keating and Armstrong [42]. They use cyclohexenyl isonitrile (1) as a universal isocyanide in an Ugi four-component condensation. The other components are varied. The reaction products, 2-acylamino-alkanoic acid amides of generic structure 2, can undergo a number of further reactions leading in parts to new types of structures and increased diversity (Scheme 3.4). If a resin with free alcoholic groups is used the acylaminoacyl moiety can be bound to the solid phase before it is subjected to further modifications (resin capture). 

This chiral auxiliary 3 has been employed in the diastereoselective Ugi four-component condensation using the auxiliary s amine, an aldehyde, formic acid, tert-butyl isocyanide and zinc chloride at ambient temperature. Fluoride induced cleavage from the polymer gave N-formylated, N-galactosylated amino acid derivates in 58-96% yield. The diastereomeric ratios ranged from 74 26 to 96 4 (Scheme 12.3). 

Multicomponent reactions can also be performed under fluorous-phase conditions as shown for the Ugi 4 component reaction [97]. To improve the efficiency of a recently reported Ugi-de-Boc cyclization strategy, a fluorous Boc group for amine protection was introduced and the Ugi multicomponent condensation was conducted under microwave irradiation conditions (Scheme 16.64). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid-tetrahydrofuran under the action of microwave irradiation. The resulting quinoxa-linones were purified by a second F-SPE to furnish the products in excellent purity. This method has also been used for benzimidazole synthesis, vdth benzoic acid as substrate. 

In a series of papers, Armstrong and co-workers " employed the elegant Ugi four-component condensation to construct munchnone precursors and, following deprotonation, munchnones. The overall sequence, which has been adapted to the solid-phase synthesis of pyrroles by Armstrong and co-workers " and, independently, by MjaUi and co-workers, is illustrated in Scheme 4.4 for the synthesis of pyrrole 38. A Rink or Wang resin can be used as a precursor to 35. The Ugi condensation leads directly to 36 and munchnone 37 formation is induced with acid. Trapping of 37 with DMAD and cleavage from the resin yields 38. 

In a synthesis of a potent selective inhibitor of Factor Xa, modified Ugi four-component condensation between tetra-O-pivaloyl- -D-glucopyranosylamine, pyridine-4-carboxaldehyde, formic acid, and ethyl isocyanoacetate gave the product 208 in high yield and with 81% de. This was subsequently converted to the desired peptidomimetic 209. ... 

This reaction has been modified from acid-catalyzed cyclization of uredo acids from palladium catalyzed MCR among aldehydes, carbon monoxide, and ureas and from Ugi five-component condensation. Alternatively, hydantoins can also be synthesized via other methods, such as the 1,3-Dipolar Cycloaddition of l-oxa-4-azabutadiene and aryl isocyanates and the decomposition of barbituric acids in alcohol. ... 

Solid-phase synthesis of pyrroles was reported by Mjalli et al. " Pyrroles were prepared via Rink resin-bound mesoionic munchnones (Scheme 11.12). Munchnones behave as azomethine ylides in 1,3-dipolar cycloaddition. Cycloadditions with alkynes give pyrroles after aromatization and spontaneous release of carbon dioxide. A set of compounds was obtained from simple starting materials, aldehyde, amine, carboxylic acid, and isocyanide via the Ugi four-component condensation. Trifluoroacetic acid released highly substituted pyrroles as amides from the Rink resin in high overall yield and purity. A related method via the miinchnone pathway was reported by Strocker et al., and two pyrroles were obtained in 4% and 17% yields. 

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. 

Perhaps the best-known MCR is the Ugi four-(or higher) component condensation (U-4CR) [29]. First reported in 1959, the Ugi-4CR describes the conversion of carbonyl compounds 9-16, amines 9-17, various types of acids 9-19 and isocyanides 9-21, the final product being peptide-like structures 9-24. A rather simplified mechanism of the Ugi-4CR is depicted in Scheme 9.4. 

Another method for preparing pyrrole rings is by Ugi-type three-component condensation (Scheme 6.184). In the protocol published by Tye and Whittaker [345], levulinic acid was reacted with two different isonitriles and four amine building blocks (1.5 equivalents) to provide a set of eight pyrrole derivatives. While the previously published protocol at room temperature required a reaction time of up to 48 h and provided only moderate product yields, the microwave method (100 °C, 30 min) optimized by a Design of Experiments (DoE) approach (see Section 5.3.4), led to high yields of the desired lactams for most of the examples studied. 

Ugi, I. Novel synthetic approach to peptides by computer planned stereoselective four component condensations of a-ferrocenyl... 

Ugi, I., Arora, A., Burghard, H., Eberle, G., Eckert, H., George, G., Gokel, G., Herlinger, H., Von Hinrichs, E., et al. Four component condensations (4 CC), a potential alternative to conventional peptide synthesis. Solution of the stereoselectivity and auxiliary group removal problems. Pept, Proc. Ear. Pept. Symp., 13th 1975, 71-92. 

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