Condensation, Ugis

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. 

Multi-component reactions where three or more components build a single product have received considerable interest for several years. Since most of these reactions tolerate a wide range of building block combinations, these types of reactions are frequently applied for combinatorial purposes. A solid-phase application towards the Ugi four component condensation (Ugi-4CC) generating a 18-member acylamino amide library appeared in 199939. The acylamino amide library was synthesised using amino-functionalised PEG-polystyrene (TentaGel S RAM) as the solid support. (Scheme 7.22). 

The four component condensation (Ugi reaction) " converts a mixture of substituted amine, isonitrile, aldehyde (or ketone) and carboxylic acid (Scheme 6) to a-acylaminocarboxylic acid amides (pathway a), to diacylamines (pathway b) and to a-aminocarboxylic acid amides (pathway... 

Scheme 1.8.5.1) or, in the case of a secondary amine 5, can rearrange to give imide 6. Both products constitute the thermodynamically most stable species in the reaction mixture. Many variations of the Ugi four component condensation (Ugi-4CC) have been published and a short compilation is depicted in Figure 1.8JJ. 

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],... 

The microwave acceleration of Ugi condensations on a sohd support have been utilized in the synthesis of an 18-membered targeted hbrary of a-acylamino amides [60], Irradiation of the four components, immobilizing the amine on TentaGel S RAM, for 3-5 min in a single-mode microwave synthesizer gave the products in moderate to excellent yields and high purity (Scheme 7). 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

Fig. 33 Microwave-assisted fluorous Ugi condensations. Reagents and conditions a MeOH, MW 100°C, 10-20 min b TFA-THF, MW 100 °C, 10-20 min. R = Ph, furyl, 3-Me-pyridil, i-Bu, MeSC2H4, PhC2H4 R = t-Bu, cylohexyl. Bn or Bu, m-xylU...

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... 

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [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. 

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. 

A combination of a multicomponent Ugi transformation and an intramolecular Diels-Alder reaction has been developed by Paulvannan [13]. Hence, condensation of the resin-bound (acid-labile ArgoGel-Rink resin) amine 10-37 with a tenfold... 

In a further example of a multicomponent synthesis, dihydrobenz[/] 1,4 oxazepin-5-ones were prepared in good yields in two steps by combining an initial three-component Ugi condensation with a subsequent Mitsunobu cyclisation to give (124 e.g. R1 = H, R2 = i-Pr, R3 = cyclohexyl, 65%) <06OBC4236>. 

A number of heteroaryl-fused 3-oxo-l,4-thiazepine-5-carboxamides, for example the indole-fused derivatives 133, have been accessed using a modification of the four-component Ugi condensation. In the case of 133, the starting point was the indolic acid 132. The yields of 133 were moderate to good (for example, R = -Pr, R2= EtO-(CH2)3, 66%) <06JOC2811>. 

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. 

Scheme 6.184 Ugi-type three-component condensation reactions.

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. 

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. 

To demonstrate the feasibility of this method for library generation, the isocyanides produced were subjected to an Ugi three-component condensation with various primary amines and carboxybenzaldehyde. The resulting 2-isoindolinone derivatives were obtained in high to excellent yields. 

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