Ugi three-component condensation

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. 

A rapid and efficient optimization of a microwave-assisted procedure for the Ugi three- component condensation of levulinic acid with an amine and an isonitrile to afford lactam derivatives was developed (Tye and Whittaker, 2004). This reaction is completed in shorter reaction times (30 min) compared to the conventional procedure (48 h) using methanol as a solvent however, ethanol was used as a solvent in the case of ethyl isocyanoacetate substrate to avoid problems with transesterification. 

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). 

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. 

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... 

Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford a-acyloxycarboxamides. Cf. Ugi reaction. 

This new three-component condensation was performed in the presence of either Brpnsted (e.g., perchloric [127] or glacial acetic acid [125]) or Lewis acids [126] in methanol at room temperature giving the desired fused imidazoles in good yields and was defined as Ugi-type 3-CR or Groebke reaction [128]. 

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 time consuming chromatographical purification of heterocycles 28 and 29 slowed down the rate of library production. A phase separation using fluorous chemistry was employed by Zhang and Lu to address the workup and purification of fused 3-aminoimidazo[ l,2-a]pyridines (such as 30) [54]. Thus, attachment of a perfluorooctanesulfonyl tag to aldehydes and subsequent Ugi three-component microwave-assisted condensations with 2-aminopyridines and isocyanides furnished the desired heterocycles 30, which were conveniently isolated by fluorous solid-phase extraction. The fluorous tag could be subsequently used as an activating group in the post-condensation modifications, such as Suzuki-Miyaura cross-coupling reactions. 

To achieve maximum efficiency, the synthesis pathways in DOS should be not more than three to five steps. To achieve skeletal complexity in DOS, it is critical to identify and to implement complexity-generating reactions that rapidly and efficiently generate complex molecular skeletons. For example, Schreiber et al. used tandem Ugi four component condensation-Diels-Alder reaction to generate complexity (Figure 9.3). 

Ugi reaction. A new catalyst for the three-component condensation is PhPO(OH)H. 

Tye and Whittaker pursued Ugi-type three-component condensations to prepare a range of pyrrole derivatives [26]. Levulinic acid was reacted with two isonitriles and four amines to afford eight different examples. Under conventional conditions, the reactions required 48 h to return moderate yields, but microwave heating in methanol at 100 °C afforded improved yields in only 30 min (i.e. in two orders of magnitude less time Scheme 3.6). 

In 2003, Portlock and coworkers [53a] demonstrated that the Petasis borono Mannich (three-component) condensation can be performed in tandem with the Ugi (four-component) condensation to provide access to six-dimensional libraries of compounds with application in the drug discovery area. 

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]. 

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>. 

Mannich and Passerini, to whom we owe the two best-known three-component reactions, are the grandparents of the four-component condensation, the Ugi reaction. Its parents are Ugi and Steinbrtick-ner, assisted by coworkers of that period. The godparents are Opitz and Merz, McFarland and Sjoberg. ... 

Scheme 2.2-48 MW-assisted three-component Ugi condensation reaction.

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