Ugi adduct

Methyl 4-formylbenzoate, benzylamine, 2-nitrobenzoic acid, and cyclohexyl isocyanide were converted to the corresponding 4CC Ugi adduct [16],... 

A new class of cyclic dipeptidyl ureas, namely 3-hydroxy-6-oxo[l,2,4]triazin-l-yl-alaninamides 12, have been synthesized using the Ugi reaction. This reaction involved an a-keto-acid acid 8, an isocyanide 9 and semicarbazones 10 to give the Ugi adducts 11, wich were then stirred with sodium ethoxide <06JOC4578>. 

The use of convertible isocyanides is not always necessary in particular cases, also normal alkyl [32,40] or aryl [30] isocyanides have been employed for this task. For example, microwave irradiation of the Ugi adduct 16 (R = uBu) at 120°C in the presence of 10% CF3CO2H gave the desired diketopiperazines 17 in good yield, without the need to use more complex convertible isocyanides. However, for the synthesis of ketopiperazines 19, butyl isocyanide was found to be unsuitable. 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

A special case of SNAr is shown in Fig. 20. It actually involves a tandem 8 2-SNAr process on an Ugi adduct containing both an alkyl and an aryl halide. In 99, the acid-derived alkyl halide behaves therefore as a masked nucleophile. Treatment with thiourea (Sn2) forms an intermediate thiouronium salt which, upon basic hydrolysis, releases the required thiolate that undergoes the SnAt process. A library of benzothiazepinones 100 was produced in this way [92]. 

Fused triazoles were synthesized in a similar manner through the Huisgen azide-alkyne cycloaddition, which was carried out by simple heating the Ugi adducts at 100°C. Five different fused triazole scaffolds 160-164 were obtained by placing the additional functions in different components or changing the distance between them and the Ugi-reacting group [131]. 

Erb W, Neuville L, Zhu JP (2009) Ugi-post functionalization, from a single set of Ugi-adducts to two distinct heterocycles by microwave-assisted palladium-catalyzed cyclizations tuning the reaction pathways by ligand switch. J Org Chem 74 3109-3115... 

El Kaim and coworkers introduced a new variation for the formation of polycyclic DKPs via Ugi/Pictet-Spengler multicomponent combination [35]. The reaction of homoveratryl isocyanide with different aldehydes, amines, and a-keto acids leads to the expected Ugi-adducts, which are not isolated. Addition of trifluoroacetic acid promotes a cyclodehydratation affording the tricyclic DKPs (Scheme 2). 

A-Boc-cr-aminoaldehyde condensation products 78 are also precursors for nucleophilic attack via an internal nucleophile onto the carbonyl derived from the carboxylic acid of the classical Ugi adduct in an acid-catalyzed process. Thus, reaction in the Ugi followed by TFA treatment and prolonged evaporation in a Savant or GeneVac evaporator (8 h) affords imidazolines 79 containing four potential points of diversity in good... 

At the beginning of the 1970s Ugi et al. [29] reported the use of (+)-a-ferrocenyle-thylamine 25a in the condensation with iso-butyraldehyde, benzoic acid and tcrt-butylisocyanide (Scheme 1.11). The Ugi adduct 26 could be obtained with different diastereomeric excesses, varying solvent, concentration and temperature in analogy [29] with the above described a-methylbenzylamine. Following this first study, different a-ferrocenylalkylamines have been employed [30, 31] and improvements in... 

Both Ugi and Passerini reactions have been explored, using 3-substituted propy-noic acids as dienophiles. The multicomponent adducts 93 have been submitted to IMDA under different conditions, depending upon the heteroatom X in the tether Ugi adducts could be converted smoothly, usually under thermal conditions, to give 94 as the major stereoisomer (less than 10% of any other stereoisomer detected). On the contrary, Passerini adducts proved to be unreactive under thermal conditions, but reacted cleanly under Me2AlCl catalysis to give bicyclic lactones in a highly stereoselective way (Scheme 1.33) [83],... 

The discovery of this behavior was of great importance because a single product was converted into a variety of products. The conversion into primary amides or other carboxylic acid derivatives depended upon the structure of the Ugi adducts. An electron-rich N-acyl moiety was required for the formation of munch -nones, otherwise the primary amide was obtained [7]. The conversion of cydo-... 

Another interesting convertible isocyanide, 2-(t-butyldimethylsilyloxymethyl)-phenyl isocyanide 21 was used by Linderman and co-workers [10] in a reaction with formic acid, benzylamine, and benzaldehyde to afford the Ugi adduct 22, which, upon acid treatment followed by basification, underwent O-desilylation and amide/ester exchange to afford the ester 23 (Scheme 2.8). A remarkable feature of 21 is the high diastereoselectivity observed when it is employed in combination with chiral aminosugar derivatives in Ugi-4CR [10]. 

The reaction of azines 107, prepared in situ from aldehydes or ketones and hydrazine, afforded the Ugi adducts 108. The acid treatment of 108 resulted in the hydrolytic cleavage of the imino group with formation of the hydrazides, which immediately cyclized to phthalazinone amides 109 (Scheme 2.39) [70]. 

An alternative procedure for the solution-phase preparation of 1,4-benzodiaze-pine-2,5-diones was reported by Hulme et al. [85]. This method combines the UDC strategy and the use of the convertible 1-isocyano-l-cyclohexene 1. The Ugi-4CR between 1, N-Boc-protected anthranilic acids, amines, and aldehydes afforded the N-Boc-protected Ugi adducts 150 which, on treatment with HCl/MeOH or 10% TFA in DCE underwent N-deprotection, cyclohexenamide cleavage, and cydi-zation to the desired l,4-benzodiazepine-2,5-diones 151 (Scheme 2.55). Hulme and Cherrier [74a] reported another high-yield one-pot solution-phase synthesis of 1,4-benzodiazepine-2,5-diones that used ethyl glyoxylate in a Ugi-4CR to give 152 and then 153 (Scheme 2.55). 

The earliest reports of constrained Ugi adducts derived from bi-functional precursors appeared in the 1960s with the preparation of penicillin derivatives such as 68, involving sequential Asinger and Ugi four-component reactions (Scheme 11.13). As such, the synthesis represents the shortest preparation of a known penicillin derivative [65], The /Mactam ring is formed after isocyanide addition to the cyclic Schiff base, followed by carboxylate nitrilium ion trapping and acyl transfer to give the final penicillin core. In this example, the amine and carboxylic acid inputs may be considered tethered. 

The Ugi four-component reaction (4CR) produced a-acetamidoamide by simply stirring a methanol solution of an aldehyde, an amine, a carboxylic acid and an isocyanide [57, 58]. The Mumm rearrangement (step 5, Scheme 5), being irreversible, drives the reaction towards the formation of the Ugi adduct in good to excellent yield under extremely mild conditions. 

Using Ugi-4CR as prototypical reaction, a possible reaction leading to twofold and fourfold cyclic adduct is shown in Scheme 17. The first Ugi adduct 58 could react further with FGi and FG2 to afford the cyclic product 59 ((1), Scheme 17). Alternatively, the adduct 58 can react with a second equivalent of a bifunctional substrate 56, FGj and FG2 to provide twofold linear Ugi adduct 60, which could be further transformed to fourfold Ugi cyclic adduct 62 via intermediate 61. The formation of higher-order ohgomers/cyclic oligomers could be competitive making this reaction quite difficult to control. However, it is expected that the overall reaction outcome could in principle be governed by the three-dimensional structure of the bifunctional inputs 56 and 57. 

The reaction indeed worked well. Thus, heating to reflux a methanolic solution of piperazine, formaldehyde, acetic acid, and cyclohexyl isocyanide afforded the split-Ugi adduct 79 in 75% yield. Note that in this reaction, the symmetric diamine has been effectively desymmetrized since one nitrogen atom was alkylated while the other was acylated. The piperidine ring in intermediate 77 has to adopt a boat conformation in order for the transacylation to take place smoothly [Scheme 5.23, reaction (a)]. 

The Passerini reaction and the Ugi reaction provide a-acyloxyamides and a-acet-amidoamides, respectively. Naturally, these reactions have been applied in the synthesis of peptides and cyclopeptides/cyclodepsipeptides [91]. Recently, the application of these reactions in the synthesis of heterocycles was reported. One of the most notable examples is Fukuyama and co-workers total synthesis of ecteinascidin 743 (Et 743) (148), a complex natural product recently commercialized as an anticancer drug (Scheme 5.46) [92]. Thus, reaction of the amine 149, the amino acid 150, 4-methoxyphenyl isocyanide (151) and acetaldehyde afforded the corresponding Ugi adduct 152 in 90% yield. After a series chemical transformations, 152 was ultimately converted to Et 743. The connection between the structure of Et 743 and the peptidic nature of Ugi adduct is not obvious, but with the deep insight of an experienced synthetic chemist, the non-trivial link can be drawn and be put into practice [93, 94]. 

Changing the aldehyde component and reaction temperature in the above reaction leads to the constmction of the y-lactam nucleus 8 (iso-cotinine analog) in good yields through a base-free one-pot process without isolation of the transient Ugi adduct (Scheme 1). 

While investigating the U-4CR using 2-aminopyridine as amine input, three industrial research groups led by Bienayme at Rhone-Poulenc [44], Groebke at Hoffmann-La Roche [45], and Blackburn at Millennium pharmaceuticals [46] discovered that the normal Ugi adduct was not produced. Instead, imidazo[l,2-a]pyridine was formed in excellent yields. The acetic acid used in these reactions did not participate in the Ugi reaction as was initially expected instead, it promoted the formation of the imidazo[l,2-a]-heterocycles 86 (Scheme 15.26). The proposed... 

Dos Santos A, El Kaun L, Grimaud L, Ramozzi R (2012) Palladiimi-catalyzed ring opening of aminocyclopropyl Ugi adducts. Synlett 2012(3) 438-442... 

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