Ugi condensations

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). 

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...

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>. 

Several biologically useful medium-sized benzo-fused heterocycles have been efficiently constructed by combining the efficiency of the Ugi condensation with a post-condensation S Ar cyclization, using an internal amino or hydroxyl nucleophile, and a nitrohalobenzoic acid 63 (Fig. 16). By introducing the additional nucleophile into the amine component, benzodiazepinones 79 [72], benzodiazoci-nones 80 [72], their benzo-fused counterparts 81 [72], benzoxazepinones 82 [72] and their fused counterparts 84 [60] and finally benzoxazocinones 83 [72] have been obtained. For the first two systems, the already described UDC strategy was exploited, whereas for the oxa heterocycles, the alcoholic or phenolic hydroxyl did... 

C=N bond formation has also been achieved starting from two additional carbonyl functions properly installed in an Ugi component. Cyclization has been accomplished in this case through a Paal-Knorr reaction of the dicarbonyl compound generated by the Ugi condensation, leading to pyrazinones [107]. 

Cheng et al. describes an efficient solution phase and solid phase synthesis of 2-oxopiperazines [29]. These reactions involve a novel Ugi condensation-A-acylimi-nium condensation reaction (Scheme 9). A carboxylic acid 50, an aldehyde 51,... 

Keung W, Bakir F, Patron AP, Rogers D, Priest CD, Darmohusodo V (2004) Novel alpha-amino amidine synthesis via scandium(III) triflate mediated 3CC Ugi condensation reaction. Tetrahedron Lett 45(4) 733-737... 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

The azalactones (19) obtained by the Ugi condensation, on thermolysis, give the piperazinediones (20) in almost quantitative yields [73AG(E)79]. 

Scheme 7.22 General depiction for microwave-assisted solid-supported Ugi condensation.

For example, aldehydes having an a-alkyl substituent have been reported to be stereochemically unstable during Ugi condensation [3], On the contrary, a-alkoxy substituted aldehydes do not racemize. 

The enantiomerically pure 3-thiazoline 50, obtained via Asinger reaction using a galactose-derived chiral auxiliary, was successfully submitted to an Ugi condensation affording the trans adduct 51 with good stereoselectivity, as reported in Scheme 1.19 [56],... 

Finally, in the most complex multicomponent reaction involving isocyanides, the 7-CC proposed by Ugi in 1993 [93], a moderate diastereoselectivity, leading to a 2 1 mixture of epimeric thiazolidines 109 was observed. The reaction is a combination between an Asinger condensation, involving an a-mercaptoaldehyde (generated from the a-bromoaldehyde and SH ) and an Ugi-type 4-CC with a monoalkyl car-boxylate as acid component (Scheme 1.38). Although the relative configuration of the major stereoisomer was not demonstrated, it is probably trans, in line with the results of Ugi condensation with chiral thiazolines, reported above in Scheme 1.19. 

An analogous synthesis was reported by Sung et al. [61]. Benzoic add or bi-functional isophthalic or terephthalic acids were employed as the acid components in the Ugi condensation. The final products 93 possessed alternating benzene/ imidazole systems and were potentially interesting for their optoelectronic properties (Scheme 2.33). 

In connection with an interest in generating /i-turn dipeptide mimetics, Piscopio and co-workers developed a solid-phase approach to the Freidinger lactam 86 via a solid-phase Ugi condensation and ring-closing metathesis (RCM) methodology [72], The resin-bound amine 85 is the equivalent of a traceless linker and the two-step protocol proceeds in good yield (Scheme 11.17). 

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>. 

Substituted oxazoline-4-carboxamides 134, present in several families of bioactive natural products, have been prepared in an efficient and general one-pot, four-component Ugi condensation of (1-keto mesylates 132, ammonia, carboxylic acids, and isonitriles, leading to intermediate diamides 133. 

Figure 5.7. Comparisons of the 3D four-point pharmacophore fingerprints exhibited by several sets [MDDR database of 62,000 biologically active compounds, a corporate registry database of 100,000 compormds used for screening, 100,000 compounds from combinatorial libraries (from a four-com-poilent Ugi condensation reaction), and 14,000 compound random subsets (MDDR, corporate) or indlividual libraries]. The four-point potential pharmacophores were calculated using 10 distance range bins and the standard six pharmacophore features.

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