Three‐component reactions involving 3‐amino‐1,2,4‐triazole, aldehydes, including salicylic aldehydes, and pyruvic acids were studied in detail. The reaction pathway and products of the heterocyclizations could be changed by variation of the reaction parameters. The broad antimicrobial activity of the products was also studied. Compound 9d showed specific anti‐influenza virus (A/H1N1) activity, with an IC50 of 0.57 μM and a CC50 of >100 μM.
The comprehensive review contains the analysis of literature data concerning reactions of heterocyclization of aminoazoles and demonstrates the application of these types of transformations in diversity-oriented synthesis. The review is oriented to wide range of chemists working in the field of organic synthesis and both experimental and theoretical studies of nitrogen-containing heterocycles.
The well-known aminoazoles, 3-amino-5-methylisoxazole and 5-amino-N-aryl-1H-pyrazole-4-carboxamides, were studied as an amine component in Ugi and Groebke–Blackburn–Bienaymé multicomponent reactions. The first example of an application of aminoazoles in an Ugi four-component reaction was discovered and novel features of a Groebke–Blackburn–Bienaymé cyclocondensation are established and discussed. The heterocycles obtained were evaluated for their antibacterial activity and several of them demonstrated a weak antimicrobial effect, but for most of the compounds a 30–50% increase in biomass of Gram-positive strains (mainly B. subtilis) compared to control was observed.
The present review includes the analysis of known literature data concerning linear and multicomponent heterocyclizations involving pyruvic acids and aminoazoles. In particular, the review demonstrates the approaches to control regio-and chemoselectivity of these types of treatments and their application to solve the matters of Diversity Oriented Synthesis.
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IntroductionThe significance of pyruvic acid in our life can be hardly overestimated. It plays a vital role as one of the most reactive substances among those of important in cellular metabolism. That is why a conclusion may be made that reactions involving pyruvic acid may help to solve some health problems and assist in finding a cure against various diseases today and in future. However, in this case no clear relationship between the electronic character of the substituents and structure of the reaction products was established.An interesting approach to the synthesis of quinoxaline derivatives via Ugi-type reaction was proposed as well (Scheme 3) [28]. Thus, the four-component reaction of the starting reagents in MeOH yielded the Ugi adducts, which by means of acid catalysis turned into quinoxalinones. Thus, the behavior of 3-amino-1,2,4-triazole (6) in the three-component condensation with aromatic aldehydes 2 and pyruvic acid (1) turned up to be quite the same to the 5-aminotetrazole (4) reactivity [45]. Refluxing 3-amino-1,2,4-triazole (6) and aromatic aldehydes 2 with pyruvic acid (1) in glacial acetic acid allowed to isolate from the reaction mixtures the pure acids 8 with good yields (Pathway B, Scheme 10). At the same time, heating the starting compounds 1, 2 and 6 in DMF led to mixtures of two regioisomeric dihydrotriazolopyrimidines 8 and 9 (Pathway D, Scheme 10). All attempts to separate these mixtures by crystallization or using HPLC were unsuccessful [45, 53].
Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner–Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combination of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity.
Four-component reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication were studied. Unusual for such a reaction type, a cascade of elementary stages led to the formation of 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines.
Reaction Products. -The three-component reactions are carried out under thermodynamic control (reflux or microwave heating) and under kinetic control (ultrasonication). The thermodynamically controlled reactions lead to pyrazolopyridines (IV) while the reactions of (I) and (II) with (V) and (IX) under kinetic control afford stable oxygen-bridged heterocycles (VI) and (X), resp. On the other hand, the use of arylpyruvic acid (VII) in the in the multicomponent reaction changes the direction toward formation of fused pyrimidine (VIII). Some compounds are tested for their antimicrobial activity but they show inferior activity compared to the reference compound. -(MURLYKINA, M. V.; SAKHNO, Y. I.; DESENKO, S. M.; KONOVALOVA, I. S.; SHISHKIN, O. V.; SYSOIEV, D. A.; KORNET, M. N.; CHEBANOV*, V. A.; Tetrahedron 69 (2013) 44, 9261-9269, http://dx.
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