Microwave-activated three-component reaction

Another example of a microwave-activated three-component reaction is the synthesis of2-anilino-7-amino-l,2,4-triazolo[l,5-d][l,3,5]triazines42 from diaminotriazoles 43, cyanoamide, and triethyl orthoformate (13TL5537). 

Thiazolidones are another class of heterocycles that attract much attention because of their wide ranging biological activity [106], They are usually synthesized by three-component condensation of a primary amine, an aldehyde, and mercapto-acetic acid with removal, by azeotropic distillation, of the water formed [107]. The reaction is believed to proceed via imine formation then attack of sulfur on the imine carbon. Finally, an intramolecular cyclization with concomitant elimination of water occurs, generating the desired product. The general applicability of the reaction is limited, however, because it requires prolonged heating with continuous removal of water. To circumvent these difficulties and to speed up the synthesis, Miller et al. developed a microwave-accelerated three-component reaction for the synthesis of 4-thiazolidinones 63 [108]. In this one-pot procedure, a primary amine, an aldehyde, and mercaptoacetic acid were condensed in ethanol under MW conditions for 30 min at 120 °C (Scheme 17.44). The desired 4-thiazolidinones 63 were obtained in 55-91% yield. 

A novel microwave-mediated three-component coupling of a-acyl bromides, pyridine and internal alkynes was carried out in the absence of a solvent on activated basic alumina to provide a collection of indolizines (Scheme 3.5)7. It was proposed that the reaction proceeded via in situ generation of a dipole from an N-acyl pyridinium salt, followed by a [3+2] cycloaddition reaction. A dedicated laboratory microwave system was... 

The application of arylpyruvic acids 256 in place of pyruvic acid in three-component reactions leads to dramatic changes in the direction of the process. Refluxing of starting compounds for 3 hours of irradiating with microwave at 170°C for 20 minutes in acetic acid yielded 3-hydroxy-4,5-diaryl-l-azolyl-2,5-dihydro-li/-2-pyrrolones 258 [203] (Scheme 3.73). Under ultrasonic irradiation in ethanol with the addition of catalytic amounts of hydrochloric acid or in acetic acid, the reaction proceeds in a different direction with the formation of pyrimidinecarboxylic acids 259. In the case of pyruvic acid the course of the three-component reaction does not so drastically depend on the activation method or solvent type as well as from temperature mode [202]. 

The three-component reactions of malononitrile 175, aldehydes 176 and 2-mercaptoacetic acid 177 (Scheme 33), in different molar ratios under microwave heating, in water, provided thiazolopyridine derivatives 178 and 179 in high yields [70]. The compounds were evaluated for their cytotoxic activity against the carcinoma cell line HCT 116 (ATTC CCL 247) and mice lymphocytes (Table 14). Compound 183 was the only one with selective cytotoxic activity towards the HTC 116 cells (Fig. 22). The compounds were also evaluated for their antioxidant... 

The Kabachnik-Fields reaction is an effective means of preparing biologically active a-amino phosphonates [64]. It involves the three component reaction of an aromatic aldehyde, an aniline, and diethylphosphite. The reaction has recently been performed using microwave irradiation with [BMIM]PF6, [BMIM]SbF6, [BMIM]BF4, and DMF as solvents and lanthanide triflates as catalysts (Scheme 7.18) [65]. The reactions were performed using a domestic microwave oven and pulsed irradiation. Catalyst activity in the ionic liquids was found to be higher than or comparable with that in DMF. It was also found that catalyst activity varied depending on the ionic liquid used. For example, Yb(OTf)3 was very active in [BMIM]BF4 but Sc(OTf)3 was more active in [BMIMjPFe. Excellent product yields were obtained. 

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. 

The structures of trisubstituted imidazoles are prevalent in natural products and pharmacologically active compounds, like the known P38 map kinase inhibitor and losartan. Besides, triarylimidazoles display various bioaclive effects such as herbi-cidal, fungicidal, analgesic, anti-inflammatory, and antithrombotic activities as well. The three-component synthesis of 2,4,5-trisubstituted imidazoles, a typical acid-catalyzed reaction, could be conducted successfully with good to excellent yields in a neutral ionic liquid, l-methyl-3-heptyl-imidazolium tetrafluoroborate ([Hemim] [BF ]), under solvent-free and microwave-assisted conditions (Fig. 12.46) [31],... 

The canthines are a tetracyclic subclass of j8-carboline alkaloids bearing an additional D-ring. Members of the canthine family have been shown to have pharmacological activity, including antifungal, antiviral, and antitumor properties. In 2003 Lindsley and coworkers described a microwave-mediated procedure for one-pot synthesis of the basic canthine skeleton [122]. The key step is an inverse-electron demand Diels-Alder reaction and subsequent chelotropic expulsion of N2, a reaction that can be achieved after a three-component condensation of an acyl hydrazide-tethered indole with a 1,2-diketone and excess ammonium acetate to form a triazine (Scheme 10.61). 

Balalaie et al. (2003) reported a one-pot, three-component condensation of benzil, benzonitrile derivatives, and primary amines on the surface of silica gel with acidic character under microwave irradiation as a new and efficient method to produce 1,2,4,5-tetrasubstituted imidazoles (Scheme 6.14). This methodology offers several advantages, such as solvent-free conditions, the use of substances without any modi-hcation or activation, high yields, shorter reaction times, and reusability of solid catalysts, and it is environmentally benign compared to the existing methodologies. 

B. Saritha, S. J. Prakash, Synlett 2003, 505-506. Solvent and catalyst free three-component coupling of carbonyl compounds, amines and triethylphosphite a new synthesis of a-aminophosphonates. (c) M. M. Kabachnik, E. V. Zobnina, I. P. Beletskaya, Synlett 2005, 1393-1396. Catalyst-free microwave-assisted synthesis of a-aminophosphonates in a three-component system RjC(0)R2-(Et0)jP(0)H-RNH2. (d) X.-J. Mu, M.-Y. Lei, J.-P. Zou, W. Zhang, Tetrahedron Lett. 2006, 47, 1125-1127. Microwave-assisted solvent-free and catalyst-free Kabachnik-Fields reactions for a-amino phosphonates. (e) G. Keglevich, A. Szekrenyi, Lett. Org. Chem. 2008, 5, 616-622. Eco-friendly accomplishment of the extended Kabachnik-Eields reaction a solvent- and catalyst-free microwave-assisted synthesis of a-aminophos-phonates and a-aminophosphine oxides, (f) K. U. Maheswara Rao, G. R. Devi, N. J. Reddy, P. Santhipriya, C. S. Reddy, Phar. Chem. 2010, 2, 51-57. Uncatalyzed three component synthesis and anti-microbial activity of a-amino phosphonates. 

Rajasekhar et al. also synthesized a new class of diethyl a-aryl/2-thienyl-a-[2-(phenylthio)phenylamino]methylphosphonates (54) via a three-component Kabachnik-Fields reaction of 2-aminodiphenylsulfide (53), substituted phenyl/heterocyclic aldehydes (44), and diethyl-phosphate (2) in the presence of heterogeneous nano-silica-supported nano-BFs SiOa under solvent-free conditions under microwave irradiation (Scheme 25). The procedure has several advantages such as short reaction time, low loading of catalyst, good yields, and reusability of the heterogeneous silica-supported nano-catalyst. The title compounds were found to exhibit considerable in vitro antibacterial and antifungal activity. 

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