Microwave-activated three-component

Yadav LDS, Kapoor R (2003) Solvent-free microwave activated three-component synthesis of thiazolo-r-triazine C-nucleosides. Tetrahedron Lett 44 8951-8954... 

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). 

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... 

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. 

Shi, L., Tu, Y.-Q., Wang, M., Zhang, F.-M., Fan, C.-A. (2004). Microwave-promoted three-component coupling of aldehyde, alkyne, and amine via C-H activation catalyzed by copper in water. Organic Letters, 6, 1001-1003. 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

It should be also noted that, in a very recent publication, Liu and coworkers were successful in applying microwave radiation within their domino approach towards the synthesis of pyrrolo[2,l-fc]quinazoline alkaloids such as deoxyvasicinone, 8-hy-droxydeoxyvasicinone, mackinazolinone and isaindigotone, which exhibit a promising broad spectrum of biological activities. In the case of isaindigotone, the authors were able to extend their strategy to a three-component procedure, which comprises the domino conversion of anthranilic acids and Boc-protected amino acids into the tricyclic core skeleton [43]. 

In a more recent study using dedicated multimode microwave reactors for chemical synthesis, which enable temperature and power control, it was demonstrated that microwave irradiation could be effectively employed to couple aromatic carboxylic acids to polystyrene Wang resin [25], if the symmetrical anhydride procedure was used, and not the three-component O-acylisourea activation method [19]. Almost quantitative loading was achieved in l-methyl-2-pyrrolidone (NMP) at 200 °C within 10 min under... 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

Microwave irradiation, for 15-20 min under solvent-free conditions, promoted the regiospecific three-component one-step cyclocondensation of benzoylacetonitrile, an aromatic aldehyde, and aminopyrimidinones 460 to give 6-cyano-5,8-dihydropyrido[2,3-, pyrimidin-4(3/7)-ones 461 rather than the isomers 462. The formation of 461 proceeds via a Michael-type addition of C-5 in aminopyrimidine 460 to the activated double bond of the arylidene-benzoylacetonitrile intermediate followed by cyclization with the removal of a water molecule. Compounds 461 were also prepared conventionally by refluxing the reactants in absolute ethanol for 40 8 h <2001TL5625>. 

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 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 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 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],... 

Kappe and co-workers also utilized microwave irradiation to facilitate a three component one-pot synthesis of a library of 3,5,6-substituted 2-pyridones 18 <04T8633>. This method utilizes a CH-acidic substrate 19, dimethylformamide dimethylacetal (DMF-DMA) and diverse active methylene nitriles 20 as building blocks. 

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. 

Pyridone and 2-quinolone analogues are well known biologically active heterocyclic scaffolds. In 2004 Kappe and coworkers generated libraries of 3,5,6-substituted 2-pyridone derivatives by rapid microwave-assisted solution-phase methods using a one-pot, two-step procedure [61]. This three-component condensation of CH-acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal (DMFDMA), and methylene-active nitriles led to 2-pyridones and fused analogues in moderate to good yields (Scheme 10.26). 

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). 

Zhu et al. described two independent one-pot three-component routes to Ceo pyrrolidines 174 and 175 involving microwave activation (Scheme 11.42) [104]. In the first approach, a solution of Ceo, 171, amino acid 172 and fluorinated benzaldehyde 173 was heated at reflux in o-dichlorobenzene under the action of microwave irradiation. The in sitw-generated fluorinated azomethine ylides undergo cydoaddition... 

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. 

At microwave frequencies, non-line-of-sight paths can be estabhshed with the use of passive repeaters as well as active repeaters. At the millimeter wavelengths involved, passive reflectors can be constructed with sufficient gain to make their use practical. The most common passive repeater is a large, flat, billboardlooking reflector that acts exactly like an optical mirror. As with an active repeater, the passive repeater must have hne of sight to both the receiver and transmitter. A single passive reflector can not act as a relay when aU three components of the link are in-line or are nearly in-line. In such a case, two closely spaced passive reflectors are required. 

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