Microwave-assisted solvent-free conditions

Shi F, Zhang G, Zhou D et al (2009) An unexpected green and facile synthesis of 2, 6-diaryl-4-styrylpyridines via multi-component reactions in microwave-assisted solvent-free conditions. Chin J Chem 27 1569-1574... 

Mohammadizadeh MR, Hasaninejad A, Bahramzadeh M (2009) Trifluoroacetic acid as an efficient catalyst for one-pot, four-component synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles under microwave-assisted, solvent-free conditions. Synth Commun 39 3232-3242... 

Nonetheless, microwave-assisted solvent-free conditions have wide applications in industrial processes and enable classification of microwave chemistry as an environmentally benign method, or green chemistry [3e-g, 28, 32). 

Scheme 4 Microwave-assisted solvent-free oxidation of alcohols to carbonyls under various conditions [42-44,47]...

Several solvent-free N-alkylation reactions have been reported which involve use of tetrabutylammonium bromide (TBAB), as a phase-transfer agent, under micro-wave irradiation conditions, an approach that is developed in Chapter 6 [36]. An experimentally simple microwave-assisted solvent-free N-arylation of primary amines with sodium tetraphenylborate or arylboronic acids, promoted by inexpensive cupric acetate on the surface of KF-alumina, has been reported. The reaction is selective for mono-N-arylation and a variety of functional groups are tolerated in the process (Scheme 8.4) [37]. 

In the second example, Hamelin et al. [47] reported the first microwave-assisted solvent-free catalyzed conditions for generation of nitrile oxide intermediates 17. In this work, a mixture of methyl nitroacetate 16 (as 1,3-dipole precursor), dimethyl acetylene dicarboxylate (DMAD) 18 (as dipolarophile), and p-toluene sulfonic acid (PTSA) as catalyst (10% w/w) was irradiated neat for 30 min. The reaction was performed in an open vessel from which water was continuously removed [48]. In this manner, the desired isoxazole adduct 19 was obtained in excellent yield (91%). 

Similar types of coupling cyclizations were investigated in a microwave-assisted solvent-free synthesis of indoles catalysed by Pd-CuI-PPh3 doped on KF-alumina (see Scheme 4) [ 11 ]. The reaction conditions influence the coupling reactions studied, and in the case of a 1 1 ratio of o-iodoaniline to alkynes of type... 

Over the past few years, a considerable number of reactions have been developed in which inorganic solid supports such as alumina, silica gel, montmorillonite, etc. appeared to be useful in terms of mildness of conditions, yield and convenience. Microwave-assisted solvent-free synthesis in organic reactiorrs has been of growing interest as an efficient, economic and clean procedure. 

The microwave-assisted solvent-free intramolecular cyclization of a-iminoester derivatives leads to the synthesis of a number of seven, eight and ten membered lactams (Zradni et al., 2007). The yield was 70-85% in 15-35 min under microwave irradiation while it takes about 108 h at 140-170°C under conventional condition. 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

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. 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

Triazoles have been obtained via microwave-assisted [3-i-2] cycloaddition, under solvent-free conditions [54], starting from organic azides and acetylenic amides at 55 °C for 30 min (Scheme 23). The complete conversion of the reagents into AT-substituted-1,2,3-triazoles 69 was achieved without decomposition and side products. A control reaction carried out at the same temperature in an oil bath did not give the cycHc products, not even after 24 h of reaction time. 

Several syntheses of annulated uracils of biological value were recently reported. The key reaction was a microwave-assisted one-pot [4 -i- 2] cycloaddition of oxazino[4,5-d]-, pyrano-[2,3-d]-, pyrido[2,3-dj- and pyrimido[4,5-djpyrimidines, in the sohd state [134] and under solvent-free conditions [135]. The synthetic approach was based on the reaction of NJ -di-methyl-5-formylbarbituric acid 208 with maleimide in the sohd state for 5 min under microwave irradiation at 120 °C to give the pyrano[2,3-d]pyrimi-dine derivative 209 in 90% yield (Scheme 76). The reaction of 208 with phenyl isocyanate under microwave irradiation in the absence of solvent... 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

A recent publication by the group of Barbarella has disclosed the rapid preparation of poorly soluble unsubstituted and modified a-quinque- and sexithiophenes by the extensive use of bromination/iodination steps and microwave-assisted Suzuki and Sonogashira cross-couplings (Scheme 6.16) [42]. Suzuki reactions were either carried out under solvent-free conditions on a strongly basic potassium fluoride/ alumina support for the synthesis of soluble oligothiophenes, or in solution phase for the preparation of the rather insoluble a-quinque- and sexithiophenes. In both cases, 5 mol% of [l,l -bis(diphenylphosphino)ferrocene]dichloropalladium(II)... 

Other methodologies feature solvent-free conditions with neat starting material, tandem or cascade, catalyzed or uncatalyzed reactions, the use of aqueous media at high temperature and nonextractive techniques for product isolation. Examples appear among the following microwave-assisted applications. 

A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP only procedures involving solvent-free conditions under the action of irradiation led to the aromatized pyridine derivatives. 

Adib M, Jahromi AH, Tavoosi N et al (2006) Microwave-assisted efficient, one-pot, three-component synthesis of 3, 5-disubstituted 1, 2, 4-oxadiazoles under solvent-free conditions. Tetrahedron Lett 47(17) 2965-2967... 

He, Y, Johansson, M. and Sterner, O. (2004) Mild microwave-assisted hydrolysis of acetals under solvent-free conditions. Synth. Commun., 34 (22), 4153-4158. 

Recently, microwave-assisted Suzuki couplings under solvent-free conditions resulting in thiophene oligomers have also been reported41. 

A microwave-assisted Fischer indole synthesis under solvent-free conditions with Montmorillonite K10 clay modified with zinc chloride was employed in a key step of the synthesis of analogues of the cytostatic natural product, Sempervirine (Scheme 3.6)8. A dedicated laboratory microwave synthesizer was utilised. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

Chemat, F. and Poux, M., Microwave-assisted pyrolysis of urea supported on graphite under solvent-free conditions, Tetrahedron Lett., 2001, 42, 3693-3695. 

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