Microwave solvent-free methods

Danks reported a microwave-assisted variant of the classical Paal-Knoor pyrrole synthesis (Scheme 3.3)5. This solvent-free method provided a considerable rate advantage (reactions complete within 2 min compared to over 12 h in conventional thermal heating) over classical procedures and even non-nucleophilic amines were condensed smoothly in the absence of Lewis acid promoters. Purification consisted of a simple silica gel filtration. The use of an early-dedicated laboratory instrument in this work is also noteworthy however, information of how the reaction temperature was controlled is not provided. 

Another advantage of using no solvent (or less solvent), is that reaction times are often shorter, especially when a ball mill or microwave reactor is used. It is likely that solvent free methods will become more widespread as the number of microwave reactors and ball mills in research laboratories increases. For the green chemist, it is also worth noting that significant efforts need to be made in greening the work up of many of the reactions presented here and elsewhere. In most cases, any VOC solvent readily available is used, when a less hazardous or bio-sourced VOC would be a better option. 

Microwave irradiation of a mixture of an acid anhydride, an amine adsorbed on silica gel, and TaCl5/Si02 is a solvent-free method for the synthesis of A-alkyl and A-aryl-imides [47]. Ni(II) promotes the conversion of an acrylamide to ethyl acrylate via a Diels-Alder adduct with (2-pyridyl)anthracene [48], Aromatic carboxylic acids [49] and mandelic acid [50] are efficiently esterified with Fc2(S04)3 XH2O as catalyst. Co(II) perchlorate in MeOH catalyzes the methanolysis of acetyl imidazole and acetyl pyrazole [51]. Hiyama et al. used FeCb as a catalyst for the acylation of a silylated cyanohydrin. The resulting ester was then cyclized to 4-amino-2(5H)-furanones (Sch. 5) [52]. 

For reasons of economy and pollution, solvent-free methods are of great interest in order to modernize classical procedures making them more clean, safe and easy to perform. Reactions on solid mineral supports, reactions without any solvent/support or catalyst, and solid-liquid phase transfer catalysis can be thus employed with noticeable increases in reactivity and selectivity. A comprehensive review of these techniques is presented here. These methodologies can moreover be improved to take advantage of microwave activation as a beneficial alternative to conventional heating under safe and efficient conditions with large enhancements in yields and savings in time. 

According to Scheme 2.1 the principles of green chemistry can be condensed to the word productively [16]. Two main goals are to eliminate or minimize the use of volatile organic solvents in modern syntheses and to reduce energy inputs. Development of new synthetic solvent-free methods with microwave assistance is an important topic of research with growing popularity, because solvent-free reactions reduce solvents usage, simplify synthesis and separation procedures, prevent waste, and avoid the hazards and toxicity associated with the use of solvents [135]. 

It should, however, be emphasized that solvent-free methods possibly suffer from technical difficulties relating to nonuniform heating, mixing, and precise determination of the reaction temperature. Nevertheless, these drawbacks are circumvented when operating with efficient mechanical stirring in open vessels in a monomode microwave reactor [23]. 

One of the earliest reports of microwave-assisted organometallic synthesis involved the preparation of arylmercuric chlorides. Heating an ethanol solution of diphenyldiazene and 2-phenylpyridine with Hg(OAc>2 inside a sealed Teflon vessel led to the formation of the desired arylmercury complexes. Yields were a little lower than conventional approaches, but reaction times were at least 30-times shorter. This chemistry was extended 10 years later when a solvent-free method was developed. Arylmercuric chlorides together with benzoquinone, barbituric acid, or thiobarbituric acid were adsorbed on basic alumina before being exposed to microwave irradiation for 1-3 min to produce derivatives (YIF = 1.3-1.5). 

Zhou FJ, Gong GX et al (2009) Microwave- assisted catalyst- free and solvent- free methods for the synthesis of quinoxalines. Synth Commun 39 3743-3754... 

Zhou JE, Gong GX, Shi KB, Zhi SJ (2009) Catalyst-free and solvent-free method for the synthesis of quinoxalines under microwave irradiation. Chin Chem Lett 20(6) 672-675. doi 10.1016/j. cclet.2009.02.007... 

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-... 

The glass plate was exposed to microwave irradiation, eluted, and viewed by standard TLC visualization procedures to assess the results of the reaction. In this particular example, the synthesis of an arylpiperazine library (Scheme 4.25) was described, but the simplicity and general utility of the approach for the rapid screening of solvent-free microwave reactions may make this a powerful screening and reaction optimization tool. The synthesized compounds were later screened for their antimicrobial activity without their removal from the TLC plate utilizing bioautogra-phical methods [84],... 

In the context of preparing analogues of chiral l,2-dimethyl-3-(2-naphthyl)-3-hy-droxy-pyrrolidines, which are known non-peptide antinociceptive agents, Collina and coworkers have reported the solvent-free dehydration of hydroxypyrrolidines to pyrrolines under microwave conditions (Scheme 6.141) [278]. In a typical experiment, the substrate was adsorbed onto a large excess of anhydrous ferric(III) chloride on silica gel and then irradiated as a powder under microwave conditions for 30 min at 150 °C. The microwave method leads to dehydration without racemiza-tion and provides higher yields in considerably shorter times than the conventionally heated process. 

Microwave effects are most likely to be observed under solvent-free reactions [3]. In addition to the preparative interest of these methods in terms of use, separation, and economical, safe and clean procedures, absorption of microwave radiation... 

Regiospecific N- or C-benzylations of 2-pyridone were observed under solvent-free conditions in the absence of base. The regioselectivity was controlled by the activation method (MW or A) or, when using microwaves, by the emitted power level or the leaving group of the benzyl halides [58] (Eq. 59). 

One-pot syntheses of diaryl-a-tetralones by Michael condensation and subsequent Robinson annulation reactions of isophorone with chalcones were performed efficiently in a solvent-free PTC system under the action of MW irradiation. Compared with conventional heating substantial rate enhancements were observed, within very short reaction times, by use of microwaves (Eq. 59 and Tab. 5.31). They were far better than those achieved by the classical method (NaOEt in EtOH under reflux for 24 h 40-56%). 

Significant improvements in yields or reaction conditions can be achieved, together with considerable simplification of operating procedures. The powerful synergistic combination of PTC and microwave techniques has certainly enabled an ever increasing number of reactions to be conducted under clean and mild conditions. The inherent simplicity of the method can, furthermore, be allied with all the advantages of solvent-free procedures in terms of reactivity, selectivity, economy, safety, and ease in manipulation. 

There are distinct advantages of these solvent-free procedures in instances where catalytic amounts of reagents or supported agents are used since they provide reduction or elimination of solvents, thus preventing pollution at source . Although not delineated completely, the reaction rate enhancements achieved in these methods may be ascribable to nonthermal effects. The rationalization of microwave effects and mechanistic considerations are discussed in detail elsewhere in this book [25, 193]. A dramatic increase in the number of publications [23c], patents [194—203], a growing interest from pharmaceutical industry, with special emphasis on combinatorial chemistry, and development of newer microwave systems bodes well for micro-wave-enhanced chemical syntheses. 

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines (1,4-DHP) has recently been reported [98]. The experimental method proposed more than a century ago remains the most widely used to synthesize these heterocycles. Since 1992 this process has been adapted to microwave irradiation under a variety of conditions to reduce the reaction time and enhance the yield. Among these experiments, Zhang [99] reported a solvent-free process starting from 3-aminocrotonate... 

Microwave irradiation in solvent-free conditions induces the cleavage of the 2,3-bond of 2-aroyl-aziridines 135 to give an azomethine ylide intermediate, which subsequently undergoes cycloadditions to a multiple bond and leads to oxazolidine, imidazoline, naphthooxazole and pyrroline derivatives 136 in good yields (Scheme 9.41) [32b], Reactions were performed at atmospheric pressure in an Erlenmeyer flask placed in a commercial domestic oven. The reactions were complete in 10-15 min while the conventional method requires 18-20 h. 

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