Solvent-free microwave processes

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

Microwave heating has also been applied in the solvent-free phosphorylation of microcrystalline cellulose (Gospodinova et al., 2002). In the isolation step of this procedure, only water and ethanol were used as additional solvents. Wax esters have been produced from vegetable oils using a solvent-free enzymatic process (Petersson et al, 2005) this is particularly noteworthy as enzymes are often intolerant to high concentrations of substrates. The examples of solvent-free procedures described here show that solvents are not always required in the transformation of naturally sourced biopolymers and also in the chemistry of small molecules that can be obtained from a biorefinery. 

In the last decade there has been an increasing demand for new extraction techniques, amenable to automation, with shortened extraction times and reduced organic solvent consumption, to prevent pollution and reduce the cost of sample preparation. Driven by these goals, advances in microwave extraction have resulted several techniques such as microwave-assisted solvent extraction (MASE) [32, 36-39], vacuum microwave hydrodistillation (VMHD) [40, 41], microwave hydrodistillation (MWHD) [42, 43], compressed air microwave distillation (CAMD) [44], microwave headspace (MHS) [5], and solvent-free microwave hydrodistillation (SEME) [45, 46]. Table 22.3 summarizes the most common microwave extraction techniques for plant matrices and lists their advantages and drawbacks. Over the years procedures based on microwave extraction have replaced some of the conventional processes and other thermal extraction techniques that have been used for decades in chemical laboratories. 

Varma moves away from the use of solvents altogether by demonstrating microwave expedited solvent-free synthetic processes. He exposes neat reactants to microwave (MW) irradiation in the presence of supported ret ents or catalysts on mineral oxides resulting in enhanced reaction rates, greater selectivity and experimental ease of manipulation. 

Other interesting variations based on environmentally friendly alternatives, such as the use of microwaves [60], ionic liquids [61], aqueous media [62], or solvent-free [63] processes have also been reported to carry out the strategies with success. 

Knoevenagel condensation of aromatic aldehydes with active methylene compounds under solvent-free, microwave irradiation conditions gives arylidene derivatives (Mogilaiah, et al., 2010a). This convenient process was catalyzed by NH- SOjNH and the yield is excellent and purity is high. 

An efficient one-pot procedure for the synthesis of ionic liquids based on nitrogen-containing heterocycles, imidazolium or pyridinium salts by following the conditions of green process has been developed (Aupoix et al., 2010). Imidazolium salts and DBU have been found to catalyze efficiently the benzoin condensation giving good yields within very short reaction time using solvent-free microwave activation conditions. 

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. 

In modern microwave synthesis, a variety of different processing techniques can be utilized, aided by the availability of diverse types of dedicated microwave reactors. While in the past much interest was focused on, for example, solvent-free reactions under open-vessel conditions [1], it appears that nowadays most of the published examples in the area of controlled microwave-assisted organic synthesis (MAOS) involve the use of organic solvents under sealed-vessel conditions [2] (see Chapters 6 and 7). Despite this fact, a brief summary of alternative processing techniques is presented in the following sections. 

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. 

The Jacobs-Gould intramolecular cyclization of diethyl N-(6-methyl-2-pyridyl)amino-methylenemalonate to 3-ethoxycarbonyl-7-methyl-l,8-naphthyrid-4-one is another reaction ideally suited to microwave heating, although conductively heated equipment was employed for laboratory-scale experiments [45]. The product is a key intermediate in the synthesis of nalidixic acid, the first of the quinolone antibacterials. The process usually is conducted at temperatures of 200-250 °C and in high dilution, with heat transfer oils such as the eutectic mixture of diphenyl ether and biphenyl. However, it proceeded rapidly, predictably and controllably under solvent-free conditions. 

Under solvent-free conditions only deethylation is observed whereas in the presence of ethylene glycol (EG), the selectivity is totally reversed and demethylation becomes the major process. In both, considerable increases in reaction rate were observed under the action of microwave irradiation when compared with classical heating (A) (Tab. 5.27). 

It is of primary interest to avoid corrosive mineral acids in synthetic processes. This can easily be achieved by use of acidic solid supports coupled with microwave irradiation. This has been applied to the preparation of quinolines [53] (Scheme 8.35). This procedure is a safe, green alternative to the use of H2S04 at more than 150 °C. In the same way, quinoxaline-2,3-diones were prepared [54] by use of single-mode irradiation. Previous attempts in solution led to explosions, but the authors successfully used solvent-free conditions with acidic supports or catalysts (the best being p-toluenesulfonic acid) and irradiation times of 3 min (Scheme 8.36). 

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... 

Pyrazole derivatives are very reluctant to participate as dienes in Diels-Alder cycloadditions that involve the pyrazole ring, because of the loss of aromatic character during the process [79]. Microwave irradiation under solvent-free conditions, however, induces pyrazolyl 2-azadienes 96 to undergo Diels-Alder cycloadditions with ni-troalkenes 97 and 98 in 5-10 min to give good yields of pyrazolo-[3,4-b]-pyridines (Scheme 9.29) [80], Under the action of classical heating only traces of the corresponding cycloadducts were detected. 

Microwave irradiation of amidoximes in the presence of an aldehydes under solvent-free conditions has been reported to give fully conjugated 1,2,4-oxadiazoles directly, a process that is notable because the amidoximes can be prepared in the same reaction vessel from a nitrile and hydroxylamine (Scheme 33) <2006TL2965>. 

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