Microwave irradiation solvent-free processes

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... 

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... 

A new series of some spiro-1,4-dihydropyridines 2 has been synthesized by Hatamjafari [42] in good yields using a four-component, solvent-free process by the condensation of isatin, a primary amine, ethyl cyanoacetate and cyclohexanone absorbed on different solid supports under microwave irradiation applying a domestic oven. The report reveals that the application of montmorillonite KIO led to higher yields as compared to other solid supports (Scheme 2). 

The last, but not least, benefit is the possibility of using solvent-free techniques coupled with microwave irradiation. This new type of activation is now more frequently employed but often the presence of solvents prevents its use for safety reasons. This difficulty can be overcame by solvent-free processes. 

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]. 

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. 

Pyrimido(4, 5-d)pyrimidine derivatives were synthesized by an efficient, facile and solvent-free procedure. These are synthesized by the reaction between aromatic aldehydes, barbituric acid and urea/ thiourea under microwave irradiation. In this process, solid alumina was used as an energy transfer medium (Kategaonkar et al., 2009). 

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 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. 

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). 

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>. 

In microwave-assisted synthesis, a homogeneous mixture is preferred to obtain a uniform heating pattern. For this reason, silica gel is used for solvent-free (open-vessel) reactions or, in sealed containers, dipolar solvents of the DMSO type. Welton (1999), in a review, recommends ionic liquids as novel alternatives to the dipolar solvents. Ionic liquids are environmentally friendly and recyclable. They have excellent dielectric properties and absorb microwave irradiation in a very effective manner. They exhibit a very low vapor pressure that is not seriously enhanced during microwave heating. This makes the process not so dangerous as compared to conventional dipolar solvents. The polar participants of organic ion-radical reactions are perfectly soluble in polar ionic liquids. 

The Lewis acid-catalyzed condensation of a,/3-unsaturated ketones 277 with amides 278 furnished 2,4,6-trisubsti-tuted-6//-l,3-oxazines 279. An environmentally benign solvent-free version of this process, based on the application of montmorillonite K-10 clay and a brief microwave irradiation, provided oxazines 278 in higher yields than in the conventional solution-phase method (Equation 26) <2004BCJ2265>. 

The hetero-Diels-Alder reaction is amongst the most efficient processes for the synthesis of six-membered heterocyclic ring systems. Solvent-free conditions have been used to improve reactions of heterodienophiles and heterodynes with low reactivities. Cado et al. (1997) have described the hetero-Diels-Alder reaction of ethyl lH-perimidine-2-acetate as heterocyclic ketene aminal with ethyl propiolate nnder solvent-free conditions with focused microwave irradiation. The new fused perimi-dines (23) were obtained in good yields (67-98%). 

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