Supported solvent-free methods

Two years later, the same research group published an alternative to the solvent-free method, since this method cannot be applied to the synthesis of insoluble thiophene oligomers such as sexithiophene [43]. Obviously, their insolubility prevents separation of the AI2O3 solid support. The effectiveness of PdCl2(dppf)/KF in solution phase was tested in the synthesis of soluble quinquethiophene from diiodoterthiophene and 2-thi-... 

Although beyond the scope of this book, a vast amount of work has been directed to supporting homogeneous catalysts on solid supports including silica, alumina and zeolites, and functionalized dendrimers and polymers [19]. These give rise to so-called solid-liquid biphasic catalysis and in cases where the substrate and product are both liquids or gases then co-solvents are not always required. In many ways solvent-free synthesis represents the ideal method but currently solvent-free methods can only be applied to a limited number of reactions [20],... 

The simplest solvent-free method involves irradiation of neat reactants in an open container. In the absence of reagents or supports, the scope for such processes appears to be limited to relatively straightforward condensations that can be conducted without added catalysts, or to intramolecular thermolytic processes such as rearrangement or elimination. 

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. 

If the copolymer is water soluble, the easiest method for generating polymersomes is direct dissolution of the dry polymer in aqueous media. However, this method cannot be used for insoluble water amphiphilic block-copolymers, for which a solvent-free or a solvent displacement method must be used. With the solvent-free method, a homogeneous amphiphilic polymer film is first deposited on a solid surface, and then subsequently hydrated in an aqueous buffer solution to form supramolecular assemblies upon desorption from the support. This is the method of choice when working under organic solvent-free conditions is mandatory, as for example for the combination with biomolecules. " When applying the solvent displacement method, the copolymer is first dissolved in an appropriate solvent, and then slowly mixed with water the reduced solubility of the copolymer drives the self-assembly process and formation of supramolecular assemblies, such as polymersomes. The organic solvent is eventually extracted, but complete removal of solvent traces is not possible and traces of organic solvents could affect sensitive biomolecules. 

The use of dry media (solvent-free) conditions, in which the reactants are absorbed on inert solid supports, in MW-heated reactions, has received a considerable amount of attention recently and has been used in the synthesis of a wide range of compounds [11-16]. These reactions generally occur rapidly and the method avoids hazards, such as explosions, associated with reactions in solvents in sealed vessels in which high pressures may be generated. Also the removal of... 

A facile method for the oxidation of alcohols to carbonyl compounds has been reported by Varma et al. using montmorillonite K 10 clay-supported iron(III) nitrate (clayfen) under solvent-free conditions [100], This MW-expedited reaction presumably proceeds via the intermediacy of nitrosonium ions. Interestingly, no carboxylic acids are formed in the oxidation of primary alcohols. The simple solvent-free experimental procedure involves mixing of neat substrates with clayfen and a brief exposure of the reaction mixture to irradiation in a MW oven for 15-60 s. This rapid, ma-nipulatively simple, inexpensive and selective procedure avoids the use of excess solvents and toxic oxidants (Scheme 6.30) [100]. Solid state use of clayfen has afforded higher yields and the amounts used are half of that used by Laszlo et al. [17,19]. 

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 facile one-pot synthesis of furopyrans takes place with aromatic aldehydes, cyclohexyl isocyanide, and 4-hydroxy-6-methyl-2-pyrone in the presence of a solid support such as Montmorillonite K-10 (Equation 62) <2005SC535>. The solvent-free reaction, which is enhanced by microwave irradiation, proceeds much more rapidly under these conditions than by conventional methods <2002TL2293>. The one-pot, three-component reaction is also reported to take place rapidly using water as solvent <2004M589>. 

In an effort to develop an economical, rapid and safe method devoid of solvent usage, Kidwai et al. investigated the dry media synthesis of antibacterial quinolines utilising alumina as the support (Scheme 3.31)51. The products were obtained in improved yield compared to that from the conventional heating method. Furthermore, the reaction times were reduced once again from hours to seconds. In a complementary solvent-free approach under microwave heating conditions, 4-alkylquinolines were successfully... 

Varma reported a facile and rapid method for the reduction of aldehydes and ketones to the respective alcohols, using alumina-supported sodium borohydride and microwave irradiation under solvent-free conditions. Aldehydes tend to react at room temperature, while for the reduction of ketones, short microwave irradiation of 30-180 s was applied to produce the corresponding alcohols in 62-92% yield. With unsaturated carbonyl compounds, reduction at the conjugated C=C bond might occur as a side reaction under these conditions (Scheme 4.9)26. 

In 2003, Balalaie and co-workers published a new paper in the area of imidazole synthesis39. In the above examples reported by Westman, ammonium acetate and primary amines act as the nitrogen source for the imidazole ring. In the Baladie novel one-pot three-component method, ammonium acetate was replaced by benzonitrile derivatives. Thus, benzil, primary amines and benzonitrile derivatives underwent a condensation reaction on acidic silica gel as the solid support, Scheme 5.23. The reaction mixtures were irradiated for 8 min in a domestic oven under solvent-free conditions to give the products in 58-92% yield. 

The development of solvent-free organic synthetic methods has thus become an important and popular research area. Reports on solvent-free reactions between solids, between gases and solids, between solids and liquid, between liquids, and on solid inorganic supports have become increasingly frequent in recent years. 

A method has been developed for obtaining the /V-alkylation of bicyclic (3-lactams (III, Fig. 20) using silica supported cesium carbonate under solvent free conditions [293]. 

Solvent-free conditions can be employed according to three main methods (a) using only neat reactants (b) reactants adsorbed onto solid supports or (c) reactants in the presence of phase transfer catalysts (in the case of anionic reactions). Besides the apparent potential benefits in solvent usage, reactions can be conducted conveniently and rapidly, often without temperature measurement in domestic microwave ovens. However, they now are often carried out under more precisely controlled conditions using monomode reactors initially introduced by the former French manufacturer Prolabo. Nowadays, several systems are available that provide facilities for the accurate measurement and monitoring of temperature throughout the reaction by modulation of emitted power with an infrared detector or an optical fibre. 

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