Solvent free approach

Following the same solvent-free approach, the synthesis of 2-aminothia-zoles was described by short irradiation (2-3 min, approximate temperature 100-115 °C) of a mixture of thiourea and substituted a-bromoacetophenones, deposited over K2CO3 [9] (Scheme 8). 

Quiroga and co-authors [101] also reported eco-friendly solvent-free approach to the synthesis of fused benzo[fjpyrazolo[3,4-b]quinolines 72 by three-component reaction of 5-aminopyrazoles, aldehydes, and p-tetralone accomplished by fusion procedure (Scheme 32). However, this method was found inapplicable for the similar reaction of a-tetralone - multicomponent procedure allowed obtaining only bispyrazolopyridines 74 instead of benzo[h]pyrazolo[3,4-b]quinolines 73. According to these experimental results, the latter were generated via preliminary synthesis of arylidentetralones 75. 

New developments in microwave-accelerated solventless organic syntheses are appearing in the literature. This expeditious and solvent-free approach involves the exposure of neat reactants to microwave irradiation in conjunction with the use of supported reagents or catalysts which are primarily of mineral origin (Varma, 1999). 

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... 

In a simple microwave-assisted and solvent-free approach, substituted isatoic anhydrides were reacted with 4-substituted prolines to afford fused 1,4-benzodiazepine derivatives67. The reactions proceeded in less than 3 min and the fused 1,4-benzo-diazepine products were obtained in very good yields (Scheme 3.42). This condensation reaction represents a practical alternative approach to the typical traditional methods. 

Similar to the solvent-free approaches discussed in Section 3.2, a combinatorial approach also has been employed to scale-up the synthesis of desired compounds100. The microwave-assisted reactions are performed on solvent-swollen polymeric beads and are classified herein as being carried out in the presence of a solvent. Examination of these supports after 20 min of microwave irradiation (700 W) revealed that neither the appearance nor swelling behaviour of the beads had altered65. 

Most of the recent literature in this field is concerned with synthetic organic reactions, supramolecular chemistry and crystal engineering. However, solvent free approaches can also be used in the extraction of natural products, although less information is available in the mainstream literature. Juice extractors can be used to afford aqueous solutions of biologically active compounds from undried plant material. An extract of Capsicum annum L. was recently prepared in this way, and then used in the green synthesis of silver nanoparticles. The actual synthesis of the nanoparticles was conducted in the aqueous phase and therefore this work will not be discussed further here. However, this solvent free approach to extraction is probably worthy of greater representation in the green chemistry literature. 

Calix[4]resorcinarenes, which can be used as supramolecular building blocks, have been prepared in high yields and purity using a solvent free approach. Equimolar quantities of the benzaldehyde and resorcinol, in the presence of /7-toluenesulfonic acid, were ground together using a mortar and pestle... 

Supramolecular self-assembly has been found to be dramatically accelerated in some cases, and this is perhaps the reason why solventless reactions have been rapidly adopted by coordination chemists. For example, the formation of a platinum-containing square is dramatically accelerated compared with the same reaction in water (Figure 2.3). In water, the reaction needed to be heated at 100 °C for 4 weeks. In a solvent free approach, approximately the same yield was achieved in 10 min at room temperature. Water and ethanol were the only solvents used in the work up of the reaction. This approach was then extended to bowl-shaped and helical supramolecular structures. 

A reversible solid-state HCl elimination reaction from a Cu(ii) pyridinium coordination complex has been reported. The reaction proceeds with a colour change from yellow (pyridinium complex) to blue (pyridine complex). This reaction suggests that other protic ligands may successfully be coordinated to metals using a solvent free approach in the future. 

Another atom-efficient process that has been studied solvent free is the Baylis-Hillman reaction.This reaction affords useful multifunctional products from an addition reaction between an electrophile (often an aldehyde) and an electron-deficient olefin. Unfortunately, under most conditions it has the significant drawback of a slow rate of reaction. However, this has been overcome through a solvent free approach that uses a high-speed ball mill (HSBM) (Figure 2.9). Previous solvent free studies of this reaction took 3-4 days to achieve completion. In contrast, using an HSBM, the reaction is complete in 30 min. Unfortunately, a chlorinated solvent was chosen for reaction work up clearly, it would be desirable to use a less hazardous VOC here. 

Organic synthesis without solvents is already a mature field despite this, many chemists still assume that solvents are a necessity for most chemical processes. Therefore, the mindset of chemists needs to change and they must be willing to take up the opportunity that a solvent free method presents. Already, many multi-tonne industrial reactions are performed solvent free, particularly gas phase reactions such as ethylene polymerization. Although solid-solid reactions are yet to be performed on such a large scale, they have been performed on the kilogram scale. Also, solvent free approaches have recently been introduced into the multi-step synthesis of a potential antituberculosis drug,... 

A Grignard type of addition of alkynes to in situ generated imines from aldehyde and amines, catalyzed by CuBr, provides an efficient solvent-free approach for the synthesis of substituted N-heterocycles such as propargyla-mines in excellent yields (Scheme 8.17). ... 

Petrukhina, M. A., Designed solvent-free approach toward organometallic networks built on directional metal-Jt-arene interactions , Coord. Chem. Rev. 2007, 251, 1690-1698. 

Significantly, advocates of solvent-free approaches promoted as major advantages that unmodified domestic microwave ovens could be used and that sample mixing and temperature measurement were unnecessary during reactions. Our group, however, began with two main alternative suppositions ... 

Scheme 8.38. Solid-supported solvent-free approach for preparation of 1,6-anhydro-jS-D-hexopyranoses.

Collman and Decreau have developed a modified solvent-free approach for preparation of new free base tris-aryl and tris-pyrimidyl corroles using MW irradiation [186]. Compared with conventional heating, the MW technique afforded higher yields and led to noticeably cleaner reaction products (Scheme 8.74). 

An efficient and rapid method for synthesis of jS-lactams under solvent-free conditions in the presence of a phase-transfer agent (18-crown-6) in a closed Teflon vessel has also been developed by Hamelin et al. [46a]. The same solvent-free approach has also been successfully used by Kidwai et al. for synthesis of N-(4-hydroxycyclohexyl)-3-mercapto-3-cyano-4-arylazetidine-2-ones [40]. The adducts... 

In the early days of MAOS, solvent-free techniques were very popular. In these procedures, the reactants are either mixed directly without use of a solvent or the reactants are preabsorbed on to a solid support before irradiation with MW. The solvent free approach enabled safe use of domestic household microwave ovens and standard open-vessel technology (Refs [16, 19, 23] and Chapters 4 and 8 in this book). 

A solvent-free approach has been used to scale up a Heck reaction to the 1 mol level. Again, this study was preceded by optimization and investigation of substituent effects. However, on 0.5-1.0 molar scale under solvent-free conditions, the reaction was markedly exothermic, self-heating to 150 °C from the 100 °C set point. It is important to stress the importance of taking every precaution when performing reaction under solvent-free conditions on larger scales. In this case, the reaction mixture was heated slowly, and an over-sized flask was used. 

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