Synthesis without solvents

Polyimide Synthesis without Solvent via a Monomeric Salt... 

A. L. Le Coent, M. Tayacout-Fayolle, F. Couenne, S. Bnamjon, J. Lieto, J. Fitremann-Gagnaire, Y. Queneau, and A. Bouchu, Kinetic parameter estimation and modelling of sucrose esters synthesis without solvent, Chem. Eng. Sci., 58 (2003) 367-376. 

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,... 

Thiiranes and Thiirenes Monocyclic Table 38 Thiirane synthesis without solvent (see Equation (37)). 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

The Kolbe-Schmitt reaction is limited to phenol, substituted phenols and certain heteroaromatics. The classical procedure is carried out by application of high pressure using carbon dioxide without solvent yields are often only moderate. In contrast to the minor importance on laboratory scale, the large scale process for the synthesis of salicylic acid is of great importance in the pharmaceutical industry. 

The residue is triturated with methanol to afford a crystalline solid. This material contains no detectable amount of starting material by paperstrip chromatography but shows two UV absorbing spots near the solvent front (methanol-formamide 2 1 vs benzene-n-hexane 1 1). An aliquot is recrystallized three times from a mixture of benzene and n-hexane to give 17a,20,20,21-bis(methylenedioxy)-11(3-hydroxy-6,16a-dimethyl-4,6-pregnadiene-3-one which is used in the subsequent step of the synthesis without further purification. 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

This chapter will deal with applications of microwave irradiation in the synthesis of heterocycles by a variety of means, excluding cycloadditions, which will be described in the next chapter. We have chosen to report first reactions in solution in organic solvents, then heterogeneous reactions without solvent under a variety of conditions, and finally to deal with emerging techniques which employ ionic liquids. 

Silica gel or zeolite HY have also been used successfully for the synthesis of imidazoles, isoxazoles, and pyrazoles [59], under irradiation, without solvent (Scheme 8.39). 

In method A the reaction is performed under reflux in CH2CI2. Method B is without solvent under irradiation. It has been shown that yields are higher and reaction times much lower for method B. This methodology was applied to the synthesis of the precursor of leucettamine B (mediator of inflammation). 

Quite recently this reaction was revisited by Kappe [91] et al. who reinvestigated the Biginelli synthesis under the action of microwave irradiation under a variety of different conditions. At atmospheric pressure in ethanol solution there is no difference from conventional heating. Under pressure the yield is reduced and byproducts are formed. In an open system rate and yield enhancements are significant and this is rationalized by the rapid evaporation of the solvent which means that this is in fact a solvent-free reaction. This was confirmed by running the reaction without solvent under the action of microwaves and with thermal heating. (Scheme 8.65)... 

This was later extended to the synthesis of novel pyrimido-[l,3-a]-pyrimidines under solvent-free conditions ethyl-2-armno-4-aryl-l,4-dihydro-6-phenylpyrimidine-5-car-boxylates react regioselectively with 3-formyl chromone or diethyl (ethoxymethylene) malonate, without solvent, to afford pyrimido-[l,3-a]-pyrimidines [92] (Scheme 8.66). 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

Texier-Boullet, F. and Foucaud, A., A convenient synthesis of dialkyl 1-hy-droxyalkanephosphonates using potassium or cesium fluoride without solvent, Synthesis, 165, 1982. 

For the synthesis of u-aryl-ZV-methylnitrones a silica gel-NaOH catalytic system has been used. The reaction proceeds without solvents and in good yields, irrespective of the electron-donor or electron-acceptor nature of the substituents in benzaldehyde. Under similar reaction conditions ketones do not undergo the reaction therefore, it makes it possible to carry out selective syntheses in cases where the system contains both aldehyde and ketone groups (154). 

V-hydroxyglycine ethyl ester affords nitrones in good yields (187). Several a-aryl-iV-methylnitrones have been produced in yields of 80% to 100% without solvents, in the presence of 3A molecular sieves (188). Using 4A molecular sieves, it was possible to carry out the synthesis of novel glycolipidic nitrones — potential antioxidant dmgs for neurodegenerative disorders (Scheme 2.22) (189). 

Figure 1. A schematic representation of the synthesis of the electrochemical double layer in UHV a) adsorption of specifically adsorbed ions without solvent b) addition of hydration water c) completion of the inner layer d) addition of solvent multilayers, e) model for the double layer at an electrode surface in solution.

An important development of the synthesis described above is derived from the observations of Scott, O Donovan and Reilly [159], which were taken up by others [109]. l-Guanyl-3,5-dimethylpyrazole nitrate reacts with alkyl- and aryl-amines in hot water, ethanol, or without solvent to give good yields of guanidines. Use of this pyrazole nitrate or other salt for obtaining guanidines now competes with older methods if yield and ease of isolation of the product are the main considerations [95, 138, 140, 143, 160-164]. 

M]0 = 5 M. A concentration of 5 M is fairly typical of a step polymerization that is often carried out with only the reactant(s) present (without solvent). The lowering of [H20] to achieve a particular Xn is less the more favorable the equilibrium (that is, the larger the K value). Thus the synthesis of polyamides (with typical K values > 102) is clearly easier from the equilibrium viewpoint than polyester synthesis (K 0.1-1). Polyesterification requires a greater lowering of [H20] than does polyamidation. It should be understood that simply to lower [H20] as much as possible is not the desired approach. One needs to control the [H20] so as to obtain the desired degree of polymerization. 

Ecofriendly Fast Batch Synthesis of Dioxolanes, Dithiolanes, and Oxathio-lanes Without Solvent Under Microwave Irradiation (Perio et al., 1998)... 

Pozarentzi, M., Stephanidou-Stephanatou, J. and Tsoleridis, C.A., An efficient method for the synthesis of 1,5-benzodiazepine derivatives under microwave irradiation without solvent, Tetrahedron Lett., 2002, 43,... 

Reduction ofimines using formates Ammonium formates and formic acid have been employed as reducing agents in the synthesis of secondary amines from imines. By simple mixing of the reagents and microwave irradiation without solvent, the amines were produced in good yields within 2.5-10 min (Scheme 4.28)51. 

Perio, B., Dozias, M.-J. and Hamelin, J., Ecoffiendly fast batch synthesis of dioxolanes, dithiolanes, and oxathiolanes without solvent under microwave irradiation, Org. Process. Res. Dev., 1998,2, 428. 

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