A simplified green chemistry approach to the Biginelli reaction using !Grindstone Chemistry"

Grindstone Chemistry––a greatly evolved version of Toda"s method of grinding solids together for solvent-free chemical reactions––has been described and its usefulness illustrated by the successful application of this technique to a simplified process for conducting the multi-component Biginelli reaction for the synthesis of physiologically active tetrahydropyrimidinones. ! 2004 Published by Elsevier Ltd. Green chemistry is destined to be a national goal in the near future. In this context, a convenient and rapid synthetic procedure that is energy efficient is highly desirable. To be of practical value, such a procedure should be suitable for large-scale operation also. We wish to describe here a technique with the descriptive title of Grindstone Chemistry that is useful for desktop synthesis as well as kilogram scale operation. The groundbreaking work of Toda et al. has shown that many reactions (but not all) can be conducted in high yield by just grinding solids together. Usually these reactions were carried out on a very small scale in an agate mortar and pestle. It has been of interest to us to extend this approach to chemical reactions on a large scale without being restricted to interactions between solids only. This modified approach has been given the name of !Grindstone Chemistry" in our laboratory. We wish to describe here some significant aspects of this type of synthesis that is also suitable for the large-scale preparation of pharmaceuticals and their intermediates. We have devised techniques for using reagent pairs that may be solid/solid, solid/liquid, or even liquid/liquid. To make the grinding process more efficient it is convenient to add to the reaction mixture some amount of crystalline MgSO4Æ7H2O, a very common, inexpensive, and water soluble chemical (available even in drug stores). The addition of this friction-enhancing solid has given very satisfactory result in promoting the reaction between liquid reagents by the grinding method. If the reaction products are water soluble, the work-up of the reaction mixture with magnesium sulfate added may be inconvenient. In such a case, sand may be used in place of magnesium sulfate; during work up the sand can be easily removed by filtration. To conduct Grindstone Chemistry on a large scale a simple and inexpensive expedient is to use a hand held electric food mixer with stainless steel rotors for grinding together the reagents in a large glass or porcelain bowl. For obtaining a better understanding of the energetics of reactions, a thermocouple connected to a computer was used for recording the !Reaction Temperature Profile" (change in the reaction temperature with the progression of time) during and after the grinding. Data from several of the successful reactions by grinding described by Tanaka led us to generalize that these reactions are all exothermic. We have concluded that after the reaction is initiated by grinding with the transfer of very small amounts of energy through friction, the reaction proceeds by itself if it is exothermic in nature; 0040-4039/$ see front matter ! 2004 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2004.09.064