Green chem.: no solvent, no catalyst, grinded Biginelli reaction

Mechanochemistry refers to the process of chemical transformation through mechanical means such as compression and friction International Union of pure and Applied Chemistry (IUPAC) defines mechanochemical reaction as the reaction promoted by direct absorption of mechanical energy After nearly a century of development, mechanochemistry has been applied in many chemical fields In the field of organic synthesis, ball mill grinding has been used for the formation of C-C, C-N, C-O and C-X bonds, heterocyclic synthesis and peptide synthesis In the field of medicine, mechanochemical methods are also used to develop eutectic and solid dispersion for enhancing solubility, melting granulation and even for the synthesis of active pharmaceutical ingredients The reaction in the ball mill has the disadvantages of lack of temperature control and scalability However, this can be overcome by using a twin-screw extruder At present, screw extruders have been used in aldol condensation, Michael reaction, imine formation reaction, Knoevenagel condensation and multi-component and multi-step reactions Recently, shreerang v Joshi, Institute of chemical technology, Mumbai, India, reported the technology of Biginelli reaction by twin-screw extruder The reaction does not need to use solvent, and has better yield and shorter reaction time than conventional method This advantage is due to the good mixing efficiency during grinding and the evaporation drive of by-product (water) Relevant research results were published in green chem (DOI: 10.1039/c9gc00036d) First of all, the author synthesized 3,4-dihydropyrimidine-2 - (1H) - one / thioone by conventional method (Table 1) The mixture of aromatic aldehyde (2 mmol), ethyl acetoacetate (2 mmol) and urea or thiourea (2 mmol) was placed in a round bottom flask and heated in an oil bath at 105-120 ℃ By optimizing the solvent and temperature, the product was obtained in 76% yield (source: Green chem.), the author synthesized 3,4-dihydropyrimidine-2 (1H) - one / thioone in a twin-screw extruder without solvent (Table 2) The operation steps are as follows: the author put the mixture of aldehyde (0.3 mol), ethyl acetoacetate (0.3 mol) and urea or thiourea (1.2 mol) into a glass mortar and gently mix them to make the liquid reagent adsorb on the solid urea or thiourea Then, the mixture is manually added into the hopper of the extruder In order to optimize the reaction, extrusion was carried out at different screw speeds in co rotating mode and at different temperatures Then, under the agitation, the extrudate was added into the cold water to form a precipitate, and then filtered by a vacuum pump The precipitate was washed with cold water, dried in vacuum and recrystallized with ethanol to obtain the pure product (source: Green chem.) through optimization, the author set the optimal parameters as: 120 ℃, screw speed 50 rpm, and the reaction yield can reach 91% According to the two processes, the new process without solvent has better yield It is also observed that the melting point of the product is higher than the reaction temperature when reacting in a flask, which will reduce the stirring efficiency According to Lechatelier's equilibrium principle, during the reaction, the by-product water will evaporate in the extrusion process and push the reaction forward (source: Green chem.) next, the author evaluated the substrate range with different aromatic aldehydes (Table 3) When the twin-screw extruder is used, the properties of substituents have no significant effect on the reaction yield The yield obtained by extrusion is also significantly higher than that obtained by the corresponding solvent-free batch reaction (source: Green chem.) conclusion: the researchers of the Institute of chemical technology of Mumbai, India, have successfully synthesized 3,4-dihydropyrimidine-2 - (1H) - one / thioketone in solvent-free condition using twin-screw extruder The Biginelli reaction by grinding has better yield and shorter reaction time.