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Green approach to the design of functionalized medicinally privileged 4-aryl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile scaffold !
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1  N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia

Abstract: The main objective of the project was to find conditions of the synthesis of pyrano[2,3-c]pyrazoles in accordance with the principles of "green" chemistry. Pyrano[2,3-c]pyrazoles possess a broad spectrum of biological activity. For example, they can be used as anticancer agents and enzyme inhibitors. Known methods for the synthesis of such compounds involve using large volumes of toxic solvents and are complicated in usage. In the course of the our work the reactions between malononitrile, 3-methyl-2-pyrazoline-5-one and benzaldehyde under solvent-free conditions and in small quantity of water in the presence of various amounts of non-toxic bases (potassium fluoride, sodium acetate, and sodium hydroxide) were studied. As a result, optimal conditions for the synthesis of 6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (one of the simplest pyrano[2,3-c]pyrazoles) have been found. These conditions were tested on synthesis of difficult functionally substituted pyrano[2,3-c]pyrazoles. Thus, it was found that in optimal conditions the reaction between malononitrile, 3-methyl-2-pyrazoline-5-one and aromatic aldehydes in small quantity of water and in the presence of 5 mol.% of sodium hydroxide leads to pyrano[2,3-c]pyrazoles selectively in high yield (more than 93%). Carrying out the reaction in water and using sodium hydroxide as the base allows to reduce the cost of the process and significantly improve its environmental friendliness. Using small amounts of water allows to use the working capacity of a chemical reactor more efficiently and to avoid significant losses at the isolation stage. Thus, the proposed process is more efficient and environmentally friendly compared to those known today.
Keywords: malononitrile, aldehydes, 3-methyl-2-pyrazoline-5-one, pyrano[2,3-c]pyrazoles, green chemistry