Heterocyclization of 2-imino-2H-chromeno-3-carbonitriles with some N,N-binucleophiles

Chromene derivatives have a wide range of biological activities: antimicrobial, antibacterial, antitumor. In this work, three-component and stepwise reactions of malononitrile and salicylic aldehydes with N,N-nucleophiles such as hydrazine hydrate, nitrobenzhydrazides and o-phenylenediamine under various conditions were investigated. New potentially biologically active chromeno[4,3-c]pyrazoles and chromeno[4,3-e][1,4]diazepines were isolated. The three-component reactions of equimolar amounts of unsubstituted hydrazine hydrate, malononitrile and salicylic aldehydes with stirring at room temperature in ethanol in the presence of triethylamine led to the formation of new dihydrochromeno[4,3-c]pyrazole-3,4-diamines 1-2. The same result was obtained by carrying out the stepwise reaction through the intermediate 2-imino-2H-chromeno-3-carbonitrile A, and its subsequent reaction with hydrazine hydrate. The reaction of malononitrile and salicylic aldehyde with less active binucleophilic reagents such as 2- and 3-nitrobenzhydrazides and isoniazid when boiled in ethanol, isopropyl alcohol or dioxane led to the formation of Schiff bases B. The reaction of malononitrile, salicylic aldehyde and 3-nitrobenzhydrazide using THF as a solvent with slight heating led to the formation of the target new (tetrahydrochromeno[4,3-c]pyrazolyl)(3-nitrophenyl)methanone 3. O-phenylenediamine, as another type of N,N-binucleophile reacts with salicylic aldehyde and malononitrile in ethanol to form the new dihydrobenzo[b]chromeno[4,3-e][1,4]diazepine 4. The corresponding stepwise reaction with 2-imino-2H-chromeno-3-carbonitrile A similarly gave the target product. This study demonstrates the applicability of a three-component reaction approach and an affordable, efficient, and ecologically friendly «green chemistry» strategy for the synthesis of chromene derivatives. The structure of the products has been confirmed by IR and NMR spectroscopy.