Study On Addition/Cyclization Reaction Of Arylidenemalonitriles And Fluoroalkylation Reagent

Malononitrile-containing compounds can be used as an important class of raw materials for the synthesis of pharmaceuticals and pesticides due to their bicyano structures that improve the physicochemical properties of the molecules and enhance their biological activity.The difluoromethylene structural unit is considered as an isopolar isomer of the carbonyl group,which can be used to enhance the stability of drugs against biodegradation and hydrolysis,and to improve the clinical efficacy of drugs by modifying their metabolism and lipophilicity.In recent years,selective introduction of difluoromethylene in organic synthesis for the development of fluorine-containing drugs as well as bioactive molecules is gradually gaining attention.In this dissertation,a series of difluoromethylene-containing cis-malonononitrile derivatives were constructed by investigating the addition/cyclization reactions of aromatic methylene-malononitrile and fluoroalkylation reagents as follows:1.Study of difluoroalkylation reactions of aromatic methylene-malononitrile and difluoroalkyl ketone de trifluoroacetic acidThe difluoroalkylation of difluoromethylene-substituted malononitrile derivatives was developed by removing trifluoroacetic acid from difluoroalkyl ketone in the presence of lithium salt and alkali to produce stableα,α-difluoro ketone anion,followed by the macker addition reaction with aromatic methylene-malononitrile.The reaction catalyst,reaction temperature,and solvent were systematically investigated,and it was found that the reaction was carried out at 6 equivalentsalents of Li Br,triethylamine as the base,and tetrahydrofuran as the solvent for 4 h at room temperature.The aromatic methylene malononitrile and trifluoromethylalkanediol ketone could undergo the addition reaction smoothly to obtain the difluoromethylene-substituted malononitrile derivatives.The reaction has a high yield,a wide range of substrates,and the product can be further derivatized.2.Study on the debromodifluoroalkylation of aromatic methylene malononitrile and2-(bromodifluoromethyl)benzothiazoleA copper-catalyzed single-electron transfer of 2-(bromodifluoromethyl)benzothiazole to produce difluoromethylbenzothiazole radicals and a radical addition reaction with aromatic methylene malononitrile was developed to give relatively stable products containing benzothiazole difluoroalkyl-substituted malononitriles.The reaction was carried out at 80 ~oC for 21 h using 40 mol%Cu and Cu I as catalysts,40 mol%1,10-phenanthroline as ligand and N-methylpyrrolidone as solvent.Aromatic methylene malononitrile and2-(bromodifluoromethyl)benzothiazole gave smoothly malononitrile analogues containing benzothiazole difluoroalkyl substituents.The reaction was performed using inexpensive copper salts as catalysts and without the addition of alkali,which is in line with the development of green chemistry.3.Study on the defluorinated cyclopropanation reaction of aromatic methylene malononitrile andα-fluorosubstituted ketonesThe reaction of C-F bond breaking of aromatic methylene malononitrile andα-fluorosubstituted ketone promoted by the non-nitrogenous base sodium carbonate was developed to obtain cyclopropane compounds containing malononitrile substitution.The reaction was carried out for 27 h at 80 ~oC using 3 equivalentsalents of sodium carbonate as the base and 1,4-dioxane as the solvent.The cyclopropanation reaction of aromatic methylene-malononitrile withα-fluorosubstituted ketones could occur smoothly to obtain cyclopropane compounds containing malononitrile substitution.