Synthesis Of Trifluoromethyl Substituted 3,4’-Pyrazolidinyl Spirooxindoles

Objective:Indole framework is a kind of special and important medicinal skeleton which present in a large number of natural products and bioactive relevant compounds.The pyrazolyl-containing compound is widely applied in the fields of medicine,pesticides,and biological agents because of various biological activities.Trifluoromethyl has strong electron-withdrawing ability,lipophilicity and metabolic stability and is often introduced into drug molecules to improve the affinity,liposolubility,metabolic stability and bioavailability in the field of medicinal chemistry.In view of the properties of the indole frameworks,pyrazolyl and trifluoromethyl,introduction of pyrazolyl and trifluoromethyl into indole framework may provide potentially important biological activities and available candidate compounds for the discovery of new drugs.Methods:（1）Isatin and ethoxycarbonyl methylenetriphenylphosphine as raw materials,we synthesized methylenindoxone compounds;（2）Benzoylhydrazide and trifluoroacetaldehyde methyl hemiacetal as raw materials,we synthesized trifluoromethyl hydrazone compounds;（3）The conditions of 1,3-dipolar cycloaddition of methylenindoxone and trifluoromethyl hydrazone were screened using chloroform as reaction solvent and 20 mol%base catalyst as initial conditions at 35℃.The types and dosage of base,solvent and other conditions were investigated in turn to observe the influence on yield,reactivity and dr.The optimal reaction conditions were obtained.（4）Under the optimum reaction conditions,the applications of substrates methylenindoxone and trifluoromethyl hydrazone were expanded,and a series of trifluoromethyl substituted 3,4’-pyrazolidinyl spirooxindoles were synthesized.Results:The optimum reaction conditions were as follows:t-Bu OK（20mol%）as base catalyst,reaction temperature at 35℃,chloroform（2.0 m L）as solvent,methylenindoxone 0.11 mmol,trifluoromethyl hydrazone 0.10 mmol.Under the optimum reaction conditions,20 trifluoromethyl substituted 3,4’-pyrazolidinyl spirooxindoles were synthesized.The yield was up to 95%and dr was up to>99:1.The structure of the product was characterized by ¹H NMR,¹³C NMR,IR and HRMS.The absolute configuration was determined by X-ray single crystal diffraction.Conclusion:Under the condition of t-Bu OK,20 highly functionalized trifluoromethyl substituted 3,4’-pyrazolidinyl spirooxindoles were synthesized by 1,3-dipolar cycloaddition.The reaction was mild,the yield and non-enantioselectivity were high.It not only provides support for the synthesis of these motifs with diverse structures,but also provides a preliminary experimental basis for the later activity testing of these compounds.