Development of new methods for the synthesis of pyrazoles, 4-iodopyrazoles, isoxazoles and 1,2,4-oxadiazoles

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2011
Kıvrak, Arif
Synthesis of five-membered heteroaromatic compounds such as pyrazoles, isoxazoles and 1,2,4-oxadiazoles are important for pharmaceutical industry and material science due to their applications. Although there are many methods to prepare such compounds, new variants continue to appear since they exhibit a wide range of biological and medicinal activities. In this thesis, new methods were developed for the synthesis of 4-iodopyrazoles, pyrazoles, isoxazoles, 1,2,4-oxadiazoles and/or 1,2,4-oxadiazepines. In the first part of the study, electrophilic cyclization of α,β-alkynic hydrazones by molecular iodine and copper iodide were investigated as new ways for the synthesis of 4-iodopyrazoles and pyrazoles, respectively. Initially, α,β-alkynic hydrazones were prepared by the reactions of propargyl aldehydes and ketones with hydrazines. Then α,β-alkynic hydrazones were treated with molecular iodine in the presence of NaHCO3, which afforded 4-iodopyrazoles in good to excellent yields. Subsequently, the same reactions were carried out with CuI in the presence of NEt3, which furnished corresponding pyrazoles in good yields. Moreover, ferrocenyl-substituted 4-iodopyrazoles and pyrazole derivatives were synthesized from corresponding ,-alkynic hydrazones by using such electrophilic cyclizations. In the second part of the study, the reactions between propargyl aldehydes and amidoximes were investigated. These reactions produced exclusively conjugate addition products. In one reaction, a new product was isolated in low yield and tentatively characterized as 7-pentyl-3-phenyl-1,2,4-oxadiazepine. Interestingly, under acidic and basic conditions, conjugate addition products afforded isoxazoles and 1,2,4-oxadiazoles, respectively. When conjugate addition products were treated with HCl, they afforded isoxazoles in good yields. On the other hand, when treated with bases such as KOH and NaH, conjugate addition products furnished 1,2,4-oxadiazoles in good to excellent yields. Reaction mechanism for the formation of isoxazoles and 1,2,4-oxadiazoles from conjugate addition products was also proposed. In the last part of the study, one-pot reactions between propargyl aldehydes and amidoximes in the presence of KOH were investigated for the synthesis of 1,2,4-oxadiazoles. As anticipated, these one-pot reactions provided corresponding 1,2,4-oxadiazoles. One-pot reactions afforded oxadiazoles in slightly lower yields as compared to their two-step syntheses but they saved time and chemicals due to easy purification. More importantly, the synthesis of 5-ferrocenyl-1,2,4-oxadiazoles was achieved by one-pot procedure since the reaction of 3-ferrocenylpropanal with amidoximes did not yield corresponding conjugate addition products. In summary, a variety of pyrazoles, 4-iodopyrazoles, isoxazoles, 1,2,4-oxadiazoles and/or 1,2,4-oxadiazepines were synthesized by new methods, which may have useful biological and medicinal activities.
Citation Formats
A. Kıvrak, “Development of new methods for the synthesis of pyrazoles, 4-iodopyrazoles, isoxazoles and 1,2,4-oxadiazoles,” Ph.D. - Doctoral Program, Middle East Technical University, 2011.