Study On Conjugate Hydrocyanation Of α, β-unsaturated Carbonyl Compounds And Aza-michael Reactions With Aromatic N-heterocycles

Michael reaction is a very important organic reaction, which is one of efficientmethod to structure C-C and C-N bonds. In this context, organic cyanating reactionand aza-Michael reaction became one of hotspot for organic synthesis in recentlyyears.The organic cyanating reaction is an important method to form C-C bond and animportant protocol for synthesis of many intermediates such as nitriles, cyanohydrins,α-aminonitriles, β-cyanoketones and so on. It is also a powerful way to synthesizesome medicine and to construct core skeleton of complex natural products. However,the traditional cyanating reactions usually use toxic inorganic or organic cyanides ascyanating regents, which can not meet the needs of "green chemistry" and sustainabledevelopment. Thus, achievement of the organic cyanating reaction using inexpensive,non-toxic “green cyanide source” instead of the traditional highly toxic cyanide is ofgreat importance.Aza-Michael reaction is an atom economy reaction and efficient way to formnew C-N bond and to synthesize β-amino carbonyl compounds. The products,β-amino carbonyl compounds, are very important organic intermediates, which can beconverted to bioactive molecules such as β-amino acids, β-lactams, nature productsand medicines. Compared to the comprehensively studied N-nucleophile, amine andhydroxylamine, weak-nucleophilic aromatic nitrogen heterocycles involvedaza-Michael reactions are rarely reported. Therefore, to explore a convenient andefficient new method for aza-Michael addition of aromatic N-heterocycles toα,β-unsaturated carbonyl compounds with broad scope of substrate represents anextremely attractive yet challenging goal.In the light of the problem occurred in the conjugate hydrocyanation ofα,β-unsaturated carbonyl compounds and their aza-Michael reaction with aromaticN-heterocycles, the conjugate hydrocyanationn of α,β-unsaturated ketones and imidesand their aza-Michael reactions with1,2,4-triazole and pyrazole were studiedsystematically in this thesis.This thesis is divided into two parts with six chapters: Part1: Conjugate Hydrocyanation of α,β-Unsaturated Carbonyl Compounds(The first three chapters)Chapter1Progress of Organic Cyanating ReactionThis chapter reviewed the application of various cyanides in organic cyanatingreaction and progress of conjugate hydrocyanation of α,β-unsaturated carbonylcompounds. The present situation of cheap, non-toxic PotassiumHexacyanoferrate(II), K4[Fe(CN)6], involved cyanating reaction and progress ofconjugate hydrocyanation of α,β-unsaturated ketones and imides were especiallyemphasized.Chapter2Conjugate Hydrocyanation of Enones Using PotassiumHexacyanoferrate(II) as an Eco-Friendly Cyanide SourceIn light of the problem of using highly toxic cyanide reagent in traditionalconjugate hydrocyanation of enones, this chapter put forward to use eco-friendlycyanide reagent to achieve the reaction. After systematic study, we explored a newmethod for conjugate hydrocyanation of enones using cheap, non-toxic K4[Fe(CN)6]as an eco-friendly cyanide source. With1mol%Cs2CO3as catalyst, a series ofβ-cyano ketones were exclusively obtained in85-93%yields via an “one-pottwo-step” procedure. The relatively mild reaction conditions, simple operation, andexpanded scope of substrate make this protocol more practical.Chapter3Cs2CO3-catalyzed Conjugate Hydrocyanation of α,β-UnsaturatedImidesAn efficient Cs2CO3-catalyzed conjugate hydrocyanation of α,β-unsaturatedimides was developed in this chapter. The reaction has features of cheap and easyavailable catalyst, low catalyst loading, short reaction time, and easy to handle. Bothof aromatic and aliphatic enones are suitable substrates. The1,4-selective adducts,β-cyano imides, were exclusively obtained in75-95%yields.Part2: Aza-Michael Reactions of α,β-Unsaturated Carbonyl Compounds withAromatic N-Heterocycles (After three chapters)Chapter4Progress of Aza-Michael Reactions of N-heterocycles This chapter reviewed the application of aromatic N-heterocycles and progress ofaza-Michael reaction of α,β-unsaturated compounds. The present situation ofaza-Michael reactions of α,β-unsaturated carbonyl compounds with aromaticN-heterocycles was especially emphasized.Chapter5Cs2CO3-Catalyzed Aza-Michael Addition of Pyrazole to EnonesIn light of the lack of aza-Michael reaction of pyrazole with enones, this chapterput forward to explore a convenient and efficient method for the reaction withexpanded scope of enones. After systematic study, a Cs2CO3-catalyzed aza-Michaeladdition of pyrazole to enones was developed. With5mol%Cs2CO3as catalyst, bothof aromatic and aliphatic enones were smoothly transformed into correspondingβ-(N1-pyrazole) ketone in86-95%yields. The protocol is also suitable to methylacrylate and nitroalkene. The adducts can be transform into γ-amino alcoholsconveniently.Chapter6Alkali Salt Catalyzed Aza-Michael Addition of1,2,4-Triazole toα,β-Unsaturated Ketones and ImidesIn this chapter, we developed a LiCl-catalyzed aza-Michael addition of1,2,4-triazole to enones and Cs2CO3-catalyzed aza-Michael addition of1,2,4-triazoleto α,β-unsaturated imides respectively. Twenty-six target products were obtained in79–95%yields. The simple reaction conditions and expanded scope of substrate makethis protocol more practical. The products can be easily transformed to correspondingβ-amino acids and γ-amino alcohols.