Conjugate Hydrocyanation Of 1,4-Enedione And Aza-Michael Addition Of β,γ-Unsaturated-α-keto Ester

Conjugate hydrocyanation is an important method for the construction of C-C bond and synthesis of nitriles in organic synthesis. It is also a powerful way to synthesize some medicine and to construct core skeleton of complex natural products. So, it has received extensive attention in organic synthesis. 1,4-Enedione has attracted noteworthy attention in recent years since it constitutes a key component of many bioactive compounds including steroids, antitumor agents, and marine natural products. The conjugate hydrocyanation of 1,4-enedione is the most direct and effective way to synthesize α-cyan-1,4-dione which is an important intermediate in organic synthesis. However, it is still not reported in detail.Since the importance in organic synthesis, especially for the construction of C-N bond and the synthesis of β–amino carbonyl compounds, the aza-Michael reaction has received much attention in recent years. However, compared to the extensively studied N-nucleophiles, amine and hydroxylamine, aromatic N-heterocycles with weak nucleophilicity to participate in the aza Michael addition reaction are less reported. Furthermore, the aza-Michael addition of benzotriazole to β,γ-unsaturated-α-keto ester has not been reported.Therefore, to explore conjugate hydrocyanation reaction of 1,4-enedione with mild reaction conditions, cheap catalyst, and simple operation as well as an efficient and suitable new method for aza-Michael addition of benzotriazole to β,γ-unsaturated-α-keto ester has certain positive significance and challenge, which can provide a new way to direct, convenient, and efficient entrance for the synthesis of α-cyan-1,4-dione and heterocyclic derivatives.In view of the shortages of research on conjugate hydrocyanation of 1,4-enedione and aza-Michael addition of aromatic N-heterocycles, we have systematically studied the conjugate hydrocyanation of 1,4-enedione and the aza-Michael addition of benzotriazole to β,γ-unsaturated-α-keto ester. Finally, the desireable results were obtained and a series of target adducts were prepared in good to excellent yields.This thesis is divided into two parts with four chapters:Part 1: Conjugate hydrocyanation of 1,4-enediones Chapter 1 Advance and application of conjugate hydrocyanation of 1,4-enediones This chapter reviewed the application and development of organic cyanation reaction with emphasis on the conjugate hydrocyanation of α,β-unsaturated ketones and application of α-cyan-1,4-dione.Chapter 2 Conjugate hydrocyanation of 1,4-enediones A Cs2CO3-catalyzed conjugate addition of TMSCN to 1,4-enedione has been developed. With 10 mol% Cs2CO3 as catalyst, a series of α-cyan-1,4-dione were achieved in 85%~98% yields after 10 min in refluxing dioxane. This protocol has the features of short reaction time, high yield, and simple work-up procedure.Part 2: Aza-Michael addition of benzotriazole to β,γ-unsaturated-α-keto estersChapter 3 Progress of aza-Michael reaction of N-heterocycles This chapter mainly summarized the application and importance of aromatic N-heterocycles and their progress in aza-Michael reaction. The present situation of aza-Michael reaction of α,β-unsaturated carbonyl compounds and other activated olefins with aromatic N-heterocycles was especially emphasized.Chapter 4 Aza-Michael addition of benzotriazole to β,γ-unsaturated-α-keto esters In this chapter, we developed a Na2CO3-catalyzed aza-Michael addition of benzotriazole to β,γ-unsaturated-α-keto ester. The reactions proceeded smoothly to give the adducts in high yields(75%~97%) both ethyl and methyl as well as isopropyl and benzyl esters. The reaction has features of cheap and easy available catalyst, high yield. The simple reaction conditions and expanded scope of substrates make this protocol more practical.