NiCl₂·6H₂O Catalyzed One-pot, Multi-component Synthesis Of Highly-substituted Piperidines

The functionalized piperidines has attracted much attention in synthetic organic and medicinal chemists. Because they are the most common building blocks in nature products. More interesting, many natural products containing piperidine ring were found to show interesting biological activities. Considering this significant applications, the development of efficient methods for the synthesis of functionalized piperidine is a subject of considerable importance.Modern organic synthesis not only pursuit of the high chemical yield, but also focus on economic value and ecological value. In the past years, chemical selectivity and atom economy are to determine the efficiency of chemical synthesis of the main criteria, and now, simple reaction steps and the post-processing of reaction have become equally important.In the field of green chemistry, the ideal synthesis should be using environmentally friendly reagents, and the yield of th products will get to 100% using a few steps. The traditional ideal of organic synthesis reaction is a reaction of raw materials react with other raw materials to form products, while in multi-component reactions, three or more reactants are mixed in a single reaction flask to generate products incorporating most of the atoms contained in the starting material (not including the generation of inorganic and organic small molecules), each intermediate product is the raw materials of next step reaction, and the the final product's structure contain all the pieces of the synthesis of the starting material. The synthesis of complex organic compounds, if use the method of traditional synthesis, to multi reaction step and the complex treatment of sludge. In MCR, several chemical bonds can be formed in one step without the need of isolating the intermediates, which reduce the separation operation, improving the efficiency of the reaction, and having clear advantages compared to the traditional methods .In this paper, we reported a multi-component one-pot synthesis of highly-substituted piperidines catalyzed by inexpensive NiCl₂·6H₂O, and the process showed considerable synthetic advantages in terms of high atom economy, low environmental impact, wide substrate scope, mild reaction condition and good yields.This thesis includes three chapters:Chapter One: Review of the piperidines Piperidine is an important heterocyclic organic intermediates. In this chapter the biological activity of piperidine compounds and synthetic applications of piperidines are reviewed, especially review the formation of piperidine ring and the multi-component reaction.Chapter Two: Study on the multi-component one-pot synthesis of highly -substituted piperidines progress of ethyl 3-oxobutanoate.In this section, we developed an one-pot, multi-component coupling of aldehyde, amine and ethyl 3-oxobutanoate catalyzed by NiCl₂·6H₂O to give a diverse range of highly-substituted piperidines. We are investigated a variety of catalysts, reaction time, solvent and temperature on the reaction to screen out the optimum reaction conditions. Twenty-three compounds were synthesized, characterized by modern spectral analysis of their structure. Compared with the reported methods advantages of this method are the following: (i) mild reaction conditions; (ii) one-pot method, easy to operate; (iii) wide range of applications.Chapter Three: Study on the multi-component one-pot synthesis of highly -substituted piperidines progress of vinyl 3-oxobutanoate.In this chapter, we summarized an effective, economical, and simple one-pot, multi-component coupling of aldehyde, vinyl 3-oxobutanoate and amine catalyzed by NiCl₂·6H₂O to give a diverse range of highly-substituted piperidines which can achieve good yield under mild conditions. The operation is very simple, and it can be carried out at a relatively cheap catalyst.