Applications Of Ruthenium-Catalyzed Olefin Metathesis Reaction In The Synthesis Of Nitrogen-Containing Heterocycles

Ring closing metathesis (RCM) reaction is a very efficient method for the construction of many functionalized carbocycles and heterocycles from acyclic diene or enyne precursors. In recent years, with the development of various good catalysts especially the ruthenium alkylidenes bearing N-heterocyclic carbene ligands, the RCM reaction has been applied widely in the synthesis of complex organic molecules, biological molecules and natural products etc. The Nobel Prize in Chemistry 2005 goes to Yves Chauvin, Robert H. Grubbs and Richard R. Schrock for the development of the metathesis method in organic synthesis, which makes olefin metathesis get more and more applications.However, it is very difficult to carry out the RCM reaction of the diallyl amines containing a basic or nucleophilic N-atom under classical RCM reaction conditions. This might be because the lone-pair electron on the N-atom could coordinate with ruthenium atom, thus poisoning the catalysts and inhibiting catalytic reactions. Accordingly, we added various catalytic amount Lewis acids into the reaction system to compete or avoid the coordination of the N-atom to the ruthenium carbene intermediate. With this metholology, the RCM reaction of such kind of diallylamines occurs smoothly. By screening the catalysts, solvents, temperature and Lewis acids, the optimal reaction conditions for this kind of reaction were gained. Our results showed that using the second generation Grubbs catalyst, with the assistance of catalytic amount of Lewis acid Ti(OⁱPr)₄, the tested basic diallyl amines can all occur RCM reaction under very mild conditions, a series of enantiopure pyrrolidine derivatives were obtained with very good yields. This kind of reaction has several advantages: Firstly, only catalytic amount of Lewis acid was needed. After the reaction, it can be removed easily by adding saturated sodium bicarbonate solution. Secondly, theα-amino acids are very cheap and easily available chiral source, many enantiopure pyrrolidine derivatives can be prepared by this way. Thirdly, the scope of the olefin metathesis reaction has been expanded by our experimental results.Though microwave-assisted RCM reaction has gained much attention in recent years, few studies have been reported about the RCM reaction of basic diallyl amines under microwave irradiation. With the use of the first and second generation Grubbs catalysts, we studied the RCM reaction of basic diallyl amines under microwave irradiation. The results demonstrated that the basicity of diallyl amines has remarkable influence on the RCM reaction. While the basicity of the N-atom is stronger, more active second generation catalyst is indispensable and the temperature needs to be reached 150℃, and mixture of pyrrolidine and pyrrole was gained. As to the diallyl amines with the weaker basicity, RCM reaction can operate favorably to produce pyrrolidine or pyrrole derivatives in the presence of the first generation Grubbs catalyst with the temperature lowered to 100℃. By using our method, pyrrolidine or pyrrole derivatives can be prepared selectively.Conjugated 1, 3-diene moiety, a type of very useful organic intermediate in organic synthesis, can be used in the synthesis of complex polycyclic systems through ring closing enyne metathesis (RCEM) reaction. For the first time, we have successfully carried out the RCEM reaction to synthesize a series of chiral pyrrolidine derivatives containing conjugated 1, 3-diene moiety from basic nitrogen-containing enynes. The studies on the RCM reaction of this kind of enynes revealed that under the catalysis of the first generation Grubbs catalyst, this kind of enynes could occur RCM reaction successfully under very mild conditions and in the absence of ethylene gas. According to the experimental results, we suppose that the RCEM reaction proceeds via coordination of the metal carbene with the alkyne moiety, and then the catalytic cycle can be accomplished successfully. Alternative possibilities will also be considered as part of a broader investigation.Five-membered lactams broadly exist in many biologically active natural products. However, few studies have been reported about synthesizing such five-membered lactam derivatives by RCEM reaction. A series of five-membered lactams containing 1, 3-diene moity were prepared by RCEM reaction, the scope of this reacrion was expanded. During our research, we found that the presence of ethylene gas is critical for the RCEM reaction. In the presence of ethylene gas, using the first generation Grubbs catalyst, various lactams were achieved in good yields, and the possible mechanism was proposed.