Michael Addition Of Pyrazolines With Different Electrophilic Reagents

Pyrazolone derivatives, representing an important class of five membered-ring lactams, have exhibited a variety of applications as pharmaceutical agents, synthetic scaffolds in medicinal and synthetic chemistry. Especially, pyrazolin-5-ones derivatives have been well known as analgesic and antipyretic agents. In this respect, the development of a facile and excellent strategy for the synthesis of new pyrazolin-5-ones derivatives seems to be attractive and highly interesting. Some examples have been documented for the synthesis of pyrazolone derivatives. However, a careful survey of the relevant literature reveals that the pyrazolines with a protecting group on the oxygen atom have not been used in any nucleophilic addition. To our delight, the pyrazolines we used showed great and interesting reactivities in some addition reactions with electrophilic reagents. In this thesis, pyrazolins with a protecting group on the oxygen atom were used as the nucleophiles, we tried them to react with nitrostyrenes, β,β-unsaturated carbonyl compounds and other electrophilic reagents. By these addition reactions, different kinds of new multiply-substituted pyrazolin-5-ones derivatives were obtained.In the first part of this thesis, we tried pyrazolin with a protecting group on the oxygen atom to react with nitrostyrenes. Initially, we used pyrazolin with Cbz as the protecting group on the oxygen atom and nitrostyrene as model substrates with DMAP as catalyst. However, after12h no desired adducts were obtained from the reaction. But a new adduct with the benzyloxycarbonyl protecting group on the nitrogen atom was obtained with95%yield. To investigate the cause for the migration, reactions of pyrazolins with Boc as the protecting groups were performed under the optimized conditions. After careful characterizations, we found that the alkoxycarbonyl protecting groups also migrated from the oxygen atom to the nitrogen atom for all cases. Then we continued to scan the reaction parameters for the key factor of the migration. We used the pyrazol-5-yl acetates (PG=Ac) as substrates to perform the reaction under the optimized condition. Surprisingly, the starting materials were totally converted into the regular Michael product and no migration product was detected. Notably, the similar products were found for all probed nitroolefins with high yields. On the basis of the above results, we supposed that the variation of the protecting group of pyrazolines directly led to different products and whether the migration would occurred.In the second part, we tried the same pyrazolin to react with α,β-unsaturated carbonyl compounds. At the beginning of this experiment, we used pyrazolin with Ac as the protecting group on the oxygen atom and methyl vinyl ketone as model substrates with DBU as catalyst. After12h, two products appeared shown by TLC plate. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel to afford the two products. After careful characterizations by NMR and single-crystal X-ray analysis, we knew that one product was the regular Michael addition product, the other was a double4-substituted pyrazolone without the protecting group on the oxygen atom. Then, the protecting group on the oxygen atom was changed into Boc, Cbz, etc., the reaction also proceeded well to give the corresponding products in moderate yields. To gain insight into the reaction mechanism, we investigated the relationship between the ratio of the two reactants and the yields of the two products. We also used the product3-3as a starting material to react with methyl vinyl ketone under the similar reaction condition. To our delight, the3-3could be partly converted into3-4with56%yield and the rest of3-3remained unreacted. This result disclosed that the3-3is probably the reaction intermediate. On the basis of experimental results, a plausible reaction mechanism for this reaction was proposed, which includes two deprotection/Michael reaction processes.All these products have been characterized by1H NMR,13C NMR, HR-MS and IR. Their structure was confirmed by X-ray analysis.