Part Ⅰ. P(Ⅲ)-Mediated Deoxygenative Geminal Electrophilic/Nucleophilic Additions of Pyrazoles to 1,2-Diketones Part Ⅱ. Study on Skeletal Editing through N-Chlorination-Induced Ring Contraction of 1,4-Bis(alkylsulfenyl)phthalazines and 3,6-Bis(methylsulfenyl)pyridazine

Abstract

Part Ⅰ. Geminal dipyrazoles have been considered important because of their biological activity as ligands. The geminal dipyrazole addition has been known but rarely reported for carbonyl groups. The reported reactions require multistep synthesis employing harmful reagents. Thus, a new synthesis method is needed. During the investigation of geminal difunctionalization in our group, a former member discovered the formation of geminal dipyrazole. On the basis of this preliminary result, the reaction was optimized, and a mechanistic study was conducted. To increase the yield, bases, hypervalent iodine oxidants, and chlorinated pyrazole were examined. Eventually, improved results were obtained when 4-methylpyrazole was employed. In addition, the substrate scope of 1,2-diketones was expanded. Part Ⅱ. Skeletal editing is a useful synthetic method for natural products and pharmacologically active molecules, particularly as late-stage modifications. Previously, N-chlorination-induced ring contraction of 1,4-dimethoxyphthalazines was studied in our group. However, this reaction required an excess amount of reagents, a long reaction time, and a high temperature. Upon DFT calculation of the reaction mechanism, it was suggested that the bicyclization step would be the rate-determining step. Moreover, a similar analysis with 1,4-bis(methylsulfenyl)phthalazine led to a substantially lower activation energy. On the basis of this result, the current study was conducted with the expectation that N-chlorination-induced ring contraction of 1,4-bis(methylsulfenyl)phthalazine would proceed under milder conditions. Unfortunately, the reaction rate was too fast to monitor the progress. Thus, the experiments were conducted with less reactive substrates such as unsymmetrical phthalazine, 1,4-bis(t-butylsulfenyl)phthalazine, and 3,6-bis(methylsulfenyl)pyridazine. However, the desired ring contraction product was not obtained.