| Ketones has been gaining popularity due to its wide application in medicine,pesticides,materials,spices and other fields.To date,a variety of approaches for the preparation of ketones have been developed.Among them,the method of derivatization of aldehydes via C-H insertion is more attractive because of its low budget,availability and abundance of variety.Although the C-H insertion of diazo compounds and aldehydes to prepare ketones has been successfully achieved,yet there exists explosiveness,toxicity and tough reaction conditions of diazo compounds,which leads to serious deficiencies in cost and safety.To our knowledge,sulfonylhydrazones are safe and effective substitutes for diazo compounds,but their intercalation reactions with aldehydes are not fully studied.Here,based on literature methods,the one-step reaction of sulfonylhydrazones and aldehydes to prepare ketones,as well as the scalability of the process and the possible reaction mechanism have been systematically studied,which laid the foundation for the further development of safe and scalable methods for preparing ketones from aldehydes.The completed work is as follows:1.N-boc-4-piperidone p-toluene sulfonylhydrazone and 4-chlorobenzaldehyde were used as model substrates,and the effects of solvent,base and reaction temperature on product yield were investigated to determine the best solvent,base and reaction temperature for the reaction.On this basis,the influence of the sulfonyl type on the reaction was investigated,and it was found that when 3-trifluoromethylbenzenesulfonylhydrazone was used as the substrate,the product yield was the highest,and the yield of tert-butyl 4-（4-bromobenzoyl）piperidine-1-carboxylate reached 94%,which was 17% higher than that in the literature.The optimum reaction conditions were obtained as follows: potassium carbonate as base,dimethyl sulfoxide as solvent,3-trifluoromethylbenzenesulfonylhydrazone as substrate,and the reaction was carried out at 110 °C for 2 hours.2.Under the optimum reaction conditions,the application range of substrates for the one-step reaction was investigated.It was found that except for 2,4,6-trimethylbenzaldehyde,which has a large steric hindrance,other aryl aldehydes,heteraryl aldehydes and alkyl aldehydes,the target product ketones can obtain the target product ketone in moderate to excellent yields（42-94%）.Moreover,the yield of the product ketone varied with the type and position of the substituent on the aromatic ring of the aromatic aldehyde;for different substituents,the yield of the product ketone:electron withdrawing substituent > electron donating substituent;for the same substituent at different positions on the aromatic ring: the yield follows the law of para >meta > ortho.For heterocyclic ketones,carbocyclic ketones,branched alkane ketones,and aldehyde-derived sulfonylhydrazone derivatives,the method can also obtain the target product in moderate to excellent yields（46-95%）,indicating that this method has a broad substrate application range.3.The key intermediate ketone,a potential drug for Alzheimer’s disease,which is difficult to obtain traditionally,was prepared by this method,and a 10-fold amplification reaction was carried out.The product yield of the scale-up reaction was consistent with that of the small test（80%）,which proved that the method has scalability and good repeatability.4.In view of the lack of clarity of the reaction mechanism in literatures,relevant mechanism exploration experiments were designed.In terms of the experimental results and related reaction mechanism,a new reaction mechanism of the reaction undergoing a five-membered cyclic transition state was proposed.High-resolution mass spectrometry confirmed the existence of the transition five-membered ring intermediate. |
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