Cyclization- Functionalization Of Alkenyl Oximes Promoted By TBN

Isoxazoline, which contains a five-membered unsaturated hetrocyclic compound is an important synthetic intermediate or target product. Such skeleton is also widely spreaded in natural product and drug. Currently, mature synthesis method toward isoazoline is based on Huisgen 1,3-diploar cyclization of nitrile oxide and alkene. Although such method is very simple and efficient, there are some serious defect, such as low regioselectivity. Our group has been committed to exploring new N-O bond cleavage isoxazolidine rearrangement reaction by the strategy of self-hydrogen transferring. During the research, one of the most important problem is to synthsize the isoxazolidine with high regioselectivity and diastereoselectivity. To address this issue, in this thesis, the author try to realize the highly selectivity synthesis of a series of isoxazolines with diverse substituents in one step using intramolecular radical cyclization strategy and transform the isoxazoline structure to cis-specific N-methylisoxazolidine. The main contents of this thesis were summarized as following three parts:1. Using t-butyl nitrite as radical initiator and the source of nitrogen monoxide, air as the oxygen source, we converted ?,?-unsaturated ketone oximes into nitrated isoxazoline and realized oxynitration of the unactived double bond without using any transition metal or toxic radical initiator. In this reaction, aliphatic substrates with or without functional groups, aryl substrates with strong electron withdrawing group or strong electron donating groups provide the corresponding nitrated products in high yields. We also sutdied the property of the nitrated substituent, which was found that not only could be used as leaving group, but also could be cleavaged under reducing conditions. Combined with our previous work, we also transformed the nitrated isoxazoline into cis-1,3-oxazinane skeleton efficiently.2. Using t-butyl nitrite as radical initiator and oxidant, abundant and inexpensive aluminum chloride as the chlorine source, we obtained the radical cross-coupling product selectively without using any transition metals and toxic radical initiator. Thereby, we realized oxychlorination of the unactived double bond and developed a novel approach of preparation chloromethyl isoxazoline. At the same time, the mechanism of this oxychlorination reation was also explored. We found it proved the existence of a carbon radical intermediate during the reaction process. Also, the chlorine radical was captured by trapping experiments.3. Using t-butyl nitrite as the radical initiator and nitrogen source, in the presence of ruthenium catalyst and additive, we converted ?,?-unsaturated ketone oxime to cyano-substituted isoxazoline efficiently and realized oxynitridation of the unactived double bond. This method has a wide range of functional group tolerance, and the reaction yields are very high. Although this method needs to use transition metal as the catalyst, a gram-scale reaction was achieved by using relatively low amount of the rutheniun catalyst.