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N, S- and N, O-containing heterocycles are ubiquitous structural motifs in pharmaceuticals, agrochemicals, and bioactive natural products. These types of compounds exhibit a broad range of bioactivities such as anti-cancer, anti-HIV, antibiotics, and antidepressants. To gain access to those heterocycles, alkene sulfenoamination and alkene oxyamination have been considered as powerful strategies because of its ability to rapidly increase the molecular complexity and functional diversity. Moreover, the wide availability of alkenes in natural products and commercial sources, in addition to the ease of synthetic accesses make these alkene functionalization strategies more appealing in the synthetic community for the modular synthesis of those heterocycles. Our group is interested in the utilization of classic halonium ion as a regioselective template for the functionalization of alkenes. The research efforts presented in this dissertation focus on the development of simple and efficient methods for alkene sulfenoamination and alkene oxyamination by demonstrating a series of alkene sulfenoamination protocols for accessing interesting N, S–containing heterocycles. In Chapter 2, a simple and convenient method for the synthesis of thiazoline from readily available chemical feedstocks such as alkenes and thioamides is described. The reaction goes through the in-situ generation of 1,2-dibromoalkane from the bromination of alkene, followed by the nucleophilic attack of thioamide on the 1,2-dibromoalkane intermediate leading to thiazoline formation. The synthetic application of this method was further demonstrated by hydrolysis of thiazoline to 1,2-amino thiol and oxidation to thiazole, a common scaffold in drugs.In Chapter 3, the regio- and stereoselective sulfenoamination of alkene with thioimidazoles for the synthesis of N, S-containing heterocycle is reported. In this reaction, Selectfluor was used as a halogen source to convert the nucleophilic sulfur reagent into an electrophilic sulfur source through the formation of a sulfur-fluorine bond. Nucleophilic attack of an alkene on the sulfur electrophile led to the formation of a thiiranium ion intermediate, then intramolecular cyclization on thiiranium ion intermediate or open carbocation resulted in the product formation. The opposite regioisomer of the product could also be achieved by using bromine as a halogen source. This method exhibited good functional group tolerance and a broad range of substrate scope in a highly regio- and stereoselective manner.In Chapter 4, an efficient approach for the synthesis of 1,4-benzothiazine via alkene sulfenoamination is presented. This method is an improvement over our previous two strategies, in which we can use a catalytic amount of an iodide salt, that offers an environmentally benign and more economic strategy for alkene sulfenoamination. Moreover, the use of unprotected aminothiophenol as a coupling partner represents another significant advance in accessing 1,4-benzothiazine. The reaction proceeds through inversion of the thiol polarity with the formation of a sulfur-iodine bond. The investigation of the mechanism suggests that both polar thiiranium and radical pathways are plausible in this reaction. In Chapter 5, the development of a method for the alkylation of arene using alcohol via carbon-carbon bond formation is disclosed. The highlighting feature of this reaction is the utilization of an alkene as a catalyst for iodonium formation that can activate an alcohol, leading to the generation of the product with an all-carbon quaternary centers. The method shows a good functional group tolerance with a wide range of arene and alcohol substrate scope. This strategy can be extended to the formation of sterically congested carbon-heteroatom bonds. In addition, this method is chemoselective for tertiary alcohols in preference to the primary and secondary alcohols. In Chapter 6, an iodide-catalyzed alkene oxyamination reaction for the synthesis of oxazolidinone is discovered. The reaction utilizes unfunctionalized carbamate as a nucleophilic coupling partner, and Selectfluor as an oxidant to oxidize iodide to iodine. The reaction proceeds through the generation of catalytic iodonium intermediate, followed by nucleophilic attack of carbamate, leading to the formation of oxazolidinone product. The complementary regioisomeric product can also be achieved utilizing NBS instead as a halogen source. |
