Synthesis of medium rings, naphthalene derivatives, oxazoles and vinyl sulfides from electron-rich alkynes

Abstract

Electron-rich alkynes are a family of versatile species in organic chemistry. Ynol ethers (alkoxy alkynes, siloxy alkynes), ynamides, and thioalkynes are the most common electron-rich alkynes. These species usually have special reactivities due to the presence of a heteroatom directly on the triple bond. Upon activation, they can react sequentially with electrophiles and nucleophiles, leading to novel processes. Many useful cascade processes can be developed due to the high versatility of these species. In this thesis, several new reactions employing electron-rich alkynes are described including the formation of medium-rings, the formal cycloaddition reactions and the hydroalkylation of electron-rich alkynes. These results are discussed in detail in the following chapters. Chapter 1 describes the importance and difficulties of preparing medium-ring compounds. A new strategy to overcome the limitations of previously reported work is develpoed. The Sun group has reported a highly efficient method for medium and large ring lactones synthesis from siloxy alkynes. However, this strategy is limited to the synthesis of lactones with alkyl or aryl substitution groups at the α-position of the carbonyl group. The TMS group protected terminal siloxy alkynes were developed. With this alkyne, a range of medium and large lactones with α-TMS substitution were successfully obtained. The TMS substituent could be easily removed or converted, thereby significantly enhancing the utility of this ring-expansion strategy for medium-ring lactone synthesis. Chapter 2 describes a Ag-catalyzed formal [6+2] cycloaddition reaction between vinylazetidines and siloxy alkynes to generate medium-sized lactams in good to excellent yields. Mechanistic studies indicate the ketene intermediate serves as the key intermediate. Nucleophilic attack followed by stereospecific 3,3’-sigmatropic rearrangement ring-opening gives the final lactams. To further confirm the ketene intermediacy, different methods were used to generate ketenes including using acyl chlorides, using phosphine catalyst and using tert-butyl ynol ether. The desired lactams were all obtained in good yields. Chapter 3 describes a [4+2] cycloaddition reaction between isobenzopyrylium ions and electron-rich alkynes including siloxy alkynes, ynamides and thioalkynes under the Lewis acid conditions. This strategy provides rapid access to diversely-functionalized useful naphthalenes, such as substituted β-naphthol, β-naphthylamine and β-naphthylthiol derivatives. Brief mechanistic studies indicate that the Lewis acid catalyst is used to form isobenzopyrylium ions in the first step. Subsequent [4+2] cycloaddition with the alkynes takes place. The bridged cyclic structure is then opened. The following processes depend on the substituent on the substrates. Chapter 4 describes a formal [3+2] cycloaddition reaction between isocyanides and siloxy alkynes to give oxazoles as the products. In this reaction, siloxy alkynes contribute a C‒O unit to cyclization. This is in contrast to the previous cyclization reactions of siloxy alkynes, where they serve as two-carbon partners. Mechanistic studies indicate that siloxy alkynes serve as the ketene precursor, followed by nucleophilic addition. Chapter 5 describes a new strategy to synthesize vinyl sulfides with single Z isomer via the hydroalkylation of thioalkynes under the catalyst of Sc(OTf)₃. There are limited reports about the hydroalkylation of thioalkynes. Compared to the previous works, this strategy is user-friendly and expedient for C‒C bond construction. A proton sponge is beneficial to this reaction to inhibit the alkyne decomposition by free proton in the reaction system.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology