Nickel-catalyzed C-alkylation of nitroalkanes with alkyl halides
Date
2020
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Publisher
University of Delaware
Abstract
This dissertation focuses on the development of novel methods for nickel-catalyzed C-alkylation of nitroalkanes and mechanistic studies of them. Nitroalkanes are versatile intermediates and can be used in a variety of C–C bond-forming transformations. They can also be converted to other useful functional groups such as amines and carbonyls. C-alkylation of nitroalkanes with alkyl halides, however, has been challenging due to competing O-alkylation. Our group has contributed to solving this century-old problem by utilizing transition-metal catalysis. ☐ In chapter 1, I will describe the development of the first general alkylation of nitroalkanes with unactivated alkyl iodides by using a nickel catalyst and diethyl zinc as external reductant. These conditions proved to be general for a variety of functionalized primary, secondary, and tertiary alkyl iodides, as well as primary nitroalkanes, providing the alkylated product in good yields. Preliminary mechanistic studies point to a radical-based mechanism. ☐ In chapter 2, I will discuss the development of photoredox/nickel dual-catalyzed alkylation of nitroalkanes with alkyl halides. The main limitation of nickel/diethylzinc condition was the low reactivity of secondary nitroalkanes. The new method proved to be general for nitromethane, primary, and more importantly secondary nitroalkanes, as well as all classes of alkyl halides. Moreover, the novel method is quite robust, allowing the reaction to be conveniently set under air. With this method, synthetically challenging tertiary nitroalkanes, and subsequently α-tertiary amines can be accessed. ☐ In chapter 3, I will describe our efforts towards understanding the mechanism of the photoredox/nickel-catalyzed alkylation of nitroalkanes. Several approaches, such as kinetic studies, racemization studies, radical clocks, etc. were taken to study the preliminary steps of the reaction. These efforts resulted in a better understanding of the reaction and demonstrated the complexity of the mechanism. Ultimately, we have proposed a novel mechanism for this transformation that will be further examined by computational studies in the near future. ☐ Finally, in chapter 4, I will discuss the development of the photoredox/nickel dual-catalyzed asymmetric alkylation of nitroalkanes with α-bromoketones. Previously, our group disclosed the asymmetric alkylation of nitroalkanes with α-bromoamides, using nickel catalysis. The novel method expands the scope of electrophiles and provides access to β-nitroketones with good control of diastereo- and enantio-selectivity. These products can be elaborated to biologically relevant amines and alcohols.
Description
Keywords
Alkyl halides, Alkylation of nitroalkanes, Nickel-catalyzed, Transition-metal catalysis