Xi-Jie Dai
Published: 2017
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"This thesis advances the knowledge in two fundamentally important organic chemical transformations: (1) cleavage of carbon-oxygen bonds and (2) formation of carbon-carbon bonds. Such advancement consists of four late transition metal-catalyzed reactions based on the oxygenated chemical feedstock, which will be discussed on a chapter-by-chapter basis. Chapter 2 introduces our initial attempts to address a 40-year-old scientific challenge in the field of alcohol deoxygenation: how to selectively and efficiently remove hydroxyl groups in organic molecules without affecting other existing functional groups. We hypothesize a single-step, redox process to solve this problem, whereby the dehydrogenative oxidation of alcohols and the Wolff-Kishner reduction are combined. As a proof-of-concept discovery, the early development of this reaction is catalyzed by iridium complexes and mediated by hydrazine under forcing reaction conditions. This deoxygenation protocol proves effective for many simple activated substrates such as benzylic and allylic alcohols. The major limitation, however, is the poor reactivity and selectivity seen in aliphatic alcohol substrates. Chapter 3 describes the adaptation of ruthenium(II) catalysis for the direct deoxygenation of primary aliphatic alcohols in a completely chemo- and regio-selective manner. Such a robust catalytic system, comprising [Ru(p-cymene)Cl2]2 and 1,2-bis(dimethylphosphino)ethane, is vital to lower the activation energy barriers to the dehydrogenative oxidation of aliphatic alcohols, and makes this step more kinetically favorable. Equally important is the combination of KOt-Bu, DMSO and t-BuOH, which promotes the subsequent Wolff-Kishner reduction at low temperature. This method is thus more practical compared with the iridium-based protocol, proceeding under milder thermal conditions. Its synthetic utility is demonstrated by the selective cleavage of carbon-oxygen bonds in both simple and complex organic molecules such as steroids and alkaloids. Chapter 4 presents a synthetic approach to utilize naturally occurring carbonyl compounds (i.e. aldehydes and ketones) as more sustainable alkyl carbanion equivalents for formation of carbon-carbon bonds via carbonyl addition reactions. Traditionally, such transformations depend on organometallic reagents which are made from petroleum-derived chemical feedstocks and a stoichiometric quantity of metal. Accessing this new chemical reactivity of carbonyl compounds attributes to the ruthenium(II) catalytic system discovered in the early deoxygenation chemistry. By controlling the basicity, preformed carbonyl-derived hydrazones can intercept another carbonyl compounds to form new carbon-carbon bonds via a Zimmerman-Traxler chair-like transition state. This chemical transformation delivers a wide range of synthetically valuable secondary and tertiary alcohols. Additional highlights include excellent functional group compatibility and good stereochemical control governed by chiral amido and phosphine ligands. Chapter 5 focuses on the further exploration of such unique 'umpolung' reactivity for formation of carbon-carbon bonds via conjugate addition reactions. Inspired by the softness of ruthenium(II) pre-catalyst, which bears a resemblance to that of 'soft' transition metals in the classical 1,4-conjugate addition, we presume that this ruthenium(II)-based catalytic system may be more effective for conducting nucleophilic conjugate additions. Indeed, a variety of highly functionalized aromatic carbonyl compounds are used as latent benzyl carbanions, to couple with electron-deficient [alpha],[beta]-unsaturated compounds including esters, ketones, sulfones, phosphonates, and amides. Two bidentate phosphine ligands (dppp and dmpe) are found to facilitate this process in a complementary manner, largely depending on electronic profiles of the carbonyl compounds. Chapter 6 summarizes all research present in this thesis and contributions to knowledge advancement. " --