Transition-Metal-Catalyzed Cross-Coupling of Organic Halides With Enone

Transition-metal-catalyzed formation of carbon-carbon bonds is one of the key synthetic transformations in organic synthesis. Traditional reactions couple an electrophile with a pre-formed organometallic reagent to achieve this transformation. However, organometallic reagents are generally reactive, air and moisture sensitive and suffer from poor functional group compatibility. Advances have been made in the synthesis, use, and handling of organometallic reagents; however, the problem of high reactivity, chemoselectivity, and functional group compatibility remains. Because organometallic reagents are generally synthesized from readily available, bench-stable organic halides, the direct coupling of electrophiles with organic halides in place of an organometallic reagent is desirable. This dissertation details our progress towards this goal for the direct addition of organic halides to carbonyl compounds.;Chapter 1 describes the development of conjugate addition reactions from its discovery to the current state-of-the-art. The limitations of the use of organometallic reagents in current methods and the ability to address these limitations with the direct use of organic halides, in the presence of a stoichiometric reducing agent, are discussed.;Conjugate additions of organic halides, and tandem conjugate addition-silyl enol ether formation using organometallic reagents have been known for some time. The work presented in this dissertation is the first report on tandem conjugate addition-silyl enol ether formation using organic halides . Chapter 2 describes the coupling of haloalkanes with &agr;,beta-unsaturated carbonyl compounds to form silyl enol ethers using a nickel/terpyridine catalyst and stoichiometric manganese reductant. Chapter 3 describes an analogous reaction for the coupling of haloarenes with cyclic alkenones using a nickel/neocuproine catalyst and manganese reductant. The method tolerates a variety of functional groups, including an electrophilic aldehyde and an acidic proton of N-aryltrifluoroacetamide (pKa ∼ 12). Preliminary mechanistic studies reveal an "umpolung" mechanism involving the formation of a nickel-silyloxyallyl species, which undergoes reduction prior to the reaction with an organic halide to form the desired silyl enol ether.;Unlike traditional cross-coupling methods, the reactions described in Chapters 2 and 3 can be assembled on the benchtop without special precautions to exclude air. The reactions proceed under mild reaction conditions to provide good yields of silyl enol ethers. The methods demonstrate that the direct coupling of organic halides with electrophiles in the presence of a stoichiometric reductant can minimize the number of steps required for a desired transformation, increase the ease of manipulation, and improve functional group compatibility.;Chapter 4 outlines a research project focused on the addition of organic halides to aldehydes and imines using a palladium catalyst. While Chapters 2 and 3 describe the use of metallic reducing agents, Chapter 4 addresses the possibility of using sulfur(IV) reagents as terminal reductants. The desired catalytic transformation is proposed to involve a novel S-O bond reductive elimination step. Stoichiometric studies to observe the desired reductive elimination from palladium and the discovery of copper-mediated radical reaction for tosylation of phenols during the course of the study are discussed.