Nickel-catalyzed reductive coupling of aryl halides with alkyl electrophiles

Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2015.The direct transition-metal catalyzed cross-coupling of two different electrophiles is a fast emerging synthetic method, as it avoids the use of carbon nucleophiles. Despite being a synthetically valuable strategy, a central challenge of cross-electrophile coupling is achieving selectivity for cross-coupled product over dimerization products. This thesis details the author’s work towards the development of cross-selective methods for the formation of Csp2-Csp3 bonds. Chapter 1 introduces the conventional cross-coupling method of forming C-C bonds and highlights the advantages of using the reductive cross-electrophile coupling approach instead. The selectivity challenges associated with reductive cross-coupling and the origins of selectivity in the cross-coupling reactions of aryl halides with allylic acetates and benzyl mesylates are discussed. Motivations towards the adaptation of our cross-electrophile coupling methods to more environmentally responsible solvents and reductants are also described. Chapter 2 details a general protocol for the coupling of aryl halides with allylic acetates and shows that high cross-selectivity can be achieved with the use of a terpyridine nickel catalyst. Strength’s of the method are presented such tolerance for electrophilic (ketone (71%), aldehyde (70%)) and acidic (sulfonamide (73%), trifluoroacetamide (64%)) substrates and the ability to couple with a variety of substituted allylic acetates. The reductive method addresses the regioselectivity and substrate availability limitations observed in past approaches to allylated arenes. Chapter 3 presents the first synthesis of diarylmethanes from benzyl mesylates and aryl halides using cobalt phthalocyanine (Co(Pc)), a new co-catalyst for radical generation that is compatible with nickel-catalysis. Studies are shown demonstrating the orthogonal reactivity of (dtbbpy)Ni and Co(Pc) and the application of this selectivity to the coupling of functionalized benzyl mesylates with aryl halides. The adaptation of the method to the less reactive benzyl phosphate ester and an enantioconvergent reaction are also presented. Chapter 4 shows studies towards the adaptation of cross-electrophile coupling to more environmentally friendly solvents and reductants. Here, a homogeneous, two electronic organic reductant, 1,2,2-tetrakis(dimethylamino)ethylene (TDAE), is shown to be effective for nickel-catalyzed cross-electrophile coupling in various green solvents such as propylene carbonate and acetonitrile. These reactions are close in yield to our best-reported results in amide or urea solvents using zinc or manganese as the reductant. Chapter 5 describes initial studies towards nickel-catalyzed decarbonylative coupling reactions of acid chloride derivatives with aryl and alkyl halides and nickel-catalyzed coupling reactions of aryl halides with small cyclic alkyl bromides and oxetane tosylate. Further optimization strategies are presented

Selective Cross-Coupling of Organic Halides with Allylic Acetates

A general protocol for the coupling of haloarenes with a variety of allylic acetates is presented. Strengths of the method are a tolerance for electrophilic (ketone, aldehyde) and acidic (sulfonamide, trifluoroacetamide) substrates and the ability to couple with a variety of substituted allylic acetates. Secondary alkyl bromides can also be allylated under slightly modified conditions, demonstrating the generality of the approach. Finally, the coupling of a reactive vinyl halide could be achieved by the use of a very hindered ligand and more reactive, branched allylic acetates

Selective Cross-Coupling of Organic Halides with Allylic Acetates

A general protocol for the coupling of haloarenes with a variety of allylic acetates is presented. Strengths of the method are a tolerance for electrophilic (ketone, aldehyde) and acidic (sulfonamide, trifluoroacetamide) substrates and the ability to couple with a variety of substituted allylic acetates. Secondary alkyl bromides can also be allylated under slightly modified conditions, demonstrating the generality of the approach. Finally, the coupling of a reactive vinyl halide could be achieved by the use of a very hindered ligand and more reactive, branched allylic acetates