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dc.contributor.advisorDeShong, Philip R.en_US
dc.contributor.authorManoso, Amy Sloveren_US
dc.date.accessioned2004-07-16T05:15:44Z
dc.date.available2004-07-16T05:15:44Z
dc.date.issued2004-04-26en_US
dc.identifier.urihttp://hdl.handle.net/1903/1664
dc.description.abstractPalladium-catalyzed cross-coupling reactions are versatile methods for the synthesis of carbon-carbon bonds. The Stille and Suzuki cross-coupling protocols have achieved prominence in the synthesis of pharmaceuticals and agrochemicals because of the high yields, tolerance for functional groups, and excellent stereoselectivities. However, there are features associated with each of these processes that limit the generality: the Stille tin reagents and byproducts are toxic; and the Suzuki boron reagents can be difficult to synthesize and purify. Environmentally benign arylsilane derivatives have emerged as powerful alternatives to conventional arylmetalloids for the Pd(0)-catalyzed aryl-aryl coupling reaction with organohalides and organo(pseudo)halides because they avoid the inherent limitations associated with traditional methodologies. It was previously reported that aryl(trialkoxy)silanes (also called siloxanes) are substrates for fluoride-promoted, Pd(0)-catalyzed coupling reactions with allylic ester and aryl derivatives providing cross-coupling products in high yields under mild conditions. However, few detailed studies of the synthesis of these useful cross-coupling reagents have been reported in the literature. In chapter one of this thesis, two methods for the synthesis of aryl siloxanes are studied and the optimal reaction conditions and the scope determined: (1) general reaction conditions for the synthesis of aryl(trialkoxy)silanes from aryl Grignard and lithium reagents and functional silanes have been developed; and (2) the scope of the palladium-catalyzed silylation of aryl halides with triethoxysilane to generate aryl(trialkoxy)silane derivatives has been expanded. In tandem, these two methods provide ready access to a wide range of aryl siloxane reagents for use in Pd(0)-mediated cross-coupling reactions, including highly functionalized siloxane intermediates in the synthesis of useful biologically active compounds. In the first part of chapter one, the synthesis of aryl siloxanes from the corresponding aryl organometallic reagent and tetraalkoxysilanes is described. Although examples in the literature have reported the use of a range of silicon electrophiles (including SiCl4 and ClSi(OR)3), tetraalkyl orthosilicates (Si(OR)4) allow for the most direct and convenient synthesis of arylsiloxanes, in that they are commercially available, inexpensive, and air and moisture stable. Using the reaction conditions developed herein, o-, m- and p-substituted bromoarenes underwent equally efficient metallation and silylation. Mixed results were obtained with heteroaromatic substrates: 3-bromothiophene, 3-bromo-4-methoxypyridine, 5-bromoindole, and N-methyl-5-bromoindole all underwent silylation in good yield, whereas a low yield of siloxane was obtained from 2-bromofuran, and 2-bromopyridine failed to be silylated. The synthesis of siloxanes via organo lithium and magnesium reagents is limited by the formation of di- and triarylated silanes (Ar2Si(OR)2, and Ar3SiOR, respectively), and dehalogenated (Ar-H) by-products. Lower temperatures allowed for the formation of predominantly monoaryl siloxanes, without requiring a large excess of the electrophile. Optimal reaction conditions for the synthesis of siloxanes from aryl Grignard reagents entailed addition of aryl magnesium reagents to 3 equiv of tetraethoxy- or tetramethoxysilane at 30 degrees C in THF. Aryl lithium species were silylated using 1.5 equiv of tetraethoxy- or tetramethoxysilane at 78 degress C in ether. The proposed mechanism of silylation involves formation of the anionic pentacoordinate monoaryl(tetraalkoxy)silicate (ArSi(OR)4-), which unexpectedly is susceptible to nucleophilic attack by a second equivalent of the aryl metalloid to form diaryl(dialkoxy)siloxane by-products. The reductive dehalogenation of the aryl halide starting material presumably occurs during the metallation step, and is an inherent limitation of the use of organometallic reagents. The second part of chapter one discusses an alternative to the preparation of arylsilanes from organomagnesium or lithium intermediates: the silylation of aryl halide derivatives by triethoxysilane (HSi(OEt)3) in the presence of a Pd catalyst. As initially reported in the literature, the silylation reaction was limited to p-substituted, electron-rich aryl iodide substrates. As described in this thesis, a more general Pd(0)-catalyst/ligand system has been developed which activates bromides and iodides: palladium (0) dibenzylideneacetone (Pd(dba)2) is activated with 2-(di-tert-butylphosphino)biphenyl (Buchwald's ligand) (1: 2 mole ratio of Pd : phosphine). Electron-rich, para- and meta-substituted aryl halides (including unprotected anilines and phenols) underwent silylation to form the corresponding aryl(triethoxy)silane in fair to excellent yield; however, ortho-substituted aryl halides failed to be silylated. Aryl chlorides were inert under the reaction conditions, and triflates were poor substrates for silylation, instead undergoing highly efficient reductive deoxygenation. The optimum silylation reagent is triethoxysilane; hexamethoxydisilane failed to be activated under a range of conditions. The major by-product of this reaction is reductive dehalogenation of the aryl halide starting material. Probable mechanisms for the silylation reaction and the reduction side-reaction are presented and discussed. The Pd-catalyzed silylation method is an excellent companion to the more traditional organometallic approach to the formation of the Ar-Si bond. Case in point, ortho-substituted aryl siloxanes are readily synthesized from the Grignard or lithium reagent. Unlike the metallation approach, the Pd-catalyzed silylation technique can be performed in the presence of a wide range of functional groups, including carbonyl-containing electrophiles, and protic moieties such as phenols or primary amines. In addition to the fluoride-promoted transfer of aryl moieties presented in chapter one, silanes have also been shown to transfer nucleophiles such as azide and cyanide anion. Chapter two presents the development of a high yielding silicon-based method for the preparation of alkyl nitriles, which serve as precursors to a variety of useful functional groups. Hypercoordinate cyanosilicate, prepared in situ by the reaction of cyanotrimethylsilane (Me3SiCN) with tetrabutylammonium fluoride (TBAF), is an effective source of nucleophilic cyanide. Primary and secondary alkyl halides and sulfonates underwent rapid and efficient cyanide displacement in the absence of phase transfer catalysts with the silicate derivative; inversion of configuration was observed for optically active alkyl halide substrates. Tetrabutylammonium fluoride was the optimum activating agent, and a full equivalent of fluoride ion was required for reaction completion. A nearly 1 : 1 stoichiometry of substrate to cyanosilicate affected formation of alkyl nitriles in acetonitrile or dioxane; in contrast, traditional methodologies typically employ a large excess of reagents, toxic phase transfer catalysts or solvents such as DMSO, or heavy-metal cyanide salts. Relative to other cyanide sources, the hypercoordinate cyanosilicate was much less basic, thereby mitigating the formation of elimination (alkene) by-products. The Me3SiCN/TBAF system is significantly less reactive and less basic than tetrabutylammonium cyanide (TBA-CN), therefore the mechanism of reaction most like involves the in situ generation of a hypercoordinate cyanosilicate, rather than disproportionation of Me3SiCN and TBAF to form TBA-CN in situ.en_US
dc.format.extent1095583 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.titleHypercoordinate Silicon Compounds In Organic Synthesis: Improved Methods For The Synthesis Of Aryl(Trialkoxy)Silane Derivatives; And Trimethylsilyl Cyanide As A Cyanide Source For Nucleophilic Substitutionen_US
dc.typeDissertationen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.contributor.departmentChemistryen_US
dc.subject.pqcontrolledChemistry, Organicen_US
dc.subject.pqcontrolledChemistry, Inorganicen_US
dc.subject.pquncontrolledpalladiumen_US
dc.subject.pquncontrolledfluorideen_US
dc.subject.pquncontrolledsilicateen_US
dc.subject.pquncontrolledbiarylen_US
dc.subject.pquncontrolledhypervalenten_US


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