Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Committee Member

Dr. R. Karl Dieter, Advisor and Department Chair

Committee Member

Dr. Daniel C. Whitehead

Committee Member

Dr. William Pennington

Committee Member

Dr. Rhett Smith

Abstract

Alkyl Grignard reagents (Et, nBu, iPr, cyclohexyl), with the exception of tBuMgCl, undergo exclusive or exceptionally highly regioselective 1,4-addition reactions to acyclic ,–,-unsaturated ketones, while aryl and heteroaryl Grignard reagents give mixed results ranging from exclusive 1,4-addition (1-naphthyl, 2-N-methylpyrrolyl) to regioselective 1,2-addition (2-furyl, 2:1). All alkyl, aryl, and heteroaryl Grignard reagents examined gave exclusive 1,4-addition reactions with ,–,-unsaturated thiol esters, with the exception of tBuMgCl which gave an 80:20 mixture of 1,4-:1,6-addition products. The high chemo- and regioselectivity observed for these reactions is attributed to a radical or radical-like pathway for the alkyl Grignard reagents and possibly a carbanion pathway for aryl Grignard reagents. The ,-dienyl thiol esters provide for a one-pot tandem 1,4-addition-nucleophilic acyl substitution reaction sequence to afford 3-substituted 4-enone moieties. Allylic opening of functionalized vinyloxiranes has been investigated with Grignard reagents and both catalytic and stoichiometric amounts of copper (I) salts. Specifically, α,β-epoxy-γ,δ-enones were found to undergo allylic opening of the epoxide ring in the presence of either CuCN or CuBr·SMe2 in THF or CH2Cl2 from -55 °C to -78 °C to give δ-substituted-β,γ-unsaturated-α-hydroxyketones in 3 hours. While reactions were conducted with stoichiometric amounts of CuCN, sub-stoichiometric (20 mol%) and catalytic ( 5-10 mol%) amounts of CuBr·SMe2 could be used to effect clean transfer of alkyl Grignard reagents to the substrates. Interestingly, it required two equivalents of the allyl and aryl Grignard reagents with stoichiometric CuBr·SMe2 to effect complete transfer in 3 hours. The CuCN-mediated reaction gave at best 70:30 mixture of the E/Z stereoisomers of the δ-substituted-β,γ-unsaturated-α-hydroxyketones. However, with the use of CuBr·SMe2 only the E-isomer was observed. A tentative model was proposed to rationalize the marked differences in the stereoselection associated with these copper salts. Allowing the reaction to warm to room temperature resulted in the oxidation of the α-hydroxy alcohol to the corresponding δ-substituted-β,γ-unsaturated dione. In the absence of any copper salts, 1,2-addition product arising from nucleophilic attack on the carbonyl carbon was obtained. Alkylmagnesium cuprates and zincates reacted with ethyl 6-bromo-α, β, γ, δ-dienoates to give exclusively the SN2 product while their lithium versions gave mixed results favoring the SN2′ product. When the substrate was changed to ethyl 6-chloro-α, β, γ, δ-dienoates, cuprates and zincates of lithium gave only the SN2′ products while their magnesium versions gave mixed results favoring the SN2′ product. These results suggest that both the leaving group ability of the halide, and the magnesium vs lithium as counter ion in the cuprate or the zincate influenced the regioselectivity of the ethyl 6-halo-α, β-γ, δ-hexadienoates and a model is proposed to explain the differences.

Share

COinS