Synthesis and Applications of Copper Hydride Complexes in Reductive Reactions

This dissertation, "Synthesis and Applications of Copper Hydride Complexes in Reductive Reactions" by Chi-ming, Kelvin, Fung, 馮志明, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled SYNTHESIS AND APPLICATIONS OF COPPER HYDRIDE COMPLEXES IN REDUCTIVE REACTIONS Submitted by Fung Chi Ming Kelvin for the degree of Doctor of Philosophy at The University of Hong Kong in October 2005 The preparation of Stryker's reagent, [(Ph P)CuH] (1.1) using silanes as 3 6 reducing agents has been examined. It was found that these homogeneous conditions increased the rate of the reaction considerably, such that the reaction time was reduced to 1-2 hours compared to the 12-16 hours required in previous syntheses. The optimized conditions consisted of treating CuCl, KO Bu, Ph P with phenyldimethylsilane in benzene as solvent to afford 1.1 in a very pure form. [(Ph P)CuD] (1.2) has also been synthesized in a similar manner using Ph SiD as 3 6 2 2 the reductant, and 1.2 should find applications in deuterium-labeling studies. Based on the preparation of 1.1, active copper hydride on polymer support has been synthesized using soluble polymer-supported triphenylphosphine 2.2b. This reagent, which possesses similar properties as 1.1, can induce reduction and reductive silylation of aldehydes and enones. However, the corresponding copper hydride reagent could not be prepared in this way using insoluble polymer 2.3. A reductive aldol cyclization catalytic in 1.1 and stoichiometric in silane has been achieved on a variety of enediones (3.3, 3.7, 3.10, 3.13, 3.16, 3.22, 3.25-3.28) and keto-enoates (3.34, 3.35, 3.41). These reactions produced β-hydroxy carbonyl compounds (3.17a-b, 3.18a-b, 3.19a, 3.20a, 3.21a, 3.29a-c, 3.30a-b, 3.31a-b, 3.32a-b, 3.33a-b, 3.36a, 3.37a, 3.44a) as the major products with good yields in one pot efficiently. The diastereoselectivity and yield of the catalytic reaction was generally lower than those observed in the stoichiometric reaction of the same substrate. This suggests that the mechanisms of these two reductive aldol reactions are different, and the role of the silane exceeds that of simply regeneration of the copper hydride. Two mechanisms have been proposed to describe the catalytic reaction. One is a reductive silylation of the enone followed by intramolecular Mukaiyama aldol reaction catalyzed by Lewis acids. The other is a direct copper enolate cyclization, the diastereoselectivity of which is modified by the presence of additional ligands, in competition with a Mukaiyama aldol reaction. The enantioselective reductive aldol cyclizations of 3.13 and 3.16 have been investigated using chiral bisphosphines instead of triphenylphosphine in the preparation of the copper hydride complex. The highest enantioselectivity was observed in the reaction of 3.16 to give 3.21a with 48% ee, using a CuCl/KO Bu/(R)-tol-BINAP/2,2'-bipyridine system at -40 C in the presence of a stoichiometric amount of tetramethyldisiloxane. The Stryker reductions of α,β,γ,δ-bisunsaturated ketones and esters (5.2-5.5, 5.7-5.8) have been investigated. These reactions proceeded mainly via 1,4-reduction to give the corresponding γ,δ-unsaturated ketones and esters (5.14a, 5.15-5.17, 5.18, 5.19) in good yields. In some cases where the reactions were sluggish, the reductions proceeded to completion by changing the solvent from toluene to cyclohexane. The addition of alcohols also led to an increase in the rate of the reaction. 1 n Ph JJ PPh 2.3 PPh