Type of Document	Dissertation
Author	Seibert, Kimberly Ann
URN	etd-07052007-142500
Title	Alternative Electrophiles in the Morita-Baylis-Hillman Reaction
Degree	Doctor of Philosophy
Department	Chemistry and Biochemistry, Department of
Advisory Committee	Advisor Name Title Gregory B. Dudley Committee Member J. Joseph Cronin, Jr. Committee Member Kenneth A. Goldsby Committee Member Marie E. Krafft Committee Member Robert A. Holton Committee Member
Keywords	Alternative Electrophiles Allylation Alkylation Cyclization Morita-Baylis-Hillman Reaction Mechanistic Studies Organocatalyzed Thioester MBH Intermediate
Date of Defense	2007-06-29
Availability	unrestricted
Abstract Discovering new carbon-carbon bond forming reactions is not only fundamental for the construction of organic molecular frameworks but is vital for the advancement of synthetic organic chemistry. The Morita–Baylis–Hillman reaction (MBH), dating back to both German and Japanese patents, is an organocatalytic three component reaction involving the coupling of the α-position of activated alkenes with carbon electrophiles under the catalytic influence of a nucleophilic species, providing a simple and convenient method for the synthesis of densely functionalized molecules. The reaction mechanism is believed to proceed through a Michael type addition-elimination sequence in which the nucleophilic catalyst undergoes a reversible Michael-type nucleophilic addition to an activated alkene to form a zwitterionic enolate. Nucleophilic addition of this zwitterionic enolate to a carbonyl electrophile in an aldol fashion generated a second zwitterionic intermediate. Subsequent proton migration and release of the catalyst furnished the desired product. Although the Morita-Baylis-Hillman reaction was discovered in the late 1960’s, it was not until the early 1980’s when researchers began to study this reaction more thoroughly. Since then, the intermolecular Morita-Baylis-Hillman reaction has seen an exponential growth in terms of all three essential components and now encompasses a wide variety of activated alkenes, electrophiles and nucleophilic catalysts. However there has been significantly less research into the intramolecular Morita-Baylis-Hillman reaction. This, coupled with the fact that simple allylic electrophiles or unactivated alkyl halides have not been used as the electrophilic partner in this intriguing reaction, has influenced my research, which is aimed at extending the scope of the intramolecular Morita-Baylis-Hillman reaction with particular interest to using new electrophiles. Recently Krafft and Haxell reported a Morita-Baylis-Hillman reaction using allylic chlorides as the electrophilic partner. It occurred to us that a natural extension of this work was to explore the feasibility of the related cycloalkylation chemistry using sp3-hybridized electrophiles. We have successfully developed a novel, entirely organomediated, one-pot convenient method for the synthesis of cyclic enones through the use of an alternative electrophile in the Morita-Baylis-Hillman reaction. The method tolerates both alkyl- and aryl-enones with and without various substitution patterns on the tether to generate five- and six-membered rings in excellent yields. We have further expanded the method to proceed using only catalytic amounts of the tributylphosphine nucleophile with little to no reduction in yields. We have extended this reaction to include thioesters as viable activated alkenes providing the cyclized MBH adducts in good to excellent yields. We have further shown the thioester substrates to form the desired products when a catalytic amount of PBu3 is employed. Additionally, we have isolated for the first time a Morita-Baylis-Hillman intermediate exhibiting an unprecedented trans-geometry of the positively charged phosphorous and negatively charged oxygen. Our results suggested the interaction of the oxygen and phosphorous, which has been long understood to provide stabilization for the intermediate, is not a requirement for a successful MBH alkylation providing new insight into the Morita-Baylis-Hillman mechanism.
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