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Development of Stereospecific Nickel-Catalyzed Cross-Coupling and Reductive Cross-Electrophile Coupling Reactions

  • Author(s): Erickson, Lucas William
  • Advisor(s): Jarvo, Elizabeth R
  • et al.
Creative Commons Attribution 4.0 International Public License
Abstract

In recent years, the Jarvo lab has developed the field of stereospecific nickel-catalyzed cross-coupling reactions of benzylic electrophiles. This chemistry allows for straightforward synthesis of asymmetric C–C bonds. The focus of this dissertation is on the study of the mechanism of these transformations, and the development of reductive cross-electrophile coupling reactions.

First, the mechanism of the nickel-catalyzed Kumada cross-coupling reaction was studied via a 13C kinetic isotope effect experiment. This experiment indicated that oxidative addition of the nickel catalyst into the C–O σ bond was the rate limiting step. Combining this data with a rate law allowed us to propose a catalytic cycle for this reaction. Additionally, the nickel-catalyzed deoxygenation of benzylic ethers was optimized for the formation of diaryl methanes. Deoxygenation performed best with a proton-rich Grignard reagent. We demonstrated that these Grignard reagents act as the hydride source for the reduction reaction.

Next, an intramolecular nickel-catalyzed reductive cross-electrophile coupling reaction of benzylic ethers and alkyl chlorides was developed. This reaction proceeds with a variety of extended aromatic and heteroaromatic groups to produce cyclopropane rings in great yields and diastereoselectivity. This is the first example of a stereospecific reductive cross-electrophile coupling reaction, as well as the first to employ alkyl ethers and alkyl halides as the electrophiles

Finally, the work on nickel-catalyzed reductive cross-electrophile coupling reactions was expanded to synthesize vinylcyclopropanes from allylic ethers and alkyl halides. This reaction occurs with both alkyl fluorides and alkyl chlorides. To the best of our knowledge, this is the first reported cross-electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds with high stereospecificity, providing selective synthesis of either diastereomer of di- and tri-substituted cyclopropanes. The utility of this methodology is demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl cyclopropanes.

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