Date of Graduation

5-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

McIntosh, Matthias C.

Committee Member

Allison, Neil T.

Second Committee Member

Stites, Wesley E.

Third Committee Member

Durham, Bill

Keywords

Breslow; [1; 3]-rearrangement; [3; 3]-rearrangement

Abstract

The formation of carbon-carbon bonds in organic chemistry is fundamentally important. One of the major reactions that chemists have widely investigated is the Claisen rearrangement. Based on the fundamental features of this rearrangement, chemists exploited the capability of the transformation and invented their own variations of Claisen-type rearrangements. Our goal in this project is to develop a novel variation of the Claisen rearrangement using azole compounds, which are common heteroaromatic ring systems that are present extensively in the biomedically important natural products. We propose here novel methodologies of preparing 2-substitution azole derivatives using aza-based Claisen rearrangement, N,X-ketene acetals that requires only weak base, possesses broad functional group compatibility, and require no cryogens.

Our strategy employs a Claisen [3,3]-rearrangement of the so-called Breslow intermediate to prepare 2-butenyl benzothiazoles. The precursor N-allyl-N,X-ketene acetals were prepared in situ from the reaction of N-allyl azolium salts with aromatic aldehydes. The details of the approach and the rearrangement results are presented in Chapter 1.

Another novel methodology we discovered to prepare 2-substituted azole derivatives is using radical fragmentation of the Breslow intermediate, which is unprecedented. Preparation of [1,3]-rearrangement products via radical reaction pathways offers possibilities to prepare complex chiral azoles that are not readily accessible via polar methods. It also provides significant information about potential decomposi-tion pathways for Breslow intermediates in N-heterocyclic carbene catalyzed reactions. These investiga-tions are the subject of Chapter 2.

Thiamine (vitamin B1) is an essential human nutrient. In 1970, Oka found that the reaction of thiamine with benzaldehyde afforded the fragmentation products thiazolyl phenyl ketone and 2,5-dimethyl pyrimidin-4-amine along with a small amount of [1,3]-rearrangement product. Kluger proposed that the decomposition of thiamine occurred via the Breslow intermediate in a polar process. We hypothesize that the fragmentation reaction is a radical process. A discussion on this matter is presented in chapter 3.

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