Date of Graduation

12-2015

Document Type

Thesis

Degree Name

Bachelor of Science

Degree Level

Undergraduate

Department

Chemistry & Biochemistry

Advisor

McIntosh, Matthias

Reader

Ganio, Matthew

Second Reader

Hershberger. Margaret

Abstract

Purpose: The growing amount of clinical resistance observed in current antifungal drugs and in anti-HIV pharmaceuticals is a concern in the medical community. The purpose of this study is to develop a mild synthetic process for biomedically relevant thiazolyl aryl ketones that can be used to develop antifungal and anti-HIV drugs. We hypothesized that the proposed synthetic technique would be more efficient, produce fewer unwanted byproducts, and be more tolerant of functional groups than existing methods.

Methods: Prior to each of the ketone reactions, the necessary salt was synthesized by mixing thiazole and 9-bromofluorene neat in a reaction tube heated to 85 °C. The reaction was monitored for the disappearance of 9-bromofluorene, at which point the heating was stopped and the solid product was triturated to remove impurities and characterized using 1H NMR analysis. For each of the various ketone reactions, the aldehyde and base were added to a reaction tube and heated to 60 °C. Once heated, a solution of the salt (3-fluorenylthiazole) was mixed with the solvent, either methanol or THF, and was added dropwise via syringe. Conversion of the aldehyde to the ketone product was monitored by thin layer chromatography (TLC). The product ketone was purified using column chromatography and analyzed for purity by 1H NMR spectroscopy. This study was the repeated for each of the chosen aldehydes. The preparation of thiazolyl salicyl ketone was further analyzed for solvent effects by the introduction of 5% and 10% water, respectively, using otherwise identical reaction conditions. In these reactions, the ketone was isolated using preparative TLC and gravity filtration to separate the silica gel from the desired product. If the ketone was produced after the addition of water, then the reaction may be able to be conducted without the use of anhydrous methanol solvent. Instead, methanol bought in bulk could be substituted and the cost of production would be substantially reduced.

Results: The 3-fluorenylthiazol salt was produced in 91% yield. The yields for the thiazolyl phenyl ketone, thiazolyl 4-fluorophenyl ketone, and the thiazolyl salicyl ketone were 11%, 50%, and 55% yield respectively. Production of thiazolyl salicyl ketone with the addition of 5% water into the solvent produced the ketone with 11% yield. Production of thiazolyl salicyl ketone with the addition of 10% water into the solvent produced a ketone with 13% yield in trial 1 and 56% yield in trial 2.

Discussion: The study found that the two-step synthesis method was successful in producing the desired ketones. These findings suggest that this reaction mechanism could be further optimized to increase reaction yield in order to produce medicinally relevant ketones under mild conditions. Also, upon the addition of water to the solvent, the thiazolyl salicyl ketone was able to be produced in moderate yields in one trial. In this particular trial, salt and salicylaldehyde were added before the solvent and the base suggesting the order that reagents were added affected the percent yield of the ketone. The success of the trial provides promising results that suggest the synthetic method could be conducted without the use of anhydrous methanol thereby decreasing the cost of synthesis by utilizing water in replacement for methanol. Also, substituting water for methanol would provide a safety advantage if enough methanol is replaced so that the solvent is no longer flammable. Overall, the results provide the conclusion that the synthetic technique could be used to produce thiazolyl aryl ketones under mild conditions.

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