C-H Insertion of Trifluoroacetate as a Model for Trifluoromethanesulfonate. A Precursor for 18F Labeling of Biomolecules Pubblico
Machost, Haleigh (Spring 2019)
Abstract
As more compounds are developed to address medical issues, methods of tracking their movement through the body are needed in order to further understand how they function within biological systems. One of the ways of tracking medicinally relevant compounds as they move through the body is positron emission tomography (PET). As certain isotopes undergo radioactive decay, they release a positron which can be detected using PET. Thus, by tracking positron emission of molecules labeled with radioactive elements through PET, the location of medical compounds in the body can be determined. 18F is a radioactive isotope which undergoes β+ decay to produce a positron in addition to 18O and a neutrino, meaning it has great potential for radioactive labeling in PET. In an effort to capitalize on the mapping potential of compounds tagged with 18F, this project investigated possible ways of synthesizing molecular precursors to 18F insertion. Primarily, new methods of directly replacing a C-H bond with a trifluoroacetate substituent group were attempted. In theory, the trifluoroacetate group would serve as a model for the introduction of trifluoromethanesulfonate, a much stronger leaving group known to be replaceable by F-. Unlike trifluoromethanesulfonate, trifluoroacetate is capable of surviving purification by silica, enabling easier purification and characterization. As such, the success of exploratory methods of the direct replacement of a C-H bond by a C-trifluoroacetate bond is easier to determine. Once a system capable C-H functionalization to form a trifluoroacetate is developed, similar conditions will be attempted in order to introduce trifluoromethanesulfonate, a known precursor for the insertion of 18F for PET.
Table of Contents
1. Introduction………………………….............…………………………………………………..1
2. Results and Discussion…………………………………………….............……………....….7
2.1. Carboxyl Directing Group……………………………………………………….……………..7
2.1.1. Remote Hydroxylation via Pt(II)/Pt(IV)………………………………..…....……..7
2.2. Attempted Direct Addition of Trifluoroacetate………………………….......…………..12
2.2.1. Palladium(II) Acetate……………………………………………………….……....…..12
2.2.2. Thallium(III) Trifluoroacetate…………………………………………………….…...15
2.3. (Quinoline-8-yl)amide Directing Group……………………………………………...….…17
2.3.1. Palladium(II) Acetate……………………………………………………………....…...18
2.3.2. Thallium(III) Trifluoroacetate…………………………………………………….…...20
2.4. Hexanoic Acid Trial……………………………………………………….......................….21
3. Conclusion and Future Directions………..............…………………………………….……23
4. Experimental……………………………………………….…………………..............…..…….23
4.1. Setup Towards Remote Hydroxylation…………………….…………………………....…..24
4.2. General Procedure for Palladium(II) Acetate Reactions…………….………..…..........24
4.3. General Procedure for Thallium(III) Trifluoroacetate Reactions …........................25
4.4. Synthesis of QA Functionalized Compound……………………….………………........…25
5. References……..............……………………………………………….…………………….….…26
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