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Development of new Fluorination Methods Directed to Fluorine-18 Labelling
Stockholm University, Faculty of Science, Department of Organic Chemistry.ORCID iD: 0000-0003-4299-8860
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the development of new fluorination reactions and their application to fluorine-18 labelling. Fluorine-18 labelled compounds are employed as tracers in Positron Emission Tomography (PET), which is a powerful non-invasive imaging method in medical diagnostics.

The first part of this thesis focuses on the development of a late-stage halogen exchange-based fluorination method for the synthesis of trifluoromethylated molecules. The first project in this area relies on the application of a copper(I)-based fluorinating reagent to furnish trifluoroacetates, trifluorotoluenes and trifluoroacetamides. The second project involves the translation of this methodology into the fluorine-18 labelling of tertiary and secondary trifluoroacetamides. The targeted substrates were labelled in high radiochemical yield and high molar activity using [18F]Bu4NF as fluorine source in the presence of an organic activator.

In the second part, the development of electrophilic fluorination reactions using a hypervalent iodine-based reagent is discussed. The first project in this area addresses the development of an electrophilic fluorine-18 fluorination reagent: [18F]fluoro-benziodoxole. The utility of this reagent was demonstrated in the labelling of [18F]fluoro-benzoxazepines. In the second project, the same [18F]fluoro-benziodoxole reagent was used in the rhodium-mediated synthesis of α-[18F]fluoroethers. High molar activities were obtained in these electrophilic labelling processes. In the third project, the fluorine-19 analog fluoro-benziodoxole was used in the palladium-catalyzed iodofluorination of allyl benzenes, styrenes and cycloalkenes. Both iodine and fluorine atoms in the product arise from the same reagent.

Place, publisher, year, edition, pages
Sockholm: Department of Organic Chemistry, Stockholm University , 2019. , p. 73
Keywords [en]
fluorine, fluorine-18, late-stage, labelling, nucleophilic, electrophilic, fluorination, positron emision tomography, PET, hypervalent iodine, benziodoxole, metal-free, DBU, copper, palladium, rhodium, carbene
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-175601ISBN: 978-91-7797-919-7 (print)ISBN: 978-91-7797-920-3 (electronic)OAI: oai:DiVA.org:su-175601DiVA, id: diva2:1368043
Public defence
2020-01-20, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 15:00 (English)
Opponent
Supervisors
Available from: 2019-12-16 Created: 2019-11-05 Last updated: 2019-11-27Bibliographically approved
List of papers
1. Synthesis of trifluoromethyl moieties by late-stage copper (I) mediated nucleophilic fluorination
Open this publication in new window or tab >>Synthesis of trifluoromethyl moieties by late-stage copper (I) mediated nucleophilic fluorination
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2017 (English)In: Journal of fluorine chemistry, ISSN 0022-1139, E-ISSN 1873-3328, Vol. 194, p. 51-57Article in journal (Refereed) Published
Abstract [en]

The nucleophilic fluorination of bromodifluoromethyl derivatives mediated by the complex (PPh3)(3)CuF is described. Under the reaction conditions, different trifluoroacetates, trifluorolcetones, trifluoroarenes and trifluoroacetamides were obtained in good yields.

Keywords
Nucleophilic fluorination, Copper, Trifluoroacetate, Trifluoromethylarene, Trifluoroacetamide
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-141365 (URN)10.1016/j.jfluchem.2016.12.017 (DOI)000393938200007 ()
Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2019-12-16Bibliographically approved
2. Efficient DBU accelerated synthesis of F-18-labelled trifluoroacetamides
Open this publication in new window or tab >>Efficient DBU accelerated synthesis of F-18-labelled trifluoroacetamides
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2016 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, no 97, p. 13963-13966Article in journal (Refereed) Published
Abstract [en]

Nucleophilic F-18-fluorination of bromodifluoromethyl derivatives was performed using [F-18] Bu4NF in the presence of DBU(1,8-diazabicyclo[5.4.0]undec-7-ene). This novel procedure provided a diverse set of [F-18] trifluoroacetamides in good to excellent radiochemical conversions. A mechanism where DBU acts as organomediator in this transformation is proposed.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-139349 (URN)10.1039/c6cc08535k (DOI)000390436700005 ()27844069 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2017-02-07 Created: 2017-02-06 Last updated: 2019-12-16Bibliographically approved
3. [F-18]fluoro-benziodoxole: a no-carrier-added electrophilic fluorinating reagent. Rapid, simple radiosynthesis, purification and application for fluorine-18 labelling
Open this publication in new window or tab >>[F-18]fluoro-benziodoxole: a no-carrier-added electrophilic fluorinating reagent. Rapid, simple radiosynthesis, purification and application for fluorine-18 labelling
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2018 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 54, no 34, p. 4286-4289Article in journal (Refereed) Published
Abstract [en]

Operationally simple radiosynthesis and purification of [F-18]fluoro-benziodoxole was developed starting from a cyclotron produced [F-18]F- precursor, [F-18]TBAF, and tosyl-benziodoxole. The synthetic utility of [F-18]fluoro-benziodoxole was demonstrated by electrophilic fluorocyclization of o-styrilamides proceeding with high RCC (typically 50-90%) and high molar activity (up to 396 GBq mol(-1)).

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-156663 (URN)10.1039/c8cc00526e (DOI)000430935200013 ()29632936 (PubMedID)
Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2019-12-02Bibliographically approved
4. Rhodium-mediated 18F-oxyfluorination ofdiazoketones using a fluorine-18-containing hypervalent iodine reagent
Open this publication in new window or tab >>Rhodium-mediated 18F-oxyfluorination ofdiazoketones using a fluorine-18-containing hypervalent iodine reagent
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2019 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 55, no 89, p. 13358-13361Article in journal (Refereed) Published
Abstract [en]

Geminal 18F-oxyfluorination of diazoketones was performed in the presence of rhodium mediators. The reactions were performed using a hypervalent iodine-based [18F]fluoro-benziodoxole reagent. By this methodology various α-[18F]fluoro ethers were obtained in high radiochemical yield (up to 98%) and molar activity (216 GBq μmol-1).

Keywords
fluorine-18, electrophilic, hypervalent iodine, PET, rhodium, diazo compound
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-175600 (URN)10.1039/c9cc06905d (DOI)000496175900002 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation, 2018.0066
Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2019-12-09Bibliographically approved
5. Palladium-Catalyzed lodofluorination of Alkenes Using Fluorolodoxole Reagent
Open this publication in new window or tab >>Palladium-Catalyzed lodofluorination of Alkenes Using Fluorolodoxole Reagent
2016 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 6, no 1, p. 447-450Article in journal (Refereed) Published
Abstract [en]

The application of an air- and moisture-stable fluoroiodane reagent was investigated in the palladium-catalyzed iodofluorination reaction of alkenes. Both the iodo and fluoro substituents arise from the fluoroiodane reagent. In the case of certain palladium catalysts, the alkene substrates undergo allylic rearrangement prior to the iodofluorination process. The reaction is faster for electron-rich alkenes than for electron-deficient ones.

Keywords
fluorination, hypervalent iodines, iodofluorination, palladium catalysis, alkenes, difunctionalization
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-126379 (URN)10.1021/acscatal.5b02022 (DOI)000367706800049 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2016-02-12 Created: 2016-02-01 Last updated: 2019-12-16Bibliographically approved

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