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Molecules 2015, 20(1), 470-486; doi:10.3390/molecules20010470

4-[18F]Fluorophenylpiperazines by Improved Hartwig-Buchwald N-Arylation of 4-[18F]fluoroiodobenzene, Formed via Hypervalent λ3-Iodane Precursors: Application to Build-Up of the Dopamine D4 Ligand [18F]FAUC 316

Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Jülich, 52425 Jülich, Germany
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Academic Editor: Derek J. McPhee
Received: 24 September 2014 / Accepted: 18 December 2014 / Published: 31 December 2014
(This article belongs to the Section Organic Synthesis)
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Abstract

Substituted phenylpiperazines are often neuropharmacologically active compounds and in many cases are essential pharmacophores of neuroligands for different receptors such as D2-like dopaminergic, serotoninergic and other receptors. Nucleophilic, no-carrier-added (n.c.a.) 18F-labelling of these ligands in an aromatic position is desirable for studying receptors with in vivo molecular imaging. 1-(4-[18F]Fluorophenyl)piperazine was synthesized in two reaction steps starting by 18F-labelling of a iodobenzene-iodonium precursor, followed by Pd-catalyzed N-arylation of the intermediate 4-[18F]fluoro-iodobenzene. Different palladium catalysts and solvents were tested with particular attention to the polar solvents dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Weak inorganic bases like potassium phosphate or cesium carbonate seem to be essential for the arylation step and lead to conversation rates above 70% in DMF which is comparable to those in typically used toluene. In DMSO even quantitative conversation was observed. Overall radiochemical yields of up to 40% and 60% in DMF and DMSO, respectively, were reached depending on the labelling yield of the first step. The fluorophenylpiperazine obtained was coupled in a third reaction step with 2-formyl-1H-indole-5-carbonitrile to yield the highly selective dopamine D4 ligand [18F]FAUC 316. View Full-Text
Keywords: fluorine-18; Hartwig-Buchwald N-arylation; dopamine D4 radioligand; iodophenyl-iodonium compounds; iodonium ylides fluorine-18; Hartwig-Buchwald N-arylation; dopamine D4 radioligand; iodophenyl-iodonium compounds; iodonium ylides
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kügler, F.; Ermert, J.; Kaufholz, P.; Coenen, H.H. 4-[18F]Fluorophenylpiperazines by Improved Hartwig-Buchwald N-Arylation of 4-[18F]fluoroiodobenzene, Formed via Hypervalent λ3-Iodane Precursors: Application to Build-Up of the Dopamine D4 Ligand [18F]FAUC 316. Molecules 2015, 20, 470-486.

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