[18F]fluorination/decarbonylation: New route to aryl [18F]fluorides

A new route to aryl [18F]fluorides without electron withdrawing ring substituents has been developed. [18F]Fluorobenzaldehydes, prepared from no-carrier-added (NCA) [18F]fluoride using nucleophilic aromatic substitution of fluoro or nitro groups, were decarbonylated using palladium on charcoal (Pd-C). By this approach 2-methoxy-4-nitrobenzaldehyde was converted to NCA 3-[18F]fluorophenol (25-30%, EOB) and 4-fluoro-2-methoxy-5-methylbenzaldehyde to carrier-added (CA) 3-[18F]fluoro-4-methylphenol (30-40%, EOB). Overall synthesis time was about 2 h. Since the 4-fluoro-2-methoxy-5-methylbenzaldehyde was in turn prepared by methylation and regiospecific formylation of 3-fluoro-4-methylphenol, the overall process represents use of a removable activating group for nucleophilic aromatic substitution with [18F]fluoride for preparation of CA and NCA aryl [18F]fluorides.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29665/1/0000754.pd

Synthesis of Substituted Dihydrobenzofurans via Tandem S_NAr/5-Exo-Trig Cyclization

A tandem S_NAr/5-exo-trig cyclization reaction is reported that converts N-alkyl- and -arylimines derived from o-fluorobenzaldehydes into 3-amino-2,3-dihydro-2,2-diarylbenzofurans in moderate to good yields. Diarylmethoxide coupling partners serve the dual role of nucleophile in the S_NAr step and catalytic base in the cyclization step. With a subset of the substrates, a further base-induced elimination of the 3-amino-2,3-dihydro-2,2-diarylbenzofuran to a phenolic enamine was observed

Fluorine-18 Labelled Building Blocks for PET Tracer Synthesis: Overview and Recent Advances in 18F-Trifluoromethylation

Orru, R.V.A. [Promotor]Windhorst, A.D. [Promotor]Vugts, D.J. [Copromotor]Herscheid, J.D.M. [Copromotor

Synthesis, characterization and antioxidant activity of prenylated and fluorine based flavonoids.

M. Sc. University of KwaZulu-Natal, Durban, 2013.Twenty flavonoids II-XXI were successfully synthesized using the Claisen-Schmidt condensation reaction between 2-hydroxy and 3-hydroxyacetophenone with various substituted fluorobenzaldehydes. The twenty flavonoids consisted of sixteen chalcones, eight of which were new novel prenyl chalcones (XIV-XXI), and four flavanones (X-XIII). The compounds were produced in yields of between 54-90%. It was shown in II-XIII that the rate of reaction is influenced electronically by the substitution patterns of the fluorine atom on the B-ring, in the order; 2',4'-difluoro > 2'-fluoro> 4'-fluoro > 3'-fluoro. All compounds were characterized by NMR, IR, UV and mass spectral analyses. Compounds II-IX bearing hydroxyl groups were subjected to antioxidant screening using the DPPH free radical scavenging assay. Antioxidant activities of these compounds were established as moderate to low in comparison to the standard, ascorbic acid. The difluoro compounds V and IX with fluorine on the ortho and para positions in the B-ring showed the highest activities, possibly due to both the position and number of fluorine atoms in the molecule

Synthesis, DNA binding studies of new pyrimidothiazepine and pyrimidobenzothiazepine derivatives

Several pyrimidothiazepine and pyrimidobenzothiazepine were synthesized starting from 6-chloro-1-methyluracil by the treatment with ethyl thioglycolate followed by the reaction with hydrazine hydrate which cyclized through refluxing with appropriate aromatic aldehydes or by the treatment with 2-aminothiophenol followed by refluxing with appropriate aromatic aldehydes respectively. The structure of newly synthesized compounds was confirmedby IR, 1H NMR, mass spectral data and elemental analysis. Further the novel derivatives were investigated for their binding and fragmentation of the nucleic acid DNA

Novel Strategies for Fluorine‐18 Radiochemistry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90272/1/1106_ftp.pd

Radiosynthesis of [18F]fluorophenyl-L-amino acids by isotopic exchange on carbonyl-activated precursors

ABSTRACT Aromatic [18F]fluoroamino acids have earlier been developed as promising probes for diagnostics using PET. However, a wider use of these radiofluorinated compounds has been limited due to radiosynthetic constraints. The work here presents an amenable three-step radiosynthesis pathway for the preparation of 2-[18F]fluoro-L-phenylalanine (2-[18F]Fphe), 2-[18F]fluoro-L-tyrosine (2-[18F]Ftyr), 6-[18F]fuoro-L-m-tyrosine (6-[18F]Fmtyr) and 6-[18F]fluoro-L-DOPA (6-[18F]FDOPA). For this, corresponding precursors were 18F-fluorinated by nucleophilic isotopic exchange, followed by either removal of an activating formyl group with Rh(PPh3)3Cl or its conversion by Baeyer-Villiger oxidation, respectively, and subsequent hydrolysis of protecting groups in acidic medium. Two efficient synthetic approaches were developed for the preparation of highly functionalized fluoro-benzaldehydes and -ketones which were used as labeling precursors. The compounds (2S,5S)-tert-butyl 2-tert-butyl-5-(2-fluoro-5-formylbenzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1a), (2S,5S)-tert-butyl 5-(5-acetyl-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1c), (2S,5S)-benzyl 2-tert-butyl-5-(2-fluoro-5-formylbenzyl)-3-methyl-4-oxoimidazolidine-1-carbo-xylate (1d), 4-fluoro-3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)me-thyl)benzal-dehyde (1e) and 1-(4-fluoro-3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)me-thyl)phenyl)ethanone (1f), could be prepared in six steps and overall yields of 41%, 48%, 37%, 27%, and 32%, respectively. (2S,5S)-tert-Butyl 5-(4-(benzyloxy)-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1b) was prepared in ten steps with an overall yield of 19% while compounds (2S,5S)-tert-butyl 5-(5-(3,5-bis(trifluoromethyl)-benzoyl)-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (1g) and (2S,5S)-tert-butyl 2-tert-butyl-5-(2-fluoro-5-(2,2,2-trifluoroacetyl)benzyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (1h) were synthesized by a novel three-step procedure in 54% and 40%, respectively. All compounds were obtained with high diasteromeric purity of > 99%. Corresponding precursors 1a, 1d, and 1e were used for the radiosynthesis of 2-[18F]Fphe while 1b was employed for 2-[18F]Ftyr making use of a decarbonylation reaction. The radiosyntheses were performed either under conventional or microwave heating. The conventional heated reactions yielded the desired products 2-[18F]Fphe and 2-[18F]Ftyr in 43% and 49% whereas 34% and 43% RCY, respectively, were obtained when microwave heating was applied. However, 38 min of total preparation time were saved with the latter method, thus providing similar amounts of product activity. The enantiomeric excess achieved for 2-[18F]Fphe was 88% while in the case of 2-[18F]Ftyr 92% was obtained. 6-[18F]Fmtyr was prepared from the Seebach-precursor 1c in 13% overall RCY with a high enantiomeric purity of > 93%. A comparable overall RCY of 11% of 6-[18F]Fmtyr was achieved with the Schöllkopf-precursor 1f while the enantiomeric purity in this case was only 87%. Precursors 1g and 1h showed a relative high RCY of the 18F-for-19F substitution, but a low one in the Baeyer-Villiger oxidation. Thus from 1g and 1h, 6-[18F]Fmtyr was obtained with an overall RCY of only 6% and 13%, respectively. However, the enantiomeric purity of the product using both precursors was > 98%. Based on earlier attempts the nucleophilic radiosynthesis of 6-[18F]FDOPA by isotopic exchange could also be optimized by changing many parameters from the previous work providing ca. 40% RCY and a high enantiomeric purity of > 96%. The specific activity of the tracers prepared here under developmental conditions was as high as that achieved by electrophilic methods. Furthermore, in preliminary studies it could be demonstrated that the automation of the three-step radiochemical synthesis developed here is principally feasible but requires further technical maturation

New Short Strategy for the Synthesis of the Dibenz[b,f]oxepin Scaffold

In this report a short and efficient synthesis of the dibenz[b,f]oxepin framework through intramolecular SNAr and McMurry reactions is described. The diaryl ethers required for the McMurry reaction have been obtained in good yields under microwave-assisted conditions of the reaction of salicylaldehydes with fluorobenzaldehydes without catalysts. Application of an intramolecular McMurry reaction to the synthesized diarylethers using TiCl4/Zn in THF gave the target dibenzo[b,f]oxepin system in 53%–55% yields

New synthetic methods for biologically active aromatic heterocycles

First part of this work details the use of phosphazene base P4–t–Bu mediated cyclodehydration towards the synthesis of heterocycles like 5,6–dihydroindolo[2,1–a]isoquinolines and 2,3–diarylbenzo[b]furans. This work also report the use of P4–t–Bu for the total syntheses of O–methylcryptaustoline iodide and amurensin H. Both total syntheses feature P4–t–Bu mediated cyclodehydration as the key steps towards the completion of the syntheses. The second part of this work is dedicated towards the synthetic efforts to develop pyrido[2,3–d]pyrimidines as effective abelson kinase inhibitors. We successfully identified compounds with comparable or higher kinase inhibitory activity than Imatinib. We also successfully developed compounds which are more aqueous soluble than PD173955, an issue which has limited its use as a drug. The third and final part of this work describes a novel and divergent methodology developed towards the syntheses of flavonoids like aurones, flavones and flavonols. This methodology describes the synthesis of a benzofuran derivative and a chromone intermediate which can be used to synthesis libraries of aurones and flavones in one step sequence respectively

Carbon–Fluorine Bond Formation

We present a selection of carbon–fluorine bond formations that have been developed in the recent past. An overview of the most common fluorination reagents is followed by fluorination reactions organized by reactivity. We have distinguished between nucleophilic and electrophilic fluorinations as well as aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for syntheses of pharmaceuticals, $^{18}$F-radiolabeling, and mechanistic investigations are provided.Chemistry and Chemical Biolog