Fluorinated cryptands

Partially fluorinated cryptands were synthesized from l,3-f>fs(bromomethyl)-2-fluorobenzene and diaza-18-crown-6 or benzodiaza-18-crown-6 in good yields these ligands formed very stable Ag(I) complexes <96CB1211>. 

The chemistry of crown ethers and cryptands has progressed a long way from then-status as chemical curiosities. Recently Metcalfe et al.U4) have outlined the development of a fluorinated cryptand as an agent for measuring intracellular [Na+]. 

Under carefully controlled conditions even complex molecules can be fluorinated. For example, the preparation of perfluoro-crown ethers (85CC1350) and perfluoro(2.2.2.)-cryptand (90JOC5933) has been described. Branched morpholines and piperazines have been directly fluorinated to their perfluoro analogues [90JFC(50)15],... 

Aromatic fluorine for halogen (F-X) exchange reactions (DMSO, 160°C, 20 min) in an [ F]fluoride-cryptand-oxalate system using 4 -halo-acetophe-nones (F, Cl, Br and I) has also been studied. The relative efficacy of the exchange is the following one F-F > F-Cl > F-Br > F-I, the radiochemical yield for the exchange F-F being similar to that of the commonly employed NO2 or +NMej displacements [113]. 

In the early days of fluorine-18-chemistry the low reactivity of p F]fluoride ion in aqueous solution constituted a major obstacle to the advance of nucleophilic radiofluorination with high specific radioactivity, a problem that would later be solved with the introduction of the cryptand Kryptofix-222 , giving the highly reactive K[ F]F-K222 complex (see Section 4.1) [3], For this reason active research for anhydrous reactive fluorine-18 labelling species continued. Scheme 1 reviews a number of these early reagents. 

While most reporter molecules have been designed to interact with cations, Plenio and Diodone [326] reported fluorine containing cryptands, which interact with perchlorate. London and Gabel [327] reported fluorobenzene boronic acid, which interacted with specific sugars. 

H. Plenio, R. Diodone, A fluorine-containing cryptand for the complexation of anions and the utility of F-19 Nmr-spectroscopy for the determination of host guest association, Z. Naturforsch. Section. B-. J. Chem. Sci. 50 (1995) 1075-1078. 

In order to illustrate this point, we report the opposite behavior of the ally and n -butyl anions in the substitution of an optically active fluorosilane, 1-NpPhMeSi—F. The first leads to inversion (91% IN) and the latter to retention (98% RN) (49), when the reactions with allyl- and n -butyllithium are carried out in the presence of a cryptand specific for lithium cation. The use of a cryptand makes it possible to study the difference in behavior of the anion species alone, since it avoids the possibility of electrophilic assistance by Li+ which could affect the apicophilicity of the fluorine atom. 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

The fluorination of haloethyl or alkanesulfonyloxyethyl aromatic compounds in conventional methods usually uses a naked fluoride ion generated from phase-transfer catalyst (i.e., potassium ion complexed by a cryptand, or a tetraalkylammonium salt) to... 

As a postscript to this story, we may add that, as a nucleophilic fluorinating agent, [i8F]-TBAFjyjj has been found to be significantly superior to cryptand-activated K F, which is the standard source in positron-emission tomography (PET). 

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