Presently, the world depends on a wide variety of new materials based on organofluorine compounds. These compounds can be used as surfactants, high resistance polymers, liquid crystals, ...agrochemicals, radiopharmaceuticals for positron emission tomography, and drugs. However, the selective formation of C–F bonds remains a challenge. This study reviews our knowledge of organofluorine compounds and describes conventional and modern selective fluorination methods for obtaining these compounds. Here, we highlight the most common fluorination reagents and describe the fluorination reactions. This review is organized by the type of fluorine transfer: nucleophilic, electrophilic, and enzymatic
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•Nucleophilic fluorodebromination using a copper (I) fluoride complex.•Trifluoroacetates, trifluoroacetamides and electron poor trifluormethyl arenes obtained in high yields.•Good ...functional group tolerance.
The nucleophilic fluorination of bromodifluoromethyl derivatives mediated by the complex (PPh3)3CuF is described. Under the reaction conditions, different trifluoroacetates, trifluoroketones, trifluoroarenes and trifluoroacetamides were obtained in good yields.
Nonpolar protic reaction media such as
t-amyl alcohol allow the aliphatic, nucleophilic fluorination reaction of primary haloalkane systems to fluoroalkanes, using tetrabutylammonium fluoride (TBAF), ...to proceed chemo-selectively at a reasonable reaction rate under mild conditions to afford the fluoro-product in high yield. As an example, the nucleophilic fluorination of 2-(3-iodopropoxy)naphthalene (
1a) as the primary haloalkane model compound, with TBAF in acetonitrile as a polar aprotic solvent, CsF in
t-amyl alcohol as a nonpolar protic solvent, and TBAF in
t-amyl alcohol for 1
h provided 2-(3-fluoropropoxy)naphthalene (
2a) in 38, 5, and 76% yields, respectively.
Nonpolar protic reaction media such as
t-amyl alcohol allow the aliphatic, nucleophilic fluorination reaction of primary haloalkane systems to fluoroalkanes, using tetrabutylammonium fluoride (TBAF), to proceed chemo-selectively at a reasonable reaction rate under mild conditions to afford the fluoro-product in high yield. As an example, the nucleophilic fluorination of 2-(3-iodopropoxy)naphthalene (
1a) as the primary haloalkane model compound, with TBAF in acetonitrile as a polar aprotic solvent, CsF in
t-amyl alcohol as a nonpolar protic solvent, and TBAF in
t-amyl alcohol for 1
h provided 2-(3-fluoropropoxy)naphthalene (
2a) in 38, 5, and 76% yields, respectively.
Two methods of nucleophilic fluorination to prepare α-fluoroacetophenones from α-bromoacetophenones by using KF with PEG-400 or TBAF with ZnF
2 are described. On the fundamental of nucleophilic ...fluorination, a novel method of one-pot fluorination to prepare α-fluoroacetophenones directly from acetophenones in DES was developed.
Two methods of nucleophilic fluorination to prepare α-fluoroacetophenones from α-bromoacetophenones by using KF with PEG-400 or TBAF with ZnF
2 are described. On the fundamental of nucleophilic fluorination, a novel method of one-pot fluorination to prepare α-fluoroacetophenones directly from acetophenones in DES was developed.
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•Mechanism is studied for SN2 fluorination using CsF promoted by tri-tert-butanolamines.•The role of OH groups in the promotor is to coordinate the nucleophile F− as Lewis acid.•The ...metal salt MF (M=Cs,K) reacts as a contact ion pair.•t-butanol solvent molecules bind to the counter-cation Cs+ to improve the reaction yield by reducing the electrostatic influence of Cs+ on F−.
Quantum chemical study is carried out to elucidate the mechanism of SN2 fluorination using CsF promoted by tri-tert-butanolamines. Focus is on the role of the hydroxyl (OH) and the amine functional groups for accelerating the reaction. Our systematic analysis indicates that the OH groups form strong interactions with the nucleophile F−. Thus, it seems that hydrogen bonding with the nucleophile may accelerate the SN2 processes rather than retard them, as conventional wisdom suggests. The origin of the experimentally observed improvement of the promotor efficiency in t-butanol solvent over that in CH3CN is examined. We show that the coordination of the solvent t-butanol molecule as Lewis base on the counter-cation Cs+ lowers the Gibbs free energy of activation.
Norepinephrine modulates cognitive processes such as working and episodic memory. Pathological changes in norepinephrine and norepinephrine transporter (NET) function and degeneration of the locus ...coeruleus produce irreversible impairments within the whole norepinephrine system, disrupting cognitive processes. Monitoring these changes could enhance diagnostic accuracy and support development of novel therapeutic components for several neurodegenerative diseases. Thus, we aimed to develop a straightforward nucleophilic fluorination method with high molar activity for the novel NET radiotracer
FNS12137 and to demonstrate the ability of
FNS12137 to quantify changes in NET expression.
We applied an
F-radiolabeling method in which a brominated precursor was debrominated by nucleophilic
F-fluorination in dimethyl sulfoxide. Radiolabeling was followed by a deprotection step, purification, and formulation of the radiotracer
The
FNS12137 brain uptake and distribution were studied with
PET/CT and
autoradiography using both adult and immature Sprague-Dawley rats because postnatal NET expression peaks at 10-20 days post birth. The NET specificity for the tracer was demonstrated by pretreatment of the animals with nisoxetine, which is well-known to have a high affinity for NET.
FNS12137 was successfully synthesized with radiochemical yields of 18.6±5.6%, radiochemical purity of >99%, and molar activity of >500 GBq/μmol at the end of synthesis. The
FNS12137 uptake showed peak standard uptake values (SUV) of over 1.5 (adult) and 2.2 (immature) in the different brain regions. Peak SUV/30 min and peak SUV/60 min ratios were calculated for the different brain regions of the adult and immature rats, with a peak SUV/60 min ratio of more than 4.5 in the striatum of adult rats. As expected,
studies demonstrated uptake of the tracer in brain areas rich in NET, particularly thalamus, neocortex, and striatum, and remarkably also in the locus coeruleus, a quite small volume for imaging with PET. The uptake was significantly higher in immature rats compared to the adult animals.
studies using autoradiography showed very strong specific binding in NET-rich areas such as the locus coeruleus and the bed nucleus of the stria terminalis, and high binding in larger grey matter areas such as the neocortex and striatum. The uptake of
FNS12137 was dramatically reduced both
and
by pretreatment with nisoxetine, demonstrating the specificity of binding.
FNS12137 was synthesized in good yield and high molar activity and demonstrated the characteristics of a good radiotracer, such as good brain penetration, fast washout, and high specific binding to NET.
One of the challenges in positron emission tomography (PET) is labelling complex aliphatic molecules.
This study aimed to develop a method of metal-catalysed radiofluorination that is site-selective ...and works in moderate to good yields under facile conditions.
Herein, we report on the optimisation of an aliphatic C-H to C-
F bond transformation catalysed by a Mn(porphyrin) complex.
The successful oxidation of 11 aliphatic molecules, including progesterone, is reported. Radiochemical Incorporations (RCIs) up to 69% were achieved within 60 min without the need for pre-activation or special equipment.
The method features mild conditions (60 °C) and promises to constitute a valuable approach to labelling of biomolecules and drug substances.
Interest in synthesis of fluorinated aminophosphonates has grown significantly in recent years due to their promising applications in medicinal and bioorganic chemistry. We report herein efficient ...and general methods for the synthesis of α- and β-monofluorinated aminophosphonates. Series of β-fluoro aminophosphonates were prepared in nucleophilic DAST-mediated fluorination of α-hydroxyphosphonates. The Horner-Wadsworth-Emmons reaction between carbonyl compounds containing an amino group and lithiated tetraethyl fluoromethylenediphosphonate was used in the synthesis of α-fluorinated-γ-aminophosphonates. Futhermore, this protocol was efficiently applied in the synthesis of dipeptide analogues α-fluorinated-γ-aminophosphonates.
The diethyl ester of 18FML-10 is a small molecule apoptotic PET probe for cancer studies. Here we report a novel multi-step synthesis of the diethyl ester of ML-10 in excellent yields via ...fluorination using Xtal-Fluor-E. In addition, a one-pot radiosynthesis of the diethyl ester of 18FML-10 from nucleophilic 18Ffluoride was completed in 23% radiochemical yield (decay corrected). The radiochemical purity of the product was ⩾99%. The diethyl ester of 18FML-10 was used in vivo to detect apoptosis in the testes of mice. In parallel studies, the dansyl-ML-10 diethyl ester was prepared and used to detect apoptotic cells in an in vitro cell based assay.
Polymer-immobilized fluorinase for the synthesis of 5′-fluoro-5′-deoxyadenosine (FDA) from S-adenosyl-l-methionine (SAM) and fluoride ion in aqueous media is described. The optimal composition of the ...poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) and the heterogeneous catalytic reaction conditions are developed to yield FDA in 45% within 150min. In PET radiochemistry, using 18Ffluoride ion in 18OH2O obtained from the cyclotron, 18FFDA was synthesized in 68% fluorination efficiency. The immobilized fluorinase is recycled for up to four runs with catalytic activity of the immobilized fluorinase enzyme remains at 80%.
•Polymer-immobilized fluorinase was suggested as catalyst for (radio)fluorination.•Optimal polymer composition and reaction conditions are established.•SAM was fluorinated with 19FF−/18FF− ions with 45% and 68% yields, correspondingly.•Recyclability of polymer-supported enzyme was proven and TON was found to be 4.
Polymer-immobilized fluorinase for the synthesis of 5′-fluoro-5′-deoxyadenosine (FDA) from S-adenosyl-l-methionine (SAM) and fluoride ion in aqueous media is described. The optimal composition of the poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) and the heterogeneous catalytic reaction conditions were developed to yield FDA in 49% within 150min. In PET radiochemistry, using 18Ffluoride ion in 18OH2O obtained from the cyclotron, 18FFDA was synthesized with 68% fluorination efficiency. The immobilized fluorinase was recycled for up to four runs with 80% of catalytic activity in the final cycle.
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