Fluorinating Reagent Research Articles

Reaction evolution of a solvate fluoride ionic liquid induced fluorination process probed by Raman spectroscopy

Currently, about 30% of new approved drugs contained fluorine atoms and most of them are made through fluorination reactions using various kinds of fluorinating reagents. In the current work, we report a facile and more accessible way to probe the fluorination evolution at different stages using a newly developed fluorinating reagent (1-ethyl-3-methylimmidazolium fluoride-ethylene glycol, [C 2 C 1 im]F-EG). Benzyl bromide was converted to benzyl fluoride using this fluorinating reagent under mild conditions. A more accessible Raman method, compared to NMR, was used to probe the reaction process due to the products having their own characteristic Raman vibrational frequencies because of the formation of different C-X bonds. Thus the yield of the product at different time scales could be then quantified based on their relative intensities, providing a fresh insight into the fluorination process. This method could be applied in other reactions to reflect the important fluorination process, which methodologically reports a facile way to probe reaction processes. • A fluoride solvate ionic liquid was used as fluorinating reagent in a fluorination reaction. • Raman spectroscopy was exclusively used to quantitatively determine the reaction products. • The reaction rate was mainly reduced logarithmically with time. • Increasing complexing molecules, ethylene glycol, in the reagent can reduce the rate greatly.

Benzoyl Fluorides as Fluorination Reagents: Reconstruction of Acyl Fluorides via Reversible Acyl C–F Bond Cleavage/Formation in Palladium Catalysis

This report describes the formation of value-added acyl fluorides by means of palladium-catalyzed acyl-exchange reactions between acyl fluorides and acid anhydrides. This method allows using a simp...

Recent Advances in Electrochemical Systems for Selective Fluorination of Organic Compounds.

Organofluorine compounds are key materials applied in daily life because of their versatile utility as functional materials, pharmaceuticals, and agrochemicals. Development of the selective fluorination of organic molecules under safe conditions is therefore one of the most important subjects in modern synthetic organofluorine chemistry. Thus, various electrophilic fluorination reagents such as XeF2, (PhSO2)2NF (NFSI), Et2NSF3 (DAST), (MeOCH2CH2)2NSF3 (Deoxofluor), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-fluoropyridinium salts, and 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead) have been developed for chemical fluorination to date and the development of new fluorinating reagents is still ongoing. Electrochemical synthesis has recently attracted much attention from the perspective of green sustainable chemistry because no hazardous reagents are required and scale-up is generally easy. Although electrochemical perfluorination of organic compounds using a nickel anode in anhydrous HF has been well-established to manufacture perfluoro-functional materials, electrochemical partial fluorination (selective electrochemical fluorination) has been underdeveloped due to the low nucleophilicity of fluoride ions and anode passivation, which interferes with electrolysis. Selective electrochemical fluorination can be commonly achieved in aprotic solvents containing fluoride ions to provide mostly mono- and difluorinated products. Electrolysis is conducted at constant potentials slightly higher than the first oxidation potential of a substrate. Constant current electrolysis is also effective for selective fluorination in many cases. Choice of the combination of a supporting fluoride salt and an electrolytic solvent is most important to accomplish efficient selective fluorination. In this Account, we focus on our recent work on the electrochemical mono- and difluorination of various organic compounds and their synthetic application. We first briefly explain our research background of electrochemical fluorination. Main factors such as the effects of fluoride salts as supporting electrolytes, electrolytic solvents, and anode materials on the selectivity and efficiency of fluorination are discussed. Next, effects of PEG oligomer additives enhancing the nucleophilicity of fluoride ions and organic solvent-free systems using poly(HF) salt ionic liquids as well as recyclable mediatory systems for electrochemical fluorination are described. The desulfurizative monofluorination of xanthate and gem-difluorination of benzothioate and dithioacetals are briefly mentioned. Regioselective anodic fluorination of various heterocyclic compounds having a phenylthio group as electroauxiliary and heterocycles containing sulfur and other heteroatoms are also described. In addition, a boryl group is shown to be a good leaving group for anodic fluorination. Moreover, electrochemically α,α-difluorinated phenylsulfides and phenylselenides are illustrated to be useful for photochemical C-H difluoromethylation of aromatic and heteroaromatic compounds. Finally, this Account also highlights highly diastereoselective fluorination of aliphatic heterocyclic and open-chain compounds, as well as new electrolytic fluorination methods using inorganic fluoride salts such as KF and CsF.

Synthesis of Highly Substituted Fluoro Chromenones in a “One‐Pot Four‐ Component Strategy” Using NFSI as a Fluorinating Reagent

AbstractAn efficient one pot four component strategy has been developed for the synthesis of highly substituted fluoro chromenone derivatives (5 a‐p) in good yields from β‐aryl thio acetanilide, aldehydes, cyclic 1,3‐diketones and NFSI (N‐Fluorobenzenesulfonimide) in presence of water. The fluoro imino chromenone intermediate 6 is isolated under the inert condition in high yield.

One-bond 1 J(15 N─19 F) spin-spin coupling constants of cationic fluorinating reagents: Insights from DFT calculations.

We have investigated, by means of density functional theory protocols, the one-bond 1 J(15 N─19 F) spin-spin coupling constants in a series of fluorinating reagents, containing the N─F bond, recently studied experimentally. The results of the calculations show a very good linear relationship with the experimental values, even though only the M06-2X(PCM)/pcJ-2//B3LYP/6-311G(d,p) level affords a very low mean absolute error. The calculations allow to analyze the various molecular orbitals contributions to the J coupling and to rationalize the observed positive sign, corresponding to a negative sign of the reduced spin-pin coupling constant K(N─F). Moreover, of the four Ramsey contributions, only the diamagnetic spin orbit is negligible, whereas the paramagnetic spin orbit and spin dipole terms decrease the magnitude of the Fermi contact (FC) term by an amount that goes from a minimum of 35% up to more than 60% of the FC term itself. Several effects have been investigated, namely, the contribution of the long-range solvent reaction field, relativistic corrections, and conformational and vibrational effects.

Open-Shell Fluorination of Alkyl Bromides: Unexpected Selectivity in a Silyl Radical-Mediated Chain Process.

We disclose a novel radical strategy for the fluorination of alkyl bromides via the merger of silyl radical-mediated halogen-atom abstraction and benzophenone photosensitization. Selectivity for halogen-atom abstraction from alkyl bromides is observed in the presence of an electrophilic fluorinating reagent containing a weak N-F bond despite the predicted favorability for Si-F bond formation. To probe this surprising selectivity, preliminary mechanistic and computational studies were conducted, revealing that a radical chain mechanism is operative in which kinetic selectivity for Si-Br abstraction dominates due to a combination of polar effects and halogen-atom polarizability in the transition state. This transition-metal-free fluorination protocol tolerates a broad range of functional groups, including alcohols, ketones, and aldehydes, which demonstrates the complementary nature of this strategy to existing fluorination technologies. This system has been extended to the generation of gem-difluorinated motifs which are commonly found in medicinal agents and agrochemicals.

Direct electrophilic fluorination of naproxen with NF-reagents

A novel effective protocol has been developed for direct fluorination of naproxen using the electrophilic fluorinating reagents 1-chloromethy1-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, F-TEDA-BF4) and N-fluorobenzenesulfonimide (NFSI) in MeCN and H2O solvents with the formation of 2-(5-fluoro-6-methoxynaphthalen-2-yl)propionic and 2-(5,5-difluoro-6-oxo-5,6-dihydronaphthalen-2-yl)propionic acids. The reaction of naproxen with an excess of Selectfluor (mol. ratio NF-reagent/naproxen = 2.2) in MeOH gives methyl 2-(5,5-difluoro-6,6-dimethoxy-5,6-dihydronaphthalen-2-yl)propionate as the main product. The mechanistic aspects of the reactions and X-ray data of products are discussed.

Direct and Regioselective Monofluorination of N-Protected Pyridone Derivatives using N-Fluorobenzenesulfonimide (NFSI).

The direct monofluorination of N-protected pyridone derivatives has been developed using a stable electrophilic fluorinating reagent, N-fluorobenzenesulfonimide (NFSI). Interestingly, the fluorine atom is regioselectively introduced at the position opposite the carbonyl group in the pyridone substrate during the reaction. This method is applicable to a wide range of substrates and allows the regioselective late-stage monofluorination of pyridone scaffolds.

Photoluminescence investigation of sol-gel glass-ceramic materials containing SrF2:Eu3+ nanocrystals

In the present paper, the nanocrystalline transparent oxyfluoride SrF2:Eu3+ glass-ceramic materials (nGCs) were synthesized via a low-temperature sol-gel method, in which trifluoroacetic acid (TFA) was used as a fluorination reagent. The thermal degradation of precursor xerogels was examined by TG/DSC analysis and the formation of SrF2 nanocrystals inside silicate xerogel host was proved by XRD measurements. Additionally, to verify the structural changes within silicate network during ceramization process, the IR-ATR measurements were also carried out. The optical properties of Eu3+ ions in precursor xerogels and fabricated nGCs were investigated based on photoluminescence excitation (PLE: λem = 611 nm) and emission (PL: λexc = 393 nm) spectra as well as luminescence decay analysis of the 5D0 excited level. It was observed, that for precursor silica xerogels the electric-dipole transition (ED) 5D0 → 7F2 was dominant, meanwhile the magnetic-dipole transition (MD) 5D0 → 7F1 had the greatest intensity for SrF2:Eu3+ nGCs. Thus, the R/O-ratio (R/O = I(5D0 → 7F2)/I(5D0 → 7F1)) was calculated to estimate the symmetry in the local framework around Eu3+ ions. Moreover, the reddish-orange photoluminescence is long-lived (about 30-fold longer) for SrF2:Eu3+ nGCs compared with xerogels. The changes in emission spectra as well as double-exponential character of luminescence decay curves recorded for obtained nGCs indicated the successful migration of optically active Eu3+ ions from amorphous silica framework to low phonon energy SrF2 nanocrystal phase.

The Fluorination of C-H Bonds: Developments and Perspectives.

This Review summarizes advances in fluorination by C(sp2 )-H and C(sp3 )-H activation. Transition-metal-catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp2 ) and C(sp3 ) sites, exploiting the reactivity of high-oxidation-state transition-metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp3 )-H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition-metal-catalyzed processes as they allow for undirected C(sp3 )-H fluorination. To date, radical C-H fluorinations mainly employ electrophilic N-F fluorination reagents but a unique MnIII -catalyzed oxidative C-H fluorination using fluoride has been developed. Overall, the field of late-stage nucleophilic C-H fluorination has progressed much more slowly, a state of play explaining why C-H 18 F-fluorination is still in its infancy.

Thermal Atomic Layer Etching of Al2O3, HfO2, and ZrO2 Using Sequential Hydrogen Fluoride and Dimethylaluminum Chloride Exposures

Atomic layer etching (ALE) of Al2O3, HfO2, and ZrO2 was accomplished using sequential exposures with hydrogen fluoride (HF) as the fluorination reagent and dimethylaluminum chloride (DMAC, AlCl(CH3...

Benzylic C[sbnd]H fluorination over supported silver catalyst

Benzylic CH fluorination is the straightforward method for the synthesis of fluoromethylarenes, which are utilized as oxygen mimics in molecules such as nucleotides, phosphate esters and sulfate esters. We reveal that silver particles supported on a metal oxide act as an efficient catalyst for the benzylic CH fluorination of 4-methylbiphenyl with 1-fluoro-4-methyl-1,3-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor II) as a fluorinating reagent to give 4-(fluoromethyl)-1,1′-biphenyl, whereas silver oxides resulted in aromatic fluorination. Among the catalysts tested, Ag/SiO2 exhibited the highest activity for fluorination to give the fluorinated product in 75% yield. This system was applicable to larger-scale fluorination. Mechanistic studies revealed that the present fluorination likely involves single electron transfer (SET) processes between Ag particles and 4-methylbiphenyl to afford radical species.

Approach for Producing New 3,3,3-Trifluoropropenylation Reagents: Introduction of a 3,3,3-Trifluoroprop-1-enyl Group for Drug Development

The chemistry of the 3,3,3-trifluoroprop-1-enyl (TFPE) group has attractive characteristics in medicinal chemistry as a new fluorine motif. However, there are no reports on the properties of this group because it is difficult to construct molecules with it. For the convenient construction of the TFPE group, a new fluorination reagent, CF3CH=CHTMS (1), was developed from commercially available chemicals with easy purification processes and excellent yields. The utility of 1 as a trifluoropropenylation reagent was exhibited in several types of reaction such as the Sonogashira cross-coupling reaction. Furthermore an indometacin analogue bearing a TFPE group showed greater pharmaceutical activity than the original indometacin. This review describes the details of these research studies under three topics: 1) synthesis of 1; 2) Sonogashira cross-coupling reaction of 1 with acetylene, followed by cyclization into an indole ring; and 3) synthesis of an indometacin analogue with a TFPE group.

Cover Feature: Decarboxylative Fluorination of 2‐Pyridylacetates (Chem. Eur. J. 31/2019)

Under catalyst-free conditions, decarboxylative fluorination of lithium 2-pyridylacetates easily occurs. An electrophilic fluorinating reagent dramatically accelerates the decarboxylation of lithium 2-pyridylacetates; this phenomenom has led to a one-pot transformation of methyl 2-pyridylacetates to 2-(fluoroalkyl)pyridines via intermediate lithium 2-pyridylacetates. The method has also been applied to the syntheses of 2-(difluoroalkyl)pyridines. More information can be found in the Communication by K. Shibatomi, et al. on page 7453.

Ligand‐Promoted Iron(III)‐Catalyzed Hydrofluorination of Alkenes

AbstractAn iron‐catalyzed hydrofluorination of unactivated alkenes has been developed. The use of a multidentate ligand and the fluorination reagent N‐fluorobenzenesulfonimide (NFSI) proved to be critical for this reaction, which afforded various fluorinated compounds in up to 94 % yield.

Ligand-Promoted Iron(III)-Catalyzed Hydrofluorination of Alkenes.

An iron-catalyzed hydrofluorination of unactivated alkenes has been developed. The use of a multidentate ligand and the fluorination reagent N-fluorobenzenesulfonimide (NFSI) proved to be critical for this reaction, which afforded various fluorinated compounds in up to 94 % yield.

Synthesis of 6-(Fluoromethyl)-19-norcholest-5(10)-en-3-ol, a Fluorinated Analogue of NP-59, using the Mild Fluorinating Reagent, TBAF(Pinacol)2

For 45 years, efforts to prepare a fluorinated analogue of the scintiscanning/SPECT agent 6-(iodomethyl)-19-norcholest-5(10)-en-3-ol (NP-59) for development of a PET imaging agent have failed due to undesired elimination reactions and unexpected rearrangements observed­ while utilizing a wide variety of fluorinating conditions (e.g., cesium­ fluoride, silver fluoride, (2-chloro-1,1,2-trifluoroethyl)diethylamine (FAR), diethylaminosulfur trifluoride (DAST), and hexa­fluoro­propene diethylamine FPA). Herein, we report the full synthesis of NP-59, followed by the four-step synthesis of 6-(fluoromethyl)-19-norcholest-5(10)-en-3-ol (FNP-59) using a recently developed mild fluorinating reagent, less prone to producing elimination reactions in the preparation of primary fluorides, TBAF(pinacol)2, with an overall yield of 16% (four steps). Also included is an evaluation of the TBAF(pinacol)2 reagent on eight test substrates to investigate its scope.

Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-Fluoroamines.

Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable β-fluoroamines in high yields and enantioselectivities. This methodology employs a chiral N-ethyl bis-urea catalyst that brings solid KF into solution as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.

Fluorination of benzene with disubstituted N-fluoropyridinium salts in acetonitrile solution: a DFT study

In this work, fluorination activities of disubstituted N-fluoropyridinium salts on the substrate of benzene in acetonitrile solution have been investigated by density functional theory. At SMD-B3LYP/6-311G(d,p) level, geometry optimizations and frequency calculations of the reactants, transition states and products were carried out in 16 fluorination reaction channels. A high level of SMD-M06-2x/6-311++G(d,p) was used to correct the single-point energy of the stationary points based on the optimized structure. On the basis of 2-nitro-substituted N-fluoropyridinium salt, nitro, cyano, chloro, methoxy groups were substituted, respectively, at 3-,4-,5-,6-position on pyridine ring to further clarify the influence of substituents and substitution sites on fluorination activity. According to the obtained potential energy surface information and substituent effect analysis, the fluorination channel of 2,6-dinitro-substituted N-fluoropyridinium salt is the most effective because of the lowest reaction energy barrier; as a result among the 16 studied N-fluoropyridinium salts, 2,6-dinitro-substituted N-fluoropyridinium salt is the most promising fluorinating reagent.

Making the SF5 Group More Accessible: A Gas-Reagent-Free Approach to Aryl Tetrafluoro-λ6 -sulfanyl Chlorides.

Modern pentafluorosulfanyl (SF5 ) chemistry has an Achilles heel: synthetic accessibility. Herein, we present the first approach to aryl-SF4 Cl compounds (key intermediates in state-of-the-art aryl-SF5 synthesis) that overcomes the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl2 ) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride, and catalytic amounts of acid. These simple, mild conditions allow direct access to aryl-SF4 Cl intermediates that either have not been or cannot be demonstrated using previous methods. Furthermore, the same approach provides access to aryl-SF3 and aryl-SeF3 compounds, which extend the applications of this chemistry beyond arene SF5 -functionalization, and demonstrate its ability to address a more general oxidative fluorination problem.