Iodonium Salt Precursors Research Articles

Diaryliodonium Salt-Based Synthesis of N-Alkoxyindolines and Further Insights into the Ishikawa Indole Synthesis.

A diaryliodonium salt-based strategy enabled the first systematic synthesis of rarely accessible N-alkoxyindolines. Mechanistic analyses suggested that the reaction likely involves reductive elimination of iodobenzene from iodaoxazepine via a four-membered transition state, followed by Meisenheimer rearrangement. Substrates with N-carbamate protection afforded indole in a manner similar to that of the Ishikawa indole synthesis. Preinstallation of a stannyl group as an iodonium salt precursor greatly expanded the substrate scope, and further mechanistic insights are discussed.

Selective synthesis of L-2-[18 F]fluoro-alpha-methylphenylalanine via copper-mediated 18 F-fluorination of (mesityl)(aryl)iodonium salt.

L-2-[18 F]fluoro-alpha-methylphenylalanine (2-[18 F]FAMP) is a promising amino acid tracer for positron emission tomography (PET) imaging, yet the low production yield of direct electrophilic radiofluorination with [18 F]F2 necessitates further optimization of the radiolabeling process. This paper describes a two-step preparation method for L-2-[18 F]fluoro-alpha-methylphenylalanine (2-[18 F]FAMP) starting from [18 F]fluoride. The (Mesityl)(L-alpha-methylphenylalanine)-2-iodonium tetrafluoroborate precursors with various protecting groups were prepared. The copper-mediated 18 F-fluorination of the iodonium salt precursors successfully produced 2-[18 F]FAMP. The highest radio chemical conversion of 57.6% was noted with N-Piv-protected (mesityl)(aryl)iodonium salt in the presence of 5 equivalent of Cu (OTf)2 . Subsequent deprotection with 57% hydrogen iodide produced 2-[18 F]FAMP within 120 min in 21.4 ± 11.7% overall radiochemical yield with >95% radiochemical purity and an enantiomeric excess >99%. The obtained 2-[18 F]FAMP showed comparable biodistribution profiles in normal mice with that of the carrier-added 2-[18 F]FAMP. These results indicate that usefulness of copper mediated 18 F-fluorination for the production of 2-[18 F]FAMP, which would facilitate clinical translation of the promising tumor specific amino acid tracer. Individual facilities could adopt either production method based on radioactivity demand and equipment availability.

Improved synthesis of 4-[18 F]fluoro-m-hydroxyphenethylguanidine using an iodonium ylide precursor.

Fluorine-18 labeled hydroxyphenethylguanidines were recently developed in our laboratory as a new class of PET radiopharmaceuticals for quantifying regional cardiac sympathetic nerve density in heart disease patients. Studies of 4-[18 F]fluoro-m-hydroxyphenethylguanidine ([18 F]4F-MHPG) and 3-[18 F]fluoro-p-hydroxyphenethylguanidine ([18 F]3F-PHPG) in human subjects have shown that these radiotracers can be used to generate high-resolution maps of regional sympathetic nerve density using the Patlak graphical method. Previously, these compounds were synthesized using iodonium salt precursors, which provided sufficient radiochemical yields for on-site clinical PET studies. However, we were interested in exploring new methods that could offer significantly higher radiochemical yields. Spirocyclic iodonium ylide precursors have recently been established as an attractive new approach to radiofluorination of electron-rich aromatic compounds, offering several advantages over iodonium salt precursors. The goal of this study was to prepare a spirocyclic iodonium ylide precursor for synthesizing [18 F]4F-MHPG and evaluate its efficacy in production of this radiopharmaceutical. Under optimized automated reaction conditions, the iodonium ylide precursor provided radiochemical yields averaging 7.8% ± 1.4% (n = 8, EOS, not decay corrected), around threefold higher than those achieved previously using an iodonium salt precursor. With further optimization and scale-up, this approach could potentially support commercial distribution of [18 F]4F-MHPG to PET centers without on-site radiochemistry facilities.

2-[18F]Fluorophenylalanine: Synthesis by Nucleophilic 18F-Fluorination and Preliminary Biological Evaluation

2-[18F]Fluorophenylalanine (2-[18F]FPhe), a promising PET tracer for imaging of cerebral infarction and tumors, was efficiently prepared from an easily accessible iodonium salt precursor using Cu-mediated radiofluorination under ‘low base’ or ‘minimalist’ conditions. Whereas significant racemization was initially observed if the ‘minimalist’ protocol was applied for radiolabeling, it was completely suppressed by the careful adjustment of 18F– preprocessing. The initial biological study revealed a higher uptake of 2-[18F]FPhe in different tumor cells in comparison to that of [18F]FET. In contrast to 4-[18F]FPhe, which suffered from rapid defluorination in vivo, 2-[18F]FPhe demonstrated a sufficient in vivo stability. Conclusively, 2-[18F]FPhe is a promising PET probe that is now readily available using Cu-mediated radiofluorination under ‘minimalist’ or ‘low base’ conditions. The simplicity of the translation of the proposed procedures to automated synthesis modules allows a broad biological evaluation of 2-[18F]FPhe. Notably, a novel protocol for the preparation of N-Boc protected amino acids from the respective Ni-Schiff base complexes was developed that avoided application of strongly acidic conditions.

Base/Cryptand/Metal‐Free Automated Nucleophilic Radiofluorination of [18F]FDOPA from Iodonium Salts: Importance of Hydrogen Carbonate Counterion

As evidenced by the number of publications and patents published in the last years, the radiosynthesis of 6‐[18F]fluoro‐3,4‐dihydroxy‐L‐phenylalanine ([18F]FDOPA) using the nucleophilic [18F]F‐ process remains currently a challenge for the radiochemists scientific community even if promising methods for the radiofluorination of electron‐rich aromatic structures were recently developed from arylboronate, arylstannane or iodonium salt precursors. In such context, based on the use of an iodonium triflate salt precursor, we optimized a fast and efficient radiofluorination route fully automated and free from any base, cryptand or metal catalyst for the radiosynthesis of [18F]FDOPA. Using this method, this clinically relevant radiotracer was produced in 64 min, 27–38 % RCY d.c. (n = 5), >99 % RCP, >99 % ee., and high Am 170–230 GBq/µmol. In addition, this optimization study clearly highlighted the important role of a triflate‐hydrogen carbonate counterion exchange during the radiolabeling process to achieve high fluorine‐18 incorporation yields.

Radiolabeled (4-Fluoro-3-Iodobenzyl)Guanidine Improves Imaging and Targeted Radionuclide Therapy of Norepinephrine Transporter-Expressing Tumors.

18F- or 131I-labeled (4-fluoro-3-iodobenzyl)guanidine (FIBG) has been a promising yet unattainable derivative of radioiodine-labeled meta-iodobenzylguanidine (MIBG), because of the complex radiofluorination method. In this study, we proposed a 2-step radiosynthetic method to obtain 18F-FIBG and evaluated the diagnostic and therapeutic potential of 18F-FIBG and 131I-FIBG in a pheochromocytoma model (PC-12). Methods:18F-FIBG was prepared from a (mesityl)(aryl)iodonium salt precursor in the presence of a copper catalyst. Biodistribution studies, PET imaging, and a therapeutic study were performed on the PC-12 xenograft mice with either 18F- or 131I-FIBG. The association between the therapeutic effect and the tumor uptake of pretherapy 18F-FIBG PET was also evaluated. Results: The copper-mediated radiofluorination method readily yielded 18F-FIBG, as well as its regioisomer, 18F-IFBG. The isolated 18F-FIBG showed a higher accumulation in the PC-12 xenograft tumor than in any other tissue. The high tumor uptake of 18F-FIBG allowed clear tumor visualization in the PET images as early as 1 h after injection, with an excellent tumor-to-background ratio. A biodistribution study with 131I-FIBG revealed its higher and prolonged retention in the tumor in comparison with 125I-MIBG. As a result, a therapeutic dose of 131I-FIBG delayed tumor growth significantly more than did 131I-MIBG. The tumor uptake of 18F-FIBG was proportional to the therapeutic effect of 131I-FIBG. Conclusion: These results suggest the potential usefulness of FIBG as a diagnostic and therapeutic agent for the management of norepinephrine transporter (NET)-expressing tumors.

Solid‐Supported Iodonium Salts for Fluorinations

AbstractSolid‐supported iodonium salt precursors have been prepared and used for the production of fluoroarenes. The importance of the resin functionality for the attachment of the iodonium salt moieties has been demonstrated. Furthermore, the production of new iodonium salt precursors for fluorination has been achieved by an alternative and improved method with respect to those previously described. The successful radiofluorination of a simple solid‐supported precursor with no‐carrier‐added (n.c.a.) [18F]fluoride shows the suitability of the method for the production of useful PET synthons.

Syntheses of meta-[F]Fluorobenzaldehyde and meta-[F]Fluorobenzylbromide from Phenyl(3-Formylphenyl) Iodonium Salt Precursors.

(18)F-labeled fluorobenzaldehydes and fluorobenzylbromides are useful synthons for the preparation of PET radiopharmaceuticals. Whereas ortho- and para-[(18)F]fluorobenzaldehydes can easily be prepared with high yields, the corresponding meta- derivatives are more problematic. In order to improve the yield of meta-[(18)F]fluorobenzaldehyde we used the corresponding diaryliodonium salt precursors, since diaryliodonium salts had already been used as precursors in preparations of (18)F-labeled electron rich, as well as electron deficient, aromatic rings. Diaryliodonium salts with different counter ions [PhIPhCHO]X (X = Cl, Br, OTs, OTf) were synthesized. (18)F radiolabeling was performed using different bases at different temperatures in the presence of a radical scavenger, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO). The best conversion (~80%) to meta-[(18)F] fluorobenzaldehyde was obtained using CsHCO(3) base at a reaction temperature of 110 °C. To study iodonium salt counter ion effects on radiofluorination, each precursor was separately treated with CsF[(18)F]/CsHCO(3) in DMF at 110 °C for 5 min in the presence of TEMPO. Our observed reactivity order was OTs<Cl<OTf<Br. Meta-[(18)F]fluorobenzaldehyde thus obtained was reduced to the corresponding alcohol with aqueous NaBH(4) at room temperature and then converted to meta-[(18)F]fluorobenzylbromide using triphenylphosphine dibromide. Formation of meta-[(18)F]fluorobenzylbromide was confirmed by HPLC and the desired product was purified on a silica Sep-Pak(®) plus cartridge.

Synthesis of meta- [18F]fluoro-Donepezil and meta- [18F]fluoro-CP118,954 from Iodonium Salt Precursors as New PET Imaging Probes for AChE

Synthesis of meta- [18F]fluoro-Donepezil and meta- [18F]fluoro-CP118,954 from Iodonium Salt Precursors as New PET Imaging Probes for AChE

Recent Trends in the Nucleophilic [(18)F]-radiolabeling Method with No-carrier-added [(18)F]fluoride.

Noninvasive imaging in living subjects with positron emission tomography (PET) provides early detection of diseases in humans. For this application, it is necessary to prepare specific molecular imaging probes labeled with positron-emitting radioisotopes such as fluorine-18 for obtaining high-quality PET imaging. In this review, we describe recent trends in the F-18 radiolabeling method for the introduction of no-carrier-added fluorine-18, which was obtained from an (18)O(p,n)(18)F reaction, into a specific molecular site, which in turn is intended to serve as an imaging agent for PET study. These labeling protocols are based on ionic liquid media (18)F radiofluorination in the presence of some water, enzymatic (18)F fluorination using fluorinase in water solution, non-polar protic alcohol media (18)F radiofluorination and its mechanism, and nucleophilic (18)F fluorination of an aromatic iodonium salt precursor.

Potential-Directed Assembly of Aryl Iodonium Salts onto Silicon {100} Hydride Terminated and Platinum Surfaces

A novel electrograft method of forming covalent bonds directly to silicon hydride or platinum surfaces has been demonstrated with the use of iodonium salt precursors. Initially, a silicon substrate is treated with a dilute hydrofluoric acid wash to ensure a hydride-passivated surface, which is immersed in a solution of iodonium salt dissolved in a solution of tetrabutylammonium tetrafluoroborate in acetonitrile. Grafting is accomplished by applying a negative bias to the silicon substrate. Directed assembly has been demonstrated with Pt substrates.

Fragmentations of (E)- and (Z)- isomers of 2-methylbuten-1-yl(aryl)iodonium triflates: competing mechanisms for enol triflate formation

We examined fragmentation reactions of (E)- and (Z)-2-methylbuten-1-yl(aryl)iodonium triflates (aryl = C6H5-, 4-(CF3)C6H4, 3,5-(CF3)2C6H4-) to afford aryl idodides and six enol triflates. Four of these vinyl triflates involve alkyl migrations followed by triflate trapping of secondary vinyl cations whereas two do not involve migrations. Fragmentation rates in dry, neutral CDCl3 were determined as were the distributions of enol triflate products. The ratios of rate constants for the (E)-/(Z)- isomers ranged between 5.0 and 8.5 and, in all salts, the rearranged enol triflate derived from migration of the alkyl moiety trans- to the aryliodonio- nucleofuge was observed in the greatest quantities. These data indicate that the fragmentation rates are significantly determined by the migratory aptitude of the trans-β-alkyl substituent and departure of the aryliodonionucleofuge occurs by anchimeric assistance. The ratios of inverted “unrearranged” enol triflate products were greater for the (Z)-isomers of the iodonium salt precursors indicating that steric effects play a role and implies that these inverted, unrearranged products are derived from inplane (σ*) SN2 reaction. The presence of the remaining, retained, unrearranged enol triflate can be explained by a ligand coupling mechanism (π* SN2) and the fragmentation mechanism(s) do not require the intermediacy of a primary vinyl cation.