Applications of iodonium salts and iodonium ylides as precursors for nucleophilic fluorination in Positron Emission Tomography

This review summarizes the applications of iodonium compounds in the rapidly developing field of Positron Emission Tomography (PET). Reactions of diaryliodonium salts with fluoride anion have found wide practical application in PET as a fast and convenient method for the introduction of the radioactive [ 18 F]-fluoride into radiotracer molecules. The best synthetic methods for the preparation of iodonium precursors for PET are described, the mechanistic aspects of nucleophilic fluorination reaction are discussed, and specific examples of the preparation of PET radioligands are provided.


Introduction
In recent years, compounds of polyvalent iodine ( 3 -and  5 -iodanes) have emerged as versatile and environmentally benign reagents for various synthetically useful chemical transformations. 1- 10Aryliodonium salts represent an important class of  3 -iodanes, particularly useful as reagents for arylation of various nucleophiles. 11,12Previously we have published a review in Arkivoc summarizing the preparation and synthetic applications of aryliodonium salts. 12The most important and synthetically useful reactions of diaryliodonium salts, Ar2IX, include the following: the direct electrophilic arylations of various nucleophiles, the transition metal mediated cross-coupling reactions, and reactions involving the generation and trapping of the benzyne intermediates.Particularly important are the reactions of diaryliodonium salts with fluoride anion, allowing efficient introduction of fluorine into an aromatic ring via aromatic nucleophilic substitution.In recent years, nucleophilic fluorination reactions of diaryliodonium salts have found wide practical application in Positron Emission Tomography (PET) as a fast and convenient method for the introduction of the radioactive [ 18 F]-fluoride into radiotracer molecules.
The purpose of the present review is to summarize the applications of iodonium compounds in the rapidly developing field of Positron Emission Tomography.In particular, the best synthetic methods for the preparation of iodonium precursors for PET will be overviewed, the mechanistic aspects of nucleophilic fluorination reactions will be discussed, and specific examples of the preparation of PET radioligands will be provided.The literature coverage is through May 2013.

Overview of PET and Radiofluorination Methods
9][20][21] PET experiments provide direct information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue.Unlike X-ray analysis, magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. 18][25][26] Fluorine-18 is the most widely used radionuclide in PET because of its favorable physical and nuclear characteristics, such as, a short but manageable half-life (t1/2 = 109.7 min), which allows sufficient time for multistep synthetic labeling reactions, and a short positron linear range in tissue (2.3 mm) which gives the highest resolution PET images of all the available positron emitters. 18luorine-18 is generally produced with a cyclotron, either as molecular fluorine gas or as [ 18 F]-fluoride.Any application of fluorine-18 in PET demands rapid and efficient chemical transformation to introduce the fluorine-18 into the tracer of interest.[ 18 F]-Fluoride anion is the preferred precursor because it can be produced in higher specific activity than molecular [ 18 F]fluorine gas.There are two common pathways for the 18 F-labelling of an aromatic ring.Electrophilic 18 F-fluorination leads only to carrier-added products because of the unavoidable addition of elemental fluorine to the target gas.The second pathway, via nucleophilic displacement of adequate leaving groups (e.g., NO2 or + NMe3), which are activated by electronwithdrawing substituents, by no-carrier-added (NCA) [ 18 F]-fluoride, is generally used for the fluorination of electron-deficient arenes.
Nucleophilic 18 F-anion is produced with a cyclotron by the nuclear reaction from enriched [ 18 O]-water. 18F-anion from the target is then trapped on an ion-exchange column, and the trapped 18 F -is then eluted from the ion-exchange resin using potassium carbonate in a water/acetonitile solution.The obtained aqueous fluoride is a poor nucleophile because of its high degree of solvation.The addition of the phase-transfer reagent Kryptofix-222 (K222; see structure 1 in Scheme 1), followed by the removal of water is usually required in order to improve the reactivity of the [ 18 F]fluoride ion for nucleophilic substitution reactions.
[ 18 F]FDG 3 is produced routinely by some 130 PET centers worldwide and is the most frequently applied radiotracer in PET. 28,29It has been shown to be a multi-purpose radiopharmaceutical with applications in a variety of diagnostic questions in neurology, oncology and cardiology.The production of [ 18 F]FDG is now fully automated, and the synthesis of [ 18 F]FDG can now be achieved in approximately 30 minutes with radiochemical yields greater than 70%. 181][32][33][34] Direct nucleophilic substitution with 18 F-anion provides a convenient one-step pathway to a wide range of labeled aromatic compounds provided that the aromatic ring is suitably activated by an electron-withdrawing group (e.g.CHO, COMe, COOMe, NO2, CN, etc.) on the ortho or para positions to the leaving group.Common leaving groups used in nucleophilic 18 F-fluorination reactions include nitro, trialkylamine, halogen, mesylate, tosylate, or triflate. 18Nitrobenzene derivatives are currently the most widely used precursors in the preparation of simple [ 18 F]fluoroaromatic compounds.However, the fluorination methods based on direct nucleophilic substitution in these aromatic precursors are not always suitable for the synthesis of the 18 F-labeled target compounds because of the harsh reaction conditions (high reaction temperatures and polar organic solvents).Moreover, these methods are reliant on the use of activated aryl groups, which limits the range of available [ 18 F]fluoroaromatic compounds to those rings which have electron-withdrawing substituents.The use of iodonium salts as precursors in nucleophilic 18 F-substitution reactions is an extremely useful alternative for the synthesis of a range of simple [ 18 F]fluoroaromatic compounds in good radiochemical yields and in short reaction times that would be otherwise unobtainable by traditional methods.
The first use of iodonium salts as a general route for the no-carrier-added (NCA) synthesis of unactivated [ 18 F]fluoroaromatic compounds with high specific activity was reported by Pike and Aigbirhio in 1995, 35 and since then the radiofluorination of diaryliodonium salts has attracted significant interest as valuable methodology for late stage introduction of fluorine into diverse aromatic substrates.The methodology introduced by Pike and Aigbirhio complements the other approaches based on nucleophilic aromatic substitution by providing a means to fluorinate electron-rich, as well as problematic electron-poor aromatic rings not easily accessed by direct substitution. 35,36

Iodonium Salts as Reagents for Nucleophilic Fluorination
Currently, aryliodonium derivatives are becoming increasingly popular reagents in PET for the efficient introduction of [ 18 F]-fluoride due to their exceptionally high reactivity in aromatic nucleophilic substitution reactions.Reactions of diaryliodonium salts with the cyclotronproduced [ 18 F]-potassium fluoride in the presence of a phase-transfer reagent Kryptofix-222 provide a fast and convenient method of [ 18 F]-fluorination as outlined in Scheme 2. The high reactivity of diaryliodonium salts Ar2IX in these reactions is explained by the "hyperleaving group ability" of the ArI group; for example, the leaving group ability of PhI is about million times greater than that of the triflate group. 37Scheme 2. General scheme of nucleophilic [ 18 F]-fluorination with iodonium salts.
Diaryliodonium salts represent the most stable and well-investigated class of organoidodine(III) compounds.The first example of these compounds, (4iodophenyl)phenyliodonium bisulfate, was prepared by Hartmann and Meyer in 1894 from iodosylbenzene and sulfuric acid. 38Diaryliodonium salts Ar2IX are air-and moisture-stable compounds, the physical properties of which are strongly affected by the nature of the anionic part X -of the molecule.In particular, diaryliodonium salts with halide anions are generally sparingly soluble in many organic solvents, whereas triflate and tetrafluoroborate salts have a better solubility.The chemistry of aryl-and heteroaryliodonium salts has been extensively covered in several reviews. 11,12,391 Synthesis of diaryliodonium and aryl(heteroaryl)iodonium salts for PET A summary of synthetic approaches to iodonium salts has been provided in our previous review.12 General synthetic routes to diaryliodonium salts typically involve the initial oxidation of an aryl iodide to a  3 -iodane, ArIX2, and then ligand exchange of ArIX2 with an arene or a nucleophilic arylating reagent (e.g., arylborates, arylstannanes, or arylsilanes) to obtain the diaryliodonium salt.In many cases a final anion exchange step is necessary.40 However, the precursors to PET ligands with functional substitution groups are usually not sufficiently stable under these reaction conditions.Therefore, a mild, reliable, and practical synthetic route is required for the preparation of iodonium salts that are used as PET precursors.
An optimized, convenient procedure for the regioselective synthesis of functionalized diaryliodonium tosylates consists of the generation of a [hydroxy(tosyloxy)iodo]arene from a functionalized (diacetoxyiodo)arene and TsOH•H2O in situ followed by treatment with an electron-rich arene, such as anisole or thiophene, or with a functionalized arylstannane.This method provides expedient regiospecific access to a wide range of functionally diverse diaryliodonium tosylates in moderate to high yields (44−98%). 44 specific example of the application of this approach to the preparation of iodonium precursors 10 in the synthesis of mGluR5 PET radioligands is shown in Scheme 4. 45 The tributylstannylarenes 9 can be obtained in 39-57% yield by treating the respective iodoarenes with Sn2Bu6 in the presence of catalytic Pd(PPh3)4 in toluene at 115 o C. All prepared diaryliodonium salts 10 are stable for at least 12 months when stored at 4-5 o C, in the dark and under argon.45 Scheme 4. Preparation of iodonium precursors in the synthesis of mGluR5 PET radioligands.

Scheme 5. Preparation of aryl(thienyl)iodonium salts for PET.
A similar procedure can be used for the synthesis of aryl(heteroaryl)iodonium salts.For example, aryl(thienyl)iodonium tosylates 12 have been prepared by treatment of tributylstannylarenes 11 with the respective [hydroxyl(tosyloxy)iodo]thiophenes (Scheme 5). 46ryl(thienyl)iodonium tosylates 12 have been utilized as precursors in the synthesis of 2-aryl-6-[ 18 F]fluorobenzothiazoles, which can be used as PET radioligands for -amyloid plaques. 46he same synthetic route has been employed for the preparation of aryl-and thienyl-derived iodonium tosylates 13 (Scheme 6). 47Aromatic radiofluorination of the iodonium tosylate precursors 13 with [ 18 F]fluoride ions has been applied successfully to access [ 18 F]flumazenil, which is an important radiopharmaceutical product for the assessment of the central benzodiazepine receptor (cBZR) concentration in the brain. 47heme 6. Preparation of iodonium tosylate precursors to [ 18 F]flumazenil.
Phenyl(3-formylphenyl)iodonium PET precursors have been conveniently synthesized by the reaction of 3-formylphenylboronic acid with an organoiodine(III) intermediate generated in situ from iodobenzene and m-chloroperoxybenzoic acid (Scheme 7). 48The initially formed phenyl(3formylphenyl)iodonium triflate 14 can be further converted into the respective chloride or bromide salts 15 by treatment with aqueous NaCl or hydrobromic acid in methanol.

Mechanism of nucleophilic substitution reactions of iodonium salts
Several general mechanistic studies on the reactions of diaryliodonium salts with nucleophiles have been published.Ochiai and co-workers performed a mechanistic study on the phenylation of -keto ester enolates with diaryliodonium salts.The addition of an aryl radical trap to the reaction did not affect the outcome, which indicates that radical pathways are unlikely and the reaction occurs by direct coupling of the ligands on the hypervalent iodine center. 49It has been found that in the reaction of unsymmetric diaryliodonium salts 16 with nucleophiles, the most electron-deficient aryl group is transferred to the nucleophile with varying selectivities in agreement with the mechanism outlined in Scheme 8.The initial ligand exchange affords the hypervalent intermediates 17 and 18, in which with the electronegative ligand Nu occupies an axial position in agreement with general principles of hypervalent bonding.Fast pseudorotation occurs between intermediates 17 and 18, which leads to two different transition states 19 and 20. 50,51Of the two possible transition states for the subsequent ligand coupling, the transition state 20 is more favorable than 19, because both the negative charge on the aromatic ring and the enhanced positive charge on the iodine(III) are stabilized more effectively by the substituents. 49heme 8. General mechanistic scheme for the reactions of diaryliodonium salts with nucleophiles.
The so-called "ortho-effect" is observed in the reactions between a nucleophile and a diaryliodonium salt where one aryl ligand has a bulky ortho-substituent, such as methyl.In these reactions the ortho-substituted aryl ligand is often coupled with the nucleophile, even if it is a more electron-rich aromatic ring. 52,53This has been explained by the predominant conformation 21 of the Ar(Ph)INu intermediate with the most bulky aryl ligand and the two lone pairs occupying the equatorial position for steric reasons since the equatorial positions are roomier than the axial positions (Scheme 9).Ligand coupling in the intermediate 21 leads to a reductive elimination of PhI and transfer of the nucleophile to the ortho-substituted aryl group situated in the equatorial position, even though it is the more electron-rich aromatic ring.Scheme 9. Explanation of enhanced reactivity of ortho-substituted aryl ligands.
5][56] DiMagno and co-workers have carried out advanced NMR studies of the interaction of diaryliodonium salts with anhydrous tetramethylammonium fluoride. 55These reactions involve the initial anion exchange with the formation of diaryliodonium fluorides, Ar2IF, followed by ligand coupling as outlined in Scheme 8.It has been found that the selectivity of nucleophilic fluorination and yields of products can be improved by changing reaction conditions. 55In particular, the use of low polarity aromatic solvents (benzene or toluene) and/or the removal of inorganic salts, result in dramatically increased yields of fluorinated arenes from diaryliodonium salts. 55t was also found that diaryliodonium salts undergo rapid, fluoride-promoted aryl exchange reactions at room temperature in acetonitrile. 54This exchange is highly sensitive to the concentration of fluoride ion in solution; the fastest exchange is observed as the fluoride concentration approaches a stoichiometric amount at 50 mM substrate concentration.It was demonstrated that free fluoride ion or a four-coordinate anionic I(III) species may be responsible for the exchange. 54The fluoride-promoted aryl exchange reaction is general and allows direct measurement of the relative stabilities of diaryliodonium salts featuring different aryl substituents.
Lee, Pike, and co-workers have studied the conformational structure and energetics of 2methylphenyl(2'-methoxyphenyl)iodonium chloride. 56X-ray structural analysis revealed that this diaryliodonium salt has a conformational dimeric structure with hypervalent iodine as a stereogenic center in each conformer.The LC-MS spectra of this iodonium chloride showed the presence of dimeric and tetrameric anion-bridged clusters in organic solution.These observations of the dimeric and higher order clusters of iodonium salts in solution are important for general understanding of the mechanism and outcome of reactions of diaryliodonium salts in organic media with nucleophiles, such as the [ 18 F]fluoride ion. 56

Selectivity of nucleophilic fluorination
The regioselectivity of the [ 18 F]-fluorination reaction is especially important in the reactions of nonsymmetrical iodonium salts (Scheme 10).The distribution of the fluorine-18 containing products depends on the stereoelectronic properties of substituents in the benzene ring; in general, the presence of electron-withdrawing substituents in the aromatic ring is favorable for the introduction of the fluoride nucleophile (see previous section for mechanistic discussion).The problem of low selectivity of the [ 18 F]-fluorinations in principle can be solved by modification of electronic and steric properties of substituents R 1 and R 2 and by optimizing the reaction conditions.Scheme 10.Nucleophilic [ 18 F]-fluorination of nonsymmetrical iodonium salts.
The synthesis of aryl fluorides by thermal decomposition of diaryliodonium tetrafluoroborates was first reported by Van der Puy in 1982. 57It was found that reactions of diphenyliodonium salts, Ph2I + X -, with different anions (X = BF4, CF3CO2, TsO, Cl) upon heating with KF in DMF afford fluorobenzene in 11-85% yield.The lowest yield of fluorobenzene (11%) was observed in the reaction of diphenyliodonium chloride with KF in DMF at 115 o C, while the thermolysis of Ph2I + BF4 -in the presence of KF at 160-170 o C without solvent gave PhF in 85% yield.The formation of benzene (2-9%) due to a parallel radical decomposition process was also observed in all these reactions. 57n 1995 Pike and Aigbirhio applied diaryliodonium salts for the preparation of 18 F-labeled aryl fluorides for the first time, using potassium [ 18 F]-fluoride in the presence of diazacrown ether Kryptofix (K2.2.2; structure 1 in Scheme 1) in acetonitrile at 85 o C or 110 o C. 35 Under these conditions, the reaction of diphenyliodonium chloride provided [ 18 F]-fluorobenzene in 31-78% radiochemical yield.The use of Kryptofix is required for the phase transfer of the [ 18 F]-fluoride ion obtained by the nuclear reaction in the cyclotron as a solution in water enriched with oxygen-18.
Further investigations have shown that the regioselectivity of [ 18 F]-fluorination is controlled by electronic factors and by the bulk of the ortho-substituents on the rings, with the latter being the dominant factor.Pike and co-workers have reported a detailed study of the reactions of several ortho-substituted iodonium salts with [ 18 F]-fluoride in acetonitrile at 85 o C. 58 It was found that the electronic effects of substituents on aromatic rings in radiochemical nucleophilic fluorination processing are similar to the reactions of iodonium salts with other nucleophiles, and fluorine-18 is introduced to the aromatic ring containing electron-withdrawing substituents.However, the presence of a bulky ortho-substituent changes the regioselectivity allowing fluorination of the electron-rich ortho-substituted ring.For example, the reaction of 2,4,6trimethylphenyl(phenyl)iodonium triflate 22 with the complex of potassium [ 18 F]-fluoride with Kryptofix exclusively affords 1-fluoro-2,4,6-trimethylbenzene 23 along with iodobenzene as a byproduct (Scheme 11). 58heme 11.Effect of a bulky ortho-substituent on the regioselectivity of fluorination.
Carroll and co-workers have published a series of papers on applications of aryliodonium salts for the preparation of fluorine-containing aromatic and heteroaromatic products. 31,59,60In particular, it has been found that the addition of radical scavengers such as TEMPO (2,2,6,6tetramethylpiperidine-1-oxyl) to the reaction mixture leads to a significant improvement of both the reproducibility of the process and the material yield of the desired fluoroarene products without affecting the regioselectivity of the process. 59For example, the reaction of iodonium salt 24 with cesium fluoride in different solvents (DMF, DMSO, acetonitrile, N,Ndimethylacetamide) in the absence of a radical trap affords a mixture of fluoroarenes 25 and 26 in the ratio 1:1 with combined yield below 5%.Carrying out this reaction in the presence of 20 mol% TEMPO leads to increased yields of 25 and 26 up to 35% with almost unchanged regioselectivity (Scheme 12). 59This methodology is potentially applicable in the production of fluorine-18 labeled radiopharmaceuticals including L-6-[ 18 F]fluoroDOPA 27, 61 which is an important radioligand for the study of brain dopaminergic neuron density in movement disorders, such as Parkinson's disease.Scheme 12. Effect of TEMPO on the reaction of iodonium salts with fluoride anion.DiMagno and co-workers have found that exceptionally electron-rich arene rings can be fluorinated with high regioselectivity by the reductive elimination reactions of 5methoxy[2.2]paracyclophan-4-yliodonium salt 28 (Scheme 13). 62,63Application of the sterically hindered cyclophane directing group allows a high degree of control in fluorination reactions of diaryliodonium salts.However, despite excellent selectivity, this approach has obvious disadvantages, such as the use of inaccessible starting compounds and complex synthetic procedures.

Reactions of aryl(heteroaryl)iodonium salts with fluoride anion
5][66] In general, a theoretical prediction that the nucleophilic substitution in the electron-rich aryl(heteroaryl)iodonium salts by fluoride ion is regioselective for the aryl ring has been confirmed by experimental observation. 64Coenen and co-workers have reported an efficient procedure for nucleophilic fluorination using aryl-(2-thienyl)iodonium salts 29 (Scheme 14). 65The 2-thienyl group is a highly electron-rich group that allows the introduction of 18 F directly into even electron-rich arenes like anisoles.It has also been found that the selectivity of the fluorination of iodonium salts 29 depends on the nature of the counteranion X -, with the highest yields of Ar 18 F (up to 60% radiochemical yield) achieved in the reactions of iodonium bromides. 65heme 14. Regioselective nucleophilic fluorination of aryl-(2-thienyl)iodonium salts reported by Coenen and co-workers. 65 contrast to Coenen's results, 65 a detailed study of nucleophilic fluorination of aryl(thienyl)iodonium salts by Carroll and co-workers has demonstrated a very low selectivity of this reaction producing a mixture of six products as illustrated in Scheme 15. 60 The authors suggested that the previous reports on the absence of 2-fluorothiophene among the reaction products of aryl-(2-thienyl)iodonium salts were misleading.This lack of detection may be due the highly volatile nature of 2-fluorothiophene (boiling point 82 o C), which may be lost under the reaction conditions or on work-up/analysis. 60heme 15.Low selectivity in nucleophilic fluorination of phenyl-(2-thienyl)iodonium tosylate reported by Carroll and co-workers. 60ys'ko, Gakh and co-workers have demonstrated that a selective synthesis of 2fluorothiophene can be accomplished by heating bis(2-thienyl)iodonium salts with potassium fluoride. 66In particular, the treatment of bis(2-thienyl)iodonium hexafluorophosphate 30 with potassium fluoride (as a mechanical mixture) at 172-175 o C for 2 hours afforded 2fluorothiophene, 2-iodothiophene, and thiophene (Scheme 16).Bis(2-thienyl)iodonium salts with more nucleophilic anions, such as trifluoroacetate, yielded only trace amounts of the desired 2fluorothiophene. 66

Preparation of specific PET radioligands using diaryliodonium salts as precursors
Numerous reports on the optimization of the [ 18 F]-fluorinations and the preparation of specific [ 18 F]-labeled radiotracers using diaryliodonium salts have been published.Wüst and co-workers have developed a convenient access to 4-[ 18 F]fluoroiodobenzene 36 employing 4,4'diiododiaryliodonium salt 35 as a precursor (Scheme 18). 67-694-[ 18 F]Fluoroiodobenzene 36 has been further utilized in Sonogashira or Stille cross-coupling reactions for the preparation of numerous radiotracers.For example, the Stille reaction with 4-[ 18 F]fluoroiodobenzene has been used for the synthesis of radiotracers for monitoring COX-2 expression by means of PET.By using optimized reaction conditions 18 F-labelled COX-2 inhibitors 37 and 38 could be obtained in radiochemical yields of up to 94% and 68%, respectively, based upon 4-[ 18 F]fluoroiodobenzene 36. 68cheme 18. Synthesis of 4-[ 18 F]fluoroiodobenzene 36 and its use in cross-coupling reactions for the preparation of radiotracers 37 and 38.
Zhang and co-workers have synthesized a PET ligand [ 18 F]DAA1106 (compound 40) from diaryliodonium salt 39 with the radioactive [ 18 F]-fluoride anion (Scheme 19). 70It is essential that the electron-rich 4-methoxyphenyl is present as the second aromatic substituent in iodonium salt 39 (Ar = 4-MeOC6H4); the reaction of analogous phenyliodonium salt (39, Ar = Ph) gave desired product 40 in only 3% yield.Compound 40 is used as a PET ligand for imaging a peripheral-type benzodiazepine receptor. 70

Scheme 19. Synthesis of PET ligand [ 18 F]DAA1106 (compound 40).
Katzenellenbogen and co-workers have reported the synthesis and evaluation of two 18 Flabeled analogues of the potent and selective PPAR agonist farglitazar. 71,72In particular, the radioligand 42 was prepared by nucleophilic fluorination of phenyliodonium salt 41 in good radiochemical yield (Scheme 20). 71Interestingly, the reactions of iodonium salts 41 bearing the 3-methoxyphenyl or 2-thienyl substituents instead of the phenyl did not afford any fluorinated product 42.Scheme 20.Synthesis of the 18 F-labeled analogue of PPAR agonist farglitazar.
Chun and Pike have developed a rapid, single-step radiosynthesis of azido-or azidomethylsubstituted [ 18 F]fluoroarenes 45 and 47 by the reaction of diaryliodonium salts 44 or 46 with nocarrier-added [ 18 F]fluoride ion within a microfluidic apparatus to synthesize previously poorly accessible 18 F-labeled click synthons in good radiochemical yields (Scheme 22). 73The radiosynthesis of synthons 47 was also possible with "wet" cyclotron-produced NCA [ 18 F]fluoride ion, in the presence of about 70 vol-% water, thus eliminating the need to dry the cyclotron-produced [ 18 F]fluoride ion and greatly enhancing the practicality of the method. 73heme 22. Radiosynthesis of azido-or azidomethyl-substituted [ 18 F]fluoroarenes.
Griffiths and co-workers reported the synthesis and characterization of phenyl(3formylphenyl)iodonium salts containing four different counter anions, TfO -, Cl -, Br -, TsO -, and the nucleophilic 18 F-fluorination of these iodonium salts leading to m-[ 18 F]fluorobenzaldehyde and m-[ 18 F]fluorobenzylbromide. 48In particular, m-[ 18 F]fluorobenzaldehyde was prepared by the reaction of phenyl(3-formylphenyl)iodonium bromide with Cs 18 F/Cs2CO3 in dimethylformamide at 100 o C for 5 min in a microwave in the presence of one equivalent of TEMPO. 48The obtained 3-[ 18 F] fluorobenzaldehyde was further reduced to benzyl alcohol and converted into 3-[ 18 F] fluorobenzyl bromide.3-[ 18 F]fluorobenzyl bromide was subsequently used in the synthesis of 18 F-radiolabeled lapatinib, a potential tracer for positron emission tomographic imaging of ErbB1/ErbB2 tyrosine kinase activity. 74im and co-workers have developed agents for radionuclide imaging -amyloid plaques in vivo based on fluorine-substituted arylbenzothiazoles 49 (Scheme 23).2-Aryl-6-[ 18  Aromatic radiofluorination of the diaryliodonium tosylate precursor 13 with [ 18 F]fluoride ions has been applied successfully to access [ 18 F]flumazenil 50 in high radiochemical yields (Scheme 24). 47Radioisotope labeled flumazenil is an important radiopharmaceutical product for the assessment of the central benzodiazepine receptor (cBZR) concentration in the brain.It was found that stability and reactivity of the diaryliodonium tosylate precursor 13 plays a key role in increasing the yield of fluorinated product 50.This reaction was extended to a viable method for use in automated synthesis with an average radiochemical yield of 64% within 60 min.[ 18 F]Flumazenil 50 was isolated by preparative HPLC after the reaction was conducted under improved conditions and exhibited sufficient specific activity of 370-450 GBq/mol, with a radiochemical purity of >99%, which is suitable for human PET studies. 47heme 24.Radiosynthesis of [ 18 F]flumazenil 50.

Iodonium Ylides as Reagents for Nucleophilic Fluorination
The use of iodonium ylides as PET precursors for labeling reactions with fluorine-18 has recently been described in a patent. 75Like the reactions of iodonium salts as precursors, even electron-rich fluoroarenes can be prepared using aryl iodonium ylides and nucleophilic nocarrier-added [ 18 F]fluoride anion.However, in contrast to the reactions of diaryliodonium salts, the reactions of the iodonium ylides have been claimed to be regiospecific. 75ryliodonium ylides, ArI + --CX2, where X is an electron-withdrawing substituent (e.g., carbonyl or sulfonyl group), represent an important class of iodonium compounds, in which a carbon with carbanionic character is present. 2Due to this charge distribution, the attack of the external nucleophile should be directed exclusively toward the aromatic ring of the Ar group, which makes aryliodonium ylides attractive candidates for use as labeling precursors of [ 18 F]fluoroarenes.
The first example of a stable phenyliodonium ylide derived from dimedone (5,5-dimethyl-1,3-cyclohexanedione) was reported by Neiland and co-workers in 1957. 76Since then, numerous stable aryliodonium ylides have been prepared and structurally investigated.Single X-ray crystallographic studies demonstrate that the geometry of aryliodonium ylides is similar to the geometry of iodonium salts with a C-I-C angle close to 90 o , which is indicative of a zwitterionic nature in the ylidic C-I bond.[79][80]

Preparation and properties of iodonium ylides
Most iodonium ylides have a relatively thermal stability and can be handled only at low temperature or generated and used in situ.The relatively stable and practically important iodonium ylides, the dicarbonyl derivatives PhIC(COR)2, 76,81-84 and bis(organosulfonyl)(phenyliodonium)methanides, PhIC(SO2R)2, [85][86][87][88] are prepared by a reaction of (diacetoxyiodo)benzene with the appropriate dicarbonyl compound or disulfone under basic conditions.A general procedure for the synthesis of phenyliodonium ylides 52 from malonate esters 51 is based on the treatment of esters 51 with (diacetoxyiodo)benzene in dichloromethane in the presence of potassium hydroxide (Scheme 25). 83An optimized method for preparing bis(methoxycarbonyl)(phenyliodonium)methanide (52, R 1 = R 2 = Me) using a similar reaction of dimethyl malonate ester with PhI(OAc)2 and KOH in acetonitrile solution was published in Organic Syntheses in 2010. 89Ylides 52 decompose slowly at room temperature but they can be kept for several weeks in a refrigerator.

Scheme 25. Preparation of phenyliodonium ylides.
Phenyliodonium ylides 52 have found some synthetic use as efficient carbene precursors, especially useful as reagents for cyclopropanation of alkenes.Practical applications of ylides 52 are, however, limited by their poor solubility (insoluble in most organic solvents except DMSO) and low stability.2-Alkoxyphenyliodonium ylides 54 derived from dialkyl malonates and bearing an ortho alkoxy substituent on the phenyl ring, can be synthesized from commercially available 2-iodophenol according to the procedure shown in Scheme 26.Ylides 54 are relatively stable compounds, have good solubility in dichloromethane, chloroform, or acetone (e.g., the solubility of ylide 54, R = Pr, in dichloromethane is 0.56 g/mL), and have higher reactivity than common phenyliodonium ylides in the Rh-catalyzed cyclopropanation, C-H insertion, and transylidation reactions under homogeneous conditions. 90Higher thermal stability and a useful reactivity pattern are also characteristic of the dimedone-derived o-alkoxyphenyliodonium ylides 56, which are prepared similarly by the reaction of diacetates 53 with dimedone 55 in methanol in the presence of KOH at 0 o C. 91 Scheme 26.Synthesis of 2-alkoxyphenyliodonium ylides.
Scheme 27.Simplified one-pot procedure for the synthesis of iodonium ylides.

Reactions of iodonium ylides with fluoride anion
Due to the carbanionic character of the ylidic carbon, the attack of an external nucleophile in principle should be directed exclusively toward the aromatic ring of the Ar group of an aryliodonium ylide.However, it was previously demonstrated that the reaction of various organic and inorganic acids with phenyliodonium ylides leads to nucleophilic substitution of the iodobenzene substituent by the anion. 92,93Gondo and Kitamura have recently reported that the reaction of iodonium ylides 59 derived from 1-phenylbutan-1,3-dione, ethyl benzoylacetate, and ethyl p-nitrobenzoylacetate with Et3N•3HF gave the corresponding fluorinated products 60 in moderate yields (Scheme 28). 94These products are formed through the C-protonation of the ylide, followed by displacement of PhI with fluoride ion.Scheme 28.Reactions of iodonium ylides with Et3N•3HF.
In sharp contrast to the reactions of aryliodonium ylides with acids, Satyamurthy and Barrio have found that the reactions of ylides with nucleophiles (F -, Cl -, Br -, etc.) in polar aprotic solvents such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylacetamide and dimethylformamide lead to regioselective substitution of the nucleophile on the aromatic ring instead of the dione ring. 75For example, heating phenyliodonium ylides 58 with dried KF-Kryptofix (K222) complex in dry DMF affords fluoroarenes 61 as main products and hydrocarbons 62 as byproducts due to a radical channel competing with the nucleophilic substitution reaction (Scheme 29).No product of fluorination of the -dicarbonyl moiety was detected in this reaction. 75This approach has been employed for the radiofluorination of protected L-DOPA derivatives. 75A radiochemically pure amino acid L-6-[ 18 F]fluoroDOPA 27 has been produced in amounts usable for human PET studies, as shown in Scheme 30.
The fluorine-18 labeled L-DOPA is a very useful PET imaging agent for mapping dopamine related brain disorders and is the PET biomarker of choice for the diagnosis of Parkinson's disease.

Conclusions
This review demonstrates that aryliodonium derivatives are becoming increasingly popular reagents in PET for the efficient introduction of [ 18 F]-fluoride due to their exceptionally high reactivity in aromatic nucleophilic substitution reactions.Reactions of diaryliodonium salts with cyclotron-produced no-carrier-added [ 18 F]-fluoride provide a fast and convenient method of [ 18 F]-fluorination.Recent synthetic and mechanistic studies have led to the development of highly regioselective methods of nucleophilic fluorination of aromatic radioligands.We anticipate that this practically important area of hypervalent iodine chemistry will continue to attract significant research activity in the future.

2 .
Overview of PET and [ 18 F]-Radiofluorination Methods 3. Iodonium Salts as Reagents for Nucleophilic Fluorination 3.1 Synthesis of diaryliodonium and aryl(heteroaryl)iodonium salts for PET 3.2 Mechanism of reactions of iodonium salts with fluoride anion 3.3 Selectivity of nucleophilic fluorination 3.4 Reactions of aryl(heteroaryl)iodonium salts with fluoride anion 3.5 Preparation of specific PET radioligands 4. Iodonium Ylides as Reagents for Nucleophilic Fluorination 4.1 Preparation and properties of iodonium ylides