Fluorinations of unsymmetrical diaryliodonium salts containing ortho -sidearms; influence of sidearm on selectivity

a Activated aromatics were reacted with two different fluoroidoane reagents 1 and 2 in the presence of triflic acid to prepare only the para -substituted diaryliodonium salts. With fluoroiodane 1 the unsymmetrical diaryliodonium salts contained an ortho -propan-2-ol sidearm, whereas the alcohol sidearm was eliminated to form an ortho -styrene sidearm in the reaction with fluoroiodane 2 . Only the diaryliodonium salts containing a styrene sidearm were fluorinated successfully to deliver para -fluorinated aromatics in good yields.


Introduction
Fluoroaromatics constitute an important class of organic compounds because of their commercial applications in pharmaceuticals, agrochemicals, liquid crystals and positron emission tomography (PET). 1 Fluorine-18 ( 18 F) is the most commonly used radionuclide for PET, mainly due to its half-life of 110 minutes, and this has created a demand for new methods for the late-stage radiofluorination of aromatics. Consequently, the number of synthetic methods available for the preparation of aromatic fluorides has increased dramatically over the last eight years, 2 and the synthesis of aryl carbon-fluorine bonds from fluoride normally requires pre-functionalisation of the aromatic with either boron, 3 tin, 4 N-arylsydnone 5 or hypervalent iodine. [6][7][8][9][10][11][12][13] The fluorination of unsymmetrical diaryliodonium salts was first reported in 1995 by Pike 6 and it has now become a wellestablished method for the introduction of [ 18 F]fluoride into aromatics. 7 Since fluoride normally attacks the most electrondeficient aromatic ring, an effective strategy for directing fluoride into the desired aryl ring is to use an unsymmetrical aryl(spectator)iodonium salt where the spectator group is an electron-rich aromatic such as 4-methoxyphenyl or 2-thienyl. [6][7][8][9] There is also an "ortho effect" in these fluorinations which overcomes the electronic effect. If one of the aromatic rings contains an ortho-substituent such as methyl, it will direct the fluorination to that ring. Sanford has shown that orthoselectivity can be reversed by using a copper catalysed fluorination of aryl(mesityl)iodonium salts and the reaction is highly selective for fluorination to occur at the less sterically hindered arene, even with highly electron-rich aromatics. 10,11 Scheme 1 Preparation of fluoroiodane reagents and diaryliodonium salts Recently, she described a two-step procedure involving an SEAr reaction between activated aromatics, MesI(OH)(OTs) and TMSOTf to generate aryl(mesityl)iodonium triflates which were used in situ in a copper-mediated radiofluorination with [ 18 F]KF. 10c Despite the presence of two ortho-methoxy groups, 2,4,6-trimethoxyphenyl was introduced by Chun in 2019 as an excellent new spectator group in the high-temperature radiofluorinations of aryl (2,4,6-trimethoxyphenyl)iodonium triflates where the aryl group was fluorinated with extremely high chemoselectivity. 12 Iodonium ylides, (diacetoxyiodo)arenes and iodoarenes oxidised by m-CPBA have also been investigated as precursors to [ 18 F]fluoroarenes. 13 In 2013 we reported the preparation of the hypervalent iodine(III) reagent 1 from cheap sources of nucleophilic fluoride (Scheme 1) and its application as a new fluorinating reagent for the fluorination of 1,3-diketones, 1,3-ketoesters and 1,3ketoamides. 14a Since then, the reaction scope of fluoroiodane 1 has extended significantly from the difluorinations of styrenes and cyclopropanes, to intramolecular fluorocyclisations of unsaturated alcohols, amines, amides and carboxylic acids, as well as to radiofluorinations. 14-16 Most of these reactions, however, required a transition metal to activate the fluoroiodane reagent 1 by coordinating to the fluorine atom. 17 We have now established that 1 can be activated by hydrogen bonding to hexafluoroisopropanol and crucially, it removed the need for transition metals. 14d We were interested in preparing fluorinated aromatics using fluoroiodane 1 and here, we report the preparation of two new classes of unsymmetrical diaryliodonium salts containing orthosidearms, 5 and 7, by a site selective SEAr reaction between activated aromatics and the fluoroiodane reagents 1 and 2 with triflic acid (Scheme 1). We will also discuss the fluorinations of these unsymmetrical diaryliodonium salts using Sanford's copper catalysed conditions to reverse the "ortho effect" and fluorinate selectively the activated aromatics.

Results and Discussion
Initially, anisole was reacted with fluoroiodane 1 and 1.5 equivalents of triflic acid in acetonitrile at room temperature to form exclusively the para-substituted diaryliodonium triflate 4a in 86% yield in just 1 hour at room temperature (Table 1). 1,3-Dimethoxybenzene and mesitylene were reacted with fluoroiodane 1 and triflic acid to form the diaryliodonium salts 4b and 4c in 91-92% yield. When the same reaction conditions Scheme 2 Metathesis reactions using NaBF4 (aq) were applied to the less activated aromatic, 2-bromoanisole, the diaryliodonium salt 4d was obtained in a moderate 58% yield. After further optimisation (see Table S3 in ESI), the yield increased to 86% when 2-bromoanisole was reacted with fluoroiodane 1 and 3 equivalents of triflic acid in acetonitrile at 0 o C for 2 hours. The optimised protocol was applied to other less activated aromatics such as diphenyl ether, methyl-2methoxybenzoate and m-xylene to form the unsymmetrical diaryliodonium salts 4e, 4f and 4g in moderate to good yields (22-69%). All the diaryliodonium triflates were obtained as stable, white powders which were purified simply by washing with hexane and diethyl ether.
The triflate counteranions in the unsymmetrical diaryliodonium salts 4 were exchanged easily by stirring the salt in dichloromethane with aqueous sodium tetrafluoroborate at room temperature for 18 hours (Scheme 2). This simple procedure delivered the diaryliodonium tetrafluoroborates 5 in good yields (79-91%).
A new analogue of the fluoroiodane reagent 1, where one of the methyl groups was replaced by a phenyl group, was then prepared by a five-step synthesis (see ESI). The phenyl group was introduced to encourage the alcohol sidearm in the diaryliodonium salts to eliminate and form an alkene in conjugation with two aromatic rings under the strong acidic conditions used in their synthesis. Hence, a new class of unsymmetrical diaryliodonium salts containing an orthostyrene sidearm was prepared by reacting a series of activated aromatics with fluoroiodane 2 and triflic acid in acetonitrile at 0 o C for 2 hours. After stirring the diaryliodonium triflates 6 in dichloromethane with an aqueous solution of sodium tetrafluoroborate, the diaryliodonium tetrafluoroborates 7a to 7h were produced in good yields (74-89%) over the two steps (Scheme 3). The reaction worked particularly well with less activated aromatics such as diphenyl ether, methyl-2methoxybenzoate and m-xylene delivering the diaryliodonium triflates 6b, 6f and 6g in better yields (85%, 90% and 89% respectively) than the same reactions with fluoroiodane 1 where the salts, 4e, 4f and 4g, were obtained in 69%, 22% and Please do not adjust margins Please do not adjust margins Scheme 3 Preparation of diaryliodonium salts 7 from fluoroiodane reagent 2 and the overall yields for the two steps are reported 51% yields respectively. In the reaction between benzyl phenyl ether and fluoroiodane 2, the benzyl protecting group was removed under the strong acidic conditions producing the pphenol salt 6c and subsequently 7c in 59% overall yield after anion exchange. Interestingly, the first general procedure for preparing para-hydroxy substituted diaryliodonium salts was only reported in 2018 by Zhdankin using Koser's reagent, triisopropylsiloxyarenes and triflic acid to deprotect the aryl silyl ethers. 18 Some arenes, however, were incompatible with the reaction (Scheme 3) including 1,3-dimethoxybenzene, 1,2dimethoxybenzene, 1-methoxy-2-methylbenzene, acetanilide and N-methylindole.
The diaryliodonium tetrafluoroborate 5a was also prepared in one-step by the direct reaction between anisole, fluoroiodane reagent 1 and the Lewis acid, boron trifluoride (Scheme 4). Unfortunately, this reaction did not work with less activated aromatics such as 2-bromoanisole. When anisole was reacted with fluoroiodane reagent 2 and boron trifluoride, the alcohol sidearm did not undergo elimination and the diaryliodonium tetrafluoroborate 8a containing a 1phenylethan-1-ol sidearm was formed in 90% yield. Before attempting to fluorinate these unsymmetrical diaryliodonium salts, the free hydroxy groups in 5a and 8a were protected with MOMCl (Scheme 4). An excess of both MOMCl and N,N-diisopropylethylamine (Hunig's base) were used to ensure complete conversion to products 9a and 10a which were isolated in excellent yields after stirring the crude products with an aqueous solution of sodium tetrafluoroborate. The last step was essential because without it, some of the salt was obtained with a chloride counteranion which affected the subsequent fluorinations.

Fluorinations
Initially, the unsymmetrical diaryliodonium salts 7a, 9a and 10a were reacted with potassium fluoride (1.1 equivalent) and 18crown-6 (0.4 equivalent) in DMF at 60 °C for 18 hours both with and without [Cu(MeCN)4]BF4 (0.2 equivalent), as reported by Sanford in the fluorination of aryl(mesityl)iodonium salts ( Table  2). 10a Without the copper catalyst the ortho-effect dominated in the fluorination of 7a (entry 1) and the aryl group containing the ortho-styrene sidearm was fluorinated producing 1-fluoro-2-(1phenylvinyl)benzene 13a in 53% yield with byproduct 4iodoanisole formed in 72% yield. However, the ortho-effect was reversed in the copper-catalysed fluorination and the desired product, 4-fluoroanisole 12a, was delivered in a moderate 39% yield (entry 2). Surprisingly, when the unsymmetrical salts, 9a and 10a, were fluorinated in the absence of copper, there was Please do not adjust margins Please do not adjust margins very little fluorination but there was still a strong ortho-effect with 4-iodoanisole being obtained in 79% and 85% yield respectively (entries 3 and 5). Under the copper-catalysed conditions (entries 4 and 6) fluorination was observed, but the ortho-effect was not reversed and the aryl groups containing the ortho-sidearms were fluorinated in 74 and 65% yields respectively. Presumably, the presence of the oxygen atoms in the sidearms of 9a and 10a, which had strong interactions with the iodine atom in the solid-state structures, were affecting the selectivity of these fluorinations. The fluorination of 7a was optimised by screening the reaction conditions, different solvents, copper catalysts and fluorinating reagents (see ESI for full details). Increasing the reaction temperature to 80 o C in entry 1 (Table 3) improved both the yield of 4-fluoroanisole 12a to 45% and the selectivity of the reaction to 90:10. Since the use of TEMPO has proved beneficial for the fluorinations of some diaryliodonium salts, 7 1 equivalent of TEMPO was used in entry 2 but it had no effect on the reaction. Both [Cu(MeCN)4]OTf and Cu(OTf)2 were good catalysts with Cu(OTf)2 providing 4-fluoroanisole in 60 % yield. The yield improved to 65% and the selectivity increased to 92:8 by reducing the reaction time to 4 hours in entry 5. The uncatalysed reaction in entry 6 proceeded in an excellent 80% yield but with the opposite selectivity (1:99). Finally, the effects of changing the counteranion from tetrafluoroborate 7a to triflate 6a (entry 7) and tosylate 11a (entry 8) were investigated under the optimised reaction conditions but only low yields of 4-fluoroanisole 12a were obtained.
Having established optimum conditions, each of the diaryliodonium tetrafluoroborates, 7a to 7h, were fluorinated using potassium fluoride and 20 mol% Cu(OTf)2 in DMF at 80 o C for 4 h ( Table 4). The salts, 7a and 7b, produced the desired pfluorinated aromatics, 12a and 12b, in good yields (61-65%) with excellent selectivities (91:9). However, p-fluorophenol 12c was only obtained in a low 20% yield in the fluorination of 7c  19 F NMR spectroscopy with an internal standard but this was probably due to the free hydroxy group in the salt. 20 In the copper-catalysed fluorinations of 7d to 7f, the fluorinated aromatics 12d to 12f were produced in good (66%) to excellent (82%-87%) yields and with high selectivities (93:7). As expected, the selectivity dropped to 75:25 in the fluorination of 7g because of the presence of the ortho-methyl group in the activated aromatic, but 2,4-dimethylfluorobenzene 12g was still formed in a good 63% yield. The selectivity was reduced further to 47:53 in the fluorination of 7h due to the bigger ethyl substituent in the ortho-position and the desired fluorinated aromatic 12h was only obtained in a low 23% yield.

Conclusions
In summary, this paper describes a convenient synthesis of para-fluorinated aromatics from activated aromatics and fluoroiodane reagent 2. Initially, two new classes of unsymmetrical diaryliodonium salts containing ortho-sidearms were prepared by a site selective SEAr reaction between activated aromatics and two different fluoroiodane reagents 1 and 2 with triflic acid. With fluoroiodane 1 the unsymmetrical diaryliodonium salts contained an ortho-propan-2-ol sidearm, whereas the alcohol sidearm was eliminated to form an orthostyrene sidearm in the reaction with fluoroiodane 2. After counteranion exchange, only the diaryliodonium tetrafluoroborates containing a styrene sidearm 7 reacted selectively with potassium fluoride under copper-catalysed conditions to form para-fluorinated aromatics 12 in good yields (61-87%).

Conflicts of interest
There are no conflicts to declare.