Electrophilic Fluorination Using A Hypervalent Iodine Reagent Derived From Fluoride †

hypervalent iodine reagent 6 for the trifluoromethylthiolation of -ketoesters, alkynes, aryl and vinyl boronic acids. Our research group is interested in designing new methods for introducing fluorine into organic molecules because of the importance of incorporating fluorine into drug candidate 35 molecules. Since Banks first reported SelectFluor in 1992, the fluoraza reagents have become increasingly popular electrophilic fluorinating reagents because they are commercially-available, shelf-stable powders that can be used to fluorinate a wide variety of substrates. The main disadvantage of these electrophilic 40

The air and moisture stable fluoroiodane 8, readily prepared on a 6 g scale by nucleophilic fluorination of the hydroxyiodane 7 with TREAT-HF, has been used as an electrophilic fluorinating reagent for the first time to monofluorinate 1,3-ketoesters and difluorinate 1,3-diketones in good isolated yields.
3][4] These reagents are normally prepared by oxidation of iodine(I) species with electrophilic reagents such as tert-butyl hypochlorite (1 → 3) and N-bromosuccinimide (1 → 2), 2 but Togni cleverly designed the 20 synthesis of the electrophilic trifluoromethylated hypervalent iodine reagent 5 using a formal umpolung of the trifluoromethyl group (Scheme 1).3a Ruppert's reagent was used as the nucleophilic source of the trifluoromethyl anion in order to displace the acetate and form an electrophilic trifluoromethylating reagent.Togni's reagent now has widespread applications including the electrophilic trifluoromethylation of -ketoesters, -nitroesters, thiols, phosphines and heteroaromatic compounds. 3Using an analogous nucleophilic route, Lu and Shen reported in 2013 the new electrophilic 30 hypervalent iodine reagent 6 for the trifluoromethylthiolation of -ketoesters, alkynes, aryl and vinyl boronic acids. 4r research group is interested in designing new methods for introducing fluorine into organic molecules 5 because of the importance of incorporating fluorine into drug candidate molecules. 6Since Banks first reported SelectFluor in 1992, 7 the fluoraza reagents have become increasingly popular electrophilic fluorinating reagents because they are commercially-available, shelf-stable powders that can be used to fluorinate a wide variety of substrates. 8The main disadvantage of these electrophilic 3 equivalents of Selectfluor in acetonitrile. 10Whilst this manuscript was in the final stages of preparation, Togni reported a nucleophilic route to the fluoroiodane 8 by halogen exchange of the chloroiodane 3 with 1.5 equivalents of spray-dried potassium fluoride in acetonitrile, 11 but both the reaction and the work up were carried out under argon.We have developed an alternative three step synthesis that also uses a nucleophilic fluorination (Scheme 2).The bromoiodane 2, synthesised using N-bromosuccinimide, was reacted with potassium hydroxide at room temperature in order to produce the hydroxyiodane 7 under mild reaction conditions.In the key step the hydroxyiodane 7 was reacted with 1.2 equivalents of triethylamine tris(hydrogen fluoride) (TREAT-HF) at room temperature to give the fluoroiodane 8 in a 94 % isolated yield after recrystallization from hexane.This is an excellent method for the preparation of 8 because there are no time-consuming purifications by column chromatography, each of the steps have been performed routinely 20 on a 6-10 g scale and the reactions do not require either dry or inert conditions.
Since one of the long term aims of this project is to prepare a new fluorinating agent that is suitable for the production of 18 Flabelled radiotracers for Positron Emission Tomography (PET) imaging, we were also interested in developing a nucleophilic route to the fluoroiodane 8 using sources of fluoride, such as potassium fluoride or tetrabutylammonium fluoride (TBAF), that can be applied to PET chemistry.Our synthetic strategy was to introduce a good leaving group onto the hypervalent iodine reagent in order to facilitate nucleophilic displacement by fluoride (Scheme 3).To this end, the new hypervalent iodine reagents, trifluoroacetoxyiodane 9 and tosyliodane 10, were synthesised by the reaction of 2-(2-iodophenyl)propan-2-ol 1 with either PhI(OCOCF 3 ) 2 or PhI(OH)(OTs) following Koser's procedure 12 and the solid-state structures of both compounds are presented in the supplementary information.When the trifluoroacetoxyiodane 9 was reacted with 1.2 equivalents of TBAF in dichloromethane, a mixture of the fluoroiodane 8 and the hydroxyiodane 7 was obtained in a 3:1 ratio.Since neither 9 40 nor 8 are hydrolysed in the presence of water, the formation of the hydroxyiodane 7 is believed to be due to the presence of tetrabutylammonium hydroxide in the TBAF.Therefore, since tetrabutylammonium hydroxide reacts with aqueous HF to give TBAF 13 and the hydroxyiodane 7 reacts with TREAT-HF to form the fluoroiodane 8, the addition of TREAT.HF was 50 investigated.With just 0.2 equivalents of TREAT-HF (Scheme 3) the fluoroiodane 8 was isolated in a 63% yield on a 1.0 g scale.The reaction between the tosyliodane 10 and TBAF in the presence of TREAT-HF was also successful giving a 100% conversion to the fluoroiodane 8 and a 46 % yield after 55 recrystallization from hexane.Neither the trifluoroacetoxyiodane 9 nor the tosyliodane 10 react with TREAT-HF (1.2 equivalents) at room temperature and in both cases unreacted starting material was recovered at the end of the reaction showing that it is the fluoride ion from the TBAF that is undergoing the nucleophilic 60 substitution to form the fluoroiodane 8.The reactivity of the fluoroiodane 8 as an electrophilic fluorinating reagent was first investigated using ethyl 3-oxo-3phenylpropanoate 11 as the model substrate (Table 1).When 2 equivalents of the fluoroiodane 8 was reacted with ethyl 3-oxo-3-65 phenylpropanoate 11 at 60 o C for 24 hours (entry 1), only an 8% conversion to the monofluorinated product 12 was obtained.The addition of TREAT-HF is essential for the fluorination and on increasing the amount from 0.9 to 2.7 equivalents the conversion to both the monofluorinated and difluorinated products increased 70 to 65% and 19% respectively (entry 4).On extending the reaction time to 48 hours in entry 5, more of the difluorinated product 13 was produced.However, the fluorination of ethyl 3-oxo-3phenylpropanoate 11 with 2.7 equivalents of TREAT-HF does not proceed in the absence of the fluoroiodane 8 (entry 6).75 Interestingly, the temperature of the reaction is an important factor with a more selective reaction towards the monofluorinated product 12 observed at 40 o C (entry 7), whilst the amount of the competing difluorinated product 13 increased at 80 o C (entry 8).
The concentration of the reaction mixture is also an important 80 factor in these fluorinations.When the concentration of the substrate was doubled from 0.12 M to 0.24 M, there was a dramatic improvement in the fluorination performed at 40 o C and the conversion to the monofluorinated product 12 increased from 54% (entry 7) to 89% (entry 9).The reaction was purified by 85 column chromatography and ethyl 2-fluoro-3-oxo-3-phenylpropanoate 12 was isolated in 63% yield.When either the reaction time was extended to 48 hours (entry 10) or the reaction was performed at 60 o C (entry 11), the amount of ethyl 2,2difluoro-3-oxo-3-phenylpropanoate 13 increased.
In summary, we have prepared fluoroiodane 8 by three different methods using either TREAT-HF or TBAF as the source of the fluoride ion.Preliminary reactivity studies have revealed 40 that it can be used to fluorinate 1,3-diketones and 1,3-ketoesters in good isolated yields and we are currently investigating further applications of 8 as an electrophilic fluorinating reagent with a range of different organic substrates.

Scheme 3
Scheme 3 Syntheses of the fluoroiodane 8 using TBAFThe fluoroiodane 8 was first prepared in 2012 by the electrophilic fluorination of 2-(2-iodophenyl)propan-2-ol 1 with 1.3 equivalents of Selectfluor in acetonitrile.10Whilst this manuscript was in the final stages of preparation, Togni reported a nucleophilic

Table 1
Optimisation of fluorination of ethyl-3-oxo-3-phenylpropanoate Determined by 1 H and 19 F NMR spectroscopy.c Isolated yield in parenthesis.d Reaction time was 48 h.
a Concentration of substrate.b e Control reaction without fluoroiodane 8.