Room Temperature Regioselective Iodination of Aromatic Ethers Mediated by SelectfluorTM Reagent F-TEDA-BF4

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Room TemperatureRegioselectiveIodinationof Aromatic Ethers Mediated by SelectfluorTM Reagent F-TEDA-BF4 Marko Ztspan”,Jernej Iskra and Stojan Stavber

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Mild introduction of iodine into aromatic molecules has been a subject of broad interestt. A variety of reagents bearing positive iodinezwere developed and new oxidizers for conversion of iodide or iodine to active iodinating species have been successfully promoted3. In recent years it has been demonstrated that F-N type of reagents, besides being able to introduce fluorine selectively into aromatic molecules4 under mild reaction conditions, also possess oxidizing properties. The commercial availability of various types of F-N reagents5 allows the broader application of this class of compounds and we report now that l-chloromethyl-4-fluoro-1,4diazoniabicyclo [2,2.2]octane bis(tetrafluoroborate) (F-TEDA) could be an excellent mediator for mild introduction of iodine into an activated phenyl ring. In a typical experiment to a solution of 1.0 mmol of F-TEDA and 0.5 mmol of iodine in 10 ml of CHSCN, 1.0 mmol of anisole was added and a reaction mixture stirred for 3 hours at 22”C. The dark colour of iodine almost disappeared atler half an hour and after a work-up procedure, the formation of 4-iodoanisole as the sole product was established. Reduction of the amount of F-TEDA to 0.5 mmol has no appreciable effect on a yield of the iodination process. In a blank experiment, under the above mentioned conditions, no reaction between anisole and F-TEDA, iodine and F-TEDA or iodine and anisole was observed. Conversion of anisole was not affected by the presence of nitrobenzene usually used as a radical scavenger, while solvent polarity played an important role in iodination, where longer reaction times were needed for complete conversion (7 hours in mixture of CH3CN and 2 of CHzCIZ HzO or CH3COOH). Finally we investigated the role of the source of iodine on iodination and potassium iodide was also found to be convenient but a larger amount of F-TEDA (1,0 mmol) was required. In this case the presence of water enhanced reactivity and complete conversion of anisole was acchieved in two hours at room temperature. Quantitative conversion was also observed afier 4 hours reaction in the presence of Me~SiI, while only 84% conversion was found after 24 hours at room temperature when MeI was used. 6305

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Scheme. Iodination of Aromatic Ethers with 12and F-TEDA in CH3 ~ 22°C R R, (/Rl H CH3 H CH,Ph H Ph F = CH3 CH3 C I Br CH3 I CH3 I COCH3 CH3 R CHO CH3 CH3 C(CH3)3 ‘ 0.51 f

React. time* Yieldb(%) 3h 89 3h 90 3h 80 24h 87 24h 89 26h 91 30h 88 IOh 90 IOh 85 3h 92 of F-TED! m

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We fbrther investigated the role of the aromatic molecule in this new iodination procedure and by using a two percent excess of iodine and a one to one molar ratio of substrate and F-TED~ the complete c (Scheme). We established that a larger substituent on the ether fimction did s m a not afl’ectthe iodination procedure since phenylbenzylether and diphenyl ether were quantitatively transformed to 4-substituted isomers at 22”C. Introduction of a halogen atom at the para position in anisole reduced the reactivity and a longer reaction time (24-30h) for almost quantitative conversion to the Z-iodosubstituted product was required. Para-methoxyacetophenone and 4-methoxyaldehyde were converted atler 10 hours to 2iodo derivatives and no side reactions on the carbonyl fictional group took place. Introduction of a large group did not effect the iodination process and afier 3 hours 2-iodo-4-t-butylanisole was isolated in excellent yield. On the basis of these reported results we can conclude that by using F-TEDA and various iodine sources regioselective iodination could be achieved, The mechanism of the reaction and the applicability of this new method to other aromatics, olefins and ketones, as well as its convenience for radiolabeling of orga~ic molecules is now under fi.uther investigation. References: 1

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Tomizawa,G.; Harasawa,K.; Kawada,K.; Tomita,K. Banks,R. E.; M O C 1 6 C C 1 5 Lal,G. S. O C 1

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F-TEDA-BF+ AirProductsandChemicalsPLC,UK. Seevers,R.H.;Counsell,R.E. C R 1

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