Mild Aromatic para-Iodination with NIS/TFA
(Rated as: excellent)
Mild and regioselective aromatic iodination with N-iodosuccinimide and trifluoroacetic acid
Tet Lett 43, 5047-5048 (2002)
A variety of aromatics compounds substituted with methoxy or methyl groups were regioselectively iodinated with N-iodosuccinimide and catalytic trifluoroacetic acid with excellent yields under mild conditions and short reaction times.
In recent years, iodoarenes have assumed increasing importance in organic synthesis because they can be easily functionalized through metal catalyzed cross-coupling reactions. Due to their potential ability as intermediates in organic syntheses and also as bioactive materials, iodination of aromatic compounds have been the subject of numerous studies. The moderate reactivity of iodine with aromatic substrates implies the addition of activating agents and recently direct iodination methods have been developed by using iodonium donating reagents: iodine-tetrabutylammoniumperoxydisulfate
However, most of these methods require hazardous or toxic reagents or high reaction temperature for a long reaction time. A combination of N-iodosuccinimide and trifluoromethane sulfonic acid (2-5 equiv.) has been used for the iodination of deactivated aromatics compounds. Iodination of activated aromatic ethers with only N-iodosuccinimide in acetonitrile has been reported more recently. Nevertheless long reaction times (6-24 h) and high reaction temperature (reflux of acetonitrile) are generally needed with this reaction. Furthermore we have noticed an influence of the amount of starting aromatic compound on the reaction time. For example iodination of 750 mg of 2-methoxynaphtalene with NIS was completed after 30 h whereas iodination of a few grams required 4 days at reflux of acetonitrile.
We have discovered that a combination of N-iodosuccinimide (1.1 equiv.) and catalytic trifluoroacetic acid (0.3 equiv.) is an excellent reagent (in term of reaction time and reaction temperature) for the regioselective iodination of activated aromatic compounds. A variety of commercially available methoxy and methyl aromatic derivatives were submitted to the reaction with NIS and cat. CF3COOH and our results are collected in Table 1. Iodination of methoxy aromatic derivatives took place with high yield at room temperature with short reaction times, between several minutes (entries 1, 2 and 7) and 1-4 h (entries 3, 5 and 6). Surprisingly, iodination of mesitylene proceeded at room temperature in 4.5 h (entry 4) whereas reaction of 2-methylnaphtalene (entry 9), meta-xylene (entry 8) and diphenylether (entry 10) required refluxing acetonitrile to be completed in 2.5-6 h.
Entropy just isn't what it used to be.