In essence, the paper describes the development of a reaction for direct conversion of aryl carboxylic acids into aryl iodides (Figure 4). These precursors are generally cheap, readily available (in a wide range of substitution patterns) and are regarded as feedstock chemicals. The second approach is work published by Bill Morandi, 4 and is attractive because it utilises benzoic acids as starting materials. They can be somewhat energetic so any scale-up work should be undertaken with all the usual diligence and safety testing. Exercise caution with any materials containing a halogen-oxygen bond. The hypoiodites looks like an interesting reagents and the chemistry appears relatively straightforward to run. The strychnine example is particularly interesting, with complete selectivity for the 4-position of the aromatic ring observed with no reported iodination of the alkene or reaction at the tertiary nitrogen. Silver mesylates, tosylates or triflates were used as precursors in the various examples described.ДЄ (carefully selected) range of small-molecule drugs with additional structural complexity worked well with good positional selectivity (Figure 3). N-heterocycles- pyridines, pyrazoles and pyrroles- substituted with carboxylic acids, esters, amines, sulfonamides, and phthalimide substituents were all well tolerated. Simple arenes worked well using this process, generally with high selectivity, however nitrobenzene and aniline both failed to iodinate-presumably due to facile side-reactions.

However, the effectiveness of NIS drops off dramatically with electron poor substrates or those with functionality-derived complexity. Really the only reagent that comes close to the hypoiodite in terms of yield is NIS in the weaky acidic solvent hexafluoroisopropanol (HFIP). Figure 2: comparison of iodination methods Figure 2 shows a comparison of the sulfonyl hypoiodite with other iodinating reagents using tetrahydrobenzo furanone as a test substrate. In addition to the obvious safety benefits, the silver salt approach could be used to generate a range of hypoiodites with different reactivity depending on the nature of the sulfonate. The in situ generation from the silver salt gave comparable results to the peroxide mode of formation. Figure 1: generation of sulfonyl hypoiodites and reaction with arenes Thankfully for those involved in the project (and anyone who subsequently implements the chemistry) an alternative in situ method was developed using silver mesylate and molecular iodine (Figure 1).

3 Attempts to make the methanesulfonate reagent by reaction of iodide with bis(methanesulfonyl) peroxide were thwarted by the fact that the peroxide precursor is explosive. Tobias Ritter has succeeded in accessing previously unexplored electrophilic iodinating agents- sulfonyl hypoiodites (although they do claim the intermediate is putative). Elemental iodine (I 2) and electrophilic iodinating reagents such as N-iodosuccinimide (NIS) and 1,3-diiodo-5,5-dimethylhydantoin (DIH) are generally not reactive enough to iodinate electron-poor aromatic or heteroaromatic systems, and if they react at all the yields are low and the reactions non-selective. They are generally more difficult to access than the corresponding chlorides or bromides due largely to the limited availability of electrophilic iodinating reagents of comparable reactivity to their lighter halogen cousins.

2 As is common in synthetic science, the intermediates you really need are the ones that are most difficult to make and iodoarenes are no exception. I sure I donвЂ™t need to reiterate how useful iodinated intermediates are in synthesis- most significantly their heightened reactivity in metal catalysed cross coupling chemistry, 1 and, more recently their application as organocatalysts in hypervalent iodine chemistry. A couple of interesting papers published recently on aryl iodination.

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