## 2 Direct \(\alpha\)-Halogenation of Aryl Ketones
### Electrophilic Halogenation
#### 2.1.2 I\({}_{2}\) as Halogenation Agent
However, for di- and tri-methoxy-substituted ketones, selective ring iodination instead of \(x\)-iodination occurred; these by-products account for a required and more tedious purification process. Alternatively to O\({}_{2}\) and H\({}_{2}\)O\({}_{2}\), [PERSON] and co-workers demonstrated that the hypervalent \(m\)-iodosylbenzoic acid could also act as a suitable oxidation agent [57]. With the reaction conditions shown in Scheme 12, a variety of aromatic and aliphatic ketones and \(\beta\)-dicarbonyls were iodinated. At the end of the reaction, the reduced form of the hypervalent iodine oxidant, \(m\)-iodobenzoic acid, could be easily removed by passing the reaction mixture through an anionic exchange resin (Amberlite IRA 900 HCO\({}_{3}\)\({}^{-}\)). Afterwards, recovery of the \(m\)-iodobenzoic acid was achieved by treating the resin with HCl. With similar drawbacks to earlier strategies, this method still allowed for 100% I-atom economy while also carrying the benefits of recycling the oxidizing reagent. Over the past two decades, numerous acid-free direct iodination protocols have been developed. These methods tolerated acid-sensitive functional groups, such as amines or alcohols. A remarkable iodination system was developed by [PERSON] and co-workers, which only required the addition of iodine (4 equiv.) to the methyl ketone in dimethylether at 90 \({}^{\circ}\)C (Scheme 13) [58]. Several aromatic \(\alpha\)-iodoketones were obtained in moderate yields (62-94%). In this reaction, the dual role of I\({}_{2}\) was highlighted as it acts as both a Lewis acid and a direct iodine source. The acid-free conditions and short reaction times were this route's main advantages. However, the use of a highly volatile solvent, the excess of I\({}_{2}\) and the inevitable generation of HI negatively impacted this direct iodination route. The corrosive nature of HI involves extra hazards and might lead to product decomposition. Using neutral conditions, [PERSON] and co-workers reported a metal-mediated iodination of ketones through the addition of CuO (1 equiv.) and I\({}_{2}\) (1 equiv.) to the substrate in MeOH (Scheme 14) [59]. The presence of electron-donating (e.g., OMe, Me) and electron-withdrawing substituents (e.g., Cl, Br) on the aryl ketones was well tolerated. The corresponding \(\alpha\)-iodoketones were obtained in 83-99% yield. For nitro-substituted aryl ketones, the yield decreased significantly to 53% and formation of the dimethyl ketal product occurred. This protocol stands out due to the use of inexpensive reagents and its excellent iodination yields. Nonetheless, a significant amount of harmful HI was generated. An iodine- and trimethylorthormate-mediated iodination was reported in 2008 (Scheme 15), yielding several aromatic ketones with a wide range of substituents (i.e., _para_-OH, -Me, -F and common protecting groups such as -OBr, -OTBS and -OAc) in good yields (64-78%) [60]. The authors claimed that the work-up drastically altered the outcome of the reaction, since the true reaction mixture contained primarily the \(\alpha\)-iodinated dimethoxy ketal product. Upon reaction completion, when the reaction was directly treated with an aqueous Na\({}_{2}\)S\({}_{2}\)O\({}_{3}\) solution followed by extraction, the \(\alpha\)-iodoketal product was mainly obtained (Scheme 15, right). However, if the reaction mixture was first stirred in water, then treated with the Na\({}_{2}\)S\({}_{2}\)O\({}_{3}\) solution, \(\alpha\)-iodoketones were obtained as the main products (Scheme 15, left). In 2010, [PERSON] and co-workers illustrated the halogenation of ketones using another iodine activator, the hypervalent [hydroxyl(tosyloxy)iodo]benzene (HTIB), in an IL, i.e., [bmim][BF\({}_{4}\)] (Scheme 16) [61]. Two different iodination agents, iodine (1.2 equiv.) and methyl iodide (3 equiv. ), were compared for a set of ketones. Although both generated the corresponding \(\alpha\)-iodoketones in similar yields, they required different reaction conditions.