## 2 Direct \(\alpha\)-Halogenation of Aryl Ketones
### Metal Halides (MX)
#### 2.1.7 Miscellaneous Halogenation Agents  
Other halogenation strategies include the use of transition metal halides. Sun demonstrated the halogenation activity of copper halides in the direct halogenation of ketones [120]. Addition of Ti-Al binary oxides (0.02 equiv.) and CuX\({}_{2}\) (2 equiv.) to phenylethanolamine, yielded the corresponding \(\alpha\)-bromo and \(\alpha\)-chloroketones in 42 and 56% isolated yield, respectively. The bromination reaction was carried out in acetonitrile, while the chlorination required formic acid as solvent. For both, the \(\alpha\),\(\alpha\)-dihalogenated species were observed as an important side product (isolated in 20% and 10% yield, respectively), highlighting this route's moderate selectivity. In contrast to [PERSON]'s route, a broader scope of \(\alpha\)-bromoketones were reported by [PERSON], [PERSON] and [PERSON] [121; 122]. Eleven ketones were brominated upon the addition of 1.5 equiv. of CuBr\({}_{2}\) (Scheme 44). At first sight, the mechanism seemed to indicate that at least 2 equiv. of CuBr\({}_{2}\) are needed to achieve full conversion; however, the first step involving the formation of the copper enolate could occur with CuBr instead. Additionally, CuBr in the presence of HBr can disproportionate back to CuBr\({}_{2}\), thus regenerating the active species. The procedure tolerated the presence of electron-donating and -withdrawing groups on the aryl substrates. NO\({}_{2}\)-substituted aromatic ketones underwent a less efficient halogenation compared to the unsubstituted aryl ketone. Nevertheless, other electron-poor substrates (i.e., bearing Cl, Br, I substituents) did not exhibit such a decrease in bromination efficiency. An inherent drawback of these CuX\({}_{2}\)-mediated reactions is the moderate halogen atom economy. Another transition metal-based protocol for the halogenation of ketones was reported by [PERSON] and co-workers using FeCl\({}_{3}\cdot\)6H\({}_{2}\)O and phenyliodinium diacetate in HOAc [123]. Addition of iron chloride (2 equiv.) and oxidant (1.2 equiv.) to the substrate, yielded 25 \(\alpha\)-chlorinated aryl ketones in moderate to good yields. The acidic reaction conditions limited the substrate scope, as it decreased this route's functional group tolerance (e.g., NH\({}_{x}\), OH). Figure 12: Other tribromide-based halogenation agents. [PERSON] and [PERSON] developed a DMSO and oxalyl bromide ((COBr)\({}_{2}\))-based bromination method for a diverse set of alkenes, alkynes and ketones (Scheme 45) [124]. The procedure leads to moderate selectivity, as the \(\alpha\)-brominated and \(\alpha\),\(\alpha\)-dibrominated products were obtained in a 1:1 ratio. Despite the relatively mild reaction conditions and short reaction times, this route does require further optimisation for more selective \(\alpha\)-bromination. Both [PERSON] and [PERSON] illustrated that 1,4-diazabicyclo[2,2,2]octane (DABCO) can be employed as a halogenation agent (Scheme 46) [125,126]. [PERSON] and co-workers used tetrameric DABCO-bromine (TBD) supported on silica or alumina to efficiently mediate the \(\alpha\)-bromination of four aromatic ketones in good yields. The non-hygroscopic supported solid performed the bromination under mild reaction conditions with an easy work-up (simple filtration). [PERSON] and co-workers, on the other hand, employed DABCO as a chlorination agent after treatment with chlorine gas, affording 1,4-dichloro-1,4-diazabicyclo[2,2,2]octane (DCDABCO) (Scheme 46). A set of alkenes, alkynes and ketones were chlorinated via this method, among which stands one, aryl ketone. The authors claim that DCDABCO can be reused for four consecutive reactions without significant loss in activity. SiCl\({}_{4}\) was also shown to be an excellent chlorinating reagent. In 2010, [PERSON] illustrated that a SiCI\({}_{4}\) and UHP/iodosylbenzene-based system mediated the chlorination of a broad range of ketones in good to excellent yields (Scheme 47, Figure 13) [127].