## 2 Direct \(\alpha\)-Halogenation of Aryl Ketones
### Electrophilic Halogenation
#### 2.1.3 NXS as Halogenation Agents
[PERSON] and co-workers had previously reported the NBS- and HClO\({}_{4}\)-SiO\({}_{2}\)-mediated halogenation affording 11 aromatic \(\alpha\)-bromoketones in good to excellent yields (77-93%) [71]. Using this process, heteroaromatic (i.e., pyridinyl, thienyl, furyl) ketone substrates were efficiently \(\alpha\)-brominated, albeit with longer reaction times (16-18 h) compared to their aromatic counterparts (8-12 h). Similarly to the aforementioned routes, the protocol demonstrated a rather moderate selectivity as the \(\alpha\),\(\alpha\)-dibrominated products were observed in some cases. Other protocols involving the use of modified SiO\({}_{2}\), such as NaHSO\({}_{4}\)-SiO\({}_{2}\) and HSO\({}_{3}\)-SiO\({}_{2}\), have also demonstrated good catalytic activity in the direct halogenation reaction. Both yielded 2-bromo-1-phenylethanolamine in 72% and 87% yield, respectively. The authors claimed that HSO\({}_{3}\)-SiO\({}_{2}\) could even be recycled and reused for three consecutive runs without significant loss in catalytic activity. Additionally, [PERSON] reported that SiCl\({}_{4}\) efficiently catalysed the direct halogenation of aromatic ketones [72]. In this procedure, SiCl\({}_{4}\) (2 equiv.) and NXS (2 equiv.) were added to the aryl ketone in CH\({}_{3}\)CN. The protocol yielded several \(\alpha\)-chloro-, \(\alpha\)-bromo- and \(\alpha\)-iodoketones in moderate to excellent yields. Other Lewis-acid-based protocols involved the use of transition metals to efficiently perform the direct halogenation of aryl ketones [73]. [PERSON] and co-workers described a Cu(OTf)\({}_{2}\)-catalysed bromination reaction that afforded \(\alpha\)-bromoketones in 65-89% yield (Scheme 21). Next to the mono-brominated product, \(\alpha\),\(\alpha\)-dibromoketones were also observed as a minor product, making this route less attractive compared to existing and more selective \(\alpha\)-bromination procedures. [PERSON] and [PERSON] designed a photochemical \(\alpha\)-bromination of cyclic and acylic ketones. This route generated seven aromatic bromoketones upon the addition of NBS (1.05 equiv.) to the substrates and subsequent UV-VIS irradiation in diethylether [74]. Thorough assessment of this route's efficiency is not possible, as bromination yields were not reported. The authors mentioned that \(\alpha\),\(\alpha\)-bromination occurred for most of the substrates, which highlights the modest selectivity of the developed procedure. In 2019, [PERSON] and co-workers developed a TiO\({}_{2}\) nanoparticle (NP)-catalysed bromination and chlorination of aromatic ketones [75]. With the corresponding NXS and \(t\)-butyl hydrogen peroxide (TBHP), 12 \(\alpha\)-haloketones were obtained in good to excellent yields (Scheme 22). The short reaction times and excellent halogenation yields can be considered as the main advantages of this route. The use of volatile and hazardous organic solvents counteracted the progress that some NXS-based methods accomplished in terms of sustainability. Thus, Togo and co-workers attempted to provide a greener bromination approach [76]. A set of ketones was halogenated upon addition of NBS (1.2 equiv.) and \(p\)TsOH\(\cdot\)H\({}_{2}\)O (0.2 equiv.) in two different ILs, i.e., [bmim][PF\({}_{6}\)] and \(N\)-butyl-\(N\)-methyl-pyrrolidinium bis(trifluormethanesulfonyl)imide ([bmpy][NTf\({}_{2}\)]) (Figure 5, left). The use of an IL not only facilitated the work-up, but also allowed the reaction medium to be reused up to seven times without significant loss in bromination efficiency. Both ILs appeared to be effective halogenation reaction media, as eight aromatic \(\alpha\)-haloketones were obtained in good to excellent yields (74-96%). [PERSON] and [PERSON] designed an alternative procedure for the \(\alpha\)-bromination in an IL, i.e., [bmim]BF\({}_{4}\) (Scheme 23) [77]. The UHP (2 equiv. )- and NXS (2 equiv. )-mediated reaction yielded four \(\alpha\)-chloro and four \(\alpha\)-bromoketones (\(p\)-H, -Me, -Cl and -NO\({}_{2}\)) in moderate to good yields (68-78% and 74-86%, respectively).