## 2 Direct \(\alpha\)-Halogenation of Aryl Ketones
### Electrophilic Halogenation
#### 2.1.3 NXS as Halogenation Agents  
The user friendliness, availability, and low cost of \(N\)-halosuccinimides (NXS) has enabled its widespread use as a halogenation reagent (Figure 3). NXS can be recycled after the reagent is consumed in the halogenation reaction, demonstrating its sustainable nature. In 2017, [PERSON] and co-workers reported a direct bromination and chlorination route optimised for aromatic ketones [66]. The procedure involved the addition of NBS (1.05 equiv.) and TMSOTf (0.05 equiv.) to the starting material and stirring the obtained solution in MeCN for three days at room temperature. Five \(\alpha\)-bromoketones (i.e., \(p\)-H, \(-\)F, \(-\)Cl, \(-\)CN and -NO\({}_{2}\)) were isolated in moderate to good yields (60-77%). Despite the straightforward work-up procedure, the extremely long reaction times have limited the widespread use of this protocol. Chlorination was also established via the addition of NCS (1 equiv.) and _para_-toluenesulfonic acid-monohydrate (\(p\)TsOH\(\cdot\)H\({}_{2}\)O) (1.5 equiv.) to the ketone. After stirring for 7 h at 80 \({}^{\circ}\)C, eight \(\alpha\)-chloroketones were obtained (Figure 4). The excess of \(p\)TsOH\(\cdot\)H\({}_{2}\)O used renders the protocol incompatible with acid-sensitive groups. Similar \(p\)TsOH-based chlorination and bromination were also described by [PERSON] and co-workers (Scheme 18) [67]. In these reactions, 1.5 equiv. of the acid and 1 equiv. of NXS yielded three \(\alpha\)-bromo (90-92%) and three \(\alpha\)-chloroketones (74-82%) with three different  
Figure 4: Chlorination scope by [PERSON] and co-workers. Figure 3: Structure of \(N\)-halosuccinimide. substituents on the aromatic ring (i.e., _p_-OMe, -Cl, -NO\({}_{2}\)). Here, again, the very limited scope puts the general nature of the method into serious doubt. A more general _p_TsOH-catalysed bromination protocol was developed by [PERSON] and co-workers using MW irradiation [68]. A solution of the ketone, NBS (1 equiv.) and _p_TSOH (0.1 equiv.) in dichloromethane (DCM) was irradiated for 30 min at 80 \({}^{\circ}\)C. This procedure yielded 11 aromatic \(\alpha\)-bromoketones in good to excellent yields (85-95%). The presence of electron-withdrawing, -donating or acid-sensitive substituents (i.e., OH) on the aryl ketones was well tolerated. The position of these substituents on the aromatic ring did not influence the bromination efficiency. The versatility of this route was further highlighted by the bromination of heteroaromatic ketones with high efficacy (93-95%). KH\({}_{2}\)PO\({}_{4}\) could also promote the direct bromination of aryl ketones as reported by [PERSON] and co-workers (Scheme 19) [69]. Under mild acidic conditions using 0.1 equiv. of KH\({}_{2}\)PO\({}_{4}\) and 1.1 equiv. of NBS, a wide variety of brominated products were isolated in moderate to excellent yields (46-94%). Nitro- and cyano-substituted aromatic ketones were less efficiently brominated. For substrates bearing OH and NH\({}_{2}\) substituents, ring bromination was exclusively observed. Moving away from Bronsted acid-based conditions, the same group highlighted silica as another efficient promoter for the bromination of aryl ketones [70]. Using the conditions depicted in Scheme 20, a wide variety of aryl ketones was successfully brominated. Substrates bearing highly electron-donating (i.e., _p_-OMe) and electron-withdrawing (i.e., NO\({}_{2}\), CN) groups did not fare well in this protocol, as their corresponding \(\alpha\)-bromoketones were obtained in yields of 64%, 42% and 45%, respectively. For some substrates, dibromination also occurred, highlighting the procedure's modest selectivity. The short reaction times, however, can be considered as the main feature of this route. Figure 19: Direct bromination of aryl ketones as reported by [PERSON] and co-workers. It should be mentioned that SiO\({}_{2}\)-catalysed \(\alpha\)-bromination is not a new concept.