## 2 Direct \(\alpha\)-Halogenation of Aryl Ketones
### Electrophilic Halogenation  
#### 2.1.1 Br\({}_{2}\) as Halogenation Agent  
The most straightforward route to \(\alpha\)-haloketones involves the reaction of enolizable aromatic ketones with electrophilic X\({}_{2}\), under acidic (or basic) conditions; these conditions are typically needed to generate the nucleophilic enol (Scheme 2). The procedure developed by [PERSON], [PERSON] and co-workers in 2014 enables the bromination of aryl ketones under acidic conditions [37]. A small excess of Br\({}_{2}\) (1.1 equiv.) was added to a solution of ketone in glacial HOAc and subsequently irradiated for 5 h in a microwave (MW). Figure 2 presents the bromination scope with respective isolated yields. The main drawback of this procedure is the use of HOAc as a solvent, which substantially limited the substrate scope; acid-sensitive functional groups (e.g., -OH, -NH\({}_{\text{x}}\)) cannot tolerate these reaction conditions. Figure 2: Scope of MW radiated bromination reported by [PERSON] and [PERSON]. Using a similar strategy, [PERSON] developed a continuous flow procedure for the \(\alpha\)-bromination of acetophenone [38]. 2-Bromo-1-phenylethanolamine was isolated in 99% yield upon treatment of the substrate with HBr and bromine in 1\(\mathcal{A}\)-dioxane (Scheme 3). The authors claimed that ring brominated or dibrominated products could not be observed, which highlights the excellent selectivity of the process. This work showcased a highly effective \(\alpha\)-bromination protocol which could be applicable on an industrial scale. However, the large-scale use of toxic and corrosive HBr and Br\({}_{2}\) reagents would require important safety measures to avoid leakage or contact of the reagents with the environment/operators, which remains a significant drawback. Attempts to substitute the Bronsted acid activation with a Lewis acid activation have shown promising results, via the in situ formation of ZnBr\({}_{2}\) from Zn dust and bromine (Scheme 4) [39]. The aqueous procedure was well tolerated by substituents (i.e., _ortho_) close to the carbonyl centre. However, the use of toxic metallic Zn and Br\({}_{2}\) counteracted the progress made in terms of a greener approach [40,41]. Another attempt to alleviate the acid sensitivity of substrates/products was developed by [PERSON] and co-workers, using a phase-vanishing protocol (Scheme 5) [42]. The reaction mixture consisted of four separate phases: (i) an aqueous phase, to trap HBr, (ii) an organic (CH\({}_{3}\)Cl) phase (Galden HT135), containing the substrate, (iii) a fluorous phase, and (iv) the bromine phase. The fluorous phase acted as a membrane to separate the Br\({}_{2}\) and the substrate-containing phase. Upon stirring, the fluorous phase enables the former to mix with the latter phase. During the reaction, HBr migrates to the aqueous layer, and at the end of the reaction, the bromine phase vanishes. This procedure thus prevented possible product decomposition induced by HBr, as the substrate and the acid were contained in different phases. This quadruple phase method simplified the purification of the desired \(\alpha\)-bromoketones. In total, five \(\alpha\)-bromoketones were isolated in good to excellent yields in this manner. It should be noted that dibrominated products were observed in trace amounts, which could complicate purification. [PERSON] et al. improved the reaction by successfully performing the \(\alpha\)-bromination of a very broad substrate scope (21) in good to excellent yields (84-99%) without any additional activator (Scheme 6) [43]. The presence of both electron-withdrawing (e.g., Cl, Br, CF\({}_{3}\)) and -donating (e.g., OMe, \(t\)-Bu, OH) groups was well tolerated. Moreover, this route's efficacy was not significantly affected by the presence of steric bulk at the _ortho_-position. In 2014, [PERSON] and co-workers published an acid-free, Br\({}_{2}\)-mediated halogenation [44].