## 4 Copper-Mediated Late-Stage Radiofluorination of Non-Activated Arenes  
In the last decade or so, significant efforts have been expended on overcoming the general limitations of the conventional nucleophilic approach in direct introduction of 18F-label into the non-activated aromatic ring (general structural component in a great number of potentially useful PET radiotracers), leading to approach commonly referred to as \"late-stage radiofluorinations.\" As the result of those efforts, several innovative 18F-labeling approaches for labeling of electron-rich arenes (heteroarenes) have been introduced using, for example, (mesytyl)(aryl)iodonium salts, spirocyclic hypervalent iodine (III) complexes, and organoboron and stannane precursors (for recent reviews see [69; 70; 71; 72; 73]). Among the methods described, Cu-catalyzed radiofluorination reactions using commercially-available CuOTf(CH\({}_{3}\)CN)\({}_{4}\) and Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) complexes as sources of copper have been found to be a particularly useful route to a diverse range of complex radiopharmaceuticals that cannot be readily accessed through conventional approaches; numerous examples are presented in recent reviews [74; 75]. However, attempts at the application of those methods to full-batch clinical production revealed several problems, including modest or fluctuating radiochemical yields, long synthesis times, and problematic protocols with relatively large amounts of precursors and catalysts, base sensitivities, and others. Therefore, in parallel to the development of methods for the Cu-mediated fluorinations, substantial efforts were expended on designing novel protocols for reprocessing [18]F]fluoride that could be more easily implemented in automated modules. Copper-mediated fluorination of (mesityl)(aryl)iodonium (MAI) salts promoted by CuOTf(CH\({}_{3}\)CN)\({}_{4}\) complex was recently introduced by the [PERSON] and [PERSON] groups [76; 77] as an alternative to the use of diaryl iodonium salt precursors pioneered in 1995 by [PERSON] [78]. Owing to their electron-deficient nature at the iodine center and simultaneous presence of an excellent leaving-group in the form of a Ph-I fragment, diaryl iodonium salts are exceptionally reactive towards nucleophilic fluorination. The most common application has been the preparation of \({}^{18}\)F-labeled aromatic building blocks [15; 79] such as 4-[\({}^{18}\)F]fluoroiodobenzene, often employed in the radiolabeling via Pd-catalyzed cross-coupling reactions [80]. Notable examples of the radiopharmaceuticals accessible via fluorination of diaryl iodonium salts are 6-[\({}^{18}\)F]fluorodopamine [81] and 6-L-[\({}^{18}\)F]FDOPA [82]. Despite the straightforward labeling approach, the later radiotracer, with growing clinical application in both neurology and oncology fields, was obtained from commercially available anisyl(aryl)iodonium triflate salt (Scheme 1, upper part) in relatively poor RCY of 15% (decay-corrected) with ca. 120 min synthesis time. Using the same precursor but applying an optimized minimalist protocol [68] under cryptand/base free conditions, RCY of 6-L-[\({}^{18}\)F]FDOPA was increased to 27-35% (decay corrected) with ca. 70 min synthesis time [83]. The major drawbacks of these methods are the requirement for high temperatures (140 \({}^{\circ}\)C) as well as the use of \"non-conventional\" solvents such as diglyme [82] or toluene [81; 83] that are not well compatible with the automated module's components [84]. In contrast, (mesityl)(aryl)iodonium (MAI) salts [77] are easily fluorinated under moderate temperatures (typically 85 \({}^{\circ}\)C, 20 min) in the commonly used polar aprotic solvents such as DMF. In the original method [77], 18-crown-6/K\({}_{2}\)CO\({}_{3}\) was suggested for the activation of the [\({}^{18}\)F]fluoride obtained in the conventional azeotropic drying procedure.