## 4 Copper-Mediated Late-Stage Radiofluorination of Non-Activated Arenes
Under these conditions, high RCC values (up to 80%) were demonstrated for a series of model substrates, however, for complex molecules, such as protected 6-L-[\({}^{18}\)F]FDOPA RCC values in order of 20% were obtained using a toylate counter ion, increasing up to 30% when a tetrafluoroborate was employed in the same role. The high fluorination efficiency (in the order of 60-90%, depending on the position of fluorine in the aromatic ring) was achieved [85] when implementing \"minimalist\" protocol [68] in the direct preparation of a series of 2,3- and 4-[\({}^{18}\)F]labeled-L-phenylalanines, starting from respective MAI precursors (Scheme 1). [\({}^{18}\)F]fluoride retained on the anion-exchange resin was eluted with a solution of the MAI precursor in MeOH/DMF, followed by fluorination reaction in the same combination of solvents without any drying or solvent replacement steps, thus significantly simplifying automation. However, the utilization  
Figure 1: Preparation of 6-L-[\({}^{18}\)F]FDOPA [82] via \({}^{18}\)F-fluorination of anisyl(aryl)iodonium salt precursors (upper part) and synthesis of 3-[\({}^{18}\)F]labeled-L-phenylalanine (lower part) using minimalist protocol [85]. of this methodology for labeling electron-rich arenes is hampered by a relatively difficult preparation of the iodonium salt precursors, in particular, polyfunctionalized iodonium salts, as well as the limited shelf-life of these compounds. Consequently, the synthesis of radiofluorinated arenes labeled in inactivated positions using arylboronic acid pinacol esters (ArrylBPin) as precursors and Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) as a catalyst has been recognized as a versatile route to a number of innovative \({}^{18}\)F-radiotracers and clinically significant radiopharmaceuticaleticals [73, 74, 75]. This approach is based on copper-promoted Chan-Lam C-F cross-coupling reaction and was brought to \({}^{18}\)F-fluorine radiochemistry in 2014 by the [PERSON]'s group [86] followed cold chemistry researches by the [PERSON]'s group [87]. In the follow-up studies, Cu-mediated radiofluorination of organoborons [88] and (hetero)aryl organostannanes [89] were developed as well, however, the applications compared to ArrylBPin precursors are more limited. As with most new approaches, this methodology was initially developed through small-scale experiments based on the use of small aliquots of aqueous [\({}^{18}\)F]F- and subsequent scale-up to production quantities required for generating clinical doses revealed numerous issues. In the first application of the method [86], a conventional K\({}_{2.2.2}\)/K\({}_{2}\)CO\({}_{3}\) protocol with azootropic drying was used to obtain reactive [\({}^{18}\)F]fluoride for the reaction catalyzed by Cu(OTf)\({}_{2}\)Py\({}_{4}\) in the presence of O\({}_{2}\) (or atmospheric air). Due to the sensitivity of the Cu-mediated process to basic conditions the \"low-base\" [\({}^{18}\)F]F- reprocessing protocol [46] (substantially reducing both base and kryptofix amounts) or the use of less basic cryptand/base combinations [90] was suggested. Results by [PERSON]'s group [86] in collaboration with other laboratories [90] demonstrated the applicability of the method to the synthesis of eight widely used radiotracers: [\({}^{18}\)F]FMTEB, [\({}^{18}\)F]FPEB, [\({}^{18}\)F]Humazenil, [\({}^{18}\)F]DAA1106, [\({}^{18}\)F]MFBG, 6-L-[\({}^{18}\)F]FDOPA, [\({}^{18}\)F]FMT, and [\({}^{18}\)F]FDA (Figure 4). The methodology was shown to be adaptable to different automation platforms where conventional ACEs (QMA, 46 mg, or PSHCO\({}_{3}\)) were used for trapping and elution of the radionuclide. Depending on the particular radiotracer, different kryptofix-based eleu  
Figure 4: Synthesis of eight radiotracers via Cu-mediated \({}^{18}\)F-fluorination of arylBPin precursors using Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) as a copper source [90]. were employed with the replacement of \"standard\" K\({}_{2}\)CO\({}_{3}\) with less basic K\({}_{2}\)C\({}_{2}\)O\({}_{4}\) or KH\({}_{2}\)PO\({}_{4}\).