## 4 Copper-Mediated Late-Stage Radiofluorination of Non-Activated Arenes
For example, in the preparation of 6-L-[18]F]PDOPA on Synthra automated module following eluent composition was used: K\({}_{2.2.2. (6.3 mg), K\({}_{2}\)C\({}_{2}\)O\({}_{4}\) (1 mg) and K\({}_{2}\)CO\({}_{3}\) (0.1 mg) in 1 mL of MeCN/H\({}_{2}\)O, 4:1. To the azeotropically dried [18]fluoride 20 \(\mu\)mol Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) and 20 \(\mu\)mol of di-Boc precursor in anhydrous DMF (400 \(\mu\)L) were added and the reaction mixture heated to 120 \({}^{\circ}\)C for 20 min, followed by acid hydrolysis (57% HI, 150 \({}^{\circ}\)C for 10 min). 6-L-[18]F]PDOPA was isolated in the RCY of 9% (non-decay corrected) after ca. 150 min synthesis time [90]. Further improvements of the methodology came with the employment of the weakly or non-basic organic salts in suitable aprotic or protic solvents such as Et\({}_{4}\)NHCO\({}_{3}\)[91] and Bu\({}_{4}\)NOTf [92] with good solubility in organic solvents. In addition to improved radiofluorination efficiency, using solutions of these PTCs in alcohols for elution of [18]F\({}^{-}\) from conventional AECs gives additional benefits for automation through the possibility to avoid time-consuming azeotropic drying and solvent replacement steps. In addition to the aforementioned commercially available PTCs, pyridinium sulfonate salts in organic solutions [93] have been found to be efficient for recovery of radionuclide from WAX column (1 cc, 30 mg) with about 80% EE. Following such procedure Cu-mediated radiofluorination of ArylBPin precursors using Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) catalyst can be performed directly in the same solvent bypassing any solvent replacement. Using 4-dimethylaminopyridinium triflate (DMAP.OTf) in DMA (110 \({}^{\circ}\)C, 20 min, commonly used conditions for fluorination of ArylBPin [86; 90]) the RCCs of 80-90% were reported for seven model boronates and ArylBPin precursor for protected 4-[18]Fluoro-D,L-phenylalanine. In the following study [94] DMAP.OTf was used in combination with Cu(OTf)\({}_{2}\). The RCCs values obtained for various model substrates in this case varied from 23 to 87%; [18]F]FMZ, GABAA\({}_{\text{A}}\) receptors radioligand, was obtained on a preparative scale in 47% isolated RCY with an average synthesis time of 60 min. The general utility of Cu(OTf)\({}_{2}\) in conjunction with pyridine as an alternative to Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) complex was previously demonstrated by [PERSON]'s group in high-yield examples of radiofluorinations of organoboron compounds, including ArylBPin precursors, arylboronic acids [88], and arylstananas [89] using K [18]F]F\({}^{-}\)/KOTf/K\({}_{2}\)CO\({}_{3}\) as the source of nucleophilic [18]fluoride. A more recent publication of [PERSON]'s group [95] on the customized [18]F]\({}^{-}\) elution techniques reports the enhancement of copper (II) triflate mediated radiofluorination of arylBPin substrates when using an aqueous solution of a weak non-ionic base such as 4-DMPA. However, using an aqueous solution necessitates the inclusion of azeotropic drying steps, making this procedure less attractive for automation. As for organic solutions of pyridinium sulfonate salts [93; 94], despite of their distinctive features allowing for operationally simple [18]F]fluoride processing protocol, their application in routine productions is quite limited: for clinical use commercially available materials (catalysts) is preferable. In current practice, the procedure for alcohol-enhanced Cu-mediated radiofluorination [91], which consists of the direct elution of the radionuclide with tetraalkylammonium salt in \(n\)BuOH into a solution of the precursor and Cu(OTf)\({}_{2}\)(Py)\({}_{4}\) in DMA followed by heating of resulting mixture under air has found broad application using various substrates. The presence of alcohol as co-solvent in Cu-mediated process has a beneficial effect on the radiofluorination efficiency leading to substantial increases in the radiochemical yield of various arylBPin substrates [96; 97; 98; 99; 100; 101; 102].