Supporting Information for:

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1 Supporting Information for: Copper Catalyzed [ 18 F]Fluorination of (Mesityl)(Aryl)Iodonium Salts Naoko Ichiishi, Allen F. Brooks, Joseph J. Topczewski, Melissa E. Rodnick and Melanie S. Sanford*, Peter J. H. Scott* Department of Chemistry, University of Michigan, 93 N. University Ave., Ann Arbor, Michigan 4819, United States Department of Radiology, University of Michigan Medical School, 131 Catherine, Ann Arbor, MI 4819, United States Interdepartmental Program in Medicinal Chemistry, University of Michigan, 428 Church St., Ann Arbor, MI 4819, United States

2 Table of Contents I. General Procedures and Materials and Methods for Synthesis of Diaryliodonium Salts and Fluorinated Standards p. S3 II. Synthesis and Characterization of Diaryliodonium Salts p. S4 III. Synthesis and Characterization of Fluorinated Standards p. S14 IV. Radiochemistry p. S16 A. General Materials and Methods p. S16 B. Radiosynthesis of 18 F-labeled Molecules p. S17 a. Manual Synthesis p. S17 b. Automated Synthesis p. S18 c. Isolated protected [ 18 F]F-DOPA 15 p. S19 d. HPLC conditions p. S2 e. Specific Activity Calculation p. S21 C. Additional Optimization Results: a. Table S1. Molar Ratio p. S23 b. Table S2. Loading Effects p. S23 c. Table S3. Temperature p. S24 d. Table S4. Time Studies p. S25 D. Radio-HPLC/Radio-TLC analysis for 18 F-labeled Compounds 2-11, 13, and 15 p. S26 V. 1 H, 13 C, and 19 F NMR Spectra p. S52 S2

3 I. General Procedures and Materials and Methods Instrumental Information. NMR spectra were obtained on a Varian MR4 (4.52 MHz for 1 H; 1.71 MHz for 13 C; MHz for 19 F), a Varian vnmrs 5 (5.1 MHz for 1 H), or a Varian vnmrs 7 ( MHz for 1 H; MHz for 13 C) spectrometer. 1 H and 13 C NMR chemical shifts are reported in parts per million (ppm) relative to TMS, with the residual solvent peak used as an internal reference. 19 F NMR spectra are referenced based on an internal standard, 1,3,5-trifluorobenzene ( 11. ppm). 1 H and 19 F multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). High performance liquid chromatography (HPLC) was performed using a Shimadzu LC-21A HT system equipped with a Bioscan B-FC-1 radiation detector. Radio-TLC analysis was performed using a Bioscan AR 2 Radio-TLC scanner with EMD Millipore TLC silica gel 6 plates (3. cm wide x 6.5 cm long). Materials and Methods. Diaryliodonium tetrafluoroborate 1, and the substrates for fluorides 3-5, 7, 8, and 11 (Table 2 in manuscript) were prepared according to a literature procedure. 1 The salts [p-omeph-i-mes]x (X = OTf, OTs, PF 6 ) were prepared according to a literature procedure. 2 MesI(OAc) 2 was obtained from TCI America. BF 3!OEt 2 was obtained from Alfa Aesar or Aldrich. m-cpba was obtained from Sigma Aldrich. Arylboronic acids were obtained from Aldrich, Frontier Scientific, Oakwood Products and Combi Blocks. Anhydrous DMF, (CH 3 CN) 4 CuOTf, and 18-crown-6 were obtained from Aldrich. 1,3,5-Trifluorobenzene was obtained from Oakwood Products. Authentic 19 F samples of compounds 2, 5, 7, 9, 1, 11 were purchased from the following vendors: 4-fluoroanisole 2 (Oakwood), 2-fluoroanisole 5 (Aldrich), 4-fluorobiphenyl 7 (Oakwood), 4-fluoroiodobenzene 9 (Oakwood), 3-methyl-fluoroacetate 1 (Acros), and 3- fluorobenzaldehyde 11 (Acros). Standards of 19 F-fluorinated compounds 3, 4, 6, 8, 13 and 15 were prepared according to literature procedure, and all spectroscopic data were in accordance with the literature. 1 All reactions were conducted under a nitrogen atmosphere or using standard Schlenk techniques unless otherwise stated. All reactions conducted at elevated temperatures were heated on a hot plate using an aluminum block. Temperatures were regulated using a thermocouple.!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 1 Ichiishi, N.; Canty, A. J.; Yates, B. F.; Sanford, M. S. Org. Lett. 213, 15, Basuli, F.; Wu, H.; Griffiths, G. L. J. Label. Compd. Radiopharm. 211, 54, 224. S3

4 II. Synthesis and Characterization of Diaryliodonium Salts BF 4 O I N H (S6a) (Mesityl)(4-acetamidophenyl)iodonium tetrafluoroborate (S6a) was prepared by the following procedure adapted from the literature. 4 (4-Acetamidophenyl)boronic acid (38 mg, 2.1 mmol, Combi Blocks) was dissolved in CH 2 Cl 2 (28 ml,.75 mm). The solution was cooled to ºC, BF 3 OEt 2 (.29 ml, 2.3 mmol, 1.1 equiv) was added, and the mixture was stirred for 1 min. 2- (Diacetoxyiodo)mesitylene (83 mg, 2.2 mmol, 1.5 equiv) was then added as a solution in CH 2 Cl 2 (6.7 ml,.33 M). The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by the addition of saturated NaBF 4 (aqueous, ~5 ml). After 3 min of vigorous stirring, the aqueous layer was extracted with CH 2 Cl 2 (2 x 5 ml). The combined organic layers were dried over MgSO 4, filtered, and concentrated under vacuum. The residue was triturated with Et 2 O at rt, collected via filtration, washed with Et 2 O, and dried under vacuum overnight, to afford S6a as a brown power (395 mg, 4% yield). 1 H NMR (7 MHz, DMSO-d 6 ): δ 1.3 (s, 1H), 7.91 (d, J = 9.1 Hz, 2H), 7.67 (d, J = 9.1 Hz, 2H), 7.2 (s, 2H), 2.6 (s, 6H), 2.29 (3H), 2.5 (s, 3H). 13 C NMR (176 MHz, DMSO-d 6 ): δ 169., 142.9, 142.4, 141.4, 135.8, 129.7, 122.9, 121.5, 15.8, 26.2, 24.1, F NMR (376 MHz, DMSO-d 6 ): δ 148.2, HRMS (ESI + ) [M-BF 4 ] + Calcd for C 17 H 19 INO + : 38.56; Found: BF 4 I I (S9a) (Mesityl)(4-iodophenyl)iodonium tetrafluoroborate (S9a) was prepared by the following procedure adapted from the literature. 3 4-Iodophenylboronic acid (372 mg, 1.5 mmol, Aldrich) was dissolved in in CH 2 Cl 2 (2 ml,.75 mm). The solution was cooled to ºC, BF 3 OEt 2 (246 mg, 1.55 mmol, 1.1 equiv) was added, and the mixture was stirred for 1 min. 2- (Diacetoxyiodo)mesitylene (62 mg, 1.55 mmol, 1.1 equiv) was then added as a solution in!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 3 Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. Chem. Sci. 212, 3, 317. S4

5 CH 2 Cl 2 (4.7 ml,.33 M). The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by the addition of saturated NaBF 4 (aqueous, ~3 ml). After 3 min of vigorous stirring, the aqueous layer was extracted with CH 2 Cl 2 (2 x 3 ml). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. The residue was triturated with Et 2 O at rt, collected via filtration, washed with Et 2 O, and dried under vacuum overnight, to provide S9a as a white powder (5 mg, 63% yield). The 1 H and 13 C NMR spectroscopic data were identical to that reported previously in the literature F NMR (376 MHz, DMSO-d 6 ): δ 148.2, HRMS (ESI + ) [M-BF 4 ] + Calcd for C 15 H 15 I + 2 : ; Found: H O BF 4 I (S11a) (Mesityl)(3-formylphenyl)iodonium tetrafluoroborate (S11a) was prepared by the following procedure adapted from the literature. 4 (3-Formylphenyl)boronic acid (15 mg, 1. mmol, Frontier Scientific) was dissolved in CH 2 Cl 2 (13 ml,.75 mm). The solution was cooled to ºC, BF 3 OEt 2 (.29 ml, 1.1 mmol, 1.1 equiv) was added, and the mixture was stirred for 1 min. 2- (Diacetoxyiodo)mesitylene (42 mg, 1.1 mmol, 1.1 equiv) was then added as a solution in CH 2 Cl 2 (3.3 ml,.33 M). The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by the addition of saturated NaBF 4 (aqueous, ~3 ml). After 3 min of vigorous stirring, the aqueous layer was extracted with CH 2 Cl 2 (2 x 3 ml). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. The residue was triturated with Et 2 O at rt, collected via filtration, washed with Et 2 O, and dried under vacuum overnight, to provide S11a as a white power (276 mg, 63% yield). 1 H NMR (7 MHz, DMSO-d 6 ): δ 9.99 (s, 1H), 8.45 (s, 1H), 8.19 (d, J = 7. Hz, 1H), 8.14 (d, J = 7. Hz, 1H), 7.72 (t, J = 7. Hz, 1H), 7.24 (s, 2H), 2.61 (s, 6H), 2.31 (s, 3H). 13 C NMR (176 MHz, DMSO-d 6 ): δ 191.6, 143.3, 141.7, 139.4, 138.4, 134.3, 132.7, 132.6, 129.9, 122.6, 115.1, 26.3, F NMR (376 MHz, DMSO-d 6 ): δ 148.2, HRMS (ESI + ) [M-BF 4 ] + Calcd for C 16 H 16 IO + : ; Found: !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 4 Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 28, 13, S5

6 I CO 2 Me NHAc! BF 4 (12) (Mesityl)(N-acetyl-4-phenylalanine)iodonium tetrafluoroborate (12) was prepared by the following 4 step synthesis. CO 2 Me I (S1) NHAc Step 1: Iodide S1 was prepared by the following procedure adapted from the literature. 5 To an ice-cold solution of L-4-iodo-phenylalanine (964 mg, 3.3 mmol, 1. equiv) in MeOH (25 ml), SOCl 2 (.35 ml, 4.8 mmol, 1.5 equiv) was added dropwise. The solution was slowly warmed to room temperature. After 2 h, the mixture was concentrated under vacuum. The residue was taken up in MeOH and reconcentrated under vacuum (2 x 25 ml). The crude methyl ester (2.52 g, 3.3 mmol) was advanced without further purification. Step 2: The crude ester prepared above (assume 3.3 mmol) was dissolved in pyridine (5 ml, 62 mmol), and acetic anhydride (1 ml, 11 mmol, 3.3 equiv) was added dropwise at room temperature. After 6 h, the reaction was poured onto 2 M HCl. The resulting solution was extracted with EtOAc (3 x 2 ml). The combined organic phases were washed with water and brine, dried over Na 2 SO 4, and concentrated under vacuum. This afforded N-acetyl-4-iodo-phenylalanine methyl ester (CAS# , 794 mg, 69% yield over 2 steps). The spectral data for this intermediate were identical to that reported in the literature. 5!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 5!Boyle, T. P; Bremmer, J. B.; Coates, J. A.; Deadman, J.; Keller, P. A.; Pyne, S. G.; Somphol, K. Euro. J. Med. Chem. 29, 44, 11.! S6

7 Step 3: Oxidation of N-acetyl-4-Iodo-phenylalanine methyl ester to the (diacetoxyiodo)arene was accomplished via a reported method. 6 A 2 ml vial was charged with N-acetyl-4-iodophenylalanine methyl ester (273 mg,.79 mmol, 1. equiv). This solid was dissolved in glacial acetic acid (8 ml) and heated to 5 ºC. Sodium perborate tetrahydrate (1.7 g, 11 mmol, 14 equiv) was added in small portions (ca. 5-1 mg every 5 min) over 1 h. The temperature was maintained at 5 ºC for 12 h, during which time the solution became cloudy white. After this time, the reaction was cooled to room temperature, poured onto water (75 ml), and extracted with CH 2 Cl 2 (3 x 2 ml). The combined organic phases were washed with water, washed with brine, dried over Na 2 SO 4, and concentrated under vacuum. This intermediate was used in the next step without further purification. Evidence for oxidation could be observed from 1 H NMR spectroscopic analysis of the crude material, which showed new aromatic signals downfield of the starting material. Approximately 8% of the starting material was oxidized based on 1 H NMR analysis. I CO 2 Me NHAc BF 4 (12) Step 4: Formation of (mesityl)(4-phenylalanine)iodonium tetrafluoroborate was accomplished by following a procedure adapted from the literature. 4 Mesitylboronic acid (285 mg, 1.7 mmol, 2.1 equiv, Aldrich) was dissolved in CH 2 Cl 2 (5 ml). The solution was cooled to ºC, BF 3 OEt 2 (225 µl, 1.8 mmol, 2.3 equiv) was added, and the mixture was stirred for 5 min. The (diacetoxyiodo)arene prepared above (assume.79 mmol) was then added dropwise as a solution in CH 2 Cl 2 (3 ml). The mixture was slowly allowed to warm to room temperature and stirred for 3.5 h. The reaction was quenched by the addition of saturated NaBF 4 (aqueous, 3 ml). After 4 h of vigorous stirring, the aqueous layer was extracted with CH 2 Cl 2 (2 x 5 ml). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (25 g Biotage SNAP silica column, gradient from % to 1% iproh in CH 2 Cl 2, R f =.5 in 15% iproh in CH 2 Cl 2 ), which afforded substrate 12 as an oil (21 mg, 1.5 mmol, 46% yield over 2 steps). The oil could be solidified by dissolving it in!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 6!McKillop, A.; Kemp, D. Tetrahedron, 1989, 45, 3299.! S7

8 CH 2 Cl 2 followed by the slow addition of hexanes. The mixture of solvents was then removed under vacuum to afford a white solid. 1 H NMR (5 MHz, CDCl 3 ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 (s, 2H), 6.42 (d, J = 7.8 Hz, 1H), 4.77 (m, 1H), 3.67 (s, 3H), 3.16 (dd, J = 14., 5.5 Hz, 1H), 3.5 (dd, J = 14., 7.1 Hz, 1H), 2.6 (s, 6H), 2.34 (s, 3H), 1.92 (s, 3H).!! 13 C NMR (126 MHz, CDCl 3 ) δ 171.5, 17.3, 144.7, 142.6, 141.6, 133.4, 133.2, 13.6, 119.7, 11., 52.9, 52.6, 37.2, 27.1, 22.8, HRMS (ESI + ) [M-BF 4 ] + Calcd for C 21 H 25 INO + 3 : ; Found: !! S8

9 I X CO 2 Me MeO OMe NHPiv (14-X) (Mesityl)(N-(tert-butylcarbonyl)-3,4-di(methoxy)-L-phenylalanine methyl ester)-2-iodonium tosylate (14-OTs) was prepared by the following 6 step synthesis. CO 2 Me PivO OPiv NHPiv (S2) Steps 1 and 2: N-(tert-butylcarbonyl)-3,4-di(tertbutylcarbonyl)-L-phenylalanine methyl ester (S2). To an ice cold solution of L-DOPA (3.34 g, 17 mmol, 1. equiv Acros) in MeOH (5 ml), SOCl 2 (1.5 ml, 21 mmol, 1.2 equiv) was added dropwise. The solution was slowly warmed to 5 ºC. After 22 h, the reaction mixture was concentrated under vacuum. To remove volatile byproducts, the mixture was re-dissolved in MeOH and re-concentrated. EtOAc (25 ml) was then added, and the solution was reconcentrated under vacuum to remove residual MeOH. The crude DOPA- NH 3 Cl-OMe was used in the next step without further purification. An aliquot of the oil prepared above (1.3 g, assume 5.2 mmol) was dissolved in pyridine (1 ml, 124 mmol) at room temperature. Pivaloyl chloride (4 ml, 32 mmol) was added dropwise. After 2 h at room temperature, the solution was poured onto 2M HCl. The resulting solution was extracted with EtOAc (3 x 2 ml). The combined organic layers were washed with water, washed with brine, dried over Na 2 SO 4, filtered, and concentrated under vacuum. Final purification via flash chromatography (1 g Biotage SNAP silica column, gradient from % to 1% EtOAc in hexanes, R f =.4 in 3% EtOAc in hexanes) afforded tris(piv)-dopa methyl ester S2 as an oil (2.2 g, 15.3 mmol, 9% yield over two steps). 1 H NMR (7 MHz, CDCl 3 ) δ 7.1 (d, J = 8.3 Hz, 1H), 6.9 (dd, J = 8.3, 2.1 Hz, 1H), 6.81 (d, J = 2. Hz, 1H), 6.13 (d, J = 7.3 Hz, 1H), 4.79 (dt, J = 7.4, 5.6 Hz, 1H), 3.69 (s, 3H), (m, 2H), 1.29 (s, 18H), 1.14 (s, 9H). S9

10 13 C NMR (176 MHz, CDCl 3 ) δ 177.9, 175.7, 175.6, 171.8, 142.3, 141.5, 134.3, 126.8, 124.4, 123.3, 52.8, 52.3, 39.2, 39.1, 38.6, 36.8, 27.3, 27.2, HRMS (ESI + ) [M+H] + Calcd for C 25 H 38 NO 7 + : ; Found: PivO I OPiv CO 2 Me NHPiv (S3) Step 3: N-(tert-butylcarbonyl)-2-iodo-3,4-di(tertbutylcarbonyl)-L-phenylalanine methyl ester (S3). Iodide S3 was prepared by the following procedure adapted from the literature. 7 A solution of tris(piv)- DOPA methyl ester S2 (2.2 g, 4.8 mmol, 1. equiv) in CH 2 Cl 2 (5 ml) was cooled in an ice bath. To this solution, solid molecular iodine (1.51 g, 6.4 mmol, 1.3 equiv) was added followed by solid [bis(trifluoroacetoxy)iodo]benzene (2.5 g, 5.8 mmol, 1.2 equiv). The solution was allowed to slowly warm to room temperature. After 24 h, the reaction was quenched by the addition of an aqueous solution of Na 2 S 2 O 3, and the deep red color of iodine rapidly faded. The resulting solution was extracted with CH 2 Cl 2 (3 x 2 ml). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. Final purification via flash chromatography (1 g Biotage SNAP silica column, gradient from % to 1% EtOAc in hexanes, R f =.5 in 3% EtOAc in hexanes) afforded iodide S3 as an oil (337 mg, 3.9 mmol, 81% yield). 1 H NMR (7 MHz, CDCl 3 ) δ 7.55 (s, 1H), 6.95 (s, 1H), 6.17 (d, J = 7.8 Hz, 1H), 4.8 (td, J = 7.9, 6.3 Hz, 1H), 3.7 (s, 3H), 3.23 (dd, J = 14.2, 6.4 Hz, 1H), 3.18 (dd, J = 14.2, 6.3 Hz, 1H), 1.3 (s, 9H), 1.28 (s, 9H), 1.14 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) δ 178.2, 175.3, 175.2, 171.9, 142.7, 141.7, 137.8, 133.7, 124.5, 95.2, 52.3, 52.2, 41.7, 39.1 (2C), 38.6, 27.3, 27.2, HRMS (ESI + ) [M+H] + Calcd for C 25 H 37 INO + 7 : ; Found: MeO I OMe CO 2 Me NHPiv (S4)!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 7 Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 212, 134, S1

11 Step 4: N-(tert-butylcarbonyl)-2-iodo-3,4-di(methoxy)-L-phenylalanine methyl ester (S4). A flask was charged with tris(piv)-iodo-dopa S3 (545 mg,.92 mmol, 1. equiv), and it was brought inside of a glove box. Sodium methoxide (113 mg, 2.1 mmol, 2.3 equiv) was added as a solid. The solids were then dissolved in DMF (6 ml) at room temperature, and the flask was sealed and removed from the glove box. After 2 h, methyl iodide (.2 ml, 3.2 mmol, 3.5 equiv) was added via syringe. After an additional 2 h at room temperature, the reaction was quenched by the addition of water. The resulting solution was extracted with EtOAc (3 x 2 ml). The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. Final purification via flash chromatography (25 g Biotage SNAP silica column, gradient from % to 1% EtOAc in hexanes, R f =.5 in 3% EtOAc in hexanes) afforded iodide S4 as an oil (337 mg,.75 mmol, 81% yield). 1 H NMR (7 MHz, CDCl 3 ) δ 7.16 (s, 1H), 6.71 (s, 1H), 6.14 (d, J = 8.2 Hz, 1H), 4.81 (td, J = 8.2, 6.1 Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.19 (dd, J = 14.2, 6.2 Hz, 1H), 3.9 (dd, J = 14.2, 6.1 Hz, 1H), 1.12 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) 178.1, 172.3, 149.4, 148.6, 131.8, 121.4, 112.5, 88.9, 56.1, 55.8, 52.8, 52.5, 42., 38.6, HRMS (ESI + ) [M+H] + Calcd for C 17 H 25 INO + 5 : ; Found: MeO SnMe 3 OMe CO 2 Me NHPiv (S5) Step 5: N-(tert-butylcarbonyl)-2-trimethylstannyl-3,4-di(methoxy)-L-phenylalanine methyl ester (S5). A 2 ml vial was charged with iodo-dopa S4 (335 mg,.75 mmol, 1. equiv), and it was brought inside of a glove box. Lithium chloride (151 mg, 3.6 mmol, 4.8 equiv) and Pd(PPh 3 ) 4 (172 mg,.15 mmol,.2 equiv) were added as solids. The combined solids were then dissolved in PhMe (1 ml) at room temperature. Hexamethylditin (.8 ml, 3.9 mmol, 5.2 equiv) was added via syringe, and the vial was sealed and removed from the glove box. The sealed vial was heated to 1 ºC. The initially yellow solution turned black during the course of the reaction. After 2 h, the vial was cooled to room temperature, and the solution was filtered through celite and concentrated under vacuum. Final purification via flash chromatography (25 g Biotage SNAP S11

12 silica column, gradient from % to 1% EtOAc in hexanes, R f =.5 in 3% EtOAc in hexanes) afforded stannane S5 as a light yellow oil (249 mg,.51 mmol, 68% yield). 1 H NMR (7 MHz, CDCl 3 ) δ 6.87 (s, 1H), 6.72 (s, 1H), 5.88 (d, J = 7.7 Hz, 1H), 4.76 (ddd, J = 9.1, 7.7, 6.2 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.69 (s, 3H), 3.14 (dd, J = 14.3, 6.2 Hz, 1H), 2.89 (dd, J = 14.3, 9.1 Hz, 1H), 1.7 (s, 9H),.33 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) δ 178., 172.8, 149.3, 147.4, 135.4, 133., 118.5, 111.9, 55.9, 55.8, 53., 52.3, 4.4, 38.5, 27.3, 7.9. HRMS (ESI + ) [M+H] + Calcd for C 2 H 34 NO 5 Sn + : ; Found: I OTs CO 2 Me MeO OMe NHPiv (14-OTs) Step 6: (Mesityl)(N-(tert-butylcarbonyl)-3,4-di(methoxy)-L-phenylalanine methyl ester)-2-iodonium tosylate (14-OTs). Formation of (mesityl)(dopa)iodonium tosylate 14-OTs was accomplished by following a procedure adapted from the literature. 8 A 2 ml vial was charged with a solution of stannane S5 (247 mg,.51 mmol, 1. equiv) in CH 2 Cl 2 (1 ml). Solid MesI(OH)(OTs) (254 mg,.59 mmol, 1.2 equiv) was added at room temperature. After 5 min, the solution was concentrated under a stream of nitrogen. Final purification via flash chromatography (25 g Biotage SNAP silica column, gradient from % to 1% iproh in CH 2 Cl 2, R f =.5 in 1% iproh in CH 2 Cl 2 ) afforded DOPA-iodonium tosylate 14-OTs as a colorless oil (233 mg,.32 mmol, 62% yield). The oil could be solidified by dissolving it in CH 2 Cl 2 followed by the slow addition of hexanes. The mixture of solvents was then removed under vacuum to afford a white solid. 1 H NMR (7 MHz, CD 3 OD) δ 8.4 (d, J = 7.8 Hz, 1H, exchanges), 7.69 (d, J = 7. Hz, 2H), 7.21 (d, J = 7. Hz, 2H), 7.19 (s, 2H), 7.13 (s, 1H), 7.6 (s, 1H), 4.58 (apparent q, J = 7.5 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H), 3.4 (dd, J = 14.5, 7.2 Hz, 1H), 3.22 (dd, J = 14.5, 8.1 Hz, 1H), 2.6 (s, 6H), 2.36 (s, 3H), 2.34 (s, 3H), 1.8 (s, 9H).!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 8 Chun, J.-H.; Pike, V. W. J. Org. Chem. 212, 77, S12

13 13 C NMR (176 MHz, CD 3 OD) δ 18.1, 171.7, 152.5, 149.9, 144.3, 142., 14.2, 133.8, 13., (2C), 125.7, 12.7, 117.6, 113.9, 15., 55.4, 55.3, 52.6, 51.7, 38.6, 38.1, 26.2, 25.4, 19.8, HRMS (ESI + ) [M OTs] + Calcd for C 26 H 35 INO + 5 : ; Found: I BF 4 CO 2 Me MeO OMe NHPiv (14-BF 4 ) (Mesityl)(N-(tert-butylcarbonyl)-3,4-di(methoxy)-L-phenylalanine methyl ester)-2-iodonium tetrafluoroborate (14-BF 4 ). Anion metathesis was conducted from 14-OTs: A solution of iodonium salt 14-OTs (64 mg,.86 mmol) in CH 2 Cl 2 was vigorously stirred with saturated LiBF 4 (aq) at room temperature for 2.5 h. After which time, the phases were separated, a small quantity of water was added so that the aqueous layer was less dense than CH 2 Cl 2 and the resulting solution was extracted with CH 2 Cl 2, dried over Na 2 SO 4, filtered, and concentrated under vacuum. This produced idodonium salt 14-BF 4 as an oil. The oil could be solidified by dissolving it in CH 2 Cl 2 followed by the slow addition of hexanes. The mixture of solvents was then removed under vacuum to afford a white solid (53 mg, 93%). 1 H NMR (7 MHz, CDCl 3 ) δ 7.33 (d, J = 8. Hz, 1H), 7.2 (s, 1H), 7.9 (s, 2H), 6.73 (s, 1H), 4.73 (td, J = 8.6, 5.6 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 3.63 (s, 3H), 3.53 (dd, J = 14.3, 9.1 Hz, 1H), 3.29 (dd, J = 14.3, 5.6 Hz, 1H), 2.57 (s, 6H), 2.32 (s, 3H), 1.13 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) 179.4, 172.9, 152.7, 149.9, 144.7, 142.4, 134.5, 13.6, 118.9, 115.5, 114.2, 16., 56.5, 56.3, 52.9, 52.8, 39.9, 38.5, 27.1, 26.8, F NMR (471 MHz, CDCl 3 ) δ , HRMS (ESI + ) [M BF 4 ] + Calcd for C 26 H 35 INO + 5 : ; Found: S13

14 III. Synthesis and Characterization of Fluorinated Standards H N O (6-19 F) F N-(4-fluorophenyl)acetamide (6-19 F) was prepared according to a literature procedure. 9 The 1 H, 13 C and 19 F NMR spectroscopic data for 6-19 F were identical to that reported. 1 (CAS: ) CO 2 Me F NHAc (13-19 F) N-(methylcarbonyl)-4-fluoro-L-phenylalanine methyl ester (13-19 F) was prepared according to the literature procedure. 1 In a glovebox, diaryliodonium tetrafluoroborate (55.3 mg.1 mmol, 1 equiv), Cu(OTf) 2 (18.1 mg,.5 mmol,.5 equiv), KF (6.4 mg,.11 mmol, 1.1 equiv), and 18- crown-6 (1.6 mg,.4 mmol,.4 equiv) were dissolved in DMF (.5 ml,.2 M) in a 4 ml vial. The vial was sealed with a Teflon-lined cap, and the reaction mixture was stirred at 6 ºC for 18 h. After cooling to room temperature, the reaction was quenched with saturated aqueous NaHCO 3. The resulting mixture was extracted with pentane (3 x 1 ml), and the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. The resulting crude residue was purified by column chromatography (silica, gradient from % to 5% EtOAc in hexanes, R f =.7 5% EtOAc in hexanes) to afford F as a colorless oil (17.3 mg,.6 mmol, 67% yield). The 1 H, 13 C and 19 F NMR spectroscopic data for F were identical to that reported. 11 HRMS (ESI + ) [M-H + ] Calculated for C 12 H 14 FNO 3 : 24.13; Found !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 9 Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 28, 13, Prakash, G. K. S.; Moran, M. D.; Mathew, T.; Olah, G. A. J. Fluorine Chem. 29, 13, Oki, H.; Oura, I.; Nakamura, T.; Ogata, K.; Fukuzawa, S. Tetrahedron: Asymmetry 29, 2, S14

15 F CO 2 Me MeO NHPiv OMe (15-19 F) (S)-N-(methylcarbonyl)-4-(methylhydroxy)-5-fluoro-L-phenylalanine methyl ester (15-19 F) was prepared according to the literature procedure. 1 In a glovebox, diaryliodonium tosylate 14-OTs (94 mg,.13 mmol, 1 equiv), Cu(OTf) 2 (1 mg,.3 mmol,.2 equiv), KF (8.6 mg,.15 mmol, 1.1 equiv), and 18-crown-6 (13. mg,.5 mmol,.4 equiv) were dissolved in DMF (1.3 ml,.2 M) in a 2 ml vial. The vial was sealed with a Teflon-lined cap, and the reaction mixture was stirred at 6 ºC for 2 h. After cooling to room temperature, the reaction was quenched with saturated aqueous NaHCO 3. The resulting mixture was extracted with CH 2 Cl 2 (3 x 1 ml), and the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated under vacuum. The resulting crude residue was purified by flash column chromatography (1 g Biotage SNAP silica column, gradient from % to 1% EtOAc in hexanes, R f =.5 in 3% EtOAc in hexanes), which afforded a nearly inseparable 6:1 mixture of DOPA-F (15-19 F) and DOPA-I (S4) (21 mg,.4 mmol, 39% yield of DOPA-F) as a faint yellow oil. The desired product could be separated by repeated column chromatography (1 g Biotage SNAP silica column, gradient from 5% to 2% iproh in hexanes, R f =.25 in 1% iproh in hexanes). 1 H NMR (7 MHz, CDCl 3 ) δ (m, 2H), 6.16 (d, J = 7.4 Hz, 1H), 4.78 (apparent q, J = 6.8 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 3.11 (dd, J = 14.1, 6.4 Hz, 1H), 3.8 (dd, J = 14.1, 6.6 Hz, 1H), 1.15 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) δ 178., 172.2, (d, J CF = 238 Hz), (d, J CF = 9.3 Hz), (d, J CF = 2.5 Hz), (d, J CF = 6.2 Hz), (d, J CF = 17.6 Hz), 99.8 (d, J CF = 28.5 Hz), 56.5, 56.1, 52.5, 52.4, 38.6, 31., F NMR (376 MHz, CDCl 3 ) δ (dd, J FH = 1.9, 2.6 Hz). HRMS (ESI + ) [M+H] + Calcd for C 17 H 25 FNO + 5 : ; Found: S15

16 III. Radiochemistry A. General Methods Material and Methods. Unless otherwise stated, reagents and solvents were commercially available and used without further purification. Ethanol was purchased from American Regent. HPLC grade acetonitrile was purchased from Fisher Scientific. 18-Crown-6 and anhydrous N,Ndimethylformamide were purchased from Sigma-Aldrich. Sterile product vials were purchased from Hollister-Stier. QMA-light Sep-Paks were purchased from Waters Corporation. QMA-light Sep-Paks were flushed with 1 ml of ethanol followed by 1 ml of.5 M sodium bicarbonate solution, and finally 1 ml of sterile water prior to use. Synthesis of [ 18 F]KF!18-crown-6!K 2 CO 3 Complex. All loading operations were conducted under ambient atmosphere. Argon was used as a pressurizing gas during automated sample transfers. Potassium [ 18 F]fluoride was prepared using a TRACERLab FX FN automated radiochemistry synthesis module (General Electric, GE). [ 18 F]Fluoride was produced via the 18 O(p,n) 18 F nuclear reaction using a GE PETTrace cyclotron (4 μa beam for 2 min generated ca. 15 mci of [ 18 F]fluoride). The [ 18 F]fluoride was delivered to the synthesis module in a 1.5 ml bolus of [ 18 O]water and trapped on a QMA-light Sep-Pak to remove [ 18 O]water. [ 18 F]Fluoride was eluted into the reaction vessel using aqueous potassium carbonate (3.5 mg in.5 ml of water). A solution of 18-crown-6 (15 mg in 1 ml of acetonitrile) was added to the reaction vessel, and the resulting solution was dried by azeotropic distillation to give dry [ 18 F]KF!18-crown-6!K 2 CO 3. Evaporation was achieved by heating the reaction vessel to 1 C and drawing vacuum for 4 min. After this time, the reaction vessel was subjected to an argon stream and simultaneous vacuum draw for an additional 4 min. Finally, N,N-dimethylformamide (8 ml) was added to the dried reagent, and the resulting solution was transferred to a sterile vial for subsequent use in reactions (approx. 3 mci of prepared 18 F reagent was transferred). S16

17 B. Radiosynthesis of 18 F Labeled Molecules a. General Procedures for Manual Synthesis of 18 F-labeled Compounds (activity of 3-7 μci per reaction). On the bench top, solid [Mes-I-Ar]X (6 μmol) was weighed into a 4 ml amber glass vial containing a stir bar and was then dissolved in DMF (35 μl). A stock solution of tetrakis(acetonitrile)copper(i) triflate (CuOTf) was prepared (14.3 mg in 1 ml of anhydrous DMF,.4 M), and aliquots of this solution were used for several reactions. A 15 μl aliquot of CuOTf solution (6 μmol) was added to the vial containing [Mes-I-Ar]X. The reaction vial was sealed under an atmosphere of ambient air with a PTFE/Silicone septum cap, and then the solution was thoroughly mixed (vortex shaker, Barnstead Thermolyne Type 167). Via a syringe, a 25 μl aliquot of [ 18 F]KF!18-crown-6!K 2 CO 3 complex (typically 3-9 μci, prepared as described above) was added to the reaction vial. 12 The vial was then heated in an aluminum block with stirring at 85 ºC for 2 min. After 2 min, the reaction was allowed to cool to room temperature. A 1 μl aliquot was withdrawn from the vial and added to 4 or 9 μl of CH 2 Cl 2 in a 4 ml vial (choice of volume of CH 2 Cl 2 was dependent on activity to minimize exposure). The CH 2 Cl 2 mixture was shaken by hand and then used for radio-tlc analysis to obtain radiochemical conversions (RCC). 13 In addition, a 1 μl aliquot of the reaction solution was used for radio-hplc analysis by diluting the sample into 5/5 MeCN/H 2 O (3 μl total volume). The RCC was determined by dividing the integrated area under the fluoroarene spot by the total integrated area of the TLC plate (see below for representative TLC traces). The RCC reported here do not reflect losses during the preparation of [ 18 F]KF 18-crown-6!K 2 CO 3.!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 12 On a typical day, several reactions (4-2) were set up together. Due to this, the time of mixing and time of incubation at room temperature prior to heating varied slightly from day to day. However, the results of the radiofluorination appear to be insensitive to this variation. 13 The reaction mixture was diluted to obtain more reproducible TLC results. Undiluted samples of the reaction showed the same RCC; however, broadening was observed as a result of the DMF, and this made accurate integration more difficult. Radio-TLCs where counted immediately after being developed. This was particularly critical when the fluoroarene was volatile (e.g., 4-fluoroanisole), because the apparent RCC was found to decrease as a function of time due to the product evaporating off of the TLC plate. S17

18 b. General Procedures for Automated Synthesis of 18 F-labeled Compounds 2 and 15 (initial activity of 1.5 Ci). The production-scale synthesis of radiolabeled arenes was conducted using a TRACERLab FX FN automated radiochemistry synthesis module (General Electric, GE). The synthesis module was pre-charged with a solution of the [Mes-I-Ar]X precursor (18 μmol) and tetrakisacetonitrile copper(i) triflate (8. mg, 2 μmol) in DMF (.75 ml) to be added from a single automated port prior to 18 F delivery. [ 18 F]Fluoride was produced via the 18 O(p,n) 18 F nuclear reaction using a GE PETTrace cyclotron (4 μa beam for 3 min generated 1,5 mci of [ 18 F]fluoride). The [ 18 F]fluoride was delivered to the synthesis module (in a 1.5 ml bolus of [ 18 O]water) and trapped on a QMA-light Sep-Pak to remove [ 18 O]water. [ 18 F]Fluoride was eluted into the reaction vessel using aqueous potassium carbonate (3. mg in.5 ml of water). A solution of 18-crown-6 (5 mg in 1 ml of acetonitrile) was added to the reaction vessel, and the resulting solution was dried by azeotropic distillation to give dry [ 18 F]KF!18-crown-6!K 2 CO 3. Evaporation was achieved by heating the reaction vessel to 1 C and drawing vacuum for 4 min. After this time, the reaction vessel was subjected to an argon stream and simultaneous vacuum draw for an additional 4 min. The reaction vessel was cooled to 5 C, DMF (.75 ml) was added, and the resulting mixture was stirred for 1 min. Prior to the Cu catalyzed reaction, 6-8 mci were present in the reactor based on readings from a detector inside the module. A preloaded solution of iodonium salt and copper (.75 ml volume) was added to the reaction vessel via automated injection, and the vessel was sealed, heated to 85 ºC, and held at that temperature for 2 min. The reaction vessel was then cooled to 5 C, and DMF (8.5 ml) was added. The additional DMF was not necessary, but was used to reduce hand exposure during sample manipulations and analysis. The resulting solution (1 ml) was transferred to a sterile vial for analysis (radio- TLC and radio-hplc). The activity transferred to the vial varied slightly from run to run and averaged 3-4 mci. The RCC was determined by dividing the integrated area under the fluoroarene spot by the total integrated area of the TLC plate (see below for representative TLC traces). The RCC reported here do not reflect losses during the preparation of [ 18 F]KF!18- crown-6!k 2 CO 3 (ca. 5% loss). S18

19 c. Procedure for Isolating protected [ 18 F]-F-DOPA 15. The production-scale synthesis and isolation of [ 18 F]-15 was conducted using a TRACERLab FX FN automated radiochemistry synthesis module (General Electric, GE). [ 18 F]Fluoride was produced via the 18 O(p,n) 18 F nuclear reaction using a GE PETTrace cyclotron (4 μa beam for 3 min generated 1,5 mci of [ 18 F]fluoride, End of Bombardment (EoB) reference as t = min). The [ 18 F]fluoride was delivered to the synthesis module (in a 1.5 ml bolus of [ 18 O]water) and trapped on a QMA-light Sep-Pak to remove [ 18 O]water. [ 18 F]Fluoride was eluted into the reaction vessel using aqueous potassium carbonate (3. mg in.5 ml of water). A solution of 18-crown-6 (5 mg in 1 ml of acetonitrile) was added to the reaction vessel, and the resulting solution was dried by azeotropic distillation to give dry [ 18 F]KF!18-crown-6!K 2 CO 3. Evaporation was achieved by heating the reaction vessel to 1 C and drawing vacuum for 4 min. After this time, the reaction vessel was subjected to an argon stream and simultaneous vacuum draw for an additional 4 min. The reaction vessel was cooled to 5 C, DMF (.75 ml) was added, and the resulting mixture was stirred for 1 min. Prior to the Cu catalyzed reaction 875 mci remained at t = 22 min based on the detector reading from the module. A preloaded solution of [Mes-I- DOPA]BF 4 14r (7.8 mg, 12 μmol) and tetrakis(acetonitrile) copper(i) triflate (12 μmol) in DMF (.75 ml total volume) was added to the reaction vessel via automated injection, and the vessel was sealed, heated to 85 ºC, and held at that temperature for an additional 2 min. After the reaction (t = 44 min), the vessel was cooled (6 C), quenched with sodium bicarbonate (1 ml of.5 M solution) and diluted with (2.5 ml of 4% MeCN/H 2 O), transferred to the intermediate vial and loaded onto the HPLC sample loop. Reverse phase purification was performed (1mm x 15mm Luna C18 column, 3 ml/min, 4% MeCN in H 2 O with.5 % TFA) and the gamma peak from min (t = 6 min) was collected. The eluent was collected and diluted into 5 ml of MilliQ water. The resulting solution was transferred through a Waters C18 1cc Sep-Pak to collect the desired product. The C18 Sep-Pak was then washed with MilliQ water (5 ml) to rinse residual acetonitrile to waste. The product was eluted into the product collection vial with ethanol (2 ml). The resulting solution was transferred to a sterile vial for analysis. The vial was counted using a calibrated CAPINTEC (CRC-15R) detector (16.5 mci at t = 66 min). A.2 ml sample was used for HPLC analysis, which confirmed the product s identify as [ 18 F]-15 in >98% radiochemical purity. The specific activity at the end of synthesis was 29 Ci/mmol. This represents a non-decay corrected radiochemical yield of >1% from the activity delivered to the module. S19

20 d. General HPLC Conditions. Two general sets of HPLC conditions were used. A gradient method (Method A) was used for all manual scale reactions (i.e., results shown in Tables 1 and 2 of the manuscript). For the reactions conducted with higher activity (>1 Ci initial activity), an isocratic method (HPLC method B) was used to determine the specific activity of the product (see below for specific activity determination). HPLC Conditions A. Condition: 5-95% gradient of (MeCN +.5%TFA) in (H 2 O +.5%TFA) Flow Rate: 1mL/min Column: Luna C-18 Column 15 x 4.6 mm. 5µm. -3 minutes 5% MeCN isocratic 3-2 minutes 5% to 95% MeCN linear increase 2-3 minutes 5% MeCN isocratic HPLC Conditions B. Condition: 4% (MeCN +.5%TFA) in (H 2 O +.5%TFA) Flow Rate: 1.5 ml/min Column: Luna C-18 Column 15 x 4.6 mm. 5µm. In section III_D below, two HPLC traces are presented for each substrate contained in Table 2 and eq The first trace (top) shows the RAD trace (black) of the diluted reaction mixture. The RAD trace is overlaid with the UV trace (254 nm or 28 nm, red) from the same injection. The wavelength shown is the wavelength where the analyte compound exhibited a greater absorptivity. Because of the physical separation of the two detectors, a horizontal offset of.2 min was applied to the UV trace. This offset was applied to all traces displayed below. The second trace shows the RAD and UV trace (254 nm or 28 nm) from the crude reaction mixture spiked with an authentic standard of the fluorinated product. This was used to confirm the identity of the radiofluorinated product. S2

21 e. Specific Activity Calculation. The specific activity of radiofluorinated products was determined by the following method. A sample of known volume of the crude reaction mixture was transferred to a vial, and the activity of the vial was counted using a calibrated CAPINTEC (CRC-15R) detector. The activity in the vial was then multiplied by the RCC to obtain the activity of the product in the vial. A concentration of activity in Ci/mL was thus obtained. An aliquot of the sample was then injected onto the HPLC using an isocratic method (HPLC Conditions B). The UV peak corresponding to the radiofluorinated product was determined by overlaying the UV and RAD traces (with a.2 min offset as described in the HPLC section). The UV area was then used to calculate the concentration of the product based on linear regression analysis of appropriate fluoroarene standards. A standard curve was generated from standard solutions, each run in duplicate (14 μm to 1.1 μm). This provided the concentration of the product in mmol/ml. Dividing the activity concentration (Ci/mL) by the HPLC-derived concentration of product (mmol/ml) provided the specific activity in Ci/mmol. This reflects an end of synthesis (EoS) specific activity. S21

22 integration of peak" Figure S1. Standard Curve for 4-Fluoroanisole 2 7# 6# 5# 4# 3# 2# 1# y = x # R² = 1# #!.5! 1! 1.5! 2! [4-fluoroanisole] (mm)" integration of peak" Figure S2. Standard Curve for Fluoromesitylene 35! 3! 25! 2! 15! 1! 5! y = x # R² =.99959#!!.5!.1!.15!.2! [fluoromesitylene] (mm)" S22

23 C. Additional Optimization Results (manual synthesis conditions): MeO BF 4 I (1) (CH 3 CN) 4 CuOTf K 18 F 18-crown-6 DMF, 85 C 2 min MeO (2) 18 F a Table S1. Molar Ratio of (CH 3 CN) 4 CuOTf: [4-OMePh I Mes]BF 4 Entry [Cu]:Ar 2 I + % RCC 1 :1 <1% (n = 11) 2 1:5 55 ± 5 (n = 3) 3 1:2 7 ± 11 (n = 11) 4 1:1 79 ± 8 (n = 28) 5 2:1 45 ± 9 (n = 3) a Reaction conditions: [4-OMePh-I-Mes]BF 4!1 (6 µmol), (CH 3CN) 4CuOTf catalyst (varies). [ 18 F]KF!18-crown-6!K 2CO 3 complex in DMF (25 µl, 3-7 µci). Total reaction volume 75 µl. MeO BF 4 I (1) (CH 3 CN) 4 CuOTf K 18 F 18-crown-6 DMF, 85 C 2 min MeO (2) 18 F Table S2. Precursor 1 and (CH 3 CN) 4 CuOTf Loading a Entry μmol (1 and CuOTf) %RCC ± 8 (n = 37) ± 4 (n = 3) ± 3 (n = 3) ± 11 (n = 3) a Reaction conditions: [4-OMePh-I-Mes]BF 4 1 (3-23 µmol), Cu catalyst (3-23 µmol ). [ 18 F]KF!18-crown-6!K 2CO 3 complex in DMF (25 µl, 3-7 µci). Total reaction volume 75 µl. S23

24 MeO Table S3. Influence of Temperature a Entry Temp ( o C) % RCC (n = 3) 1 2 BF 4 I 6 85 (MeCN) 4 CuOTf K 18 F 18-crown-6 DMF, Temp 2 min 39 ± 8 76 ± ± ± 12 a Reaction conditions: [4-OMePh-I-Mes]BF 4 1 (6 µmol), Cu catalyst (6 µmol). [[ 18 F]KF!18-crown-6!K 2CO 3 complex in DMF (25 µl, 3-7 µci). Total reaction volume 75 µl. Note: as the temperature increases, the UV trace of the HPLC analysis became noticeably more complicated, suggesting that side reactions occur at high temperatures. MeO 18 F S24

25 MeO BF 4 I (MeCN) 4 CuOTf K 18 F 18-crown-6 DMF, 85 C Time MeO 18 F Table S4. Time Points for the Fluorination of [4-OMePh I Mes]BF 4 Entry Time (min) % RCC (n = 2) ± ± ± ± ± ± 8 a Reaction conditions: [4-OMePh-I-Mes]BF 4 1 (6 µmol), Cu catalyst (6 µmol). [ 18 F]KF!18-crown-6!K 2CO 3 complex in DMF (25 µl, 3-7 µci). Total reaction volume 75 µl. Note: General procedure for manual synthesis was followed and each vial was stopped at the different times shown in Table S4. TLC analysis was conducted immediately, without dilution. S25

26 D. Radio-HPLC/Radio-TLC analysis for 18 F-labeled Compounds 2-11, 13, and F MeO (2) HPLC Conditions: General HPLC Condition A 4-[ 18 F]fluoroanisole 2 RAD trace overlaid with UV trace (28 nm) 6 RAD 2614_4-OMe-1 UV Detector Ch2-28nm 2614_4-OMe Minutes 4-[ 18 F]fluoroanisole 2 RAD trace overlaid with UV trace (28 nm) spiked with 4-fluoroanisole RAD 2614_4-OMe-1_spiked 25uL stock UV Detector Ch2-28nm 2614_4-OMe-1_spiked 25uL stock Minutes S26

27 18 F MeO (2) 12 Radio-TLC Conditions: 2% EtOAc/Hexane QUICKSTART - pome2-3b.r1 1 8 Counts [ 18 F]fluoroanisole 2 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield 14 Replicate TLC Yield % 1 % (5%F-Mes) % 2 % (3% F-Mes) % % % 6 92.% Average 86% Average % (4% F-Mes) Standard Deviation 9% Standard Deviation - F-Mes = [ 18 F]fluoromesitylene!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 14 Representative radiochemical conversions are shown in this table from n = 37. All the yields shown here were obtained from reactions run on the same day.!! Position (mm) S27

28 MeO 18 F MeO (3) HPLC Conditions: General HPLC Condition A [ 18 F]3,4-(dimethoxyl)fluorobenzene 3 RAD trace overlaid with UV trace (28 nm) 6 RAD UV Detector Ch2-28nm _3,4-OMe _3,4-OMe Minutes [ 18 F]3,4-(dimethoxyl)fluorobenzene 3 RAD trace overlaid with UV trace (28 nm) spiked with with 3,4-(dimethoxyl)fluorobenzene RAD 2514_3,4-OMe_spiked w 25uL stock UV Detector Ch2-28nm 2514_3,4-OMe_spiked w 25uL stock Minutes S28

29 MeO 18 F MeO (3) 2 Radio-TLC Conditions: 5% EtOAc/Hexanes! QUICKSTART OMe-1.R1 15 Counts Position (mm) [ 18 F] 3,4-(dimethoxyl)fluorobenzene 3 TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % % 2 % % % 5 6.4% Average 51% Average % Standard Deviation 6% Standard Deviation - S29

30 MeO 18 F MeO OMe (4) HPLC Conditions: General HPLC Condition A [ 18 F](3,4,5-trimethoxy)fluorobenzene 4 RAD trace overlaid with UV trace (28 nm) Minutes [ 18 F](3,4,5-trimethoxy)fluorobenzene 4 RAD trace overlaid with UV trace (28 nm) spiked with 3,4,5-trimethoxyfluorobenzene Minutes S3

31 MeO 18 F MeO OMe (4) Radio-TLC Conditions: 5% EtOAc/Hexanes 15 QUICKSTART OMe-2-5%.R1 1 Counts Position (mm) [ 18 F](3,4,5-trimethoxy)fluorobenzene 4 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % % 2 % % % % Average 14% Average % Standard Deviation 2% Standard Deviation - S31

32 OMe 18 F (5) HPLC Conditions: General HPLC Condition A 2-[ 18 F]fluoroanisole 5 RAD trace overlaid with UV trace (28 nm) RAD UV Detector Ch2-28nm _2-OMe _2-OMe Minutes 2-[ 18 F]fluoroanisole 5 RAD trace overlaid with UV trace (28 nm) spiked with 2-fluoroanisole RAD 2514_2-OMe-1 spiked with 25uL stock UV Detector Ch2-28nm 2514_2-OMe-1 spiked with 25uL stock Minutes S32

33 OMe 18 F (5) 12 Radio-TLC Conditions: 2% EtOAc/Hexane QUICKSTART - 2-OMe-6.R1 1 8 Counts Position (mm) 2-[ 18 F]fluoroanisole 5 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % % 2 % % 4 32.% % Average 3% Average % Standard Deviation 8% Standard Deviation - S33

34 O 18 F N H (6) HPLC Conditions: General HPLC Condition A 4-[ 18 F]fluorophenylacetamide 6 RAD trace overlaid with UV trace (28 nm) Minutes 4-[ 18 F]fluorophenylacetamide 6 RAD trace overlaid with UV trace (28 nm) spiked with 4- fluorophenylacetamide Minutes S34

35 O 18 F N H (6) 25 Radio-TLC Conditions: 8% EtOAc/Hexane QUICKSTART - NHAc-1.R1 2 Counts Position (mm) 4-[ 18 F]fluorophenylacetamide 6 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % 2 65.% 2 % % Average 66% Average % Standard Deviation 2% Standard Deviation - S35

36 18 F Ph (7) HPLC Conditions: General HPLC Condition A 4-[ 18 F]fluorobiphenyl 7 RAD trace overlaid with UV trace (254 nm) RAD 2614_biphen-1 UV Detector Ch1-254nm 2614_biphen Minutes 4-[ 18 F]fluorobiphenyl 7 RAD trace overlaid with UV trace (254 nm) spiked with 4-fluorobiphenyl 4 RAD 2614_biphen-1_spiked 25uL stock UV Detector Ch1-254nm 2614_biphen-1_spiked 25uL stock Minutes S36

37 18 F Ph (7) Radio-TLC Conditions: 1% EtOAc 1 QUICKSTART - biphen r1 8 Counts Position (mm) 4-[ 18 F]fluorobiphenyl 7 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 3% % 2 1% % Average 51% Average 2% Standard Deviation 8% Standard Deviation - S37

38 O Me H H H (8) 18 F HPLC Conditions: General HPLC Condition A [ 18 F]fluoro-estrone 8 RAD trace overlaid with UV trace (254 nm) RAD 2614_estrone-1-2 UV Detector Ch1-254nm 2614_estrone Minutes [ 18 F]fluoro-estrone 8 RAD trace overlaid with UV trace (254 nm) spiked with fluoro-estrone 1 RAD 2614_estrone-1-2_spiked_25uLstock UV Detector Ch2-28nm 2614_estrone-1-2_spiked_25uLstock Minutes S38

39 O Me H H H (8) 18 F 8 Radio-TLC Conditions: 5% EtOAc/Hexanes QUICKSTART - ES-3.R1 6 Counts Position (mm) [ 18 F]fluoro-estrone 8 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % % 2 % % Average 67% Average % Standard Deviation 2% Standard Deviation - S39

40 18 F I (9) HPLC Conditions: General HPLC Condition A 4-[ 18 F]fluoro-iodobenzene 9 RAD trace overlaid with UV trace (28 nm) Minutes 4-[ 18 F]fluoro-iodobenzene 9 RAD trace overlaid with UV trace (28 nm) spiked with 4-fluoroiodobenzene Minutes S4

41 18 F I (9) 4 Radio-TLC Conditions: 5% EtOAc/Hexanes 3 Counts Position (mm) 4-[ 18 F]fluoro-iodobenzene 9 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 1.9% % 2 1.4% % Average 35% Average 1.7% Standard Deviation 8% Standard Deviation.4% S41

42 18 F O (1) OMe HPLC Conditions: General HPLC Condition A Methyl 3-[ 18 F]fluorobenzoate 1 RAD trace overlaid with UV trace (28 nm) RAD _mCO2Me_1 UV Detector Ch2-28nm _mCO2Me_ Minutes Methyl 3-[ 18 F]fluorobenzoate 1 RAD trace overlaid with UV trace (28 nm) spiked with methyl-3- fluorobenzoate 8 RAD _mCO2Me_spiked.1 UV Detector Ch2-28nm _mCO2Me_spiked Minutes S42

43 18 F O (1) OMe 6 Radio-TLC Conditions: 1% EtOAc QUICKSTART - 3-CO2Me-2.R1 5 4 Counts Position (mm) Methyl 3-[ 18 F]fluorobenzoate 1 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % 2 61.% 2 % 3 6.1% Average 58% Average % Standard Deviation 4% Standard Deviation - S43

44 H O 18 F (11) HPLC Conditions: General HPLC Condition A 3-[ 18 F]fluorobenzaldehyde 11 RAD trace overlaid with UV trace (254 nm) Minutes 3-[ 18 F]fluorobenzaldehyde 11 RAD trace overlaid with UV trace (254 nm) spiked with 3- fluorobenzaldehyde Minutes S44

45 H O 18 F (11) 8 Radio-TLC Conditions: 1% EtOAc/Hexanes QUICKSTART - mcho r1 6 Counts Position (mm) 3-[ 18 F]fluorobenzoate 11 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % 2 35% 2 % % Average 35% Average % Standard Deviation 1% Standard Deviation - S45

46 CO 2 Me 18 F NHAc (13) HPLC Conditions: General HPLC Condition A [ 18 F]fluoro-L-phenylalanine 13 RAD trace overlaid with UV trace (254 nm) Minutes [ 18 F]fluoro-L-phenylalanine 13 RAD trace overlaid with UV trace (254 nm) spiked with fluoro-lphenylalanine! Minutes S46

47 CO 2 Me 18 F NHAc (13) 25 Radio-TLC Conditions: 1% EtOAc QUICKSTART - PheAc-1.R1 2 Counts Position (mm) 4-[ 18 F]fluoro-L-phenylalanine 13 Raw TLC Yields Reaction under standard conditions Control Reactions without CuOTf Replicate TLC Yield Replicate TLC Yield % 1 % % 2 % % Average 23% Average % Standard Deviation 6% Standard Deviation - S47