Electronic Supporting Information. Synthesis and Reactivity of 18 F-Labeled α,α-difluoro-α-aryloxyacetic Acids

Transcript

1 Electronic Supporting Information Synthesis and Reactivity of 18 F-Labeled α,α-difluoro-α-aryloxyacetic Acids Tanatorn Khotavivattana,, Samuel Calderwood,, Stefan Verhoog, Lukas Pfeifer, Sean Preshlock, Neil Vasdev,,# Thomas L. Collier,,#,^ and Véronique Gouverneur*, Chemistry Research Laboratory, University of xford, Mansfield Road, xford X1 3TA, U.K. Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, 55 Fruit Street, Boston, USA. # Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, USA. ^Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, New York, USA. 1

2 Table of Contents 1. General Experimental Information 3 2. General Experimental Procedures and Characterisation Data Aryl-CFHC2Et Aryl-CFBrC2Et (1) Aryl-CF2C2Et (2) Aryl-CF2C2H (3) Post-Fluorination Reactions ptimisation Table ptimization for the synthesis of [ 18 F]2a from 1a (S1) ptimization for the synthesis of [ 18 F]3a from 1a (S2) ptimization for the synthesis of [ 18 F]4 from [ 18 F]3a (S3) ptimization for the synthesis of 6 from 3a (S4) General Radiochemical Procedures Radio-HPLC Traces Post-Fluorination Functionalization Specific Activity Calculation References NMR Spectra Aryl-CFHC2Et Aryl-CFBrC2Et (1) Aryl-CF2C2Et (2) Aryl-CF2C2H (3) Post-Fluorination Reactions 98 2

3 1. General Experimental Information All NMR spectra were recorded on Bruker DPX200, DPX250, AV400, AVC500, AVB500 and DRX500 spectrometers. 1 H and 13 C NMR spectra are reported as chemical shifts (δ) in parts per million (ppm) relative to the solvent peak using the Bruker internal referencing procedure (edlock). 19 F NMR spectra are referenced relative to CFCl 3 in CDCl 3. Coupling constants (J) are reported in units of hertz (Hz). The following abbreviations are used to describe multiplicities s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br s (broad singlet). High resolution mass spectra (HRMS, m/z) were recorded on a Bruker MicroTF spectrometer using positive electrospray ionization (ESI + ) or on a Micromass GCT spectrometer using filed ionization (FI + ) or chemical ionization (CI + ). Infrared spectra were recorded either as the neat compound or in a solution using a Bruker Tensor 27 FT-IR spectrometer. Absorptions are reported in wavenumbers (cm -1 ) and only peaks of interest are reported. ptical rotations were measured on a PerkinElmer Polarimeter model 341 Specific rotations are reported in 10-1 deg cm 2 g -1 and concentrations in g/100 ml. Melting points of solids were measured on a Griffin apparatus and are uncorrected. IUPAC names were obtained using the ACD/I- Lab service. Solvents were purchased from Fisher, Rathburn or Sigma-Aldrich. When dry solvents were required they were purified by expression through an activated alumina column built according to the procedures described by Pangborn and Grubbs. 1 Chemicals were purchased from Acros, Alfa Aesar, Fisher, Fluorochem, Sigma-Aldrich and used as received. Reactions were monitored by thin layer chromatography (TLC) carried out on Merck Kiesegel 60 F254 plates, silica gel column chromatography was performed over Merck silica gel C60 (40-60 μm). 3

4 2. General Experimental Procedures and Characterisation Data Aryl-CFBrC 2Et precursors (1), Aryl-CF 2C 2Et references (2), Aryl-CF 2C 2H references (3) and other fluorinated references were purchased from commercial sources, or synthesised based on procedures detailed below. General Procedure A: Preparation of Aryl-CFHC 2Et from Phenols 2 To a suspension of K 2C 3 (25 mmol) in a solution of an appropriate phenol (10 mmol) in DMF (20 ml) was slowly added ethyl bromofluoroacetate (15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The reaction mixture was poured on to water, extracted with Et 2 (3 100 ml), dried over MgS 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography. General Procedure B: Preparation of Aryl-CFBrC 2Et (1) from Aryl-CFHC 2Et To a solution of Aryl-CHFC 2Et (4.0 mmol) in CCl 4 (30 ml) was added N-bromosuccinimide (2.4 mmol). The reaction was allowed to stir for 16 hours at room temperature under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography. General Procedure C: Preparation of Aryl-CF 2C 2Et (2) from Phenols 2 To a suspension of K 2C 3 (25 mmol) in a solution of an appropriate phenol (10 mmol) in DMF (20 ml) was slowly added ethyl bromodifluoroacetate (15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. The reaction mixture was poured on to water, extracted with Et 2 (3 100 ml), dried over MgS 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography. General Procedure D: Preparation of Aryl-CF 2C 2H (3) from Aryl-CF 2C 2Et (2) 2 To a solution of an Aryl-CF 2C 2Et (5.0 mmol) in Et 2 (25 ml) was added 5 M aq. NaH (25.0 mmol). The reaction mixture was stirred at room temperature for 3 hours before diluting with Et 2. The reaction mixture was extracted with sat. aq. NaHC 3 (3 x 20 ml). The combined aqueous layers were acidified to ph 1 and extracted with Et 2 (3 x 20 ml), then the combined organic phases were washed with brine, dried over MgS 4 and concentrated in vacuo. Products were purified by washing with n-pentane. 2.1 Aryl-CFHC2Et Ethyl (4-tert-butylphenoxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (13.8 g, mmol), 4-tert-butylphenol (6.00 g, 40.0 mmol), ethyl bromofluoroacetate (7.10 ml, 60.0 mmol) and DMF (80 ml). The crude product was purified by silica gel column chromatography (eluent: 10 % Et 2 in petroleum ether) to provide the title compound (7.92 g, 78 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.37 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 5.95 (d, J = 60.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.32 (s, 9H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.8 Hz), (d, J = 3.2 Hz), 147.3, 126.6, 117.0, (d, J = Hz), 62.5, 34.3, 31.4, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 60.7 Hz); IR: ν 2964, 1769, 1608, 1511, 1364, 1216, 1185, 1097, 1014, 965, 833; HRMS (ESI) for C 14H 19FNa 3 [M+Na] + requires found Data consistent with literature values. 2 4

5 Ethyl (biphenyl-4-yloxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (3.46 g, 25.0 mmol), 4-phenylphenol (1.70 g, 10.0 mmol), ethyl bromofluoroacetate (1.77 ml, 15.0 mmol) and DMF (20 ml). The crude product was purified by silica gel column chromatography (eluent: 15 % Et 2 in petroleum ether) to provide the title compound (2.57 g, 94 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 4H), (m, 2H), (m, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.04 (d, J = 59.9 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 155.1, 140.1, 137.5, 128.9, 128.4, 127.2, 126.8, 117.7, (d, J = Hz), 62.5, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 60.7 Hz); IR: ν 1768, 1608, 1518, 1486, 1217, 1103, 1007, 838; HRMS (ESI) for C 16H 15FNa 3 [M+Na] + requires found ; Mp C. Data consistent with literature values. 2 Ethyl fluoro(phenoxy)acetate The title compound was prepared following general procedure A using potassium carbonate (6.91 g, 50.0 mmol), phenol (1.88 g, 20.0 mmol), ethyl bromofluoroacetate (3.55 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 20 % Et 2 in n-pentane) to provide the title compound (1.28 g, 32 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 3H), 5.98 (d, J = 59.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), (d, J = 3.2 Hz), 129.8, 124.4, 117.4, (d, J = Hz), 62.5, 14.0; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 60.7 Hz). Data consistent with literature values. 3 Ethyl (4-bromophenoxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (10.4 g, 75.0 mmol), 4-bromophenol (5.19 g, 30.0 mmol), ethyl bromofluoroacetate (5.32 ml, 45.0 mmol) and DMF (60 ml). The crude product was purified by silica gel column chromatography (eluent: 10 % Et 2 in n-pentane) to provide the title compound (4.46 g, 54 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.47 (dt, J 1 = 2.7 Hz, J 2 = 9.1 Hz, 2H), 7.03 (dt, J 1 = 2.4 Hz, J 2 = 9.1 Hz, 2H), 5.91 (d, J = 59.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), (d, J = 3.2 Hz), 132.8, (d, J = 1.6 Hz), 117.2, (d, J = Hz), 62.7, 14.0; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 60.7 Hz); IR: ν 1765, 1584, 1486, 1384, 1211, 1175, 1099, 1071, 1008, 965, 825; HRMS (ESI) for C 10H 10BrFNa 3 [M+Na] + requires found Data consistent with literature values. 2 5

6 Ethyl (3-bromophenoxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (10.4 g, 75.0 mmol), 3-bromophenol (5.19 g, 30.0 mmol), ethyl bromofluoroacetate (5.32 ml, 45.0 mmol) and DMF (60 ml). The crude product was purified by silica gel column chromatography (eluent: 10 % Et 2 in n-pentane) to provide the title compound (6.88 g, 83 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 1H), (m, 1H), 5.94 (q, J = 59.2, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), (d, J = 2.4 Hz), 130.9, 127.6, 122.8, 121.0, 116.1, (d, J = Hz), 62.7, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 59.0 Hz); IR: ν 1761, 1582, 1474, 1382, 1209, 1102, 1023, 965, 884; HRMS (ESI) for C 10H 10BrFNa 3 [M+Na] + requires found Data consistent with literature values. 2 Ethyl (2-bromophenoxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (6.91 g, 50.0 mmol), 2-bromophenol (3.46 g, 20.0 mmol), ethyl bromofluoroacetate (3.55 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 20 % Et 2 in n-pentane) to provide the title compound (4.68 g, 85 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.60 (dd, J 1 = 1.5 Hz, J 2 = 7.8 Hz, 1H), (m, 1H), 7.23 (dt, J 1 = 1.4 Hz, J 2 = 8.1 Hz, 1H), (m, 1H), 5.91 (d, J = 59.2 Hz, 1H), (m, 2H), 1.38 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), (d, J = 3.2 Hz), 133.8, 128.8, 126.0, 119.2, (d, J = 1.6 Hz), (d, J = Hz), 62.6, 14.0; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 59.0 Hz); IR: ν 1766, 1579, 1477, 1445, 1384, 1218, 1134, 1095, 1028, 965, 857; HRMS (EI/FI) for C 10H 10BrF 3 [M] + requires found Data consistent with literature values. 2 Ethyl 2-fluoro-2-(2-fluorophenoxy)acetate The title compound was prepared following general procedure A using K 2C 3 (6.91 g, 50.0 mmol), 2- fluorophenol (1.79 ml, 20.0 mmol), ethyl bromofluoroacetate (3.55 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 0-10% Et 2 in n-pentane) to provide the title compound (2.68 g, 12.4 mmol, 62%) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 1 H), (m, 3 H), 6.02 (d, J = 59.2 Hz, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), (dd, J = 1.6, Hz), (dd, J = 2.4, 11.1 Hz), (d, J = 7.2 Hz), (d, J = 4.0 Hz), 120.5, (d, J = 18.3 Hz), (dd, J = 1.6, Hz), 62.6, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = (dd, J = 3.4, 59.5 Hz), (m); IR (neat): ν 3076, 2987, 2942, 2906, 2365, 2329, 1764, 1604, 1503, 1459, 1415, 1377, 1352, 1303, 1261, 1229, 1193, 1122, 1090, 1058, 1017, 961, 858, 818, 754, 676; HRMS (ESI) for C 10H 10F 2Na 3 [M+Na] + requires found

7 tert-butyl 4-hydroxybenzoate To a solution of 4-hydroxybenzoic acid (6.91 g, 50.0 mmol), 4-DMAP (244 mg, 2.00 mmol) and tertbutanol (150 ml) in THF (220 ml) at rt was slowly added DCC (11.3 g, 55.0 mmol) dissolved in THF (80 ml). The resulting solution was stirred at rt for 23 h. The formed solid was filtered off and the filtrate was washed with aq. Na2C3 (0.30 M), dried over MgS4 and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (eluent: 0-15% Et2 in n- pentane) to give the title compound (5.50 g, 28.3 mmol, 57%) as a white solid. ( 1 H NMR, 400 MHz, CDCl3): δ = (m, 2 H), 7.48 (br s, 1 H), (m, 2 H), 1.60 (s, 9 H); ( 13 C NMR, 101 MHz, CDCl3): δ = 166.7, 160.3, 131.7, 123.6, 115.2, 81.3, Data consistent with literature values. 11 tert-butyl 4-(2-ethoxy-1-fluoro-2-oxoethoxy)benzoate The title compound was prepared following general procedure A using K 2C 3 (5.18 g, 37.5 mmol), tertbutyl 4-hydroxybenzoate (2.91 g, 15.0 mmol), ethyl bromofluoroacetate (2.66 ml, 22.5 mmol) and DMF (30 ml). The crude product was purified by silica gel column chromatography (eluent: 0-12% Et 2 in n-pentane) to provide the title compound (3.41 g, 11.4 mmol, 76%) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): = (m, 2 H), (m, 2 H), 6.02 (d, J = 59.2 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 1.57 (s, 9 H), 1.35 (t, J = 7.2 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): = 164.8, (d, J = 31.0 Hz), (d, J = 2.4 Hz), 131.5, 128.0, 116.5, (d, J = Hz), 81.0, 62.7, 28.1, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): = (d, J = 59.5 Hz); IR (neat): ν 2980, 2934, 2903, 2874, 2364, 2329, 1766, 1709, 1604, 1508, 1467, 1452, 1420, 1368, 1294, 1217, 1161, 1102, 1057, 1014, 959, 852, 770, 695; HRMS (ESI) for C 15H 19FNa 5 [M+Na] + requires found Ethyl (4-benzoylphenoxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (6.91 g, 50.0 mmol), 4-hydroxybenzophenone (3.96 g, 20.0 mmol), ethyl bromofluoroacetate (3.55 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 30 % Et 2 in n-pentane) to provide the title compound (5.50 g, 91 % yield) as a pale yellow oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.85 (dt, J 1 = 2.3 Hz, J 2 = 8.8 Hz, 2H), (m, 2H), 7.59 (tt, J 1 = 1.9 Hz, J 2 = 7.5 Hz, 1H), (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.08 (d, J = 59.2 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 195.3, (d, J = 31.0 Hz), (d, J = 2.4 Hz), 137.5, 133.5, 132.4, 132.3, 129.8, 128.3, 116.6, (d, J = Hz), 62.8, 13.9; ( 19 F NMR, 7

8 377 MHz, CDCl 3): δ = (d, J = 59.0 Hz); IR: ν 1766, 1656, 1600, 1505, 1447, 1278, 1218, 1174, 1151, 1096, 1025, 939, 924, 848; HRMS (ESI) for C 17H 16FNa 3 [M+H] + requires found Data consistent with literature values. 2 Ethyl (3-cyanophenoxy)(fluoro)acetate The title compound was prepared following general procedure A using potassium carbonate (6.91 g, 50.0 mmol), 3-cyanophenol (2.38 g, 20.0 mmol), ethyl bromofluoroacetate (3.55 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 25 % Et 2 in n-pentane) to provide the title compound (2.33 g, 52 % yield) as a white crystal. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 2H), 5.97 (q, J = 58.9, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 30.2 Hz), (d, J = 2.4 Hz), 130.8, 128.1, 122.1, 120.8, 117.8, 113.7, (d, J = Hz), 62.8, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 59.0 Hz); IR: ν 2234, 1762, 1582, 1482, 1436, 1384, 1228, 1156, 1095, 1018, 966, 859; HRMS (EI/FI) for C 11H 10FN 3 [M] + requires found ; Mp C. Ethyl fluoro[4-(trifluoromethyl)phenoxy]acetate The title compound was prepared following general procedure A using potassium carbonate (6.91 g, 50.0 mmol), 4-(trifluoromethyl)phenol (3.24 g, 20.0 mmol), ethyl bromofluoroacetate (3.55 ml, 30.0 mmol) and DMF (60 ml). The crude product was purified by silica gel column chromatography (eluent: 10 % Et 2 in n-pentane) to provide the title compound (4.74 g, 89 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.63 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.02 (d, J = 59.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 157.9, (q, J = 4.0 Hz), (q, J = 32.9 Hz), (q, J = Hz), (d, J = 1.6 Hz), (d, J = Hz), 62.8, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = 62.1 (s, 3F), (d, J = 59.0 Hz, 1F); IR: ν 1766, 1616, 1517, 1325, 1222, 1166, 1113, 1065, 1113, 1065, 1014, 966, 840; HRMS (EI/FI) for C 11H 10F 4 3 [M] + requires found Data consistent with literature values. 2 2-(4-Hydroxyphenyl)-1H-isoindole-1,3(2H)-dione To a suspension of phthalic anhydride (5.92 g, 40.0 mmol) in MeH (100 ml) was added 4- aminophenol (4.80 g, 44.0 mmol). The mixture was heated to 70 C over night, before it was cooled to rt and concentrated in vacuo. Recrystallisation from MeH gave the title compound (6.56 g, 27.4 mmol, 69%) as a white solid. ( 1 H NMR, 400 MHz, DMS-d 6): δ = 9.77 (br s, 1 H), (m, 4 H), (m, 2 H), (m, 2 H); ( 13 C NMR, 101 MHz, DMS-d 6): δ = 167.4, 157.3, 134.6, 131.6, 128.8, 123.3, 122.9, Data consistent with literature values. 12 8

9 Ethyl 2-(4-(1,3-dioxoisoindolin-2-yl)phenoxy)-2-fluoroacetate The title compound was prepared following general procedure A using K 2C 3 (5.06 g, 36.6 mmol), 2- (4-hydroxyphenyl)-1H-isoindole-1,3(2H)-dione (3.50 g, 14.6 mmol), ethyl bromofluoroacetate (2.59 ml, 22.0 mmol) and DMF (30 ml). The crude product was purified by silica gel column chromatography (eluent: 20-70% Et 2 in n-pentane) to provide the title compound (2.94 g, 8.55 mmol, 58%) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2 H), (m, 2 H), (m, 2 H), (m, 2 H), 5.98 (d, J = 59.4 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 167.1, (d, J = 31.0 Hz), (d, J = 3.2 Hz), 134.4, 131.5, 128.0, 127.9, 123.7, 118.0, (d, J = Hz), 62.6, 13.9; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 59.5 Hz); IR (neat): ν 3073, 2987, 2365, 2329, 1764, 1711, 1606, 1512, 1464, 1387, 1295, 1222, 1173, 1122, 1089, 1018, 958, 884, 830, 791, 716; MP: 103 C; HRMS (ESI) for C 18H 15FN 5 [M+H] + requires found Aryl-CFBrC2Et (1) Ethyl (4-tert-butylphenoxy)(bromo)fluoroacetate (1a) The title compound was prepared following general procedure B; To a solution of ethyl (4-tertbutylphenoxy)(fluoro)acetate (1.62 g, 6.37 mmol) in CCl 4 (30 ml) was added N-bromosuccinimide (680 mg, 3.82 mmol). The reaction was allowed to stir for 16 hours at room temperature under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 2 % Et 2 in n-pentane) to provide the title compound (465 mg, 37 % yield) as a pale yellow oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.41 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 149.5, 149.4, 126.3, (d, J = 1.6 Hz), (d, J = Hz), 63.9, 34.5, 31.3, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 57.4 (s); IR: ν 2965, 1770, 1510, 1368, 1306, 1207, 1182, 1104, 1015, 919, 859; HRMS (EI/FI) for C 14H 18BrF 3 [M] + requires found Ethyl (biphenyl-4-yloxy)(bromo)fluoroacetate (1b) The title compound was prepared following general procedure B; To a solution of ethyl (biphenyl-4- yloxy)(fluoro)acetate (2.51 g, 9.15 mmol) in CCl 4 (40 ml) was added N-bromosuccinimide (979 mg, 5.5 mmol). The reaction was allowed to stir for 16 hours at 70 C under UV light irradiation. The reaction mixture was cooled to room temperature, then the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 5% Et 2 in n-pentane) to provide the title compound (732 mg, 38 % yield) as a white solid. 9

10 ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 4H), (m, 2H), (m, 3H), 4.48 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 151.1, 140.0, 139.6, 128.8, 128.2, 127.6, 127.1, (d, J = 2.4 Hz), (d, J = Hz), 64.1, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 57.6 (s); IR: ν 1515, 1485, 1371, 1305, 1204, 1171, 1100, 1008, 919, 855; HRMS (EI/FI) for C 16H 14BrF 3 [M] + requires found ; Mp C. Ethyl bromo(phenoxy)fluoroacetate (1c) The title compound was prepared following general procedure B; to a solution of ethyl fluoro(phenoxy)acetate (793 mg, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 70 C under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 5 % Et 2 in n-pentane) to provide the title compound (208 mg, 31 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 151.8, 129.5, 126.5, 121.8, (d, J = Hz), 64.0, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 57.5 (s); IR: ν 1767, 1592, 1488, 1371, 1305, 1193, 1164, 1098, 1013, 924, 848; HRMS (EI/FI) for C 10H 10BrF 3 [M] + requires found Ethyl (4-bromophenoxy)(bromo)fluoroacetate (1d) The title compound was prepared following general procedure B; to a solution of ethyl (4- bromophenoxy)(fluoro)acetate (1.11 g, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 70 C under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 3 % Et 2 in n-pentane) to provide the title compound (299 mg, 35 % yield) as a pale yellow oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.53 (dt, J 1 = 2.7 Hz, J 2 = 9.1 Hz, 2H), (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 30.2 Hz), 150.7, 132.6, 123.6, 119.9, (d, J = Hz), 64.1, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 58.4 (s); IR: ν 3301, 1760, 1666, 1609, 1543, 1509, 1411, 1372, 1312, 1209, 1103, 1016, 835; HRMS (EI/FI) for C 10H 9Br 2F 3 [M] + requires found Ethyl (3-bromophenoxy)(bromo)fluoroacetate (1e) The title compound was prepared following general procedure B; to a solution of ethyl (3- bromophenoxy)(fluoro)acetate (1.11 g, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 70 C under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column 10

11 chromatography (eluent: 5 % Et 2 in n-pentane) to provide the title compound (221 mg, 26 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 152.1, 130.6, 129.8, (d, J = 2.4 Hz), 122.4, 120.5, (d, J = Hz), 64.1, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 58.4 (s); IR: ν 2971, 1766, 1582, 1471, 1371, 1304, 1199, 1148, 1100, 1013, 924, 874; HRMS (EI/FI) for C 10H 9Br 2F 3 [M] + requires found Ethyl (2-bromophenoxy)(bromo)fluoroacetate (1f) The title compound was prepared following general procedure B; to a solution of ethyl (2- bromophenoxy)(fluoro)acetate (1.11 g, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 70 C under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 5 % Et 2 in n-pentane) to provide the title compound (195 mg, 23 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.65 (dd, J 1 = 1.5 Hz, J 2 = 8.1 Hz, 1H), 7.47 (dt, J 1 = 1.7 Hz, J 2 = 8.3 Hz, 1H), 7.36 (td, J 1 = 1.5 Hz, J 2 = 7.8 Hz, 1H), 7.18 (td, J 1 = 1.5 Hz, J 2 = 7.7 Hz, 1H), 4.46 (qd, J 1 = 1.5 Hz, J 2 = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.8 Hz), 149.2, 133.9, 128.4, 127.6, (d, J = 2.4 Hz), (d, J = 1.6 Hz), (d, J =303.6 Hz), 64.1, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 56.7 (s); IR: ν 1767, 1473, 1445, 1371, 1305, 1212, 1147, 1099, 1047, 1031, 1012, 923, 850; HRMS (EI/FI) for C 10H 9Br 2F 3 [M] + requires found Ethyl 2-bromo-2-fluoro-2-(2-fluorophenoxy)acetate (1g) The title compound was prepared following general procedure B using NBS (997 mg, 5.60 mmol), ethyl fluoro(2-fluorophenoxy)acetate (865 mg, 4.00 mmol) and CCl 4 (20 ml). The crude product was purified by silica gel column chromatography (eluent: 0-5% Et 2 in n-pentane) to provide the title compound (235 mg, 0.80 mmol, 20%) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.51 (tt, J = 1.8, 7.9 Hz, 1 H), (m, 1 H), (m, 2 H), 4.55 (q, J = 7.3 Hz, 2 H), 1.51 (t, J = 7.2 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 30.2 Hz), (d, J = Hz), (d, J = 11.9 Hz), (d, J = 7.2 Hz), (d, J = 1.6 Hz), (d, J = 4.0 Hz), (d, J = 18.3 Hz), (d, J = Hz), 64.1, 13.7; ( 19 F NMR, 377 MHz, CDCl 3): δ = (d, J = 10.3 Hz), (m); IR (neat): ν 3076, 2988, 2905, 2364, 2329, 1841, 1768, 1601, 1500, 1458, 1403, 1374, 1303, 1258, 1189, 1148, 1096, 1012, 951, 919, 859, 820, 757, 699; HRMS (ESI) for C 10H 9BrF 2Na 3 [M+Na] + requires found

12 tert-butyl 4-(1-bromo-2-ethoxy-1-fluoro-2-oxoethoxy)benzoate (1h) The title compound was prepared following general procedure B using NBS (854 mg, 4.80 mmol), tertbutyl 4-(2-ethoxy-1-fluoro-2-oxoethoxy)benzoate (1.19 g, 4.00 mmol) and CCl 4 (20 ml). The crude product was purified by silica gel column chromatography (eluent: 0-3% Et 2 in n-pentane) to provide the title compound (394 mg, 1.04 mmol, 26%) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2 H), (m, 2 H), 4.44 (dq, J = 0.7, 7.2 Hz, 2 H), 1.59 (s, 9 H), 1.40 (t, J = 7.2 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 164.6, (d, J = 30.2 Hz), 154.7, 131.0, 130.1, (d, J = 2.4 Hz), (d, J = Hz), 81.3, 64.1, 28.1, 13.7; ( 19 F NMR, 377 MHz, CDCl 3): δ = (s); IR (neat): ν 3079, 2979, 2934, 2902, 2872, 2367, 2328, 1931, 1770, 1714, 1602, 1505, 1466, 1450, 1404, 1367, 1293, 1250, 1204, 1157, 1105, 1012, 922, 853, 775, 736, 693, 649; HRMS not found using ESI, EI, FI. Ethyl (4-benzoylphenoxy)(bromo)fluoroacetate (1i) The title compound was prepared following general procedure B; to a solution of ethyl (4- benzoylphenoxy)(fluoro)acetate (1.21 g, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 70 C under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 20 % Et 2 in n-pentane) to provide the title compound (208 mg, 23 % yield) as a pale yellow oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.89 (dt, J 1 = 2.2 Hz, J 2 = 8.8 Hz, 2H), (m, 2H), 7.62 (tt, J 1 = 1.9 Hz, J 2 = 7.3 Hz, 1H), (m, 2H), (m, 2H), 4.47 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 195.4, (d, J = 30.2 Hz), 154.7, 137.3, 135.5, 132.7, 131.8, 130.0, 128.4, (d, J = 2.4 Hz), (d, J = Hz), 64.2, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 59.0 (s); IR: ν 1768, 1660, 1599, 1501, 1447, 1372, 1276, 1203, 1164, 1099, 1014, 921, 856; HRMS (EI/FI) for C 17H 14BrF 4 [M] + requires found Ethyl (3-cyanophenoxy)(bromo)fluoroacetate (1j) The title compound was prepared following general procedure B; to a solution of ethyl (3- cyanophenoxy)(fluoro)acetate (893 mg, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 60 C and UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 20 % Et 2 in n-pentane) to provide the title compound (113 mg, 16 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 4H), 4.46 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 31.0 Hz), 151.7, 130.6, 130.2, (d, J = 1.6 Hz), (d, J 12

13 = 2.4 Hz), 117.5, 113.7, (d, J = Hz), 64.3, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 59.3 (s); IR: ν 2235, 1768, 1581, 1481, 1432, 1372, 1306, 1234, 1158, 1102, 1012, 910, 857; HRMS (EI/FI) for C 11H 9BrFN 3 [M] + requires found Ethyl bromo(fluoro)[4-(trifluoromethyl)phenoxy]acetate (1k) The title compound was prepared following general procedure B; to a solution of ethyl fluoro[4- (trifluoromethyl)phenoxy]acetate (1.06 g, 4.0 mmol) in CCl 4 (20 ml) was added N-bromosuccinimide (427 mg, 2.4 mmol). The reaction was allowed to stir for 16 hours at 60 C under UV light irradiation. The solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (eluent: 5 % Et 2 in n-pentane) to provide the title compound (160 mg, 19 % yield) as a pale yellow oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.69 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (d, J = 30.2 Hz), 154.1, (q, J = 33.1 Hz), (q, J = 3.7 Hz), (q, J = Hz), (d, J = 2.4 Hz), (d, J =304.4 Hz), 64.2, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 59.2 (s, 1F), 62.3 (s, 3F) ; IR: ν 1771, 1615, 1513, 1325, 1211, 1170, 1128, 1065, 1016, 924, 858; HRMS (EI/FI) for C 11H 9BrF 4 3 [M] + requires found Ethyl 2-bromo-2-(4-(1,3-dioxoisoindolin-2-yl)phenoxy)-2-fluoroacetate (1l) The title compound was prepared following general procedure B using NBS (427 mg, 2.40 mmol), ethyl [4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenoxy](fluoro)acetate (1.37 g, 4.00 mmol) and CCl 4 (20 ml). The crude product was purified by silica gel column chromatography (eluent: 0-50% Et 2 in n- pentane) to provide the title compound (162 mg, 0.38 mmol, 10%) as a white solid alongside some recovered substrate (888 mg, 2.59 mmol). ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2 H), (m, 2 H), (m, 2 H), (m, 2 H), 4.46 (q, J = 7.0 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 167.0, (d, J = 30.2 Hz), 150.7, 134.5, 131.5, 129.9, 127.4, 123.8, (d, J = 1.6 Hz), (d, J = Hz), 64.1, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = (s); IR (neat): ν 3073, 2986, 1768, 1716, 1606, 1506, 1466, 1377, 1301, 1211, 1163, 1108, 1079, 1010, 953, 918, 876, 839, 792, 754, 715, 650; MP: 105 C; HRMS not found using ESI, EI, FI. 2.3 Aryl-CF2C2Et (2) Ethyl (4-tert-butylphenoxy)(difluoro)acetate (2a) The title compound was prepared following general procedure C using potassium carbonate (3.46 g, 25.0 mmol), 4-tert-butylphenol (1.50 g, 10.0 mmol), ethyl bromodifluoroacetate (3.21 ml, 25.0 mmol) 13

14 and DMF (20 ml). The crude product was purified by silica gel column chromatography (eluent: 4 % Et 2 in petroleum ether) to provide the title compound (1.97 g, 72 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.38 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.33 (s, 9H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 41.3 Hz), 149.3, 147.1, 126.4, 121.1, (t, J = Hz), 63.5, 34.5, 31.3, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.3 (s); IR: ν 2966, 1777, 1509, 1377, 1341, 1179, 1136, 1108, 1016, 853; HRMS (ESI) for C 14H 18F 2Na 3 [M+Na] + requires found Data consistent with literature values. 2 Ethyl (biphenyl-4-yloxy)(difluoro)acetate (2b) The title compound was prepared following general procedure C using potassium carbonate (3.46 g, 25.0 mmol), 4-phenylphenol (1.70 g, 10.0 mmol), ethyl bromodifluoroacetate (3.21 ml, 25.0 mmol) and DMF (20 ml). The crude product was purified by silica gel column chromatography (eluent: 3% EtAc in n-hexane) to provide the title compound (1.60 g, 55 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 4H), (m, 2H), (m, 1H), 7.31 (d, J = 8.8 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 41.3 Hz), 148.8, , 139.4, 128.8, 128.2, 127.5, 127.1, 121.9, (t, J = Hz), 63.7, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.3 (s); IR: ν 1775, 1515, 1486, 1378, 1341, 1171, 1134, 1008, 854; HRMS (ESI) for C 16H 14F 2Na 3 [M+Na] + requires found ; Mp C. Data consistent with literature values. 2 Ethyl difluoro(phenoxy)acetate (2c) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), phenol (1.88 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 2 % Et 2 in n- pentane) to provide the title compound (1.37 g, 32 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 3H), 4.41 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 41.3 Hz), 149.5, 129.6, 126.3, 121.6, (t, J = Hz), 63.6, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.2 (s); IR: ν , 1378, 1341, 1191, 1130, 1005, 858; HRMS (ESI) for C 10H 10F 2Na 3 [M+Na] + requires found Ethyl (4-bromophenoxy)(difluoro)acetate (2d) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), 4-bromophenol (3.46 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 3 % Et 2 in n-pentane) to provide the title compound (2.02 g, 34 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.49 (dt, J 1 = 2.7 Hz, J 2 = 9.1 Hz, 2H), (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.9 Hz), 148.4, 132.7, 14

15 123.4, 119.6, (t, J = Hz), 63.8, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.6 (s); IR: ν 1777, 1485, 1378, 1342, 1198, 1136, 1069, 1012, 848; HRMS (EI/FI) for C 10H 9BrF 2 3 [M] + requires found Ethyl (3-bromophenoxy)(difluoro)acetate (2e) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), 3-bromophenol (3.46 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 1 % Et 2 in n-pentane) to provide the title compound (1.15 g, 20 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), (m, 1H), (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.9 Hz), 149.9, 130.6, 129.6, 125.1, 122.5, 120.3, (t, J = Hz), 63.8, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.6 (s); IR: ν 1776, 1585, 1472, 1341, 1136, 1012, 858; HRMS (EI/FI) for C 10H 9BrF 2 3 [M] + requires found Ethyl (2-bromophenoxy)(difluoro)acetate (2f) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), 2-bromophenol (3.46 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 2 % Et 2 in n-pentane) to provide the title compound (2.11 g, 36 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.63 (dd, J 1 = 1.2 Hz, J 2 = 7.8 Hz, 1H), (m, 2H), (m, 1H), 7.14 (ddd, J 1 = 2.0 Hz, J 2 = 6.9 Hz, J 3 = 7.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.9 Hz), 146.8, 133.8, 128.4, 127.5, 123.0, 116.5, (t, J = Hz), 63.8, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.0 (s); IR: ν 1776, 1473, 1446, 1378, 1341, 1212, 1136, 1048, ; HRMS (EI/FI) for C 10H 9BrF 2 3 [M] + requires found Ethyl 2,2-difluoro-2-(2-fluorophenoxy)acetate (2g) The title compound was prepared following general procedure C using K 2C 3 (6.91 g, 50.0 mmol), 2- fluorophenol (1.79 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 0-7% Et 2 in n-pentane) to provide the title compound (2.25 g, 9.62 mmol, 48%) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.33 (qt, J = 1.3, 7.9 Hz, 1 H), (m, 1 H), (m, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.5 Hz), (d, J = Hz), (td, J = 2.2, 12.3 Hz), (d, J = 7.2 Hz), 124.4, (d, J = 4.0 Hz), (d, J = 18.3 Hz), (t, J = Hz), 63.7, 13.5; ( 19 F NMR, 377 MHz, CDCl 3): δ = (s, 2F), (m, 1F); IR (neat): ν 2990, 2943, 2364, 2329, 1777, 1603, 1502, 1459, 1410, 1382, 1339, 15

16 1261, 1187, 1133, 1090, 1013, 941, 894, 851, 792, 751, 695; HRMS (ESI) for C 10H 9F 3Na 3 [M+Na] + requires found tert-butyl 4-(2-ethoxy-1,1-difluoro-2-oxoethoxy)benzoate (2h) The title compound was prepared following general procedure C using K 2C 3 (3.46 g, 25.0 mmol), tertbutyl 4-hydroxybenzoate (1.94 g, 10.0 mmol), ethyl bromodifluoroacetate (1.92 ml, 15.0 mmol) and DMF (20 ml). The crude product was purified by silica gel column chromatography (eluent: 0-15% Et 2 in n-pentane) to provide the title compound (965 mg, 3.05 mmol, 31%) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2 H), (m, 2 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.58 (s, 9 H), 1.36 (t, J = 7.1 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 164.7, (t, J = 40.9 Hz); (t, J = 1.6 Hz), 131.1, 129.9, 120.7, (t, J = Hz), 81.3, 63.8, 28.1, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = (s); IR (neat): ν 2981, 2935, 2904, 2876, 1778, 1714, 1604, 1506, 1466, 1451, 1407, 1375, 1338, 1294, 1253, 1207, 1158, 1106, 1011, 962, 855, 757, 696; HRMS (ESI) for C 15H 18F 2Na 5 [M+Na] + requires found Ethyl (4-benzoylphenoxy)(difluoro)acetate (2i) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), 4-hydroxybenzophenone (3.96 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 5 % Et 2 in n-pentane) to provide the title compound (2.26 g, 35 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.84 (dt, J 1 = 2.2 Hz, J 2 = 8.8 Hz, 2H), (m, 2H), (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 195.3, (t, J = 41.0 Hz), 152.6, 137.2, 135.3, 132.6, 131.8, 129.9, 128.3, 120.8, (d, J = Hz), 63.8, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.5 (s); IR: ν 1776, 1660, 1599, 1502, 1448, 1378, 1276, 1167, 1014, 938, 924, 855; HRMS (ESI) for C 17H 15F 2 4 [M+H] + requires found Data consistent with literature values. 2 Ethyl (3-cyanophenoxy)(difluoro)acetate (2j) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), 3-cyanophenol (2.38 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 20 % Et 2 in n-pentane) to provide the title compound (197 mg, 4 % yield) as a pale yellow oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 1H), (m, 3H), 4.41 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.1 Hz), 149.5, 130.7, 130.0, 126.3, 125.1, 16

17 117.5, 113.8, (t, J = Hz), 64.0, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.8 (s); IR: ν 2236, 1775, 1582, 1483, 1432, 1378, 1342, 1238, 1148, 1010, 854; HRMS (EI/FI) for C 11H 9F 2N 3 [M] + requires found Ethyl difluoro[4-(trifluoromethyl)phenoxy]acetate (2k) The title compound was prepared following general procedure C using potassium carbonate (6.91 g, 50.0 mmol), 4-(trifluoromethyl)phenol (3.24 g, 20.0 mmol), ethyl bromodifluoroacetate (3.85 ml, 30.0 mmol) and DMF (40 ml). The crude product was purified by silica gel column chromatography (eluent: 1 % Et 2 in n-pentane) to provide the title compound (1.36 g, 24 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.66 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.5 Hz), , (q, J = 33.1 Hz), (q, J = 3.7 Hz), (q, J = Hz), 121.6, (t, J =274.2 Hz), 63.4, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = 62.4 (s, 3F), 76.7 (s, 2F); IR: ν 1779, 1617, 1515, 1379, 1325, 1212, 1126, 1065, 1017, 857; HRMS (EI/FI) for C 11H 9F 5 3 [M] + requires found Ethyl 2-(4-(1,3-dioxoisoindolin-2-yl)phenoxy)-2,2-difluoroacetate (2l) The title compound was prepared following general procedure C using K 2C 3 (2.76 g, 20.0 mmol), 2- (4-hydroxyphenyl)-1H-isoindole-1,3(2H)-dione (1.91 g, 8.0 mmol), ethyl bromodifluoroacetate (1.54 ml, 12.0 mmol) and DMF (16 ml). The crude product was purified by silica gel column chromatography (eluent: 20-70% Et 2 in n-pentane) to provide the title compound (294 mg, 0.81 mmol, 10%) as a white, crystalline solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2 H), (m, 2 H), (m, J = 8.9 Hz, 2 H), (m, J = 8.8 Hz, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 167.0, (t, J = 41.1 Hz), (t, J = 2.2 Hz), 134.5, 131.6, 129.7, 127.6, 123.8, 122.2, (t, J = Hz), 63.8, 13.8; ( 19 F NMR, 377 MHz, CDCl 3): δ = (s); IR (neat): ν 3113, 3072, 2989, 2941, 2905, 1917, 1857, 1774, 1709, 1605, 1512, 1464, 1391, 1341, 1292, 1221, 1173, 1125, 1080, 1013, 951, 890, 849, 781, 714, 639; MP: C; HRMS (ESI) for C 18H 14F 2N 5 [M+H] + requires found Aryl-CF2C2H (3) 4-tert-Butylphenoxy)(difluoro)acetic acid (3a) The title compound was prepared following general procedure D using ethyl (4-tertbutylphenoxy)(difluoro)acetate (1.63 g, 6.0 mmol), 5 M aq. NaH (6 ml, 30.0 mmol) and MeCN (30 ml); (1.40 g, 96 % yield, white solid). 17

18 ( 1 H NMR, 400 MHz, CDCl 3): δ = 9.90 (brs, 1H), 7.40 (dt, J 1 = 2.6 Hz, J 2 = 9.1 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 1.33 (s, 9H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 42.9 Hz), 149.6, 146.7, 126.6, 121.1, (t, J = Hz), 34.5, 31.3; ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.6 (s); IR: ν 2965, 1765, 1509, 1366, 1176, 1105, 1016, 833, 804; HRMS (ESI) for C 12H 14F 2Na 3 [M+Na] + requires found ; Mp C. Data consistent with literature values. 2 (Biphenyl-4-yloxy)(difluoro)acetic acid (3b) The title compound was prepared following general procedure D using ethyl (biphenyl-4- yloxy)(difluoro)acetate (640 mg, 2.19 mmol), 4 M aq. NaH (5.5 ml, 22.0 mmol) and MeCN (25 ml); (588 mg, 100 % yield, grey solid). ( 1 H NMR, 400 MHz, CDCl 3): δ = 9.77 (brs, 1H), (m, 4H), (m, 2H), (m, 1H), 7.33 (d, J = 8.6 Hz, 2H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 42.9 Hz), 148.5, 139.9, 139.7, 128.9, 128.4, 127.6, 127.1, 121.9, (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.6 (s); IR: ν 3063, 1776, 1519, 1487, 1452, 1248, 1208, 1190, 1174, 1155, 1101, 1008, 850; HRMS (ESI) for C 14H 9F 2 3 [M- H] - requires found ; Mp C. Data consistent with literature values. 2 Difluoro(phenoxy)acetic acid (3c) The title compound was prepared following general procedure D using ethyl difluoro(phenoxy)acetate (865 mg, 4.0 mmol), 5 M aq. NaH (4 ml, 20.0 mmol) and MeCN (20 ml); (742 mg, 99 % yield, yellow oil). ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.81 (brs, 1H), (m, 2H), (m, 3H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 42.9 Hz), 149.1, 129.7, 126.6, 121.6, (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.7 (s); IR: ν 1762, 1591, 1491, 1189, 1025, 1004, 855; HRMS (EI/FI) for C 8H 6F 2 3 [M] + requires found (4-Bromophenoxy)(difluoro)acetic acid (3d) The title compound was prepared following general procedure D using ethyl (4- bromophenoxy)(difluoro)acetate (1.48 g, 5.0 mmol), 5 M aq. NaH (5 ml, 25.0 mmol) and MeCN (25 ml); (880 mg, 76 % yield, white solid). ( 1 H NMR, 400 MHz, CDCl 3): δ = (brs, 1H), 7.52 (dt, J 1 = 2.7 Hz, J 2 = 8.8 Hz, 2H), (m, 2H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 42.1 Hz), 148.1, 132.8, 123.4, 120.0, (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 77.0 (s); IR: ν 1765, 1484, 1194, 1068, 1013; HRMS (EI/FI) for C 8H 5BrF 2 3 [M] + requires found ; Mp C. 18

19 (3-Bromophenoxy)(difluoro)acetic acid (3e) The title compound was prepared following general procedure D using ethyl (3- bromophenoxy)(difluoro)acetate (590 mg, 2.0 mmol), 5 M aq. NaH (2 ml, 10.0 mmol) and MeCN (10 ml); (382 mg, 71 % yield, pale yellow solid). ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.37 (brs, 1H), (m, 2H), (m, 1H), (m, 1H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 41.3 Hz), 149.5, 130.8, 129.9, 125.1, 122.6, 120.3, (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.9 (s); IR: ν 3574, 1761, 1580, 1462, 1245, 1191, 1142, 1062, 873; HRMS (ESI) for C 8H 4BrF 2 3 [M-H] - requires found ; Mp C. (2-Bromophenoxy)(difluoro)acetic acid (3f) The title compound was prepared following general procedure D using ethyl (2- bromophenoxy)(difluoro)acetate (1.18 g, 4.0 mmol), 5 M aq. NaH (4 ml, 20.0 mmol) and MeCN (20 ml); (1.03 g, 96 % yield, pale yellow oil). ( 1 H NMR, 400 MHz, CDCl 3): δ = (brs, 1H), 7.65 (dd, J 1 = 1.2 Hz, J 2 = 7.8 Hz, 1H), (m, 2H), 7.18 (ddd, J 1 = 2.0 Hz, J 2 = 6.9 Hz, J 3 = 7.8 Hz, 1H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 41.1 Hz), 146.4, 133.9, 128.5, 127.9, 1231, 116.5, (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 76.5 (s); IR: ν 1766, 1472, 1445, 1149, 1047, 1030, 855; HRMS (EI/FI) for C 8H 5BrF 2 3 [M] + requires found ,2-Difluoro-2-(2-fluorophenoxy)acetic acid (3g) The title compound was prepared following general procedure D using ethyl difluoro(2- fluorophenoxy)acetate (234 mg, 1.00 mmol), aq. NaH (5.0 M; 1.00 ml, 5.00 mmol) and MeCN (5.00 ml). After work-up the title compound (152 mg, 0.74 mmol, 74%) was obtained as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = (br s, 1 H), (m, 1 H), (m, 1 H), (m, 2 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 42.1 Hz), (d, J = Hz), (td, J = 1.6, 12.7 Hz), (d, J = 7.2 Hz), 124.5, 124.5, (d, J = 18.3 Hz), (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = (s), (m, 1 F); IR (neat): ν 3499, 3078, 2896, 2719, 2560, 2362, 2342, 1920, 1763, 1610, 1601, 1501, 1461, 1388, 1260, 1184, 1147, 1098, 1029, 941, 872, 861, 820, 795, 750; HRMS (ESI) for C 8H 4F 3 3 [M-H] - requires found

20 2-(4-(tert-Butoxycarbonyl)phenoxy)-2,2-difluoroacetic acid (3h) The title compound was prepared following general procedure D using tert-butyl 4-(2-ethoxy-1,1- difluoro-2-oxoethoxy)benzoate (125 mg, 0.40 mmol), aq. NaH (5.0 M; 400 µl, 2.00 mmol) and MeCN (2.00 ml). After work-up the title compound (85 mg, 0.29 mmol, 74%) was obtained as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 9.23 (br s, 1 H), (m, 2 H), (m, 2 H), 1.52 (s, 9 H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 165.8, (t, J = 41.1 Hz), 152.9, 131.3, 129.5, 120.8, (t, J = Hz), 82.4, 28.1; ( 19 F NMR, 377 MHz, CDCl 3): δ = (s); IR (neat): ν 3085, 3038, 3010, 2984, 2940, 2697, 2542, 1782, 1680, 1604, 1504, 1475, 1458, 1431, 1413, 1396, 1373, 1322, 1297, 1277, 1262, 1251, 1199, 1156, 1121, 1095, 1017, 977, 965, 927, 873, 842, 818, 769, 737, 715; MP: C; HRMS (ESI) for C 13H 14F 2Na5 [M+Na] + requires found (4-Benzoylphenoxy)(difluoro)acetic acid (3i) The title compound was prepared following general procedure D using ethyl (4- benzoylphenoxy)(difluoro)acetate (1.28 g, 4.0 mmol), 5 M aq. NaH (4 ml, 20.0 mmol) and Et 2 (20 ml); (1.05 mg, 95 % yield, white solid). ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.59 (brs, 1H), 7.86 (d, J = 8.6 Hz, 2H), (d, J = 7.3 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 197.1, (t, J = 41.3 Hz), 153.0, 136.8, 134.9, 133.1, 132.2, 130.2, 128.5, 120.9, (t, J = Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 77.0 (s); IR: ν 1774, 1645, 1598, 1503, 1448, 1279, 1168, 1016, 926, 851; HRMS (ESI) for C 15H 9F 2 4 [M-H] - requires found Data consistent with literature values. 2 (3-Cyanophenoxy)(difluoro)acetic acid (3j) The title compound was prepared following general procedure D using ethyl (3- cyanophenoxy)(difluoro)acetate (145 mg, 0.6 mmol), 5 M aq. NaH (0.6 ml, 3.0 mmol) and MeCN (30 ml); (125 mg, 98 % yield, white solid). ( 1 H NMR, 400 MHz, CDCl 3): δ = 9.94 (brs, 1H), (m, 4H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 40.5 Hz), 149.4, 130.9, 130.4, 126.7, 125.3, 117.2, (t, J = Hz), 113.5; ( 19 F NMR, 377 MHz, CDCl 3): δ = 77.2 (s); IR: ν 2242, 1770, 1582, 1483, 1433, 1239, 1160, 931; HRMS (ESI) for C 8H 4BrF 2 3 [M-H] - requires found ; Mp C. 20

21 Difluoro[4-(trifluoromethyl)phenoxy]acetic acid (3k) The title compound was prepared following general procedure D using ethyl difluoro[4- (trifluoromethyl)phenoxy]acetate (1.14 g, 4.0 mmol), 5 M aq. NaH (4 ml, 20.0 mmol) and MeCN (20 ml); (508 mg, 50 % yield, white solid). ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.80 (brs, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = Hz), 151.7, (q, J = 33.1 Hz), (q, J = 3.7 Hz), (q, J = Hz), 121.7, (t, J =274.2 Hz); ( 19 F NMR, 377 MHz, CDCl 3): δ = 62.5 (s, 3F), 71.2 (s, 2F); IR: ν 1769, 1615, 1515, 1326, 1125, 1065, 1018, 846, 807; HRMS (EI/FI) for C 9H 5F 5 3 [M] + requires found ; Mp C. 2-(4-(1,3-Dioxoisoindolin-2-yl)phenoxy)-2,2-difluoroacetic acid (3l) and 2-((4-(Carboxydifluoromethoxy)phenyl)carbamoyl)benzoic acid (3l-2) Following general procedure D using ethyl [4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2- yl)phenoxy](difluoro)acetate (60 mg, 0.17 mmol), aq. NaH (5.0 M; 170 µl, 0.83 mmol) and MeCN (830 μl) a mixture (40 mg) of two compounds 3l and 3l-2 was obtained in a ratio of 0.04:1.00 as determined by 1 H NMR as a white solid. ( 1 H NMR, 400 MHz, Acetone-d 6): δ = (m, 4H), (m, 2H), (m, 2H); ( 19 F NMR, 377 MHz, Acetone-d 6): δ = (s); HRMS (ESI) for C 16H 10F 2N 5 [M+H] + requires found ( 1 H NMR, 400 MHz, Acetone-d 6): δ = 7.97 (ddd, J = 7.6, 1.2, 0.5 Hz, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 2H); ( 13 C NMR, 101 MHz, Acetone-d 6): δ = , , (t, J = 40.7 Hz), (t, J = 2.0 Hz), , , , , , , , , , (t, J = Hz); ( 19 F NMR, 377 MHz, Acetone-d 6): δ = (s); HRMS (ESI) for C 16H 12F 2N 6 [M+H] + requires found

22 2.5 Post-Fluorination Reactions N-(2-Fluoro-4-iodophenyl)methanesulfonamide The title compound was prepared following a procedure reported in the literature. 5 A cooled solution of 2-fluoro-4-iodoaniline (3.56 g, 15.0 mmol) in pyridine (20 ml) at 0 C was drop-wise treated with methanesulfonyl chloride (1.74 ml, 22.5 mmol). After being stirred for 3 h at room temperature, the mixture was diluted with water and extracted with ethyl acetate several times. The combined organic layers were washed with water and brine, dried over MgS 4, and concentrated in vacuo. The residue was purified by recrystalisation in DCM/n-pentane to afford the title compound (3.78 g, 80 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.42 (d, J = 8.3 Hz, 2H), 7.25 (t, J = 8.2 Hz, 1H), 6.70 (brs, 1H), 2.97 (s, 3H); ( 19 F NMR, 377 MHz, CDCl 3): δ = (t, J = 8.9 Hz). Data consistent with literature values. 5 N-(4-Cyano-2-fluorophenyl)methanesulfonamide The title compound was prepared following a procedure reported in the literature. 5 A mixture of N-(2- fluoro-4-iodophenyl)methanesulfonamide (2.52 g, 8 mmol), zinc cyanide (564 mg, 4.8 mmol), and tetrakis(triphenylphosphine) palladium (462 mg, 0.4 mmol) in dimethylformamide (18 ml) was heated at 80 C for 8 h. The mixture was diluted with water and extracted with ethyl acetate several times. The combined organic layers were washed with water and brine, dried over MgS 4, and concentrated in vacuo. The residue was purified by recrystalisation in DCM/n-pentane to afford the title compound (1.25 g, 73 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.66 (t, J = 8.2 Hz, 1H), (m, 2H), 6.91 (brs, 1H), 3.07 (s, 3H); ( 19 F NMR, 377 MHz, CDCl 3): δ = (t, J = 9.1 Hz). Data consistent with literature values. 5 (3-Fluoro-4-(methylsulfonamido)phenyl)methanaminium chloride The title compound was prepared following a procedure reported in the literature. 5 A stirred suspension of N-(4-cyano-2-fluorophenyl)methanesulfonamide (1.07 g, 5 mmol), 5% palladium on carbon (100 mg) and several drops of concentrated hydrochloric acid in MeH (25 ml) was hydrogenated under a balloon of hydrogen for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 3-fluoro-4-(methylsulfonylamino)benzyl amine salt as a white solid (1.02 g, 80 % yield). ( 1 H NMR, 400 MHz, CD 3D): δ = 7.49 (t, J = 8.3 Hz, 1H), 7.28 (dd, J1 = 2.0 Hz, J2 = 11.1 Hz, 1H), 7.21 (dd, J1 = 2.1 Hz, J2 = 8.3 Hz, 1H), 4.04 (s, 2H), 2.95 (s, 3H); ( 19 F NMR, 377 MHz, CD 3D): δ = (dd, J1 = 8.3 Hz, J2 = 11.1 Hz). Data consistent with literature values. 5 22

23 2-(4-(tert-Butyl)phenoxy)-2,2-difluoro-N-(3-fluoro-4-(methylsulfonamido)benzyl)acetamide (4) The title compound was prepared following a procedure reported in the literature. 6 To a solution of 4-tert-Butylphenoxy)(difluoro)acetic acid (48.8 mg, 0.2 mmol) in THF (2 ml) were added DMTMM (4- (4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methylmorpholinium chloride) (86 mg, 0.3 mmol), NMM (23 μl, 0.2 mmol) and Et 3N (88 μl, 0.6 mmol). After being stirred for 4 h, the reaction mixture was added (3- fluoro-4-(methylsulfonamido)phenyl)methanaminium chloride (64 mg, 0.25 mmol). After additional 10 h, the reaction mixture was diluted with DCM, washed with water and brine, dried over MgS 4, and concentrated in vacuo. Purification of the residue by column chromatography (EtAc/n-pentane = 1:1) afforded the title compound (5.8 mg, 7 %) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.49 (t, J = 8.3 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), (m, 4H), 6.82 (brs, 1H), 6.49 (brs, 1H), 4.46 (d, J = 6.1 Hz, 2H), 2.97 (s, 3H), 1.25 (s, 9H); ( 19 F NMR, 377 MHz, CDCl 3): δ = 77.0 (s, 2F), (t, J = 9.1 Hz, 1F). Data consistent with literature values. 6 2-Bromo-N,N-dimethylbenzenesulfonamide The title compound was prepared following a procedure reported in the literature. 7 To a solution of 2-bromobenzene-1-sulfonyl chloride (7.67 g, 30.0 mmol) in THF (20 ml) was slowly added dimethylamine (6.77 ml, 60.0 mmol) at 0 C. The reaction mixture was stirred at room temperature for 6 hours. The reaction was then poured into water and the mixture was extracted with DCM. The combined organic phases were washed with brine, dried over MgS 4 and concentrated in vacuo to provide the title compound (7.30 g, 92 % yield) as a beige solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.08 (dd, J 1 = 1.7 Hz, J 2 = 7.6 Hz, 1H), 7.75 (dd, J 1 = 1.2 Hz, J 2 = 7.8 Hz, 1H), 7.45 (td, J 1 = 1.2 Hz, J 2 = 7.6 Hz, 1H), 7.39 (td, J 1 = 1.7 Hz, J 2 = 7.6 Hz, 1H), 2.90 (s, 6H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 137.7, 135.7, 133.5, 132.3, 127.4, 120.3, Data consistent with literature values. 7 Di-tert-butyl (4-bromobenzene-1,2-diyl)biscarbamate To a solution of 4-bromobenzene-1,2-diamine (2.81 g, 15.0 mmol) in DCM (45 ml) was added di-tertbutyl dicarbonate (17.2 ml, 75.0 mmol) and 2M NaH (aq) (18.8 ml, 37.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with DCM and the combined organic phases were washed with brine, dried over MgS 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 30% EtAc in n-hexane) to provide the title compound (4.88 g, 84 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.77 (s, 1H), 7.33 (s, 1H), 7.23 (dd, J 1 = 2.2 Hz, J 2 = 8.6 Hz, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 1.52 (s, 9H), 1.52 (s, 9H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 153.7, 153.4, 146.8, 131.8, 127.9, 126.4, 125.7, 118.2, 81.3, 28.3; IR: ν 3300, 2980, 1700, 1594, 1515, 1413, 1393, 1368, 1238, 1155, 1051, 1024, 910, 855; HRMS (EI/FI) for C 16H 23N 2 4 [M] + requires found ; Mp C. Data consistent with literature values. 8 23

24 Di-tert-butyl (4-(2,2,5,5-tetramethylborolan-1-yl)-1,2-phenylene)dicarbamate To a mixture of bis(pinacolato)diboron (1.62 g, 6.38 mmol), Pd(dppf)Cl 2. CH 2Cl 2 (350 mg, 0.43 mmol) and potassium acetate (833 mg, 8.5 mmol) was added degassed DMF (10 ml) under N 2 atmosphere. To the reaction mixture was added di-tert-butyl (4-bromobenzene-1,2-diyl)biscarbamate (1.64 g, 4.25 mmol) and stirred at 80 C for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 10% EtAc in n-pentane) to provide the title compound (1.11 g, 60 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = (m, 2H), 7.60 (dd, J 1 = 1.0 Hz, J 2 = 8.1 Hz, 1H), 7.13 (s, 1H), 6.51 (s, 1H), 1.50 (s, 9H), 1.50 (s, 9H), 1.32 (s, 12H); ( 13 C NMR, 101 MHz, CDCl 3): δ = 154.2, 153.1, 135.0, 132.9, 131.6, 127.3, 121.7, 83.7, 80.9, 80.6, 28.2, 28.2, 24.8; IR: ν 3310, 2972, 1737, 1418, 1366, 1231, 1156, 1095, 855; HRMS (ESI) for C 22H 35 6N 2BNa [M+Na] + requires found ; Mp C. Data consistent with literature values. 9 Di-tert-butyl (2'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-3,4-diyl)dicarbamate To a solution of di-tert-butyl (4-(2,2,5,5-tetramethylborolan-1-yl)-1,2-phenylene)dicarbamate (109 mg, 0.25 mmol) and 2-bromo-N,N-dimethylbenzenesulfonamide (66.0 mg, 0.25 mmol) in DME (2.0 ml) and H 2 (0.5 ml) was added Na 2C 3 (126 mg, 1.5 mmol) and Pd(dppf)Cl 2. CH 2Cl 2 (20.4 mg, mmol). The reaction mixture was stirred at 100 C for 16 hours then concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 30% Et 2 in n-pentane) to provide the title compound (84.4 mg, 69 % yield) as a yellow solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.03 (dd, J 1 = 1.2 Hz, J 2 = 7.8 Hz, 1H), (m, 4H), 7.24 (td, J 1 = 1.5 Hz, J 2 = 7.8 Hz, 1H), 7.11 (dd, J 1 = 2.0 Hz, J 2 = 8.3 Hz, 1H), 6.73 (brs, 2H), 2.32 (s, 6H), 1.46 (s, 9H), 1.43 (s, 9H); ( 13 C NMR, 126 MHz, CDCl 3): δ = 153.8, 153.7, 140.6, 137.2, 136.5, 132.9, 132.2, 130.4, 130.1, 129.3, 127.7, 126.6, 125.4, 123.0, 81.0, 36.0, 28.3, 28.3; IR: ν 3319, 2977, 2363, 1725, 1702, 1590, 1525, 1480, 1393, 1368, 1323; HRMS (EI/FI) for C 24H 33N 3 6S [M] + requires found ; Mp C. 3',4'-Diamino-N,N-dimethylbiphenyl-2-sulfonamide To a flask containing di-tert-butyl (2'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-3,4-diyl)dicarbamate (1.02 g, 2.08 mmol) was added 2M HCl in Et 2 (40 ml, 80 mmol) and 1.25 M HCl in MeH (16 ml, 20 mmol). The reaction mixture was stirred at room temperature for 4 hours then concentrated in vacuo. The residue was dissolved in DCM and the solution was washed with sat. NaHC 3(aq) and brine, dried over MgS 4 and concentrated in vacuo to provide the title compound (534 mg, 88 % yield) as a brown solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = 8.08 (dd, J 1 = 1.2 Hz, J 2 = 7.8 Hz, 1H), 7.50 (td, J 1 = 1.5 Hz, J 2 = 7.5 Hz, 1H), 7.41 (td, J 1 = 1.5 Hz, J 2 = 7.5 Hz, 1H), 7.28 (dd, J 1 = 1.2 Hz, J 2 = 7.8 Hz, 1H), 6.81 (t, J = 1.0 Hz, 1H), 6.87 (t, J = 1.2 Hz, 1H), 3.43 (brs, 4H), 2.38 (s, 6H); ( 13 C NMR, 126 MHz, CDCl 3): δ = 141.9, 137.4, 134.6, 24

25 133.7, 133.2, 132.0, 131.4, 130.3, 127.0, 121.4, 118.4, 115.7, 36.2; IR: ν 3417, 3349, 1627, 1587, 1517, 1465, 1314, 1276, 1153, 1071, 966, 816; HRMS (ESI) for C 14H 18 2N 3S [M+H] + requires found ; Mp C. 2-(2-{Difluoro[4-(trifluoromethyl)phenoxy]methyl}-1H-benzimidazol-5-yl)-N,Ndimethylbenzene sulfonamide (5) To a mixture of difluoro[4-(trifluoromethyl)phenoxy]acetic acid (218 mg, 0.85 mmol) and 3',4'- diamino-n,n-dimethylbiphenyl-2-sulfonamide (248 mg, 0.85 mmol) was added 6M HCl (aq) (2.0 ml). The reaction mixture was stirred at 110 C for 16 hours. The reaction mixture was concentrated in vacuo then purified by silica gel column chromatography (eluent: 30% EtAc in n-pentane) to provide the title compound (80.1 mg, 18 % yield) as a white solid. ( 1 H NMR, 400 MHz, CDCl 3): δ = (brs, 1H), 8.02 (dd, J 1 = 8.1 Hz, J 2 = 13.5 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.45 (td, J 1 = 1.2 Hz, J 2 = 7.6 Hz, 1H), (m, 2H), 7.28 (d, J = 7.6 Hz, 1H), (m, 1H), 2.32 (s, 3H), 2.24 (s, 3H); ( 13 C NMR, 126 MHz, CDCl 3) 152.0, (t, J = 39.1 Hz), 141.8, 141.4, 137.3, , 133.2, 132.3, (q, J = 33.1 Hz), (t, J = 6.2 Hz), (q, J = 3.6 Hz), 125.0, (q, J = Hz), 122.1, 121.2, 120.1, (t, J = Hz), 113.9, 110.8, 36.4, 36.2; ( 19 F NMR, 377 MHz, CDCl 3): δ = 62.3 (s, 3F), 65.9 (s, 2F); IR: ν 2974, 1742, 1449, 1370, 1322, 1220, 1162, 1125, 1066, 966; HRMS (ESI) for C 23H 18 3N 3F 5NaS [M+Na] + requires found ; Mp C. Data consistent with literature values tert-Butyl-4-(difluoromethoxy)benzene (6) To a solution of an appropriate (4-tert-butylphenoxy)(difluoro)acetic acid (488.4 mg, 2.0 mmol) in 1:1 acetone/water (8 ml) was added AgN 3 (339.8 mg, 2.0 mmol) and K 2S 2 8 (2.16 g, 8.0 mmol). The reaction mixture was stirred at 50 o C for 2 hours before diluting with water. The aqueous layer was extracted with DCM (3 x 10 ml), then the combined organic phases were washed with brine, dried over MgS 4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 1 % Et 2 in n-pentane) to provide the title compound (199.4 mg, 50 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.38 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.49 (t, J = 74.3 Hz, 1H), 1.33 (s, 9H); ( 13 C NMR, 101 MHz, CDCl 3): δ = (t, J = 2.8 Hz), 148.4, 126.7, 119.1, (t, J = Hz), 34.4, 31.4; ( 19 F NMR, 377 MHz, CDCl 3): δ = 80.4 (d, J = 74.6 Hz). Data consistent with literature values. 2 25

26 4-(4-(tert-Butyl)phenoxy)-4,4-difluorobutan-2-one (7) The title compound was isolated along with the synthesis of 1-tert-butyl-4-(difluoromethoxy)benzene (6). Purification by silica gel column chromatography (eluent: 1 % Et 2 in n-pentane) provided the title compound (16.3 mg, 3 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.37 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 3.26 (t, J = 10.6 Hz, 2H), 2.37 (s, 3H), 1.32 (s, 9H); ( 13 C NMR, 126 MHz, CDCl 3): δ = 200.1, 149.1, 148.0, 126.4, 120.7, 50.1, 34.5, 31.4, 30.3; ( 19 F NMR, 377 MHz, CDCl 3): δ = 65.9 (s, 2F); IR: 2964, 1722, 1510, 1412, 1365, 1335, 1265, 1202, 1171, 1121, 1017, 978; HRMS (ESI) for C 14H 18F 2Na 2 [M+Na] + requires found (tert-Butyl)-2-((4-(tert-butyl)phenoxy)difluoromethyl)-1-(difluoromethoxy)benzene (8) The title compound was isolated along with the synthesis of 1-tert-butyl-4-(difluoromethoxy)benzene (6). Purification by silica gel column chromatography (eluent: 1 % Et 2 in n-pentane) provided the title compound (14.0 mg, 4 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.79 (d, J = 2.5 Hz, 1H), 7.53 (dd, J 1 = 2.4 Hz, J 2 = 8.5 Hz, 1H), 7.39 (dt, J 1 = 2.5 Hz, J 2 = 8.8 Hz, 2H), (m, 3H), 6.50 (t, J = 74.7 Hz, 1H), 1.36 (s, 9H), 1.34 (s, 9H); ( 13 C NMR, 126 MHz, CDCl 3): δ = 200.1, 149.1, 148.0, 126.4, 120.7, 50.1, 34.5, 31.4, 30.3; ( 19 F NMR, 377 MHz, CDCl 3): δ = 65.7 (s, 2F), 79.9 (d, J = 74.6 Hz, 2F); IR: 2964, 1508, 1366, 1317, 1255, 1131, 1105, 1036; HRMS (EI/FI) for C 22H 26F 4 2 [M] + requires found (4-(tert-Butyl)phenoxy)propan-2-one (9) The title compound was isolated along with the synthesis of 1-tert-butyl-4-(difluoromethoxy)benzene (6). Purification by silica gel column chromatography (eluent: 1 % Et 2 in n-pentane) provided the title compound (15.8 mg, 4 % yield) as a colourless oil. ( 1 H NMR, 400 MHz, CDCl 3): δ = 7.41 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), 7.05 (dt, J 1 = 2.6 Hz, J 2 = 8.8 Hz, 2H), 3.70 (s, 2H), 2.37 (s, 3H), 1.32 (s, 9H); ( 13 C NMR, 126 MHz, CDCl 3): δ = 200.1, 149.1, 148.0, 126.4, 120.7, 50.1, 34.5, 31.4, 30.3; IR: 3402, 2962, 1742, 1613, 1515, 1207, 1179, 1145, 1110, 1016, 832; HRMS (EI/FI) for C 13H 18 2 [M] + requires found

27 3. ptimisation Table 3.1 ptimization for the synthesis of [ 18 F]2a from 1a (S1) entry solvent concentration (mm) additive (equiv) temp ( o C) t (min) [ 18 F]2a RCC (%) n 1 MeCN ± MeCN ± MeCN ± MeCN ± MeCN ± MeCN ± MeCN ± MeCN ± MeCN ± t-buh ± MeCN 100 AgN 3 (1.0) ± MeCN 100 NaI (1.0) ±

28 3.2 ptimization for the synthesis of [ 18 F]3a from 1a (S2) entry solvent conc. (mm) additive (equiv) temp ( o C) [ 18 F]2a RCC (%) [ 18 F]2a RCC (%) 1 MeCN 17 K 2C 3 (1.4) ± ± MeCN 17 K 2C 3 (2.8) ± 6 14 ± MeCN 17 K 2C 3 (1.4), K (2.4) 80 1 ± 1 82 ± MeCN 17 K 2C 3 (1.4), 18-crown-6 (2.4) ± ± MeCN 33 K 2C 3 (1.4), K (2.4) 80 < 1 73 ± a MeCN 17 K 2C 3 (1.4), K (2.4) 80 < 1 80 ± b MeCN 17 K 2C 3 (1.4), K (2.4) 80 < 1 80 ± a MeCN 17 K 2C 3 (1.4), K (1.4) 80 4 ± 3 70 ± MeCN 17 NEt 4HC 3 (1.4) ± 8 6 ± MeCN 17 NBu 4H (1.4) ± 0 1 ± MeCN 17 Cs 2C 3 (1.4) ± 1 36 ± MeCN 17 LiH (1.4) 80 9 ± 4 22 ± MeCN 17 CsH. H 2 (1.4) ± ± MeCN/H 2 (59:1) 17 Cs 2C 3 (1.4) ± 2 7 ± MeCN/H 2 (59:1) 17 LiH (1.4) ± 2 43 ± MeCN/H 2 (59:1) 17 CsH. H 2 (1.4) 80 5 ± 3 18 ± DMS 17 K 2C 3 (1.4), K (2.4) 80 < 1 2 ± DMF 17 K 2C 3 (1.4), K (2.4) 80 < 1 60 ± t-buh 17 K 2C 3 (1.4), K (2.4) 80 < 1 45 ± acetone 17 K 2C 3 (1.4), K (2.4) 50 < 1 81 ± acetone ± acetone 33 K 2C 3 (1.4), K (2.4) 50 < 1 74 ± acetone 50 K 2C 3 (1.4), K (2.4) 50 < 1 83 ± a acetone 17 K 2C 3 (1.4), K (2.4) 50 2 ± 1 79 ± a acetone 17 K 2C 3 (1.4), K (1.4) 50 4 ± 2 72 ± a acetone 17 K 2C 3 (1.4) ± 10 6 ± 1 2 a 10 min reaction; b 5 min reaction n 28

29 3.3 ptimization for the synthesis of [ 18 F]4 from [ 18 F]3a (S3) entry coupling reagent (mmol) additive (mmol) solvent [ 18 F]4 RCC (%) n 1 HATU (0.06) - DMF 8 ± HBTU (0.06) - DMS 2 ± DCC (0.06) HBt (0.04) DMF 6 ± 1 2 entry X coupling reagent (equiv) base (equiv) additive (equiv) [ 18 F]4 RCC (%) n DMTMM (0.06) NEt 3 (0.12) - 16 ± DMTMM (0.06) NEt 3 (0.12) NMM (0.04) 18 ± DMTMM (0.12) NEt 3 (0.24) - 12 ± DMTMM (0.12) NEt 3 (0.24) NMM (0.08) 10 ±

30 3.4 ptimization for the synthesis of 6 from 3a (S4) entry metal salt AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 Ag2C3 Ag2C3 Ag2C3 AgN3 AgN3 AgN3 4 equiv AgN3 4 equiv AgN3 Ag(pico)2 Ag(pico)2 AgN3 AgN3 Cu2 oxidant additive solvent temp 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv (NH4)2S28 4 equiv (NH4)2S28 4 equiv (NH4)2S28 4 equiv (NH4)2S28 4 equiv (NH4)2S28 6 (% 19 F) 3a (% 19 F) - 1:1 Acetone/H2 50 o C 53 % 1 % - 1:1 MeCN/H2 80 o C 6 % - - 1:1 THF/H2 80 o C 1 % 93 % - 1:1 dioxane/h2 100 o C 17 % 54 % - 1:1 DMF/H2 100 o C 9 % 36 % - 1:1 DMS/H2 100 o C 12 % 22 % K2C3 1:1 Acetone/H2 50 o C equiv K222 1:1 Acetone/H2 50 o C 9 % 84 % K2C3 2 equiv K222 1:1 Acetone/H2 50 o C 3 % 88 % - 1:1 Acetone/H2 50 o C 37 % 2 % - 1:1 MeCN/H2 80 o C 6 % - K2C3 1:1 Acetone/H2 50 o C :1 Acetone/H2 50 o C 41 % 1 % - 1:1 MeCN/H2 80 o C 7 % - K2C3 1:1 Acetone/H2 50 o C 39 % - K2C3 1:1 Acetone/H2 50 o C 30 % - K2C3 2 equiv K222 1:1 Acetone/H2 50 o C 3 % 97 % - - 1:1 Acetone/H2 50 o C - 45 % - - 1:1 MeCN/H2 80 o C equiv Selectfluor 4 equiv Selectfluor - 1:1 Acetone/H2 50 o C 33 % - - 1:1 MeCN/H2 80 o C 7 % Acetone 50 o C % 30

31 Cu2 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 AgN3 - - MeCN 80 o C % 2 equiv K2S28 K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28 4 equiv K2S28-1:1 Acetone/H2 50 o C 50 % 7 % - 1:1 Acetone/H2 50 o C 26 % 62 % HCl 1:1 Acetone/H2 50 o C % Hantzsch ester 1:1 Acetone/H2 50 o C 25 % 38 % 1,4 CHD 1:1 Acetone/H2 50 o C 1 % 99 % 1,3 CHD 1:1 Acetone/H2 50 o C 8 % 91 % CuI 1:1 Acetone/H2 50 o C 47 % 19 % - Acetone 50 o C % - 4:1 Acetone/H2 50 o C 5 % 119 % - 1:4 Acetone/H2 50 o C 38 % 2 % - 1:1 Acetone/H2 rt 4 % 78 % TEMP 1:1 Acetone/H2 50 o C 11 % 86 % 2 equiv TEMP 1:1 Acetone/H2 50 o C % - 1:1 Acetone/D2 50 o C 35 % 18 % - - 1:1 Acetone-d6/H2 1:1 Acetone-d6/D2 50 o C 50 o C 4 % + (5 %) a 3 % + (5 %) a 4 % 3 % 1:1 Acetone/H2 50 o C 4 % 96 % 1:1 Acetone/H2 50 o C 53 % 16 % 1:1 Acetone/H2 50 o C 35 % 11 % 1:1 Acetone/H2 50 o C 19 % 38 % H-Si(SiMe 3) 3 1:1 Acetone/H2 50 o C 1 % 66 % 1:1 THF/H2 50 o C Trace 95 % 1:1 MeCN/H2 80 o C 14 % Trace 1:1 Dioxane/H2 100 o C 20 % 80 % 31

32 53 AgN3 54 AgN3 55 AgN3 56 AgN3 57 AgN equiv K2S28 4 equiv K2S28 2 equiv Selectfluor 4 equiv Selectfluor 4 equiv Selectfluor 2 equiv XeF2 2 equiv XeF2 2 equiv XeF2 1:1 DMF/H2 100 o C 34 % 46 % 1:1 DMS/H2 100 o C 9 % 19 % - 1:1 Acetone/H2 50 o C 18 % 32 % - 1:1 Acetone/H2 50 o C - 1:1 MeCN/H2 80 o C - DCM rt 2 equiv TBAF DCM rt 33 % + (12 %) b 7 + (12 %) b 0 % + (25 %) b 0 % + (13 %) b 0 % 0 % 0 % 32 % 2 equiv HF.pyridine DCM rt 0 % 0 % a Yield of Aryl-CF 2D product; b Yield of Aryl-CF 3 product. 32

33 4. General Radiochemical Procedures 4.1 [ 18 F]Fluoride Preparation [ 18 F]Fluoride was produced by Erigal (Keele, UK) via the 18 (p,n) 18 F reaction and delivered as [ 18 F]fluoride in [ 18 ]water. Radiosynthesis and azeotropic drying was performed on a NanoTek automated microfluidic device (Advion). [ 18 F]Fluoride was separated from 18 -enriched-water using anion exchange cartridges (MP1, RTG, Tennessee, USA) and subsequently released with 550 μl of a solution of K 2.2.2/K 2C 3 (kryptofix (15 mg) and K 2C 3 (3 mg) in 1 ml of MeCN/H 2, 4:1) into the concentrator to form [ 18 F]KF/K The solution was dried with five cycles of azeotropic drying with acetonitrile (300 μl) and redissolved in anhydrous acetonitrile (1000 μl). [ 18 F]KF/K (ca. 30 MBq) was dispensed as aliquots of this stock solution into a v-vial containing the necessary reagents and a magnetic stirrer. 4.2 Analysis For all reactions, an aliquot was removed for analysis by radio-tlc and radio-hplc. Radio-TLC was carried out on Merck Kiesegel 60 F254 plates in EtAc/Hexane (1:1) or Methanol and analysed using a plastic scintillator/pmt detector. Radio-HPLC analysis was performed using a Dionex Ultimate 3000 dual channel HPLC system with a shared auto-sampler, parallel UV-detectors and LabLogic NaI/PMTradiodetectors with Flowram analogue output. A representative radio-hplc trace of the crude reaction mixture, with UV trace (254 nm) of authentic reference material overlaid, is shown below. HPLC Gradient Settings: Water + 0.1% TFA/ MeCN + 0.1% TFA, 1 ml/min, Waters Nova-Pak C18 Column, 4 μm, 3.9 x 150 mm: 0 1 min (5 % MeCN + 0.1% TFA) isocratic 1 11 min (5 % to 95 % MeCN + 0.1% TFA) linear increase min (95 % MeCN + 0.1% TFA) isocratic min (95 % to 5 % MeCN + 0.1% TFA) linear decrease min (5 % MeCN + 0.1% TFA) isocratic. Reported radiochemical conversions are decay corrected and calculated by radio-tlc taking into account the radiochemical purity as determined by radio-hplc. 4.3 Procedure for small scale [ 18 F]Fluorination-hydrolysis To a V-vial containing K 2C 3 (2 mg, mmol), K (9 mg, mmol) and a magnetic stirrer bar was added [ 18 F]KF/K in MeCN. A solution of appropriate starting material (0.01 mmol) in acetone (200 μl) was added via syringe. The sealed vial was heated at 50 C for 20 minutes, before being quenched with water (200 μl). An aliquot was removed for analysis by radio-tlc and radio-hplc for radiochemical yield and product identification. 33

34 4.4 Procedure for determination of isolated RCY and SA of [ 18 F]3a [ 18 F]Fluoride was separated from 18 -enriched-water using an anion exchange cartridge (Waters Sep- Pak Accell Plus QMA Carbonate Plus Light Cartridge, 46 mg Sorbent per Cartridge, 40 µm Particle Size, 50/pk (Part # )) and subsequently released with 900 μl of a solution of K 2.2.2/K 2C 3 (kryptofix (15 mg) and K 2C 3 (3 mg) in 1 ml MeCN/H 2, 4:1). The solution was dried with six cycles of azeotropic drying with acetonitrile (150 μl). To the v-vial containing the dried [ 18 F]KF/K residue was added a solution of ethyl bromo(4-tert-butylphenoxy)fluoroacetate in acetone (250 μl), which was then heated to 50 C for 20 minutes. After cooling to room temperature the reaction mixture was diluted into 8 ml of H 2 and loaded onto a Sep-Pak Light C18 cartridge (activated with 1 ml MeH followed by 10 ml of H 2), followed by washing with H 2 (2 x 1mL). 1 ml of air was then flushed through the cartridge, after which [ 18 F]3a was eluted with CH 3CN (3 x 500 l) to give a stock solution of [ 18 F]3a for post-fluorination studies. An aliquot of this solution was analysed by radio-hplc for to assess product identity and radiochemical purity. UV trace of authentic reference Crude radiohplc trace Two reactions were performed, starting from 5130 MBq and 2620 MBq [ 18 F]fluoride in [ 18 ]water; 1750 MBq and 971 MBq of 4-tert-butylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3a) were isolated respectively. RCY = 36 ± 2 % (n = 2). SA of [ 18 F]3a in the collected fraction was assessed by injection of an aliquot on an analytical Synergi 4µm Hydro-RP 80A, 150 x 4.6 mm with 45% MeCN + 0.1% TFA/55% H % TFA (isocratic 1 ml/min), monitoring with UV (220 nm) and radioactive traces. The SA was decay corrected to the end of synthesis. 34

35 4.5 Procedure for determination of isolated RCY and SA of [ 18 F]3k [ 18 F]Fluoride was separated from 18 -enriched-water using an anion exchange cartridge (Waters Sep- Pak Accell Plus QMA Carbonate Plus Light Cartridge, 46 mg Sorbent per Cartridge, 40 µm Particle Size, 50/pk (Part # )) and subsequently released with 900 μl of a solution of K 2.2.2/K 2C 3 (kryptofix (15 mg) and K 2C 3 (3 mg) in 1 ml MeCN/H 2, 4:1). The solution was dried with six cycles of azeotropic drying with acetonitrile (150 μl). To the v-vial containing the dried [ 18 F]KF/K residue was added a solution of ethyl bromo(4-tert-butylphenoxy)fluoroacetate in acetone (250 μl), which was then heated to 50 C for 20 minutes. After cooling to room temperature the reaction mixture was diluted into 8 ml of H 2 and loaded onto a Sep-Pak Light C18 cartridge (activated with 1 ml MeH followed by 10 ml of H 2), followed by washing with H 2 (2 x 1mL). 1 ml of air was then flushed through the cartridge, after which [ 18 F]3k was eluted with CH 3CN (3 x 500 l) to give a stock solution of [ 18 F]3k for post-fluorination studies. An aliquot of this solution was analysed by radio-hplc for to assess product identity and radiochemical purity. UV trace of authentic reference Crude radiohplc trace Two reactions were performed, starting from 5140 MBq and 2870 MBq [ 18 F]fluoride in [ 18 ]water; 1550 MBq and 900 MBq of 4-tert-butylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3k) were isolated respectively. RCY = 31 ± 1 % (n = 2). SA of [ 18 F]3k in the collected fraction was assessed by injection of an aliquot on an analytical Synergi 4µm Hydro-RP 80A, 150 x 4.6 mm with 35% MeCN + 0.1% TFA/65% H % TFA (isocratic 1 ml/min), monitoring with UV (220 nm) and radioactive traces. The SA was decay corrected to the end of synthesis. 35

36 5. Radio-HPLC Traces Ethyl (4-tert-butylphenoxy)([ 18 F]difluoro)acetate ([ 18 F]2a) Ethyl (biphenyl-4-yloxy)([ 18 F]difluoro)acetate ([ 18 F]2b) 4-tert-Butylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3a) 36

37 (Biphenyl-4-yloxy)([ 18 F]difluoro)acetic acid ([ 18 F]3b) [ 18 F]Difluoro(phenoxy)acetic acid ([ 18 F]3c) (4-Bromophenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3d) 37

38 (3-Bromophenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3e) (2-Bromophenoxy)( [ 18 F]difluoro)acetic acid ([ 18 F]3f) 2,2-[ 18 F]Difluoro-2-(2-fluorophenoxy)acetic acid ([ 18 F]3g) 38

39 2-(4-(tert-Butoxycarbonyl)phenoxy)-2,2-[ 18 F]difluoroacetic acid ([ 18 F]3h) (4-Benzoylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3i) (3-Cyanophenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3j) 39

40 [ 18 F]Difluoro[4-(trifluoromethyl)phenoxy]acetic acid ([ 18 F]3k) 2-(4-(1,3-Dioxoisoindolin-2-yl)phenoxy)-2,2-[ 18 F]difluoroacetic acid ([ 18 F]3l) and 2-((4-(Carboxy[ 18 F]difluoromethoxy)phenyl)carbamoyl)benzoic acid 40

41 6. Post-Fluorination Functionalization 6.1 Radiosynthesis of 2-(4-(tert-Butyl)phenoxy)-2,2-[ 18 F]difluoro-N-(3-fluoro-4-(methyl sulfonamido)benzyl)acetamide ([ 18 F]4) To a V-vial containing a magnetic stirrer bar and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium chloride (DMTMM) (16.6 mg, 0.06 mmol) and (3-fluoro-4- (methylsulfonamido)phenyl)methanaminium chloride (10 mg, 0.04 mmol) was added 4-tertbutylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3a) in MeCN (~30 MBq). A solution of NEt 3 (17 μl, 0.12 mmol) in THF (300 μl) was added, after which the sealed vial was allowed to stir for 20 minutes at room temperature. After the reaction, an aliquot was removed for analysis by radio-tlc and HPLC to determine radiochemical conversion and product identity. Analysis was performed using Gradient A with a Phenomenex Synergi Hydro RP 80 Å column (4 μm, 4.6 x 150 mm) at a flow rate 1 ml/min. 2-(4-(tert-Butyl)phenoxy)-2,2-[ 18 F]difluoro-N-(3-fluoro-4-(methylsulfonamido)benzyl)acetamide ([ 18 F]4) UV trace of authentic reference Crude radiohplc trace 41

42 6.2 Radiosynthesis of 2-(2-{[ 18 F]difluoro[4-(trifluoromethyl)phenoxy]methyl}-1Hbenzimidazol-5-yl)-N,N-dimethylbenzene sulfonamide ([ 18 F]5) To a V-vial containing a magnetic stirrer bar was added [ 18 F]difluoro[4-(trifluoromethyl)phenoxy]acetic acid ([ 18 F]3k) in MeCN (~30 MBq). The solvent was then removed at 50 C under a stream of nitrogen for approximately 5 minutes. A solution of 3',4'-diamino-N,N-dimethylbiphenyl-2-sulfonamide in 6 M HCl (200 μl) was added, then the sealed vial was allowed to stir for 20 minutes at 110 o C. After the reaction, an aliquot was removed for analysis by radio-tlc and HPLC to determine radiochemical conversion and product identity. Analysis was performed using Gradient A with a Phenomenex Synergi Hydro RP 80 Å column (4 μm, 4.6 x 150 mm) at a flow rate 1 ml/min. 2-(2-{[ 18 F]Difluoro[4-(trifluoromethyl)phenoxy]methyl}-1H-benzimidazol-5-yl)-N,Ndimethylbenzene sulfonamide ([ 18 F]5) UV trace of authentic reference Crude radiohplc trace 42

43 6.3 Radiosynthesis and isolation of 1-tert-butyl-4-([ 18 F]difluoromethoxy)benzene ([ 18 F]6) To a V-vial containing a magnetic stirrer bar was added 4-(tert-butylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3a) in MeCN (~30 MBq). The solvent was then removed at 50 C under a stream of nitrogen for approximately 5 minutes. Then acetone (200 μl) was added followed by a solution of AgN 3 (0.2 mg, 0.01 mmol) in H 2 (100 μl) and a solution of K 2S 2 8 (11 mg, 0.04 mmol) in H 2 (100 μl). The sealed vial was allowed to stir for 20 minutes at 50 C. After the reaction, the mixture was injected onto a reverse phase HPLC column (Phenomenex Luna C18(2) 100Å, 250 x 10mm). Flow rate 4 ml/min (70 % MeCN) [ 18 F]1-tert-butyl-4-(difluoromethoxy)benzene ([ 18 F]6) was eluted at 16.5 min. Two reactions were performed, starting from 1756 MBq and 836 MBq of 4-tertbutylphenoxy)([ 18 F]difluoro)acetic acid ([ 18 F]3a) (after solvent removal); 408 MBq and 179 MBq of 1- tert-butyl-4-([ 18 F]difluoromethoxy)benzene ([ 18 F]6) were isolated respectively. RCY = 22 ± 1 % (n = 2). 1-tert-Butyl-4-([ 18 F]difluoromethoxy)benzene ([ 18 F]6): Eluent system = 70 % MeCN isocratic UV trace of authentic reference Crude radiohplc trace SA of [ 18 F]6 in the collected fraction was assessed by injection of an aliquot on an analytical Synergi 4µm Hydro-RP 80A, 150 x 4.6 mm with 45% MeCN + 0.1% TFA/55% H % TFA (isocratic 1 ml/min), monitoring with UV (220 nm) and radioactive traces. The SA was decay corrected to the end of synthesis. 43