The Journal of Organic Chemistry
Article
(ESI+) m/z: 218 [M+H]+. HRMS (ESI+) m/z: calcd for
C8H9FNO3S: 218.0287 [M+H]+; found 218.0297 [M+H]+.
4-Methoxybenzene-1-sulfonyl Fluoride (4b). Yield (570 mg,
Cyclone 18 Twin cyclotron (ANSTO, Camperdown, Australia)
using the 18O(p, n)18F nuclear reaction. Microfluidic radiosyntheses
were performed in Discovery Mode using a NanoTek LF Microfluidic
Synthesis System (Advion, Ithaca, NY) connected to a standard laptop
using the NanoTek software, V1.4.0 GMP Lite. Microreactors were
made of fused silica tubing (100 μm × 2 m), coiled tightly into a brass
ring containing a thermoresistant polymer to hold the tubing in place.
[18F]1b−12b and [18F]14b were purified by HPLC using a Waters
515 pump, a Linear UVis 200 detector (λ = 254 nm) together with a
Carroll and Ramsey model 105S gamma detector. [18F]1b−12b
samples from the microfluidic reactor were purified using a
Phenomenex Luna C18 column (150 × 4.6 mm, 5 μm) at 1.2 mL/
min with CH3CN/H2O/TFA (55:45:0.1, v/v) as the mobile phase,
with the following exceptions: [18F]2b (52.5% CH3CN); [18F]7b
(65% CH3CN); [18F]8b (65% CH3CN); [18F]9b (70% CH3CN);
[18F]10b (90% CH3CN); [18F]11b (70% CH3CN). [18F]2b, [18F]4b,
[18F]5b, [18F]11b and [18F]14b samples from the conventional
radiosynthetic methods were purified using Phenomenex Luna C18
columns (250 × 10 mm, 5 or 10 μm) at 2 mL/min with CH3CN/
H2O/TFA (70:30:0.1, v/v) as the mobile phase (90:10:0.1, v/v for
[18F]11b). Specific activity values for [18F]4b and [18F]11b were
obtained by measuring the radioactivity injected and the UV
absorbance associated with the radioactive peak by analytical HPLC.
The concentration of the sample was found by comparison of the UV
area under the curve to the concentration calibration curve of the
analogous reference standard. Radioactivity was measured using a
Capintec R15C dose calibrator. Isolated radiochemical yields of [18F]
1b−12b, 14b were collected HPLC yields calculated as a percentage of
the initial radioactivity injected. Solid phase extraction Sep-pak C18
Light cartridges were purchased from Waters Corporation (Milford,
MA) and activated with 5 mL of EtOH and 20 mL of H2O.
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62%); clear oil. H NMR (400 MHz, CDCl3): δ 7.93 (dt, J = 9.2 Hz,
3.2 Hz, 2H, CH × 2), 7.05 (dt, J = 8.8 Hz, 2.8 Hz, 2H, CH × 2), 3.91
(s, 3H, OCH3). 13C NMR (100 MHz, CDCl3): δ 165.4, 130.9, 124.1
(J = 24 Hz), 56.0. 19F NMR (376 Hz, acetone-d6): δ 65.7. IR (cm−1):
1595, 1501, 1398, 1267, 1206, 1172, 807, 750, 670.
4-Nitrobenzene-1-sulfonyl Fluoride (5b). Yield (400 mg, 42%);
beige crystals; mp 75−77 °C (lit.37 77.5−78.5 °C). H NMR (400
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MHz, CDCl3): δ 8.48 (dt, J = 8.8 Hz, 2.4 Hz, 2H, CH × 2), 8.24 (dt, J
= 8.8 Hz, 2.4 Hz, 2H, CH × 2). 13C NMR (100 MHz, CDCl3): δ
152.0, 138.5 (J = 27 Hz), 130.2, 125.0. 19F NMR (376 Hz, acetone-
d6): δ 64.0. IR (cm−1): 1609, 1532, 1417, 1348, 1214, 784, 615.
4-Fluorobenzene-1-sulfonyl Fluoride (6b). Yield (152 mg,
52%); yellow oil. 1H NMR (400 MHz, acetone-d6): δ 8.23 (q, J = 5.2
Hz, 2H), 7.60 (t, J = 8.4 Hz, 2H). 13C NMR (100 MHz, acetone-d6): δ
166.7, 132.8 (J = 11 Hz), 129.6 (J = 25 Hz), 118.4 (J = 23 Hz). 19F
NMR (376 Hz, acetone-d6): δ −101.9, 64.9. IR (cm−1): 1592, 1407,
1209, 837, 754, 672.
4-Chlorobenzene-1-sulfonyl Fluoride (7b). Yield (163 mg,
62%); white powder; mp 47−48 °C (lit.38,39 38.4−39.8 °C; 48−49
°C). 1H NMR (400 MHz, acetone-d6): δ 8.14 (dt, J = 8.4 Hz, 1.6 Hz,
2H), 7.86 (dt, J = 8.4 Hz, 2.4 Hz, 2H). 13C NMR (100 MHz, acetone-
d6): δ 143.3, 132.1 (J = 24 Hz), 131.4, 131.2. 19F NMR (376 Hz,
acetone-d6): δ 64.5. IR (cm−1): 1572, 1473, 1405, 1209, 1088, 775,
740, 648.
4-Bromobenzene-1-sulfonyl Fluoride (8b). Yield (194 mg,
63%); beige solid; mp 52−54 °C (lit.38 58.1−59.8 °C). 1H NMR (400
MHz, acetone-d6): δ 8.04 (q, J = 8.8 Hz, 4H). 13C NMR (100 MHz,
acetone-d6): δ 134.4, 132.6 (J = 26 Hz), 132.0, 131.0. 19F NMR (376
Hz, acetone-d6): δ 64.5. IR (cm−1): 1573, 1468, 1403, 1207, 1065, 770,
731, 640.
Microfluidic Procedure. No-carrier-added (n.c.a.) aqueous [18F]-
fluoride (500−2300 MBq) was trapped onto an anion-exchange resin
(MP1) and eluted with a solution of K2CO3 (5 mg/mL) and Kryptofix
[2.2.2] (20 mg/mL) in CH3CN/H2O (90:10 v/v, 450 μL).
Subsequent azeotropic drying (2 × 500 μL L) was performed at
95 °C, followed by the addition of 500 μL of CH3CN. The loop of
pump 1 was filled with the precursor solution (0.5−10 mg/mL in
CH3CN), while the loop of pump 3 was filled with the dried K18F/K222
complex. Equal volumes of K18F/K222 and the precursor (10 μL) were
released from each pump and pushed through the microreactor at a
flow rate of 20 μL/min, at temperatures between 30 and 180 °C. The
crude product was released from the microreactor with 200 μL of
CH3CN into an Eppendorf tube, before 300 μL of H2O was added and
the whole sample was injected onto an analytical HPLC system for
analysis and purification.
4-Iodobenzene-1-sulfonyl Fluoride (9b). Yield (176 mg, 57%);
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beige powder; mp 70 °C. H NMR (400 MHz, acetone-d6): δ 8.24
(dd, J = 1.6 Hz, 8.8 Hz, 2H), 7.88 (dd, J = 2.0 Hz, 8.8 Hz, 2H). 13C
NMR (100 MHz, acetone-d6): 140.5, 133.1 (J = 25 Hz), 130.5, 105.2.
19F NMR (376 Hz, acetone-d6): δ 64.3. IR (cm−1): 1567, 1469, 1403,
1207, 767, 724, 602.
2,4,6-Trimethylbenzene-1-sulfonyl Fluoride (10b). Yield (550
mg, 59%); white powder; mp 71−73 °C (lit.40 73−73.5 °C). 1H NMR
(400 MHz, CDCl3): δ 7.03 (s, 2H, CH × 2), 2.64 (d, J = 1.6 Hz, 6H,
CH3 × 2), 2.34 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 145.2,
140.2, 132.0 (J = 1 Hz), 129.3 (J = 20 Hz), 22.5 (J = 2 Hz), 21.3. 19F
NMR (376 Hz, CD3CN-d3): δ 72.3. IR (cm−1): 1604, 1440, 1392,
1204, 748, 663. MS (EI) m/z: 202 [M+]. HRMS (ESI+) m/z: calcd
for C9H12FO2S: 203.0542 [M+H]+; found 203.0543 [M+H]+.
2,4,6-Triisopropylbenzene-1-sulfonyl Fluoride (11b). Yield
Conventional Procedure. An aqueous H[18F] solution (100−
500 MBq) was added to a 2.5 mL vial containing a solution of
Kryptofix [2.2.2] (1.24−1.83 mg, 12.4−18.3 μL in CH3CN, 2 equiv)
and K2CO3 (0.23−0.34 mg, 2.3−3.4 μL in H2O, 1 equiv). The solvent
was evaporated under a stream of N2 at 100 °C under vacuum and the
residue was azeotropically dried with 3 × 1 mL anhydrous CH3CN.
The precursor 2a, 4a, 5a, 11a or 14a (0.5 mg, 1 equiv) was dissolved
in anhydrous CH3CN (1 mL) and added to the dried K18F/K222
complex before being heated at 100 °C for 2 min. (For reactions at
30 °C, the reaction vial was cooled in H2O for 5 min before the
addition of the precursor). A 200 μL aliquot was added to 500 μL of
mobile phase and purified using HPLC to yield [18F]2b (30 °C: 86
3% RCY, n = 3; 100 °C: 87 3% RCY, n = 4), [18F]4b (30 °C: 84
2% RCY, n = 3; 100 °C: 88 1% RCY, n = 3), [18F]5b (30 °C: 77
7% RCY, n = 4; 100 °C: 74 6% RCY, n = 4), [18F]11b (100 °C: 64
1% RCY, n = 3) and [18F]14b (100 °C: 58 11% RCY, n = 3).
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(310 mg, 65%); white crystals; mp 68−69 °C. H NMR (400 MHz,
CDCl3): δ 7.28 (s, 2H, CH × 2), 4.02−3.94 (m, 2H, CH × 2), 3.00−
2.93 (m, 1H, CH), 1.33−1.29 (m, 18H, CH3 × 6). 13C NMR (100
MHz, CDCl3): δ 155.5, 150.9, 128.1 (J = 19 Hz), 124.1, 34.5, 30.3 (J =
2 Hz), 24.6. 19F NMR (376 Hz, CD3CN-d3): δ 67.1. IR (cm−1): 2960,
1599, 1431, 1399, 1363, 1205, 846, 764, 667.
Thiophene-2-sulfonyl Fluoride (12b). Yield (181 mg, 60%);
yellow oil. 1H NMR (400 MHz, acetone-d6): δ 8.35 (ddd, J = 5.2 Hz,
1.6 Hz, 0.4 Hz, 1H), 8.14 (dt, J = 4.0 Hz, 1.6 Hz, 1H), 7.45 (ddd, J =
4.8 Hz, 4.0 Hz, 0.8 Hz, 1H). 13C NMR (100 MHz, acetone-d6): δ
139.4 (J = 3 Hz), 138.8 (J = 2 Hz), 131.3 (J = 30 Hz), 129.8. 19F NMR
(376 Hz, acetone-d6): δ 70.2. IR (cm−1): 1400, 1204, 1024, 859, 767,
672.
4-Formylbenzene-1-sulfonyl Fluoride (14b). Yield (62 mg,
29%); white powder; mp 59−60 °C (lit.18 60 °C). H NMR (400
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[18F]4b was also produced in 72
heated at 100 °C for 30 s.
11% RCY (n = 3) after being
MHz, acetone-d6): δ 10.26 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 8.32 (d, J
= 8.8 Hz, 2H). 13C NMR (100 MHz, acetone-d6): δ 192.1, 142.5,
137.7 (J = 25 Hz), 131.5, 130.2. 19F NMR (376 Hz, acetone-d6): δ
63.9. IR (cm−1): 2866, 1702, 1407, 1205, 773, 697, 605. MS (ESI+)
m/z: 188 [M+H]+.
Competition Studies. Addition of an Unprotected Amino Acid.
The radiosynthesis was performed using the conventional method.
The precursor 4a (0.5 mg, 2.42 μmol) and D-tyrosine (0.44 mg, 2.42
μmol) were dissolved in anhydrous CH3CN (1 mL) and added to the
dried K18F/K222 complex before being heated at 100 °C for 2 min. A
Radiochemistry. Aqueous H[18F] was produced on a GE
PETtrace cyclotron (Cyclotek, Bundoora, Australia) or an IBA
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dx.doi.org/10.1021/jo401759z | J. Org. Chem. 2013, 78, 11262−11270