546
N. Vasdev et al. / Tetrahedron Letters 50 (2009) 544–547
Caution: Precautionary measures should be established prior to
repeating aspects of this work, particularly when 18F and the highly
toxic 2-methylaziridine and/or anhydrous HF are employed. All
work with 2-methylaziridine should be carried out in a well venti-
lated fume-hood, and appropriate safety precautions should be
taken. Before commencing work with anhydrous HF, first-aid treat-
ment procedures should be available and known to all laboratory
personnel.
Acknowledgements
The authors gratefully acknowledge the assistance of Armando
Garcia, Winston T. Stableford, Min Wong, and for production of
[
18F]-fluoride. We also thank Dr. Iain D. G. Watson for helpful dis-
cussions, and Dr. Raman Chirakal and Rezwan Ashique for their
expertise with the anhydrous HF reaction. Financial support for
this work was provided by the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Canadian Institutes
for Health Research in the form of a Collaborative Health Research
Projects Grant (CHRPJ 322787-06), and an NSERC Postdoctoral
Fellowship to K.A.S.
References and notes
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Figure 2. (a) X-ray crystal structure of 6 and (b) overlay of the X-ray crystal
structures of 6 and N-isopropylbenzamide.
[
18F]5. A C-18 solid-phase extraction cartridge purification was
conducted prior to quantitative catalytic hydrogenation, to prepare
the new amines, [18F]1 and [18F]2. Characterization of both regioi-
somers was performed by in situ benzoylation of the mixture
(65% conversion) to prepare N-acyl fluoroamines
[
[
18F]6 and
18F]7 in an 85:15 ratio, as identified by HPLC ( Fig. 1) and
corresponded to an 8% decay-corrected radiochemical yield from
[
18F]-fluoride (n = 3).
As part of our ongoing studies of the N-isopropyl and N-fluoro-
isopropyl moieties in PET radiopharmaceutical discovery, we
recently reported the single-crystal structure of N-isopropylbenza-
mide.26 Figure 2a shows the X-ray crystal structure of compound
16. Farrokhzad, S.; Diksic, M.; Yamamoto, L. Y.; Feindel, W. Can. J. Chem. 1984, 62,
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6
27, and Figure 2b shows its overlay with N-isopropylbenzamide
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and shows that both compounds have similar geometries. In the
molecular structure of 6, the –CH3 group and the –CH2F group
bonded to C8 are disordered, with equal occupancies, over the
two sites which correspond to an interchange of these groups.
One of the disordered half occupancy F atoms is, in turn, rotation-
ally disordered about the C–C bond with relative occupancies
0.40:0.10. In the crystal structure, molecules are linked in one-
dimensional chains via intermolecular N–HÁ Á ÁO hydrogen bonds.
This represents the first X-ray crystal structure of the N-fluoroiso-
propyl moiety.
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25. Reactive [K222][18F] was prepared and azeotropically dried with anhydrous
CH3CN as previously described.28 Compound 3 (4 mg, 20
lmol) in 250 lL
3. Conclusion
DMSO was added, and the mixture was vortexed prior to heating at 80 °C for
30 min. The reaction mixture was removed from heat and diluted with 5 mL
H2O, and loaded onto a C18 solid-phase extraction cartridge (Sep-PakÒ light;
activated with 5 mL CH3CN, followed by 5 mL H2O). The cartridge was
subsequently washed with 5 mL H2O, and the crude mixture containing
This work demonstrates the feasibility of preparing [18F]fluoro-
amines by ring-opening of Cbz-protected azridines and a rare
example of regioselective fluoride attack at the 2° carbon of an
unsymmetrical aziridine. Further studies are underway to study
the influence of the nitrogen substituent on the regioselectivity
of ring-opening of substituted aziridines with [18F]- or 19F-fluoride.
Extension of this chemistry to symmetrical aziridines and other
unsymmetrical aziridines to create new [18F]fluoroamines and
radiopharmaceuticals is also ongoing in our laboratory.
intermediates [18F]4 and [18F]5 was eluted with 2 Â 500
lL anhydrous CH3CN
into a 5-mL glass V-vial (Wheaton) containing 10 mg of activated palladium on
charcoal (10%). The vial was sealed with a Teflon septum and a hydrogen
balloon was applied, followed by stirring at room temperature for 30 min, at
which point a solution containing Bz-Cl (3 lL), DIPEA (5 lL) and 17 lL CH3CN
was added. Upon heating at 70 °C in an oil bath for 10 min, the crude reaction
mixture was filtered and passed through a C-18 Sep-Pak as described above
prior to analysis by analytical HPLC (Fig. 1). Compounds [18F]6 and [18F]7 were
concurrently isolated by semi-preparative HPLC (mobile phase: 25/75 MeOH/