Regioselective ring opening of 2-methylaziridine derivatives with 18F- and 19F-fluoride

Article abstract of DOI:10.1016/j.tetlet.2011.05.139

Regioselectivity of the nucleophilic ring opening of N-benzoyl (Bz) and N-benzyloxycarbonyl (Cbz) activated 2-methylaziridines with anhydrous tetramethylammonium fluoride, anhydrous hydrogen fluoride, and ¹⁹F or [¹⁸F]-labelled potassium cryptand fluoride ([K₂₂₂][ ^18/19F]) were investigated. Whereas all reactions with rigorously anhydrous N(CH₃)₄F did not ring-open the aziridines, reactions with anhydrous HF exclusively yielded the 2-fluoropropanamine derivatives. Reactions of Bz-protected and Cbz-protected 2-methylaziridine with [K₂₂₂][^18/19F] yielded the 2-fluoropropanamine and 1-fluoro-2-propanamine derivatives as the major products, respectively, and represents the first example of regiocontrol during ring opening of aziridines with [¹⁸F]-fluoride.

Full text of DOI:10.1016/j.tetlet.2011.05.139

Tetrahedron Letters 52 (2011) 4114–4116
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective ring opening of 2-methylaziridine derivatives with 18F- and 19F-
fluoride
Erik M. van Oosten a,b, Michael Gerken c, Paul Hazendonk c, Roxanne Shank c, Sylvain Houle a,d
,
Alan A. Wilson a,d, Neil Vasdev a,d,
⇑
a PET Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada M5T 1R8
b Department of Chemistry, University of Toronto, Toronto, ON, Canada M5S 3H6
c Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4
d Department of Psychiatry, University of Toronto, Toronto, ON, Canada M5T 1R8
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselectivity of the nucleophilic ring opening of N-benzoyl (Bz) and N-benzyloxycarbonyl (Cbz) acti-
vated 2-methylaziridines with anhydrous tetramethylammonium fluoride, anhydrous hydrogen fluoride,
and 19F or [18F]-labelled potassium cryptand fluoride ([K222][18/19F]) were investigated. Whereas all reac-
tions with rigorously anhydrous N(CH3)4F did not ring-open the aziridines, reactions with anhydrous HF
exclusively yielded the 2-fluoropropanamine derivatives. Reactions of Bz-protected and Cbz-protected 2-
methylaziridine with [K222][18/19F] yielded the 2-fluoropropanamine and 1-fluoro-2-propanamine deriv-
atives as the major products, respectively, and represents the first example of regiocontrol during ring
opening of aziridines with [18F]-fluoride.
Received 20 April 2011
Revised 25 May 2011
Accepted 26 May 2011
Available online 2 June 2011
Dedicated to Professor Gary J. Schrobilgen
for his lifelong achievements in fluorine
chemistry
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aziridine
Fluorine-18
Ring opening
Fluoroamines
Ring opening of aziridines by fluoride ions have been rarely ex-
plored1–4 compared with nucleophilic additions of other halides to
aziridines despite the synthetic versatility of such reactions.5 The
compounds and radiopharmaceuticals. We,14,15 and others,16,17
are particularly interested in such amines for the development of
[
18F]-labelled b-blockers for cardiac or central nervous system
short-lived isotope fluorine-18 (18F, t = 109.7 min) is routinely
imaging, and such radiotracers rely on the rapid introduction of
N-[18F]-fluoroalkyl moieties. Our previous work demonstrated
the feasibility of preparing [18F]-fluoroamines through ring open-
ing of an activated aziridine with [18F]-fluoride and represents a
rare example of regioselective fluoride attack (85%) at the 2° car-
bon of an unsymmetrical aziridine.9 Specifically, the ring opening
of N-benzyloxycarbonyl (Cbz)-protected 2-methylaziridine (1)
with [18F]-labelled fluoride yielded the N-protected 1-[18F]fluoro-
2-propanamine ([18F]2) and 2-[18F]fluoro-1-propanamine ([18F]3)
derivatives, which were used to prepare [18F]4 and [18F]5, respec-
tively, by catalytic hydrogenation and acylation with benzoyl chlo-
ride (Bz–Cl) (Scheme 1).
It has been established that altering either the reaction condi-
tions or the substituent on nitrogen can have dramatic effects on
the regioselectivity of aziridine ring opening.18,19 As fluoride attack
of an unsymmetrical aziridine can occur at either the secondary or
tertiary carbon, the goal of the present work is to attempt to con-
trol the regioselectivity and evaluate the efficiency of ring opening
of 2-methylaziridine, a model unsymmetrical aziridine, by fluoride.
The ring opening of N-acyl and N-carbamyl aziridines with 18F- and
½
incorporated into radiopharmaceuticals for molecular imaging
with positron emission tomography (PET), and this technology re-
lies on new facile synthetic methodologies that enable the stereo-
selective and regioselective introduction of radionuclides into
organic compounds.6–8 Our laboratory9 and others10–13 have ex-
plored the potential of nucleophilic ring opening of aziridines with
[
18F]-fluoride as a flexible synthetic pathway to synthesize struc-
turally diverse radiopharmaceuticals. To date, no attempts have
been made to control the regioselectivity in the ring opening of
aziridines with no-carrier-added [18F]-fluoride ion, the most com-
monly used radiofluorinating agent for preparation of radiophar-
maceuticals with high specific activity.
Small versatile nucleophilic synthons such as [18F]fluoropropyl-
amines can complement the electrophilic [18F]-labelled synthons
commonly employed in PET radiochemistry, such as [18F]-fluoroal-
kyl halides, and may be used to prepare arrays of [18F]-labelled
⇑
Corresponding author. Tel.: +1 416 979 4680; fax: +1 416 979 4656.
E-mail address: neil.vasdev@utoronto.ca (N. Vasdev).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.139

E. M. van Oosten et al. / Tetrahedron Letters 52 (2011) 4114–4116
4115
H
N
18F
Cbz
Cbz
18F
18F]2
+
H
N
H
N
[
18F]KF, K222
[
1. Pd/C, H2, CH3CN
18F
+
Bz
Bz
N
1
Cbz
.
18F
DMSO, Δ
2. Bz-Cl, DIPEA, Δ
H
[
18F]4
[
18F]5
N
[
18F]3
85
:
15
Scheme 1. Ring opening of 2-methylaziridine by [18F]-fluoride, followed by deprotection and acylation.9
19F-fluoride sources was investigated in the present work. Regiose-
lectivity and efficiency of ring opening of N-activated 2-methylaz-
iridines with anhydrous hydrogen fluoride (aHF), anhydrous
tetramethylammonium fluoride (TMAF),20 or potassium cryptand
fluoride [K222][18/19F] were assessed and carried out as described
in Table 1.
warm from À40 °C to room temperature over several hours. No
reaction was observed under these conditions, with exception of
fluoride attack at CH3CN to form bifluoride.27
Our previous work demonstrated that [K222][18F] is capable of
ring opening N-Cbz-2-methylaziridine (1) with an unusual reactiv-
ity of fluoride primarily at the 2° carbon, yielding 2 as the major
product (Scheme 1).9 Both 19F- and 18F-labelled potassium crypt-
and fluoride were reacted with 1 and 6 in the present investiga-
tions. The potassium cryptand fluoride reactions22 (Table 1;
entries 3 and 8) provide an excellent predictor of the regioselectiv-
ity of ring opening observed in the radiochemical experiments
(Table 1; entries 4, 5, 9 and 10). Applying microwave heating had
no effect on regioselectivity, but significantly increased radiochem-
ical yields and reduced reaction times (Table 1; entries 5 and 10,
respectively). Compared with the Cbz-activated azirdine (1), reac-
tions of the Bz-activated aziridine (6) with [K222][18/19F] showed an
opposite display of regioselectivity, favouring nucleophilic attack
at the 3° carbon (Table 1; entries 3–6 and 8–10, respectively), as
illustrated by the respective HPLC radiochromatograms (Fig. 1).
This reactivity parallels that of anhydrous HF experiments in the
present work, as well as previous reactions with substituted sec-
ondary aziridines in anhydrous HF.19,24 These experiments repre-
sent the first example of regiocontrol during ring opening of
aziridines with [18F]-fluoride and should prove applicable to radio-
pharmaceutical development.
Alvernhe and coworkers19,23 prepared
a,b-fluoroamines by ring
opening of N-benzoyl-2-methylaziridine (6) with Olah’s reagent, or
its modified forms, and found that fluoride attack occurred exclu-
sively at the 3° carbon resulting in the formation of 5, as well as
the rearrangement product, 5-methyl-2-phenyl-2-oxazoline.
While this work,19 and the work of Wade,24 has also demonstrated
the dominant selectivity towards the 3° carbon of substituted sec-
ondary aziridines with anhydrous HF, to our knowledge, no at-
tempt has been made to test the reactivity of N-activated
aziridines with this reagent. Both reactions of 1 and 6 with neat
anhydrous HF21 in the present study resulted in fluoride addition
at the 3° carbon to produce 3 and 5, respectively, in good yields
(Table 1; entries 1 and 6, respectively).
Nucleophilic ring opening of the aziridines 1 and 6 (130–
150 lmol) were also studied under non-protic fluoro-basic condi-
tions (Table 1; entries 2 and 7, respectively), in fluoroplastic
NMR tubes. Equimolar quantities of anhydrous N(CH3)4F were
transferred at À130 °C under rigorously dry conditions25, and re-
acted with 1 or 6 (130–150 l
mol) in anhydrous CH3CN26 (ca
0.5 mL). The reaction system was subsequently monitored by
Our NMR spectroscopic analysis of the resulting fluoroamines
indicated that their spectra are more complicated than previously
low-temperature 19F NMR spectroscopy while being allowed to
Table 1
Reaction conditions for fluorination of N-activated 2-methylaziridines
a - d
R
18/19F
R
N
H
+
R
N
N
H
18/19F
R = Cbz (1)
or Bz (6)
2 or 4
3 or 5
Entry
Aziridine
Fluorinating agent
Solvent
Temp (°C)
Time (min)
Yielda (%)
Amine product
2b (%)
3b (%)
1
2
3
4
5
aHFc
aTMAF
Neat
CH3CN
DMSO
DMSO
DMSO
rt
10
53
0
14
40
52
0
-
86
100
-
14
d
À40 to rt
Cbz
Bz
N
[K222][F]e
[K222][18F]f
[K222][18F]
90
30
30
5
90
85
15
120 (MW)g
85
15
4b (%)
5b (%)
6
7
8
9
10
aHFc
aTMAF
Neat
CH3CN
DMSO
DMSO
DMSO
rt
10
76
0
10
22
43
0
-
0
20
20
100
-
100
80
d
À40 to rt
N
[K222][F]e
[K222][18F]f
[K222][18F]
90
30
30
5
90
120 (MW)g
80
a
b
c
d
e
f
Reported percent yields include both regioisomers; radiochemical yields are isolated and reported relative to starting [18F]-fluoride, uncorrected for decay.
Regioselectivity was determined by 19F NMR spectroscopy and/or HPLC.
see Ref. 21.
performed over several hours with incremental warming (+5 °C) and monitored by 19F NMR spectroscopy reference.
see Ref. 22.
As previously described9 with minor modifications.
MW = microwave (BiotageÒ initiator) heating.
g

4116
E. M. van Oosten et al. / Tetrahedron Letters 52 (2011) 4114–4116
5. Aziridines and epoxides in organic synthesis; Yudin, A. K., Ed.; Wiley Weinheim:
Chichester, 2006.
6. Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501–1516.
7. Cai, L. S.; Lu, S. Y.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853–2873.
8. Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem., Int. Ed. 2008, 47,
8998–9033.
9. Vasdev, N.; van Oosten, E. M.; Stephenson, K. A.; Zadikian, N.; Yudin, A. K.;
Lough, A. J.; Houle, S.; Wilson, A. A. Tetrahedron Lett. 2009, 50, 544–547.
10. Farrokhzad, S.; Diksic, M.; Yamamoto, L.; Feindel, W. Can. J. Chem. 1984, 62,
2107–2112.
11. Gillings, N. M.; Gee, A. D. ‘‘Aziridines in the Synthesis of 11C and 18F-Labelled
Amino Acids’’; 12th International Symposium on Radiopharmaceutical
Chemistry, 1997, Uppsala, Sweden.
12. Lehel, S.; Horvath, G.; Boros, I.; Mikecz, P.; Márián, T.; Szentmiklósi, A. J.; Trón,
L. J. Labelled Compd. Radiopharm. 2000, 43, 807–815.
13. Roehn, U.; Becaud, J.; Mu, L. J.; Srinivasan, A.; Stellfeld, T.; Fitzner, A.; Graham,
K.; Dinkelborg, L.; Schubiger, A. P.; Ametamey, S. M. J. Fluorine Chem. 2009, 130,
902–912.
14. Stephenson, K. A.; van Oosten, E. M.; Wilson, A. A.; Meyer, J. H.; Houle, S.;
Vasdev, N. Neurochem. Int. 2008, 53, 173–179.
15. Stephenson, K. A.; Wilson, A. A.; Meyer, J. H.; Houle, S.; Vasdev, N. J. Med. Chem.
2008, 51, 5093–5100.
16. Kopka, K.; Law, M. P.; Breyholz, H. J.; Faust, A.; Holtke, C.; Riemann, B.; Schober,
O.; Schafers, M.; Wagner, S. Curr. Med. Chem. 2005, 12, 2057–2074.
17. van Waarde, A.; Vaalburg, W.; Doze, P.; Bosker, F. J.; Elsinga, P. H. Curr. Pharm.
Des. 2004, 10, 1519–1536.
Figure 1. HPLC radiochromatograms showing the comparison following ring
opening reactions of [K222][18F] with 1 (Table 1, entry 4; top; isolated following
deprotection and acylation with Bz–Cl) or 6 (Table 1, entry 9; bottom), by minor
modifications to our previously described radiofluorination and chromatography
conditions.9
18. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021.
19. Alvernhe, G. M.; Ennakoua, C. M.; Lacombe, S. M.; Laurent, A. J. J. Org. Chem.
1981, 46, 4938–4948.
20. Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng, J. A. J. Am. Chem. Soc.
1990, 112, 7619–7625.
described.19,28 Multi-NMR (1H, 13C and 19F) spectroscopic analysis
was carried out on the high-order spin system for 1-fluoro-2-prop-
anamine (formate salt)19,28 and of 5. The 1H and 19F NMR spectro-
scopic results indicate that the 1-fluoro-2-propanamine moiety
conforms to an ABCD3X spin system and the 2-fluoropropanamine
group (5) represents a combination of A3BCDX and A3BEFX spin
systems,29 and is attributed to the stereocenter within this group.
As regiocontrol during ring opening of aziridines with fluoride
sources was demonstrated herein, our laboratories are synthesiz-
ing and characterizing new 18F- and 19F-fluoroamines via this
methodology and applying this work to radiopharmaceutical
production.
CAUTION: Precautionary measures should be established prior
to repeating aspects of this work, particularly when 18F and the
highly toxic and volatile 2-methylaziridine and/or anhydrous HF
(also highly corrosive) are employed. Before commencing work
with anhydrous HF, first-aid treatment procedures should be avail-
able and known to all laboratory personnel.
21. Anhydrous HF was dried over K2NiF6, where the purple colour of the HF
indicated the absence of water. The reactions in aHF (ca. 10 mmol, distilled at
1
À78 °C) were carried out in well-dried
4-in. FEP (copolymer of
mol of 1 or
perfluoroethylene and perfluoropropylene) tubes using 310–370
l
6. Following the reaction, aHF was removed under vacuum, diluted with
CH2Cl2 and filtered through K2CO3, prior to workup and PTLC purification.
22. In an oven-dried 5 mL glass V-vial containing 2 mL 10:90 (v/v) H2O/CH3CN was
dissolved KF (ca. 50 mg), followed by an equimolar amount of KryptofixÒ 222.
The mixture was azeotropically dried at 100 °C by stepwise addition of
anhydrous CH3CN, under a stream of N2. Upon reaching dryness, N-protected
2-methylaziridine (0.2 equiv) in 2 mL of anhydrous DMSO was added and the
reaction was allowed to occur for 30 min at 90 °C. The reaction mixture was
then diluted with 30 mL H2O and extracted with 30 mL CH2Cl2. The aqueous
phase was washed with an additional 30 mL CH2Cl2, and the combined organic
layers were washed with 30 mL of a saturated sodium chloride solution, dried
over Na2SO4, filtered, and concentrated. The reaction mixture was purified by
PTLC (30/70 EtOAc/Hex (v/v)).
23. Alvernhe, G.; Lacombe, S.; Laurent, A. Tetrahedron Lett. 1980, 21, 289–292.
24. Wade, T. N. J. Org. Chem. 1980, 45, 5328–5333.
25. Vasdev, N.; Pointner, B. E.; Chirakal, R.; Schrobilgen, G. J. J. Am. Chem. Soc. 2002,
124, 12863–12868.
26. Winfield, J. M. J. Fluorine Chem. 1984, 25, 91–98.
Acknowledgements
27. Christe, K. O.; Wilson, W. W. J. Fluorine Chem. 1990, 47, 117–120.
28. Posakony, J. J.; Tewson, T. J. Synthesis 2002, 766–770.
The authors gratefully acknowledge the assistance of Armando
Garcia and Winston T. Stableford for production of [18F]-fluoride.
We also thank Dr. Iain D. G. Watson, Dr. Matthew D. Moran and
Dr. Alex Bain for helpful discussions. Financial support for this
work was provided by the Natural Sciences and Engineering Re-
search Council of Canada (NSERC; Discovery Grants to M. G and
P. H.) and by both NSERC and the Canadian Institutes for Health Re-
search in the form of a Collaborative Health Research Projects
Grant to N.V. (CHRPJ 322787-06).
29. 1-fluoro-2-propanamine (HCOOH salt) in MeOD: 1H NMR (499.8 MHz) d ppm,
3
4
relative to TMS) D 1.380 (dd, JHH = 6.882 Hz, JHF = 1.262 Hz, 3H), C 3.674
3
3
(dddq, JHH = 3.189 Hz; 6.4 Hz; 6.882 Hz, JHF = 19.369 Hz; 1H), B 4.533 (ddd,
2JHH = À10.401 Hz, JHH = 6.416 Hz, JHF = 47.201 Hz, 1H),
A 4.696 (ddd,
3
2
2JHH = À10.401 Hz, JHH = 3.189 Hz, JHF = 46.7 Hz, 1H). 13C NMR (125.7 MHz)
3
2
1
2
d ppm, relative to TMS) 85.0 (d, JCF = 172 Hz), 48.9 (d, JCF = 19.7 Hz), 14.3 (d,
3JCF = 6.5 Hz). 19F NMR (470.3 MHz) d ppm, relative to ext. CFCl3): X À231.91
2
3
4
(m, JHF = 46.681 Hz; 47.201 Hz, JHF = 19.369 Hz, JHF = 1.262 Hz). (RMS
deviation = 0.016 Hz (0.000032 ppm), 191 transitions assigned).
Compound 5 in CDCl3: 1H NMR (299.9 MHz) d ppm, relative to TMS A 2.605 (dd,
3JHH = 6.266 Hz, JHF3 = 23.584 Hz, 3H), C 4.790 (E 4.907) (two sets of ddd,
3
2JHH = À14.193 Hz, JHH = 7.093 Hz, JHF = 18.116 Hz, 1H), D 4.895 (F 4.907)
3
2
3
3
(two sets of ddd, JHH = À14.193 Hz, JHH = 3.761 Hz, JHF = 26.177 Hz, 1H), B
3
2
6.121 (dddq, JHH = 3.761 Hz; 7.093 Hz; 6.266 Hz, JHF = 49.2 Hz; 1H), 8.70 (m,
2H), 8.76 (m, 1H), 9.21 (m, 2H). 13C NMR (75.4 MHz) d ppm, relative to TMS)
225.6, 186.9, 154.9, 151.3, 148.4, 148.0, 147.3, 109.3 (d, 1JCF = 167 Hz), 64.9 (d,
References and notes
1. Hu, X. E. Tetrahedron 2004, 60, 2701–2743.
2JCF = 22.8 Hz), 38.0 (d, JCF = 22.3 Hz). 19F NMR (282.2 MHz) d ppm, relative to
2
2. Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Synlett 2004, 2218–2220.
3. Fan, R.-H.; Zhou, Y.-G.; Zhang, W.-X.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2004, 69,
335–338.
4. Noritake, S.; Shibata, N.; Kawai, H.; Pandy, M. K.; Nakamura, S.; Toru, T.
Heterocycl. Commun. 2009, 15, 105–113.
2
3
ext. CFCl3):
X
À177.95 (m, JHF = 49.2 Hz, JHF = 18.2 Hz; 22.6 Hz; 26.1 Hz,
4JHF = 9.4 Hz). (RMS deviation = 0.019 Hz (0.000038 ppm), 381 transitions
assigned).