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O
N
MeO OMe
Rev. 2008, 37, 308–319.
1 (1.5 equiv)
F
3. For reviews of enantioselective fluorinations, see: (a) Lectard, S.; Hamashima,
Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708–2732; (b) Ma, J.-A.; Cahard, D.
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G. G.; Fainzilberg, A. A. Russ. Chem. Rev. 1999, 68, 653–684.
H2SO4 (0.1 equiv)
9
N
OMe
MeOH
50 C, 52%
BnO
O
BnO
O
F
5. For reviews on the chemistry of Selectfluor™, see: (a) Nyffeler, P. T.; Durón, S.
G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44,
192–212; (b) Stavber, S.; Zupan, M. Acta Chim. Slov. 2005, 52, 13–26; (c) Singh,
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1 (1.1 equiv)
10
OR
N
Cbz
N
Cbz
H2O / MeCN
4
C
r.t., 92%
6. Poss, A. J.; Shia, G. A. Tetrahedron Lett. 1999, 40, 2673–2676.
7. See for example: (a) Lal, G. S. J. Org. Chem. 1993, 58, 2791–2796; (b)
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Hoffmann-Roeder, A. Chem. Eur. J. 2010, 16, 7319–7330.
Scheme 6. Synthesis of b-fluoroamines using electrophilic fluorination.
F
SiMe3
1, MeOH / MeCN
OMe
N
Cbz
N
Cbz
80%
BF3 OEt2, CH2Cl2
-78
99%
11
C
F
F
OH
(i) BH3 THF / THF
N
Cbz
N
Cbz
(ii) H2O2, NaOH
60%
13
12
(i) Pr4N+ RuO4 (0.5 mol%),
NMO, 4Å MS, CH2Cl2
F
14
N
(ii) H2, Pd, EtOH
60%
Scheme 7. Application of electrophilic fluorination to the synthesis of
fluoropyrrolizidine 14.
a
12. (a) Ge, P.; Kirk, K. L. J. Fluorine Chem. 1997, 84, 45–47; (b) Ge, P.; Kirk, K. L. J. Org.
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In conclusion, the use of sulfuric acid as a catalyst has been
demonstrated to facilitate the direct fluorination of ketones using
the commercially available electrophilic fluorinating reagent
Selectfluor™. Methanol or acetonitrile were shown to be the best
solvents for the reaction. In the case of reaction in the presence
of methanol,
a-fluoroketone or ketal products could be observed
depending upon the ketone substrate employed. Further kinetic
and mechanistic studies will be necessary to more fully establish
the mechanism for the transformation, but by analogy with bro-
mination reactions, reaction presumably occurs through either
the corresponding enols or enol ethers, with the sulfuric acid pro-
moting the formation of these nucleophilic intermediates. The
reactions generally occurred in good yields and with excellent
selectivity for the formation of the monofluorinated products. Ena-
mides could also be fluorinated using Selectfluor™, although the
greater nucleophilic character of these compounds was such that
a sulfuric acid catalyst was unnecessary.
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6611–6625.
Acknowledgments
23. Toullec, J.; El-Alaoui, M. J. Org. Chem. 1986, 51, 4054–4061.
24. For a review, see: Toullec, J. Adv. Phys. Org. Chem. 1982, 18, 1–77.
25. Similar observations have been made for
and Cohen, I. J. Am. Chem. Soc. 1930, 52, 2827–2835.
26. Representative experimental procedure for the formation of fluorotetralone 3a: To
1-tetralone (1.33 mL, 10.0 mmol) and Selectfluor™ (4.25 g, 12.0 mmol) in
a
-bromination reactions, see Ref.23
We thank the Natural Sciences and Engineering Research Coun-
cil (NSERC) of Canada, AstraZeneca and the Ontario Research and
Development Fund for financial support. We thank Dr. A.B. Young
for MS analyses.
MeOH (5.0 mL), was treated concd H2SO4 (53 lL, 1.00 mmol). The mixture was
stirred under N2 at 50 °C overnight, filtered and the solvent was removed in
vacuo. Ether was added and washed with water and brine and dried over
MgSO4. The crude product was purified by flash chromatography (10% of EtOAc
in hexane) to afford fluorotetralone 3a (1.44 g, 93%). 1H NMR (400 MHz, CDCl3)
d 8.07 (d, J = 8.0 Hz, 1H), 7.53 (m, 1H), 7.36 (dd, J = 8.0, 8.0 Hz, 1H), 7.27 (d,
J = 8.0 Hz, 1H), 5.15 (ddd, J = 47.5, 13.0, 5.0 Hz, 1H), 3.14 (m, 2H), 2.62–2.54 (m,
1H), 2.41–2.33 (m, 1H). 19F NMR (400 MHz, CDCl3) d À190.6 (dm, J = 47.5 Hz).
References and notes
1. For an overview of fluorination methods and the importance of fluorine in
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(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
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27. For a discussion of the effects controlling
or enol intermediates, see Refs.23–25
a-bromination via either enol ether
28. Representative experimental procedure for the formation of 4-(3-fluoro-4,4-
dimethoxypiperidine-1-carbonyl)benzonitrile 4b: To 4-(4-oxopiperidine-1-