A practical and convenient fluorination of 1,3-dicarbonyl compounds using aqueous HF in the presence of iodosylbenzene

Article abstract of DOI:10.1021/ol200632d

Chemical equations presented. A simple, practical, and convenient fluorination of 1,3-dicarbonyl compounds was achieved by direct use of aqueous hydrofluoric acid and iodosylbenzene (PhIO). The reaction of ethyl benzoylacetate with the reagent system of a

Full text of DOI:10.1021/ol200632d

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2392–2394
A Practical and Convenient Fluorination of
1,3-Dicarbonyl Compounds Using
Aqueous HF in the Presence of
Iodosylbenzene
Tsugio Kitamura,* Satoshi Kuriki, Mohammad Hasan Morshed, and Yuji Hori
Department of Chemistry and Applied Chemistry, Graduate School of Science and
Engineering, Saga University, Honjo-machi, Saga 840-8502, Japan
kitamura@cc.saga-u.ac.jp
Received March 10, 2011
ABSTRACT
A simple, practical, and convenient fluorination of 1,3-dicarbonyl compounds was achieved by direct use of aqueous hydrofluoric acid and
iodosylbenzene (PhIO). The reaction of ethyl benzoylacetate with the reagent system of aqueous HF and PhIO in CH2Cl2 gave ethyl 2-fluoro-2-
benzolyacetate in 98% yield. Other 1,3-dicarbonyl compounds including β-keto esters and 1,3-diketones underwent the fluorination reaction to
give the corresponding fluorinated products in good yields.
Introduction of fluoride atom(s) into a molecule
brings about valuable properties, which are applicable to
pharmaceuticals, agrochemicals, and materials bearing
an outstanding property. The synthetic method for
organofluorine compounds includes direct fluorination
replacing an atom or group by a fluorine atom and an
indirect procedure using a fluorinated component as a
building block.1 Although direct fluorination reactions
have been conducted by using a molecular fluorine or
other electrophilic fluorinating reagents, there still remain
many drawbacks such as the possibility of explosion due to
instability, difficulty of handling, and the requirement of
specific apparatus. Recently, the chemistry of hypervalent
iodine compounds has accomplished remarkable progress,
and it has been proven that hypervalent iodine compounds
are useful to organic synthesis.2 Among them, difluoroio-
doarenes (ArIF2) attract much attention as a stable
fluorination reagent.3 Various difluoroiodoarenes are pre-
pared by fluorination of iodoarenes with powerful fluor-
inating reagents such as F2 and XeF2,5 conveniently by
4
direct replacement of dichloroiodoarenes with HF in the
presence of HgO,6 and more simply by reaction of iodo-
sylarenes with HF.7 For a fluorination reaction, however,
difluoroiodoarenes must be activated by a HF reagent
such as HF-amine complexes.3,8 Accordingly, HF is essen-
tial both for the preparation of ArIF2 and for the fluorina-
tion reaction.
To develop a convenient fluorination reaction, it is
better to conduct both the preparation of ArIF2 and their
activation for a fluorination reaction in one pot. Thus, we
used an easily available aqueous hydrofluoric acid for this
purpose. The aqueous HF was considered to play the
following important roles in the fluorination reaction: (1)
as the reagent for the synthesis of ArIF2 and (2) as the
(3) Yoneda, N. J. Fluorine Chem. 2004, 125, 7–17.
(4) Neumann, D.; Ruther, G. J. Fluorine Chem. 1980, 15, 213–222.
(5) Zupan, M.; Pollak, A. Chem. Commun. 1975, 715–716.
(6) Carpenter, W. J. Org. Chem. 1966, 31, 2688–2689.
(7) (a) Sawaguchi, M.; Ayuba, S.; Hara, S. Synthesis 2002, 1802–
1803. (b) Arrica, M. A.; Wirth, T. Eur. J. Org. Chem. 2005, 395–403.
(8) Sawaguchi, M.; Hara, S.; Yoneda, N. J. Fluorine Chem. 2000, 105,
313–317.
(1) (a) Olah, G. A.; Chambers, R. D.; Prakash, G. K. S. Synthetic
Fluorine Chemistry; John Wiley: New York, 1992. (b) Hudlicky, M.;
Pavlath, A. E. Chemistry of Organic Fluorine Compounds II; American
Chemical Society: Washington, DC, 1995. (c) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell Publishing: Oxford, 2004.
(2) For recent reviews on hypervalent iodine compounds, see: (a)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358. (b)
Zhdankin, V. V. ARKIVOC 2009, No. i, 1–62.
r
10.1021/ol200632d
Published on Web 04/07/2011
2011 American Chemical Society

activating agent for the fluorination reaction, as shown in
Scheme 1.
Table 1. Optimization of the Fluorination Reaction of 1aa
Scheme 1. Role of HF
iodine
time
(h)
yield
(%)b
entry
reagent
1
2
3
4
PhI(OAc)2
PhI(OAc)2
PhI(OCOCF3)2
PhIO
24
12
24
24
39
43
0
98
a The reaction was conducted at 40 °C by using 55% aqueous HF (10
mmol HF), a hypervalent iodine reagent (1.2 mmol), and 1a (1 mmol) in
CH2Cl2 (2 mL). b Isolated yield.
In order to prove the above-mentioned hypothesis, we
planned the fluorination reaction of 1,3-dicarbonyl com-
pounds. Synthesis of 2-fluoro-1,3-dicarbonyl compounds
has so far been performed by the fluorination reaction of
1,3-dicarbonyl compounds with F29 and various fluorinat-
ing agents such as XeF2,10 fluoroxy compounds,11 and
fluoronitrogen compounds.12 However, those many are
dangerous or expensive. The fluorination reaction of 1,
3-dicarbonyl compounds was recently reported by Hara and
Yoneda.13 They indicated that difluoroiodotoluene was a
useful fluorinating reagent. However, the difluoroiodoto-
luene was prepared by the reaction of iodosyltoluene with
aqueous HF.7 According to the above hypothesis, we
examined the direct fluorination of 1,3-dicarbonyl com-
pounds using a commercially available aqueous hydro-
fluoric acid and a hypervalent iodine compound, to
develop a convenient fluorination reaction. Here we want
to report for the first time a practical, direct fluorination of
Table 2. Direct Fluorination of 1,3-Dicarbonyl Compounds
with PhIO/aq. HF Reagent Systema
(9) Chambers, R. D.; Greenhall, M. P.; Hutchinson, J. Tetrahedron
1996, 52, 1–8.
(10) (a) Zajc, B.; Zupan, M. J. Chem. Soc., Chem. Commun. 1980,
759–760. (b) Yemul, S. S.; Kagan, H. B.; Setton, R. Tetrahedron Lett.
1980, 21, 277–280. (c) Zajc, B.; Zupan, M. J. Org. Chem. 1982, 47, 573–
575.
(11) (a) Inman, C. E.; Oesterling, R. E.; Tyczkowski, E. A. J. Am.
Chem. Soc. 1958, 80, 6533–6535. (b) Machleidt, H.; Hartmann, V.
Liebigs Ann. Chem. 1964, 679, 9–19. (c) Lerman, O.; Rozen, S. J. Org.
Chem. 1983, 48, 724–727. (d) Rozen, S.; Brand, M. Synthesis 1985, 665–
667. (d) Rozen, S.; Hebel, D. J. Org. Chem. 1990, 55, 2621–2623. (e)
Rozen, S.; Menahem, Y. Tetrahedron Lett. 1979, 20, 725–728. (f)
Stavber, S.; Zupan, M. J. Chem. Soc., Chem. Commun. 1981, 795–796.
(12) (a) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.;
Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563–8575. (b)
Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56, 4925–4929. (c)
Banks, R. E.; Murtagh, V.; Tsiliopoulos, E. J. Fluorine Chem. 1991, 52,
389–401. (d) Xu, Z.-Q.; DesMarteau, D. D.; Gotoh, Y. J. Fluorine Chem.
1992, 58, 71–79. (e) Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1992,
57, 4281–4284. (f) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. J.
Chem. Soc., Chem. Commun. 1994, 343–344. (g) Davis, F. A.; Han, W.;
Murphy, C. K. J. Org. Chem. 1995, 60, 4730–4737. (h) Cabrera, I.;
Appel, W. K. Tetrahedron 1995, 51, 10205–10208. (i) Umemoto, T.;
Nagayoshi, M.; Adachi, K.; Tomizawa, G. J. Org. Chem. 1998, 63,
3379–3385. (j) Frantz, R.; Hintermann, L.; Perseghini, M.; Broggini, D.;
Togni, A. Org. Lett. 2003, 5, 1709–1712. (k) Gupta, O. D.; Shreeve, J. M.
Tetrahedron Lett. 2003, 44, 2799–2801. (l) Stavber, G.; Zupan, M.;
Stavber, S. Tetrahedron Lett. 2007, 48, 2671–2673.
a Reaction conditions: substrate (1 mmol), PhIO (1.2 mmol), 55%
aqueous HF (10 mmol HF), and CH2Cl2 (2 mL) at 40 °C. b At room
temperature.
(13) (a) Hara, S.; Sekiguchi, M.; Ohmori, A.; Fukuhara, T.; Yoneda,
N. Chem. Commun. 1996, 1899–1900. (b) Yoshida, M.; Fujikawa, K.;
Sato, S.; Hara, S. ARKIVOC 2003, No. vi, 36–42.
Org. Lett., Vol. 13, No. 9, 2011
2393

To find the scope of the fluorination reaction, several
1,3-dicarbonyl compounds were examined. The results
are given in Table 2. Similarly, 3-ketoesters including
aliphatic and aromatic 3-ketoesters 1bÀ1e gave good to
high yields of 2-fluorinated 3-ketoesters 2bÀ2e. Among
them, aliphatic 3-ketoesters showed higher reactivity
than aromatic ones. In addition to 3-ketoesters, 1,3-
diketones 1fÀ1h and 3-ketoamides 1i and 1j also under-
went fluorination to give the corresponding 2-fluori-
nated products 2fÀ2j.
Scheme 2. Possible Mechanism
A possible mechanism for a fluorination reaction of 1,
3-dicarbonyl compounds is shown in Scheme 2. First,
PhIF2 should be formed in situ by reaction of PhIO with
HF.7 This reaction took place, and PhIF2 was isolated in
the reaction without the substrate 1.14 The reaction of
PhIF2 with 1 is considered to proceed effectively after
enolization of 1 because it has been reported that the enol
form of 1 reacts with hypervalent iodine compounds.3 The
resulting 2-iodanyl-1,3-dicarbonyl compound readily un-
dergoes displacement by a fluoride ion due to the high
leaving ability of the phenyliodonio group,15 to give the
fluorine-containing product 2.
In summary, we have developed a practical and con-
venient fluorination reaction of a 1,3-dicarbonyl com-
pound just by mixing with aqueous HF and PhIO. This
simple and easy procedure is applicable to a wide variety of
fluorination reactions. The scope of this fluorination will
be reported in the near future.
1,3-dicarbonyl compounds using aqueous hydrofluoric
acid in the presence of a hypervalent iodine compound.
The fluorination reaction was conducted by treating a
mixture of a hypervalent iodine compound and aqueous
HF with a 1,3-dicarbonyl compound in CH2Cl2.
To optimize the reaction conditions, three easily
available hypervalent iodine compounds [PhI(OAc)2,
PhI(OCOCF3)2, and PhIO] were examined by using ethyl
3-oxo-3-phenylpropionate (1a) as the substrate in the
fluorination reaction (Table 1). First, PhI(OAc)2 was
employed because it was the most stable hypervalent
iodine reagent among them. After mixing PhI(OAc)2
(1.2 mmol) with aqueous HF (55%, 10 mmol HF) in
CH2Cl2 (2 mL), 1a (1 mmol) was added and then the
mixture was stirred at 40 °C for 24 h. After separation by
column chromatography, 2-fluoro-3-oxo-3-phenylpropio-
nate (2a) was obtained in 39% yield. The yield was slightly
increased to 43% when the reaction was carried out for
12 h. Next, the fluorination reaction with PhI(OCOCF3)2
was conducted but 2a was not obtained. Finally, it was
found that PhIO was the best reagent. Under the same
conditions the reaction with PhIO gave 2a in 98% yield.
Supporting Information Available. Experimental pro-
cedures, spectral data, and 1H and 13C NMR spectra of
for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Although the mechanism via the intermediate of an enolate
structure has been proposed in the literature,3 it is reasonable to consider
the mechanism through an iodanyl ketone intermediate judging from the
R-tosyloxylation of ketones and 1,3-dicarbonyl compounds.16
(16) (a) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.;
Wettach, R. H. J. Org. Chem. 1982, 47, 2487–2489. (b) Moriarty, R. M.;
Koser, G. F. Synthesis 1990, 431–447.
(14) According to the literature,2b it is good to use it without
isolation.
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Org. Lett., Vol. 13, No. 9, 2011