Selective anodic fluorination of flavones

Article abstract of DOI:10.1055/s-1998-5738

Anodic fluorination of flavone and 6-chloroflavone was carried out using Et₃N·3HF and Et₄NF·4HF as supporting electrolytes. The former supporting electrolyte provided 3-monofluorinated flavones 2 preferentially while the latter one gave 2,3-difluorinated flavones 3 predominantly. It was also found that the yields of 2 increased significantly at a higher temperature as 30°C. Furthermore, it was confirmed that 2 was formed by dehydrofluorination of 3 with free Et₃N in Et₃N·3HF.

Full text of DOI:10.1055/s-1998-5738

September 1998
SYNLETT
973
Selective Anodic Fluorination of Flavones1
Yankun Hou, Seiichiro Higashiya, and Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8502, Japan
Fax +81 45 924-5489; E-mail fuchi@echem.titech.ac.jp
Received 28 April 1998
Abstract: Anodic fluorination of flavone and 6-chloroflavone was
carried out using Et N•3HF and Et NF•4HF as supporting electrolytes.
anhydrous acetonitrile containing Et N•3HF or Et NF•4HF using a
3 4
divided cell with an anion exchange membrane at ambient temperature
3
4
9
The former supporting electrolyte provided 3-monofluorinated flavones
2 preferentially while the latter one gave 2,3-difluorinated flavones 3
predominantly. It was also found that the yields of 2 increased
except for two cases (see Table 1).
As shown in Table 1, a conventional supporting electrolyte, Et N•3HF
3
10
provided monofluorinated product 2 preferentially. In this case,
o
significantly at a higher temperature as 30 C. Furthermore, it was
difluorinated product 3 was not formed. At a higher temperature such as
o
confirmed that 2 was formed by dehydrofluorination of 3 with free Et N
3
30 C, the yield of 2 increased significantly. Such a temperature effect
in Et N•3HF.
3
has never been reported on the anodic partial fluorination so far.
However, the reason is not clear at present. In sharp contrast, a different
7
type of supporting electrolyte, Et NF•4HF gave mainly difluorinated
Although many methods of preparation of fluoroorganics have been
developed to date, the construction of ring-fluorinated heterocyclic
systems has been less explored. Recently, selective electrochemical
fluorination has been shown to be a highly efficient new tool to
synthesize various fluoroorganic compounds. The reaction can be
carried out under mild conditions using a relatively simple equipment to
avoid hazardous or toxic reagents which are necessary in chemical
4
product 3 as a stereoisomeric mixture and only a small amount of 2 was
formed. Since Et N•3HF contains a appreciable amount of free Et N,
2 seems to be formed by dehydrofluorination of 3 with free Et N during
11
3
3
3
the electrolysis. In fact, 3 was treated with Et N•3HF / MeCN to provide
3
2 in reasonable yield as 63%(Scheme 1).
2
fluorination. However, only limited successful examples of anodic
fluorination of heterocycles have been reported to date, and in all the
cases, low yields and poor selectivities appear to be the major problems
3
in electrochemical synthesis.
From these viewpoints, we have developed highly selective anodic
1,4
fluorination of various kinds of heterocyclic compounds. On the other
Scheme 1
hand, flavone and its derivatives are commonly used as precursors for
many pharmaceutical products such as anticancer. It is also well
5
recognized that incorporation of fluorine atoms into the organic
molecules used for medicines can profoundly influence their biological
properties.
From these results, the reaction mechanism can be shown in Scheme 2.
Since the double bond of the enol ether moiety is most easily oxidized,
anodic oxidation takes place selectively at the olefin to generate the
radical cation intermediate A as shown in Scheme 2. Then, this radical
cation reacts with a fluoride ion followed by further oxidation to form
cationic intermediate B, which provides the difluorinated product 3. As
explained above (Scheme 1), 2 should be formed from 3. Since 2a is
more easily oxidized by 0.08 V than the starting flavone 1a, 4 seems to
be formed by further oxidation of 2.
6
With these facts in mind, anodic fluorination of biologically interesting
flavone 1a and its chloro derivative 1b was attempted by using a
conventional supporting electrolyte, Et N•3HF and a recently developed
3
7
supporting electrolyte, Et NF•4HF. So far, a few limited examples of
4
anodic fluorination of oxygen-containing heterocycles have been
8
reported but their yields were low except for α-phenylthiolactones.
Anodic fluorination of 1 was carried out with platinum electrodes in

974
LETTERS
SYNLETT
Sakaguchi, Y.; Maehara, Y.; Newman, R. Cancer Res. 1992, 52,
3306.
(6) Biomedicinal Aspects of Fluorine Chemistry, Filler, R.;
Kobayashi, Y. Eds.; Kodansha & Elsevier Biomedical, Tokyo,
1982.
(7) Momota, K.; Morita, M.; Matsuda, Y. Electrochim. Acta 1993, 38,
1231.
(8) Fuchigami, T.; Shimojo, M.; Konno, A. J. Org. Chem. 1995, 60,
3459.
(9) A typical procedure for the anodic fluorination of flavone 1a is as
follows. Anodic oxidation of 1a (1 mmol) was carried out with
2
platinum plate electrodes (3x2 cm ) in 0.2 M Et NF•4HF or 0.33
4
-
M Et N•3HF (20 equiv. of F to 1a)/MeCN (20 mL) using a
3
divided cell with an anion exchange membrane (IE-DF34-5
TOSOH) under a nitrogen atmosphere at room temperature.
2
Constant current (3.3 mA/cm ) was passed. After the electrolysis,
Scheme 2
the electrolyte was neutralized with saturated NaHCO solution
3
and the resulting aqueous solution was extracted with ether
repeatedly. After the combined extracts were dried over anhydrous
Thus, we have shown efficient and selective anodic fluorination of
biologically interesting oxygen-containing heterocycles, flavones.
Furthermore, we have demonstrated for the first time fluorinated
product selectivity greatly depending on the kind of supporting fluoride
salts. These findings seem to be of importance for developing selective
anodic fluorination of organic molecules.
MgSO , trans-2,3-fluoroflavone 3a and 2,3,3-trifluoroflavone 4a
4
were isolated by silica gel chromatography (hexane:CHCl =5:1).
3
Or, crude products were treated with Et N•3HF / MeCN (stirring
3
at room temperature for 3 h). After evaporation, the pure
monofluorinated flavone 2a was obtained by recrystallization
from methanol. In the case of 6-chloroflavone (1b), in order to
dissolve the starting materials completely in the electrolytic
Acknowledgment. We thank Morida Chemical Industrials Co. Ltd. for
solution, a small amount of CH Cl was added.
2
2
a generous gift of Et NF•4HF.
4
1
19
(10) 3-Fluoroflavone (2a): H NMR δ 7.42~8.30 (m, 9H); F NMR δ
+
+
-84.26 (s). MS (EI) m/z: 240 (M ), 212 (M -CO). Anal. Calcd for
H FO : C, 75.00; H, 3.78; F, 7.91. Found: C, 74.86; H, 3.89; F,
7.92. trans-2,3-Difluoroflavone (3a): H NMR δ 7.19~8.05 (m,
9H), 4.80 (d, 46.85 Hz); F NMR δ -114.92 (dd, 46.89Hz, 20.23
Hz), -39.85 (d, 20.22 Hz). MS (EI) m/z: 260 (M ), 240 (M -HF),
References and Notes
C
15
9
2
(1) Anodic Partial Fluorination of Organic Compounds. Part 28. Part
27: Fuchigami, T.; Narizuka, S.; Konno, A.; Momota, K.
Electrochim. Acta 1998, 43, 1985.
1
19
+
+
+
+
(2) Childs, W. V.; Christensen, L.; Klink, F. W.; Koipin, C. F. In
Organic Electrochemistry, 3rd ed.; Lund, H.; Baizer, M. M., Eds.;
Marcel Dekker: New York, 1991; Chapter 24. Fuchigami, T.; Rev.
Heteroatom Chem. 1994, 10, 155. Fuchigami, T.; Konno, A. J.
Org. Synth. Chem. Jpn. 1997, 55, 301.
212 (M -HF-CO), 183 (M -Ph). HRMS m/z calcd for
C
H
F O , 260.0649, found 260.0645. cis-2,3-Difluoroflavone
15 10
2 2
19
(3a): F NMR δ -135.93 (dd, 45.96 Hz, 15.63 Hz), -52.09 (dd,
28.50 Hz, 15.63 Hz). 2,3,3-Trifluoroflavone (4a): H NMR δ
7.20~8.06 (m, 9H); F NMR δ -60.88 (dd, 285.87 Hz, 11.49 Hz),
1
19
(3) Gambaretto, G. P.; Napoli, M.; Franccarro, C.; Conte, L. J.
Fluorine Chem. 1982, 19, 427. Ballinger, J. R.; Teare, F. W.
Electrochim. Acta 1985, 30, 1075. Makino, K.; Yoshioka, H. J
Fluorine Chem. 1988, 39, 435. Meurs, J. H. H.; Eilenberg, W.
Tetrahedron 1991, 47, 705. Sono, M.; Morita, N.; Shimizu, Y.;
Tori, M. Tetrahedron Lett. 1994, 35, 9237.
-48.59 (t, 11.49 Hz), -36.78 (dd, 285.87 Hz, 11.03 Hz). MS (EI)
+
+
+
m/z: 278 (M ), 259 (M -F), 231 (M -F-CO). HRMS m/z calcd.
for C H FO , 278.0555, found 278.0553. 3-Fluoro-6-
9
5
2
1
19
chloroflavone (2b): H NMR δ 7.52~8.27 (m, 8H); F NMR δ -
+
+
+
83.81 (s). MS (EI) m/z: 274 (M ), 246 (M -CO), 207 (M -CO-
CF). HRMS m/z calcd for H ClFO 274.0197, found
274.0211. 2,3-Difluoro-6-chloroflavone (3b): MS (EI) (cis, trans
isomeric mixture) m/z: 294 (M ), 274 (M -HF), 246 (M -HF-
CO), 217 (M -Ph). HRMS m/z calcd for C H ClF O 294.0259,
C
15
8
2
(4) Konno, A.; Naito, W.; Fuchigami, T. Tetrahedron Lett. 1992, 33,
7017. Narizuka, S.; Fuchigami, T. J. Org. Chem. 1993, 58, 4200.
Fuchigami, T.; Narizuka, S.; Konno, A. J. Org. Chem. 1992, 57,
3755. Narizuka, S.; Fuchigami, T. Bioorg. Med. Chem. Lett. 1993,
5, 1293. Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem.
1997, 62, 8773.
+
+
+
+
15
9
2 2
19
found 294.0253. trans form: F NMR δ -115.01 (dd, 46.89 Hz,
20.22 Hz), -40.12 (d, 20.22 Hz). cis form: F NMR δ -135.90
19
(dd, 45.90 Hz, 15.63 Hz), -52.09 (dd, 28.24 Hz, 15.63 Hz). 2,3,3-
19
Trifluoro-6-chloroflavone (4b): F NMR δ -61.18 (dd, 285.87
(5) Thomas, A. G.; Andrew, S. K.; George, R.; Brenda, W.; Jeff, W.
Biochem. Pharm. 1996, 52, 1787. Greg, R. H.; James, R. H. J. Bio.
Chem. 1997, 272, 5396. Wu, K.; Knox, R.; Sun, X. Z.; Chen, S.
Arch. Biochem. Biophys. 1997, 347, 221. Futami, H.; Eader, L. A.;
Komschlies, K. L.; Wiltrout, R. H. Cancer Res. 1991, 51, 6595.
Hz, 11.48 Hz), -48.69 (t, 11.48), -36.81 (dd, 285.87 Hz, 11.04
+
+
+
Hz). MS (EI) m/z: 312 (M ), 274 (M -2F), 265 (M -F-CO).
HRMS m/z calcd. for C H ClF O 312.0165, found 312.0146.
15
8
3 2
(11) Chen, S.; Hitakeyama, T.; Fukuhara, T.; Hara, S.; and Yoneda, N.
Electrochim. Acta 1997, 42, 1951.