Electrolytic partial fluorination of organic compounds. 32. Regioselective anodic mono- and difluorination of flavones

Full text of DOI:10.1021/jo981979y

3
346
J . Org. Chem. 1999, 64, 3346-3349
Ta ble 1. Oxid a tion P oten tia ls (P ea k P oten tia ls, Ep ox) of
F la von e a n d Its Der iva tivesa
Electr olytic P a r tia l F lu or in a tion of
1
Or ga n ic Com p ou n d s. 32. Regioselective
An od ic Mon o- a n d Diflu or in a tion of
F la von es
Yankun Hou, Seiichiro Higashiya, and
Toshio Fuchigami*,†
substrate
Epox
(V vs SSCE)
Department of Electronic Chemistry, Tokyo Institute of
Technology, Midori-ku, Yokohama 226-8502, J apan
no.
R
1
1b
1
a
H
CH3
Cl
2.50
2.36
2.52
Received September 30, 1998
c
In tr od u ction
a In 0.1 M Bu N‚BF /CH CN. Sweep rate: 100 mV/s.
4 4 3
Recently, selective electrochemical fluorination has
Ta ble 2. Effect of Su p p or tin g Electr olyte on An od ic
P a r tia l F lu or in a tion of F la von e 1a a
been shown to be a highly efficient new tool for synthe-
sizing various fluoroorganic compounds. The reaction can
be carried out under mild conditions using relatively
yield (%)
supporting
run
electrolyte
2a
3a (cis/trans)
4a
simple equipment and also avoids hazardous or toxic
reagents which are necessary in chemical fluorination.2,3
1
2
3
4
Et3N‚3HF
Et3N‚5HF
Et4NF‚3HF
4
43
9
3
0
6
4
6
9
28 (3/1)
54 (2/1)
68 (2/1)
However, only limited examples of selective anodic
fluorination of heterocycles have been reported to date,
and in all cases, low yields and poor selectivities appeare
to be the major problems in electrochemical synthesis.4
Therefore, highly selective anodic fluorination of various
nitrogen- and/or sulfur-containing heterocyclic com-
pounds has been developed in our group.3,5 However, only
a few examples of anodic fluorination of oxygen-contain-
ing heterocycles have been reported so far. Although
Et NF‚4HF
7
a
2
Constant current (3.3 mA/cm ) electrolysis was carried out at
room temperature, and 3.5 F/mol of electricity was passed.
atoms into the organic molecules used for medicines can
significantly alter their biological function.9
With these facts in mind, anodic fluorination of biologi-
cally interesting flavones 1 was attempted by using a
6
7
R-phenylthiolactones and 1,3-oxathiolanones were ef-
ficiently fluorinated, aromatic oxygen-containing hetero-
cyclic compounds such as benzofuran and furan did not
give any isolable fluorinated products due to their
instability.4b On the other hand, flavone and its deriva-
tives are commonly used as precursors for many phar-
maceutical products such as anticancer pharmaceuticals.8
It is also well recognized that incorporation of fluorine
conventional Et
recently developed Et
3
N‚3HF supporting electrolyte and a
10
4
NF‚4HF supporting electrolyte.
Resu lts a n d Discu ssion
Oxid a tion P oten tia l of F la von e a n d Its Der iva -
tives. The oxidation potentials of 1a -1c were deter-
mined using a platinum electrode in 0.1 M Bu
4
4
N‚BF /
MeCN and a SSCE (sodium saturated calomel electrode)
reference electrode by cyclic volammetry. All the com-
†
Tel: +81 45 924 5406. Fax: +81 45 924 5489. E-mail: fuchi@
echem.titech.ac.jp.
pounds chosen in the present study showed irreversible
(
1) Part 31: Dawood, K. M.; Fuchigami, T. J . Org. Chem. 1999, 64,
38.
2) Childs, W. V.; Christensen, L.; Klink, F. W.; Koipin, C. F. In
ox
oxidation peaks. The first oxidation peak potentials (E
p
)
1
(
were observed in the range of 2.36-2.52 V as shown in
Table 1. 6-Methylflavone 1b was oxidized at a less
positive potential compared with the other two deriva-
tives, owing to the electron-donating methyl substituent
on the benzene ring.
An od ic F lu or in a tion of F la von e a n d Der iva tives.
Anodic fluorination was carried out at platinum elec-
trodes in anhydrous acetontrile using a divided cell fitted
with an anion exchange membrane. Various fluoride salts
were used as both the supporting electrolyte and fluoride
ion source. A constant current was applied until the
starting material, flavone 1, was almost consumed. The
results of 1a are summarized in Table 2 and Scheme 1.
As shown in Table 2, the conventional supporting
Organic Electrochemistry, 3rd ed.; Lund, H., Baizer, M. M., Eds.;
Marcel Dekker: New York, 1991; Chapter 24.
(
3) (a) Fuchigami, T. Rev. Heteroat. Chem. 1994, 10, 155. (b)
Fuchigami, T.; Konno, A. J . Org. Synth. Chem. J pn. 1997, 55, 301.
4) (a) Gambaretto, G. P.; Napoli, M.; Franccarro, C.; Conte, L. J .
(
Fluorine Chem. 1982, 19, 427. (b) Ballinger, J . R.; Teare, F. W.
Electrochim. Acta 1985, 30, 1075. (c) Makino, K.; Yoshioka, H. J .
Fluorine Chem. 1988, 39, 435. (d) Meurs, J . H. H.; Eilenberg, W.
Tetrahedron 1991, 47, 705. (e) Sono, M.; Morita, N.; Shimizu, Y.; Tori,
M. Tetrahedron Lett. 1994, 35, 9237.
(5) (a) Hou, Y.; Higashiya, S.; Fuchigami, T. J . Org. Chem. 1997,
6
2, 8773. (b) Fuchigami, T.; Narizuka, S.; Momota, K. Electrochim.
Acta 1998, 43, 1985. (c) Fuchigami, T.; Higashiya, S.; Hou, Y.; Dawood,
K. M. Rev. Heteroat. Chem. 1999, 19, 67 and references therein.
(
6) Fuchigami, T.; Shimojo, M.; Konno, A. J . Org. Chem. 1995, 60,
459.
7) Higashiya, S.; Narizuka, S.; Konno, A.; Maeda, T.; Momota, K.;
Fuchigami, T. J . Org. Chem. 1999, 64, 133.
8) (a) Thomas, A. G.; Andrew, S. K.; George, R.; Brenda, W.; J eff,
3
(
(
electrolyte, Et
3
N‚3HF provided monofluorinated product
W. Biochem. Pharm. 1996, 52, 1787. (b) Greg, R. H.; J ames, R. H. J .
Biol. Chem. 1997, 272, 5396. (c) Wu, K.; Knox, R.; Sun, X. Z.; Chen, S.
Arch. Biochem. Biophys. 1997, 347, 221. (d) Futami, H.; Eader, L. A.;
Komschlies, K. L.; Wiltrout, R. H. Cancer Res. 1991, 51, 6595. (e)
Sakaguchi, Y.; Maehara, Y.; Newman, R. Cancer Res. 1992, 52, 3306.
2
a preferentially. In this case, difluorinated product 3a
was not formed. In sharp contrast, the other supporting
electrolytes gave mainly difluorinated product 3a as a
stereoisomeric mixture and only a small amount of 2a
(
9) (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.,
Kobyashi, Y., Eds: Kodansha & Elsevier Biomedical: Tokyo, 1982.
b) Fluorine in Bioorganic Chemistry; Welch, J . T., Eswarakrishnan,
S., Eds.; Wiley: New York, 1991.
(
(10) Momota, K.; Morita, M.; Matsuda, Y. Electrochim. Acta 1993,
38, 1231.
1
0.1021/jo981979y CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/09/1999

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3347
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 4. An od ic P a r tia l F lu or in a tion of F la von e a n d
Der iva tives Usin g Et3N‚3HF a s a Su p p or tin g Electr olyte
substrate
no.
yield (%)
temp charge passed
run
R
(°C)
(F/mol)
2
3
4
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
H
H
CH3
CH3
Cl
rt
30
rt
30
rt
30
3.5
3.5
3.0
3.0
4.8
4.8
43
58
0
0
6
19
2
2
9
19 trace
20 trace
41
62
0
0
Ta ble 3. Effect of Tem p er a tu r e on An od ic P a r tia l
F lu or in a tion of F la von e 1a Usin g Et3N‚3HF a s a
Su p p or tin g Electr olyte
Cl
24
Ta ble 5. An od ic P a r tia l F lu or in a tion of F la von e a n d
Der iva tives Usin g Et4NF ‚4HF a s a Su p p or tin g
Electr olytea
yield (%)
temperature
run
(°C)
2a
4a
substrate
no.
yield (%)
1
2
3
4
5
-10
0
10
20
30
9
27
31
43
58
trace
3
4
6
19
charge passed
(F/mol)
run
1
R
2
3 (cis/trans)
4
1a
1b
1c
H
3.5
3.0
4.8
7
68 (2/1)
0
29 (3/1)
0
54 (2/1)
0
9
9
4
4
9
9
b
b
b
6
3
2
2
3
CH3
Cl
a
25
2
3
.5 F/mol of electricity was passed.
4
0
was formed. This product distribution dependency on the
choice of the supporting fluoride salt has not been
previously reported for the case of anodic partial fluori-
a
The reactions were carried out at room temperature. b The
yield of 2 obtained after dehydrofluorination of crude product 3
with Et3N‚3HF/MeCN.
nation. Since Et
3
N‚3HF contains a considerable amount
N, 2a seems to be formed by dehydrofluori-
nation of 3a with free Et N during the electrolysis. In
fact, 3a treated with Et N‚3HF/MeCN produced 2a in
1
1
of free Et
3
fluorine atom was mainly introduced into the 3-position
of 1b and 1c as shown in Table 4. When a higher
temperature such as 30 °C was used, the 2c and 4c yields
increased significantly in a manner similar to that of the
case of 1a . However, in contrast to the 1a and 1c cases,
the fluorination of 1b became more complicated, and the
yield of 2b did not increase even at a higher tempera-
tures. This can be attributed to the 1b benzylic protons
being easily subject to nucleophilic substitution. In fact,
3
3
good yield as high as 82% (Scheme 2).
Next, the effect of temperature on the anodic fluorina-
tion was investigated. Anodic fluorination using 1a as a
model compound was carried out using Et N‚3HF at
3
various temperatures as shown in Table 3. When the
temperature increased, the yield of 2a also significantly
increased and a 58% 2a yield was obtained at 30 °C. On
the other hand, the 2a yield decreased sharply at lower
temperatures such as -10 °C. Such temperature effects
have also not been previously reported for the case of
anodic partical fluorination. Although, the reason is
19
the benzylic fluorination was confirmed by F NMR. In
sharp contrast, Et NF‚4HF produced different main
4
products, the corresponding difluorinated products 3. As
already explained, 2a was found to be derived from 3a .
Therefore, conversion of 3b,c to 2b,c was also similarly
attempted. The yields obtained by dehydrofluorination
of crude products with Et
Table 5.
It is notable that trifluorinated product 4 was always
produced regardless of which supporting fluoride salt was
used. To clarify the trifluoroflavones 4 formation mech-
anism, anodic oxidation of monofluoroflavone 2a was
used as a model compound under the same electrolytic
conditions used for anodic fluorination of 1a . Only
trifluoroflavone 4a was produced in reasonable yield as
shown in Scheme 4, and no difluorinated flavone 3a was
formed at all.
presently not clear, the increased amount of free Et
3
N
in Et
3
N‚3HF produced at a higher temperature12 is
3 3
N/CH CN are summarized in
expected to facilitate dehydrofluorination of 3a formed
during the electrolysis, resulting in an increase 2a yield.
Then, this anodic fluorination method was applied to
the flavone derivatives 1b and 1c, which have a chloro
or a methyl group on the benzene ring. Et
Et NF‚4HF were used as the supporting electrolyte as
shown in Scheme 3. The results are summarized in
Tables 4, and 5. Typically, when Et N‚3HF was used, a
3
N‚3HF and
4
3
(
11) Chen, S.; Hitakeyama, T.; Fukuhara, T.; Hara, S.; Yoneda, N.
Electrochim. Acta 1997, 42, 1951.
12) We found that the amount of free Et
with increase of temperature: Furuta, S.; Fuchigami, T. Unpublished
results.
Since 2a is more easily oxidized at a 0.08 bias voltage
than the starting flavone 1a , 4 seems to have been formed
by further oxidation of 2. Although acetamidation com-
(
3 3
N in Et N‚3HF increased

3
348 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
Sch em e 4
Sch em e 6
Ta ble 6. Ch em ica l F lu or in a tion of F la von e 1a Usin g
Sch em e 5
N-F lu or op yr id in iu m Sa lts
N-fluoro-
pyridinium
salt (X)
yield (%)
reaction
solvent time (h)
run
temp
rt
reflux CH3CN
reflux CH2Cl2
2a
3a 4a
1
2
3
4
5
Cl
Cl
Cl
H
CH3CN
10
4
4
10
6
trace
17
21
0
0
0
0
0
0
0
4
4
0
0
rt
CH3CN
H
reflux CH3CN
0
or hazardous reagents. In recent years, N-F type reagents
such as N-fluoropyidinium salts19 and 1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate) (F-TEDA)20 have been developed and have been
shown to be effective fluorinating reagents. Fluorination
of compound 1a as a model compound with various
N-fluoropyridinium triflates was attempted (Scheme 6),
and the results are summarized in Table 6. A less
powerful N-fluoropyridinium salt did not produce any
fluorinated products, and the starting material 1a was
almost all recovered. On the other hand, a more powerful
N-fluoro(2,6-dichloro)pyridinium salt provided the mono-
fluorinated product 2a under reflux; however, the yield
was very low. Therefore, this electrochemical fluorination
is a superior procedure to the conventional chemical
fluorination methods.
In summary, we have successfully carried out anodic
partial fluorination of flavones, and we have also dem-
onstrated for the first time fluorinated product distribu-
tion greatly depending on the kind of supporting fluoride
salts. These findings are of importance for further
development of anodic partical fluorination of organic
molecules.
monly takes place in chemical13 and electrochemical2
fluorination of olefines,13 it is noted that no product
related to acetamidation was detected in the anodic
fluorination of 1.
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 5. Then, this radical cation reacts
with a fluoride ion followed by further oxidation to form
cationic intermediate B,14 which provides the difluori-
nated products 3. It is noted that the cis-difluoro isomer
of 3 was always formed as a major product in such
reactions.16 This is probably due to the adsorption of the
intermediate B on the anode. Similar adsorption effects
leading to the preferable formation of a cis-difluoro
isomer have been reported by Laurent et al.1
7,18
As
already explained (Scheme 1), 2 should be formed from
by dehydrofluorination with Et N in Et N‚3HF.
It is well-known that methods for the introduction of
fluorine into organic compounds require expensive and/
Exp er im en ta l Section
3
3
3
Ca u tion : Et
4
NF‚4HF and Et N‚5HF were obtained from
3
Morita Chemical Industries Co. Ltd. They are toxic and may
cause serious burns if they come in contact with unprotected
skin, while Et
4
NF‚3HF and Et N‚3HF are much less aggressive.
3
(
13) Zupan, M.; Skulj, P.; Stavber, S. Chem. Lett. 1998, 641.
However, proper safety precautions should be taken at all
(14) Recently, Laurent et al. reported anodic fluorination of 2-phen-
21
times. It is therefore recommended to provide hand protection.
ylthiochromen-4-one in a quite similar manner to that of flavones using
1
19
H NMR and F NMR spectra were recorded at 270 and 254
MHz, respectively, using CDCl as a solvent. The chemical shifts
for H and F NMR are given in δ ppm downfield from internal
6 6
Me Si and C [δ (CFCl ) of the C F reference is -162.2 ppm],
1
5
3
Et N‚3HF/MeCN to provide 3-mono- and 2,3,3-trifluoroproducts.
3
Since they did not obtain 2,3-difluorinated product (similar to 3), they
propsed that 3-fluoro-2-phenylthiochromen-4-one was directly formed
from 3-fluoro cationic intermediate as follows:
1
19
4
6
F
6
3
respectively. Fluorinated anion-exchange membrane (IE-DF34-5
TOSOH) is purchased from Tosoh Corporation, J apan.
An od ic F lu or in a tion of F la von e a n d Its Der iva tives. A
typical procedure for anodic fluorination of flavone 1a is as
follows. Anodic oxidation of 1a (1 mmol) was carried out with
(
15) Andres, D.; Dietrich, U.; Laurent, E.; Marquet, B. Tetrahedron
997, 53, 647.
16) However, the separation of the trans and cis isomers was
platinum plate electrodes (3 cm × 2 cm) in 0.2 M Et
4
NF‚4HF or
1
-
(
0.33 M Et
3
N‚3HF (20 equiv of F to 1a )/MeCN (20 mL) using a
unsuccessful in most cases. The cis isomers could not be isolated in
all cases due to their instability. The stereochemistry of 3 was
determined on the basis of the vicinal fluorine-hydrogen coupling
divided cell with an anion exchange membrane (IE-DF34-5
TOSOH) under a nitrogen atmosphere at room temperature. A
2
constant current (3.3 mA/cm ) was passed. After the electrolysis,
constants of 19
F NMR similar to the case of 2-amino-1-fluoro-1-
phenylcyclohexane reported by Wade and Guedj: Wade, T. N.; Guedj,
R. Tetrahedron Lett. 1978, 3247.
(19) (a) Umemoto, T.; Tomizawqa, G. Bull. Chem. Soc. J pn. 1986,
59, 3625 (b) Umemoto, T.; Tomizawa, G. J . Org. Chem. 1995, 60, 6563.
(20) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, L.;
Syvret, R. G. J . Chem. Soc., Chem. Commun. 1992, 595.
(
17) Bensadat, A.; Laurent, E.; Tardivel, R. Nouv. J . Chem. 1981,
, 397.
18) Laurent, E.; Tardival, R.; Benotmane, H.; Bensadat, A. Bull.
Soc. Chim. Fr. 1990, 127, 468.
5
(
(21) Peters, D.; Metchen, R. J . Fluorine Chem. 1996, 79, 161.

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3349
HF - CO), 197 (M+ - Ph). HRMS: m/z calcd for C16
H F O ,
12 2 2
the electrolyte was neutralized with a satutated NaHCO
solution and the resulting aqueous solution was extracted with
ether repeatedly. After the combined extracts were dried over
3
1
9
274,0805, found 274.0793. Tr a n s for m : F NMR δ -114.85 (dd,
19
20.22, 46.88 Hz), -40.42 (d, 20.22 Hz). Cis for m : F NMR δ
-135.90 (dd, 16.08, 45.96 Hz), -51.59 (dd, 16.08, 28.10).
anhydrous MgSO
fluoroflavone 4a were isolated by silica gel chromatography
hexane:CHCl ) 5:1), or crude products were treated with Et N‚
HF/MeCN (stirring at room tempeture for 3 h). Pure mono-
4
, trans-2,3-difluoroflavone 3a and 2,3,3-tri-
,3,3-Tr iflu or o-6-m eth ylfla von e (4b): 19F NMR δ -61.04
2
(
3
3
3
(
dd, 11.95, 285.87), -48.69 (t, 11.49), -36.76 (dd, 11.03, 285.87).
+
+
+
MS (EI) m/z: 292 (M ), 254 (M - 2F), 226 (M - 2F - CO).
fluorinated flavone 2a was obtained by recrystallization from
methanol. In the anodic fluorination of 6-chloroflavone (1c), to
dissolve the starting materials completely in the electrolytic
HRMS: m/z calcd for C16
H
11
F
3
O
2
, 292.0711, found 292.0699.
1
3
-F lu or o-6-ch lor ofla von e (2c): H NMR δ 7.52-8.27 (m,
H); F NMR δ -83.81 (s). MS (EI) m/z: 276 (M + 2), 274
M ), 258 (M - O), 246 (M - CO), 138 (M - CO - CF - Ph).
HRMS: m/z calcd for C15 ClFO 274.0197, found 274.0211.
2,3-Diflu or o-6-ch lor ofla von e (3c): MS (EI) (cis and trans
isomeric mixture) m/z: 296 (M + 2), 294 (M ), 274 (M - HF),
46 (M - HF - CO), 217 (M - Ph). HRMS: m/z calcd for
1
9
+
8
(
2 2 3
solution, 20 mL of CH Cl /CH CN (1:2) was used as an electro-
+
+
+
+
lytic solvent. The results shown in Tables 2-6 are easily
H
8
2
reproducible.
-F lu or ofla von e (2a ): H NMR δ 7.42-8.30 (m, 9H); 19F
1
3
+
+
+
+
+
NMR δ -84.26 (s). MS (EI) m/z: 240 (M ), 212 (M - CO). Anal.
Calcd for C15 FO : C, 75.00; H, 3.78; F, 7.91. Found: C, 74.86;
H, 3.89; F, 7.92.
,3-Diflu or ofla von e (3a ). Tr a n s for m : 1H NMR δ 7.19-
+
+
2
C
H
9
2
1
9
15 9 2 2
H ClF O 294.0259, found 294.0253. Tr a n s for m : F NMR
δ -115.01 (dd, 46.89 Hz, 20.22 Hz), -40.12 (d, 20.22 Hz). Cis
2
for m : 19F NMR δ -135.90 (dd, 45.90 Hz, 15.63 Hz), -52.09 (dd,
1
9
8
4
.05 (m, 9H), 4.80 (d, 46.85 Hz, 1H); F NMR δ -114.92 (dd,
2
8.24 Hz, 15.63 Hz).
2,3,3-Tr iflu or o-6-ch lor ofla von e (4c): 19F NMR δ -61.18
6.89 Hz, 20.23 Hz), -39.85 (d, 20.22 Hz). MS (EI) m/z: 260
+
+
+
+
(
M ), 240 (M - HF), 212 (M - HF - CO), 183 (M - Ph).
HRMS: m/z calcd for C15
H
10
F
2
O
2
, 260.0649, found 260.0645. Cis
for m : F NMR δ -135.93 (dd, 45.96 Hz, 15.63 Hz), -52.09 (dd,
8.50 Hz, 15.63 Hz).
,3,3-Tr iflu or ofla von e (4a ): 1H NMR δ 7.20-8.06 (m, 9H);
F NMR δ -60.88 (dd, 285.87 Hz, 11.49 Hz), -48.59 (t, 11.49
(dd, 285.87 Hz, 11.48 Hz), -48.69 (t, 11.48), -36.81 (dd, 285.87
1
9
+
+
+
Hz, 11.04 Hz). MS (EI) m/z: 314 (M + 2), 312 (M ), 274 (M
-
2
+
2
2F), 265 (M - F - CO). HRMS: m/z calcd for C15H ClF O ,
8
3
2
312.0165, found 312.0146.
1
9
+
Hz), -36.78 (dd, 285.87 Hz, 11.03 Hz). MS (EI) m/z: 278 (M ),
2
Ack n ow led gm en t. This study was financially sup-
ported by Novartis Foundation (J apan) for the Promo-
tion of Science. We also thank Morita Chemical Indus-
tries Co. Ltd. and Chichibu Onoda Cement Co. for their
+
+
59 (M - F), 231 (M - F-CO). HRMS: m/z calcd for
, 278.0555, found 278.0553.
15 9 3 2
C H F O
1
3
-F lu or o-6-m eth ylfla von e (2b): H NMR δ 7.38-8.22 (m,
19
+
8
2
H), 2.41 (s, 3H); F NMR δ -84.22 (s). MS (EI) m/z: 254 (M ),
26 (M - CO), 208 (M+ - CF - CH
, 254.0743, found 254.0743.
,3-Diflu or o-6-m eth ylfla von e (3b): MS (EI) (cis and trans
+
), 134 [M - (PhCtCF)].
+
3
generous gifts of Et NF‚4HF and N-fluoropyridinium
4
HRMS: m/z calcd for C16H11FO
2
salts, respectively.
2
+
+
+
isomeric mixture) m/z: 274 (M ), 254 (M - HF), 226 (M
-
J O981979Y