Electrochemical partial fluorination of organic compounds. 74. Efficient anodic synthesis of 2-fluoro- and 2,3-difluoro-2,3-dihydrobenzofuran derivatives

Article abstract of DOI:10.1021/jo035871g

Anodic fluorination of 3-substituted benzofuran derivatives in a variety of fluoride salts resulted in the formation of three fluorinated products; two stereoisomers of 2,3-difluoro-2,3-dihydrobenzofuran (cis and trans) and cis-2-fluoro-3-hydroxy-2,3-dihydrobenzofuran derivatives. Dehydrofluorination of the main products, cis-difluoro derivatives, furnished the nonaromatic 2-fluoro-3-benzofuranyledene derivatives instead of the aromatic 2-fluorobenzofuran derivatives.

Full text of DOI:10.1021/jo035871g

Electr och em ica l P a r tia l F lu or in a tion of Or ga n ic Com p ou n d s. 74.
Efficien t An od ic Syn th esis of 2-F lu or o- a n d
2
,3-Diflu or o-2,3-d ih yd r oben zofu r a n Der iva tives1
†
,‡
Kamal M. Dawood and Toshio Fuchigami*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt, and Department of
Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama, J apan
fuchi@echem.titech.ac.jp
Received December 25, 2003
Anodic fluorination of 3-substituted benzofuran derivatives in a variety of fluoride salts resulted
in the formation of three fluorinated products; two stereoisomers of 2,3-difluoro-2,3-dihydroben-
zofuran (cis and trans) and cis-2-fluoro-3-hydroxy-2,3-dihydrobenzofuran derivatives. Dehydroflu-
orination of the main products, cis-difluoro derivatives, furnished the nonaromatic 2-fluoro-3-
benzofuranyledene derivatives instead of the aromatic 2-fluorobenzofuran derivatives.
In tr od u ction
SCHEME 1
The benzofuran moiety is incorporated in various
natural products2 and pharmaceuticals.3 Fluorinated
heterocycles have also proved to be highly biologically
4
active compounds. Recently, copious literature concern-
ing electrochemical fluorination of sulfur-containing het-
5
erocycles has been reported; however, limited examples
of selective anodic fluorination of oxygen-containing
heterocycles were studied.6 More than 10 years ago,
anodic fluorination of furan and benzofuran was at-
tempted; however, their fluorinated products were un-
stable and not isolable.7 These facts prompted us to
†
Cairo University.
Tokyo Institute of Technology.
‡
(
1) Part 73: Murakami, S.; Ishii, H.; Fuchigami, T. J . Fluorine
Chem. 2004, 125, 609.
2) (a) Walker, J . A.; Rossen, K.; Reamer, R. A.; Volante, R. P.;
Reider, P. J . Tetrahedron Lett. 1999, 40, 4917. (b) Ganzalez, A,. G.;
Barrera, J . B.; Yanes, A. C.; Diaz, J . G.; Rodriguez, E. M. Phytochem-
istry 1989, 28, 2520. (c) Carvalho, C. F.; Sargent, M. V. J . Chem. Soc.,
Perkin Trans. 1 1984, 1605.
perform, for the first time, anodic mono- and difluorina-
(
tion of 3-substituted benzofurans.8
Resu lts a n d Discu ssion
(
3) (a) Vinh, T. K.; Ahmadi, M.; Delgado, P. O. L.; Prerez, S. F.;
Walters, H. M.; Smith, H. J .; Nicholls, P. J .; Simons, C. Bioorg. Med.
Chem. Lett. 1999, 9, 2105. (b) Tomaszewski, Z.; J ohnson, M. P.; Haung,
X.; Nichols, D. E. J . Med. Chem. 1992, 35, 2061. (c) Ellingboe, J . W.;
Alessi, T. R.; Dolak, T. M.; Nguyen, T. T.; Tomer, J . D.; Guzzo, F.;
Bagli, J . F.; McCaleb, M. L. J . Med. Chem. 1992, 35, 1176.
Syn th esis of 3-Su bstitu ted Ben zofu r a n Der iva -
tives 5a -d . Compounds 5a ,b were prepared by the
reaction of 3-coumaranone (1) with ethoxycarbonyl me-
9
thylenetriphenylphosphorane (2a ) and acetylmethylene-
(
4) (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.,
Kobayashi, Y., Eds.; Kondansha & Elsevier Biomedical: Tokyo, 1982.
b) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
triphenylphosphorane (2b),10 in refluxing xylene, while
compound 5c was obtained by the reaction of 1 with
diethyl (cyanomethyl)phosphonate (3)11 under refluxing
tetrahydrofuran in the presence of sodium hydride
(
Wiley: New York, 1991. (c) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J . R., Welch, J . T. Eds.; ACS Symposium Series
6
39; American Chemical Society: Washington, DC, 1996. (d) Narizuka,
S.; Fuchigami, T. Bioorg. Med. Chem. Lett. 1995, 5, 1293. (e) Hiyama,
T. Organofluorine Compounds: Chemistry and Applications; Springer:
Berlin, 2000.
(Scheme 1). Furthermore, the synthesis of 3-methylben-
zofuran (5d ) was achieved through a multistep procedure
(5) (a) Fuchigami, T. In Advances in Electron-Transfer Chemistry;
Mariano, P. S., Eds.; J AI Press: Greenwich, CT, 1999; Vol. 6. (b)
Fuchigami, T., Higashiya, S., Hou, Y., Dawood, K. M. Rev. Heteroatom
Chem. 1999, 19, 67. (c) Fuchigami, T. In Organic Electrochemistry,
(8) Dawood, K. M.; Fuchigami, T. Synlett 2003, 1631.
(9) Deshpande, A. R.; Paradkar, M. V. Indian J . Chem. 1992, 31B,
526.
(10) (a) Chan, H. T. J .; Elix, J . A.; Ferguson, B. A. Synth. Commun
1972, 2, 409. (b) Tomaszewski, Z.; J ohnson, M. P.; Huang, X.; Nichols,
D. E. J . Med. Chem. 1992, 35, 2061.
(11) Ellingboe, J . W.; Alessi, T. R.; Dolak, T. M.; Nguyen, T. T.;
Tomer, J . D.; Guzzo, F.; Bagli, J . F.; McCaleb, M. L. J . Med. Chem.
1992, 35, 1176.
4
1
th ed.; Lund, H., Hammerich, O., Eds.; Dekker: New York, 2001; pp
035-1050.
(6) (a) Dawood, K. M.; Fuchigami, T. J . Org. Chem. 2001, 66, 7691.
(
(
b) Hou, Y.; Higashiya, S.; Fuchigami, T. J . Org. Chem. 1999, 64, 3346.
c) Hasegawa, M.; Ishii, H.; Fuchigami, T. Tetrahedron Lett. 2002, 43,
1
503.
(7) Meurs, J . H.; Eilenberg, W. Tetrahedron 1991, 47, 705.
1
0.1021/jo035871g CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/03/2004
5
302
J . Org. Chem. 2004, 69, 5302-5306

Electrochemical Partial Fluorination of Organic Compounds
ox
TABLE 1. F ir st Oxid a tion P oten tia ls (Ep ) of Sta r tin g
TABLE 2. An od ic F lu or in a tion of Com p ou n d s 5a ,b,d
Su bstr a tes 5a -d
ox
compd
Y
Ep (V vs SCE)
5
5
5
5
a
b
c
d
COOEt
COCH3
CN
1.80
1.71
1.94
1.64
H
a
In 0.1 M Bu4NF‚BF4/MeCN. Sweep rate 100 mV s-1
.
utilizing 2-hydroxyacetophenone (4) with ethyl chloro-
acetate followed by basic hydrolysis and then thermal
cyclization in acetic anhydride in the presence of sodium
acetate12 (Scheme 1).
yield %b
charge
over-
all
passeda
sub-
supporting
electrolyte
6, cis/
7, cis/
yield
(%)
Oxid a tion P oten tia ls of 3-Su bstitu ted Ben zofu -
run strate
F/mol
trans
trans
ox
r a n Der iva tives 5a -d . The oxidation potentials (E
p
)
1
2
3
5a Et NF‚4HF/DME
5a Et
5a Et
10
7
4
6a , 21/5 7a , 14/none
6a , 40/7 7a , 10/traces
6a , 55/5 7a , 40/none
40
57
100
4
of benzofuran derivatives 5a -d were measured by cyclic
voltammetry in 0.1 M anhydrous acetonitrile solution
4
NF‚4HF/MeCN
NF‚4HF/
4
MeCNc
containing Bu
saturated calomel electrode (SCE) as a reference elec-
4
4
N‚BF using platinum electrodes versus
4
5
5a Et
4
NF‚4HF/
4
5
6a , 78/10 7a , 7/traces
6a , 75/18 7a , 6/traces
95
99
c,d
MeCN
5a Et3N‚3HF/
trode. All compounds 5a -d showed irreversible oxidation
c,d
MeCN
ox
waves in cyclic voltammograms, and their E
p
values
6
7
8
9
5a Et
5b Et
5b Et
5b Et
4
4
4
4
NF‚3HF/MeCN
NF‚4HF/DME
NF‚4HF/MeCN
7
10
4
6a , 51/8 7a , 12/traces
6b, 36/7 7b, 8/tracese
6b, 56/10 7b, 10/traces
6b, 76/14 7b, 3/tracese
71
51
76
93
are listed in Table 1. The oxidation potentials of the
starting substrates are markedly affected by the type of
the substituent functionality and are in the following
e
NF‚4HF/
4
c,d
MeCN
order: CN > COOEt > COCH
3
> H. The electron transfer
10
5b Et
5d Et
5d Et
4
NF‚3HF/MeCN
NF‚4HF/MeCN
NF‚4HF/
4
4
4
6b, 51/7 7b, 12/3e
6d , 35/5 7d , 5/traces
73
45
93
1
1
1
2
4
4
seems to take place from the furan moiety of the benzo-
furan ring. Therefore, as the electron-withdrawing ability
of the substituents at the furan ring increases, the
oxidation potential increases.
6d
7d , 14/3
MeCNc
a
2
Constant-current electrolysis (6 mA/cm ) using an undivided
b
19
cell. Anode and cathode were Pt plates (2 × 2 cm). Based on
F
NMR. c Constant-potential electrolysis was applied. Under a
d
An od ic F lu or in a tion of 3-Su bstitu ted Ben zofu r a n
Der iva tives 5a -d . First, anodic fluorination of ethyl (3-
benzofuranyl)acetate (5a ), as a model example, was ex-
tensively studied under various conditions. In all cases,
e
nitrogen atmosphere. (2-Fluorobenzofuran-3-ylidene)acetone (8b)
19
was detected by MS and F NMR in 2-5% yield.
SCHEME 2
1
19
three fluorinated products were obtained. H, F, and
1
3
C NMR spectra of the electrolysis products showed that
there are two isolable isomers of 2,3-difluoro-2,3-dihy-
drobenzofuran derivative 6a (cis/trans isomers) and cis-
2
-fluoro-3-hydroxy-2,3-dihydrobenzofuran derivative 7a
as shown in Table 2. The overall fluorination yield and
the product selectivity were greatly affected by the elec-
trolysis conditions. Acetonitrile was found to be a more
convenient electrolytic solvent (runs 3-5) than dimethox-
yethane (DME) (run 1). When constant-potential elec-
trolysis was applied (runs 3-5), the overall fluorination
yield was almost quantitative; however, the overall yield
was reduced to its half value when constant-current
cis isomer of 6a and the yield of 2-fluoro-3-hydroxy-2,3-
dihydrobenzofuran derivative 7a increased sharply (run
3). This finding can be attributed to the air moisture,
which suppresses the fluorination process and facilitates
the attack of hydroxide ions. This result was confirmed
by conducting similar electrolysis in the presence of a few
drops of water where difluorinated products could not be
detected at all and the only obtained product was cis-2-
fluoro-3-hydroxy-2,3-dihydrobenzofuran derivative 7a as
shown in Scheme 2.
electrolysis was applied (run 2). Et NF‚4HF proved to
4
be a powerful fluorinating agent under optimum condi-
tions (run 3). Among the three fluorination products, cis-
2
,3-difluoro-2,3-dihydrobenzofuran derivative 6a was the
major one regardless of the electrolysis conditions as
shown in Table 2. This can be accounted for by the occur-
rence of the fluorination process at the anode surface.
Constant-potential electrolysis under a nitrogen atmo-
sphere resulted in the formation of the cis isomer of 6a
predominantly (run 4). However, similar electrolysis
under a normal atmosphere furnished a low yield of the
Next, anodic fluorination of the other benzofuran deriv-
atives 5b-d was conducted under similar electrolytic
conditions, and the results are listed in Tables 2 and 3.
As shown in Table 2 (runs 7-10), anodic fluorination of
1-(3-benzofuranyl)-2-propanone (5b) proceeds in a man-
ner similar to that for the ester 5a , where three isolable
fluorinated products 6b (cis/trans) and 7b (cis) were
obtained in overall good yields. The best results were
(12) Nielek, S.; Lesiak, T. Chem. Ber. 1982, 115, 1247.
recorded with the application of Et
4
NF‚4HF inacetonitrile
J . Org. Chem, Vol. 69, No. 16, 2004 5303

Dawood and Fuchigami
SCHEME 3
TABLE 3. An od ic F lu or in a tion of Com p ou n d 5c
3-Methylbenzofuran devoid of an electron-withdrawing
group (5d ) was similarly fluorinated using Et NF‚4HF
4
in acetonitrile under both constant-current and -potential
electrolyses (runs 11 and 12, respectively, Table 2) to give
the corresponding cis/trans difluoro and monofluoro de-
rivatives 6d and 7d , respectively. The fluorination yield
under constant-potential electrolysis conditions is almost
twice of that obtained under constant-current electrolysis
conditions.
A proposed mechanism of the formation of 2,3-difluoro-
and 2-fluoro-2,3-dihydrobenzofuran derivatives 6 and 7
is depicted in Scheme 3. The fluorination reaction seems
to take place by electron transfer from the olefin moiety
of the benzofuran ring to give the radical cation A fol-
lowed by fluoride ion attack at the position R to ring
oxygen to give the fluoro radical B, which undergoes
further oxidation to give the cation C. The resulting ca-
tion C seems to adsorb on the anode surface. There are
three possible pathways to capture the cation C: (a) a
fluoride ion attacks at the anode surface to give the cis
form of 6, (b) a fluoride ion attacks in the bulk of the
electrolytic solution to give the trans form of 6, and (c)
water attacks at the anode surface to give the cis form
yield %b,c
charge
supporting
electrolyte
passed
F/mol
6c, cis/
trans
overall
yield (%)
run
8c
a
1
2
3
Et4NF‚4HF/MeCN
Et4NF‚4HF/MeCN
Et3N‚3HF/MeCN
4
4
4
33/7
40/13
35/16
7
5
47
58
67
d
d
16
a
2
Constant-current electrolysis (6 mA/cm ) using an undivided
b
19
c
cell under a nitrogen atmosphere. Based on F NMR. Traces
1
9
of 2-fluoro-3-hydroxybenzofuran 7c were detected by F NMR [δ
49.24 (d, J ) 62.88 Hz)]. Constant-potential electrolysis (1.94
d
-
V vs SCE) was applied.
of 7. Et N‚3HF is known to contain a considerable am-
3
13
ount of free triethylamine. Therefore, it is reasonable
using constant-potential electrolysis under a nitrogen
to explain the formation of compound 8c during the elec-
atmosphere (run 9). Traces of both the trans form of 7b
and dehydrofluorination product 8b were detected by 19
trolysis of 5c using Et
3
3
N‚3HF since Et N should promote
F
the elimination of the acidic proton adjacent to the
strongly electron-withdrawing cyano group of the cation
C.
NMR and mass spectra (Table 2).
In the case of anodic fluorination of 3-benzofuranac-
etonitrile (5c), only the cis and trans isomers of the 2,3-
difluoro-2,3-dihydrobenzofuran derivative 6c were ob-
tained; the expected 2-fluoro-3-hydroxy-2,3-dihydroben-
zofuran derivative 7c could not be obtained. However,
the dehydrofluorination product 8c was obtained instead
of 7c (Table 3). The yield of 8c was slightly increased
Attempts to perform chemical fluorination of 5a -d
1
4
using well-known N-fluoropyridinium triflates failed,
which attests to the advantages of using electrochemical
fluorination methodology.
Treatment of cis-2,3-difluoro-2,3-dihydrobenzofuran 6a
with piperidine at room temperature resulted in dehy-
drofluorination to give the nonaromatic 2-fluoro-3-
when the supporting electrolyte Et
run 3, Table 3). As shown in Table 3, it was noticed that
3
N‚3HF salt was used
(
(ethoxycarbonyl) methylenebenzofuran derivative 8a in-
the overall fluorination yield was sharply decreased in
comparison with the case of anodic fluorination of 5a and
(
13) Chen, S.; Hitakeyama, T.; Fukuhara, T.; Hara, S.; Yoneda, N.
Electrochim. Acta 1999, 42, 1951.
14) (a) Umemoto, T.; Tomizawa, J . Bull. Chem. Soc. J pn. 1986, 59,
3625. (b) Umemoto, T.; Tomizawa, J . J . Org. Chem. 1995, 60, 6563.
5
b. This may be attributed to the higher oxidation pot-
ential of compound 5c than those of compounds 5a ,b
Table 1).
(
(
5
304 J . Org. Chem., Vol. 69, No. 16, 2004

Electrochemical Partial Fluorination of Organic Compounds
SCHEME 4
(m, 2H); 19F NMR δ -56.09 (ddt, 1F, J ) 57.34, 18.49, 3.7 Hz),
stead of its aromatized isomer 9a , as shown in Scheme
1
3
-
66.89 (m, 1F); C NMR (DEPT) δ 14.12 (CH
CH , J ) 26.27, 3.9 Hz), 61.22 (CH ), 111.48, 113.95 (dd, J )
35.87, 45.83 Hz), 122.86, 124.46, 132.90, (CH), 98.03 (dd, J
183.33, 29.06 Hz), 123.32, 159.48, 167.85 (C); MS (m/z) 242
3
), 36.59 (dd,
4
. The structure of 8a was established on the basis of its
1
19
13
2
2
H, F, and C NMR spectra (see Experimental Section).
Similar results were obtained when compounds 6b,c were
dehydrofluorinated under the same conditions. However,
the dehydrofluorination of compound 6d could not be
achieved by treatment with piperidine either at room
temperature or under refluxing conditions, and 6d was
mostly recovered.
2
)
(
+
+
M ), 222 (M - HF), 193, 165, 149, 127, 101, 84. Anal. Calcd
for C12 : C, 59.50; H, 4.99. Found: C, 59.36; H, 5.01.
E t h yl (2,3-Diflu or o-2,3-d ih yd r o-3-b en zofu r a n yl)a ce-
ta te (6a ) Tr a n s F or m : yellow oil; H NMR δ 1.23 (t, 3H, J )
7.09 Hz), 2.91 (ddd, 1H, J ) 26.87, 15.83, 1.32 Hz), 3.19 (ddd,
12 2 3
H F O
1
1
H, J ) 15.83, 9.93, 3.79 Hz), 4.17 (q, 2H, J ) 7.09 Hz), 6.39
Finally, when 8a was treated with piperidine under
refluxing conditions, it afforded the corresponding 2-pi-
peridylbenzofuran derivative 10a in high yield, as shown
in Scheme 4.
In conclusion, we have found that the introduction of
a substituent at the 3-position of a benzofuran moiety
dramatically changed its behavior toward anodic fluori-
nation to a positive pathway in contrast to the unsub-
stituted benzofuran ring. This finding opens a new
avenue toward anodic fluorination of oxygen-containing
heterocycles.
(
(
(
dd, 1H, J ) 60.84, 1.81 Hz), 6.96 (d, 1H, J ) 8.07 Hz), 7.08
dd, 1H, J ) 7.58, 7.09 Hz), 7.38 (m, 2H); 19F NMR δ -63.64
ddd, 1F, J ) 61.03, 16.65, 3.7 Hz), -87.69 (m, 1F); MS (m/z)
+
+
2
42 (M ), 222 (M - HF), 165, 149, 145, 101, 89. Anal. Calcd
: C, 59.50; H, 4.99. Found: C, 59.41; H, 5.09.
-(2,3-Diflu or o-2,3-d ih yd r o-3-ben zofu r a n yl)-2-p r op a n -
on e (6b) Cis F or m : mp 50-51 °C; H NMR (CDCl ) δ 2.28
for C12
12 2 3
H F O
1
1
3
(s, 3H), 3.11 (ddd, 1H, J ) 34.29, 18.13, 3.29 Hz), 3.61 (ddd,
1H, J ) 18.13, 10.88, 3.63 Hz), 6.57 (dd, 1H, J ) 57.70, 9.73
Hz), 7.07 (dd, 2H, J ) 8.24, 7.25 Hz), 7.40 (d, 2H, J ) 7.25
Hz); 19F NMR δ -55.71 (dd, 1F, J ) 57.33, 18.49 Hz), -67.18
+
+
(
1
m, 1F); MS (m/z) 212 (M ), 192 (M - HF), 177, 149, 127,
01, 75. Anal. Calcd for C11 C, 62.26; H, 4.75.
Found: C, 62.27; H, 4.50.
1-(2,3-Diflu or o-2,3-d ih yd r o-3-ben zofu r a n yl)-2-p r op a n -
10 2 2
H F O :
Exp er im en ta l Section
9
Ethyl (3-benzofuranyl)acetate (5a ), 1-(3-benzofuranyl)-2-
1
1
0
11
3
on e (6b) Tr a n s F or m : yellow oil; H NMR (CDCl ) δ 2.24 (s,
propanone (5b), (3-benzofuranyl))acetonitrile (5c), and
3
-methylbenzofuran (5d )12 were synthesized according to
3H), 2.98 (dd, 1H, J ) 26.54, 16.65 Hz), 3.34 (ddd, 1H, J )
1
2
1
1
6.32, 11.54, 3.63 Hz), 6.28 (d, 1H, J ) 60.84 Hz), 6.99 (dd,
reported procedures.
H, J ) 8.07, 7.25 Hz), 7.40 (m, 2H); 19F NMR δ -63.54 (dd,
An od ic F lu or in a tion of Ben zofu r a n Der iva tives 5a -
+
F, J ) 61.04, 14.79 Hz), -88.11 (m, 1F); MS (m/z) 212 (M ),
d . Electrolysis was performed with platinum electrodes (2 ×
+
92 (M - HF), 177, 149, 127, 101, 75, 43. Anal. Calcd for
2
2
cm ) in a 0.3 M solution of the appropriate fluoride salt in
11 10 2 2
C H F O : C, 62.26; H, 4.75. Found: C, 62.14; H, 4.60.
dimethoxyethane or acetonitrile (20 mL) containing the ap-
propriate benzofuran derivatives 5a -d (1 mmol). The elec-
trolysis was conducted in an undivided cell either under a
nitrogen atmosphere or open air conditions at room temper-
(
2,3-Diflu or o-2,3-d ih yd r o-3-b e n zofu r a n yl)a ce t on i-
1
tr ile (6c) Cis F or m : mp 65-66 °C; H NMR (CDCl
m, 2H), 6.24 (dd, 1H, J ) 60.34, 11.54 Hz), 7.06 (d, 1H, J )
8.08 Hz), 7.16 (dd, 1H, J ) 7.75, 7.58 Hz), 7.49 (dd, 1H, J )
3
) δ 3.20
(
-
2
ature. Constant-current (6 mA cm ) or controlled-potential
electrolyses were applied until the starting substrates were
completely consumed (monitored by TLC and GC-MS). The
products were purified by silica gel column chromatography
using ethyl acetate/hexane (1:5) as an eluent. In all cases, the
cis isomers of difluorinated products were collected first
followed by their trans isomers. After that, the cis-2-fluoro-3-
hydoxybenzofuran derivatives were collected followed by their
trans isomers. All collections were evaporated under reduced
pressure, and each residue was purified again by a preparative
thin-layer chromatography (25 TLC aluminum sheets 20 × 20
cm silica gel 60 F254, Merck) using ethyl acetate/hexane eluent
8
(
(
.08, 7.58 Hz), 7.63 (d, 1H, J ) 7.75 Hz); 19F NMR δ -56.84
dd, 1F, J ) 61.03, 16.65 Hz), -62.63 (m, 1F); MS (m/z) 195
+
M ), 155, 147, 127, 120, 101, 75, 63, 51. Anal. Calcd for
10 7 2
C H F NO: C, 61.54; H, 3.62; N, 7.18. Found: C, 61.76; H,
3
.62; N, 7.13.
(2,3-Diflu or o-2,3-d ih yd r o-3-b e n zofu r a n yl)a ce t on i-
1
tr ile (6c) Tr a n s F or m : yellow oil; H NMR (CDCl
3
) δ 3.05
(m, 2H), 5.97 (d, 1H, J ) 60.01 Hz), 7.02 (d, 1H, J ) 8.08 Hz),
7.19 (dd, 1H, J ) 7.58, 7.42 Hz), 7.45 (dd, 1H, J ) 7.91, 7.58
Hz), 7.57 (d, 1H, J ) 7.42 Hz); 19F NMR δ -62.15 (dd, 1F, J )
+
61.03, 12.95 Hz), -88.99 (m, 1F); MS (m/z) 195 (M ), 155, 127,
(1:5). The R
f
values for the fluorination products of compound
7 2
120, 101, 75, 63, 51, 40. Anal. Calcd for C10H F NO: C, 61.54;
5
a (as a model example) (6a (cis), 6a (trans), and 7a (cis)) were
H, 3.62; N, 7.18. Found: C, 61.76; H, 3.51; N, 7.11.
0
.46, 0.74, and 0.80, respectively.
E t h yl (2,3-Diflu or o-2,3-d ih yd r o-3-b en zofu r a n yl)a ce-
2,3-Diflu or o-2,3-d ih yd r o-3-m eth ylben zofu r a n (6d ) Cis
1
F or m : colorless oil; H NMR δ 1.83 (dd, 3H, J ) 21.27, 4.45
1
ta te (6a ) Cis F or m : mp 54-55 °C; H NMR (CDCl
3
) δ 1.31
Hz), 6.10 (dd, 1H, J ) 60.18, 12.36 Hz), 7.06 (m, 2H), 7.40 (m,
(
3
7
t, 3H, J ) 7.25 Hz), 3.06 (ddd, 1H, J ) 34.95, 17.31, 3.79 Hz),
2H); 19F NMR δ -56.97 (dd, 1F, J ) 62.88, 16.65 Hz), -67.21
+
.45 (ddd, 1H, J ) 17.31, 10.06, 3.63 Hz), 4.42 (q, 2H, J )
.25 Hz), 6.51 (dd, 1H, J ) 57.87, 9.56 Hz), 7.07 (m, 2H), 7.41
(m, 1F); MS (m/z) 170 (M ), 155, 122, 96, 75, 63, 51. Anal. Calcd
for C
9
H
8
F
2
O: C, 63.53; H, 4.74. Found: C, 63.38; H, 4.85.
J . Org. Chem, Vol. 69, No. 16, 2004 5305

Dawood and Fuchigami
2
,3-Diflu or o-2,3-dih ydr o-3-m eth ylben zofu r an (6d) Tr an s
1H, J ) 8.10, 7.58 Hz), 7.51 (d, 1H, J ) 7.58 Hz); 19F NMR δ
1
13
F or m : colorless oil; H NMR δ 1.80 (dd, 3H, J ) 21.10, 1.35
-41.75 (dd, J ) 59.18, 5.55 Hz); C NMR (DEPT) δ 14.30
Hz), 6.10 (dd, 1H, J ) 61.99, 1.86 Hz), 7.06 (m, 2H), 7.36 (m,
3 2
(CH ), 61.01 (CH ), 108.62 (d, CH, J ) 232.51 Hz), 111.38,
1
9
2
(
H); F NMR δ -62.24 (dd, 1F, J ) 61.04, 13.13 Hz), -84.55
114.07, 122.33, 122.72, 133.96 (CH), 121.49, 122.74, 161.57,
+
+
m, 1F); MS (m/z) 170 (M ), 155, 127, 122, 101, 96, 75, 63, 51.
169.50 (C); MS (m/z) 222 (M ), 193, 177, 149, 101, 84. Anal.
Eth yl (2-F lu or o-3-h yd r oxy-2,3-d ih yd r o-3-ben zofu r a n -
Calcd for C12
4.97.
3
H11FO : C, 64.86; H, 4.99. Found: C, 64.81; H,
1
yl)a ceta te (7a ) Cis F or m : yellow oil; H NMR δ 1.33 (t, 3H,
J ) 7.25 Hz), 2.95 (dd, 1H, J ) 17.47, 3.95 Hz), 3.15 (dd, 1H,
J ) 17.47, 5.44 Hz), 4.28 (q, 2H, J ) 7.25 Hz), 4.42 (s, 1H),
(2-F lu or o-2-h yd r oben zofu r a n -3-ylid en e)a ceton e (8b):
1
mp 79-80 °C; H NMR (CDCl ) δ 2.39 (s, 3H), 6.78 (d, 1H, J
3
6
2
.16 (d, 1H, J ) 61.66 Hz), 6.97-7.10 (m, 2H), 7.32-7.38 (m,
) 5.44 Hz), 7.03 (m, 2H), 7.16 (d, 1H, J ) 56.88 Hz), 7.41 (dd,
1
9
13
19
H); F NMR δ -50.71 (ddd, J ) 61.03, 5.55, 3.70 Hz);
), 37.63 (d, CH , J ) 7.27 Hz), 61.53
), 111.15, 116.88 (d, J ) 239.22 Hz), 122.75, 123.85, 131.26
C
1H, J ) 8.08, 7.58 Hz), 7.52 (d, 1H, J ) 7.75 Hz); F NMR δ
-42.44 (dd, J ) 57.34, 5.55 Hz); 13C NMR (DEPT) δ 31.51
NMR (DEPT) δ 14.13 (CH
CH
CH), 80.12, 127.24, 158.28, 172.58 (C); MS (m/z) 240 (M ),
20 (M - HF), 204, 146, 133, 118, 105, 91, 77. Anal. Calcd
for C12 : C, 60.00; H, 5.45. Found: C, 60.20; H, 5.54.
-(2-F lu or o-3-h yd r oxy-2,3-d ih yd r o-3-ben zofu r a n yl)-2-
3
2
(
(
2
2
(CH ), 106.90, 110.31, 111.37, 121.05 (d, J ) 221.34 Hz),
3
+
122.26, 134.01 (CH), 119.58, 121.33, 146.51, 161.98, 195.92 (C);
+
+
MS (m/z) 192 (M ), 177, 149, 131, 115, 101, 75, 43. Anal. Calcd
H
13FO
4
for C H FO : C, 68.74; H, 4.72. Found: C, 68.44; H, 4.76.
1
1
9
2
1
(
2-F lu or o-2-h yd r ob en zofu r a n -3-ylid en e)a cet on it r ile
1
p r op a n on e (7b) Cis F or m : yellow oil; H NMR δ 1.68 (s,
1
(
8c): mp 98-99 °C; H NMR (CDCl
Hz), 6.51 (d, 1H, J ) 63.14 Hz), 7.04 (d, 1H, J ) 8.25 Hz),
.16 (dd, 1H, J ) 7.75, 7.58 Hz), 7.49 (dd, 1H, J ) 8.07, 7.75
3
) δ 5.68 (d, 1H, J ) 5.77
3
4
7
H), 2.99 (d, 1H, J ) 13.85 Hz), 3.15 (d, 1H, J ) 15.66 Hz),
.51 (s, 1H), 6.17 (d, 1H, J ) 62.65 Hz), 6.98-7.12 (m, 2H),
7
1
9
.39-7.51 (m, 2H); F NMR δ -49.87 (d, J ) 62.88 Hz); MS
19
Hz), 8.12 (d, 1H, J ) 7.58 Hz); F NMR δ -39.01 (dd, J )
6
8
+
(
m/z) 210 (M ), 192, 181, 175, 149, 131, 115, 101, 77, 43. Anal.
Calcd for C11 : C, 62.85; H, 5.27. Found: C, 62.71; H,
.34.
-F lu or o-3-h yd r oxy-2,3-d ih yd r o-3-m et h ylb en zofu r a n
+
2.88, 5.55 Hz); MS (m/z) 175 (M ), 156, 149, 127, 120, 100,
7, 75, 63, 50. Anal. Calcd for C10 FNO: C, 68.57; H, 3.45,
H
11FO
3
H
6
5
N, 8.00. Found: C, 68.79; H, 3.61; N, 7.65.
2
Syn th esis of Eth yl (2-P ip er id yl-2-h yd r oben zofu r a n -3-
ylid en e)a ceta te (10). To a solution of the ethyl (2-fluoro-2-
hydrobenzofuran-3-ylidene)acetate (8a ) (1 mmol) in dry ace-
tonitrile (10 mL) was added piperidine (0.22 mL, 2.2 mmol).
The reaction mixture was heated under reflux for 2 h and then
left to cool to room temperature. The crude oily product was
passed through silica gel column chromatography using a
hexane/ethyl acetate mixture (5:1) as the eluent to afford the
corresponding piperidyl benzofuranylidene derivative 10 as a
1
(
4
(
7d ) Cis F or m : mp 66-67 °C; H NMR δ 1.66 (d, 3H, J )
.28 Hz), 2.18 (s, 1H), 5.92 (d, 1H, J ) 61.83 Hz), 6.90-7.08
1
9
m, 2H), 7.29-7.35 (m, 2H); F NMR δ -52.27 (dm, J ) 81.03
13
Hz); C NMR (DEPT) δ 19.10 (CH
3
, d, J ) 6.71 Hz), 111.18,
1
1
6
6
17.42 (d, J ) 240.35 Hz), 122.80, 123.19, 131.02 (CH), 79.70,
+
29.66, 157.99 (C); MS (m/z) 168 (M ), 153, 133, 105, 91, 77,
5, 51. Anal. Calcd for C
4.29; H, 5.19.
9 9 2
H FO : C, 64.28; H, 5.39. Found: C,
Dir ect An od ic Syn th esis of Com p ou n d 7a . Potentio-
static electrolysis of 5a (1 mmol) was performed in a 0.3 M
solution of Et NF‚4HF in acetonitrile (20 mL) containing water
0.5 mL). The electrolysis was conducted in an undivided cell
yellow oil: 1H NMR (CDCl
3
) δ 1.25 (t, 3H, J ) 7.25 Hz), 1.37-
.47 (m, 2H), 1.52-1.63 (m, 4H), 2.41-2.60 (m, 4H), 4.20 (q,
H, J ) 7.25 Hz), 4.80 (d, 1H, J ) 0.82 Hz), 7.26 (m, 2H), 7.45
1
2
4
(
(dd, 1H, J ) 7.42, 1.32 Hz), 7.66 (s, 1H), 7.81 (dd, 1H, J )
in open air at room temperature. The electrolysis was applied
until the starting substrate 5a was completely consumed
monitored by TLC and GC-MS). The reaction mixture was
passed through silica gel column chromatography using hex-
ane/ethyl acetate eluent (5:1) to give only one product. Spectral
data and elemental analysis were completely consistent with
compound 7a .
13
7
5
1
.58, 1.48 Hz); C NMR (DEPT) δ 14.35 (CH
1.70, 60.77 (CH ), 65.24, 111.25, 121.18, 122.50, 124.30,
43.68 (CH), 115.95, 127.12, 155.16, 170.48 (C); MS (m/z) 288
3
), 24.27, 26.20,
2
(
+
+
(M
+ 1), 287 (M ), 222, 214, 131, 84. Anal. Calcd for C17
: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.74; H, 7.26; N,
.74.
21
H -
NO
4
3
Deh ydr oflu or in ation of cis-2,3-Dih ydr oben zofu r an De-
r iva tives 6a -c. To a stirred solution of the appropriate
benzofuran derivative 7a -c (1 mmol) in dry acetonitrile (10
mL) was added piperidine (0.12 mL, 1.2 mmol). The reaction
mixture was stirred at room-temperature overnight. After the
precipitated piperidyl hydrofluoride salt was removed by
filtration, the filtrate was evaporated under vacuum. The solid
product thus formed was recrystallized from hexane/ethyl
acetate (3:1) to afford the corresponding pure benzofura-
nylidene derivatives 8a -c.
Ack n ow led gm en t. This work was supported by
Grant-in-Aid for Scientific Research on Priority Area (A)
Exploitation of Multi-Element Cyclic Molecules” from
the Ministry of Education, Culture, Sports, Science and
Technology, J apan. K.M.D. is greatly indebted to the
J SPS for awarding him a postdoctoral fellowship (1999-
2001).
“
Su p p or tin g In for m a tion Ava ila ble: General part and
general experimental method. This material is available free
of charge via the Internet at http://pubs.acs.org.
Eth yl (2-F lu or o-2-h yd r oben zofu r a n -3-ylid en e)a ceta te
1
(
8a ): mp 70-71 °C; H NMR (CDCl
3
) δ 1.35 (t, 3H, J ) 7.25
Hz), 4.29 (q, 2H, J ) 7.25 Hz), 6.44 (dd, 1H, J ) 5.60, 1.32
Hz), 7.04 (m, 2H), 7.20 (dd, 1H, J ) 58.36, 1.32 Hz), 7.41 (dd,
J O035871G
5
306 J . Org. Chem., Vol. 69, No. 16, 2004