Electrolytic partial flourination of organic compounds. 55. Highly regio- and stereoselective anodic monoflourination of 2,3-dihydrochroman-4-one and chromone derivatives

Article abstract of DOI:10.1021/jo0105437

Anodic monoflourination at the position α to the oxygen atom of the (E)-3-benylidene-2,3-dihydrochroman-4-one derivatives was successfully carried out to provide the corresponding 2-flourochromanones selectively. This is the first regioselective electrochemical flourination of fused-type, oxygen-containing heterocyclic compounds. Anodic flourination of a chromone derivative also gave a similar flourinated chromanone stereoselectively.

Full text of DOI:10.1021/jo0105437

J . Org. Chem. 2001, 66, 7691-7695
7691
Electr olytic P a r tia l F lu or in a tion of Or ga n ic Com p ou n d s. 55.1
High ly Regio- a n d Ster eoselective An od ic Mon oflu or in a tion of
2
,3-Dih yd r och r om a n -4-on e a n d Ch r om on e Der iva tives
Kamal M. Dawood†,‡ and Toshio Fuchigami*,†
Department of Electronic Chemistry, Tokyo Institute of Technology, 4259 Nagatsuta,
Midori-ku, Yokohama 226-8502, J apan, and Department of Chemistry, Faculty of Science,
Cairo University, Giza, Egypt
fuchi@echem.titech.ac.jp
Received May 29, 2001
Anodic monofluorination at the position R to the oxygen atom of the (E)-3-benzylidene-2,3-dihy-
drochroman-4-one derivatives was successfully carried out to provide the corresponding 2-fluoro-
chromanones selectively. This is the first regioselective electrochemical fluorination of fused-type,
oxygen-containing heterocyclic compounds. Anodic fluorination of a chromone derivative also gave
a similar fluorinated chromanone stereoselectively.
In tr od u ction
synthetic routes to fluorinated heterocycles. The advan-
tageous electrochemical method has been profoundly
proven to be more applicable than the conventional,
The chroman-4-one moiety is an integral part of many
natural products. Chroman-4-one derivatives have also
2
hazardous chemical methods.1
0-12
Recently, we developed
drawn much attention due to their anti-human-immu-
1
3
the selective anodic fluorination of flavones and aryl-
thioethylenecarbonates14 as examples of oxygen-contain-
ing heterocycles. Crown ethers were also anodically
fluorinated; however, R,ω-difluoro products due to ring
opening were formed. On the other hand, furan, ben-
zofuran,16 and morpholines were anodically fluorinated;
however, their fluorinated products were either not
isolable due to their instability or isolable in very poor
yields with low selectivity.
3
nodeficiency-virus (HIV-1), that causes acquired immune
4
deficiency syndrome, and broad pharmacological activi-
ties. Moreover, the biological potency of fluorinated
heterocycles has been widely documented.5
-95-9
There-
1
5
fore, considerable efforts have been paid to explore new
17
*
To whom correspondence should be addressed. Tel/Fax: +81-45-
9
24-5406.
†
Tokyo Institute of Technology.
‡
Cairo University.
(
1) Part 54: Dawood, K. M.; Ishii, H.; Fuchigami, T. J . Org. Chem.
These results prompted us to conduct, for the first time,
a successful highly regioselective anodic direct fluorina-
tion at the position R to the ring oxygen atom of the
2
001, 66, 7030.
2) (a) Pohler, P.; Tamm, C. Tetrahedron Lett. 1967, 3479. (b)
(
Sidwell, W. T. L.; Tamm, C. Tetrahedron Lett. 1970, 475. (c) Mcpherson,
D. D.; Cordell, G. A.; Soejarto, D. D.; Pezzuto, J . M.; Fong, H. H. S.
Phytochemistry 1983, 22, 2835. (d) Chenera, B.; West, M. L.; Finkel-
stein, J . A.; Dreyer, G. B. J . Org. Chem. 1993, 58, 5605. (e) Tsui, W.
Y.; Brown, G. D. Phytochemistry 1996, 43, 871. (f) Crouch, N. R.;
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Bangani, V.; Crouch, N. R.; Mulholland, D. A. Phytochemistry 1999,
1
8
biologically active chroman-4-one derivatives 2a -c.
Resu lts a n d Discu ssion
Syn th esis of Sta r tin g Ch r om a n -4-on e a n d Ch r o-
m on e Der iva tives 2 a n d 3. When an equimolar amount
of chroman-4-one (1) and the appropriate aromatic alde-
hyde were heated at 80-90 °C, in the presence of a cat-
alytic amount of piperidine, the corresponding (E)-3-ben-
5
1, 947.
3) (a) Flavin, M. T.; Rizzo, J . D.; Khilevich, A.; Kucherenko, A.;
(
Sheinkman, A. K.; Vilaychack, V.; Lin, L.; Chen, W.; Greenwood, E.
M.; Pengsuparp, T.; Pezzuto, J . M.; Hughes, S. H.; Flavin, T. M.;
Cibulski, M.; Boulanger, W. A.; Shone, R. L.; Xu, Z. Q. J . Med. Chem.
1
996, 39, 1303. (b) Xu, Z. Q.; Bucheit, R. W.; Stup, T. L.; Flavin, M.
1
9
T.; Khilevich, A.; Rezzo, J . D.; Lin, L.; Zembower, D. E. Bioorg. Med.
Chem. Lett. 1998, 8, 2179. (c) Ishikawa, T.; Oku, Y.; Tanaka, T.;
Kumamoto, T. Tetrahedron Lett. 1999, 40, 3777.
zylidene-2,3-dihydrochroman-4-one derivatives 2a -c
were obtained in good yields. However, heating of 1 with
(
4) (a) Al-Nakib, T.; Bezjak, V.; Meegan, M. J .; Chandy, R. Eur. J .
Med. Chem. 1990, 25, 455. (b) Kataoka, K. I.; Shiota, T.; Takeyasu,
T.; Muchizuki, T.; Taneda, K.; Ota, M.; Hanabe, H.; Yamaguchi, Y. J .
Med. Chem. 1995, 38, 3174. (c) Bruno, O.; Schenone, S.; Ranise, A.;
Bondavilli, F.; D ´ı Amico, M.; Filippili, W.; Berrino, L.; Rossi, F. Farmaco
996, 51, 137. (d) Harlow, G. R.; Halpert, J . R. J . Biol. Chem. 1997,
72, 5396. (e) Kitajima, J .; Ishikawa, T.; Tanaka, Y.; Ida, Y. Chem.
(9) Hiyama, T. Organofluorine Compounds: Chemistry and Ap-
plications; Springer: Berlin, 2000.
(10) Fuchigami, T. In Advances in Electron-Transfer Chemistry;
Mariano, P. S., Ed.; J AI Press: Greenwich, CT, 1999; Vol. 6.
(11) Fuchigami, T.; Higashiya, S.; Hou, Y.; Dawood, K. M. Rev.
Heteroat. Chem. 1999, 19, 67.
1
2
Pharm. Bull. 1999, 47, 1448.
5) Walker, S. B. Fluorine Compounds as Agrochemicals; Fluoro-
chem Limited: Glossop, 1989.
6) (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;
(12) Fuchigami, T. In Organic Electrochemistry, 4th ed.; Lund, H.,
Hammerich, O., Eds.; Dekker: New York, 2001; pp 1035-1050.
(13) Hou, Y.; Higashiya, S.; Fuchigami, T. J . Org. Chem. 1999, 64,
3346.
(14) Ishii, H.; Yamada, N.; Fuchigami, T. Chem. Commun. 2000,
1617.
(15) (a) Hou, Y.; Fuchigami, T. Tetrahedron Lett. 1999, 40, 7819.
(b) Ishii, H.; Hou, Y.; Fuchigami, T. Tetrahedron 2000, 56, 8877.
(16) Meurs, J . H.; Eilenberg, W. Tetrahedron 1991, 47, 705.
(17) Gambaretto, G. B.; Napoli, M.; Franccaro, C.; Conte, L. J . J .
Fluorine Chem. 1982, 19, 427.
(18) Dawood, K. M.; Fuchigami, T. Tetrahedron Lett. 2001, 42, 2513.
(19) Levai, A.; Schag, J . B. Pharmazie 1979, 34, 749.
(
(
(
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.
7) Yoshioka, H.; Nakayama, C.; Matsuo, N. J . Synth. Org. Chem.
J pn. 1984, 42, 809.
8) Narizuka, S.; Fuchigami, T. Bioorg. Med. Chem. Lett. 1995, 5,
293.
(
(
1
1
0.1021/jo0105437 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

7
692 J . Org. Chem., Vol. 66, No. 23, 2001
Dawood and Fuchigami
Sch em e 1
Ta ble 2. An od ic F lu or in a tion of
E)-3-Ben zylid en e-2,3-d ih yd r och r om a n -4-on es (2a -c)
(
supporting
run substrate electrolyte/solvent
charge passed
(F/mol)
yield
(%)
a
b
1
2
3
4
5
6
7
8
9
0
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
Et4NF‚4HF/DMEc
Et4NF‚4HF/DME
Et4NF‚4HF/MeCN
Et4NF‚4HF/CH2Cl2
Et4NF‚4HF (neat)
Et4NF‚3HF/DME
Et3N‚4HF/DME
6.5
5.5
3.0
3.0
6.0
7.0
8.5
8.5
7.0
6.5
72 (64)
d
17
21
27
0
68
52
35
b
b
e
b
b
b
Et3N‚3HF/DME
b
b
Et4NF‚4HF/DME
Et4NF‚4HF/DME
60 (56)
59 (58)
1
a
Calculated on the basis of 19NMR, and the figures in paren-
b
theses are isolated yields. A small amount of an unidentified
product was formed. c An undivided cell was used. d A considerable
amount of an unidentified, insoluble white polymeric product was
formed. e The starting material 2a was completely recovered.
Ta ble 1. Oxid a tion P oten tia ls (Ep ox) of Sta r tin g
Su bstr a tes
(4a ) on the basis of its elemental analysis and spectral
data. Therefore, a fluorine atom attacks selectively the
position R to the ring oxygen atom of 2a to furnish 4a in
moderate to good yields. Among various electrolytic
conditions, the use of Et
run 1) was the most effective for the formation of the
fluorinated product 4a .
An undivided cell was not suitable for the anodic
synthesis of 4a (run 2). In this case, the fluorination yield
decreased drastically due to the formation of an undesir-
able, insoluble white polymeric product. Other electrolytic
solvents such as acetonitrile (run 3) or hardly oxidizable
dichloromethane (run 4) were also not effective, and the
4
NF‚4HF/DME in a divided cell
compd. no.
Ar
Epox (V vs SSCE)a
(
1
2.10
2.01
2.08
2.06
2.17
2
2
2
3
a
b
c
C6H5
4-ClC6H4
4-BrC6H4
4-ClC6H4
a
In 0.1 M Bu4N‚BF4/MeCN. Sweep rate: 100 mV s-1
.
Sch em e 2
commonly reported acetamidation during fluorination of
olefines2
0,21
was not observed at all. Anodic fluorination
did not proceed under neat conditions (run 5), and the
starting material 2a was completely recovered. When
DME was used, a large excess amount of electricity was
required due to the simultaneous oxidation of DME and
2
. Even when a large excess amount of electricity was
passed, no difluorinated product was formed at all (runs
and 8). This can be explained as follows: DME has a
7
4
-chlorobenzaldehyde at 170 °C resulted in the direct
higher ability to solvate the cationic part of fluoride salts
to enhance the nucleophilicity of fluoride ions, and the
formation of 3-(4-chlorobenzyl)chromone (3) in good yield
as shown in Scheme 1.
overoxidation of the products is suppressed by the
Oxidation P oten tials of Ch r om an -4-on e an d Ch r o-
22-24
oxidation of DME itself during the electrolysis.
A
ox
m on e Der iva tives. The oxidation peak potentials (E
p
)
possible mechanism for regioselective monofluorination
of 2a is depicted in Scheme 3. Initial electron transfer is
assumed to take place at the olefin moiety of 2a to give
the radical cation A which undergoes deprotonation and
further electron transfer to give the carbocation B. It was
reported that isomerization occurs readily when the
migrating double bond moves into conjugation with an
of chroman-4-one and chromone derivatives 1, 2a -c, and
were measured by cyclic voltammetry using a divided
cell at a platinum anode in 0.1 M Bu /anhydrous
3
4
N‚BF
4
acetonitrile. These oxygen-containing heterocycles ex-
hibited irreversible oxidation peaks, and all the values
of E
ox
p
are higher than 2 V versus the standard saturated
calomel electrode (SSCE) as listed in Table 1. Interest-
ingly, 2b is more easily oxidized than 3, and 2a -c have
lower oxidation potentials than 1, which means that the
electron transfer may take place from the olefin moiety
rather than from oxygen.
An od ic F lu or in a tion of Ch r om a n -4-on e Der iva -
tives 2a -c. Constant current anodic oxidation of (E)-3-
benzylidene-2,3-dihydrochroman-4-one (2a ), as a model
compound, was conducted using appropriate fluoride
salts in dimethoxyethane (DME) and acetonitrile (MeCN).
As shown in Scheme 2 and Table 2, highly regioselective
anodic monofluorination proceeded, and only one fluori-
nated product was obtained regardless of the electrolytic
conditions used. The fluorinated product was ascertained
as (E)-3-benzylidene-2,3-dihydro-2-fluorochroman-4-one
25
aromatic benzene nucleus. Therefore, it is conceivable
that intermediate B isomerizes into C, followed by the
predominant reaction of a fluoride ion with the cationic
intermediate C to give 4a . Benzylic nucleophilic substitu-
tion easily takes place; however, there was no evidence
for the formation of the benzylic fluorinated product 5a .
(20) Childs, W. V.; Christenen, L.; Klink, F. W.; Koipin, C. F. In
Organic Electrochemistry, 3rd ed.; Lund, H., Baizer, M. M., Eds.; Mercel
Dekker: New York, 1991; Chapter 24.
(
(
21) Zupan, M.; Skulj, P.; Stavber, S. Chem. Lett. 1998, 641.
22) Dawood, K. M.; Higashiya, S.; Hou, Y.; Fuchigami, T. J .
Fluorine Chem. 1999, 93, 159.
(23) Dawood, K. M.; Fuchigami, T. J . Org. Chem. 1999, 64, 138.
(24) Hou, Y.; Fuchigami, T. J . Electrochem. Soc. 2000, 147, 4567.
(25) Andrieux, J .; Barton, D. H. R.; Patin, H. J . Chem. Soc., Perkin
Trans. 1 1977, 359.

Electrolytic Fluorination of Organic Compounds
J . Org. Chem., Vol. 66, No. 23, 2001 7693
Sch em e 3
Sch em e 4
Ta ble 3. An od ic F lu or in a tion of
To generalize this interesting finding, we extended the
anodic fluorination to other chroman-4-one derivatives
3
-(4-Ch lor oben zyl)ch r om on e (3)
supporting electrolyte/
solvent
charge passeda
(F/mol)
yield
(%)
2
b,c, and similar results were obtained as shown in Table
b,c
run
2
(runs 9 and 10). In both cases, a fluorine atom was
1
2
3
Et4NF‚4HF/DME
Et4NF‚4HF/MeCN
Et3N‚4HF/DME
12
4.5
10
20
6
18
inserted regioselectively at the position R to the ring
oxygen atom of 2b,c to afford the corresponding 2-fluo-
rochroman-4-ones 4b,c in moderate yields as shown in
Scheme 2.
N-Fluoropyridinium salts are well known as powerful
reagents for chemical fluorinations.26,27 However, the
reaction of N-fluoro-2,6-dichloropyridinium triflate (6)
with the chromanone derivative 2a in dichlorometh-
ane at either room temperature or refluxing conditions
was unsuccessful, and 2a was completely recovered
a
-2
Constant current electrolysis (6 mA cm ) using a divided cell
was applied. b Calculated on the basis of F NMR. 3-(4-Chlo-
robenzylidene)-1-benzopyran-2,4-dione (7) as a byproduct was
isolated in 10-14% yield.
19
c
(Scheme 4).
An od ic F lu or in a tion of 3-(4-Ch lor oben zyl)ch r o-
m on e (3). Furthermore, anodic fluorination of 3-(4-chloro-
benzyl)chromone (3) was similarly attempted, and the
results are outlined in Table 3. Interestingly, we found
that the anodic fluorination of 3 offers stereoselective
Sch em e 5
access to 4b (Scheme 5). When Et
4
NF‚4HF/DME and
Et N‚4HF/DME in a divided cell were employed, 4b was
3
obtained in reasonable yield (runs 1 and 3). Since the
oxidation potential of 3 is rather high (2.17 V vs SSCE),
acetonitrile was expected to give much better results than
DME; however, acetonitrile was not effective (run 2). In
all cases, an appreciable amount of 3-(4-chlorobenzyli-
dene)-1-benzopyran-2,4-dione (7) was isolated as a byprod-
uct (cf. Experimental Section). Formation of 4b from 3
is in sharp contrast to our previous report for the anodic
fluorination of flavones.13 In the case of flavones, 3-fluo-
roflavone and 2,3-difluoroflavanone derivatives were
formed as shown in Scheme 6. In this work, the expected
fluorinated products 8 and 9, however, were not detected
at all. Thus, anodic fluorination of chromanone 2b and
homoisoflavone 3 provided the same regioselectively
monofluorinated product 4b having the same stereose-
lectivity with respect to the olefin moiety. This result is
quite interesting from the mechanistic point of view. A
proposed mechanism for the anodic synthesis of 4b from
3 is outlined in Scheme 7. A fluoride ion is assumed to
attack the radical cation D to form E, which is further
oxidized to give the fluorocarbocation F , followed by
elimination of a proton from the benzylic methylene
2
8
group of F to afford the thermodynamically more stable
2-fluorochroman-4-one derivative 4b rather than its
9
isomer. The E form of 3-benzylidene-2,3-dihydrochro-
man-4-one (2a ) is normally predominant over its Z
form.2
9,30
For this reason, stereoselective synthesis of 4b
from 3 is consequently quite reasonable.
(
26) Umemoto, T.; Tomizawa, G. Bull. Chem. Soc. J pn. 1986, 59,
625.
27) Umemoto, T.; Tomizawa, G. J . Org. Chem. 1995, 60, 6563.
3
(
(28) Hoshino, Y.; Takeno, N. Bull. Chem. Soc. J pn. 1994, 67, 2873.

7
694 J . Org. Chem., Vol. 66, No. 23, 2001
Dawood and Fuchigami
Sch em e 6
Sch em e 7
1
13
Sch em e 8
shifts for H NMR and C NMR are given in δ ppm downfield
19
from internal TMS, and the chemical shifts for F NMR are
given in δ ppm downfield from internal C [δ (CFCl ) of the
6
F
6
3
6 6
C F reference is -162.2 ppm]. The 3-benzylidene-2,3-dihy-
drochroman-4-one 2a -c derivatives were synthesized follow-
ing the known reported procedure.19
Syn th esis of 3-(4-Ch lor oben zyl)ch r om on e (3). To a
mixture of 4-chromanone (1) (1.48 g, 10 mmol) and 4-chlo-
robenzaldehyde (1.4 g, 10 mmol) was added a catalytic amount
of piperidine (0.5 mL). The reaction mixture was heated under
reflux at 170 °C for 2 h and then cooled. The solid product
was recrystallized from ethanol to give 3 in 1.59 g (59%) yield.
Finally, the synthetic application of the 2-fluorochro-
man-4-one derivative 4b was also attempted. Thus, treat-
ment of 4b with piperidine in acetonitrile at room tem-
perature furnished the 2-piperidylchroman-4-one deriva-
tive 10 in an excellent yield as shown in Scheme 8.
1
mp 131-132 °C. H NMR: δ 3.78 (s, 2H), 7.25-7.44 (m, 6H),
7
2
1
.62 (m, 1H), 7.66 (s, 1H), 8.22 (d, 1H, J ) 8.08 Hz). MS (m/z):
+
+
+
+
72 (M + 2), 271 (M + 1), 270 (M ), 269 (M - 1), 249, 207,
49, 134, 121, 105, 77. Anal. Calcd for C16 : C, 70.99;
H
11ClO
2
Con clu sion s
H, 4.10. Found: C, 71.19; H, 4.26.
An odic Flu or in ation of Ch r om an -4-on e an d Ch r om on e
In conclusion, we have developed two anodic stereo-
selective routes for direct fluorination at the position R
to the ring oxygen atom of chroman-4-ones. This is the
first report of successful regioselective electrochemical
direct fluorination of fused-type, oxygen-containing het-
erocyclic compounds. The methodology seems to be of
potential synthetic value.
-
2
Der iva tives. Constant current electrolysis (6 mA cm ) was
2
conducted at a platinum anode and cathode (2 × 2 cm ) in a
solution of an appropriate fluoride salt (0.3 M) in dimethoxy-
ethane (30 mL) to which chromanone 2 or chromone 3
derivative (1 mmol) was added. An H-type divided cell with a
glass membrane under a nitrogen atmosphere at ambient
temperature was used, and the electrolysis was carried out
until the starting substrate was almost completely consumed.
After the electrolysis was complete, the fluoride salts were
removed by passing the resulting electrolytic solution through
a short column on silica gel using ethyl acetate as an extracting
eluent. The collected solution was evaporated under vacuum.
The yield of the fluorinated product was then calculated on
the basis of the 19F NMR spectrum using a certain amount of
monofluorobenzene as an internal standard, where the yield
was calculated on the basis of the integral ratios between the
monofluorobenzene and the resulted fluorinated product.
Exp er im en ta l Section
1H NMR, 19F NMR, and 13C NMR spectra were recorded at
2
3
70, 254, and 68 MHz, respectively, in CDCl . The chemical
(
29) Keane, D. D.; Marathe, K. G.; O’Sullivan, W. I.; Philbin, E. M.;
Simons, R. M.; Teague, P. C. J . Org. Chem. 1970, 35, 2286.
30) Bennett, P.; Donnelly, J . A.; Meaney, D. C.; O’Boyle, P. J . Chem.
Soc., Perkin Trans. 1 1972, 1554.
(

Electrolytic Fluorination of Organic Compounds
J . Org. Chem., Vol. 66, No. 23, 2001 7695
Finally, the product was purified through long-column chro-
matography on silica gel using a hexane/ethyl acetate eluent
mixture (5:1).
3-(4-Ch lor oben zylid en e)-1-ben zop yr a n -2,4-d ion e (7).
1
mp 162-163 °C (EtOH). H NMR (CDCl
3
): δ 7.42-7.57 (m,
4H), 7.73-7.81 (m, 3H), 8.25 (dd, 1H, J ) 7.92, 1.65 Hz), 8.33
(s, 1H). 13C NMR (CDCl
): δ 118.31, 124.76, 124.85, 126.21,
126.38, 128.68, 130.91, 134.50, 135.47, 139.87, 155.99, 159.06,
(
E )-3-Be n zylid e n e -2,3-d ih yd r o-2-flu or och r om a n -4-
3
1
on e (4a ). mp 69-70 °C. H NMR: δ 6.76 (d, 1H, J ) 45.20
+
+
Hz), 7.33-7.49 (m, 7H), 7.63 (dd, 1H, J ) 8.58, 7.26 Hz), 7.96
174.61, 190.73. MS (m/z): 286 (M + 2), 285 (M + 1), 284
1
3
+
(
(
1
1
(
s, 1H), 8.17 (d, 1H, J ) 7.92 Hz). C NMR (CDCl
3
): δ 87.75
(M ), 254, 252, 234, 176. Anal. Calcd for C H ClO : C, 67.50;
1
6
9
3
d, J ) 173.3 Hz), 118.06, 123.77, 124.06, 125.33, 125.71,
H, 3.19. Found: C, 67.58; H, 3.41.
-(4-Ch lor ob en zylid en e)-2-(1-p ip er id yl)-2,3-d ih yd r o-
ch r om a n -4-on e (10). To a solution of the 2-fluorochroman-
-one derivative 4b (0.144 g, 0.5 mmol) in acetonitrile (10 mL)
26.19, 128.44, 128.68, 133.87, 137.48, 137.79, 153.53, 153.69,
3
1
9
56.15, 175.54. F NMR: δ -101.40 (d, J ) 45.04 Hz). MS
+
+
m/z): 254 (M ), 234 (M - HF), 205, 178, 133, 117, 92, 76.
4
Anal. Calcd for C16
H, 4.55.
2
H11FO : C, 75.58; H, 4.36. Found: C, 75.92;
was added piperidine (0.1 mL, 1 mmol). The reaction mixture
was stirred at room temperature for 12 h. After the reaction
was complete, the solvent was evaporated under vacuum, and
the residue was passed through column chromatography using
(
E)-3-(4-Ch lor oben zylid en e)-2,3-d ih yd r o-2-flu or och r o-
1
m a n -4-on e (4b). mp 93-94 °C. H NMR (CDCl
3
): δ 6.69 (d,
H, J ) 45.19 Hz), 7.29-7.42 (m, 6H), 7.62 (dd, 1H, J ) 8.58,
.93 Hz), 7.98 (s, 1H), 8.14 (d, 1H, J ) 7.91 Hz). 13C NMR
) (DEPT): δ 87.25 (d, J ) 173.3 Hz), 118, 125.33, 125.53,
27.6, 127.7, 128.53, 133.89, 153.15, 153.33 (CH’s), 123.29,
1
6
(
1
1
-
+
hexane/ethyl acetate (3:1) to afford 0.16 g (91%) of 10. mp
1
5
4
7
1
1
3
9-60 °C. H NMR: δ 1.46-1.58 (m, 6H), 2.36-2.43 (m, 4H),
CDCl
3
.74 (s, 1H), 7.23-7.44 (m, 7H), 7.60-7.66 (dd, 1H, J ) 8.4,
13
.1 Hz), 8.16 (s, 1H). C NMR: δ 24.65, 26.32, 53.03, 64.49,
1
9
23.6, 134.44, 136.17, 156.04, 175.33 (C’s). F NMR:
δ
17.96, 124.96, 125.24, 125.86, 128.43, 129.53, 133.35, 139.70,
+
+
102.50 (d, J ) 45.04 Hz). MS (m/z): 290 (M + 2), 289 (M
+
+
54.30, 155.97, 176.58. MS (m/z): 354 (M + 1), 353 (M ), 352,
+
+
1), 288 (M ), 268 (M - HF), 233, 205, 176, 149, 121, 83.
11, 298, 269, 234, 177, 121, 84. Anal. Calcd for C21 20ClNO :
H
2
Anal. Calcd for C16
H
10ClFO : C, 66.56; H, 3.49. Found: C,
2
C, 71.28; H, 5.70; N, 3.69. Found: C, 71.61; H, 5.98; N, 3.82.
6
6.74; H, 3.77.
E)-3-(4-Br om oben zylid en e)-2,3-d ih yd r o-2-flu or och r o-
(
1
m a n -4-on e (4c). mp 80-81 °C. H NMR (CDCl
1
3
): δ 6.69 (d,
Ack n ow led gm en t. We thank the J apan Society for
the Promotion of Science (J SPS) for financial support
(Grant-in-Aid for Scientific Research No. 1299307 and
No. 13029034). K.M.D. is greatly indebted to the J SPS
for awarding him a postdoctoral fellowship (1999-2001).
H, J ) 45.19 Hz), 7.34-7.52 (m, 6H), 7.67 (dd, 1H, J ) 7.91,
1
9
6
-
+
.93 Hz), 7.99 (s, 1H), 8.17 (d, 1H, J ) 7.92 Hz). F NMR: δ
+
+
102.76 (d, J ) 45.04 Hz). MS (m/z): 334 (M + 2), 333 (M
+
1), 332 (M ), 314, 313, 312, 233, 205, 176, 126, 92, 83. Anal.
Calcd for C16
H, 3.25.
2
H10BrFO : C, 57.68; H, 3.03. Found: C, 57.59;
J O0105437