Facile synthesis of 1,7,8-trifluoro-2-naphthol via DMAP catalyzed cycloaromatization

Article abstract of DOI:10.1016/j.jfluchem.2013.11.005

A facile synthesis of 1,7,8-trifluoro-2-naphthol, an important synthetic intermediate for liquid crystal compounds with a 1,7,8-trifluoronaphthalene structure, was developed starting from 4-bromo-1,2-difluorobenzene via DMAP catalyzed intramolecular cycloaromatization in 51% overall yield for the 6 steps.

Full text of DOI:10.1016/j.jfluchem.2013.11.005

Journal of Fluorine Chemistry 157 (2014) 41–47
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Facile synthesis of 1,7,8-trifluoro-2-naphthol via DMAP catalyzed
cycloaromatization
a
b
a,
Keisuke Araki , Tomohiro Katagiri , Munenori Inoue *
a
Sagami Chemical Research Institute (SCRI), 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
b
Department of Applied Chemistry, Graduate School of Engineering, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile synthesis of 1,7,8-trifluoro-2-naphthol, an important synthetic intermediate for liquid crystal
compounds with a 1,7,8-trifluoronaphthalene structure, was developed starting from 4-bromo-1,2-
difluorobenzene via DMAP catalyzed intramolecular cycloaromatization in 51% overall yield for the 6
steps.
Received 18 October 2013
Received in revised form 2 November 2013
Accepted 4 November 2013
Available online 12 November 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
1
,7,8-Trifluoro-2-naphthol
Liquid crystal compounds
Deoxyfluorination
Suzuki–Miyaura vinylation
Intramolecular cycloaromatization
1
. Introduction
demonstrated an intermolecular cycloaromatization between
2
-(2,3-difluorophenyl)acetyl chloride and acetylene equivalents
such as acetylene, vinyl chloride, and (trimethylsilyl)acetylene in
the presence of AlCl to produce 7,8-difluoro-2-naphthol, which
Recently, many liquid crystal (LC) compounds for active matrix
liquid crystal displays (AM-LCDs) contain fluorine atoms. The
introduction of fluorine atoms into LC compounds dramatically
improve their physical properties, such as broadening the nematic
range, increasing the dielectric anisotropy value (De), and
decreasing the ion solvation ability, which are beneficial for high
performance AM-LCDs in terms of attaining wide view-angle, fast
switching time, and low power consumption [1]. During
exploration of laterally fluorinated LC compounds with large
negative dielectric anisotropy, Manero et al. first reported LC
compounds possessing a 1,7,8-trifluoronaphthalene moiety as a
novel core structure in 1995 [2]. Since then, Kusumoto et al. has
intensively developed their derivatives such as compounds A and
B (Fig. 1), exhibiting high absolute dielectric anisotropy values
3
was then fluorinated at the C-1 position with a N-fluoropyridinium
salt. Although these patent procedures are a straightforward way
to construct the 2-naphthol skeleton, it was difficult to avoid
difluorination at the C-1 fluorination step of 7,8-difluoro-2-
naphthol. Therefore, it was required to reduce the resulting over
fluorinated product (1,1,7,8-tetrafluoro-1,2-dihydronaphthalene-
4
2-one) by NaBH to the desired 1,7,8-trifluoro-2-naphthol (1) [4].
Since there still remains a requirement to improve the synthetic
method of 1, we initiated a project for the synthesis of 1. Herein, we
wish to disclose a facile synthesis of 1,7,8-trifluoro-2-naphthol (1)
from 4-bromo-1,2-difluorobenzene (4) via DMAP catalyzed
intramolecular cycloaromatization.
(
ꢀ7.5 for A) [3].
Most of LC compounds with the 1,7,8-trifluoronaphtahlene unit
2
. Results and discussion
have been synthesized from a common intermediate, 1,7,8-
trifluoro-2-naphthol (1), because 1 can be easily functionalized
to introduce alkyl, alkoxy, and aryl groups at the C2 and C6
positions [4]. Several synthetic procedures for 1 were reported by
Kusumoto et al. [5a,5c] and Yokota et al. [5b] and they
Our synthetic plan for 1,7,8-trifluoro-2-naphthol (1) is outlined
in Scheme 1. The key element in this scheme consists of the
intramolecular cycloaromatization [6–9] of (2-vinylaryl)acetic
acid 2 that already contains three requisite fluorine atoms to
elaborate the core 2-naphthol structure. In this reaction, we
expected that activation of the carboxylic acid residue of 2 with
*
Corresponding author. Tel.: +81 467 77 4208; fax: +81 467 77 4113.
2 2
(COCl) or Ac O in the presence of a base would lead to
E-mail address: inoue@sagami.or.jp (M. Inoue).
intermediate I, which would give rise to 1 through intramolecular
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.11.005

4
2
K. Araki et al. / Journal of Fluorine Chemistry 157 (2014) 41–47
F
F
a) LDA; OHC-CO Et
2
8
1
F7
6
2
OH
in toluene (22%)
F
F
OH
CO Et
or THF (5%)
F
F
-
78~0 ºC, 1 h
2
1
F
F
F
F
Br
b) LDA; (EtO
-78 ºC, 15 min;
NaBH , EtOH
ºC, 15 min (86%)
2
C)
2
, THF
Br
F
OMe
F
Pr
4
5
H
H
4
0
O
Pr
Pr
2
LDA, THF;
F
O
NaBH
4
EtOH
A
B
H
H
(
EtO C)
2 2
F
CO Et
2
Fig. 1. 1,7,8-Trifluoro-2-naphthol (1) and its LC derivatives.
-
78 ºC, 30 min
20%)
0
ºC, 30 min
95%)
Br
(
(
acylation followed by tautomerization. The vinyl group in 2 would
be introduced by Suzuki–Miyaura vinylation [10,11] of arylfluor-
oacetate 3, which would be synthesized from 4-bromo-1,2-
difluorobenzene (4), via (ethoxycarbonyl)hydroxymethylation at
the C-3 position and deoxyfluorination of the resulting alcohol.
On the basis of these tactics, our synthesis commenced with the
reaction of 4-bromo-1,2-difluorobenzene (4) and an ethyl glyox-
alate equivalent. As shown in Scheme 2, we initially pursued
the coupling reaction of an aryllithium, generated by lithiation at
the C-3 position of 4 with LDA [12], with ethyl glyoxalate in toluene
or THF. Unfortunately, only a low amount of the desired product
6
Scheme 2. Synthesis of arylglycolate 5.
yield and use a cheaper catalyst/phosphine ligand combination,
we next applied Molander’s modified condition [PdCl -PPh
Cs CO in THF-H O (9:1)] [10b] to the reaction, giving a 47% yield
of 7 (entry 2). After carrying out detailed investigation of bases
(Et N, Na CO , K PO , and K CO ) (entries 3–6), the reaction
proceeded most effectively by using 5 mol% of PdCl and 15 mol%
of PPh in the presence of 3 eq. of K CO in THF–H O (9:1), offering
2
3
,
2
3
2
3
2
3
3
4
2
3
2
3
2
3
2
5
was obtained (22% and 5% yield, respectively). On the other hand,
treatment of the aryllithium reagent with diethyl oxalate gave a
0% yield of the corresponding arylglyoxylate 6, which was then
reduced by NaBH to furnish the desired arylglycolate 5 in 95%.
(2-vinylaryl)acetate 7 in 91% yield (entry 5). To further improve
the reaction efficiency, we performed the reaction with a less
2
amount of catalyst (2 mol% of PdCl
the yield was decreased to 74% (entry 7). Fortunately, in a solvent
system of THF-H O (1:1) the reaction catalyzed by 1 mol% of PdCl
and 3 mol% of PPh proceeded to give 7 in 90% yield (entry 8).
Using 2,4,6-trivinylcyclotriboroxane-pyridine complex [19] in-
stead of vinylBF K was ineffective (entry 9).
2 2
) in THF-H O (9:1), however,
4
Since the low yield of 6 from 4 was due to the instability of 6, the
one-pot acylation–reduction procedure improved the yield,
producing 5 in 86% yield.
With the desired arylglycolate 5 in hand, we next explored
deoxyfluorination of the resulting hydroxyl group of 5. We
undertook deoxyfluorination of 5 with several commercially
2
2
3
3
Having obtained the key intermediate 7, a synthetic equivalent
of (2-vinylaryl)acetic acid 2, in hand, the stage was now set to test
the crucial intramolecular cycloaromatization. In 1997, Myers [6]
available deoxyfluorinating reagents, such as DAST (Et
2
NSF
] [14], Ishikawa reagent
) [15], TFEMDA (Me N-CF -CHF ) [16], and
N-CF -CHClF) [17], as shown in Table 1.
3
)
[
(
13], Deoxo-Fluor [(MeOCH
Et N-CF -CHF-CF
2
CH
2
)
2
NSF
3
and Hirama [7] coincidentally reported the cycloaromatization of
i
2
2
3
2
2
2
2-(2-vinylphenyl)acetyl chloride derivatives with Pr
2
NEt to
Yarovenko reagent (Et
2
2
produce the corresponding 2-naphthol derivatives in good yield.
Thus, we initially prepared acid chloride 8 by hydrolysis of (2-
vinylaryl)acetate 7 in aq. NaOH–MeOH, followed by treatment of
the resulting (2-vinylaryl)acetic acid 2 with oxalyl chloride in the
Each deoxyfluorination except using Ishikawa reagent (entry 3)
proceeded to produce the desired arylfluoroacetate 3 in moderate
to good yield (47–78%). Especially, the addition of HF-pyridine into
the reaction mixture was effective (entries 4–6) [18] and the best
result was obtained by treatment of 5 with TFEDMA in the
presence of HF-pyridine, affording a 78% yield of 3 (entry 5).
Succeeded in the synthesis of arylfluoroacetate 3, we turned
our attention to introduce the requisite vinyl group by Suzuki–
Miyaura cross-coupling reaction as depicted in Table 2. In 2002,
Molander et al. reported the facile preparation of potassium
presence of DMF as shown in Scheme 3. We then attempted the
i
cycloaromatization upon treatment of 8 with Pr
2
NEt in benzene,
unfortunately yielding no desired product 1 at all. Instead,
unwanted dimer 9 was isolated in 97% yield from 7. Presumably,
this result can be attributed to the prompt esterification of 1,
formed through the expected cycloaromatization, with unreacted
acid chloride 8.
vinyltrifluoroborate (vinylBF
Suzuki–Miyaura vinylations [10a]. Taking advantage of their
original condition [PdCl Cl , and Et N], 3 was
(dppf)ꢁ(CH
allowed to react with vinylBF to furnish the desired
2-vinylaryl)acetate 7 in 75% (entry 1). To improve the reaction
3
K) and the usage of it to various
F
F
F
F
2
2
2
)
2
3
(COCl)
2
F
NaOH
F
K
CO
2
Et
CO H
2
3
(
DMF, CH Cl2
MeOH-H O
2
2
rt, 2 h 30 min
7
8
rt, 90 min
2
F
F
F
F
F
F
F
F
F
F
cyclo-
aromatization
O
F
Pri
O
F
LG
2
CO H
F
2
NEt
F
O
F
COCl
1
PhH
rt, 20 h
I (LG=leaving group)
2
9 (97% in 3 steps)
F
F
F
F
F
Suzuki-Miyaura
vinylation
(ethoxycarbonyl)-
hydroxymethylation; F
F
F
OH
CO Et
8
2
deoxyfluorination
Br
Br
3
4
1
Scheme 1. Synthetic strategy for 1,7,8-trifluoro-2-naphthol (1).
Scheme 3. Intramolecular cycloaromatization of acid chloride 8.

K. Araki et al. / Journal of Fluorine Chemistry 157 (2014) 41–47
43
Table 1
Deoxyfluorination of arylglycolate 5.
F
OH
CO Et
F
F
F
F
CO Et
2
2
(see below)
Br
Br
5
3
a
Entry
Condition
Yield
b
1
2
3
4
5
6
DAST (2.0 eq.), CH
2
Cl
2
, rt, 19 h
Cl , rt, 19 h
Ishikawa reagent (2.5 eq.), CH Cl , rt, 24 h
Deoxo-Fluor (1.2 eq.), HF-py (3.5 eq.), CH Cl
67%
47%
0%
c
Deoxo-Fluor (1.5 eq.), CH
2
2
d
2
2
c
2
2
, rt, 22 h
76%
78%
68%
e
TFEDMA (1.0 eq.), HF-py (3.8 eq.), 1,2-dichloroethane, 80 8C, 7 h
Yarovenko reagent (1.5 eq.), HF-py (7.0 eq.), 1,2-dichloroethane, 80 8C, 7 h
f
a
b
c
d
e
f
Isolated yield.
DAST = Et N-SF
Deoxo-Fluor = (MeOCH
Ishikawa reagent = Et N-CF
TFEDMA = Me N-CF -CHF
2
Yarovenko reagent = Et N-CF -CHClF.
2
3
.
2
CH
2
)
2
N-SF
3
.
2
2
-CHF-CF .
3
2
2
2
.
2
Table 2
Suzuki–Miyaura vinylation of arylfluoroacetate 3.
vinyl-M
F
F
F
F
catalyst,base
F
F
CO Et
CO Et
2
2
solvent, temp., time
(see below)
B
r
3
7
a
Entry
Vinyl-M
Catalyst
Base
Solvent, temperature, time
Yield
1
2
3
4
5
6
7
8
9
vinylBF
3
3
3
3
3
3
3
3
K (1.2 eq.)
K (1.2 eq.)
K (1.2 eq.)
K (1.2 eq.)
K (1.2 eq.)
K (1.2 eq.)
K (1.2 eq.)
K (1.2 eq.)
Pd(dppf)Cl
2
ꢁ(CH
2
Cl
2
)
2
(0.05 eq.)
(0.15 eq.)
(0.15 eq.)
(0.15 eq.)
(0.15 eq.)
(0.15 eq.)
(0.06 eq.)
(0.03 eq.)
(0.15 eq.)
Et
Cs
Et
3
N (1.2 eq.)
CO (3.0 eq.)
N (1.2 eq.)
EtOH, 85 8C, 13 h
75%
47%
24%
20%
91%
58%
74%
90%
1.3%
vinylBF
vinylBF
vinylBF
vinylBF
vinylBF
vinylBF
vinylBF
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
(0.05 eq.), PPh
(0.05 eq.), PPh
(0.05 eq.), PPh
(0.05 eq.), PPh
(0.05 eq.), PPh
(0.02 eq.), PPh
(0.01 eq.), PPh
(0.05 eq.), PPh
3
2
3
THF-H
2
O (9:1), 85 8C, 19 h
3
3
3
3
3
3
3
3
EtOH, 85 8C, 13 h
K
K
3
PO
CO
4
(3.0 eq.)
(3.0 eq.)
THF-H
THF-H
THF-H
THF-H
THF-H
THF-H
2
O (9:1), 85 8C, 19 h
2
O (9:1), 85 8C, 12 h
2
O (9:1), 85 8C, 12 h
2
O (9:1), 85 8C, 12 h
2
O (1:1), 85 8C, 24 h
2
O (9:1), 85 8C, 15 h
2
3
Na
2
CO
3
(3.0 eq.)
(3.0 eq.)
(3.0 eq.)
(3.0 eq.)
K
K
K
2
2
2
CO
CO
CO
3
3
3
2,4,6-trivinylcyclotriboroxane-
pyridine complex (1.2 eq.)
a
Isolated yield.
Table 3
Cycloaromatization of (2-vinylphenyl)acetic acid 2.
F
F
F
F
F
F
F
F
F
F
O
F
NaOH
MeOH-H
F
AcCl, base
F
OR
F
O
F
CO Et
CO H
2
2
+
toluene
reflux
2
O
rt, 90 min
(
see below)
K CO
2 3
MeOH
rt, 30 min
7
2
10: R=Ac
: R=H
9
1
(
95%)
a
a
Entry
AcCl (eq.)
Base
Time (h)
Yield of 10 (from 7)
Yield of 9 (from 7)
1
2
3
4
5
6
7
8
9
3.0
5.0
2.0
1.0
3.0
3.0
3.0
3.0
2.0
DMAP (3.0 eq.)
DMAP (5.0 eq.)
DMAP (2.0 eq.)
DMAP (1.0 eq.)
18
13
24
18
17
20
12
12
12
87%
98%
86%
0%
0%
0%
b
b
20%
45%
b
b
Et
Pyridine (3.0 eq.)
Et N (3.0 eq.), DMAP (0.1 eq.)
3
N (3.0 eq.)
26%
71%
b
b
54%
22%
3
50%
89%
0%
0%
Pyridine (3.0 eq.), DMAP (0.1 eq.)
Pyridine (2.0 eq.), DMAP (0.1 eq.)
b
b
38%
24%
a
Isolated yield.
b
1
Due to the difficulty of separation of 10 and 9, the yields of 10 and 9 were calculated based on the isolated yield and the H NMR ratio of a mixture of 10 and 9.

4
4
K. Araki et al. / Journal of Fluorine Chemistry 157 (2014) 41–47
+
anhydride 11 from 2 with AcCl and DMAP, followed by the
DMAP mediated formation of acylammonium salt I as a reactive
N Me
2
-
0
F
F
AcCl
O
F
F
AcO
DMAP F
OAc
O
intermediate. The intramolecular electrophilic acylation of I’,
followed by tautomerization furnished 2-naphthol 1. Then, the
resultant 2-naphthol 1 was immediately acetylated in the
presence of AcCl to furnish 10, however, as a competitive
DMAP
F
N
2
-
DMAP
HCl
1
1
I'
-
0
reaction 1 was also acylated with I to produce the undesired
DMAP
AcOH
product 9. Since we treated ester 9 with AcCl (3 eq.) and DMAP
(3 eq.) in refluxing toluene to give rise to 10 in 83% yield
(Scheme 5), the formation of 9 from 1 should be regarded as a
reversible reaction. Therefore, even while undesired dimer
F
F
F
F
F
F
O
F
DMAP I'
DMAP I'
F
O
F
F
F
OH
9
formed during the cycloaromatization, 9 was transformed
9
1
to phenol 1 in the presence of a sufficient amount of AcCl and
DMAP, which was eventually acetylated to give 10. As Suzuki
et al. suggested [8], there might be other possible reactive
intermediates involved in this reaction. The acid anhydride
11 underwent elimination by DMAP to form ketene II, which
was cyclized via Cope rearrangement followed by acetylation to
produce 10. Alternatively, Cope cyclization of ketene diacetate
III, generated via enol acetylation of acid anhydride 11, followed
by aromatization might produce 1,7,8-trifluoro-2-naphthyl
acetate (10).
AcCl
F
F
F
F
F
F
F
OAc
OAc
OAc
C
C
O
II
III
10
Scheme 4. Plausible mechanism of the formation of naphthyl acetate 10 from (2-
vinylaryl)acetic acid 2.
3. Conclusion
Encouraged by this result, we then planned to use naphthol
protecting reagents to inhibit the unwanted dimer formation.
During the synthesis of furaquinocins, Suzuki et al. constructed
their 2-naphthol moiety by the cycloaromatization of a (2-
vinylphenyl)acetic acid derivative with 3 eq. of acetyl chloride
In summary, we have established the facile synthetic route to
1,7,8-trifluoro-2-naphthol (1), an important synthetic precursor
for liquid crystal (LC) compounds, from 4-bromo-1,2-difluoroben-
zene (4) in 51% overall yield for the 6 steps. (Ethoxycarbonyl)hy-
droxymethylation of 4, followed by deoxyfluorination of the
resulting arylglycolate 5 in the presence of TFEDMA and HF-
pyridine furnished arylfluoroacetate 3, which was subjected to
(
AcCl) and 3 eq. of 4-(dimethylamino)pyridine (DMAP) [8]. We
envisaged that a combination of AcCl and DMAP would serve as
naphthol capture reagents as well as carboxylic acid activating
reagents. Accordingly, as depicted in Table 3, we carried out
cycloaromatization by treatment of (2-vinylphenyl)acetic acid
Suzuki–Miyaura vinylation with vinylBF K catalyzed by 1 mol% of
2
PdCl and 3 mol% of PPh in THF-H O (1:1), affording (2-
3
2
3
2
1
with 3 eq. of AcCl and 3 eq. of DMAP in toluene under reflux for
8 h, which resulted in the formation of the expected naphthyl
vinylphenyl)acetate 7. Exposure of (2-vinylaryl)acetic acid 2,
obtained by hydrolysis of 7, to acetyl chloride, pyridine, and a
catalytic amount of DMAP gave rise to 2-naphthyl acetate 10 via
cycloaromatization. Finally, methanolysis of 10 produced the
desired 1,7,8-trifluoro-2-naphthol (1). Since this developed
method was short and efficient, it could be applicable to the
industrial scale preparation of 1.
acetate 10 in 87% yield from 7 (entry 1). Increasing amounts of
AcCl (5 eq.) and DMAP (5 eq.) improved the yield to 98% (entry
2
same result (entry 3), decreasing amounts of AcCl (1 eq.) and
DMAP (1 eq.) lowered the yield to 20% with the formation of 9 in
). While the reaction with 2 eq. of AcCl and DMAP gave the
4
5% (entry 4). We next surveyed bases such as Et
however, the yield of 10 decreased and undesired dimer
formed (entries 5–6). Since we realized DMAP is essential
for this reaction, a DMAP catalyzed cycloaromatization (0.1 eq.
of DMAP and 3 eq. of Et N) was examined, affording a 50% yield
3
N and pyridine,
4. Experimental
9
4.1. General
3
of 10 (entry 7). After further investigation, we fortunately found
that the reaction in the presence of a catalytic amount of DMAP
All reactions involving air- and moisture-sensitive reagents
were carried out using oven-dried glassware and standard syringe-
septum cap techniques. Routine monitoring of reaction was carried
out using glass-supported Merck silica gel 60 F254 TLC plates. Flash
column chromatography was performed on Kanto Chemical Silica
(
0.1 eq.) and pyridine (3 eq.) produced 10 in good yield (89%,
entry 8). An attempt of the direct cycloaromatization of ester
by exposure to DMAP in the absence of AcCl in refluxing
7
toluene was failed.
Gel 60 N (spherical, neutral 40–50 mm). All solvents and reagents
Finally, methanolysis of the resulting acetate 10 with K
MeOH provided 1,7,8-trifluoro-2-naphthol (1) as a white solid
in 95% (51% overall yield for the 6 steps from 4).
As shown in Scheme 4, we assumed that the key intramolec-
ular cycloaromatization was initiated by the formation of acid
2
CO
3
in
were obtained from commercial suppliers and were used without
further purification. Melting points were taken on a Mettler Toledo
MP70 melting point system and were uncorrected. Infrared (IR)
spectral measurements were carried out with a HORIBA FT-720
1
13
19
spectrometer. H, C, and F NMR spectra were measured with a
Bruker AVANCE III spectrometer. Chemical shifts are expressed in
1
parts per million using tetramethylsilane (
d
= 0, H NMR) and CFCl
3
F
F
F
F
F
F
AcCl
DMAP
19
19
O
(d = 0, F NMR) as standard substances. F NMR spectra were
F
O
F
F
OAc
1
recorded with H decoupling. Chemical shifts are expressed in
ppm. Multiplicities are indicated by s (singlet), brs (broad singlet),
d (doublet), brd (broad doublet), t (triplet), q (quartet), dd (doublet
of doublet), brdd (broad doublet of doublet), ddd (doublet of
doublet of doublet), dddd (doublet of doublet of doublet
of doublet) and m (multiplet).
toluene
reflux, 24 h
9
10
(
83% for 10
6% for 9)
+
Scheme 5. Conversion of dimer 9 to naphthyl acetate 10.

K. Araki et al. / Journal of Fluorine Chemistry 157 (2014) 41–47
45
4
.2. Preparation of ethyl 2-(6-bromo-2,3-difluorophenyl)-2-
the resulting mixture was stirred at ꢀ78 8C for 1 h. To the reaction
hydroxyacetate (5)
mixture was added dropwise diethyl oxalate (0.68 mL, 5.0 mmol)
and the resulting mixture was stirred at ꢀ78 8C for 15 min. NaBH
4
4
.2.1. Preparation of ethyl 2-(6-bromo-2,3-difluorophenyl)-2-
oxoacetate (6)
To stirred solution of N,N-diisopropylamine (0.7 mL,
.0 mmol) in THF (5.0 mL) was added dropwise a solution of n-
(188 mg, 5.0 mmol) and ethanol (5.0 mL) were added sequentially,
then the reaction mixture was warmed to 0 8C and stirred at 0 8C
for 15 min. The reaction mixture was quenched with saturated
a
5
4
NH Cl aq. (5.0 mL) and the resulting mixture was stirred at room
BuLi in n-hexane (1.59 M, 3.1 mL, 5.0 mmol) at 0 8C under Ar and
the resulting solution was stirred at 0 8C for 20 min to prepare
lithium diisopropylamide (LDA). To the prepared solution of LDA
was added dropwise a solution of 4-bromo-1,2-difluorobenzene
temperature for 15 min. The reaction mixture was extracted with
ethyl acetate (10 mL ꢂ 1, 5.0 mL ꢂ 2). The extract was washed with
4
water (5.0 mL) and brine (5.0 mL), then dried over MgSO .
Concentration of the solvent in vacuo afforded a residue, which
was purified by silica gel column chromatography (hexane/ethyl
acetate) to give 5 (1.27 g, 86%) as a light yellow solid.
(
4) (965 mg, 5.0 mmol) in THF (5.0 mL) at ꢀ78 8C over 15 min and
the resulting mixture was stirred at ꢀ78 8C for 1 h. To the resulting
mixture was added dropwise diethyl oxalate (0.68 mL, 5.0 mmol)
and the reaction mixture was stirred at ꢀ78 8C for 30 min. The
reaction mixture was quenched with 1.0 M HCl (5.0 mL) and the
aqueous layer was extracted with ether (5.0 mL ꢂ 3). The extract
was washed with water (5.0 mL) and brine (5.0 mL), then dried
4.3. Preparation of ethyl 2-(6-bromo-2,3-difluorophenyl)-2-
fluoroacetate (3)
To a stirred solution of 2-(6-bromo-2,3-difluorophenyl)-2-
over MgSO
residue, which was purified by silica gel column chromatography
hexane/ethyl acetate) to give 6 (170 mg, 20%) as a white solid. mp.
4
. Concentration of the solvent in vacuo afforded a
hydroxyacetate (5) (148 mg, 0.50 mmol) in HF-py (70%, 0.05 mL,
1.9 mmol) and CH Cl (0.95 mL) was added N,N-dimethyl-1,1,2,2-
2 2
tetrafluoroethylamine (TFEDMA) (0.12 mL, 0.50 mmol) at room
temperature under Ar and the resulting solution was stirred at
80 8C for 7 h. The reaction mixture was cooled to 0 8C and the
(
4
1
8
4
2
9.5–51.6 8C. IR (neat): 3080, 2993, 2960, 2924, 2854, 2362, 2339,
743, 1716, 1464, 1274, 1255, 1215, 1167, 1122, 1092, 1061, 872,
ꢀ
1 1
27, 744, 739 cm . H NMR (400 MHz, CDCl
3
):
d
7.39 (ddd, J = 9.0,
3
reaction mixture was quenched with saturated NaHCO aq.
.0, 2.0 Hz, 1H), 7.24 (brdd, J = 9.0, 8.5 Hz, 1H), 4.43 (q, J = 7.0 Hz,
(2.0 mL) and the aqueous layer was extracted with ethyl acetate
13
H), 1.41 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl
3
):
d
182.1 (d,
(5.0 mL ꢂ 1, 2.0 mL ꢂ 2). The extract was washed with water
J
CF = 1.5 Hz, 1C), 159.6 (s, 1C), 149.7 (dd, JCF = 252, 13 Hz, 1C), 149.1
dd, JCF = 258, 15 Hz, 1C), 128.9 (dd, JCF = 5.9, 4.4 Hz, 1C), 127.8 (d,
CF = 14 Hz, 1C), 120.9 (brd, JCF = 18 Hz, 1C), 114.1 (dd, JCF = 3.7,
4
(3.0 mL) and brine (3.0 mL), then dried over MgSO . Concentration
(
J
of the solvent in vacuo afforded a residue, which was purified by
silica gel column chromatography (hexane/ethyl acetate) to give 3
(116 mg, 78%) as a yellow oil. IR (neat): 2987, 1766, 1477, 1279,
19
2
ꢀ
.2 Hz, 1C), 63.5 (s, 1C), 13.8 (s, 1C). F NMR (376 MHz, CDCl
135.6 (d, JFF = 20 Hz, 1F), ꢀ137.0 (d, JFF = 20 Hz, 1F). Anal. Calcd
for C10 BrF : C, 40.98; H, 2.41. Found: C, 41.27; H, 2.55.
3
): d
ꢀ
1 1
1216, 1066, 1028, 887, 814 cm . H NMR (400 MHz, CDCl
(dddd, J = 9.0, 4.5, 2.3, 1.0 Hz, 1H), 7.17 (ddd, J = 9.0, 8.0, 1.8 Hz, 1H),
.23 (d, J = 46 Hz, 1H), 4.34 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.4 Hz, 3H).
3
): d 7.41
H
7
2 3
O
6
1
3
4.2.2. Preparation of ethyl 2-(6-bromo-2,3-difluorophenyl)-2-
C NMR (100 MHz, CDCl
3
): d 166.9 (d, JCF = 27 Hz, 1C), 150.0 (ddd,
hydroxyacetate (5) by reduction of 6
JCF = 257, 13, 2.9 Hz, 1C), 149.8 (ddd, JCF = 251, 13, 2.2 Hz, 1C), 128.8
To a stirred solution of ethyl 2-(6-bromo-2,3-difluorophenyl)-
-oxoacetate (6) (290 mg, 0.99 mmol) in EtOH (1.0 mL) was added
(ddd, JCF = 5.8, 4.4, 1.5 Hz, 1C), 124.7 (dd, JCF = 19, 12 Hz, 1C), 119.8
(brd, JCF = 18 Hz, 1C), 118.7 (brdd, JCF = 6.6, 3.5 Hz, 1C), 84.4 (ddd,
2
19
NaBH
solution was stirred at 0 8C for 30 min. The reaction mixture was
quenched with 13% NH Cl aq. (2.0 mL) and the aqueous layer was
extracted with ethyl acetate (5.0 mL ꢂ 3). The extract was washed
with water (2.0 mL) and brine (2.0 mL), then dried over MgSO
4
(37.8 mg, 1.0 mmol) at 0 8C under Ar and the resulting
J
CF = 188, 2.6, 2.5 Hz, 1C), 62.4 (s, 1C), 13.9 (s, 1C). F NMR
(376 MHz, CDCl ):
ꢀ134.5 (dd, JFF = 20, 5.4 Hz, 1F), ꢀ137.0 (d,
FF = 20 Hz, 1F), ꢀ183.2 (d, JFF = 5.4 Hz, 1F). Anal. Calcd for
BrF : C, 40.43; H, 2.71. Found: C, 40.54; H, 2.65.
3
d
4
J
C
10
H
8
3 2
O
4
.
Concentration of the solvent in vacuo afforded a residue, which was
purified by silica gel column chromatography (hexane/ethyl
acetate) to give 5 (276 mg, 95%) as a light yellow solid. mp.
4.4. Preparation of ethyl 2-(2,3-difluoro-6-vinylphenyl)-2-
fluoroacetate (7)
4
1
CDCl
0.3–41.8 8C. IR (neat): 3467 (br), 2985, 1736, 1712, 1475, 1277,
2
4.4.1. Suzuki–Miyaura vinylation of 3 catalyzed by 5 mol% of PdCl in
ꢀ1 1
209, 1088, 1022, 885, 860, 810, 644 cm
): 7.36 (ddd, J = 8.9, 4.5, 2.1 Hz, 1H), 7.08 (dd, J = 8.9, 0.7 Hz,
H), 5.62 (d, J = 4.9 Hz, 1H), 4.30 (q, J = 7.3 Hz, 2H), 3.63 (d,
.
H NMR (400 MHz,
THF/H
To a stirred solution of ethyl 2-(6-bromo-2,3-difluorophenyl)-
2-fluoroacetate (3) (297 mg, 1.0 mmol) in THF/H O (2.0 mL, 9:1)
2
O (9:1)
3
d
1
2
13
J = 4.9 Hz, 1H), 1.26 (t, J = 7.3 Hz, 3H). C NMR (100 MHz, CDCl
71.84 (d, JCF = 1.5 Hz, 1C), 149.9 (dd, JCF = 250, 13 Hz, 1C), 149.7
dd, JCF = 254, 14 Hz, 1C), 128.5 (dd, JCF = 5.9, 4.4 Hz, 1C), 128.3 (d,
CF = 13 Hz, 1C), 118.3 (brd, JCF = 18 Hz, 1C), 118.2 (brs, 1C), 68.8
3
):
d
was sequentially added potassium vinyltrifluoroborate (161 mg,
1.2 mmol), potassium carbonate (415 mg, 3.0 mmol), triphenyl-
phosphine (39.3 mg, 0.15 mmol) and palladium(II) chloride
(8.9 mg, 0.05 mmol). The resulting suspension was degassed in
three times and stirred at 85 8C for 12 h. To the reaction mixture
was added 2.4 M HCl (2.5 mL) at room temperature and the
aqueous layer was extracted with ethyl acetate (5.0 mL ꢂ 3). The
extract was washed with water (5.0 mL) and brine (5.0 mL), then
1
(
J
1
9
(
(
dd, JCF = 2.6, 2.6 Hz, 1C), 62.8 (s, 1C), 13.9 (s, 1C). F NMR
376 MHz, CDCl ):
ꢀ137.0 (d, JFF = 20 Hz, 1F), ꢀ137.7 (d,
BrF : C, 40.70; H, 3.07.
3
d
JFF = 20 Hz, 1F). Anal. Calcd for C10
H
9
2 3
O
Found: C, 40.65; H, 2.77.
4
dried over MgSO . Concentration of the solvent in vacuo afforded a
4
.2.3. One pot acylation–reduction procedure for 5 from 4
To stirred solution of N,N-diisopropylamine (0.7 mL,
.0 mmol) in THF (5.0 mL) was added dropwise a solution of n-
residue, which was purified by silica gel column chromatography
(hexane/ethyl acetate) to give 7 (221 mg, 91%) as a colorless oil. IR
(neat): 2985, 1763, 1743, 1500, 1292, 1219, 1207, 1065, 1030,
a
5
ꢀ1 1
BuLi in n-hexane (2.69 M, 1.9 mL, 5.0 mmol) at 0 8C under Ar and
the resulting solution was stirred at 0 8C for 20 min to prepare
lithium diisopropylamide (LDA). To the prepared solution of LDA
was added dropwise a solution of 4-bromo-1,2-difluorobenzene
825 cm
. H NMR (400 MHz, CDCl ): d 7.30–7.17 (m, 2H), 6.96
3
(ddd, J = 17, 11, 2.0 Hz, 1H), 6.20 (d, J = 46 Hz, 1H), 5.64 (d, J = 17 Hz,
1H), 5.41 (d, J = 11 Hz, 1H), 4.34–4.21 (m, 2H), 1.27 (t, J = 7.1 Hz,
1
3
3H). C NMR (100 MHz, CDCl
3
): d 167.7 (dd, JCF = 27, 1.5 Hz, 1C),
(
4) (964 mg, 5.0 mmol) in THF (5.0 mL) at ꢀ78 8C over 15 min and
149.6 (ddd, JCF = 250, 13, 1.2 Hz, 1C), 149.0 (ddd, JCF = 251, 14,

4
6
K. Araki et al. / Journal of Fluorine Chemistry 157 (2014) 41–47
19
4
.4 Hz, 1C), 135.4 (d, JCF = 3.7 Hz, 1C), 132.0 (brs, 1C), 122.5 (ddd,
J
CF = 9.5, 9.5 Hz, 1C). 81.5 (ddd, JCF = 189, 6.6, 3.0 Hz, 1C). F NMR
J
CF = 5.9, 4.4, 2.2 Hz, 1C), 121.2 (dd, JCF = 19, 9.5 Hz, 1C), 119.1 (s,
C), 118.5 (brd, JCF = 17 Hz, 1C), 81.6 (ddd, JCF = 186, 5.9, 2.2 Hz, 1C),
(376 MHz, CDCl ):
3
d
ꢀ134.1 (ddd, JFF = 52, 5.5, 2.7 Hz, 1F), ꢀ137.6
1
6
J
J
(d, JFF = 20 Hz, 1F), ꢀ139.0 (dd, JFF = 16, 5.5 Hz, 1F), ꢀ140.5 (brd,
1
9
2.2 (s, 1C), 13.9 (s, 1C). F NMR (376 MHz, CDCl
3
):
d
ꢀ138.1 (d,
J
FF = 20 Hz, 1F), ꢀ145.2 (dd, JFF = 52, 16 Hz, 1F), ꢀ181.8 (d,
FF = 2.7 Hz, 1F). Anal. Calcd for C20 : C, 60.62; H, 2.54.
FF = 21 Hz, 1F), ꢀ141.1 (dd, JFF = 21, 2.7 Hz, 1F), ꢀ182.2 (d,
FF = 2.7 Hz, 1F). Anal. Calcd for C12 : C, 59.02; H, 4.54.
J
10 6 2
H F O
H
11
F
3
O
2
Found: C, 60.41; H, 2.64.
Found: C, 59.17; H, 4.73.
4.6. Preparation of 1,7,8-trifluoro-2-naphthyl acetate (10)
4
.4.2. Suzuki–Miyaura vinylation of 3 catalyzed by 1 mol% of PdCl
THF/H O (1:1)
To a stirred solution of ethyl 2-(6-bromo-2,3-difluorophenyl)-
-fluoroacetate (3) (891 mg, 3.0 mmol) in THF/H O (6.0 mL, 1:1)
was sequentially added potassium vinyltrifluoroborate (482 mg,
.6 mmol), potassium carbonate (1.24 g, 9.0 mmol), triphenylpho-
sphine (23.6 mg, 0.089 mmol) and palladium(II) chloride (5.3 mg,
.030 mmol). The resulting suspension was degassed in three
2
in
2
To a stirred solution of ethyl 2-(2,3-difluoro-6-vinylphenyl)-2-
2
fluoroacetate (7) (244 mg, 1.0 mmol) in MeOH/H O (3.0 mL, 2:1)
2
2
was added sodium hydroxide (100 mg, 2.5 mmol) at room
temperature. The resulting solution was stirred at room tempera-
ture for 1 h 30 min. The reaction mixture was quenched with 2.4 M
HCl (2.5 mL) and extracted with diethyl ether (4.0 mL ꢂ 3). The
extract was washed with water (2.0 mL) and brine (2.0 mL), then
3
0
times and stirred at 85 8C for 24 h. To the reaction mixture was
added 2.4 M HCl (7.5 mL) at room temperature and the aqueous
layer was extracted with ethyl acetate (8.0 mL ꢂ 3). The extract
was washed with water (5.0 mL) and brine (5.0 mL), then dried
4
dried over MgSO . Concentration of the solvent in vacuo afforded
crude 2-(2,3-difluoro-6-vinylphenyl)-2-fluoroacetic acid (2)
(246 mg) as a white solid, which was used in the next step
without further purification. To a stirred solution of 2-(2,3-
difluoro-6-vinylphenyl)-2-fluoroacetic acid (2) (246 mg) in tolu-
ene (5.0 mL) was sequentially added 4-(dimethylamino)pyridine
(12.2 mg, 0.10 mmol), pyridine (0.24 mL, 3.0 mmol) and acetyl
chloride (0.21 mL, 3.0 mmol). The resulting suspension was stirred
under reflux for 12 h 30 min. The reaction mixture was cooled to
room temperature and quenched with 1.1 M HCl (2.2 mL), then the
aqueous layer was extracted with ethyl acetate (5.0 mL ꢂ 3). The
extract was washed with water (3.0 mL) and brine (3.0 mL), then
over MgSO
residue, which was purified by silica gel column chromatography
hexane/ethyl acetate) to give 7 (656 mg, 90%) as a colorless oil.
4
. Concentration of the solvent in vacuo afforded a
(
4.5. Preparation of 1,7,8-trifluoro-2-naphthyl 2-(2,3-difluoro-6-
vinylphenyl)-2-fluoroacetate (9)
To a stirred solution of ethyl 2-(2,3-difluoro-6-vinylphenyl)-2-
fluoroacetate (7) (244 mg, 1.0 mmol) in MeOH/H
2
O (4.0 mL, 1:1)
4
dried over MgSO . Concentration of the solvent in vacuo afforded a
was added sodium hydroxide (112 mg, 2.8 mmol) at room
temperature. The resulting solution was stirred at room tempera-
ture for 1 h 30 min. The reaction mixture was quenched with 2.4 M
HCl (2.5 mL) and extracted with diethyl ether (3.0 mL ꢂ 3). The
extract was washed with water (2.0 mL) and brine (2.0 mL), then
residue, which was purified by silica gel column chromatography
(hexane/ethyl acetate) to give 10 (214 mg, 89%) as a white solid.
mp. 119.0–120.4 8C. IR (neat): 2359, 2343, 2328, 1759, 1631, 1481,
ꢀ
1
1373, 1356, 1261, 1250, 1203, 1173, 910, 849, 829, 679, 652 cm
.
1
H NMR (400 MHz, CDCl
9.1, 7.2 Hz, 1H), 7.24 (dd, J = 9.3, 7.2 Hz, 1H), 2.40 (s, 3H). C NMR
(100 MHz, CDCl ): 168.2 (s, 1C), 147.9 (ddd, JCF = 252, 6.6, 1.5 Hz,
3
): d 7.62–7.56 (m, 2H), 7.35 (ddd, J = 9.8,
13
dried over MgSO
crude 2-(2,3-difluoro-6-vinylphenyl)-2-fluoroacetic acid (2)
248 mg), which was used in the next step without further
purification. To a stirred solution of 2-(2,3-difluoro-6-vinylphe-
nyl)-2-fluoroacetic acid (2) (248 mg) in CH Cl (4.0 mL) was added
4
. Concentration of the solvent in vacuo afforded
3
d
(
1C), 147.8 (ddd, JCF = 248, 12, 2.2 Hz, 1C), 143.9 (ddd, JCF = 257, 15,
2.2 Hz, 1C), 135.4 (brd, JCF = 12 Hz, 1C), 130.5 (brs, 1C), 124.2 (ddd,
2
2
JCF = 7.3, 5.1, 2.2 Hz, 1C), 124.0 (brs, 1C), 122.1 (brs, 1C), 117.5 (dd,
N,N-dimethylformamide (0.025 mL, 0.32 mmol) and oxalyl chlo-
ride (0.13 mL, 1.5 mmol) at room temperature. The resulting
solution was stirred at room temperature for 2 h 30 min and
concentrated in vacuo to afford crude 2-(2,3-difluoro-6-vinylphe-
nyl)-2-fluoroacetyl chloride (8). To a stirred solution of 2-(2,3-
difluoro-6-vinylphenyl)-2-fluoroacetyl chloride (8) in benzene
J
CF = 21, 1.5 Hz, 1C), 115.9 (brdd, JCF = 9.5, 9.5 Hz, 1C), 20.4 (s, 1C).
1
9
F NMR (376 MHz, CDCl
3
):
d
ꢀ134.8 (dd, JFF = 53, 5.4 Hz, 1F),
ꢀ139.6 (dd, JFF = 18, 5.4 Hz, 1F), ꢀ145.6 (dd, JFF = 53, 18 Hz, 1F).
Anal. Calcd for C12
2.82.
7 3 2
H F O : C, 60.01; H, 2.94. Found: C, 60.02; H,
(
3
5.0 mL) was added N,N-diisopropylethylamine (0.52 mL,
.0 mmol) and the resulting suspension was stirred at room
temperature for 20 h. The reaction mixture was quenched with
.7 M HCl (3.5 mL) and the aqueous layer was extracted with ethyl
, then
4.7. Preparation of 1,7,8-trifluoro-2-naphthol (1)
To a stirred solution of 1,7,8-trifluoro-2-naphthyl acetate (10)
(181 mg, 0.75 mmol) in MeOH (10 mL) was added potassium
carbonate (208 mg, 1.61 mmol) and the resulting suspension was
stirred at room temperature for 30 min. The reaction mixture was
1
acetate (3.0 mL ꢂ 3). The extract was dried over MgSO
4
concentration of the solvent in vacuo afforded a residue, which was
purified by silica gel column chromatography (hexane/ethyl
acetate) to give 9 (192 mg, 97%) as an orange solid. mp. 115.5 8C
quenched with 13% NH
acetate (3.0 mL ꢂ 3). The extract was washed with water (3.0 mL)
and brine (3.0 mL), then dried over MgSO . Concentration of the
4
Cl aq. (2.0 mL) and extracted with ethyl
(dec.). IR (neat): 2360, 2343, 2328, 1792, 1784, 1649, 1633, 1502,
4
1
1
7
7
483, 1456, 1356, 1292, 1263, 1242, 1211, 1169, 1076, 1055, 1026,
solvent in vacuo afforded a residue, which was purified by silica gel
column chromatography (hexane/ethyl acetate) to give 1 (143 mg,
95%) as a white solid. mp. 104.0–105.7 8C. IR (neat): 3344 (brs),
1647, 1633, 1487, 1464, 1373, 1348, 1261, 1244, 1234, 1200, 1176,
ꢀ
1 1
3
014, 931, 849, 825, 706, 654 cm . H NMR (400 MHz, CDCl ): d
.62–7.57 (m, 2H), 7.40–7.25 (m, 3H), 7.21 (dd, J = 9.0, 6.7 Hz, 1H),
.07 (ddd, J = 17, 11, 2.0 Hz, 1H), 6.57 (d, J = 46 Hz, 1H), 5.75 (d,
13
ꢀ1
1
J = 17 Hz, 1H), 5.53 (d, J = 11 Hz, 1H). C NMR (100 MHz, CDCl
65.4 (d, JCF = 28 Hz, 1C), 149.7 (brdd, JCF = 251, 13 Hz, 1C), 149.2
ddd, JCF = 252, 14, 4.4 Hz, 1C), 147.8 (ddd, JCF = 249, 12, 1.5 Hz, 1C),
3
):
d
1014, 845, 825, 820, 651 cm . H NMR (400 MHz, CDCl d 7.54–
3
):
7.48 (m, 2H), 7.24–7.16 (m, 2H), 5.59 (brs, 1H). C NMR (100 MHz,
CDCl ): 147.9 (ddd, JCF = 247, 12, 2.2 Hz, 1C), 143.1 (ddd, JCF = 242,
7.3, 1.5 Hz, 1C), 142.8 (ddd, JCF = 255, 15, 1.5 Hz, 1C), 141.3 (brd,
CF = 14 Hz, 1C), 127.2 (brs, 1C), 124.5 (ddd, JCF = 5.1, 2.2, 2.2 Hz,
1C), 124.2 (ddd, JCF = 8.0, 5.1, 2.2 Hz, 1C), 118.3 (brs, 1C), 115.6
1
3
1
(
3
d
147.6 (ddd, JCF = 261, 6.6, 1.5 Hz, 1C), 143.8 (ddd, JCF = 258, 15,
1.5 Hz, 1C), 135.8 (d, JCF = 3.8 Hz, 1C), 134.4 (d, JCF = 12 Hz, 1C),
131.7 (s, 1C), 130.7 (s, 1C), 124.3 (m, 1C), 124.2 (m, 1C), 122.9 (brs,
1C), 121.2 (s, 1C), 120.3 (dd, JCF = 19, 9.5 Hz, 1C), 120.1 (s, 1C), 119.2
J
19
(ddd, JCF = 9.5, 9.5, 2.2 Hz, 1C), 115.0 (dd, JCF = 21, 1.4 Hz, 1C).
F
(d, JCF = 17 Hz, 1C), 117.9 (brd, JCF = 21 Hz, 1C), 115.7 (brdd,
NMR (376 MHz, CDCl ):
3
d
ꢀ140.3 (dd, JFF = 18, 4.1 Hz, 1F), ꢀ148.3

K. Araki et al. / Journal of Fluorine Chemistry 157 (2014) 41–47
47
[
[
2] J. Manero, R.W. Fuss, B. Hornung, Chem. Abstr. 124 (1996) 260617.
3] (a) T. Matsumoto, Y. Nagashima, T. Kusumoto, Chem. Abstr. 143 (2005) 376544;
(
3
(
dd, JFF = 48, 18 Hz, 1F), ꢀ151.7 (dd, JFF = 48, 4.1 Hz, 1F). Anal. Calcd
for C10 O: C, 60.62; H, 2.54. Found: C, 60.72; H, 2.59.
5 3
H F
b) C.-Z. Li, S. Takehara, Y. Nagashima, T. Kusumoto, Chem. Abstr. 144 (2006)
02158.
4] T. Kusumoto, Y. Nagashima, S. Takehara, T. Matsumoto, Chem. Abstr. 140 (2004)
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[
[
4
.8. Conversion of 9 to 10
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5] (a) T. Matsumoto, T. Kusumoto, Chem. Abstr. 142 (2005) 373571;
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difluoro-6-vinylphenyl)-2-fluoroacetate (9) (79.2 mg, 0.20 mmol)
in toluene (4.0 mL) was sequentially added 4-(dimethylamino)-
pyridine (73.3 mg, 0.60 mmol) and acetyl chloride (0.043 mL,
(c) Y. Nagashima, T. Kusumoto, Chem. Abstr. 148 (2008) 225781.
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[
[
[
0
2
.60 mmol). The resulting suspension was stirred under reflux for
4 h. The reaction mixture was cooled to room temperature and
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T. Matsumoto, K. Suzuki, J. Am. Chem. Soc. 120 (1998) 11633–11644.
9] (a) J.H. Rupard, T. de Paulis, A. Janowsky, H.E. Smith, J. Med. Chem. 32 (1989)
2261–2268;
quenched with 1.0 M HCl (1.0 mL), then the aqueous layer was
extracted with ethyl acetate (10 mL ꢂ 1, 5.0 mL ꢂ 3). The extract
was washed with water (10 mL) and brine (10 mL), then dried over
[
(
b) S.G. Gilbreath, C.M. Harris, T.M. Harris, J. Am. Chem. Soc. 110 (1988)
172–6179;
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6
(
4
MgSO . Concentration of the solvent in vacuo afforded a residue,
which was purified by preparative layer chromatography (chloro-
1
form) to give a 29:1 mixture (calculated by H NMR) of 10 and 9
(
(83.8 mg, 83% for 10 and 6% for 9).
[
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We thank Mrs. A. Sato at A Rabbit Science Japan Co., Ltd., for
elemental analysis. We greatly thank Tosoh F-Tech, Inc., for the
generous gifts of Deoxo-Fluor, Yarovenko reagent and TFEMDA.
[
[
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