Ring-fluorinated naphthalene and indene synthesis via 6- and 5-endo-trig cyclizations of gem-difluoroalkenes by carbon nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2004.01.004

The intramolecular vinylic substitution of gem-difluoroalkenes is accomplished with sp³ and sp² carbon nucleophiles (2-arylethyllithium and aryllithium) in a 6-endo-trig and a normally disfavored 5- endo-trig fashion, leading to the

Full text of DOI:10.1016/j.jfluchem.2004.01.004

Journal of Fluorine Chemistry 125 (2004) 585–593
Ring-fluorinated naphthalene and indene synthesis via 6- and
5-endo-trig cyclizations of gem-difluoroalkenes
by carbon nucleophiles
Junji Ichikawaa,*, Hiroyuki Miyazakib, Kotaro Sakodaa, Yukinori Wadaa
aDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bDepartment of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
Received 17 October 2003; received in revised form 28 December 2003; accepted 6 January 2004
Abstract
The intramolecular vinylic substitution of gem-difluoroalkenes is accomplished with sp3 and sp2 carbon nucleophiles (2-arylethyllithium
and aryllithium) in a 6-endo-trig and a normally disfavored 5-endo-trig fashion, leading to the synthesis of 3-fluoro-1,2-dihydronaphthalenes
and 3-fluoroindenes, respectively. The dihydronaphthalenes are readily aromatized on treatment with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) to afford 2-fluoronaphthalenes.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Fluoronaphthalene; Fluoroindene; Baldwin’s rules; 5-Endo-trig cyclization; 6-Endo-trig cyclization; Gem-difluoroalkene; Nucleophilic
substitution; Addition–elimination; Organolithium
1. Introduction
Their remarkable reactivity toward substitution is due to (i)
the electrophilic activation of the carbon–carbon double
bond by the two fluorines and (ii) the leaving group ability
of the fluoride ions.
Fluorinated carbocyclic p-systems are units of increasing
significance in pharmaceuticals, agrochemicals, and materi-
als due to their biological activities and physical properties
[1,2]. Introduction of fluorine into aromatic and alicyclic p-
systems is usually achieved by the Balz–Schiemann reaction
or by use of various fluorinating reagents [3–5]. However,
lack of regioselectivity, the necessity of multistep proce-
dures, and difficulties in handling these fluorinating reagents
continue to be problems with these conventional methods.
Therefore, the development of efficient methods for the
selective construction of those fluorinated carbocycles
remains a highly desirable goal.Recently, we have intro-
duced a new concept for the synthesis of five- and six-
membered ring-fluorinated heterocyclic compounds, such as
indoles, benzo[b]furans, benzo[b]thiophenes, 2-pyrrolines,
2,3-dihydrofurans, 2,3-dihydrothiophenes, isochromenes,
isothiochromenes, quinolines, and isoquinolines [6–11].
This flexible methodology is based on vinylic nucleophilic
substitution (SNV) of the fluorines in gem-difluoroalkenes
via intramolecular addition–elimination processes [12–14].
We expected that our ‘‘intramolecular substitution’’ con-
cept could easily be adapted to the construction of carbo-
cyclic p-systems, such as naphthalene and indene nuclei. For
these ring constructions, intramolecular carbon nucleophiles
must be employed, and particularly for the construction of
the indene nucleus, 5-endo-trig cyclizations that are dis-
favored by Baldwin’s rules must proceed [15–17]. Herein we
wish to report the results of our studies on the intramolecular
cyclization of gem-difluoroalkenes with sp3 and sp2 carbon
nucleophiles leading to the synthesis of ring-fluorinated
naphthalene and indene derivatives.
2. Results and discussions
2.1. Synthesis of 2-fluorinated naphthalene derivatives
For the synthesis of 2-fluoronaphthalenes, we adopted
the following two methods in order to generate the intramo-
lecular carbon nucleophiles: (i) metal–halogen exchange of
iodomethyl groups (ICH2ꢀ ! ꢀCH2ꢀ), (ii) deprotonation
* Corresponding author. Tel.: þ81-3-5841-4345; fax: þ81-3-5841-4345.
E-mail address: junji@chem.s.u-tokyo.ac.jp
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.01.004

586
J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
I
(0.8 eq)
MsO
R
3
1) n-BuLi (2.1 eq)
–78 ˚C, 30 min
cat. Pd0, CuI (1.0 eq)
R
F2C
MsO
CF3CH2OTs
CF2
C
r.t., 6 h
/ THF–HMPA
2) R3B (1.1 eq)
–78 ˚C →r.t., 4 h
/ THF
BR2
1
2
4a R = n-Bu : 54%
4b R = s-Bu : 77%
cat. Pd0 : 2 mol% Pd2(dba)3•CHCl3-PPh3 (1 : 4)
R
R
KCN (2.0 eq)
NaI (1.5 eq)
r.t., 14 h / acetone
cat. 18-Crown-6
F2C
NC
F2C
reflux, 10 h / CH3CN
I
5a R = n-Bu : 71%
5b R = s-Bu : 73%
6a R = n-Bu : 82%
6b R = s-Bu : 73%
Scheme 1. Preparation of the substrates 5 and 6.
R
R
R
t-BuLi (2.2 eq)
F2C
F
F2C
–78 ˚C →r.t., 5 h
Li
I
/ hexane–Et O
2
(4 : 1)
5
7a R = n-Bu : 96%
7b R = s-Bu : 91%
Scheme 2. Synthesis of 3-fluoro-1,2-dihydronaphthalenes 7.
of active methylenes next to a cyano group (CH2ðCNÞꢀ
in excellent yield (Scheme 2). The synthesis of such
1-monofluorinated cycloalkenes is limited to the method
via difluorination of cyclic ketones and dehydrofluorination
[21]. Addition of a polar solvent, such as THF or HMPA as a
cosolvent resulted in a drastic decrease in the yield of 7.
Furthermore, we attempted conversion of thus obtained
dihydronaphthalenes 7 into 2-fluoronaphthalenes 8 by oxida-
tion. Dehydrogenation of 7 was examined with palladium on
charcoal, tetrachloro-1,4-benzoquinone (chloranil), or 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). On treat-
ment of 7 with 3 eq. of DDQ in refluxing benzene, the desired
aromatization proceeded to afford 2-fluoronaphthalenes 8a,b
in good yield (Table 1, Entries 5, 6).
!
ꢀCHðCNÞꢀ). Thus, we designed b,b-difluorostyrenes 5
and 6 bearing 2-iodoethyl and 2-cyanoethyl groups at the
o-position as precursors of 2-fluoronaphthalenes. These sub-
strates 5 and 6 were prepared as outlined in Scheme 1 via the
one-pot sequence that we have previously established for a
wide range of gem-difluoroalkenes [18]. 2,2-Difluorovinyl-
boranes 2 were prepared in situ from 2,2,2-trifluoroethyl
p-toluenesulfonate 1 and trialkylboranes. The coupling reac-
tions of 2 with aryl iodide 3 were conducted in the presence of
palladium catalyst and CuI, followed by replacement of the
OMs group by I and CN groups, leading to 5 and 6.
According to the reported procedure for lithium–halogen
exchange for primary alkyl iodides [19,20], o-(2-iodoethyl)-
styrenes 5a,b were treated with 2.2 eq. of tert-butyllithium to
generate carbon nucleophiles. The desired intramolecular
substitution of the carbanions for the vinylic fluorines
occurred to afford 3-fluoro-1,2-dihydronaphthalenes 7a,b
Table 1
Synthesis of 2-fluoronaphthalenes 8
Entry
R
Reagent (eq.)
Solvent
Conditions
Yield (%)
1
2
3
4
5
6
n-Bu (7a)
n-Bu (7a)
n-Bu (7a)
n-Bu (7a)
n-Bu (7a)
s-Bu (7b)
10% Pd–C (0.038)
Chloranil (1.2)
DDQ (1.2)
Diglyme
Xylene
Reflux 48 h
Reflux 6 h
Reflux 12 h
Reflux 2 h
Reflux 3 h
Reflux 3 h
Trace (8a)
26 (8a)
35 (8a)
43 (8a)
71 (8a)
70 (8b)
Benzene
Diglyme
Benzene
Benzene
DDQ (2.0)
DDQ (3.0)
DDQ (3.0)

J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
587
Next, we examined the generation of carbanions via
2.2. Synthesis of 3-fluorinated indene
abstraction of an a-hydrogen of a cyano group by a
base instead of the above-mentioned lithium–halogen
exchange. This would allow construction of naphthalene
derivatives bearing a cyano group, a versatile substituent
that can be readily converted into other functional
groups, such as carboxy, aminomethyl, and amino groups.
When difluorostyrene 6a bearing a cyanoethyl group was
treated with 1 eq. of butyllithium [22], the expected
cyclization proceeded to give 3-fluoro-1,2-dihydro-
2-naphthonitrile 9a along with recovered starting material
6a. Using 2 eq. of butyllithium or tert-butyllithium raised
the yield of 9a to 47% or 39%, respectively (Table 2,
Entries 1 and 2). To prevent the attack of butyllithium
at the terminal difluoromethylene and the cyano carbons,
we tried a bulky amide base, such as lithium diisopropy-
lamide (LDA) or lithium hexamethyldisilazide (LiHMDS).
The reaction with LiHMDS (2 eq.) afforded 9a in 23%
yield along with the oxidized product 10a in 52%
yield, giving rise to an increase in the total yield of the
cyclized products 9a and 10a up to 75% (Table 2, Entry 4).
In order to obtain 10 as a single cyclized product, oxidative
post-treatment was conducted. The crude products includ-
ing 9 and 10 were treated with DDQ (3 eq.) under reflux
in benzene for 3 h to afford 3-fluoro-2-naphthonitriles
10a,b in 68 and 58% yield from 6a,b, respectively (Entries
5 and 6).
In order to construct the five-membered ring of the indene
nucleus, the normally disfavored 5-endo-trig cyclization
must proceed in the intramolecular substitution of gem-
difluoroalkenes by phenyl or benzyl anions. Since we have
already accomplished this type of 5-endo-trig cyclization by
sp3 carbanions [26] (see also [27] for 5-endo carbocycliza-
tion of gem-difluoroalkenes in the presence of SnCl4), a
phenyl anion of an sp2 carbon nucleophile was adopted to
broaden the scope of the nucleophilic 5-endo-trig ring
closures (for the nucleophilic 5-endo-trig cyclization, see
[9] and references therein). We expected the nucleophilic
5-endo-trig cyclization to proceed due to the unique proper-
ties of gem-difluoroalkenes: (i) the electrostatic attraction
between the cationic CF2 carbon and nucleophilic center
(anion) would allow initial ring formation and (ii) the
successive elimination of fluoride ion could suppress the
reverse ring opening, thus functioning as a ‘‘lock’’. On the
basis of these considerations, we designed difluoroallylben-
zenes 13 bearing bromine or iodine at the ortho position as
precursors for 3-fluoroindenes, which were prepared as
depicted in Schemes 3 and 4.
The acid chloride generated in situ from carboxylic acid
11 and thionyl chloride was treated with benzene in the
presence of aluminum chloride to undergo Friedel–Crafts
acylation, leading to 20-bromodeoxybenzoin 12. Thus
obtained 12 was difluoromethylated with dibromodifluoro-
methane and tris(dimethylamino)phosphine in THF via
Wittig-type reaction [28] to give a-(o-bromophenyl-
methyl)-b,b-difluorostyrene 13a (Scheme 3).
The corresponding iodide 13b was prepared as follows
(Scheme 4): dilithiated pivalanilide 140 was generated in situ
from 14 [29] to undergo the SN2’ reaction of a-trifluoro-
methylstyrene [30] leading to o-(3,3-difluoro-2-phenylallyl)-
pivalanilide 16. Thus obtained 16 was hydrolyzed with
hydrochloric acid to give o-(3,3-difluoroallyl)aniline 17.
Thus, the ‘‘cyclization–dehydrogenation’’ sequence
provides a synthetic method for 2-fluorinated naph-
thalenes 8 and 10 with or without a cyano group at the
3-position. Such compounds are less accessible by con-
ventional electrophilic methods. Electrophilic fluorination
of naphthalenes affords 1-fluoronaphthalenes as major
products and is severely deactivated by electron-with-
drawing groups [3–5] (for the synthesis of fluoronaphtha-
lenes, see [23,24]; for the synthesis of naphthalenes, see
[25]).
Table 2
Synthesis of fluoronaphthonitrile derivatives 9 and 10
Entry
R
Base (eq.)
Conditions
9 (%)
10 (%)
1
n-Bu (6a)
n-Bu (6a)
n-Bu (6a)
n-Bu (6a)
n-Bu (6a)
s-Bu (6b)
n-BuLi (2.0)
t-BuLi (2.0)
LDA (1.2)
ꢀ78 ꢁC ! RT, 7 h
ꢀ78 ꢁC ! RT, 5 h
ꢀ78 ꢁC ! RT, 11 h
ꢀ78 ꢁC ! RT, 1 h
ꢀ78 ꢁC ! RT, 6 h
ꢀ78 ꢁC ! RT, 6 h
47 (9a)
39 (9a)
30 (9a)
23 (9a)
0 (9a)
7 (10a)
3 (10a)
2
3
41 (10a)
52 (10a)
68 (10a)
58 (10b)
4
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (3.0)
5a
6a
0 (9b)
a The crude products were treated with DDQ (3 eq.) in refluxing benzene for 3 h.

588
J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
OH
Ph
Ph
1) SOCl2 (1.4 eq)
CF2Br2 (2.0 eq)
reflux, 2 h / benzene
P(NMe2)3 (4.0 eq)
O
O
F2C
Br
Br
Br
2) AlCl3 (3.0 eq)
r.t., 2 h / THF
reflux, 2 h / benzene
13a 24 %
12 78 %
Scheme 3. Preparation of the substrate 13a.
11
Scheme 4. Preparation of the substrate 13b.
Transformation of the amino group in 17 via diazotization
afforded b,b-difluoro-a-(o-iodophenylmethyl)styrene 13b.
We examined the cyclization of 13a,b via their lithium–
halogen exchange reaction. The results are summarized in
Table 4. On treatment of 13a with tert-butyllithium in diethyl
ether, monofluoroalkene 20 was obtained as a major product
by the direct substitution of tert-butyllithium for the vinylic
fluorine (Table 3, Entry 1). Screening of alkyllithiums for
metal–halogen exchange and reaction conditions revealed the
following: After iodide 13b was treated with 1 eq. of
butyllithium in Et2O–hexane (1:4) at ꢀ110 8C, conducting
the cyclization at room temperature raised the yield of indene
18 up to 52% (Entry 5). Since the formation of alkylated
indenes 21 and benzyldifluorostyrene 19 suggested that
deprotonation of indene 18 by aryllithium 130 decreased
the yield (Entries 5 and 6, Scheme 5), NaH or LDA was
added for deprotonation of 18 in order to prevent quenching
130 with 18, but the expected results were not obtained.
Thus, we have accomplished the 5-endo-trig cyclization
with an sp2 carbon nucleophile as well as sp3 carbon
nucleophiles [26], providing a regioselective entry to less
accessible 3-fluoroindenes (for the synthesis of indenes
bearing a fluorine on the five-membered ring, see: 3-fluor-
oindene: [31], 1-fluoroindene: [32]).
Table 3
Synthesis of 3-fluoroindene 18
Entry
X
RLi (eq.)
Solvent
Conditions
Yield (%)
18
19
20
21
1
2
3
4
5
6
Br (13a)
Br (13a)
I (13b)
I (13b)
I (13b)
I (13b)
t-BuLi (2.2)
t-BuLi (2.2)
t-BuLi (2.2)
s-BuLi (1.1)
n-BuLi(1.0)
MeLi (1.0)
Et2O
ꢀ78 8C, 0:5 h ! RT, 1 h
26
31
41
51
52
47
10
38
26
24
19
17
34 (20a)
21 (20a)
17 (20a)
0
0
0
0
0
Et2O–hexane (1:4)
Et2O–hexane (1:4)
Et2O–hexane (1:4)
Et2O–hexane (1:4)
Et2O–hexane (1:4)
ꢀ100 8C, 0:5 h ! RT, 1 h
ꢀ110 8C, 1 h ! ꢀ78 8C, 1 h ! RT, 2 h
ꢀ110 8C, 1 h ! ꢀ78 8C, 1 h ! RT, 2 h
ꢀ110 8C, 1 h ! ꢀ78 8C, 1 h ! RT, 2 h
ꢀ110 8C, 1 h ! ꢀ78 8C, 1 h ! RT, 2 h
0
5 (21b)
12 (21c)
14 (20c)

J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
Ph
F2C
589
Ph
F2C
Li
RI
LiI
13’
19
Li+
Ph
Ph
Ph
R
–
F
F
F
18
18’
21
Scheme 5. Generation and alkylation of indenyl anion 180.
2.3. Conclusion
stirred for 6 h at room temperature, the reaction was quenched
with phosphate buffer (pH 7). The mixture was filtered
through Celite, and then organic materials were extracted
with AcOEt three times. The combined extracts were washed
with brine and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
thin layer chromatography on silica gel (hexane–AcOEt 5:1)
to give 4a (275 mg, 54%) as a pale yellow liquid.
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J ¼ 7:0 Hz),
1.27–1.36 (4H, m), 2.27 (2H, br s), 2.87 (3H, s), 3.04 (2H, t,
J ¼ 7:2 Hz), 4.38 (2H, t, J ¼ 7:2 Hz), 7.15 (1H, d,
J ¼ 7:3 Hz), 7.24–7.32 (3H, m). 13C NMR (126 MHz,
CDCl3) d 13.7, 22.3, 29.0, 29.5 (d, JCF ¼ 2 Hz), 32.5,
37.2, 69.5, 90.8 (dd, JCF ¼ 22, 18 Hz), 127.1, 128.2, 129.6,
130.5 (d, JCF ¼ 4 Hz), 133.7 (d, JCF ¼ 4 Hz), 134.9, 152.8
(dd, JCF ¼ 290, 285 Hz). 19F NMR (471 MHz, CDCl3) dF
68.0 (1F, dt, JFF ¼ 46 Hz, JFH ¼ 3 Hz), 72.7 (1F, d,
JFF ¼ 46 Hz). IR (neat) 2958, 2861, 1741, 1359, 1236,
1176, 958, 906, 804, 765 cmꢀ1. MS (20 eV) m/z 318 (Mþ;
21), 180 (100), 129 (50). HRMS calcd. for C15H20O3SF2
318.1102 (Mþ); found 318.1102.
In carbocyclization of gem-difluoroalkenes, 6-endo-trig
and 5-endo-trig ring closures are successfully achieved to
construct naphthalene and indene frameworks, showing that
not only heteroatom nucleophiles but also sp3 and sp2 carbon
nucleophiles can be adapted to this intramolecular substitu-
tion. Thus, the scope of this methodology has been expanded
in terms of six- and five-membered ring formation.
3. Experimental
3.1. General experimental procedure
NMR spectra were obtained on a JEOL JNM-A-500, a
JEOL-EX-270, or a Bruker DRX-500 spectrometer. Chemi-
cal shift values were given in ppm relative to internal Me4Si
1
(for H and 13C NMR: d-value) or internal C6F6 (for 19F
NMR: dF-value). IR spectra were recorded on a Horiba
FT-300S or a JEOL JIR-WINSPEC50 spectrometer. Mass
spectra were taken with a JEOL JMS-DX-300 or a JEOL
JMS-SX-102A spectrometer. Elemental analyses were per-
formed with a YANAKO MT-3 CHN Corder apparatus.
3.2.2. 2-[o-(1-sec-Butyl-2,2-difluorovinyl)phenyl]ethyl
methansulfonate (4b)
Compound4bwasprepared bythemethoddescribed for 4a
usingbutyllithium(32 ml,1.57 Minhexane,50 mmol),2,2,2-
trifluoroethyl p-toluenesulfonate (6.0 g, 24 mmol), tri-sec-
butylborane (26 ml, 1.0 M in THF, 26 mmol), HMPA
(24 ml), triphenylphosphine(496 mg,1.89 mmol),tris(diben-
zylideneacetonyl)bispalladium-chloroform (1/1) (489 mg,
0.47 mmol), 3 (6.2 g, 19 mmol), and copper(I) iodide
(4.5 g, 24 mmol). Purification by column chromatography
on silica gel (hexane–AcOEt 5:1) to give 4b (4.7 g, 77%)
as a pale yellow liquid.
1H NMR (270 MHz, (CD3)2SO, 90 8C) d 1.20–2.18 (8H,
m), 2.72–2.94 (1H, m), 3.43 (2H, t, J ¼ 6:7 Hz), 3.48 (3H, s),
4.82 (2H, t, J ¼ 6:7 Hz), 7.49–7.90 (4H, m). 13C NMR
(68 MHz, (CD3)2SO, 90 8C) d 11.2, 17.3, 27.0, 31.5, 35.2,
36.5, 68.9, 94.5 (d, JCF ¼ 25, 16 Hz), 126.1, 126.1, 127.6,
128.8, 129.8, 135.3, 151.7 (dd, JCF ¼ 287, 283 Hz). 19F NMR
(254 MHz, (CD3)2SO, 110 8C) dF 70.7 (1F, br s), 75.8 (1F, br
s). IR (neat) 2966, 2937, 1732, 1358, 1230, 1174, 1059, 958,
804, 761 cmꢀ1. MS (20 eV) m/z 318 (Mþ; 18), 193 (100), 173
3.2. Synthesis of 2-fluorinated naphthalene derivatives
3.2.1. 2-[o-(1-Butyl-2,2-difluorovinyl)phenyl]ethyl
methansulfonate (4a)
Butyllithium (3.0 ml, 1.40 M in hexane, 4.2 mmol) was
added to a solution of 2,2,2-trifluoroethyl p-toluenesulfonate
(1, 509 mg, 2.0 mmol) in THF (10 ml) at ꢀ78 8C over 10 min
under nitrogen. The reaction mixture was stirred for 20 min at
ꢀ78 8C, and then tributylborane (2.2 ml, 1.0 M in THF,
2.2 mmol) was added at ꢀ78 8C. After being stirred for
1 h, the reaction mixture was warmed to room temperature
and stirred for an additional 3 h. The solution was treated with
hexamethylphosphoric triamide (HMPA, 2 ml), triphenyl-
phosphine (42 mg, 0.16 mmol), and tris(dibenzylideneaceto-
nyl)bispalladium-chloroform (1/1) (41 mg, 0.040 mmol) and
stirred for 15 min. To the solution was added 2-(o-iodophe-
nyl)ethyl methansulfonate (3, 522 mg, 1.6 mmol) and cop-
per(I) iodide (381 mg, 2.0 mmol). After the mixture was

590
J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
(76). HRMS calcd. for C15H20O3SF2 318.1102 (Mþ); found
318.1070.
extracts were washed with brine and dried over Na2SO4.
After removal of the solvent under reduced pressure, the
residue was purified by thin layer chromatography on silica
gel (hexane–AcOEt 5:1) to give 6a (63 mg, 82%) as a
colorless liquid.
3.2.3. a-Butyl-b,b-difluoro-o-(2-iodoethyl)styrene (5a)
To a solution of 4a (208 mg, 0.65 mmol) in acetone (3 ml)
was added sodium iodide (147 mg, 0.65 mmol) at room
temperature under nitrogen. After the mixture was stirred
for 6 h, the reaction was quenched with phosphate buffer
(pH 7). Organic materials were extracted with AcOEt three
times. The combined extracts were washed with brine and
dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by thin layer
chromatography on silica gel (hexane) to give 5a (163 mg,
71%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J ¼ 6:9 Hz),
1.26–1.36 (4H, m), 2.18–2.36 (2H, m), 3.15 (2H, t,
J ¼ 8:2 Hz), 3.29 (2H, t, J ¼ 8:2 Hz), 7.12 (1H, d,
J ¼ 7:0 Hz), 7.23–7.21 (3H, m). 13C NMR (126 MHz,
CDCl3) d 3.7, 13.8, 22.3, 29.1, 29.6 (d, JCF ¼ 11 Hz),
37.6, 90.8 (dd, JCF ¼ 22, 22 Hz), 126.9, 128.2, 128.9,
130.5 (d, JCF ¼ 2 Hz), 133.0 (d, JCF ¼ 4 Hz), 139.8, 152.8
(dd, JCF ¼ 290, 290 Hz). 19F NMR (471 MHz, CDCl3) dF
72.6 (1F, d, JFF ¼ 47 Hz), 67.9 (1F, d, JFF ¼ 47 Hz). IR (neat)
2956, 2860, 1740, 1466, 1234, 1173, 1126, 1012, 968,
754 cmꢀ1. MS (20 eV) m/z 350 (Mþ; 93), 223 (100), 231
(99). HRMS calcd. for C14H17F2I 350.0345 (Mþ); found
350.0341.
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J ¼ 6:9 Hz),
1.29–1.35 (4H, m), 2.27 (2H, br s), 2.58 (2H, t, J ¼ 7:7 Hz),
2.94 (2H, t, J ¼ 7:7 Hz), 7.15 (1H, d, J ¼ 7:0 Hz), 7.25–7.35
(3H, m). 13C NMR (126 MHz, CDCl3) d 13.8, 18.4, 22.4,
28.6, 29.2, 29.6 (dd, JCF ¼ 3, 3 Hz), 90.7 (dd, JCF ¼ 22,
22 Hz), 119.2, 127.3, 128.5, 128.8, 130.6 (d, JCF ¼ 2 Hz),
133.1 (d, JCF ¼ 4 Hz), 136.8 (d, JCF ¼ 2 Hz), 152.7 (dd,
JCF ¼ 290, 290 Hz). 19F NMR (471 MHz, CDCl3) dF 72.9
(1F, d, JFF ¼ 46 Hz), 68.2 (1F, d, JFF ¼ 46 Hz). IR (neat)
2958, 2931, 2861, 2249, 1740, 1450, 1236, 1132, 968,
764 cmꢀ1. MS (20 eV) m/z 249 (Mþ; 16), 207 (100). HRMS
calcd. for C15H17NF2 249.1329 (Mþ); found 249.1311.
3.2.6. 3-[o-(1-sec-Butyl-2,2-
difluorovinyl)phenyl]propanitrile (6b)
Compound 6b was prepared by the method described for
6a using 5b (1.50 g, 4.3 mmol) acetonitrile (8 ml), potas-
sium cyanide (558 mg, 8.6 mmol), and catalytic amount of
18-crown-6. Purification by column chromatography on
silica gel (hexane–AcOEt 10:1) gave 6b (781 mg, 73%)
as a colorless liquid.
1H NMR (500 MHz, (CD3)2SO, 100 8C) d 0.95 (3H, t,
J ¼ 6:8 Hz), 1.04 (3H, br s), 1.37 (1H, br s), 1.48–1.62 (1H,
m), 2.43 (1H, br s), 2.77 (2H, t, J ¼ 7:3 Hz), 2.92 (2H, t,
J ¼ 7:3 Hz), 7.16 (1H, d, J ¼ 7:5 Hz), 7.28 (1H, dd,
J ¼ 7:5, 7.5 Hz), 7.35 (1H, dd, J ¼ 7:5, 7.5 Hz), 7.43
(1H, d, J ¼ 7:5 Hz). 13C NMR (126 MHz, (CD3)2SO,
100 8C) d 11.0, 16.4, 17.2, 27.0, 27.3, 35.2, 94.4 (d,
JCF ¼ 22, 17 Hz), 118.9, 126.0, 127.6, 127.9, 130.0,
131.5, 137.1, 151.6 (dd, JCF ¼ 291, 284 Hz). 19F NMR
(254 MHz, (CD3)2SO, 100 8C) dF 70.8 (1F, br s), 75.9
(1F, br s). IR (neat) 2968, 2935, 2877, 2249, 1734, 1458,
1232, 1059, 935, 760 cmꢀ1. MS (20 eV) m/z 249 (Mþ; 16),
200 (100), 159 (68). HRMS calcd. for C15H17NF2 249.1329
(Mþ); found 249.1315.
3.2.4. a-sec-Butyl-b,b-difluoro-o-(2-iodoethyl)styrene (5b)
Compound 5b was prepared by the method described for
5a using 4b (4.7 g, 14.6 mmol), acetone (20 ml) sodium
iodide (3.3 g, 22 mmol). Purification by column chromato-
graphy on silica gel (hexane) gave 5b (3.7 g, 73%) as a
colorless liquid.
1H NMR (500 MHz, (CD3)2SO, 100 8C) d 0.97–1.60 (8H,
m), 2.40 (1H, br s), 3.14 (2H, t, J ¼ 7:9 Hz), 3.14 (2H, t,
J ¼ 7:9 Hz), 7.12 (1H, d, J ¼ 7:5 Hz), 7.27 (1H, ddd,
J ¼ 7:5, 7.5, 1.2 Hz), 7.32 (1H, ddd, J ¼ 7:5, 7.5,
1.3 Hz), 7.39 (1H, d, J ¼ 7:5 Hz). 13C NMR (126 MHz,
(CD3)2SO, 100 8C) d 3.7, 11.1, 17.3, 26.9, 35.3, 36.3, 94.5
(d, JCF ¼ 24, 19 Hz), 126.0, 127.6, 128.1, 129.3, 130.0,
138.9, 151.6 (dd, JCF ¼ 290, 284 Hz). 19F NMR
(254 MHz, (CD3)2SO, 100 8C) dF 70.8 (1F, br s), 75.8
(1F, br s). IR (neat) 2966, 2933, 1731, 1459, 1284, 1230,
1170, 1058, 944, 757 cmꢀ1. MS (20 eV) m/z 350 (Mþ; 77),
223 (100), 167 (44). HRMS calcd. for C14H17F2I 350.0345
(Mþ); found 350.0331.
3.2.7. 4-Butyl-3-fluoro-1,2-dihydronaphthalene (7a)
To a solution of 5a (1.01 g, 2.88 mmol) in Et2O–hexane
(1:4, 20 ml) was added tert-butyllithium (3.87 ml, 1.64 M in
pentane, 6.35 mmol) at ꢀ78 8C under nitrogen. After being
stirred for 1 h, the reaction mixture was warmed to room
temperature and stirred for an additional 4 h. After the
reaction was quenched with phosphate buffer (pH 7),
organic materials were extracted with AcOEt three times.
The combined extracts were washed with brine and dried
over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatogra-
phy on silica gel (hexane) to give 7a (567 mg, 96%) as a
colorless liquid.
3.2.5. 3-[o-(1-Butyl-2,2-difluorovinyl)phenyl]propanitrile
(6a)
To a solution of 5a (107 mg, 0.306 mmol) in acetonitrile
(3 ml) was added potassium cyanide (40 mg, 0.67 mmol)
and catalytic amount of 18-crown-6 under nitrogen. After
the reaction mixture was refluxed for 10 h, phosphate buffer
(pH 7) was added to quench the reaction. Organic materials
were extracted with AcOEt three times. The combined
1H NMR (500 MHz, CDCl3) d 0.93 (3H, t, J ¼ 7:2 Hz),
1.39 (2H, tq, J ¼ 7:2, 7.2 Hz), 1.44–1.57 (2H, m), 2.48–2.56

J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
591
(4H, m), 2.94 (2H, td, J¼8.4 Hz, JHF ¼ 2:7 Hz), 7.06–7.12
(2H, m), 7.17–7.22 (2H, m). 13C NMR (126 MHz, CDCl3) d
13.9, 22.6, 23.0 (d, JCF ¼ 4 Hz), 24.8 (d, JCF ¼ 25 Hz), 28.9
3.2.10. 1-sec-Butyl-2-fluoronaphthalene (8b)
Compound 8b was prepared by the method described for
8a using 7b (90 mg, 0.44 mmol), benzene (6 ml), DDQ
(300 mg, 1.32 mmol). Purification by thin layer chromato-
graphy on silica gel (hexane) gave 8b (63 mg, 70%) as a
colorless liquid.
(d, JCF ¼ 7 Hz), 30.5 (d, JCF ¼ 2 Hz), 114.3 (d, JCF
¼
15 Hz), 122.8 (d, JCF ¼ 6 Hz), 125.7 (d, JCF ¼ 2 Hz),
126.5, 127.3, 133.2, 134.5 (d, JCF ¼ 7 Hz), 158.4 (d,
JCF ¼ 265 Hz). 19F NMR (471 MHz, CDCl3) dF 57.3 (t,
JFH ¼ 3 Hz). IR (neat) 2956, 2872, 1680, 1487, 1452,
1365, 1227, 1180, 1151, 760 cmꢀ1. MS (20 eV) m/z 204
(Mþ; 96), 162 (100). HRMS calcd. for C14H17F 204.1314
(Mþ); found 204.1316.
1H NMR (500 MHz, CDCl3) d 0.86 (3H, t, J ¼ 7:2 Hz),
1.46 (3H, dd, J ¼ 7:2 Hz, JHF ¼ 1:2 Hz), 1.81–2.03 (2H,
m), 3.50–3.62 (1H, m), 7.19 (1H, dd, JHF ¼ 11:3 Hz,
J ¼ 9:0 Hz), 7.40 (1H, dd, J ¼ 7:6, 7.3 Hz), 7.50 (1H, dd,
J ¼ 8:2, 7.3 Hz), 7.66 (1H, dd, J ¼ 9:0 Hz, JHF ¼ 5:4 Hz),
7.80 (1H, d, J ¼ 7:6 Hz), 8.14 (1H, d, J ¼ 8:2 Hz). 13C
NMR (126 MHz, CDCl3) d 12.9, 19.6 (d, JCF ¼ 4 Hz), 28.8
(d, JCF ¼ 4 Hz), 33.8, 116.8 (d, JCF ¼ 29 Hz), 123.7, 124.4
(d, JCF ¼ 3 Hz), 126.4, 126.6 (d, JCF ¼ 11 Hz), 128.3 (d,
JCF ¼ 10 Hz), 128.9, 131.0, 133.1 (d, JCF ¼ 8 Hz), 159.1 (d,
JCF ¼ 246 Hz). 19F NMR (471 MHz, CDCl3) dF 48.9 (br s).
IR (neat) 2946, 2873, 1598, 1515, 1463, 1394, 1222, 929,
808, 744 cmꢀ1. MS (20 eV) m/z 202 (Mþ; 31), 173 (100),
171 (13). HRMS calcd. for C14H15F 202.1158 (Mþ); found
202.1127.
3.2.8. 4-sec-Butyl-3-fluoro-1,2-dihydronaphthalene (7b)
Compound7bwas prepared bythe methoddescribed for7a
using 5b (312 mg, 0.892 mmol), Et2O–hexane (1:4, 18 ml),
tert-butyllithium (1.20 ml, 1.64 M in pentane, 1.96 mmol).
Purification by thin layer chromatography on silica gel (hex-
ane) gave 7b (167 mg, 91%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) d 0.91 (3H, t, J ¼ 7:3 Hz),
1.29 (3H, dd, J ¼ 7:3 Hz, JHF ¼ 1:2 Hz), 1.60–1.71 (1H,
m), 1.74–1.84 (1H, m), 2.44–2.50 (2H, m), 2.76 (1H, ddq,
J ¼ 14:7, 7.3, 7.3 Hz), 2.83–2.94 (2H, m), 7.05–7.12 (2H,
m), 7.17 (1H, ddd, J ¼ 7:4, 7.4, 0.9 Hz), 7.31 (1H, d,
J ¼ 7:4 Hz). 13C NMR (126 MHz, CDCl3) d 12.8, 19.1
(d, JCF ¼ 3 Hz), 25.6 (d, JCF ¼ 26 Hz), 28.2 (d,
JCF ¼ 4 Hz), 29.3 (d, JCF ¼ 7 Hz), 33.5, 118.5 (d,
JCF ¼ 11 Hz), 123.2 (d, JCF ¼ 7 Hz), 125.6, 126.4, 127.4,
133.6, 135.4 (d, JCF ¼ 8 Hz), 159.4 (d, JCF ¼ 267 Hz). 19F
NMR (471 MHz, CDCl3) dF 61.3 (br s). IR (neat) 2962,
3.2.11. 4-Butyl-3-fluoro-1,2-dihydro-2-naphthonitrile (9a)
To a solution of butyllithium (0.24 ml, 1.41 M in hexane,
0.34 mmol) in THF (1.5 ml) was added 6a (41 mg,
0.17 mmol) in THF (1.5 ml) at ꢀ78 8C. After being stirred
for 1 h, the reaction mixture was warmed to room tempera-
ture and stirred for an additional 6 h. The reaction was
quenched with phosphate buffer (pH 7). Organic materials
were extracted with AcOEt three times, and the combined
extracts were washed with brine and dried over Na2SO4.
After removal of the solvent under reduced pressure, the
residue was purified by thin layer chromatography on silica
gel (hexane–AcOEt 10:1) to give 9a (18 mg, 47%) as a pale
yellow liquid.
1H NMR (500 MHz, CDCl3) d 0.93 (3H, t, J ¼ 7:3 Hz),
1.39 (2H, tq, J ¼ 7:3, 7.3 Hz), 1.44–1.59 (2H, m), 2.51–2.62
(2H, m), 3.18–3.33 (2H, m), 3.72 (1H, td, J ¼ 6:0 Hz,
JHF ¼ 6:0 Hz), 7.17–7.30 (4H, m). 13C NMR (126 MHz,
CDCl3) d 13.8, 22.6, 23.4 (d, JCF ¼ 4 Hz), 28.2 (d,
JCF ¼ 27 Hz), 30.2 (d, JCF ¼ 2 Hz), 33.1 (d, JCF ¼ 3 Hz),
117.6, 118.6 (d, JCF ¼ 12 Hz), 123.9 (d, JCF ¼ 7 Hz), 127.3
(d, JCF ¼ 2 Hz), 127.8, 128.0, 129.0, 132.1 (d, JCF ¼ 6 Hz),
149.4 (d, JCF ¼ 266 Hz). 19F NMR (471 MHz, CDCl3) dF
50.9 (s). IR (neat) 2958, 2241, 1680, 1489, 1454, 1236,
1190, 1157, 1111, 764 cmꢀ1. MS (20 eV) m/z 229 (Mþ; 44),
187 (100). HRMS calcd. for C15H16NF 229.1267 (Mþ);
found 229.1261.
2836, 1666, 1484, 1452, 1224, 1180, 1149, 921, 759 cmꢀ1
.
MS (20 eV) m/z 204 (Mþ; 88), 175 (100), 147 (40). HRMS
calcd. for C14H17F 204.1314 (Mþ); found 204.1335.
3.2.9. 1-Butyl-2-fluoronaphthalene (8a)
To a solution of 7a (61 mg, 0.30 mmol) in benzene (6 ml)
was added DDQ (202 mg, 0.89 mmol) under nitrogen. The
reaction mixture was refluxed for 3 h, and then filtered
through Celite. After removal of the solvent under reduced
pressure, the residue was purified by thin layer chromato-
graphy on silica gel (hexane) to give 8a (43 mg, 71%) as a
colorless liquid.
1H NMR (500 MHz, CDCl3) d 0.96 (3H, t, J ¼ 7:6 Hz),
1.46 (2H, tq, J ¼ 7:6, 7.4 Hz), 1.66 (2H, tt, J ¼ 7:9, 7.4 Hz),
3.07 (2H, td, J ¼ 7:9 Hz, JHF ¼ 2:2 Hz), 7.22 (1H, dd,
J ¼ 9:2 Hz, JHF ¼ 9:2 Hz), 7.42 (1H, dd, J ¼ 7:6,
7.6 Hz), 7.52 (1H, dd, J ¼ 8:1, 7.6 Hz), 7.67 (1H, dd,
J ¼ 9:2 Hz, JHF ¼ 5:5 Hz), 7.82 (1H, d, J ¼ 7:6 Hz), 7.99
(1H, d, J ¼ 8:1 Hz). 13C NMR (126 MHz, CDCl3) d 14.0,
22.8, 24.1 (d, JCF ¼ 4 Hz), 32.3, 116.0 (d, JCF ¼ 27 Hz),
122.6 (d, JCF ¼ 27 Hz), 123.6 (d, JCF ¼ 7 Hz), 124.5 (d,
JCF ¼ 3 Hz), 126.5, 127.9 (d, JCF ¼ 10 Hz), 128.7, 130.8,
133.0 (d, JCF ¼ 6 Hz), 158.2 (d, JCF ¼ 243 Hz). 19F NMR
(471 MHz, CDCl3) dF 43.7 (m). IR (neat) 2958, 2873, 1628,
1516, 1468, 1392, 1227, 806, 744, 665 cmꢀ1. MS (20 eV)
m/z 202 (Mþ; 53), 159 (100), 133 (32). HRMS calcd. for
C14H15F 202.1158 (Mþ); found 202.1135.
3.2.12. 4-Butyl-3-fluoro-2-naphthonitrile (10a)
Butyllithium (0.42 ml, 1.53 M in hexane, 0.65 mmol) was
added to a THF (1 ml) solution of 1,1,1,3,3,3-hexamethyl-
disilazane (HMDS, 0.14 ml, 0.65 mmol) at ꢀ78 8C under
nitrogen. The reaction mixture was stirred for 30 min, and
then 6a (81 mg, 0.33 mmol) in THF (2 ml) was added at
ꢀ78 8C. After being stirred for 1 h, the reaction mixture was

592
J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
warmed to room temperature and stirred for an additional
3 h. After the reaction was quenched with phosphate buffer
(pH 7), organic materials were extracted with AcOEt three
times. The combined extracts were washed with brine and
dried over Na2SO4. After removal of the solvent under
reduced pressure, the crude products were treated with
DDQ (111 mg, 0.45 mmol) in refluxing benzene (4 ml)
for 3 h, and then filtered through Celite. After removal of
the solvent under reduced pressure, the residue was purified
by thin layer chromatography on silica gel (hexane–AcOEt
10:1) to give 10a (50 mg, 68%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) d 0.97 (3H, t, J ¼ 7:5 Hz),
1.45 (2H, qt, J ¼ 7:5, 7.5 Hz), 1.61–1.69 (2H, m), 3.08 (2H,
dt, J ¼ 7:8 Hz, JHF ¼ 2:3 Hz), 7.55 (1H, dd, J ¼ 7:6,
7.5 Hz), 7.68 (1H, dd, J ¼ 7:9, 7.5 Hz), 7.86 (1H, d,
J ¼ 7:6 Hz), 8.01 (1H, d, J ¼ 7:9 Hz), 8.06 (1H, d,
JHF ¼ 6:4 Hz). 13C NMR (126 MHz, CDCl3) d 13.9, 22.7,
24.2 (d, JCF ¼ 4 Hz), 32.0, 101.1 (d, JCF ¼ 22 Hz), 114.8,
123.9 (d, JCF ¼ 6 Hz), 124.8 (d, JCF ¼ 15 Hz), 126.3 (d,
JCF ¼ 2 Hz), 129.3, 129.6, 129.7, 133.8 (d, JCF ¼ 2 Hz),
134.8 (d, JCF ¼ 6 Hz), 155.5 (d, JCF ¼ 249 Hz). 19F NMR
(471 MHz, CDCl3) dF 45.2–45.3 (m). IR (neat) 2958, 2931,
2235, 1741, 1628, 1448, 1254, 777, 750, 665 cmꢀ1. MS
(20 eV) m/z 227 (Mþ; 58), 184 (100). HRMS calcd. for
C15H14NF 227.1110 (Mþ); found 227.1125.
(12, 83 mg, 0.30 mmol) was added, and then the mixture was
stirred for 2 h. After the reaction was quenched with phos-
phate buffer (pH 7), organic materials were extracted with
AcOEt three times. The combined extracts were washed
with brine and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
thin layer column chromatography on silica gel (AcOEt–
hexane 1:10) to give 13a (22.4 mg, 24%) as a colorless
liquid.
1H NMR (500 MHz, CDCl3) d 3.85 (2H, dd, JHF ¼ 2:1,
2.1 Hz), 7.02 (1H, td, J ¼ 7:0, 3.0 Hz), 7.13–7.16 (2H, m),
7.21 (1H, tt, J ¼ 7:0, 3.0 Hz), 7.25–7.29 (4H, m), 7.51 (1H,
d, J ¼ 7:9 Hz). 13C NMR (126 MHz, CDCl3) d 34.0, 90.4
(dd, JCF ¼ 21, 15 Hz), 124.6, 127.4, 127.4, 128.0, 128.2 (dd,
JCF ¼ 3, 3 Hz), 128.4, 129.6, 132.8, 133.0 (dd, JCF ¼ 4,
4 Hz), 137.4, 154.5 (dd, JCF ¼ 292, 289 Hz). 19F NMR
(254 MHz, CDCl3) dF 72.4 (1F, d, JFF ¼ 37 Hz), 73.1
(1F, d, JFF ¼ 37 Hz). IR (neat) 3059, 2918, 1728, 1444,
1242, 1099, 974, 748, 731, 694 cmꢀ1
.
3.3.2. o-(3,3-Difluoro-2-phenylallyl)aniline (17)
To a solution of pivalanilide (14) (165 mg, 1.00 mmol) in
THF (2.5 ml) was added butyllithium (1.6 ml, 1.56 M in
hexane, 2.5 mmol) dropwise at 0 8C under argon. After the
mixture was stirred at 0 8C for 2 h and at room temperature
for 20 h, a-trifluoromethylstyrene (15, 121 mg, 0.70 mmol)
3.2.13. 4-sec-Butyl-3-fluoro-2-naphthonitrile (10b)
and
N,N,N’,N’-tetramethylethylenediamine
(116 mg,
Compound 10b was prepared by the method described for
10a using butyllithium (0.40 ml, 1.64 M in hexane,
0.66 mmol), THF (2 ml), HMDS (106 mg, 0.66 mmol),
6b (55 mg, 0.22 mmol) in THF (2 ml), DDQ (149 mg,
0.66 mmol), and benzene (4 ml). Purification by thin layer
chromatography on silica gel (hexane–AcOEt 5:1) give 10b
(29 mg, 58%) as a colorless liquid.
1.0 mmol) were added at ꢀ78 8C. After the solution was
heated to reflux for 5 h, the reaction was quenched with
phosphate buffer (pH 7). The mixture was filtered through
Celite, and then organic materials were extracted with
AcOEt three times. The combined extracts were washed
with brine and dried over Na2SO2. After removal of the
solvent under reduced pressure, the residue was treated with
aqueous hydrochloric acid (2.5 ml, 12 M, 30 mmol) in EtOH
(2.5 ml). The reaction mixture was heated to reflux for 16 h,
and the reaction was quenched with phosphate buffer (pH 7).
The mixture was extracted with AcOEt three times. The
combined extracts were washed with brine and dried over
Na2SO4. After removal of the solvent under reduced pres-
sure, the residue was purified by thin layer column chro-
matography on silica gel (AcOEt–hexane 1:3) to give 17
(100 mg, 58%) as a pale yellow liquid.
1H NMR (500 MHz, CDCl3) d 3.46 (2H, br s), 3.51 (2H,
dd, JHF ¼ 2:0, 2.0 Hz), 6.57 (1H, dd, J ¼ 7:6, 1.0 Hz), 6.62
(1H, td, J ¼ 7:6, 1.0 Hz), 6.93 (1H, br d, J ¼ 7:6 Hz), 6.98
(1H, td, J ¼ 7:6, 1.0 Hz), 7.16–7.20 (1H, m), 7.22–7.25 (4H,
m). 13C NMR (126 MHz, CDCl3) d 29.6, 90.4 (dd, JCF ¼ 21,
14 Hz), 115.6, 118.6, 122.2 (dd, JCF ¼ 3, 3 Hz), 127.4,
127.4, 128.1 (dd, JCF ¼ 3, 3 Hz), 128.3, 129.3, 133.3 (dd,
JCF ¼ 3, 3 Hz), 144.2, 154.0 (dd, JCF ¼ 292, 287 Hz). 19F
NMR (471 MHz, CDCl3) dF 71.4 (1F, d, JFF ¼ 41 Hz), 72.2
(1F, d, JFF ¼ 41 Hz). IR (neat) 1716, 1622, 1495, 1456,
1234, 1101, 985, 744, 694, 603, 576 cmꢀ1. Anal. calcd. for
C15H13NF2: C, 73.45; H, 5.34; N, 5.71%. Found: C, 73.64;
H, 5.50; N, 5.67%.
1H NMR (500 MHz, CDCl3) d 0.83 (3H, t, J ¼ 7:2 Hz),
1.47 (3H, dd, J ¼ 7:2 Hz, JHF ¼ 1:4 Hz), 1.82–2.03 (2H,
m), 3.58 (1H, tq, J ¼ 7:2, 7.2 Hz), 7.54 (1H, dd, J ¼ 7:9,
7.7 Hz), 7.67 (1H, dd, J ¼ 8:2, 7.7 Hz), 7.87 (1H, d,
J ¼ 7:9 Hz), 8.09 (1H, d, JHF ¼ 6:1 Hz), 8.18 (1H, d,
J ¼ 8:2 Hz). 13C NMR (126 MHz, CDCl3) d 12.8, 19.3,
28.6 (d, JCF ¼ 4 Hz), 34.0, 101.9 (d, JCF ¼ 22 Hz), 114.7,
123.5, 124.0, 126.1, 128.8 (d, JCF ¼ 11 Hz), 129.6, 129.8,
134.2, 135.0 (d, JCF ¼ 8 Hz), 156.4 (d, JCF ¼ 251 Hz). 19F
NMR (471 MHz, CDCl3) dF 49.6 (br s). IR (neat) 2966,
2933, 2875, 2233, 1626, 1506, 1442, 1207, 748, 607 cmꢀ1
.
MS (20 eV) m/z 227 (Mþ; 75), 198 (100), 184 (35). HRMS
calcd. for C15H14NF 227.1110 (Mþ); found 227.1096.
3.3. Synthesis of 3-fluorinated indene
3.3.1. a-(o-Bromophenylmethyl)-b,b-difluorostyrene (13a)
To a solution of dibromodifluoromethane (126 mg,
0.60 mmol) in THF (2 ml), tris(dimethylamino)phosphine
(196 mg, 1.2 mmol) was added at ꢀ78 8C under argon. The
mixture was stirred for 30 min at that temperature, and
then warmed to room temperature. 20-Bromodeoxybenzoin

J. Ichikawa et al. / Journal of Fluorine Chemistry 125 (2004) 585–593
593
3.3.3. b,b-Difluoro-a-(o-iodophenylmethyl)styrene (13b)
Acknowledgements
o-(3,3-Difluoro-2-phenylallyl)aniline (17, 4.04 g, 16 mmol)
was dissolved in aqueous hydrochloric acid (20 ml, 4.5 M,
90 mmol), and then treated with a solution of sodium nitrite
(1.37 g, 20 mmol) in water (3 ml) at below 5 8C. After
30 min, excess reagent was decomposed by the addition with
amidosulfuric acid (320 mg, 3.3 mmol), and a cold solution
of potassium iodide (27.3 g, 165 mmol) in water (82 ml) was
added dropwise. The reaction mixture was stirred at
room temperature in the dark for 8 h. Organic materials
were extracted with CH2Cl2 three times, and the combined
extracts were washed with brine and dried over Na2SO4.
After removal of the solvent under reduced pressure, the
residue was purified by column chromatography on silica gel
(hexane–Et3N 100:1). Further purification was conducted by
gel permeation chromatography (GPC, CHCl3) to give 13b
(2.29 g, 39%) as a colorless liquid.
We gratefully acknowledge the financial support for this
research by Central Glass Co. Ltd.
References
[1] R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine
Chemistry: Principles and Commercial Applications, Plenum Press,
New York, 1994.
[2] J.T. Welch, Ed. Selective Fluorination in Organic and Bioorganic
Chemistry, American Chemical Society, Washington, DC, 1991.
[3] J.H. Clark, D. Wails, T.W. Bastock, Aromatic Fluorination, CRC
Press, Boca Raton, 1996.
[4] M. Hudlicky, A.E. Pavlath (Eds.), Chemistry of Organic Fluorine
Compounds II, American Chemical Society, Washington, DC, 1995.
[5] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991 (Chapters 1 and 12).
[6] J. Ichikawa, Y. Wada, T. Okauchi, T. Minami, Chem. Commun.
(1997) 1537–1538.
1H NMR (500 MHz, CDCl3) d 3.80 (2H, s), 6.84 (1H, t,
J ¼ 7:4 Hz), 7.12 (1H, d, J ¼ 7:4 Hz), 7.17 (1H, d,
J ¼ 7:4 Hz), 7.19–7.22 (1H, m), 7.25–7.28 (4H, m), 7.79
(1H, d, J ¼ 7:9 Hz). 13C NMR (126 MHz, CDCl3) d 39.1,
90.6 (dd, JCF ¼ 21, 14 Hz), 100.8, 127.4, 128.1 (dd, JCF ¼ 4,
4 Hz), 128.2, 128.3, 128.4, 128.8, 132.9 (dd, JCF ¼ 4, 4 Hz),
139.5, 140.4 (dd, JCF ¼ 2, 2 Hz), 154.5 (dd, JCF ¼ 293,
289 Hz). 19F NMR (471 MHz, CDCl3) dF 72.6 (1F, d,
JFF ¼ 36 Hz), 73.5 (1F, d, JFF ¼ 36 Hz, JFH ¼ 2 Hz). IR
[7] J. Ichikawa, M. Fujiwara, Y. Wada, T. Okauchi, T. Minami, Chem.
Commun. (2000) 1887–1888.
[8] Y. Wada, J. Ichikawa, T. Katsume, T. Nohiro, T. Okauchi, T. Minami,
Bull. Chem. Soc. Jpn. 74 (2001) 971–977.
[9] J. Ichikawa, Y. Wada, M. Fujiwara, K. Sakoda, Synthesis (2002)
1917–1936.
[10] J. Ichikawa, Y. Wada, H. Miyazaki, T. Mori, H. Kuroki, Org. Lett. 5
(2003) 1455–1458.
[11] Y. Wada, T. Mori, J. Ichikawa, Chem. Lett. (2003) 1000–1001.
[12] R.D. Chambers, Fluorine in Organic Chemistry, Antony Rowe,
Chippenham, 1973 (Chapter 1).
(neat) 1716, 1437, 1238, 1012, 991, 744, 729, 692 cmꢀ1
.
HRMS: calcd. for C15H11F2I (Mþ) 355.9874, found
355.9889.
[13] B.E. Smart, Characteristics of C–F systems, in: R.E. Banks, B.E.
Smart, J.C. Tatlow (Eds.), Organofluorine Chemistry: Principles and
Commercial Applications, Plenum Press, New York, 1994 (Chapter 3).
[14] M. Hudlicky, Chemistry of Organic Fluorine Compounds, second
ed., Ellis Horwood, Chichester, 1976 (Chapter 5).
3.3.4. 3-Fluoro-2-phenylindene (18)
Butyllithium (0.35 ml, 1.57 M in hexane, 0.55 mmol) was
added to a solution of 13b (195 mg, 0.55 mmol) in Et2O–
hexane (1:4, 14 ml) at ꢀ110 8C over 10 min under argon.
The reaction mixture was stirred for 1 h at that temperature,
and then stirred at ꢀ78 8C for 1 h. After the mixture was
stirred at room temperature for an additional 2 h, the reac-
tion was quenched with phosphate buffer (pH 7). Organic
materials were extracted with Et2O three times. The com-
bined extracts were washed with brine and dried over
MgSO4. After removal of the solvent under reduced pres-
sure, the residue was purified by thin layer chromatography
on silica gel (pentane) and then by GPC (CHCl3) to give 18
(59 mg, 52%) as a white solid.
[15] J.E. Baldwin, J. Chem. Soc., Chem. Commun. (1976) 734–736.
[16] J.E. Baldwin, J. Cutting, W. Dupont, L.I. Kruse, L. Silberman, R.C.
Thomas, Chem. Commun. (1976) 736–731.
[17] J.E. Baldwin, R.C. Thomas, L.I. Kruse, L. Silberman, J. Org. Chem.
42 (1977) 3846–3852.
[18] J. Ichikawa, J. Fluorine Chem. 105 (2000) 257–263, references
therein.
[19] W.F. Bailey, E.R. Punzalan, J. Org. Chem. 55 (1990) 5404–5406.
[20] E. Negishi, D.R. Swanson, C.J. Rousset, J. Org. Chem. 55 (1990)
5406–5409.
[21] D.R. Strobach, G.A. Boswell Jr, J. Org. Chem. 36 (1971) 818–820.
[22] E.M. Kaiser, C.R. Hauser, J. Org. Chem. 33 (1968) 3402–3404.
[23] K.K. Laali, G.I. Borodkin, J. Chem. Soc. Perkin 2 (2002) 953–957,
references therein.
[24] T. Shamma, H. Buchholz, G.K.H. Prakash, G.A. Olah, Isr. J. Chem.
39 (1999) 207–210, references therein.
1H NMR (500 MHz, CDCl3)
d
3.68 (2H, d,
[25] T.V.V. Ramakrishna, P.R. Sharp, Org. Lett. 5 (2002) 877–879,
references therein.
JHF ¼ 6:0 Hz), 7.26 (2H, tdd, J ¼ 8:0, 1.2 Hz,
JHF ¼ 2:4 Hz), 7.33 (1H, t, J ¼ 7:6 Hz), 7.37–7.44 (4H,
m), 7.70 (2H, dd, J ¼ 8:0, 1.2 Hz). 13C NMR (126 MHz,
CDCl3) d 34.6 (d, JCF ¼ 4 Hz), 117.7 (d, JCF ¼ 3 Hz), 118.1
(d, JCF ¼ 2 Hz), 124.0 (d, JCF ¼ 3 Hz), 126.2, 126.7 (d,
JCF ¼ 7 Hz), 126.9, 127.1 (d, JCF ¼ 2 Hz), 128.7, 133.4 (d,
JCF ¼ 5 Hz), 137.6 (d, JCF ¼ 25 Hz), 139.3 (d, JCF ¼ 8 Hz),
156.0 (d, JCF ¼ 277 Hz). 19F NMR (471 MHz, CDCl3) dF
30.8 (td, JFH ¼ 6, 2 Hz). IR (neat) 3045, 1626, 1493, 1371,
1070, 912, 752, 717, 688 cmꢀ1. HRMS: calcd. for C15H11F
(Mþ) 210.0845, found 210.0849.
[26] J. Ichikawa, K. Sakoda, Y. Wada, Chem. Lett. (2002) 282–283.
[27] A. Saito, M. Okada, Y. Nakamura, O. Kitagawa, H. Horikawa, T.
Taguchi, J. Fluorine Chem. 123 (2003) 75–80.
[28] W.A. Vinson, K.S. Prickett, B. Spahic, P.R.O. de Montellano, J. Org.
Chem. 48 (1983) 4661–4668.
[29] W. Fuhrer, H.W. Gschwend, J. Org. Chem. 44 (1979) 1133–1136.
´ ´
[30] J.-P. Begue, D. Bonnet-Delpon, M.H. Rock, J. Chem. Soc. Perkin
Trans. 1 (1996) 1409–1413.
[31] R.A. Moss, S. Xue, R.R. Sauers, J. Am. Chem. Soc. 118 (1996)
10307–10308.
[32] W.E. Barnette, J. Am. Chem. Soc. 106 (1984) 452–454.