Friedel-crafts cyclization of 1,1-difluoroalk-1-enes: Synthesis of benzene-fused cyclic ketones via α-fluorocarbocations

Article abstract of DOI:10.1055/s-2004-834910

1,1-Difluoroalk-1-enes bearing a phenyl group at the C-3, -4, or -5 position, readily obtained from 2,2,2-trifluoroethyl p-toluenesulfonate, are treated with FSO₃H·SbF₅ to undergo Friedel-Crafts cyclization in (CF₃)₂CHOH. The cyclization takes place via α-fluorocarbocations, followed by spontaneous hydrolysis of the C-F bond to afford bicyclic ketones including a five, six, or seven-membered ring in good yield.

Full text of DOI:10.1055/s-2004-834910

PAPER
39
Friedel–Crafts Cyclization of 1,1-Difluoroalk-1-enes: Synthesis of Benzene-
Fused Cyclic Ketones via a-Fluorocarbocations
F
riedel–C
u
rafts Cycliza
n
tion of 1,1-D
j
ifluoro
i
alk-1-enes Ichikawa,*a Hideharu Jyono,b Takao Kudo,b Masaki Fujiwara,a Misaki Yokotaa
a
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58414345; E-mail: junji@chem.s.u-tokyo.ac.jp
b
Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
Received 10 August 2004; revised 2 September 2004
would preferably occur on the inner carbon of the olefinic
part, leading to terminal carbocations rather than tertiary
cations. Herein we report the Friedel–Crafts cyclization of
1,1-difluoroalk-1-enes bearing an aryl group 1, which
Abstract: 1,1-Difluoroalk-1-enes bearing a phenyl group at the C-
3, -4, or -5 position, readily obtained from 2,2,2-trifluoroethyl p-tol-
uenesulfonate, are treated with FSO3H·SbF5 to undergo Friedel–
Crafts cyclization in (CF3)2CHOH. The cyclization takes place via
a-fluorocarbocations, followed by spontaneous hydrolysis of the provides a variety of fused bicyclic ketones 2.6
C–F bond to afford bicyclic ketones including a five, six, or seven-
Initially, the 1,1-difluoroalk-1-enes 1a–h bearing an aryl
membered ring in good yield.
group at the C-3, -4, or -5 position were designed as the
Key words: Friedel–Crafts cyclization, difluoroalkene, bicyclic
Friedel–Crafts substrates. We have already established a
ketone, a-fluorocarbocation, fluoroalcohol solvent
one-pot synthesis of 1,1-difluoroalk-1-enes from com-
mercially available 2,2,2-trifluoroethyl p-toluene-
sulfonate (3) via boron-mediated alkylation followed by
Fluorine possesses a-carbocation stabilizing effect caused
by donation of its unshared electron pair to the vacant p-
palladium-catalyzed coupling reaction with organoha-
lides (Scheme 2). Monosubstituted difluoroalkenes 1a–d
were readily prepared by protonolysis of in situ generated
difluorovinylboranes 4 via the corresponding vinylcopper
species 5 (Scheme 2, Eq. 1); disubstituted difluoroalkenes
1e–h were prepared by the cross-coupling reaction of vi-
nylcoppers 5 with aryl or benzyl halides in good yield
orbital of the a-carbon, despite its leaving group ability as
a fluoride ion (F–) due to its high electronegativity.1 In
contrast to a number of theoretical and mechanistic stud-
ies on fluorinated carbocations,2 their synthetic applica-
tions are quite limited.3 Furthermore, there are few reports
on reactions utilizing both of the two properties men-
from 3 (Scheme 2, Eq. 2). Both reactions were conducted
tioned above.4 Recently, we have reported such an exam-
as a one-pot operation.7
ple, the fluorine-directed Nazarov cyclization of 2,2-
difluorovinyl vinyl ketones, which proceeds via a-fluoro-
carbocations, generated by silylation of the carbonyl oxy-
We attempted the regioselective protonation of 1,1-di-
fluoroalk-1-enes 1 to generate a-fluorocarbocations,
gen with TMSOTf, to afford b-fluorocyclopentenones
with accompanying loss of a fluoride ion (Scheme 1).5
R
R
H
i, ii
iii
CF3CH2OTs
CF2
C
CF2
C
(1)
BR2
TMS
O
O
O
+
3
4
i
n-Bu
n-Bu
CH3
n-Bu
CH3
1a 38% (50%)a
1b 81%
R = (CH2)2Ph
R = CH2CHMePh
R = (CH2)2(2-Np)b
R = (CH2)3Ph
CF2
CF2
F
1c 65%
Scheme 1 The Nazarov cyclization of 2,2-difluorovinyl vinyl keto-
1d 83%
nes
Reagents and conditions: i. TMSOTf (1.0 equiv), CH2Cl2–HFIP
(1:1), r.t., 10 min.
R
iv
(2)
CF2
C
Ar
R = n-Bu, Ar = CH2Ph
R = (CH2)2Ph, Ar = Ph
62%
43%
45%
80%
1e
1f
Our interest in fluorine-containing carbocations prompted
us to investigate: (i) the generation of a-fluorocarboca-
tions from simple 1,1-difluoroalk-1-enes without a carbo-
nyl group; and (ii) their reaction with an intramolecular
aryl group instead of an alkenyl group. The a-cation-sta-
bilizing effect was expected to direct the reaction of 1,1-
difluoroalk-1-enes with a protic acid, so that protonation
R = CH2CHEtPh, Ar = Ph
R = CH2CHMePh, Ar = Ph
1g
1h
Scheme 2 Synthesis of 1,1-difluoroalk-1-enes.
a 19F NMR yield relative to internal PhCF3 standard. b Np = Naphthyl.
Reagents and conditions: i. n-BuLi (2.1 equiv), THF, –78 °C, 0.5 h;
ii. BR3 (1.2 equiv), THF, –78 °C → r.t. or reflux, 4 h; iii. CuI (2.0
equiv), THF–HMPA (4:1), r.t., 0.5–12 h; iv. ArX (0.9 equiv), CuI (1.0
equiv), Pd2(dba)3·CHCl3 (0.02 equiv), Ph3P (0.08 equiv), THF–
HMPA (4:1), r.t., 1–15 h.
SYNTHESIS 2005, No. 1, pp 0039–0046
x
x
.
x
x
.2
0
0
4
Advanced online publication: 17.11.2004
DOI: 10.1055/s-2004-834910; Art ID: F11304SS
© Georg Thieme Verlag Stuttgart · New York

40
J. Ichikawa et al.
PAPER
which were expected to get trapped by the aryl moieties. straction of a fluoride ion from 8e again by Magic Acid,
Treatment of a model substrate 1e with trifluoromethane- followed by spontaneous hydrolysis of the C–F bond in
sulfonic acid or fluorosulfonic acid–antimony pentafluo- 10e to afford 2e (Scheme 3).
ride (1:1) (Magic Acid, FSO3H·SbF5) in dichloromethane
(Table 1, entries 1 and 2) led to a simple addition product,
n-Bu
n-Bu
FSO3H·SbF5
2-benzyl-1,1-difluorohexyl trifluoromethanesulfonate (6)
or 1-phenyl-2-trifluoromethylhexane (7).8 Since the addi-
tion of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a co-
solvent brought about a dramatic improvement in the
fluorine-directed Nazarov cyclizations,5 we adopted HFIP
as a solvent in the attempted cyclization. Treatment with
10 equivalents of trifluoromethanesulfonic acid or 1
equivalent of Magic Acid in HFIP promoted the Friedel–
Crafts cyclization, leading to 2e in 22% or 34% yield, re-
spectively, instead of the expected difluoroindan 8e (en-
tries 4 and 5). The yield of 2e was raised up to 72% by
using two equivalents of Magic Acid (entry 6). It is noted
that antimony pentafluoride also promoted the reaction in
HFIP to give 2e in 79% yield (entry 7). While only a trace
amount of 2e was obtained on treatment of 1e with SbF5
in CCl2FCClF2, addition of 2 equivalents of HFIP to the
reaction mixture afforded 2e in 36% yield (entries 8 and
9). These results indicate that a proton source is necessary
for this cyclization and that HFIP is a superior solvent for
cationic reactions due to its high ionizing power and low
nucleophilicity.5,9,10
+
CF2
SbF6
9e
CF2
1e
-
FSO3H·SbF5
n-Bu
n-Bu
+
-
– H+
– F
-
F
F
SbF6
F
10e
8e
H2O
n-Bu
– HF
O
2e
Scheme 3 A plausible mechanism of the synthesis of bicyclic
ketone 2e
To confirm the generation of the intermediary carbocation
10e in Scheme 3, we tried to trap it with nucleophiles
(Table 2). After treatment of 1e with FSO3H·SbF5 (2
equiv) in HFIP, two equivalents of benzenethiol was add-
ed to the reaction mixture. 2-Butyl-3-phenylthioindene
(11a) was obtained in 71% yield via the reaction of cation
10e accompanied by loss of hydrogen fluoride (Table 2,
entry 1). This yield was in good accordance with that of
indanone 2e obtained by hydrolysis of 10e (Table 1, entry
6). In the case of aromatic compounds as nucleophiles, the
intermolecular Friedel–Crafts reaction of 10e occurred to
provide 11b and 11c, albeit in low yield (Table 2, entries
2 and 3). These results strongly support the generation of
the second fluorocarbocation 10e, which allows further
functionalization of the formed bicyclic system.
Table 1 The Friedel–Crafts Cyclization of Difluoroalkene 1e
n-Bu
Acid
n-Bu
CF2
1e
O
2e
Entry Acid (equiv)
Solvent
Conditions
Yield
(%)
1
2
3
4
5
6
7
8
9
CF3SO3H (2)
FSO3H·SbF5 (1)
FSO3H·SbF5 (1)
CF3SO3H (10)
FSO3H·SbF5 (1)
FSO3H·SbF5 (2)
SbF5 (2)
CH2Cl2
CH2Cl2
r.t., 6 h
0a
0b
–45 °C, 10 min
Under the conditions outlined above, other difluoroalk-
enes 1a–c,f–h underwent rapid cyclization to afford the
corresponding six-membered ketones, 1-tetralones 2a–
CCl2FCClF2 –25 °C, 10 min 13
HFIP
HFIP
HFIP
HFIP
r.t., 15 h
22
0 °C, 10 min
0 °C, 10 min
0 °C, 10 min
34
Table 2 Trapping of a-Fluorocarbocation 10e with Nucleophiles
72
n-Bu
i
ii
n-Bu
n-Bu
+
79
CF2
F
Nu
11
SbF5 (2)
CCl2FCClF2 0 °C, 10 min
trace
36
1e
10e
SbF5 (2), HFIP (2) CCl2FCClF2 0 °C, 10 min
Reagents and conditions: i. FSO3H·SbF5 (2.0 equiv), HFIP, 0 °C, 10
min; ii. NuH.
a 2-Benzyl-1,1-difluorohexyl trifluoromethanesulfonate (6) was ob-
tained in 65% yield.
b 1-Phenyl-2-trifluoromethylhexane (7) was obtained in 87% yield.
Entry
NuH (equiv)
PhSH (2)
Conditions
0 °C, 10 min
reflux, 3 h
Product Yield (%)
1
2
11a
11b
71
21
The obtained results suggest the following mechanism:
The Friedel–Crafts type ring closure occurred via a,a-di-
fluorocarbocation 9e generated by protonation of 1e to
give the corresponding cyclized intermediate 8e. a-Fluo-
rocarbocation 10e was subsequently generated via ab-
m-dimethoxy-
benzene (10)
3
PhH (42)
r.t., 10 h
11c
27
Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York

PAPER
Friedel–Crafts Cyclization of 1,1-Difluoroalk-1-enes
41
Table 4 Effect of Fluorine on the Cyclization Reaction
c,f–h in good to high yield as shown in Table 3. The cy-
clization of 1c proceeded regioselectively at the a-posi-
tion of the naphthalene ring to give tricyclic ketones 2ca
and 2cb in a ratio of 8:1 (entry 7). Moreover, seven-mem-
bered ketone, 1-benzosuberone (2d) was obtained by this
cyclization (entry 8). These benzene-fused cyclic ketones,
1-indanones, 1-tetralones, and 1-benzosuberones are an
important class of compounds,11 because of their use as
building blocks for bioactive compounds.12
i
+
CX2
O
X
1a (X = F)
12 (X = Br)
13 (X = Cl)
14
2a
Reagents and conditions: i. FSO3H·SbF5 (2.0 equiv), HFIP, 0 °C.
In order to confirm the effect of fluorine on the Friedel–
Crafts cyclizations, we compared the reactions of 1h and
the corresponding monofluorinated (E and Z) and fluo-
rine-free substrates under the same conditions
[FSO3H·SbF5 (2 equiv), HFIP, 0 °C, 10 min]. Whereas 1h
gave 2h in 85% yield, the monofluorinated and the fluo-
rine-free substrates gave a complex mixture of products,
probably due to the lack of control over the regioselectiv-
ity in the initial protonation of the double bonds.
Entry
X
Substrate
Time (min) 2a (%)
14 (%)
1
2
3
F
1a
12
13
10
30
60
82
65
52
0
18
34
Cl
Br
demonstrate the advantage of a fluorine substituent in the
synthesis of bicyclic ketones from dihaloalkenes.15
In addition, a comparison between fluorine and other
halogen (chlorine and bromine) substituents was conduct-
ed. The cyclizations of dihaloalkenes 12 and 13 were ex-
amined under the same conditions. While fluorinated
substrate 1a exclusively gave 2a,14 vinyl halides 14
(X = Cl, Br) were obtained from 12 or 13 along with 2a.
Furthermore, both reactions of 12 and 13 were decelerat-
ed, compared to that of 1a (Table 4). These results clearly
In conclusion, we have developed a fluorine-activated
Friedel–Crafts cyclization of 1,1-difluoroalk-1-enes bear-
ing an aryl group to provide benzene-fused cyclic ketones
via a-fluorocarbocations, generated by the regioselective
protonation of the double bonds. Thus, we have disclosed
a new aspect of fluorine in electrophilic reactions by the
combined use of its a-cation-stabilizing effect and leaving
group ability.
Table 3 Synthesis of Bicyclic Ketones 2a
Entry Substrate
R1
–
R2
–
Time (min) Product
Yield (%) trans/cisb
n-Bu
1
1e
1a
10
2e
2a
72
–
n-Bu
CF2
O
R2
R2
2
H
H
10
82
–
R1
CF2
R1
O
3
4
5
6
7
1b
1f
H
Me
H
10
10
10
10
30
2b
2f
83
87
83
85
68
–
Ph
Ph
Ph
–
–
1g
1h
1c
Et
Me
–
2g
2h
75:25
65:35
–
CF2
O
O
2cα
(8:1)
2cβ
8
1d
–
–
10
2d
23c
–
CF2
O
a Reagents and conditions: FSO3H·SbF5 (2.0 equiv), HFIP, 0 °C.
b Ratio was determined by HPLC.13
c FSO3H·SbF5 (10 equiv) was used.
Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York

42
J. Ichikawa et al.
PAPER
NMR spectra were recorded at the indicated field strengths. Chem-
ical shift values are given in ppm relative to internal Me4Si (for 1H
HRMS: m/z calcd for C11H12F2 (M+): 182.0907; found: 182.0914.
NMR: d = 0.00), CDCl3 (for 13C NMR: d = 77.0), and C6F6 (for 19
F
1,1-Difluoro-4-(2-naphthyl)but-1-ene (1c)
NMR: d = 0.00). THF was distilled from sodium benzophenone
ketyl prior to use. HFIP was distilled from molecular sieves 4Å, and
stored over molecular sieves 4Å. HMPA was distilled from CaH2
and stored over molecular sieves 4Å. Column chromatography and
preparative TLC (PTLC) were performed on silica gel (Kanto
Chemical Co. Inc., Silica Gel 60 and Wako Pure Chemical Indus-
tries, Ltd., B5-F), respectively.
BuLi (13.3 mL, 1.53 M in hexane, 20.4 mmol) was added to a THF
(50.0 mL) solution of 2,2,2-trifluoroethyl p-toluenesulfonate (2.46
g, 9.68 mmol) at –78 °C over 10 min under N2. The reaction mixture
was stirred for 30 min at –78 °C, and then tris[2-(2-naphthyl)eth-
yl]borane [prepared by adding BH3·THF complex (11.0 mL, 1.08 M
in THF, 11.9 mmol) to a solution of 2-vinylnaphthalene (5.00 g,
32.4 mmol) in THF (10.0 mL) at 0 °C, and stirring the mixture for
3 h at r.t.] was added at –78 °C over 30 min. After stirring for 1 h,
the mixture was warmed up to r.t. and stirred for an additional 1 h,
and then heated at reflux for 2 h. The resulting solution was cooled
to 0 °C and treated with HMPA (12.5 mL) and CuI (3.70 g, 19.4
mmol). After stirring the mixture for 0.5 h at r.t., phosphate buffer
(pH 7) was added to quench the reaction. The mixture was filtered,
and the organic materials were extracted with Et2O (3 ×). The com-
bined Et2O extracts were washed with H2O and dried (Na2SO4). Af-
ter removal of the solvent under reduced pressure, the residue was
purified by column chromatography on silica gel (pentane) to give
1c (1.37 g, 65%) as a colorless liquid.
1,1-Difluoro-4-phenylbut-1-ene (1a); Typical Procedure
BuLi (7.00 mL, 1.50 M in hexane, 10.5 mmol) was added to a THF
(35.0 mL) solution of 2,2,2-trifluoroethyl p-toluenesulfonate (127
g, 5.00 mmol) at –78 °C over 10 min under N2. The reaction mixture
was stirred for 30 min at –78 °C, and then tris(2-phenethyl)borane
[prepared by adding BH3·THF complex (6.10 mL, 0.98 M in THF,
6.00 mmol) to a solution of styrene (1.89 mL, 16.5 mmol) in THF
(3.2 mL) at 0 °C, and stirring the mixture for 2.5 h at r.t.] was added
at –78 °C over 30 min. After stirring for 1 h, the mixture was
warmed up to r.t. and stirred for an additional 3 h. The resulting so-
lution was cooled to 0 °C and treated with hexamethylphosphoric
triamide (HMPA, 8.5 mL) and CuI (1.90 g, 10.0 mmol). After stir-
ring the mixture for 0.5 h at r.t., phosphate buffer (pH 7) was added
to quench the reaction. The mixture was filtered, and the organic
materials were extracted with Et2O (3 ×). The combined extracts
were washed with H2O and dried (Na2SO4). After removal of the
solvent under reduced pressure, the residue was purified by column
chromatography on silica gel (pentane) to give 1a (315 mg, 38%) as
a colorless liquid.
IR (neat): 3054, 2927, 1745, 1600, 1508, 1303, 1222, 1162, 1012,
815, 746 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.39 (2 H, dtdd, J = 7.6, 7.6 Hz,
JH,F = 1.8, 1.8 Hz), 2.84 (2 H, t, J = 7.6 Hz), 4.18 (1 H, dtd,
JH,F = 25.3 Hz, J = 7.6 Hz, JH,F = 2.7 Hz), 7.32 (1 H, dd, J = 8.1, 1.5
Hz), 7.41–7.47 (2 H, m), 7.61 (1 H, s), 7.75 (2 H, d, J = 8.1 Hz),
7.80 (1 H, d, J = 8.1 Hz).
13C NMR (126 MHz, CDCl3): d = 23.9 (d, JC,F = 4 Hz), 35.8 (d,
JC,F = 2 Hz), 77.3 (dd, JC,F = 22, 21 Hz), 125.3, 126.0, 126.6, 127.1,
127.5, 127.6, 128.0, 132.1, 133.6, 138.4, 156.4 (dd, JC,F = 288, 286
Hz).
IR (neat): 3026, 2926, 1736, 1603, 1493, 1450, 1375, 1028, 760,
700 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.29 (2 H, dtdd, J = 7.6, 7.6 Hz,
JH,F = 1.5, 1.5 Hz), 2.68 (2 H, t, J = 7.6 Hz), 4.15 (1 H, dtd,
JH,F = 24.1 Hz, J = 7.6 Hz, JH,F = 2.4 Hz), 7.16–7.22 (3 H, m), 7.29
(2 H, t, J = 7.6 Hz).
19F NMR (470 MHz, CDCl3): d = 70.9 (1 F, ddt, JF,F = 47 Hz,
JF,H = 27, 3 Hz), 72.9 (1 F, d, JF,F = 47 Hz).
HRMS: m/z calcd for C14H12F2 (M+): 218.0907; found: 218.0896.
13C NMR (126 MHz, CDCl3): d = 24.1 (d, JC,F = 4 Hz), 35.7 (d,
JC,F = 2 Hz), 77.3 (dd, JC,F = 22, 22 Hz), 126.1, 128.4, 128.4, 141.0,
156.3 (dd, JC,F = 287, 287 Hz).
19F NMR (470 MHz, CDCl3): d = 70.7 (1 F, ddt, JF,F = 47 Hz,
JF,H = 24, 2 Hz), 72.7 (1 F, d, JF,F = 47 Hz).
1,1-Difluoro-5-phenylpent-1-ene (1d)
Compound 1d was prepared by the method described for 1a in THF
(24.0 mL) from 2,2,2-trifluoroethyl p-toluenesulfonate (1.31 g, 5.15
mmol), BuLi (6.40 mL, 1.69 M in hexane, 10.8 mmol), tris(3-phe-
nylpropyl)borane [prepared by adding BH3·THF complex (5.70
mL, 1.00 M in THF, 5.70 mmol) to a solution of allylbenzene (2.01
g, 17.0 mmol) in THF (5.0 mL) at 0 °C, and stirring the mixture for
2 h at r.t.], HMPA (6.0 mL), and CuI (1.96 g, 10.3 mmol). Purifica-
tion by column chromatography on silica gel (pentane) gave 1d
(777 mg, 83%) as a colorless liquid.
HRMS: m/z calcd for C10H10F2 (M+): 168.0751; found: 168.0747.
1,1-Difluoro-4-phenylpent-1-ene (1b)
Compound 1b was prepared by the method described for 1a using
THF (25.0 mL), 2,2,2-trifluoroethyl p-toluenesulfonate (1.27 g,
5.00 mmol), BuLi (6.6 mL, 1.59 M in hexane, 10.5 mmol), tris(2-
phenylpropyl)borane [prepared by adding BH3·THF complex (6.21
mL, 0.98 M in THF, 6.00 mmol) to a solution of a-methylstyrene
(2.15 mL, 16.5 mmol) in THF (6.0 mL) at 0 °C, and stirring the mix-
ture for 3 h at r.t.], HMPA (6.3 mL), and CuI (1.90 g, 10.0 mmol).
Purification by column chromatography on silica gel (pentane) gave
1b (738 mg, 81%) as a colorless liquid.
IR (neat): 3030, 2939, 1747, 1603, 1497, 1454, 1308, 1228, 1030,
899, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.70 (2 H, tt, J = 7.6, 7.6 Hz), 2.01
(2 H, dtdd, J = 7.6, 7.6 Hz, JH,F = 1.5, 1.5 Hz), 2.62 (2 H, t, J = 7.6
Hz), 4.15 (1 H, dtd, JH,F = 25.6 Hz, J = 7.6 Hz, JH,F = 2.4 Hz), 7.15–
7.21 (3 H, m), 7.28 (2 H, t, J = 7.6 Hz).
13C NMR (126 MHz, CDCl3): d = 21.8 (d, JC,F = 4 Hz), 31.2 (dd,
JC,F = 3, 3 Hz), 35.2, 77.7 (dd, JC,F = 22, 22 Hz), 125.9, 128.4,
128.4, 141.9, 156.4 (dd, JC,F = 287, 287 Hz).
19F NMR (470 MHz, CDCl3): d = 70.3 (1 F, ddt, JF,F = 48 Hz,
JF,H = 26, 2 Hz), 72.6 (1 F, dd, JF,F = 48 Hz, JF,H = 2 Hz).
IR (neat): 3152, 3095, 1778, 1528, 1482, 1205, 788, 723 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.25 (3 H, d, J = 7.0 Hz), 2.23 (2
H, dddd, J = 7.7, 7.5 Hz, JH,F = 1.8, 1.8 Hz), 2.72 (1 H, dq, J = 7.5,
7.0 Hz), 4.02 (1 H, dqd, JH,F = 24.6 Hz, J = 7.7 Hz, JH,F = 2.6 Hz),
7.13–7.31 (5 H, m).
13C NMR (68 MHz, CDCl3): d = 21.3, 30.9 (dd, JC,F = 4, 4 Hz), 39.9
(dd, JC,F = 3, 2 Hz), 76.5 (dd, JC,F = 23, 21 Hz), 126.3, 127.0, 128.5,
146.1, 156.6 (dd, JC,F = 287, 286 Hz).
HRMS: m/z calcd for C11H12F2 (M+): 182.0907; found: 182.0917.
2-Benzyl-1,1-difluorohex-1-ene (1e)
BuLi (5.10 mL, 1.59 M in hexane, 8.11 mmol) was added to a THF
(16.0 mL) solution of 2,2,2-trifluoroethyl p-toluenesulfonate (980
mg, 3.85 mmol) at –78 °C over 40 min under N2. The reaction mix-
19F NMR (94 MHz, CDCl3): d = 70.7 (1 F, dd, JF,F = 48 Hz,
JF,H = 25 Hz), 73.2 (1 F, d, JF,F = 48 Hz).
Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York

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Friedel–Crafts Cyclization of 1,1-Difluoroalk-1-enes
43
ture was stirred for 30 min at –78 °C, and then tributylborane (4.2
mL, 1.0 M in THF, 4.2 mmol) was added at –78 °C over 30 min. Af-
ter stirring for 1 h, the mixture was warmed up to r.t. and stirred for
an additional 3 h. The resulting solution was cooled to 0 °C and
treated with HMPA (4.0 mL), Ph3P (82 mg, 0.31 mmol), and
phenylbutyl)borane [prepared by adding BH3·THF complex (3.5
mL, 0.98 M in THF, 3.4 mmol) to a solution of 2-phenylbut-1-ene
(1.24 g, 9.4 mmol) in THF (3.4 mL) at 0 °C, and stirring the mixture
for 5 h at r.t.], HMPA (4.0 mL), Ph3P (60.0 mg, 0.23 mmol),
Pd2(dba)3·CHCl3 (59 mg, 0.057 mmol), iodobenzene (0.29 mL, 2.56
mmol), and CuI (541 mg, 2.84 mmol). Purification by PTLC on sil-
ica gel (hexane–EtOAc, 10:1) gave 1g (310 mg, 45%) as a colorless
liquid.
tris(dibenzylideneacetonyl)bispalladium-chloroform
(1:1)
[Pd2(dba)3·CHCl3, 82 mg, 0.079 mmol], and stirred for 10 min. To
the mixture was added benzyl bromide (598 mg, 3.49 mmol) and
CuI (743 mg, 3.91 mmol). After stirring the mixture for 15 h at r.t.,
phosphate buffer (pH 7) was added to quench the reaction. The mix-
ture was filtered, and the organic materials were extracted with
CH2Cl2 (3 ×). The combined extracts were washed with brine and
dried (Na2SO4). After removal of the solvent under reduced pres-
sure, the residue was purified by PTLC on silica gel (hexane–
EtOAc, 10:1) to give 1e (453 mg, 62%) as a colorless liquid.
IR (neat): 3062, 2962, 1736, 1495, 1452, 1236, 1124, 1072, 758,
698 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.70 (3 H, t, J = 7.3 Hz), 1.58 (1
H, ddq, J = 16.8, 9.5, 7.3 Hz), 1.70 (1 H, dqd, J = 16.8, 7.3, 5.2 Hz),
2.40 (1 H, dddd, J = 9.5, 8.2, 7.0, 5.2 Hz), 2.65 (1 H, dddd, J = 14.4,
8.2 Hz, JH,F = 2.4, 1.2 Hz), 2.71 (1 H, dddd, J = 14.4, 7.0 Hz,
JH,F = 2.7, 2.7 Hz), 7.03 (2 H, d, J = 7.1 Hz), 7.15–7.20 (3 H, m),
7.21–7.28 (3 H, m), 7.33 (2 H, t, J = 7.1 Hz).
13C NMR (126 MHz, CDCl3): d = 12.0, 28.6, 34.7, 45.4 (d, JC,F = 2
Hz), 91.2 (dd, JC,F = 22, 13 Hz), 126.2, 127.2, 127.3, 128.2, 128.4,
128.4 (dd, JC,F = 3, 3 Hz), 133.6 (dd, JC,F = 4, 4 Hz), 144.1, 153.9
(dd, JC,F = 290, 290 Hz).
IR (neat): 2950, 1745, 1605, 1495, 1455, 1270, 1220, 1115, 1035,
700 cm–1.
1H NMR (60 MHz, CDCl3): d = 0.86 (3 H, m), 1.03–1.56 (4 H, m),
1.64–2.08 (2 H, m), 3.28 (2 H, dd, JH,F = 2.0, 2.0 Hz), 7.19 (5 H, s).
13C NMR (67 MHz, CDCl3): d = 13.8, 22.2, 25.3, 29.4, 32.2 (d,
JC,F = 2 Hz), 88.9 (dd, JC,F = 18, 16 Hz), 126.4, 128.5, 128.6, 138.8
(d, JC,F = 3 Hz), 153.9 (dd, JC,F = 284, 284 Hz).
19F NMR (94 MHz, CDCl3): d = 65.5 (2 F, s).
19F NMR (470 MHz, CDCl3): d = 69.7 (1 F, d, JF,F = 43 Hz), 70.4 (1
F, d, JF,F = 43 Hz).
HRMS: m/z calcd for C18H18F2 (M+): 272.1377; found: 272.1361.
Anal. Calcd for C13H16F2: C, 74.26; H, 7.67. Found: C, 73.86; H,
7.81.
1,1-Difluoro-2,4-diphenylpent-1-ene (1h)
Compound 1h was prepared by the method described for 1f using
THF (25.0 mL), 2,2,2-trifluoroethyl p-toluenesulfonate (1.27 g,
5.00 mmol), BuLi (6.50 mL, 1.61 M in hexane, 10.5 mmol), tris(2-
phenylpropyl)borane [prepared by adding BH3·THF complex (6.12
mL, 0.98 M in THF, 6.0 mmol) to a solution of a-methylstyrene
(2.15 mL, 16.5 mmol) in THF (6.6 mL) at 0 °C, and stirring the mix-
ture for 3 h at r.t.], HMPA (6.3 mL), Ph3P (106 mg, 0.40 mmol),
Pd2(dba)3·CHCl3 (104 mg, 0.10 mmol), iodobenzene (0.50 mL, 4.5
mmol), and CuI (955 mg, 5.01 mmol). Purification by PTLC on sil-
ica gel (hexane) gave 1h (925 mg, 80%) as a colorless liquid.
1,1-Difluoro-2,4-diphenylbut-1-ene (1f)
BuLi (1.40 mL, 1.51 M in hexane, 2.10 mmol) was added to a THF
(5.0 mL) solution of 2,2,2-trifluoroethyl p-toluenesulfonate (254
mg, 1.00 mmol) at –78 °C over 10 min under N2. The reaction mix-
ture was stirred for 30 min at –78 °C, and then tris(2-phenethyl)bo-
rane [prepared by adding BH3·THF complex (1.20 mL, 0.92 M in
THF, 1.1 mmol) to a solution of styrene (0.38 mL, 3.3 mmol) in
THF (1.2 mL) at 0 °C, and stirring the mixture for 2 h at r.t.] was
added at –78 °C over 30 min. After stirring for 1 h, the mixture was
warmed up to r.t. and stirred for an additional 3 h. The resulting so-
lution was cooled to 0 °C and treated with HMPA (1.3 mL), Ph3P
(21 mg, 0.080 mmol), and Pd2(dba)3·CHCl3 (21 mg, 0.020 mmol)
and stirred for 10 min. To the mixture was added iodobenzene (0.10
mL, 0.90 mmol) and CuI (190 mg, 1.0 mmol). After stirring the
mixture for 1 h at r.t., phosphate buffer (pH 7) was added to quench
the reaction. The mixture was filtered, and organic materials were
extracted with EtOAc (3 ×). The combined extracts were washed
with brine and dried (Na2SO4). After removal of the solvent under
reduced pressure, the residue was purified by PTLC on silica gel
(hexane–EtOAc, 10:1) to give 1f (96 mg, 43%) as a colorless liquid.
IR (neat): 2960, 1735, 1490, 1450, 1240, 1125, 960, 760, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.23 (3 H, d, J = 6.4 Hz), 2.58–
2.72 (3 H, m), 7.12 (2 H, d, J = 7.3 Hz), 7.18 (1 H, tt, J = 7.3, 1.2
Hz), 7.22–7.29 (5 H, m), 7.35 (2 H, t, J = 7.3 Hz).
13C NMR (126 MHz, CDCl3): d = 21.1, 36.3, 37.7 (dd, JC,F = 3, 3
Hz), 91.3 (dd, JC,F = 22, 14 Hz), 126.2, 126.9, 127.3, 128.3, 128.4,
128.4, 133.5 (dd, JC,F = 4, 4 Hz), 146.2, 154.1 (dd, JC,F = 290, 287
Hz).
19F NMR (470 MHz, CDCl3): d = 70.0 (1 F, d, JF,F = 43 Hz), 70.5 (1
F, d, JF,F = 43 Hz).
HRMS: m/z calcd for C17H16F2 (M+): 258.1220; found: 258.1190.
IR (neat): 3062, 2927, 1736, 1497, 1458, 1232, 1120, 1018, 764,
696 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.62–2.73 (4 H, m), 7.13 (2 H, d,
J = 7.3 Hz), 7.19 (2 H, t, J = 7.3 Hz), 7.24–7.34 (4 H, m), 7.37 (2 H,
t, J = 7.3 Hz).
13C NMR (126 MHz, CDCl3): d = 29.7, 34.0 (dd, JC,F = 3, 3 Hz),
91.8 (dd, JC,F = 22, 3 Hz), 126.1, 127.3, 128.3 (dd, JC,F = 3, 3 Hz),
128.4, 128.4, 128.7, 133.5 (dd, JC,F = 4, 4 Hz), 141.0, 153.7 (dd,
JC,F = 291, 291 Hz).
19F NMR (470 MHz, CDCl3): d = 70.2 (1 F, d, JF,F = 42 Hz), 70.6 (1
F, dt, JF,F = 42 Hz, JF,H = 3 Hz).
HRMS: m/z calcd for C16H14F2 (M+): 244.1063; found: 244.1063.
3,4-Dihydro-1(2H)-naphthalenone (1-Tetralone, 2a)
1,1-Difluoro-4-phenylbut-1-ene (1a; 62 mg, 0.37 mmol) in HFIP
(1.0 mL) was added to a solution of FSO3H·SbF5 (237 mg, 0.75
mmol) in HFIP (2.0 mL) at 0 °C under N2. After stirring the mixture
for 10 min at 0 °C, phosphate buffer (pH 7) was added to quench the
reaction. Organic materials were extracted with CH2Cl2 (3 ×). The
combined organic extracts were washed with H2O and dried
(Na2SO4). After removal of the solvent under reduced pressure, the
residue was purified by PTLC on silica gel (hexane–EtOAc, 5:1) to
give 2a (44 mg, 82%) as a colorless liquid.
IR (neat): 3066, 2945, 1686, 1601, 1454, 1325, 1286, 1227, 1026,
764 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.15 (2 H, tt, J = 6.3, 6.3 Hz), 2.66
(2 H, t, J = 6.3 Hz), 2.97 (2 H, t, J = 6.3 Hz), 7.25 (1 H, d, J = 7.6
Hz), 7.31 (1 H, dd, J = 7.6, 7.6 Hz), 7.47 (1 H, ddd, J = 7.6, 7.6, 1.1
Hz), 8.04 (1 H, dd, J = 7.6, 1.1 Hz).
1,1-Difluoro-2,4-diphenylhex-1-ene (1g)
Compound 1g was prepared by the method described for 1f using
THF (16.0 mL), 2,2,2-trifluoroethyl p-toluenesulfonate (722 mg,
2.84 mmol), BuLi (4.30 mL, 1.39 M in hexane, 5.96 mmol), tris(2-
Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York

44
J. Ichikawa et al.
PAPER
13C NMR (126 MHz, CDCl3): d = 23.3, 29.7, 39.2, 126.6, 127.2,
1H NMR (500 MHz, CDCl3): d = 1.78–1.84 (2 H, m), 1.88 (2 H, tt,
J = 6.4, 6.4 Hz), 2.71–2.75 (2 H, m), 2.93 (2 H, t, J = 6.4 Hz), 7.20
(1 H, d, J = 7.6 Hz), 7.30 (1 H, t, J = 7.6 Hz), 7.42 (1 H, td, J = 7.6,
1.2 Hz), 7.72 (1 H, dd, J = 7.6, 1.2 Hz).
128.8, 132.6, 133.4, 144.5, 198.4.
MS (70 eV): m/z (%) = 146 (M+, 97), 118 (100), 90 (96).16
3,4-Dihydro-4-methyl-1(2H)-naphthalenone (4-Methyl-1-tetra-
lone, 2b)
13C NMR (126 MHz, CDCl3): d = 20.9, 25.3, 32.5, 40.9, 126.6,
128.6, 129.7, 132.2, 138.9, 141.3, 206.2.
Compound 2b was prepared by the method described for 2a using
HFIP (2.0 mL), FSO3H·SbF5 (180 mg, 0.57 mmol), and 1b (52 mg,
0.28 mmol) in HFIP (1.0 mL). Purification by PTLC on silica gel
(hexane–EtOAc, 5:1) gave 2b (38 mg, 83%) as a colorless liquid.
MS (70 eV): m/z (%) = 160 (M+, 100), 131 (69), 104 (76).16
2-Butyl-1-indanone (2e)
Compound 2e was prepared by the method described for 2a using
HFIP (2.0 mL), FSO3H·SbF5 (111 mg, 0.35 mmol), and 1e (37 mg,
0.175 mmol) in HFIP (1.0 mL). Purification by PTLC on silica gel
(hexane–EtOAc, 20:1) gave 2e (24 mg, 72%) as a colorless liquid.
IR (neat): 2970, 1690, 1600, 1460, 1335, 1290, 1195, 1010, 770
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.40 (3 H, d, J = 7.0 Hz), 1.85–
1.95 (1 H, m), 2.20–2.28 (1 H, m), 2.59 (1 H, ddd, J = 17.4, 8.6, 4.5
Hz), 2.79 (1 H, ddd, J = 17.4, 8.5, 4.4 Hz), 3.05–3.13 (1 H, m), 7.30
(1 H, t, J = 7.9 Hz), 7.32 (1 H, d, J = 7.9 Hz), 7.50 (1 H, td, J = 7.9,
1.5 Hz), 8.03 (1 H, dd, J = 7.9, 1.5 Hz).
13C NMR (126 MHz, CDCl3): d = 20.7, 30.5, 32.8, 36.3, 126.5,
127.2, 127.4, 131.8, 133.6, 148.9, 198.4.
IR (neat): 2925, 1710, 1470, 750 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (3 H, t, J = 7.2 Hz), 1.30–1.49
(5 H, m), 1.92–2.00 (1 H, m), 2.60–2.66 (1 H, m), 2.80 (1 H, dd,
J = 17.1, 3.7 Hz), 3.31 (1 H, dd, J = 17.1, 7.9 Hz), 7.34 (1 H, t,
J = 7.6 Hz), 7.44 (1 H, dd, J = 7.6, 1.0 Hz), 7.56 (1 H, td, J = 7.6,
1.0 Hz), 7.74 (1 H, d, J = 7.6 Hz).
MS (70 eV): m/z (%) = 160 (M+, 100), 145 (69), 132 (74), 118 (62),
13C NMR (126 MHz, CDCl3): d = 14.0, 22.7, 29.6, 31.2, 32.9, 47.5,
123.8, 126.6, 127.3, 134.6, 136.9, 153.8, 209.1.
104 (64).16
Anal. Calcd for C13H16O: C, 82.94; H, 8.57. Found: C, 82.64; H,
8.53.
1,2-Dihydro-4(3H)-phenanthrenone (2ca) and 3,4-Dihydro-
1(2H)-anthracenone (2cb)
Compounds 2ca and 2cb were prepared by the method described for
2a using HFIP (4.0 mL), FSO3H·SbF5 (317 mg, 1.00 mmol), and 1c
(110 mg, 0.50 mmol). Purification by PTLC on silica gel (hexane–
EtOAc, 10:1) gave 2ca (59 mg, 60%) as a pale yellow liquid and
2cb (8 mg, 8%) as a colorless solid.
3,4-Dihydro-2-phenyl-1(2H)-naphthalenone (2f)
Compound 2f was prepared by the method described for 2a using
HFIP (2.0 mL), FSO3H·SbF5 (138 mg, 0.44 mmol), and 1f (40 mg,
0.16 mmol) in HFIP (1.0 mL). Purification by PTLC on silica gel
(hexane–EtOAc, 10:1) gave 2f (32 mg, 87%) as a colorless solid.
IR (KBr): 3050, 1680, 1600, 1460, 1230, 765, 740, 700 cm–1.
2ca
IR (neat): 3456, 2945, 1676, 1448, 1348, 1176, 918, 750 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.40–2.47 (2 H, m), 3.05 (1 H,
ddd, J = 16.7, 4.7, 4.7 Hz), 3.12 (1 H, ddd, J = 16.7, 7.9, 7.9 Hz),
3.80 (1 H, dd, J = 8.9, 6.7 Hz), 7.19 (2 H, d, J = 7.4 Hz), 7.25–7.30
(2 H, m), 7.34 (3 H, t, J = 7.4 Hz), 7.50 (1 H, td, J = 7.4, 1.2 Hz),
8.10 (1 H, dd, J = 7.4, 1.2 Hz).
13C NMR (126 MHz, CDCl3): d = 28.7, 31.2, 54.4, 126.7, 126.9,
127.8, 128.4, 128.5, 128.8, 132.8, 133.4, 139.7, 144.0, 198.2.
1H NMR (500 MHz, CDCl3): d = 2.17 (2 H, tt, J = 6.7, 6.1 Hz), 2.77
(2 H, t, J = 6.7 Hz), 3.09 (2 H, t, J = 6.1 Hz), 7.29 (1 H, d, J = 8.2
Hz), 7.47 (1 H, td, J = 8.2, 0.9 Hz), 7.60–7.63 (1 H, m), 7.77 (1 H,
d, J = 8.2 Hz), 7.89 (1 H, d, J = 8.2 Hz), 9.41 (1 H, d, J = 8.2 Hz).
13C NMR (126 MHz, CDCl3): d = 23.0, 31.6, 41.1, 125.8, 126.6,
127.0, 127.2, 128.3, 128.8, 131.3, 132.7, 134.2, 146.8, 200.5.
Anal. Calcd for C16H14O: C, 86.45; H, 6.35. Found: C, 86.39; H,
6.30.
Anal. Calcd for C14H12O: C, 85.68; H, 6.16. Found: C, 85.42; H,
6.19.
4-Ethyl-2-phenyl-3,4-dihydro-1(2H)-naphthalenone (2g)
Compound 2g was prepared by the method described for 2a using
HFIP (2.0 mL), FSO3H·SbF5 (114 mg, 0.36 mmol), and 1g (50 mg,
0.18 mmol) in HFIP (1.0 mL). Purification by PTLC on silica gel
(hexane–EtOAc, 10:1) gave 2g (38 mg, 83%, trans/cis = 75:25) as
a colorless liquid. The trans/cis mixture was separated by PTLC on
silica gel (hexane–butyl acetate–benzene, 50:1:6).
2cb
IR (KBr): 2922, 2852, 1670, 1508, 1458, 1196, 1117, 814, 746
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.17 (2 H, tt, J = 6.4, 6.1 Hz), 2.74
(2 H, t, J = 6.4 Hz), 3.11 (2 H, t, J = 6.1 Hz), 7.44 (1 H, t, J = 7.8
Hz), 7.53 (1 H, t, J = 7.8 Hz), 7.66 (1 H, s), 7.76 (1 H, d, J = 7.8 Hz),
7.93 (1 H, d, J = 7.8 Hz), 8.60 (1 H, s).
13C NMR (126 MHz, CDCl3): d = 23.3, 30.0, 39.7, 125.9, 126.7,
trans-2g
127.0, 128.6, 128.8, 129.0, 130.7, 131.6, 135.8, 139.3, 198.9.
IR (neat): 3062, 2960, 1684, 1599, 1497, 1456, 1309, 1232, 750,
698 cm–1.
HRMS (FAB): m/z calcd for C14H13O ([M + H]+): 197.0967; found:
197.0958.
1H NMR (500 MHz, CDCl3): d = 1.07 (3 H, t, J = 7.3 Hz), 1.82 (1
H, ddq, J = 14.0, 7.3, 7.3 Hz), 1.85 (1 H, ddq, J = 14.0, 7.3, 7.3 Hz),
2.37 (1 H, ddd, J = 13.4, 4.6, 3.7 Hz), 2.58 (1 H, ddd, J = 13.4, 13.4,
4.6 Hz), 2.94 (1 H, dddd, J = 7.3, 7.3, 4.6, 3.7 Hz), 3.97 (1 H, dd,
J = 13.4, 4.6 Hz), 7.20 (2 H, dd, J = 7.4, 1.3 Hz), 7.24–7.36 (5 H,
m), 7.51 (1 H, td, J = 7.4, 1.3 Hz), 8.07 (1 H, dd, J = 7.4, 1.3 Hz).
6,7,8,9-Tetrahydro-5H-benzo[a]cyclohepten-5-one (1-Benzo-
suberone, 2d)
Compound 2d was prepared by the method described for 2a using
HFIP (2.0 mL), FSO3H·SbF5 (274 mg, 0.87 mmol), and 1d (78 mg,
0.43 mmol) in HFIP (1.0 mL). Purification by PTLC on silica gel
(hexane–EtOAc, 10:1) gave 2d (16 mg, 23%) as a colorless liquid.
13C NMR (126 MHz, CDCl3): d = 12.6, 28.1, 34.5, 39.3, 49.4, 126.8,
126.9, 127.9, 128.5, 128.6, 128.7, 131.9, 133.3, 140.3, 148.1, 198.3.
IR (neat): 3064, 2939, 1676, 1599, 1454, 1261, 1201, 1109, 964,
769 cm–1.
HRMS: m/z calcd for C18H18O (M+): 250.1358; found: 250.1339.
Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York

PAPER
Friedel–Crafts Cyclization of 1,1-Difluoroalk-1-enes
IR (neat): 2930, 1585, 1480, 1465, 1390, 760, 740, 720 cm–1.
45
cis-2g
IR (neat): 3062, 2962, 1684, 1599, 1558, 1497, 1456, 1221, 746,
1H NMR (270 MHz, CDCl3): d = 0.90 (3 H, t, J = 7.4 Hz), 1.34 (2
H, tq, J = 7.4, 7.4 Hz), 1.56 (2 H, tt, J = 7.5, 7.4 Hz), 2.72 (2 H, t,
J = 7.5 Hz), 3.56 (2 H, s), 7.00–7.20 (8 H, m), 7.35–7.41 (1 H, m).
13C NMR (68 MHz, CDCl3): d = 13.9, 22.6, 29.4, 31.8, 41.0, 120.1,
123.4, 124.6, 125.1, 126.5, 127.0, 128.7, 136.4, 141.5, 144.9, 157.4,
157.4.
698 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.00 (3 H, t, J = 7.5 Hz), 1.79 (1
H, ddq, J = 14.0, 7.6, 7.5 Hz), 2.17 (1 H, dqd, J = 14.0, 7.5, 4.0 Hz),
2.19 (1 H, ddd, J = 14.0, 13.1, 11.9 Hz), 2.43 (1 H, ddd, J = 13.1,
4.3, 4.0 Hz), 3.19 (1 H, dddd, J = 11.9, 7.6, 4.0, 4.0 Hz), 3.79 (1 H,
dd, J = 14.0, 4.3 Hz), 7.20–7.24 (2 H, m), 7.29 (1 H, tt, J = 7.9, 1.5
Hz), 7.33–7.39 (3 H, m), 7.49 (1 H, d, J = 7.9 Hz), 7.57 (1 H, td,
J = 7.9, 1.5 Hz), 8.10 (1 H, dd, J = 7.9, 1.5 Hz).
13C NMR (126 MHz, CDCl3): d = 10.2, 26.1, 36.3, 39.2, 54.9, 126.3,
126.5, 127.0, 128.0, 128.5, 128.6, 133.2, 133.4, 140.0, 146.5, 198.3.
HRMS: m/z calcd for C18H18O (M+): 250.1358; found: 250.1352.
HRMS: m/z calcd for C19H20S (M+): 280.1286; found: 280.1276.
2-Butyl-3-(2,4-dimethoxyphenyl)indene (11b)
2-Benzyl-1,1-difluorohex-1-ene (1e; 27.6 mg, 0.13 mmol) in HFIP
(1.0 mL) was added to a solution of FSO3H·SbF5 (85.2 mg, 0.27
mmol) in HFIP (2.0 mL) at 0 °C under N2. After stirring the mixture
for 10 min, 1,3-dimethoxybenzene (186 mg, 1.35 mmol) was added.
After the mixture was heated at reflux for 3 h, phosphate buffer (pH
7) was added to quench the reaction. Organic materials were ex-
tracted with CH2Cl2 (3 ×). The combined organic extracts were
washed with brine and dried (Na2SO4). After removal of the solvent
under reduced pressure, the residue was purified by PTLC on silica
gel (hexane–EtOAc, 20:1) to give 11b (8.7 mg, 21%) as a colorless
liquid.
4-Methyl-2-phenyl-3,4-dihydro-1(2H)-naphthalenone (2h)
Compound 2h was prepared by the method described for 2a using
HFIP (2.0 mL), FSO3H·SbF5 (167 mg, 0.53 mmol), and 1h (66 mg,
0.26 mmol) in HFIP (1.0 mL). Purification by PTLC on silica gel
(hexane–EtOAc, 10:1) gave 2h (51 mg, 85%, trans/cis = 65:35) as
a colorless liquid (trans-2h) and a colorless solid (cis-2h). The
trans/cis mixture was separated by PTLC on silica gel (hexane–bu-
tyl acetate–benzene, 50:1:6).
IR (neat): 2950, 1605, 1580, 1505, 1465, 1350, 1210, 1160, 1130,
1040 cm–1.
trans-2h
1H NMR (500 MHz, CDCl3): d = 0.85 (3 H, t, J = 7.4 Hz), 1.29 (2
H, qt, J = 7.4, 7.3 Hz), 1.45–1.58 (2 H, m), 2.33–2.43 (2 H, m), 3.42
(1 H, d, J = 22.6 Hz), 3.48 (1 H, d, J = 22.6 Hz), 3.72 (3 H, s), 3.86
(3 H, s), 6.55–6.59 (2 H, m), 6.97 (1 H, d, J = 7.3 Hz), 7.08–7.20 (3
H, m), 7.40 (1 H, d, J = 7.3 Hz).
13C NMR (126 MHz, CDCl3): d = 14.0, 22.7, 29.1, 31.8, 40.3, 55.3,
55.4, 98.9, 104.3, 117.1, 119.7, 123.2, 123.5, 125.9, 131.6, 135.3,
142.3, 146.2, 147.0, 158.5, 160.3.
IR (neat): 3064, 2927, 1686, 1601, 1452, 1298, 1238, 995, 762, 698
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (3 H, d, J = 7.0 Hz), 2.21 (1
H, ddd, J = 13.4, 4.9, 4.8 Hz), 2.62 (1 H, ddd, J = 13.4, 11.3, 4.6
Hz), 3.22 (1 H, qdd, J = 7.0, 4.8, 4.6 Hz), 4.02 (1 H, dd, J = 11.3,
4.9 Hz), 7.18 (2 H, dd, J = 7.6, 1.5 Hz), 7.25 (1 H, tt, J = 7.6, 1.5
Hz), 7.30–7.35 (4 H, m), 7.52 (1 H, td, J = 7.6, 1.5 Hz), 8.08 (1 H,
dd, J = 7.6, 1.5 Hz).
HRMS: m/z calcd for C21H24O2 (M+): 308.1776; found: 308.1771.
13C NMR (126 MHz, CDCl3): d = 21.3, 31.5, 37.9, 49.7, 126.7,
126.9, 127.8, 128.1, 128.5, 128.5, 131.8, 133.7, 139.9, 148.7, 198.3.
2-Butyl-3-phenylindene (11c)
Anal. Calcd for C17H16O: C, 86.40; H, 6.82. Found: C, 86.30; H,
6.91.
Compound 11c was prepared by the method described for 11b using
HFIP (2.0 mL), FSO3H·SbF5 (175.4 mg, 0.55 mmol), 1e (56.3 mg,
0.27 mmol) in HFIP (1.0 mL), and benzene (1.0 mL, 11 mmol). The
reaction was carried out at r.t. for 10 h. Purification by PTLC on sil-
ica gel (hexane–EtOAc, 50:1) gave 11c (18 mg, 27%) as a colorless
liquid.
cis-2h
IR (KBr): 3064, 2964, 1676, 1601, 1452, 1331, 1223, 1005, 748,
698 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.48 (3 H, d, J = 6.7 Hz), 2.21 (1
H, ddd, J = 14.0, 13.1, 11.9 Hz), 2.37 (1 H, ddd, J = 13.1, 4.3, 4.3
Hz), 3.27 (1 H, dqd, J = 11.9, 6.7, 4.3 Hz), 3.81 (1 H, dd, J = 14.0,
4.3 Hz), 7.20–7.22 (2 H, m), 7.29 (1 H, tt, J = 7.5, 1.2 Hz), 7.34–
7.38 (3 H, m), 7.46 (1 H, d, J = 7.5 Hz), 7.57 (1 H, td, J = 7.5, 1.2
Hz), 8.10 (1 H, dd, J = 7.5, 1.2 Hz).
13C NMR (126 MHz, CDCl3): d = 20.1, 33.4, 40.6, 55.2, 126.4,
126.6, 127.0, 127.9, 128.5, 128.6, 132.6, 133.6, 139.9, 147.9, 198.3.
HRMS: m/z calcd for C17H16O (M+): 236.1201; found: 236.1194.
IR (neat): 2940, 1500, 1465, 1395, 770, 720, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.86 (3 H, t, J = 7.4 Hz), 1.31 (2
H, tq, J = 7.6, 7.4 Hz), 1.54 (2 H, tt, J = 7.8, 7.6 Hz), 2.49 (2 H, t,
J = 7.8 Hz), 3.46 (2 H, s), 7.13–7.23 (3 H, m), 7.32–7.46 (6 H, m).
13C NMR (126 MHz, CDCl3): d = 13.9, 22.7, 28.7, 32.2, 40.5, 119.4,
123.5, 124.0, 126.2, 127.0, 128.4, 129.2, 135.7, 138.7, 142.5, 145.4,
146.5.
HRMS: m/z calcd for C19H20 (M+): 248.1565; found: 248.1582.
2-Butyl-3-phenylthioindene (11a)
Acknowledgment
2-Benzyl-1,1-difluorohex-1-ene (1e; 43 mg, 0.21 mmol) in HFIP
(1.0 mL) was added to a solution of FSO3H·SbF5 (133 mg, 0.42
mmol) in HFIP (2.0 mL) at 0 °C under N2. After stirring for 10 min
at 0 °C, the mixture was treated with benzenethiol (43 mL, 0.42
mmol) and stirred for 10 min. THF (2.0 mL) was then added and the
mixture was stirred for 30 min at r.t. The mixture was poured into
aq NaHCO3 to quench the reaction. Organic materials were extract-
ed with CH2Cl2 (3 ×). The combined extracts were washed with
brine and dried (Na2SO4). After removal of the solvent under re-
duced pressure, the residue was purified by PTLC on silica gel (hex-
ane) to give 11a (41 mg, 71%) as a colorless liquid.
We gratefully acknowledge the financial support and a generous
gift of HFIP from Central Glass Co., Ltd.
References
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Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York

46
J. Ichikawa et al.
PAPER
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Kawamura, M.; Shimada, S. Tetrahedron Lett. 2004, 1741;
and references cited therein. (c) For a review on the
intramolecular aromatic Friedel–Crafts Reaction, see:
Heaney, H. In Comprehensive Organic Synthesis, Vol. 2;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, Chap. 3.3.
(3) For reports where the effect of fluorine on carbocations was
advantageously applied in organic synthesis, see:
(a) Johnson, W. S.; Daub, G. W.; Lyle, T. A.; Niwa, M. J.
Am. Chem. Soc. 1980, 102, 7800. (b) Johnson, W. S.; Lyle,
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P. V.; Johnson, W. S.; Jones, G. S.; Tham, F. S.; Kullnig, R.
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therein. (d) Morikawa, T.; Kumadaki, I.; Shiro, M. Chem.
Pharm. Bull. 1985, 33, 5144.
(4) For recent reports on the allylic rearrangement of
fluoroallylalcohol derivatives, see: (a) Funabiki, K.; Sawa,
K.; Shibata, K.; Matsui, M. Synlett 2002, 1134.
(b) Ichikawa, J.; Fujiwara, M.; Miyazaki, S.; Ikemoto, M.;
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references cited therein. (c) Yamazaki, T.; Hiraoka, S.;
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(5) (a) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J.
Org. Chem. 1995, 60, 2320. (b) Ichikawa, J.; Fujiwara, M.;
Okauchi, T.; Minami, T. Synlett 1998, 927.
(6) For reports on the Friedel–Crafts reaction of fluorinated
allylic cations, see: (a) Gyenes, F.; Purrington, S. T.; Liu,
Y.-S. J. Org. Chem. 1999, 64, 1366. (b) Kobayashi, Y.;
Nagai, T.; Kumadaki, I.; Takahashi, M.; Yamauchi, T.
Chem. Pharm. Bull. 1984, 32, 4382.
(7) Ichikawa, J. J. Fluorine Chem. 2000, 105, 257.
(8) For reports on the protonation of 1,1-difluoroethylene with
FSO3H·SbF5 to give 1,1,1-trifluoroethane or 1,1-difluoro-
ethyl fluorosulfonate, see: Olah, G. A.; Mo, Y. K. J. Org.
Chem. 1972, 37, 1028.
(12) For recent examples, see: (a) Vukics, K.; Fodor, T.; Fischer,
J.; Fellegvári, I.; Lévai, S. Org. Process Res. Dev. 2002, 6,
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(13) The configuration of 1h was assigned by 1H NMR
measurement. The 1H NMR spectrum for the major isomer
of 1h exhibits a large geminal coupling constant (Jgem = 13.4
Hz) between the protons Hax and Heq at C-3. Hax is coupled
to the C-2 and C-4 protons with coupling constant values of
11.3 Hz and 4.6 Hz, which are consistent with typical axial-
axial and axial-equatorial values, respectively. In the 1H
NMR spectrum of the minor isomer of 1h, two large axial-
axial coupling constants are observed between the C-3 axial
proton and the C-2 proton and between the C-3 axial proton
and the C-4 proton (J32 = 14.0 Hz, J34 = 11.9 Hz). Moreover,
the observed NOEs between the C-2 axial proton and the
methyl proton of the major isomer and between the C-2 axial
proton and the C-4 axial proton of the minor isomer support
this assignment. Stereochemistry was assigned for 2g on the
basis of the proton coupling constants in a similar manner.
(14) Vinyl fluoride 14 (X = F) was not detected by 19F NMR
measurement of the reaction mixture.
(9) Bégué, J. P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004,
18.
(15) For discussions on the ability of halogens to stabilize
carbocations, see: Christe, K. O.; Zhang, X.; Bau, R.; Olah,
G. A.; Prakash, G. K. S.; Sheehy, J. A. J. Am. Chem. Soc.
2000, 122, 481; and references cited therein.
(10) For recent reports on the cationic reactions conducted in
HFIP, see: (a) Ohwada, A.; Nara, S.; Sakamoto, T.;
Kikugawa, Y. J. Chem. Soc., Perkin Trans. 1 2001, 3064.
(b) Bjurling, E.; Björkman, A.; Andersson, C.-M.
Organometallics 2001, 20, 990.
(16) The spectroscopic data (1H, 13C NMR and IR) of 2a,b,d are
in agreement with the reported data: (a) Pouchert, C. J.;
Behnke, J. The Aldrich Library of 13C and 1H FT NMR
Spectra; Aldrich Chemical Company, Inc.: Milwaukee,
1992. (b) Pouchert, C. J. The Aldrich Library of Infrared
Spectra 3rd ed.; Aldrich Chemical Company, Inc.:
Milwaukee, 1981.
Synthesis 2005, No. 1, 39–46 © Thieme Stuttgart · New York