Intramolecular Diels-Alder reaction of α-fluoroacrylate derivatives promoted by novel bidentate aluminum Lewis acid

Article abstract of DOI:10.1016/j.jfluchem.2005.01.019

Intramolecular Diels-Alder (IMDA) reaction of α-fluoroacrylate derivatives 1a-e having 1,7,9-decatrienoate system is efficiently promoted by the novel bidentate Lewis acid A generated in situ by mixing 3,3′,5,5′-tetrabromo-1,1′-biphenyl-2,2′-diol (Br ₄BIPOL, 1 mol) and trimethylaluminum (2 mol). The IMDA reaction of α-fluoroacrylates proceeds via endo-boat transition state as in the case of the corresponding non-fluorinated acrylate.

Full text of DOI:10.1016/j.jfluchem.2005.01.019

Journal of Fluorine Chemistry 126 (2005) 709–714
www.elsevier.com/locate/fluor
Intramolecular Diels–Alder reaction of a-fluoroacrylate derivatives
promoted by novel bidentate aluminum Lewis acid
*
Akio Saito, Hikaru Yanai, Wataru Sakamoto, Kosuke Takahashi, Takeo Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1423-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 13 January 2005; received in revised form 26 January 2005; accepted 26 January 2005
Available online 16 March 2005
Dedicated to Professor Iwao Ojima on the occasion of his 60th birthday.
Abstract
Intramolecular Diels–Alder (IMDA) reaction of a-fluoroacrylate derivatives 1a–e having 1,7,9-decatrienoate system is efficiently
promoted by the novel bidentate Lewis acid A generated in situ by mixing 3,30,5,50-tetrabromo-1,10-biphenyl-2,20-diol (Br4BIPOL, 1 mol) and
trimethylaluminum (2 mol). The IMDA reaction of a-fluoroacrylates proceeds via endo-boat transition state as in the case of the
corresponding non-fluorinated acrylate.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Diels–Alder reaction; a-Fluoroacrylate; 1,10-Biphenyl-2,20-diol derivative; Alkylaluminum; Bidentate Lewis acid
1. Introduction
reaction is more unfavorable [15–20]. Towards to this issue,
we have demonstrated that a bidentate Lewis acid, which has
bis-aluminated triflic amide structure, can nicely promote the
IMDA reactionofestertethered 1,7,9-decatrienoates [21–23].
The efficiency of this bidentate Lewis acid is possibly due to
extensive restriction to the cisoid conformation and decrease
in LUMO level of the dienophile part through the bidentate
coordination of the ester group (Scheme 1).
It has been well documented that the intramolecular
Diels–Alder (IMDA) reaction is a powerful mean for the
stereoselective construction of highly functionalized poly-
cyclic molecules [1–7]. In the IMDA reaction, the tether
moiety connecting diene and dienophile parts often plays an
important role on the reactivity of the substrate and the
stereochemical outcome of the product [8]. For example,
contrary to the IMDA reaction of hydrocarbon substrates or
amide-tethered triene compounds, that of ester tethered
substrates generally requires high temperature and long
reaction time to get the cyclized product, but in some cases
even fails to obtain any cyclized product [9–14]. The low
reactivity of ester tethered substrate is explained by a
preference of transoid geometry due to repulsive dipole
interaction between carbonyl-oxygen and ethereal oxygen
and steric repulsion between two alkyl substituents (R1 and
R2), thereby the cisoid form, in which the diene and
dienophile are in close proximity required for the IMDA
Due to the unique physical and chemical properties of
organofluorine compounds brought about by incorporation of
fluorine atom into the molecule, organofluorine compounds
have been attracting much attention, in particular in the field
ofmedicinalchemistryandmaterialscience[24–26]. Itwould
be expected that the Diels–Alder reaction of fluorinated
dienophiles provides a powerful mean for the construction of
fluorinated cyclic compounds. Indeed, several examples of
fluorine-modified biologically active compounds such as
L-glutamate [27–29], cantharidin and endothall [30],
D-homosteroids [31], which were synthesized using the
Diels–Alder reaction, were reported. In these examples, the
intermolecular Diels–Alder reactions were employed, and as
far as we know, there has been only one report on the
intramolecular version using a trifluoromethylated olefin as a
* Corresponding author. Fax: +81 426 76 3257.
E-mail address: taguchi@ps.toyaku.ac.jp (T. Taguchi).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.01.019

710
A. Saito et al. / Journal of Fluorine Chemistry 126 (2005) 709–714
acidic Lewis acids TfN(AlMe2)2 or TfN[Al(i-Bu)2]2 were
examined. However, any significant improvement was not
realized. Further efforts to find out an effective catalyst were
made by changing the basic structure of the ligand, and 1,10-
biphenyl-2,20-diol (BIPOL) was found to be an employable
ligand. As shown in entry 2, the bis-aluminated BIPOL
generated from 1,10-biphenyl-2,20-diol (1.1 equiv.) and
Me2AlCl (2.0 equiv.) promoted the IMDA reaction of 1a
at room temperature to give 2a in 30% yield. Modification of
BIPOL moiety by introducing bromine atoms led to more
effective ligand. Thus, on using a combination of 3,30-
dibromo-1,10-biphenyl-2,20-diol (Br2BIPOL) or 3,30,5,50-
tetrabromo derivative (Br4BIPOL) and Me2AlCl increase in
the yield of 2a was observed, while with these Lewis acid
defluorination of the cyclized product 2a could not be
prevented (entries 3, 4). A combination of Br4BIPOL and
Me3Al instead of Me2AlCl provided better results. That is, in
the presence of 1.1 molar equivalent of Br4BIPOL/2Me3Al
relative to 1a, the IMDA product 2a was obtained in 51%
yield after 22 h at room temperature along with the recovery
of 1a (30%, entry 5), while at higher reaction temperature
(60 8C) a significant decrease in the yield of 2a due to
defluorination reaction was observed (entry 8). The best
result with 1a was obtained when the reaction was carried
out at room temperature using 1.5 molar equivalent of the
present Lewis acids (entry 6). On the other hand,
monodentate Lewis acid generated from mono-methylated
Br4BIPOL (Br4BIPOL-OMe) and Me3Al (1 equiv.) was
found to be less effective. Thus, under the same reaction
conditions with this Lewis acid, the IMDA product 2a was
obtained in only 23% yield along with the recovery of 1a in
41% (entry 9). The cis-fused ring system in the product 2a
was determined based on the correlation between the
fluorine atom and the angular hydrogen atom observed in the
19F-1H HOESY experiment [33].
Scheme 1.
dienophile part [32]. Related to our ongoing study on the
IMDA reaction of ester-tethered 1,7,9-decatrienoates effi-
ciently promoted by a bidentate aluminated Lewis acid, we
have examined the IMDA reaction of 1,7,9-decatrienoates
having a-fluoroacrylate moiety. We found that the novel
bidentate Lewis acid A generated in situ by mixing 3,30,5,50-
tetrabromo-1,10-biphenyl-2,20-diol (Br4BIPOL) and tri-
methylaluminum (2 equiv.) can efficiently promote the
IMDA reaction of a-fluoroacrylate derivatives 1 having
1,7,9-decatrienoate system (Scheme 2). These results are
the first successful examples of the IMDA reaction of
a-fluoroacrylate derivatives and the detail is reported in this
paper.
2. Results and discussion
The IMDA reaction of 3,5-hexadienyl 2-fluoroacrylate 1a
was conducted under the various reaction conditions, in
particular to find out an effective Lewis acid catalyst
(Table 1). When the triflic amide-based aluminated Lewis
acid TfN[Al(Me)Cl]2 (1.1 equiv.), which showed the best
efficiency as the catalyst in the IMDA reaction of non-
fluorinated 1,7,9-decatrienoates was employed, the starting
triene 1a was consumed within 6 h at ꢀ24 8C giving rise to
the desired cycloadduct 2a in 35% yield along with the
isolation of the defluorinated by-product 3 in some extent
(entry 1). Since it was confirmed from the separate
experiment that defluorination of the cycloadduct 2a leading
to 3 is promoted by the Lewis acid TfN[Al(Me)Cl]2, less
As mentioned above, since we could find out an effec-
tive catalyst for the IMDA reaction of 3,5-hexadienyl
2-fluoroacrylate 1a, we next examined the substituent effect
Scheme 2.

A. Saito et al. / Journal of Fluorine Chemistry 126 (2005) 709–714
711
Table 1
Effect of bidentate Lewis acids on IMDA reaction of a-fluoroacrylate 1a
Entry Lewis acid (equiv.)
Temperature Time Yielda (%)
(8C)
(h)
2
3
Scheme 3.
1
TfN[Al(Me)Cl]2 (1.1)
ꢀ24
rt
6
9
35 NDb
30 NDb
39 NDb
46 14
2
BIPOL + 2Me2AlCl (1.1)
Br2BIPOL + 2Me2AlCl (1.1)
Br4BIPOL + 2Me2AlCl (1.1)
Br4BIPOL + 2Me3Al (1.1)
Br4BIPOL + 2Me3Al (1.5)
Br4BIPOL + 2Me3Al (2.0)
Br4BIPOL + 2Me3Al (1.1)
3
rt
8
4c
5d
6e
7f
8g
9h
rt
3
rt
22
8
51
65
0
0
rt
rt
8
64 Trace
41 26
60
10
8
Br4BIPOL-OMe + Me3Al (3.0) rt
23 0
a
Isolated yield.
b
c
d
e
f
Not determined.
18% of 1a was recovered.
30% of 1a was recovered.
13% of 1a was recovered.
9% of 1a was recovered.
ClCH2CH2Cl was used as solvent.
41% of 1a was recovered
g
h
Scheme 4.
The structures of the products 2b–e were determined by
19F-1H HOESY data or X-ray crystallographic analysis.
Based on the structures of the products 2a–e, all of which
have cis-fused bicyclic structure, the IMDA reaction of a-
fluoroacrylates proceeds via endo-boat transition state as in
the case of the corresponding non-fluorinated acrylate
[11,21]. These results may indicate that fluorine atom well
mimics hydrogen in the present IMDA reaction, since the
IMDA reaction of methacrylate 1i (a-methyl instead of
a-fluoro derivative 1b) gave a diastereomer mixture of the
cyclized products due to the steric interaction between
a-methyl and 5-hydrogen substituents [21,22] (Scheme 3).
6-Methyl derivative 1c gave the IMDA product as a mixture
of 2c-cis and 2c-trans in a ratio of 5.3: 1, which would be
formed via endo-boat-equatorial transition state and endo-
boat axial transition state, respectively (Scheme 4).
.
in the substrate 1b–e on the reactivity and the diastereos-
electivity. Results are summarized in Table 2. With these
substrates, reaction proceeded at room temperature using 1.5
molar equivalent of Br4BIPOL/2Me3Al to obtain the IMDA
product in good yield and the position of substituent showed
significant influence on the reactivity. Compared to the
model substrate 1a, 5-methyl derivative 1b showed a similar
reactivity to give the cyclized product 2b in 71% yield as a
single isomer (entry 2). Reaction of 6-methyl derivative 1c
required longer time (24 h) to give the product 2c in 61%
yield as a mixture of stereoisomers in a ratio of 5.3:1 (entry
3, see also Scheme 4). Both 8-methyl and 10-methyl
derivatives 1d, 1e gave the corresponding IMDA product 2d,
2e as a single isomer. While 1d showed high reactivity to
give 2d in 88% yield after 6 h, 1e reacted slowly to give 2e in
moderate yield (42%). Contrary to a-fluoroacrylate 1a, the
chloro derivative 1f or the methyl derivative 1g did not
react even at higher temperature (entries 6 and 7) and the
corresponding acrylate itself 1h showed somewhat lower
reactivity to obtain the IMDA product 2h in 58% yield after
42 h at 80 8C (entry 8 versus entry 1).
In conclusion, we have demonstrated that a novel
bidentate Lewis acid A in situ generated from Br4BIPOL
and Me3Al can promote the IMDA reaction of a-
fluoroacrylate derivatives to give the cycloadduct in good
yield and with excellent stereoselectivity. These results are
the first examples of the IMDA reaction of fluorinated triene
systems and provide useful method for the stereoselective
construction of fluorinated polycyclic molecules.
3. Experimental details
General: 2,20-Biphenyl-1,10-binol, trimethylaluminum
(1.0 M in hexane) and dimethylaluminum chloride (1.0 M

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A. Saito et al. / Journal of Fluorine Chemistry 126 (2005) 709–714
Table 2
IMDA reaction of a-fluoroacrylate derivatives
Entry
1
X
R1
R2
R3
R4
Temperature (8C)
Time (h)
Yielda (%)
drb
2
1
1
1a
1b
1c
1d
1e
F
H
H
H
H
rt
8
8
65
0
0
8
0
0
Single isomer
Single isomer
5.3:ld
2
3c
F
Me
H
H
H
H
rt
71
F
Me
H
H
H
rt
24
6
61
4
F
H
Me
H
H
rt
88
Single isomer
Single isomer
5c
6e
7e
8e
a
F
H
H
Me
H
rt
12
12
41
42
42
1f
Cl
Me
H
H
H
H
80
80
80
No reaction
No reaction
58
1gf
1hf
H
H
H
H
H
H
H
H
4
Single isomer
Isolated yield.
Based on 1H-NMR.
b
c
d
e
f
Trace amount of 3c or 3e (< 5% yield) was obtained.
A ratio of cis/trans.
Solvent; ClCH2CH2Cl.
Ref. [21].
in hexane) are available commercially. 3,30,5,50-Tetra-
bromo-2,20-biphenyl-1,10-diol (Br4BIPOL) was prepared
according to the reported procedure [34]. All reactions were
carried out under argon atmosphere. 1H- and 13C-NMR
spectra were taken on a Bruker dpx400 spectrometer, and
chemical shifts were reported in parts per million (ppm)
using CHCl3 (7.26 ppm) in CDCl3 for 1H-NMR, and CDCl3
(77.01 ppm) for 13C-NMR as an internal standard, respec-
tively. 19F-NMR spectra were taken on a Bruker dpx400
spectrometer, and chemical shifts were reported in parts per
million using benzotrifluoride as a standard. Infrared (IR)
spectra were recorded on a JASCO FT/IR-620 infrared
spectrophotometer. Mass spectra (MS) were obtained on a
VG Auto Spec. Medium pressure liquid chromatography
(MPLC) was performed using prepacked column (silica gel,
50 mm) with RI detector.
were prepared from the corresponding dienyl alcohol and 2-
fluoroacryloyl fluoride.
3.1.1. (3E)-3,5-hexadienyl 2-fluoroacrylate (1a)
Colorless oil. IR (neat) n cmꢀ1; 1746. 1H-NMR
(400 MHz, CDCl3) d; 2.49 (2H, dd, J = 13.9, 6.8 Hz),
4.28 (2H, t, J = 6.8 Hz), 5.03 (1H, bd, J = 10.2 Hz), 5.15
(1H, bd, J = 16.6 Hz), 5.32 (1H, dd, J = 13.0, 3.2 Hz), 5.63–
5.70 (1H, m), 5.66 (1H, dd, J = 43.0, 3.2 Hz), 6.14 (1H, dd,
J = 13.9, 10.5 Hz), 6.30 (1H, dd, J = 16.6, 10.2, 10.2 Hz).
13C-NMR (100.6 MHz, CDCl3) d; 31.7, 64.9, 102.7 (d,
J = 15.2 Hz), 116.4, 128.8, 133.8, 136.6, 153.3 (d,
J = 262.2 Hz), 160.3 (d, J = 36.6 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢀ54.4 (1F, dd, J = 43.0, 13.0 Hz)
EI-MS m/z: 45.0 [M-C8H11O2]+, 73.0 [M-C7H11O]+. Anal.
Calcd for C9H11FO2: C, 63.52; H, 6.52. Found: C, 63.48; H,
6.39.
3.1. General procedure for preparation of
a-fluoroacrylate derivatives (1)
3.1.2. (1S*,3E)-1-methyl-3,5-hexadienyl
2-fluoroacrylate (1b)
To a solution of 3,5-hexadiene-1-ol (491 mg, 5.0 mmol)
in CH2Cl2 (10 mL), 2-fluoroacryloyl fluoride [35] (2.2 M in
ether, 2.50 mL, 5.5 mmol) and triethylamine (0.63 mL,
6.0 mmol) were added at 0 8C. After being stirred at room
temperature for 2 h, the reaction mixture was quenched by
H2O and extracted with diethyl ether. The organic layer was
washed with brine and dried over MgSO4. Purification by
column chromatography (hexane/ether = 25:1) gave the
product 1a (731 mg, 4.2 mmol, 82%). By a similar
procedure for the preparation of 1a, the substrates 1b–e
A 68% yield. Colorless oil. IR (neat) n cmꢀ1; 1745.
1H-NMR (400 MHz, CDCl3) d; 1.30 (3H, d, J = 6.3 Hz),
2.15–2.78 (2H, m), 5.02 (1H, d, J = 10.7 Hz), 5.05–5.11
(1H, m), 5.13 (1H, d, J = 16.9 Hz), 5.30 (1H, dd, J = 13.0,
3.1 Hz), 5.60–5.64 (1H, m), 5.62 (1H, dd, J = 44.0, 3.1 Hz),
6.11 (1H, dd, J = 16.0, 10.7 Hz), 6.29 (1H, ddd, J = 16.9,
10.7, 10.7 Hz). 13C-NMR (100.6 MHz, CDCl3) d; 19.8,
39.2, 72.7, 102.8 (d, J = 15.4 Hz), 116.7, 128.9, 134.7,
137.0, 154.0 (d, J = 262.7 Hz), 160.3 (d, J = 36.7 Hz). 19F-
NMR (376.5 MHz, CDCl3) d; ꢀ54.2 (1F, dd, J = 44.0,

A. Saito et al. / Journal of Fluorine Chemistry 126 (2005) 709–714
713
13.0 Hz) EI-MS m/z: 73.0 [M-C7H11O]+. Anal. Calcd
for C10H13FO2: C, 65.20; H, 7.11. Found: C, 64.97;
H, 7.13.
column chromatography (hexane/ether = 25:1) to give the
product 1f (368 mg, 2.0 mmol, 39%).
3.2.1. (3E)-3,5-hexadienyl 2-chloroacrylate (1f)
3.1.3. (2R*,3E)-2-methyl-3,5-hexadienyl 2-fluoroacrylate
(1c)
Colorless oil. IR (neat) n cmꢀ1; 1734. 1H-NMR
(400 MHz, CDCl3) d; 2.50 (3H, dd, J = 13.4, 6.7 Hz),
4.28 (2H, dd, J = 6.7, 6.7 Hz), 5.03 (1H, d, J = 10.0z), 5.14
(1H, d, J = 16.9 Hz), 5.61–5.72 (1H, m), 5.99 (1H, d,
J = 1.3 Hz), 6.15 (1H, J = 15.2, 10.4 Hz), 6.32 (1H, J = 16.9,
15.2, 10.9 Hz), 6.50 (1H, d, J = 1.3 Hz). 13C-NMR
(75 MHz, CDCl3) d; 31.8, 65.5, 116.3, 125.7, 128.8,
131.4, 133.7, 136.5, 161.7. ESI-MS m/z: 187 [M + H]+.
HRMS Calcd for C9H12ClO2 [M + H]+: 187.0526. Found:
187.0524.
An 83% yield. Colorless oil. IR (neat) n cmꢀ1; 1746. 1H-
NMR (400 MHz, CDCl3) d; 1.09 (3H, d, J = 6.8 Hz), 2.59–
2.70 (1H, m), 4.05–4.20 (2H, m), 5.03 (1H, d, J = 10.2 Hz),
5.16 (1H, d, J = 17.9 Hz), 5.31 (1H, dd, J = 13.0, 3.2 Hz),
5.55–5.64 (1H, m), 5.65 (1H, dd, J = 43.0, 3.2 Hz), 6.12 (1H,
dd, J = 15.1, 10.3 Hz), 6.31 (1H, ddd, J = 17.9, 10.2,
10.2 Hz). 13C-NMR (100.6 MHz, CDCl3) d; 17.0, 36.3, 69.9,
103.1 (d, J = 15.2 Hz), 116.8, 132.1, 135.4, 137.2, 153.7 (d,
J = 262.2 Hz), 160.7 (d, J = 36.5 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢀ54.3 (1F, dd, J = 43.0, 13.0 Hz).
EI-MS m/z: 184 [M]+. Anal. Calcd for C10H13FO2: C, 65.20;
H, 7.11. Found: C, 65.20; H, 7.12.
3.3. General procedure of Lewis acid mediated IMDA
reactions of 1,7,9-decatrienoate derivatives
After a suspension of Br4BIPOL (82 mg, 0.55 mmol) in
CH2Cl2 (4.5 mL) was treated with trimethylaluminum
(1.0 M in hexane, 1.1 mL, 1.1 mmol) for 30 min at room
temperature, 1a (85.0 mg, 0.50 mmol) in CH2Cl2 (2.5 mL)
was added at room temperature. After being stirred for 8 h at
the same temperature, the reaction mixture was quenched
by 1 M HCl and extracted with diethyl ether. The organic
layer was washed with brine and dried over MgSO4.
Purification by column chromatography on silica gel
(hexane/AcOEt = 5:1) gave the product 2a (55.5 mg, 65%
yield).
3.1.4. (3E)-4-methyl-3,5-hexadienyl 2-fluoroacrylate (1d)
An 87% yield. Colorless oil. IR (neat) n cmꢀ1; 1744. 1H-
NMR (400 MHz, CDCl3) d; 1.77 (3H, s), 2.56 (2H, dd,
J = 14.1, 7.0 Hz), 4.26 (2H, t, J = 7.0 Hz), 4.99 (1H, d,
J = 10.7 Hz), 5.14 (1H, d, J = 17.4 Hz), 5.31 (1H, dd,
J = 13.0, 3.2 Hz), 5.46 (1H, dd, J = 7.0, 7.0 Hz), 5.65
(1H, dd, J = 43.0, 3.2 Hz), 6.37 (1H, dd, J = 17.4, 10.7 Hz).
13C-NMR (100.6 MHz, CDCl3) d; 11.8, 27.6, 64.9, 102.6
(d, J = 15.2 Hz), 111.9, 126.4, 137.0, 140.9, 153.3
(d, J = 262.0 Hz), 160.4 (d, J = 36.4 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢀ54.2 (1F, dd, J = 43.0, 13.0 Hz).
EI-MS m/z: 45.0 [M-C8H11O2]+, 73.0 [M-C7H11O]+, 93.0
[M-C3H4FO2]+. Anal. Calcd for C10H13FO2: C, 65.20; H,
7.11. Found: C, 65.22; H, 7.12.
3.3.1. (4aS*,8aS*)-8a-fluoro-3,4,4a,7,8,8a-hexahydro-1H-
isochromen-1-one (2a)
Colorless oil. IR (neat) n cmꢀ1; 1743. 1H-NMR
(400 MHz, CDCl3) d; 0.50–0.64 (1H, m), 0.77–0.92 (1H,
m), 1.01–1.16 (1H, m), 1.21–1.36 (3H, m), 1.88–2.02 (1H,
m), 3.63–3.88 (2H, m), 5.06–5.15 (1H, m), 5.52–5.63 (1H,
m). 13C-NMR (100.6 MHz, CDCl3) d; 22.6 (d, J = 7.8 Hz),
27.0 (d, J = 3.5 Hz), 28.5 (d, J = 22.3 Hz), 38.2 (d,
J = 21.9 Hz), 67.7, 91.5 (d, J = 180.6 Hz), 125.0 (d,
J = 4.3 Hz), 128.9, 168.6 (d, J = 23.9 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢀ85.3 (1F, m). EI-MS m/z: 170.0
[M]+. Anal. Calcd for C9H11FO2: C, 63.52; H, 6.52. Found:
C, 63.40; H, 6.58.
3.1.5. (3E,5E)-3,5-heptadienyl 2-fluoroacrylate (1e)
An 76% yield. Colorless oil. IR (neat) n cmꢀ1; 1744. 1H-
NMR (400 MHz, CDCl3) d; 1.73 (3H, d, J = 6.7 Hz), 2.45
(2H, dd, J = 13.7, 6.8 Hz), 4.26 (2H, dd, J = 6.8, 6.8 Hz),
5.31 (1H, dd, J = 14.0, 3.2 Hz), 5.42–5.53 (1H, m), 5.57–
5.68 (1H, m), 5.65 (1H, dd, J = 43.0, 3.2 Hz), 5.96–6.15 (2H,
m). 13C-NMR (100.6 MHz, CDCl3) d; 18.0, 31.7, 65.2,
102.6 (d, J = 15.1 Hz), 125.3, 128.6, 131.1, 133.4, 153.3
(d, J = 262.0 Hz), 160.3 (d, J = 36.6 Hz). 19F-NMR
(376.5 MHz, CDCl3) d; ꢀ54.4 (1F, dd, J = 14.0, 43.0 Hz).
EI-MS m/z: 184 [M]+. Anal. Calcd for C10H13FO2: C, 65.20;
H, 7.11. Found: C, 65.02; H, 7.10.
3.3.2. (3S*,4aS*,8aS*)-8a-fluoro-3-methyl-3,4,4a,7,8,
8a-hexahydro-1H-isochromen-1-one (2b)
An 71% yield. Colorless oil. IR (neat) n cmꢀ1; 1736. 1H-
NMR (400 MHz, CDCl3) d; 1.37 (3H, d, J = 6.3 Hz), 1.42
(1H, ddd, J = 14.6, 11.9, 11.9 Hz), 1.90–2.24 (4H, m), 2.27–
2.38 (1H, m), 2.73–2.82 (1H, m), 4.63 (1H, dtd, J = 18.0,
6.3, 2.5 Hz), 5.50 (1H, bd, J = 10.1 Hz), 5.76–5.83 (1H, m).
13C-NMR (100.6 MHz, CDCl3) d; 21.4, 21.5 (d, J = 5.4 Hz),
27.3 (d, J = 23.5 Hz), 37.4 (d, J = 6.1 Hz), 38.4 (d,
J = 22.8 Hz), 75.8, 91.1 (d, J = 181.4 Hz), 125.3, 126.8,
170.1 (d, J = 23.8 Hz). 19F-NMR (376.5 MHz, CDCl3) d;
ꢀ91.6 (1F, ddd, J = 30.0, 22.0, 10.0 Hz). EI-MS m/z: 184
3.2. Preparation of a-chloroacrylate derivative (1f)
A mixture of 3,5-hexadiene-1-ol (491 mg, 5.0 mmol),
2-chloroacrylic acid (530 mg, 5.0 mmol) and 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDC-
HCl, 1.0 g, 5.5 mmol) in CH2Cl2 (5.0 mL) were stirred at
room temperature for 5 h. After the reaction mixture was
quenched by the addition of H2O followed by extractive
workup (diethyl ether), the residue was purified by silica gel

714
A. Saito et al. / Journal of Fluorine Chemistry 126 (2005) 709–714
[M]+. Anal. Calcd for C10H13FO2: C, 65.20; H, 7.11. Found:
C, 65.03; H, 6.96.
Anal. Calcd for C10H13FO2: C, 65.20; H, 7.11. Found: C,
65.12; H, 7.02.
3.3.3. (4R*,4aR*,8aS*)-8a-fluoro-4-methyl-3,4,4a,7,8,
8a-hexahydro-1H-isochromen-1-one (2c-cis) and
(4R*,4aS*,8aR*)-8a-fluoro-4-methyl-3,4,4a,7,8,8a-
hexahydro-1H-isochromen-1-one (2c-trans)
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An 61% yield (diastereomer mixture). Colorless oil. IR
(neat) n cmꢀ1; 1752. 1H-NMR (400 MHz, CDCl3) d; for cis-
isomer: 1.04 (3H, d, J = 6.9 Hz), 1.73–1.87 (1H, m), 2.04–
2.20 (1H, m), 2.23–2.34 (1H, m), 2.54–2.65 (1H, m), 2.65–
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(100.6 MHz, CDCl3) d; for cis-isomer: 12.4, 23.9 (d,
J = 10.3 Hz), 27.3, 29.8 (d, J = 21.3 Hz), 43.3 (d,
J = 20.3 Hz), 72.3, 92.2 (d, J = 179.1 Hz), 120.2 (d,
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for trans-isomer: 14.7, 21.9 (d, J = 6.4 Hz), 28.2 (d, J = 23.
1 Hz), 35.2 (d, J = 4.0 Hz), 45.1 (d, J = 21.6 Hz), 72.8, 91.2
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ddd, J = 29.0, 20.0, 9.0 Hz). EI-MS m/z: 184 [M]+. Anal.
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7.11.
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hexahydro-1H-isochromen-1-one (2d)
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An 88% yield. White crystals. mp: 102–104 8C. IR (KBr)
n cmꢀ1; 1745. 1H-NMR (400 MHz, CDCl3) d; 1.72 (3H, s),
1.77–1.89 (1H, m), 1.96–2.18 (3H, m), 2.22–2.35 (2H, m),
2.59–2.69 (1H, m), 4.32–4.40 (2H, m), 5.58 (1H, bs). 13C-
NMR (100.6 MHz, CDCl3) d; 21.3, 21.8 (d, J = 6.1 Hz),
27.1 (d, J = 5.8 Hz), 28.1 (d, J = 23.0 Hz), 43.5 (d,
J = 22.3 Hz), 68.6, 92.5 (d, J = 182.2 Hz), 123.5, 130.8,
170.1 (d, J = 23.8 Hz). 19F-NMR (376.5 MHz, CDCl3) d;
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C10H13FO2: C, 65.20; H, 7.11. Found: C, 65.16; H, 7.01.
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An 42% yield. White crystals. IR (KBr) n cmꢀ1; 1743.
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1.50 (1H, ddd, J = 4.0, 14.0, 10.6 Hz), 1.72–1.84 (1H, m),
2.08–2.17 (1H, m), 2.22–2.31 (1H, m), 2.48–2.60 (1H, m),
2.66–2.69 (1H, m), 4.29–4.42 (2H, m), 5.52 (1H, ddd,
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J = 8.1 Hz), 36.0 (d, J = 23.5 Hz), 38.5 (d, J = 23.6 Hz),
68.4, 91.4 (d, J = 184.2 Hz), 124.2, 134.0, 170.5 (d,
J = 23.4 Hz). 19F-NMR (376.5 MHz, CDCl3) d; ꢀ90.1
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