Carbocyclization reactions of terminally difluorinated alkenyl active methine compounds mediated by SnCl4 and amine

Article abstract of DOI:10.1016/S0022-1139(03)00138-6

Carbocyclization of terminally difluorinated 3-butenyl active methine compounds 1a-1e proceeded through the 5- endo mode, upon treating with SnCl₄ and triethylamine to give fluorocyclopentene derivatives 3a-3e. Iodocarbocyclization of dimethyl

Full text of DOI:10.1016/S0022-1139(03)00138-6

Journal of Fluorine Chemistry 123 (2003) 75–80
Carbocyclization reactions of terminally difluorinated alkenyl active
methine compounds mediated by SnCl4 and amine
Akio Saitoa, Midori Okadab, Yuko Nakamurab, Osamu Kitagawaa,
Hiroaki Horikawab, Takeo Taguchia,*
aTokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
bTokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Received 25 February 2003; received in revised form 28 April 2003; accepted 5 May 2003
Dedicated to Professor Ronald Eric Banks on the occasion of his 70th birthday
Abstract
Carbocyclization of terminally difluorinated 3-butenyl active methine compounds 1a–1e proceeded through the 5-endo mode, upon treating
with SnCl4 and triethylamine to give fluorocyclopentene derivatives 3a–3e. Iodocarbocyclization of dimethyl 2-(4,4-difluorobut-3-enyl)-
malonate (1a) mediated by I2, SnCl4 and amine provided 2,2-difluoro-3-iodocyclopentane-1,1-dicarboxylate 4a through the 5-endo mode,
while in the case of 2-(5,5-difluoropent-4-enyl)malonate (1f) 5-exo mode cyclization reaction took place to give difluoroiodomethylcy-
clopentane derivative 5f.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Carbocyclization; Difluoroolefin; SnCl4; Fluorocyclopentane; Fluorocyclopentene
1. Introduction
variety of heteroatom as well as carbon nucleophiles through
addition–elimination process to give a variety of fluorinated
five-membered ring compounds [12–15].
Development of new synthetic methods for fluorine-con-
taining carbocyclic compounds is an important subject, in
particular related to efficient preparation of targeted fluorine-
modified biologically active compounds. Electrophilic fluor-
ination of an enolate or an equivalent such as a silyl enol
ether derived from cyclic ketones is one of several general
and important methods [1–3]. Nucleophilic fluorination of
hydroxyl group and carbonyl group in the aliphatic ring
compounds, for example, by means of (diethylamino)sulfur
trifluoride (DAST) or related reagents, is also widely used
[4–6]. Building block chemistry often provides highly reli-
able and efficient means for the preparation of densely
functionalized compounds [7–11], and thus new reactions
and new methods based on building block chemistry attract
much attention. For example, on the basis of unique pro-
perties of 1,1-difluorovinylidene double bond (CF2¼C),
Ichikawa et al. demonstrated that the 5-endo-trig cycliza-
tions smoothly proceed for 1,1-difluoro-1-alkenes having a
We reported that carbocyclization (iodocarbocyclization
[16–19] and intramolecular carbometalation [20–22]) of
active methine compounds having an unactivated unsatu-
rated carbon–carbon bond in the a-substituent can be effec-
tively promoted by a Lewis acid such as TiCl4 or SnCl4 and
amine or by Ti(OR)4. Scheme 1 shows typical examples with
4-pentenylmalonate, which gave the iodocarbocyclization
product and the carbostannylation product nearly quantita-
tively. The characteristic features of these intramolecular
cyclization reactions are the mode of cyclization and the
high stereoselectivities. Regarding the cyclization mode, it
should be noted that only exo cyclizations are achieved; that
is, 5-exo, 6-exo and 3-exo cyclizations smoothly proceed,
while any endo mode cyclizations regardless of the chain
length do not effectively proceed.
As an extension of our carbocyclization reactions to
terminally difluorinated alkenyl active methine compounds,
we have focused our attention to examine the fluorine
substituent effect on the cyclization mode with a hope to
develop new synthetic methods for fluorinated carbocyclic
systems.
* Corresponding author. Tel.: þ81-426-76-3257; fax: þ81-426-76-3257.
E-mail address: taguchi@ps.toyaku.ac.jp (T. Taguchi).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00138-6

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A. Saito et al. / Journal of Fluorine Chemistry 123 (2003) 75–80
terminally gem-difluoro-3-butenyl derivatives of phospho-
noacetate 1c, cyanoacetate 1d and acetoacetate 1e giving
rise to the corresponding fluorocyclopentene compounds
3b–3d. The decrease in the pKa value of these active methine
compounds as compared with that of malonate 1a resulted in
lower reactivity as well as lower yields of the products, in
particular in the cases of cyanoacetate 1d and acetoacetate
1e, requiring a large excess amount of SnCl4 for the reaction
to proceed (entries 4, 5).
Scheme 1. Iodocarbocyclization and intramolecular carbometalation.
With 2-(5,5-difluoropent-4-enyl)malonate (1f) neither
6-endo nor 5-exo cyclization proceeded under the various
reaction conditions using SnCl4 and amine. This is a sharp
contrast to the result with the hydrocarbon counterpart,
4-pentenylmalonate [22]. That is, reaction of dimethyl
4-pentenylmalonate with SnCl4 and Et3N proceeds easily
at room temperature to afford the 5-exo cyclized product in
quantitative yield. This organostannane compound having a
six-membered coordination structure between stannane and
carbonyl–oxygen is extremely stable (see Scheme 1). The
present SnCl4–Et3N mediated reaction was applied to the
ortho-substituted difluorinated styrene derivative 1g, which
would have a conformational advantage for the cyclization
reaction due to the presence of benzene ring as the tether.
However, neither 6-endo nor 5-exo cyclization was observed
under the Lewis acid mediated conditions. In the case of this
styrene derivative 1g, a nucleophilic addition–elimination
process via 6-endo-trig smoothly proceeded to give the
dihydronaphtharene 3g in 65% yield when treating with
NaH in DMF at room temperature for 3 h [15] (Scheme 2).
2. Results and discussion
The attempted cyclization of dimethyl 2-(4,4-difluorobut-
3-enyl)malonate (1a) was conducted under various reaction
conditions. While Ti(Oi-Pr)4, TiCl4–Et3N, ZnCl2–Et3N,
Et2Zn did not work at all resulting in recovery of 1a, SnCl4
(1.8 eq.) and Et3N (1.0 eq.) in CH2Cl2 at room temperature
promoted the 5-endo cyclization to give 2-flurorocyclopent-
2-ene-1,1-dicarboxylate 3a in 88% yield (Table 1, entry 1).
With the corresponding hydrocarbon substrate, dimethyl 3-
butenymalonate, such 5-endo cyclization was not observed
upon treating with SnCl4 and Et3N. The reaction pathway
possibly involves the formation of a Sn-enolate of the
malonate moiety, which attacks the double bond activated
by coordination to SnCl4 to give the intramolecular carbos-
tannylation intermediate 2a followed by fluoride b-elimina-
tion. The fluoride b-elimination step should be an
irreversible and crucial step for this 5-endo type cyclization
to proceed. It is noted that, however, the cyclized product
3a did not form when lithium or sodium enolate of the
malonate 1a was used (n-BuLi, THF, reflux or NaH, DMF,
100 8C).
Similar to the case of the malonate 1a, the SnCl4–Et3N
system was also effective for the 5-endo cyclization of the
Next, we examined the iodocarbocyclization reactions of
the difluorinated substrates. We found that iodocarbocycli-
zation of the 2-(4,4-difluorobut-3-enyl)malonate (1a) pro-
ceeds when 1a is treated with I2 (2.2 eq.), SnCl4 (2.7 eq.) and
2,6-dimethoxypyridine (DMP, 2.2 eq.) giving rise to 5-endo
cyclization product 4a in 70% yield along with the formation
of the fluorocyclopentene 3a in 5% yield (Scheme 3). In a
similar manner, the dibenzyl malonate 1b gave the iodocy-
clopentane compound 4b in 73% yield. The product ratio
varied with the amine used. For example, the use of Et3N
instead of DMP resulted in lower yield of the iodide 4a
(55%) with the increased yield of 3a (30%). TiCl4 was less
effective than SnCl4. Thus, treatment of 1a with TiCl4
(1.8 eq.), Et3N (1.5 eq.) and I2 (1.5 eq.) in refluxing CH2Cl2
Table 1
Carbocyclization of 4,4-difluoro-3-butenyl active methine compounds 1
Entry
1
SnCl4–Et3N Temperature
Time
(h)
3
Yield
(%)a
(eq.)
1
2
3
4
5
1a
1b
1c
1d
1e
1.8/1.0
1.8/1.0
3.6/2.2
15.0/2.0
15.0/2.0
RT
6
10
8
3a
3b
3c
3d
3e
88
RT
RT
34b
85
Reflux
Reflux
18
18
43
38c
a Isolated yield.
b Recovery of 1b was 27%.
c Recovery of 1e was 31%.
Scheme 2.

A. Saito et al. / Journal of Fluorine Chemistry 123 (2003) 75–80
77
under the radical conditions (Bu3SnH or (TMS)3SiH, cat.
AIBN in toluene, 70 8C).
In conclusion, carbocyclization (carbostannylation and
iodocarbocyclization) of terminally difluorinated alkenyl
active methine compounds can be effectively mediated by
the SnCl4-amine system to give the fluorinated carbocycles.
Scheme 3. Iodocarbocyclization of 1a and 1b.
3. Experimental details
General: 1H- and 13C-NMR spectra were taken on a
Brucker AM400 or a Varian Gemini-300 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 Brucker AM400
spectrometer, and chemical shifts were reported in parts per
million using benzotrifluoride as a standard. Infrared (IR)
spectra were recorded on a Perkin-Elmer FTIR-1710 infrared
spectrophotometer. Mass spectra (MS) were obtained on a
Hitachi M-80 or VG Auto Spec. Medium pressure liquid
chromatography (MPLC) was performed using prepacked
column (silica–gel, 50 mm) with UV detector.
Scheme 4. Iodocarbocyclization of 1f and 1g.
for 18 h gave 4a in only 30% yield. Contrary to the successful
iodocarbocyclization reaction with the difluorinated 3-bute-
nylmalonate 1a, the corresponding hydrocarbon counterpart,
dimethyl 3-butenylmalonate, did not give the iodocarbocy-
cliation product regardless of the cyclization mode (5-endo
or 4-exo manner). Under similar reaction conditions for 4a
from 1a, iodocarbocyclization of 2-(5,5-difluoropent-4-
enyl)malonate (1f) or the styrene derivative 1g proceeded
in 5-exo mode to give (difluoroiodomethyl)cyclopentane
derivative 5f (58% yield) and indane derivative 5g (80%
yield), respectively (Scheme 4). The cyclization mode is the
same as in the case of the analogous hydrocarbon derivative
[19,22].
Two examples of functional conversion of the iodocarbo-
cyclized products 4b and 5f are shown in Scheme 5. Con-
version of the iodide 4b to the hydroxyl compound 6 could
be achieved in 80% yield (conversion yield) by oxygenative
radical procedure [23] using benzotrifluoride (BTF) as a
solvent. Dehydroiodination of 5f proceeded by simply treat-
ing with DBU to give difluoromethylene compound 7 in
90% yield. Furthermore, with both 4b and 5f, reduction of
iodo substituent to hydrogen can be easily accomplishes
3.1. Preparation of dimethyl 2-(4,4-difluorobut-3-
enyl)malonate (1a): general procedure for the preparation
of difluorinated alkenylactive methine compounds
Under an argon atmosphere, dimethyl malonate (3.90
mmol) was treated with NaH (60%, 2.32 mmol) in THF
(10 ml) for 30 min and then 4,4-difluorobut-3-enyl mesylate
(1.93 mmol), NaI (0.96 mmol) and DMF (3 ml) was added.
After being stirred for 4 h at 80 8C, addition of NH4Cl aq.
followed by extractive work-up and purification of the
extracts by silica–gel column chromatography (hexane
and ethyl acetate, 4:1) gave 1a in 92% yield.
Dimethyl 2-(4,4-difluorobut-3-enyl)malonate (1a): Color-
less oil. IR (neat) n (cmꢀ1): 2960, 1748, 1436. H-NMR
1
(400 MHz, CDCl3) d: 1.95–2.09 (4H, m), 3.38 (1H, t, J ¼
7:0 Hz), 3.75 (6H, s), 4.12 (1H, dtd, J ¼ 25:0, 7.5, 2.2 Hz).
13C-NMR (100.6 MHz, CDCl3) d: 20.1 (d, J ¼ 4:4 Hz),
23.4, 50.7, 52.5, 76.6 (dd, J ¼ 22:8, 20.8 Hz), 156.6
(dd, J ¼ 286:8, 286.8 Hz), 169.5. 19F-NMR (376.5 MHz,
CDCl3) d: ꢀ27.6 (1F, dd, J ¼ 45:0, 25.0 Hz), ꢀ25.0 (1F, d,
J ¼ 45:0 Hz). MS (EI) m/z: 223 (Mþ þ 1), 202, 191.
HRMS; Calcd. for C9H13F2O4 (Mþ þ 1): 223.0773, Found:
223.0782.
Dibenzyl 2-(4,4-difluorobut-3-enyl)malonate (1b): Color-
less oil. IR (neat) n (cmꢀ1): 1747. 1H-NMR (400 MHz,
CDCl3) d: 1.98–2.06 (4H, m), 3.46 (1H, t, J ¼ 7:2 Hz),
4.10 (1H, dtd, J ¼ 25:0, 7.8, 2.6 Hz), 5.13 (2H, d,
J ¼ 12:3 Hz), 5.17 (2H, d, J ¼ 12:3 Hz), 7.26–7.35 (10H,
m). 13C-NMR (100.6 MHz, CDCl3) d: 20.0 (d, J ¼ 4:5 Hz),
28.3, 51.1, 67.2, 76.6 (dd, J ¼ 22:8, 20.8 Hz), 128.2, 128.4,
128.5, 135.2, 156.5 (dd, J ¼ 287:6, 286.5 Hz), 168.5. 19F-
NMR (376.5 MHz, CDCl3) d: ꢀ27.5 (1F, dd, J ¼ 45:0,
Scheme 5.

78
A. Saito et al. / Journal of Fluorine Chemistry 123 (2003) 75–80
25.0 Hz), ꢀ25.0 (1F, d, J ¼ 45:0 Hz). MS (EI) m/z: 374
(Mþ), 283. HRMS; Calcd. for C14H13F2O4 (Mþ ꢀ C7H7):
283.0782, Found: 283.0789.
J ¼ 22:9, 20.3 Hz), 126.3, 126.4, 127.4, 129.1, 130.0,
131.6 (dd, J ¼ 8:0, 8.0 Hz), 154.3 (dd, J ¼ 291:2,
288.3 Hz), 168.6. 19F-NMR (376.5 MHz, CDCl3) d:
ꢀ27.4 (1F, dd, J ¼ 33:6, 4.2 Hz), ꢀ26.8 (1F, dd,
J ¼ 33:6, 28.6 Hz). MS (EI) m/z: 237 (Mþ þ 1), 205.
HRMS; Calcd. for C14H14F2O4 (Mþ): 283.0782, Found:
283.0786.
Ethyl 2-(diethoxyphosphoryl)-6,6-difluorohex-5-enoate
(1c): Colorless oil. IR (neat) n (cmꢀ1): 1739, 1647, 1254,
1051, 1024, 969. 1H-NMR (400 MHz, CDCl3) d: 1.28 (3H, t,
J ¼ 7:1 Hz), 1.32 (3H, t, J ¼ 7:2 Hz), 1.33 (3H, t,
J ¼ 7:3 Hz), 1.85–2.15 (4H, m), 2.93 (1H, ddd, J ¼ 23:2,
10.6, 3.6 Hz), 4.10–4.24 (7H, m). 13C-NMR (100.6 MHz,
CDCl3) d: 13.8, 16.0, 16.1, 20.8 (dd, J ¼ 16:0, 4.4 Hz), 26.4,
44.6 (d, J ¼ 131:7 Hz), 61.2, 62.5 (d, J ¼ 7:7 Hz), 62.6 (d,
J ¼ 7:4 Hz), 76.4 (dd, J ¼ 21:2, 21.2 Hz), 156.4 (dd,
J ¼ 287:3, 287.3 Hz), 168.6 (d, J ¼ 4:9 Hz). 19F-NMR
(376.5 MHz, CDCl3) d: ꢀ27.7 (1F, dd, J ¼ 45:0,
25.0 Hz), ꢀ24.9 (1F, d, J ¼ 45:0 Hz). MS (þEI) m/z: 315
(Mþ þ 1). HRMS; Calcd. for C12H21F2O5P (M ): 314.1095,
Found: 314.1088.
3.2. Preparation of dimethyl 2-fluorocyclopent-2-ene-1,
1-dicarboxylate (3a)
Under an argon atmosphere, a mixture of 1a (0.32 mmol),
SnCl4 (0.57 mmol) and Et3N (0.32 mmol) in CH2Cl2 (1 ml)
was stirred for 6 h at room temperature, and then to the
reaction mixture was added 5% HCl. Extractive work-up and
purification of the extracts by silica–gel column chromato-
graphy (hexane and ethyl acetate, 4:1) gave 3a (0.28 mmol,
88% yield).
Dimethyl 2-fluorocyclopent-2-ene-1,1-dicarboxylate (3a):
Colorless oil. IR (neat) n (cmꢀ1): 3028, 2960, 2864, 1740.
1H-NMR (400 MHz, CDCl3) d: 2.28–2.35 (2H, m), 2.59
(2H, t, J ¼ 7:1 Hz), 3.77 (6H, s), 5.32 (1H, t, J ¼ 2:4 Hz).
13C-NMR (100.6 MHz, CDCl3) d: 23.9 (d, J ¼ 7:8 Hz),
31.8 (d, J ¼ 3:6 Hz), 53.0, 62.4 (d, J ¼ 19:1 Hz), 108.5
(d, J ¼ 10:5 Hz), 155.6 (d, J ¼ 283:4 Hz), 169.5 (d,
J ¼ 4:4 Hz). 19F-NMR (376.5 MHz, CDCl3) d: ꢀ63.8
(1F, t, J ¼ 6:0 Hz). MS (EI) m/z: 202 (Mþ), 170, 143.
HRMS; Calcd. for C9H11FO4 (Mþ): 202.0634, Found:
202.0641.
Methyl 2-cyano-6,6-difluorohex-5-enoate (1d): Colorless
oil. IR (neat) n (cmꢀ1): 2318, 1750. H-NMR (400 MHz,
1
CDCl3) d: 2.04 (2H, td, J ¼ 7:9, 7.0 Hz), 2.22 (2H, dt,
J ¼ 7:9, 7.9 Hz), 3.53 (2H, t, J ¼ 7:0 Hz), 3.83 (3H, s),
4.16 (1H, dtd, J ¼ 24:7, 7.9, 2.1 Hz). 13C-NMR
(100.6 MHz, CDCl3) d: 19.7 (d, J ¼ 4:7 Hz), 29.4, 36.4,
53.6, 75.7 (dd, J ¼ 23:9, 20.4 Hz), 115.9, 156.9 (dd,
J ¼ 288:8, 287.2 Hz), 166.2. 19F-NMR (376.5 MHz,
CDCl3) d: ꢀ26.2 (1F, dd, J ¼ 42:2, 24.7 Hz), ꢀ23.8 (1F,
d, J ¼ 42:2 Hz). MS (EI) m/z: 189 (Mþ). HRMS; Calcd. for
C8H9F2NO2 (Mþ): 189.0601, Found: 189.0593.
Methyl 2-acetyl-6,6-difluorohex-5-enoate (1e): Colorless
oil. IR (neat) n (cmꢀ1): 1747, 1718. H-NMR (400 MHz,
1
Dibenzyl 2-fluorocyclopent-2-ene-1,1-dicarboxylate (3b):
Colorless oil. IR (neat) n (cmꢀ1): 1737, 1680. 1H-NMR
(400 MHz, CDCl3) d: 2.29 (2H, tdd, J ¼ 6:4, 6.4, 2.5 Hz),
2.58 (2H, t, J ¼ 6:4 Hz), 5.15 (4H, s), 5.31 (1H, t,
J ¼ 2:5 Hz), 7.21–7.29 (10H, m). 13C-NMR (100.6 MHz,
CDCl3) d: 24.0 (d, J ¼ 7:7 Hz), 31.7 (d, J ¼ 3:6 Hz),
62.8 (d, J ¼ 18:9 Hz), 67.5, 108.8 (d, J ¼ 15:3 Hz),
127.8, 128.2, 128.5, 135.2, 155.9 (d, J ¼ 283:6 Hz),
168.8 (d, J ¼ 4:2 Hz). 19F-NMR (376.5 MHz, CDCl3) d:
ꢀ63.4 (1F, t, J ¼ 6:4 Hz).þMS (EI) m/z: 354 (Mþ). HRMS;
Calcd. for C21H19FO4 (M ): 354.1267, Found: 354.1260.
Ethyl 1-diethoxyphosphoryl-2-fluorocyclopent-2-ene-1-
carboxylate (3c): Colorless oil. IR (neat) n (cmꢀ1): 1736,
1679, 1254, 1025. 1H-NMR (400 MHz, CDCl3) d: 1.30 (3H,
t, J ¼ 7:1 Hz), 1.32 (6H, t, J ¼ 7:1 Hz), 2.27–2.40 (2H, m),
2.52–2.70 (2H, m), 4.10–4.30 (6H, m), 5.30 (1H, dd,
J ¼ 5:4, 2.8 Hz). 13C-NMR (100.6 MHz, CDCl3) d: 13.8,
16.2, 16.2, 24.2 (d, J ¼ 7:7, 4.0 Hz), 30.4 (dd, J ¼ 3:8,
3.8 Hz), 57.4 (dd, J ¼ 143:8, 19.4 Hz), 61.9, 63.0 (d,
J ¼ 6:9 Hz), 63.2 (d, J ¼ 7:1 Hz), 107.7 (dd, J ¼ 10:6,
10.5 Hz), 155.9 (dd, J ¼ 281:1, 12.0 Hz), 168.9 (d,
J ¼ 4:6 Hz). 19F-NMR (376.5 MHz, CDCl3) d: ꢀ60.6
(1F, dtd, J ¼ 12:0, 6.0, 6.0 Hz). MS (EI) m/z: 295 (Mþ).
HRMS; Calcd. for C12H21FO5P (Mþ): 295.1111, Found:
295.1065.
CDCl3) d: 1.88–2.04 (4H, m), 2.22 (3H, s), 3.44 (1H, t,
J ¼ 7:0 Hz), 3.74 (3H, s), 4.11 (1H, dtd, J ¼ 25:0, 7.8,
2.3 Hz). 13C-NMR (100.6 MHz, CDCl3) d: 20.1 (d,
J ¼ 4:3 Hz), 27.6, 29.0, 52.5, 58.5, 76.7 (dd, J ¼ 20:5,
20.5 Hz), 156.9 (dd, J ¼ 288:8, 287.2 Hz), 169.9, 202.4.
19F-NMR (376.5 MHz, CDCl3) d: ꢀ27.7 (1F, dd, J ¼ 46:0,
25.0 Hz), ꢀ25.1 (1F, d, J ¼ 46:0 Hz). MS (EI) m/z: 206
(Mþ). HRMS; Calcd. for C9H12F2O3 (Mþ): 206.0755,
Found: 206.0732.
Dimethyl 2-(5,5-difluoropent-4-enyl)malonate (1f): Col-
orless oil. IR (neat) n (cmꢀ1): 3004, 2960, 1750. H-NMR
1
(400 MHz, CDCl3) d: 1.35–1.43 (2 H, m), 1.87–1.95 (2H,
m), 2.01 (2H, qt J ¼ 7:5, 1.7 Hz), 3.36 (1H, t, J ¼ 7:5 Hz),
3.74 (6H, s), 4.12 (1 H, dtd, 25.3, 7.9, 2.5 Hz). 13C-NMR
(100.6 MHz, CDCl3) d: 21.8 (d, J ¼ 4:1 Hz), 27.1, 28.0,
51.4, 52.5, 77.2 (t, J ¼ 21:5 Hz), 156.4 (dd, J ¼ 287:0,
287.0 Hz), 169.7. 19F-NMR (376.5 MHz, CDCl3) d:
ꢀ28.4 (1F, m), ꢀ26.1 (1F, ddm, 47, 17 Hz). MS (EI) m/z:
237 (Mþ þ 1), 205. HRMS; Calcd. for C10H15F2O4
(Mþ þ 1): 237.0938, Found: 237.0939.
Dimethyl 2-[2-(2,2-difluorovinyl)benzyl]malonate (1g):
Colorless oil. IR (neat) n (cmꢀ1): 1747. 1H-NMR
(400 MHz, CDCl3) d: 3.46 (1H, t, J ¼ 7:2 Hz), 3.76
(2H, d, J ¼ 7:2 Hz), 3.78 (6H, s), 6.28 (1H, dd, J ¼ 27:3,
4.2 Hz), 6.95–7.08 (1H, m), 7.13–7.24 (3H, m). 13C-NMR
(100.6 MHz, CDCl3) d: 38.4, 53.4, 55.9, 109.1 (dd,
Methyl 1-cyano-2-fluorocyclopent-2-ene-1,1-dicarboxy-
late (3d): Colorless oil. IR (neat) n (cmꢀ1): 2360, 1743.

A. Saito et al. / Journal of Fluorine Chemistry 123 (2003) 75–80
79
1H-NMR (400 MHz, CDCl3) d: 2.46–2.54 (2H, m),
2.59–2.75 (2H, m), 3.88 (3H, s), 5.48 (1H, t, J ¼ 2:5 Hz).
13C-NMR (100.6 MHz, CDCl3) d: 24.7 (d, J ¼ 6:9 Hz),
34.5 (d, J ¼ 3:2 Hz), 50.5 (d, J ¼ 21:4 Hz), 54.2, 110.0
(d, J ¼ 8:9 Hz), 116.6, 153.5 (d, J ¼ 284:8 Hz), 166.8. 19F-
NMR (376.5 MHz, CDCl3) d: ꢀ62.9 (1F, t, J ¼ 5:0 Hz). MS
(EI) m/z: 169 (Mþ). HRMS; Calcd. for C8H8FNO3 (Mþ):
169.0539, Found: 169.0531.
Dimethyl 2-(difluoroiodomethyl)cyclopentane-1,1-dicar-
boxylate (5f): Colorless oil. IR (neat) n (cmꢀ1): 3024,
2960, 1740, 1734. H-NMR (400 MHz, CDCl3) d: 1.49–
1
1.62 (1H, m), 1.88–2.02 (2H, m), 2.11–2.28 (2H, m), 2.59
(1H, dt, J ¼ 13:6, 8.7 Hz), 3.70 (3H, s), 3.74 (3H, s), 3.86
(1H, dtd, J ¼ 26:7, 8.0, 4.1 Hz). 13C-NMR (100.6 MHz,
CDCl3) d: 21.5, 30.1, 36.0, 52.9 (d, J ¼ 33:9 Hz), 60.1 (t,
J ¼ 17:4 Hz), 61.0, 102.3 (t, J ¼ 318:3 Hz), 169.4, 171.0.
19F-NMR (376.5 MHz, CDCl3) d: 17.8 (1F, dd, J ¼ 170:0,
26.7 Hz), 28.3 (1F, d, J ¼ 170:0 Hz). MS (EI) m/z: 363
(Mþ þ 1), 331, 283, 235 (Mþ ꢀ I), 187, 175. Anal. Calcd.
for C10H13F2O4I: C, 33.17; H, 3.62, Found: C, 33.16; H,
3.54.
Dimethyl 1-(difluoroiodomethyl)indan-2,2-dicarboxylate
(5g): Colorless solid. mp 80–82 8C IR (KBr) n (cmꢀ1): 1737.
1H-NMR (400 MHz, CDCl3) d: 3.54 (1H, d, J ¼ 16:7 Hz),
3.70 (3H, s), 3.79 (3H, s), 4.19 (1H, d, J ¼ 16:7 Hz), 4.67
(1H, dd, J ¼ 14:7, 10.0 Hz), 7.23–7.28 (2H, m), 7.34 (1H,
dd, J ¼ 7:8, 7.5 Hz), 7.51 (1H, d, J ¼ 7:5 Hz). 13C-NMR
(100.6 MHz, CDCl3) d: 39.5, 53.1, 53.5, 62.9 (t, J ¼
4:6 Hz), 63.4 (t, J ¼ 19:9 Hz), 101.9 (t, J ¼ 317:3 Hz),
124.8, 127.0, 127.2, 129.4, 137.1, 140.9, 168.1, 170.5.
19F-NMR (376.5 MHz, CDCl3) d: ꢀ28.6 (1F, dd,
J ¼ 185:6, 10.0 Hz), ꢀ22.3 (1F, dd, J ¼ 185:6, 14.3 Hz).
MS (EI) m/z: 283 (Mþ ꢀ I). HRMS; Calcd. for C14H13F2O4
(Mþ ꢀ I): 283.0782, Found: 283.0768.
Methyl 1-acetyl-2-fluorocyclopent-2-ene-1-carboxylate
(3e): Colorless oil. IR (neat) n (cmꢀ1): 1747, 1719. H-
1
NMR (400 MHz, CDCl3) d: 2.22–2.32 (2H, m), 2.27 (3H, s),
2.43–2.62 (2H, m), 3.79 (3H, s), 5.35 (1H, ddd, J ¼ 2:5,
2.4, 0.7 Hz). 13C-NMR (100.6 MHz, CDCl3) d: 23.9
(d, J ¼ 8:1 Hz), 27.1, 30.3 (d, J ¼ 4:2 Hz), 53.0, 68.5
(d, J ¼ 18:8 Hz), 109.0 (d, J ¼ 10:6 Hz), 156.5 (d,
J ¼ 282:3 Hz), 171.4, 202.5. 19F-NMR (376.5 MHz,
CDCl3) d: ꢀ62.9 (1F, br. s). MS (EI) m/z: 186 (Mþ). HRMS;
Calcd. for C9H11FO3 (Mþ): 186.0692, Found: 186.0681.
3.3. Preparation of dimethyl 2,2-difluoro-3-
iodocyclopentane-1,1-dicarboxylate (4a)
Under an argon atmosphere, a mixture of 1a (0.32 mmol),
I2 (0.71 mmol), SnCl4 (0.85 mmol) and 2,6-dimethoxypyr-
idine (0.70 mmol) in CH2Cl2 (1 ml) was stirred for 26 h at
room temperature, and then to the reaction mixture was
added 5% HCl. Extractive work-up and purification of the
extracts by silica–gel column chromatography (hexane and
ethyl acetate, 4:1) gave 4a (0.22 mmol, 70% yield) and 3a
(15.5 mmol, 5% yield).
3.4. Reaction of 1g with NaH
Under an argon atmosphere, a mixture of 1g (0.49 mmol)
and NaH (60%, 0.64 mmol) in DMF (5 ml) was stirred
for 3 h at room temperature, and then to the reaction
mixture was added 5% HCl. Extractive work-up and
purification of the extracts by silica–gel column chromato-
graphy (hexane and ethyl acetate, 4:1) gave 3g (0.32 mmol,
65% yield).
Dimethyl 2,2-difluoro-3-iodocyclopentane-1,1-dicarbox-
ylate (4a): Colorless oil. IR (neat) n (cmꢀ1): 2957, 1739,
1436, 1285. 1H-NMR (400 MHz, CDCl3) d: 2.11–2.25 (2H,
m), 2.39–2.51 (1H, m), 2.74–2.84 (1H, m), 3.78 (3H, s), 3.84
(3H, s), 4.66–4.86 (1H, m). 13C-NMR (100.6 MHz, CDCl3)
d: 20.6 (dd, J ¼ 24:2, 24.2 Hz), 30.8 (d, J ¼ 5:9 Hz), 31.0
(d, J ¼ 3:3 Hz), 53.4 (d, J ¼ 18:1 Hz), 60.3 (dd J ¼ 28:0,
19.7 Hz), 124.2 (dd, J ¼ 271:1, 250.0 Hz), 165.8, 168.4 (d,
J ¼ 11:0 Hz). 19F-NMR (376.5 MHz, CDCl3) d: ꢀ51.5 (1F,
dd, J ¼ 232:3, 4.3 Hz), ꢀ33.7 (1F, dd, J ¼ 232:3, 25.6 Hz).
MS (EI) m/z: 328 (Mþ ꢀ HF), 317, 269. HRMS; Calcd. for
C9H10FO4I (Mþ ꢀ HF): 327.9607, Found: 327.9608.
Dibenzyl 2,2-difluoro-3-iodocyclopentane-1,1-dicarbox-
ylate (4b): Colorless oil. IR (neat) n (cmꢀ1): 1737, 1680.
1H-NMR (400 MHz, CDCl3) d: 2.12–2.24 (2H, m), 2.36–
2.47 (1H, m), 2.76–2.87 (1H, m), 4.77 (1H, d, J ¼ 25:6,
11.0, 9.4, 4.3 Hz), 5.20 (2H, d, J ¼ 12:0 Hz), 5.25 (2H, d,
J ¼ 12:0 Hz), 7.20–7.23 (2H, m), 7.26–7.34 (8H, m). 13C-
NMR (100.6 MHz, CDCl3) d: 20.6 (dd, J ¼ 24:0, 24.0 Hz),
30.8 (d, J ¼ 9:3 Hz), 30.8, 60.5 (dd J ¼ 27:9, 19.5 Hz),
68.0, 68.8, 124.3 (dd, J ¼ 271:0, 250.0 Hz), 127.9, 128.0,
128.3, 128.5, 128.6, 128.6, 134.5, 134.9, 165.0, 167.7 (d,
J ¼ 10:9 Hz). 19F-NMR (376.5 MHz, CDCl3) d: ꢀ51.1 (1F,
dd, J ¼ 232:0, 4.3 Hz), ꢀ33.7 (1F, dd, J ¼ 232:0, 25.6 Hz).
MS (EI) m/z: 409 (Mþ ꢀ C7H7). HRMS; Calcd. for
C14H12F2O4I (Mþ ꢀ C7H7): 408.9748, Found: 408.9757.
Dimethyl 3-fluoro-1H-naphthalene-2,2-dicarboxylate
(3g): Colorless solid. mp 94–96 8C IR (KBr) n (cmꢀ1):
1
1750. H-NMR (400 MHz, CDCl3) d: 3.63 (1H, d, J ¼
12:0 Hz), 3.68 (1H, d, J ¼ 12:0 Hz), 3.79 (6H, s), 6.28
(1H, d, J ¼ 12:6 Hz), 7.04 (1H, d, J ¼ 6:5 Hz), 7.12–7.20
(3H, m). 13C-NMR (100.6 MHz, CDCl3) d: 37.2 (d,
J ¼ 2:6 Hz), 53.4, 58.2 (d, J ¼ 18:7 Hz), 108.2 (d, J ¼
18:7 Hz), 126.3, 126.4, 127.4, 127.4, 129.1, 130.6 (d,
J ¼ 8:0 Hz), 156.2 (d, J ¼ 272:2 Hz), 168.6. 19F-NMR
(376.5 MHz, CDCl3) d: ꢀ47.4 (1F, ddd, J ¼ 12:6, 3.0,
3.0 Hz). MS (EI) m/z: 264 (Mþ). HRMS; Calcd. for
C14H13FO4 (Mþ): 264.0798, Found: 264.0781. Anal.
Calcd. for C14H13FO4: C, 63.63; H, 4.96, Found: C,
63.58; H, 5.14.
3.5. Dimethyl 2,2-difluoro-3-hydoxycyclopentane-1,
1-dicarboxylate (6)
Dioxygen was bubbled at 0 8C into a solution of 4b
(0.10 mmol) and Bu3SnH (32 mmol) in BTF (2 ml) for

80
A. Saito et al. / Journal of Fluorine Chemistry 123 (2003) 75–80
1 h, and then under O2 atmosphere the solution was stirred
for 10 days at 0 8C. Extractive work-up and purification of
the extracts by silica–gel column chromatography (hexane
and ethyl acetate, 3:1) gave 6 (38 mmol, 38% yield) and 4b
(53 mmol, 53% yield).
References
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Dimethyl 2,2-difluoro-3-hydoxycyclopentane-1,1-dicar-
boxylate (6): Colorless oil. IR (neat) n (cmꢀ1): 2957,
1739, 1436, 1285. H-NMR (400 MHz, CDCl3) d: 1.62–
1
[6] R. Fernandez, S. Castillon, Tetrahedron 55 (1999) 8497.
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1.75 (1H, m), 2.16–2.29 (2H, m), 2.44 (1H, ddd, J ¼ 10:8,
9.9, 1.8 Hz), 2.87 (1H, d, J ¼ 8:1 Hz), 4.28–4.39 (1H, m),
5.11 (2H, s), 5.12 (2H, s), 7.18–7.26 (10H, m). 13C-NMR
(100.6 MHz, CDCl3) d: 27.6, 28.3 (d, J ¼ 4:2 Hz), 63.1
(dd, J ¼ 24:3, 22.1 Hz), 67.8, 68.0, 73.8 (dd J ¼ 29:7,
19.6 Hz), 128.0, 128.0, 128.4, 128.5, 128.5, 134.6, 134.8,
166.3 (d, J ¼ 3:8 Hz), 167.4 (d, J ¼ 5:1 Hz). 19F-NMR
(376.5 MHz, CDCl3) d: ꢀ56.6 (1F, dd, J ¼ 244:9,
7.7 Hz), ꢀ47.3 (1F, dd, J ¼ 244:9, 11.9 Hz). MS (EI) m/z:
390 (Mþ). HRMS; Calcd. for C21H20F2O5 (Mþ): 390.1279,
Found: 390.1256.3.6.
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1917.
Dimethyl
2-(2,2-difluoromethylene)cyclopentane-1,1-
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243.
dicarboxylate (7): Colorless oil. IR (neat) n (cmꢀ1): 3032,
1
2964, 1760, 1742. H-NMR (400 MHz, CDCl3) d: 1.74–
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Chem. 63 (1998) 9470.
1.82 (2H, m), 2.35 (1H, t, J ¼ 7:0 Hz), 2.36 (1H, t,
J ¼ 7:0 Hz), 2.43 (2H, ddd, J ¼ 10:8, 7.0, 3.5 Hz), 3.76
(6H, s). 13C-NMR (100.6 MHz, CDCl3) d: 24.8, 26.9, 37.9,
53.0, 61.1, 91.5 (dd, J ¼ 15:9, 28.9 Hz), 153.0 (dd,
J ¼ 291:2, 284.7 Hz), 170.4. 19F-NMR (376.5 MHz,
CDCl3) d: ꢀ20.8 (1F, d, J ¼ 43:4 Hz), ꢀ21.8 (1F, dt,
J ¼ 43:4, 3.5 Hz). MS (EI) m/z: 235 (Mþ þ 1), 234 (Mþ),
175. Anal. Calcd. for C10H12F2O4: C, 51.28; H, 5.16, Found:
C, 51.33; H, 5.29.
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