An efficient synthesis of fluorocyclopentenes using fluoroalkylidenecarbenes

Article abstract of DOI:10.1016/j.tetlet.2007.11.019

An efficient synthesis of fluorocyclopentenes is described. By treatment of (2-fluoroalkenyl)iodonium salts with potassium tert-butoxide, (α-fluoroalkylidene)carbenes were generated efficiently to give fluorocyclopentenes via 1,5-C-H insertion. Fluorocyclopentenes having a functionality, such as chlorine, acetoxy, or ketone, and a spiro fluorocyclopentene were synthesized in good yields.

Full text of DOI:10.1016/j.tetlet.2007.11.019

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 76–79
An efficient synthesis of fluorocyclopentenes using
fluoroalkylidenecarbenes
Tong Guan, Kohei Takemura, Hisanori Senboku, Masanori Yoshida* and Shoji Hara
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 19 September 2007; revised 10 October 2007; accepted 2 November 2007
Available online 7 November 2007
Abstract—An efficient synthesis of fluorocyclopentenes is described. By treatment of (2-fluoroalkenyl)iodonium salts with potassium
tert-butoxide, (a-fluoroalkylidene)carbenes were generated efficiently to give fluorocyclopentenes via 1,5-C–H insertion. Fluoro-
cyclopentenes having a functionality, such as chlorine, acetoxy, or ketone, and a spiro fluorocyclopentene were synthesized in good
yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Fluoroalkene synthesis has received considerable atten-
tion from biological and medicinal chemists because
the introduction of a fluorine atom into the double bond
of a biologically active compound can dramatically
enhance its bioactivity.1,2 Therefore, much attention
has been paid for the fluoroalkene synthesis, and many
successful methodologies of terminal and internal fluoro-
alkene synthesis have been developed.3,4 However, only
a few methods for the synthesis of fluorocycloalkenes,
especially fluorocyclopentenes, have been reported so
far.5–8 Since a cyclopentene moiety is a common struc-
ture in natural organic molecules, it would be worth-
while developing an efficient method for synthesizing
fluorocyclopentenes to develop fluorinated pharmaceu-
ticals. In 1993, Ochiai et al. reported that a fluorocyclo-
pentene could be synthesized by 1,5-C–H insertion of
an (a-fluoroalkylidene)carbene, which was generated
by a-elimination of (Z)-(2-fluorohexadec-1-enyl)(phenyl)-
iodonium tetrafluoroborate using tetrabutylammo-
nium fluoride (TBAF) as a base. However, the
fluorocyclopentene was obtained in only 17% yield and
no other products were mentioned in their paper.8
Moreover, there was no method for efficient synthesis
of fluoroalkenyliodonium salts at that time.9 Recently,
we found that various (Z)-(2-fluoroalkenyl)iodonium
salts 1 could be synthesized efficiently by the reaction
of alkynyliodonium salts, which can be readily prepared
from terminal alkynes,10 with diluted aqueous HF.11 In
this context, we decided to investigate the synthesis of
fluorocyclopentenes using 1. First, we attempted to syn-
thesize a fluorocyclopentene by the reaction of a fluoro-
alkenyliodonium salt with TBAF according to the
reported procedure.8 The results obtained by using
(Z)-(11-acetoxy-2-fluoroundec-1-enyl)(phenyl)iodonium
tetrafluoroborate (1a) as a starting material revealed
that TBAF worked not only as a base but also as a fluo-
ride source to afford a small amount of fluorocyclopen-
tene, 3-(6-acetoxyhexyl)-1-fluorocyclopentene (2a, 9%),
and a relatively large amount of 11-acetoxy-1,2,2-triflu-
oroundecane (3, 21%)12 with many minor products
(Scheme 1).8,11,13
We therefore investigated the reaction conditions to
obtain a fluorocyclopentene efficiently using a simple
fluoroalkenyliodonium salt, (Z)-(2-fluorododec-1-enyl)-
(phenyl)iodonium tetrafluoroborate (1b), as a starting
material (Table 1). A screening of bases showed that
potassium tert-butoxide, t-BuOK, can dramatically
increase the yield of fluorocyclopentene, and 3-heptyl-
1-fluorocyclopentene (2b) was obtained in 66% yield
(Table 1, entry 1). Other bases, including KOH (42%),
NaOEt (39%), LDA (17%) and DBU (16%), gave lower
yields than that obtained by using t-BuOK (Table 1,
entries 2–5). The use of benzene, THF, and chloro-
benzene as solvents gave 2b in a range of 26–37% yields,
and CH2Cl2 was found to be a good solvent for this
reaction (Table 1, entries 1 and 6–8). Finally, the best
result (2b, 74%) was obtained by the reaction of 1b with
t-BuOK (3 equiv) in CH2Cl2 at a low substrate concen-
tration (0.01 M) (Table 1, entry 10).14
*
Corresponding author. Tel./fax: +81 11 706 6557; e-mail:
myoshida@eng.hokudai.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.019

T. Guan et al. / Tetrahedron Letters 49 (2008) 76–79
77
(CH2)6-OAc
AcO-(CH2)9
(CH2)6-OAc
I(Ph)BF4
TBAF-5H2O
CH2Cl2
+
F
F
F
F
F
1a
3, 21%
2a, 9%
TBAF as base
AcO-(CH2)9
F
(CH2)6-OAc
F
H
"
1,5-C-H insertion"
2a
3
I(Ph)BF4
F
TBAF as fluoride source
AcO-(CH2)9
AcO-(CH2)9
H2O
F
F
F
F
F
I(Ph)BF4
I(Ph)BF4
Scheme 1.
Table 1. Optimization of reaction conditionsa
Table 2. Synthesis of 2a
C7H15
Base
R
t-BuOK
C7H15
R
Solvent
CH2Cl2
F
I(Ph)BF4
1b
F
I(Ph)BF4
F
F
1
2
2b
Yieldb (%)
Entry
R
Yieldb (%)
Entry
Base
Solvent
1
2
3
AcO-(CH2)6
Cl-(CH2)6
t-BuCO-(CH2)5
2a, 68
2c, 64
2d, 71
1
2
3
4
5
6
7
8
t-BuOK
KOH
NaOEt
LDA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Benzene
THF
Chlorobenzene
CH2Cl2
CH2Cl2
66
42
39
17
16
27
26
37
70
74
DBU
O
O
O
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
4
O
F
F
I(p-Tol)BF4
2e, 71
9c
10d
a Reagents and conditions: 1 (0.5 mmol), t-BuOK (1.5 mmol), CH2Cl2
(50 mL, 0.01 M), rt, 24 h.
b Isolated yield.
a Unless otherwise mentioned, reactions were carried out with 1b
(0.5 mmol) and a base (0.75 mmol) in a solvent (10 mL, 0.05 M) at rt
for 24 h.
b Isolated yield of 2b.
c CH2Cl2 (50 mL, 0.01 M).
Table 3. Effect of substituents of the aryliodanyl group of fluoroalken-
yl(aryl)iodonium salts on the synthesis of 2ba
d Base (1.5 mmol), CH2Cl2 (50 mL, 0.01 M).
C7H15
t-BuOK
2b
Under the same reaction conditions, the fluoroalkenyli-
odonium salt 1a was also successfully converted into
fluorocyclopentene 2a in 68% yield, while the treatment
of 1a with TBAF gave only 9% yield as shown in
Scheme 1 (Table 2, entry 1). Fluoroalkenyliodonium
salts 1c and 1d having a functional group, for example,
Cl or t-BuCO, could be converted into fluorocyclopent-
enes 2c and 2d, respectively, in good yields (Table 2,
entries 2 and 3). The 1,5-C–H insertion of an (a-fluoro-
alkylidene)carbene into an acetal C–H bond also pro-
ceeded smoothly to afford a spiro product 2e in 71%
yield (Table 2, entry 4).
CH2Cl2
F
I(Ar)BF4
1
Entry
1
Yieldb (%)
1
2
1f, Ar = p-Tol
1g, Ar = p-Cl–C6H4
74
70
I(p-Tol)BF4
C7H15
1h, (
3
76
F
E
)-isomer of 1f
a Reagents and conditions: 1 (0.5 mmol), t-BuOK (1.5 mmol), CH2Cl2
(50 mL, 0.01 M), rt, 24 h.
b Isolated yield.
Next, we studied the effect of substituents of the aryl-
iodanyl group of fluoroalkenyliodonium salts (Table 3,
entries 1 and 2). (Z)-(2-Fluorododec-1-enyl)(p-tolyl)-
iodonium tetrafluoroborate (1f) and (Z)-(2-fluorododec-
1-enyl)(p-chlorophenyl)iodonium tetrafluoroborate (1g)
were prepared and subjected to the reaction condi-
tions.11,15,16 By comparison with the reaction using 1b,
it was found that neither the chlorine nor the methyl
group has a significant influence on the yield of 2b
(74% from 1f and 70% from 1g) or on the reaction rate.
In addition, the stereoisomer of 1f, (E)-(2-fluorododec-
1-enyl)(p-tolyl)iodonium tetrafluoroborate (1h),17 also

78
T. Guan et al. / Tetrahedron Letters 49 (2008) 76–79
4. Fluoroalkene synthesis by the Horner–Wadsworth–
Emmons reaction, see: (a) Zhang, X.; Burton, D. J. J.
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Zhu, Y.-F.; Kim, K.-I.; McCarthy, J. R. J. Org. Chem.
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gave 2b in a similar yield (76%) under the same reaction
conditions (Table 3, entry 3). These results indicate that
the 1,5-C–H insertion occurred via an (a-fluoroalkyl-
idene)carbene, not an (a-fluoroalkylidene)carbenoide,
as in the reaction using the usual alkenyliodonium
salts.18
In summary, we found that (a-fluoroalkylidene)carbenes
can be generated efficiently by the reaction of (2-fluoro-
alkenyl)iodonium salts with potassium tert-butoxide in
dichloromethane. The 1,5-C–H insertion of (a-fluoro-
alkylidene)carbenes smoothly proceeded to give fluoro-
cyclopentenes having a functional group, for example,
OAc, Cl, or t-BuCO, in good yields. A spiro fluorocyclo-
pentene was also obtained by the 1,5-C–H insertion of a
fluoroalkylidenecarbene into an acetal C–H bond.
Acknowledgment
Financial support was partially provided by the Forum
on Iodine Utilization (FIU), presently the Society of
Iodine Science (SIS).
6. Fluorocyclopentene synthesis by HF elimination from
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.019.
7. Fluorocyclopentene synthesis by ring expansion of cyclo-
butylfluorocarbenes: Zuev, P. S.; Sheridan, R. S.; Albu, T.
V.; Truhlar, D. G.; Hrovat, D. A.; Borden, W. T. Science
2003, 299, 867.
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References and notes
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amount of impurities. Therefore, the yield of 3 was
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1
determined by H NMR using an internal standard. For
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14. Experimental procedure and spectra data for the synthesis
of 2b: In a round-bottomed flask were placed (Z)-(2-
fluorododec-1-enyl)(phenyl)iodonium tetrafluoroborate
(1b) (238 mg, 0.5 mmol), CH2Cl2 (50 mL), and potassium
tert-butoxide (168 mg, 1.5 mmol) at room temperature,
and the mixture was stirred for 24 h at room temperature.
The reaction mixture was poured into a satd aq NH4Cl
(30 mL) and the organic phase was separated. The
aqueous phase was extracted with Et2O (20 mL) three
times. The combined organic phase was dried over MgSO4
and concentrated under reduced pressure. The product, 1-
fluoro-3-heptylcyclopentene (2b), was isolated by column
chromatography (silicagel; hexane) in 74% yield (68 mg,
0.37 mmol); dH (CDCl3) 0.88 (3H, t, J 6.7 Hz), 1.22–1.56
(13H, m), 2.08–2.15 (1H, m), 2.36–2.44 (2H, m), 2.54–2.64
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Normant, J. F. Synthesis 1982, 297.

T. Guan et al. / Tetrahedron Letters 49 (2008) 76–79
79
(1H, m), 4.94–4.98 (1H, m); dF (CDCl3) À122.2 (1F, s); dC
(CDCl3) 14.1, 22.7, 27.4, 27.7 (d, J 7.7 Hz), 28.6 (d, J
21.8 Hz), 29.3, 29.8, 31.9, 36.9 (d, J 1.9 Hz), 40.0 (d, J
7.7 Hz), 106.5 (d, J 8.6 Hz), 162.0 (d, J 278.8 Hz); m (KBr)/
cmÀ1 2954, 2925, 2855, 1679, 1460, 1350, 1164, 821, 723;
[HR EI-MS: calcd for C12H21F (M): 184.1627. Found:
M+, 184.1629].
15. Sawaguchi, M.; Ayuba, S.; Hara, S. Synthesis 2002, 1802.
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17. Yoshida, M.; Kawakami, K.; Hara, S. Synthesis 2004,
2821.
18. For reviews on alkylidenecarbenes and -carbenoides (a)
Knorr, R. Chem. Rev. 2004, 104, 3795; (b) Stang, P. J.
Chem. Rev. 1978, 78, 383.