Synthesis of monofluoromethylcyclopropanes from alkenes without using freons: Novel synthesis of chlorofluoromethyl phenyl sulfide and its application in cyclopropanation

Article abstract of DOI:10.1246/cl.130570

Chlorofluoromethyl phenyl sulfide was prepared from the reaction of chloromethyl phenyl sulfide with Selectfluor. Monofluorocyclopropanation of an alkene was achieved via cyclopropanation using a fluorocarbene derived from the product chlorofluoromethyl phenyl sulfide, followed by oxidation and desulfurization.

Full text of DOI:10.1246/cl.130570

doi:10.1246/cl.130570
Published on the web July 20, 2013
1377
Synthesis of Monofluoromethylcyclopropanes from Alkenes without Using Freons:
Novel Synthesis of Chlorofluoromethyl Phenyl Sulfide and Its Application in Cyclopropanation
Masayuki Kirihara,*1 Tomomi Ogata,1 Atsushi Itou,1 Sayuri Naito,1 Mari Kishida,1
Kento Yamazaki,1 Hidetsugu Tabata,2 and Hideyo Takahashi2
1Department of Materials and Life Science, Shizuoka Institute of Science and Technology,
2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555
2Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605
(Received June 19, 2013; CL-130570; E-mail: kirihara@ms.sist.ac.jp)
Chlorofluoromethyl phenyl sulfide was prepared from the
reaction of chloromethyl phenyl sulfide with Selectfluor·.
Monofluorocyclopropanation of an alkene was achieved via
cyclopropanation using a fluorocarbene derived from the product
chlorofluoromethyl phenyl sulfide, followed by oxidation and
desulfurization.
R1
R2
R3
R4
X
H
F
R3
R4
R1
R2
base
CHFX2
X=Cl or Br
(Freons)
CFX
reduction
n-BuLi or
P(NMe2)3, CsF or
TiCl4, LiAlH4 or
Mg, LiCl
F
R3
R4
R1
R2
Cyclopropanes are important synthetic intermediates owing
to their unique chemical properties. They are also important in
the biological sciences and medicinal chemistry. In fact, there are
numerous natural products and artificial pharmaceutics contain-
ing cyclopropane moieties.1 A large number of organofluorine
compounds are similarly important in material sciences and
medicinal chemistry, because the introduction of fluorine atoms
into organic compounds results in dramatic physical and chemi-
cal changes.2 Therefore, fluorinated cyclopropanes are important
and have received much attention, especially in medicinal
chemistry.3 Among them, monofluorocyclopropane moieties
are attractive groups, with one of their most important applica-
tions being sitafloxacin, which has a monofluorocyclopropane
moiety and is used as an antibacterial pharmaceutical agent.4
Monofluorocyclopropanes have traditionally been prepared
through the halofluorocyclopropanation of alkenes with subse-
quent reduction of the halogen atom (Scheme 1).5 Although
these methods are reliable, Freons (chlorofluorocarbon and
related compounds) are required as reagents.5 Freons have been
heavily regulated because of their destructive effects on the
ozone layer.6 They are no longer commercially available and are
thus very difficult to obtain. Therefore, it has become almost
impossible to use these standard methods.
CFCl3 (Freon)
Scheme 1. Preparations of monofluorocyclopropanes using
Freons.
H
F
Et2Zn
NaI
R1
R2
CHBr2F
(Freon)
CHI2F
R3
R4
R1
R2
R3
R4
acetone
Scheme 2. Simmons-Smith reaction using fluorodiiodo-
methane.
PhSNa, BnMe3NCl
PhS CHClF
CHCl2F
benzene, H2O
1
(Freon)
base
1) H+
2) Ca, NH3
F
SPh
F
H
CO2t-Bu
F
PhS
C
CO2t-Bu
CO2H
Scheme 3. Synthesis of a monofluorocyclopropane using 1.
Monofluorocyclopropanes can also be synthesized through
a Simmons-Smith reaction with alkenes using fluorodiiodo-
methane (not commercially available) as the reagent.7 Although
fluorodiiodomethane itself is not a Freon, it is typically prepared
from dibromofluoromethane (Scheme 2), which is a Freon, and
is therefore also impossible to obtain.
Chlorofluoromethyl phenyl sulfide (1) has also been used as
a building block for the synthesis of monofluorocyclopropanes
from alkenes. The treatment of chlorofluoromethyl phenyl
sulfide with a base produces fluoro(phenylthio)carbene, and the
resulting carbene reacts with alkenes to afford the corresponding
fluoro(phenylsulfanyl)cyclopropanes.8 Desulfurization of the
fluoro(phenylsulfanyl)cyclopropane provides the desired mono-
fluorocyclopropane.8 Unfortunately, chlorofluoromethyl phenyl
sulfide is also not commercially available and has traditionally
been prepared through the reaction of sodium phenylthiolate with
dichlorofluoromethane, another Freon (Scheme 3).9
As described above, because of the use of Freons in the
traditional synthetic methods, it has been very difficult lately
to synthesize monofluorocyclopropanes from alkenes. To over-
come this difficulty, we have developed a novel synthetic route
to 1 without the use of Freons, and describe the results in this
communication.
It has been reported that fluoromethyl phenyl sulfide can be
synthesized through the reaction of Selectfluor· with thioani-
sol,10 or the reaction of N,N-diethylaminosulfur trifluoride
(DAST) with methyl phenyl sulfoxide in the presence of
antimony chloride.11 We planned to synthesize 1 through the
reaction of Selectfluor· with chloromethyl phenyl sulfide or
the reaction of DAST with chloromethyl phenyl sulfoxide. The
chlorination of fluoromethyl phenyl sulfide using sulfanyl
chloride12 or N-chlorosuccinimide13 and deoxygenative chlori-
Chem. Lett. 2013, 42, 1377-1379
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1378
SelectfluorTM (1 equiv), rt
CH3CN
S
S
Ph
CHClF
1 (65%)
Ph
CH2Cl
Scheme 4. Synthesis of 1 without using Freons.
Table 1. Reaction of 1 with 1,1-disubstituted alkenes or a
1-monosubstituted alkene, and further transformation to mono-
fluorocyclopropanes
Scheme 5. Stereochemistry of 4c.
S
PhS
F
Ph
CHClF
R1
R2
t-Bu
R1
R2
F
1
m-CPBA (3 equiv)
CHCl3, -20 oC to rt,
(3 equiv)
S
F
S
aq. NaOH, BnNEt3Cl
CH2Cl2, 45 oC, 9 h
2
8 h
H
O
H
t-Bu
2c
PhSO2
m-CPBA (3 equiv)
F
H
F
Mg (15 equiv)
HgCl2 (0.1 equiv)
PhS
F
R1
R2
R1
R2
R1
R2
S
CHCl3
MeOH
t-Bu
F
S
-20 oC to rt, 16 h
50 oC, 3.5 h
F
3
5
4
H
t-Bu
not obtained
Entry Alkene
3
4
5
H
2c'
O
O
O
H
F
Ph
F
S
S
F
H
H
Ph
Ph
Scheme 6. Origin of the stereoselectivity.
Ph
Ph
Ph
Ph
Ph
1
2
Ph
4a (quant.)
Ph
O
3a (quant.)a
5a (92%)
S
F
O
H
Ph
H
S
Ph
1)
Ph
Ph
CHClF
O
O
aq. NaOH, BnNEt3Cl
H
F
(3 equiv)
1
H
H
Ph
Ph
Ph
S
F
Ph
Ph
S
F
CH2Cl2, 45 oC, 9 h
Ph
Ph
trace
O
Ph
2) m-CPBA (3 equiv)
Ph
CHCl3, -20 oC to rt, 8 h
5b (60%)a
4b (84%)a
H
H
3b (86%)a
S
Ph
F
Ph
Ph
Ph
O
Ph
Ph
O
O
Ph
Ph
S
H
H
H
F
F
trace
S
F
Ph
H
H
Ph
H
H
3
Scheme 7. The reaction with 1,2-disubstituted alkenes.
t-Bu
carbons of the cyclopropane ring), so they were obtained as a
mixture of diastereomers. They were then oxidized further by
using m-CPBA to produce the corresponding sulfones 4.17
Desulfurization of 4 was achieved by using magnesium metal
in the presence of a catalytic amount of mercury chloride19 to
provide the desired monofluorocyclopropanes 5.20 For the
monofluorocyclopropanes 4c and 5c, a single stereoisomer was
obtained in each case (Entry 3). The stereochemistry of 4c was
determined to be as depicted in Scheme 5 according to the X-ray
crystallography results.21 Additionally, the desulfurization of
a 2-substituted-1-fluoro-1-sulfonylcyclopropane using metallic
magnesium has been found to proceed with retention of
configuration.24 As a result, 5c may be a cis-isomer, but further
spectroscopic elucidation is necessary.
The fluoro(phenylsulfanyl)carbene, which was produced
from 1, attacked (4-t-butylphenyl)ethylene from a less hindered
site to afford 2c stereoselectively, as shown in Scheme 6.
In contrast to the reaction of 1,1-disubstituted alkenes, 1,2-
disubstituted alkenes are almost inert to the fluoro(phenylsul-
fanyl)carbene derived from 1, forming trace amounts of the
cyclopropanes under the same conditions (Scheme 7), presum-
ably owing to steric hindrance.
t-Bu
t-Bu
5c (77%)
3c (84%)a
t-Bu
4c (60%)
aMixture of stereoisomers.
nation of fluoromethyl phenyl sulfoxide using sulfinyl chloride14
were also examined. The reaction of chloromethyl phenyl
sulfide13 with Selectfluor· produced the desired 1 in 65%
yield.15 On the other hand, the other reactions were unsuccessful
(Scheme 4).
1 synthesized by this method was pure enough to be used
for the cyclopropanation of an alkene without further purifica-
tion (Table 1). Treatment of 1,1-disubstituted alkenes or a
1-monosubstituted alkene with 1 in aqueous base in the presence
of a phase-transfer catalyst provided the 1-fluoro-1-(phenyl-
sulfanyl)cyclopropanes 2. Since these cyclopropanes were not
stable enough to be purified, they were subsequently oxidized
with m-chloroperbenzoic acid (m-CPBA) to afford the corre-
sponding sulfoxides 3.16 The sulfoxides 3 have two or three
stereogenic centers (one chiral sulfur, and one or two chiral
Chem. Lett. 2013, 42, 1377-1379
© 2013 The Chemical Society of Japan
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1379
(7 mL) was added dropwise to the solution over 5 min, and the resulting
mixture was stirred at ¹20 °C for 2 h, and then the reaction mixture was
warmed to room temperature and stirred for an additional 5 h. Saturated
aqueous sodium hydrogen carbonate (10 mL) was added, and the
resulting mixture was extracted with chloroform (10 mL © 3). The
combined extract was washed with brine, and dried over magnesium
sulfate. The solvent was evaporated and the residue was purified by
silica gel column chromatography with n-hexane-ethyl acetate as eluent
to afford 1-fluoro-1-(phenylsulfinyl)cyclopropane 3 as a mixture of
diastereomers.
In conclusion, a synthetic method for the preparation of
chlorofluoromethyl phenyl sulfide without using Freons has
been developed. The chlorofluoromethyl phenyl sulfide prepared
through this method can be used for the synthesis of mono-
fluorocyclopropane from 1-monosubstituted alkenes or 1,1-
disubstituted alkenes. This method is the sole Freons-free
procedure for the synthesis of monofluorocyclopropanes from
alkenes.25,26
17 General procedure of the oxidation of 3 with m-chloroperbenzoic
acid: A solution of m-chloroperbenzoic acid (262.3 mg, 1.50 mmol) in
chloroform (5 mL) was added dropwise over 5 min to a stirred solution
of 3 (a mixture of diastereomers, 0.6 mmol) in chloroform (10 mL) at
¹20 °C under a nitrogen atmosphere. The resulting mixture was stirred
under the same conditions for 2 h, and then the reaction mixture
was warmed to room temperature and stirred for an additional 14 h.
Saturated aqueous sodium hydrogen carbonate (10 mL) was added, and
the resulting mixture was extracted with chloroform (10 mL © 3). The
combined extract was washed with brine, and dried over magnesium
sulfate. The solvent was evaporated and the residue was purified by
silica gel column chromatography with n-hexane-ethyl acetate as eluent
to afford the 1-fluoro-1-phenylsulfonylcyclopropane 4.18 As we
mentioned in Table 1, 4a and 4c were obtained as a single compound.
Either stereoisomer of 4b could not be obtained in a pure form at this
stage.
References and Notes
1
2
3
4
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D. L. S. Brahms, W. P. Dailey, Chem. Rev. 1996, 96, 1585.
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Chemother. 2002, 46, 1800. b) T. Akasaka, Y. Onodera, M. Tanaka, K.
Sato, Antimicrob. Agents Chemother. 1999, 43, 530. c) M. Nakashima,
T. Uematsu, K. Kosuge, K. Umemura, H. Hakusui, M. Tanaka,
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5
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H. Yamanaka, F. Namigata, W. Funasaka, J. Org. Chem. 1970, 35, 33.
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Tamura, M. Hashimoto, Y. Kobayashi, T. Katoh, K. Nakatani, M.
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3889. c) O. Tamura, M. Hashimoto, Y. Kobayashi, T. Katoh, K.
Nakatani, M. Kamada, I. Hayakawa, T. Akiba, S. Terashima,
Tetrahedron Lett. 1992, 33, 3483.
18 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
19 G. H. Lee, E. B. Choi, E. Lee, C. S. Pak, Tetrahedron Lett. 1993, 34,
4541.
6
7
20 Desulfurization of 4: To a stirred solution of 4 (1.00 mmol) in
methanol, magnesium powder (365.3 mg, 15.0 mmol) and mercury
chloride (30.7 mg, 0.11 mmol) were added at 50 °C under a nitrogen
atmosphere, and stirred for 3.5 h. The reaction mixture was poured into
hydrochloric acid (0.5 M, 100 mL), and the resulting mixture was
extracted with ethyl acetate (5 mL © 3). The extract was washed with
saturated aqueous sodium hydrogen carbonate (7 mL) and brine (7 mL).
Then, the extract was dried over anhydrous magnesium sulfate, and the
solvent was evaporated. The residue was purified by silica gel column
chromatography with n-hexane-ethyl acetate as eluent to afford the
monofluorocyclopropane 5.18 As we mentioned in Table 1, 5a and 5c
were obtained as a single compound. One of the stereoisomer of 5b was
obtained in a pure form.
8
9
Y. Ishida, T. Yafune, J. Ooki, K. Hayano, Jpn. Kokai Tokkyo Koho
JPA1995017945, 1993.
a) H. Uno, K. Sakamoto, F. Semba, H. Suzuki, Bull. Chem. Soc. Jpn.
1992, 65, 210. b) A. K. Saikia, S. Tsuboi, J. Org. Chem. 2001, 66, 643.
10 G. S. Lal, J. Org. Chem. 1993, 58, 2791.
11 S. F. Wnuk, M. J. Robins, J. Org. Chem. 1990, 55, 4757.
12 F. G. Bordwell, B. M. Pitt, J. Am. Chem. Soc. 1955, 77, 572.
13 T. Harada, A. Karasawa, A. Oku, J. Org. Chem. 1986, 51, 842.
14 R. Tanikaga, K. Miyashita, N. Ono, A. Kaji, Synthesis 1982, 131.
15 Preparation of chlorofluoromethyl phenyl sulfide (1): To a stirred
solution of chloromethyl phenyl sulfide13 (353 mg, 2.00 mmol) in
acetonitrile (2 mL) was added a solution of Selectfluor· (1062 mg,
3.00 mmol) in acetonitrile (20 mL) at 0 °C under a nitrogen atmosphere,
and the mixture was stirred for 25 min under the same condition. The
reaction mixture was evaporated in vacuo to remove the solvent, and
carbon tetrachloride (20 mL) was added to the residue. The resulting
suspension was filtered through a glass filter and the filtrate was
evaporated in vacuo to provide chlorofluoromethyl phenyl sulfide
(228.0 mg, 65%) as a colorless oil. Chlorofluoromethyl phenyl sulfide
(1):9 1H NMR (CDCl3): ¤ 7.30 (1H, d, J = 57 Hz), 7.36-7.39 (3H, m),
7.56-7.79 (2H, m); 19F NMR (CDCl3): ¤ ¹99.44 (1F, d, J = 57 Hz); IR
(neat) cm¹1: 2400, 1443, 762.
21 Single-crystal X-ray analysis: All measurements were made on a
RIGAKU R-AXIS RAPID imaging plate area detector graphite
monochromated Cu K¡ radition. The data were collected at a temper-
ature of ¹100 °C. The structure was solved by direct method SIR9222
and expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. All calculations were performed using Crystal
Structure (CrystalStructure 4.023) crystallographic software package.
Crystal data for 4c: C19H21O2SF: mp 125-126 °C, Mr = 332.43,
Cu K¡ (- = 1.54187 ¡), monoclinic, P21/c, colorless prism 0.30 ©
0.15 © 0.05 mm3, crystal dimensions a = 6.0428(2) ¡, b = 14.6851(3)
¡, c = 19.1851(4) ¡, ¡ = 90°, ¢ = 99.550(2)°, £ = 90°, T = 173 K,
¹3
Z = 4,
18.324 cm
V = 1702.41(6) ¡3,
D
calcd = 1.297 g cm
,
®Cu K¡ =
¹1
,
F000 = 704.00, GOF = 1.859,
Rint = 0.0382, R1 =
0.0608, wR2 = 0.1894. CCDC-963046.
22 SIR92: A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr. 1994, 27,
435.
16 General procedure of the reaction of a carbene derived from
chlorofluoromethyl phenyl sulfide (1) with an alkene, and subse-
23 CrystalStructure 4.0: Crystal Structure Analysis Package, Rigaku and
Rigaku/MSC, The Woodlands, TX 77381, USA, 2010.
24 A. Toyota, Y. Ono, C. Kaneko, I. Hayakawa, Tetrahedron Lett. 1996,
37, 8507.
25 Recently, Hu et al. reported an enantioselective monofluorocyclopro-
panation of ¡,¢-unsaturated amides using (S)-N-tosyl-S-methyl-S-
phenylsulfoximine.26 This method is also Freon-free, and enantiose-
lectively provides monofluorocyclopropanes in high yields. This
reaction proceeds through a Michael-type addition-elimination reac-
tion, therefore, it can be applicable only to electronic deficient alkenes
such as ¡,¢-unsaturated amides.
quent oxidation: To
a stirred solution of 1 (3.50 mmol) and
benzyltriethylammonium chloride (98.5 mg, 0.40 mmol) in dichloro-
methane (1.2 mL) was added a solution of sodium hydroxide (600 mg,
15 mmol in 1.2 mL of water). A solution of an alkene (1.10 mmol) in
dichloromethane (5 mL) was added to the mixture at 45 °C, and the
resulting suspension was stirred under the same condition for 9 h. Water
(10 mL) was added to the reaction mixture, and the mixture was
extracted with dichloromethane (10 mL © 3). The extract was washed
with brine, dried over magnesium sulfate, and the solvent was
evaporated. The resulting residue was dissolved in chloroform
(7 mL), and the solution was cooled to ¹20 °C. A solution of
m-chloroperbenzoic acid (579.8 mg, 3.30 mmol) in dichloromethane
26 X. Shen, W. Zhang, L. Zhang, T. Luo, X. Wan, Y. Gu, J. Hu, Angew.
Chem., Int. Ed. 2012, 51, 6966.
Chem. Lett. 2013, 42, 1377-1379
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/