Chemistry of trichlorofluromethane: Synthesis of chlorofluromethyl phenyl sulfone and fluoromethyl phenyl sulfone and some of their reactions

Article abstract of DOI:10.1021/jo000825r

It was observed that the reaction of CFCl₃ with thiophenoxide gave only 10% of the corresponding thioether. On the other hand, these thioethers could be prepared in excellent yield from diaryl disulfides and CFCl₃ in the presence of sodium hydroxymethanesulfinate in aqueous DMF at 4 atm pressure of nitrogen. Dechlorination of the thioether (PhSCFCl₂) with different reducing agents were studied. Most of the reducing agents eliminated both fluorine and chlorine functionalities or gave the hydrolyzed products. But its sulfone on treatment with Zinc in methanol gave monochlorofluoromethyl and fluoromethyl phenyl sulfone in good yields. Darzens reaction of these compounds was also studied.

Full text of DOI:10.1021/jo000825r

VOLUME 66, NUMBER 3
FEBRUARY 9, 2001
© Copyright 2001 by the American Chemical Society
Articles
Ch em istr y of Tr ich lor oflu or om eth a n e: Syn th esis of
Ch lor oflu or om eth yl P h en yl Su lfon e a n d F lu or om eth yl P h en yl
Su lfon e a n d Som e of Th eir Rea ction s
Anil K. Saikia and Sadao Tsuboi*
Department of Environmental Chemistry and Materials, Okayama University,
Tsushima, Okayama 700-8530, J apan
stsuboi6@cc.okayama-u.ac.jp
Received May 30, 2000
It was observed that the reaction of CFCl3 with thiophenoxide gave only 10% of the corresponding
thioether. On the other hand, these thioethers could be prepared in excellent yield from diaryl
disulfides and CFCl3 in the presence of sodium hydroxymethanesulfinate in aqueous DMF at 4
atm pressure of nitrogen. Dechlorination of the thioether (PhSCFCl2) with different reducing agents
were studied. Most of the reducing agents eliminated both fluorine and chlorine functionalities or
gave the hydrolyzed products. But its sulfone on treatment with Zinc in methanol gave monochlo-
rofluoromethyl and fluoromethyl phenyl sulfone in good yields. Darzens reaction of these compounds
was also studied.
In tr od u ction
in recent years. In continuation of our research on
R-mono- and R,R-dihalogenated compounds,5 we were
interested in Darzens condensation reaction of R-halo-
genated sulfones with various carbonyl compounds. We
now report a synthetic method for the preparation of
chlorofluoromethyl phenyl sulfone and fluoromethyl phen-
yl sulfone and their reactions with different carbonyl
compounds.
Fluorine functionality plays an important role in the
biologically active compounds.1 Several â-fluorophenethyl-
amines,2 â-fluoroamino acids,1 3-fluoroalkylamines,3 and
vinyl fluorides4 have been proved to be irreversible
inhibitors of certain enzymes. Therefore, fluorine chem-
istry has been the subject of increased research activity
* To whom correspondence should be addressed. Tel./Fax: 81-86-
251-8898.
Resu lts a n d Discu ssion
(1) (a) Seiler, N.; J ung, M. J .; Koch-Weser, J . Enzyme-Activated
Irreversible Inhibitors; Elsevier/North-Holland Biomedical Press: Am-
sterdam, 1978. (b) Rando, R. R. Pharmacol. Rev. 1984, 36, 111. (c)
Banks, R. E. Organofluorine Chemicals and their Industrial Applica-
tions; Royal Society of Chemistry: London, 1979; Vol. 123, pp 154, 169.
(d) Fuller, R.; Kobayashi, Y. Biomedical Aspects of Fluorine Chemistry;
Kodansha/Elsevier: New York, 1982.
(2) LeTourneau, M. E.; McCarthy, J . R. Tetrahedron Lett. 1984, 25,
5227.
(3) McDonald, I. A.; Lacoste, J . M.; Bey, P.; Wagner, J .; Palfreyman,
M. G. J . Am. Chem. Soc. 1984, 106, 3354.
Following the literature procedure for the preparation
of fluorinated thioethers,6 we observed that the reaction
(4) (a) Boys, M. L.; Collington, E. W.; Finch, H.; Swanson, S.;
Whitehead, J . F. Tetrahedron Lett. 1988, 29, 3365. (b) McCarthy, J .
R.; Matthews, D. P.; Stemerick, D. M.; Huber, E. W.; Bey, P.; Lippert,
B. J .; Snyder, R. D.; Sunkara, P. S. J . Am. Chem, Soc. 1991, 113, 7439.
(c) McCarthy, J . R.; Matthews, D. P.; Edwards, M. L.; Stemerick, D.
M.; J arvi, E. T. Tetrahedron Lett. 1990, 31, 5449.
10.1021/jo000825r CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/18/2001

644 J . Org. Chem., Vol. 66, No. 3, 2001
Ta ble 1. P r ep a r a tion of r-Ha loth ioeth er s
Saikia and Tsuboi
Sch em e 1. Red u ction of r-Ha loth ioeth er s
entry
R
product 2/yield (%)a
a
b
c
d
H
CH3
Cl
72 (52)
84 (40)
91 (64)
45 (16)
NO2
a
Yield was based on the amount of the starting material
consumed, and the yield within the parentheses was the isolated
yield.
of CFCl3 with potassium thiophenoxide in DMF under
an atmosphere of nitrogen gave only 10% of dichloro-
fluoromethyl phenyl sulfone. Increasing the pressure up
to 2.5 atm of nitrogen also resulted in a low yield (21%).
Claude et al.7 had reported that the reaction of CFCl3
with diphenyl disulfide in the presence of sodium dithion-
ite and sodium dihydrogenphosphate in aqueous DMF
yielded 13% of dichlorofluoromethyl phenyl sulfide. We
synthesized the thioethers 2 by slightly modifying the
Claude’s method using sodium hydroxymethanesulfinate
in aqueous DMF under 4 atm of nitrogen in 45-91% yield
as shown in Table 1.
Sch em e 2. Syn th esis of Ch lor oflu or om eth yl a n d
F lu or om eth yl P h en yl Su lfon e
The reduction of the compound 2a with zinc in metha-
nol8 gave dehalogenated product, methyl phenyl sulfide
(3), in 42% yield. On the other hand, the reduction with
tributyltin hydride and AIBN9 afforded the compound 4
in 56% yield. The reduction with tin and hydrochloric acid
in ethanol furnished only the hydrolyzed product, ethyl
phenyl thiocarbonate (5), in 54% yield, whereas the
reduction with SnCl2 in hydrochloric acid10 or Al-SnCl2-
MeOH11 systems afforded disulfide (6) quantitatively as
shown in Scheme 1.
We observed that when sulfide 2 was initially oxidized
with hydrogen peroxide in acetic acid to the correspond-
ing sulfone and then reduced with zinc in methanol, a
mixture of chlorofluoromethyl phenyl sulfone (PhSO2-
CHClF) and fluoromethyl phenyl sulfone (PhSO2CH2F)
was obtained. Thus, the reaction of 2a with hydrogen
peroxide (8 equiv) in acetic acid afforded the sulfone 7 in
90% yield along with the sulfoxide 8 in 5% yield.
Similarly, hydrogen peroxide oxidation of 4 gave 86% of
the sulfone 9 and sulfoxide 10 in 9% yield. The compound
10 showed two sets of signals in 1H and 19F NMR and
therefore consists of a pair of diastereomers. Refluxing
7 with 1 equiv of zinc in methanol for 7 h, the sulfone 9
was isolated in 80% yield; however, when 3 equiv of zinc
was used in methanol and the reaction was run for 16 h,
76% yield of fluoromethyl phenyl sulfone (11) was
obtained, along with the compound 9 in 16% yield
(Scheme 2). The reason for complete dehalogenation of
sulfide (2a ) is that the lone pairs on sulfur makes the
fluorine-carbon bond more labile for elimination.
Da r zen s Con d en sa tion of th e Com p ou n d 9. Vogt
and Tavares12 prepared epoxy sulfones by treating chlo-
romethyl tolyl sulfone with aldehydes and ketones in the
presence of potassium tert-butoxide. Makosza13 and co-
workers showed that R,â-epoxy sulfones can be simply
prepared from R-chlorosulfones and carbonyl compounds
under phase-transfer conditions in 60-90% yields. Durst
et al.14 also studied the condensation of R-chlorosulfones
with different carbonyl compounds using n-BuLi or LDA
as a base and obtained halohydrin sulfones in excellent
yields which were then cyclized to the corresponding
epoxide in the presence of potassium hydroxide. In this
paper, some reactions of the sulfone 9 with different
aldehydes and ketones were carried out, and the results
were summarized in Table 2 and Scheme 3. The reaction
of 9 with aromatic aldehydes and ketones under phase-
transfer condition using THF as a solvent and benzyl-
triethylammonium fluoride (TEBA) as catalyst gave
rearranged products 11 and 15, without isolation of the
epoxy sulfone 13. When acetonitrile was used as a
solvent, the compound 16 was also obtained in 23% yield.
The formation of compounds 11, 15. and 16 can be
(5) Tsuboi, S.; Yamafuji, N.; Utaka, M. Tetrahedron: Asymmetry
1997, 8, 375 and references therein.
(6) Wakselman, C.; Tordeux, M. J . Org. Chem. 1985, 50, 4047.
(7) J ean-Louis, C.; Bernard, L.; Roland, N.; Marc, T.; Claude, W.
Eur. Pat. Appl. EP 374,061 (Cl. C07B 45/06), 20 J une, 1990.
(8) Daiichi Kogyo Seiyaku Co., Ltd. J pn. Kokai Tokkyo Koho J P 58,-
222,038 [83,222,038] (Cl. C07C19/08), 23 Dec, 1983; Chem. Abstr. 1984,
100, 156218w.
(9) (a) Yamanaka, H.; Shimamura, T.; Teramura, K.; Ando, T. Chem.
Lett. 1972, 921. (b) Ando, T.; Ishihara, T.; Ohtani, E.; Sawada, H. J .
Org. Chem. 1981, 46, 4446.
(12) Vogt, P. F.; Tavares, D. E. Can. J . Chem. 1969, 47, 2875.
(13) J onczyk, A.; Banko, K.; Makosza, M. J . Org. Chem. 1975, 40,
267.
(10) Rinkes, I. J . Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II, p 393.
(11) Torii, S.; Tanaka, H.; Yanashita, S.; Hotate, M.; Suzuki, A.;
Okuma, Y. J pn. Pat. 0201414, 1990.
(14) Durst, T.; Tin, K. C.; Reinach-Hirtzbach, F. D.; Decesare, J .
M.; Ryan, M. D. Can. J . Chem. 1979, 57, 258.

Chemistry of Trichlorofluoromethane
J . Org. Chem., Vol. 66, No. 3, 2001 645
Ta ble 2. Da r zen s Con d en sa tion P r od u cts of Su lfon e
carbonyl compound 12
products (% yield)
R1
R2
reaction conditions
reaction time/h
14
11
15
a
b
c
d
a
b
c
d
e
C6H5
p-CH3C6H5
C6H5
CH3(CH2)4
C6H5
p-CH3C6H5
C6H5
H
H
C6H5-
H
H
H
C6H5
H
50% NaOH/THF/rta
4
4
4
- - -
- - -
- - -
15
17
- - -
15
20
60
50% NaOH/THF/rta
50% NaOH/THF/rta
50% NaOH/THF/rta
4
aldol product (17, 85%)b
ButOK/THF / -35 °C to rt
ButOK/THF / -35 °C to rt
ButOK/THF / -35 °C to rt
ButOK/THF / -35 °C to rt
ButOK/THF / -35 °C to rt
16
16
16
16
16
25
28
- - -
58
31
32
- - -
- - -
- - -
30
31
60
- - -
- - -
CH3(CH2)4
(CH3)2CHCH2
H
60
a
b
TEBA was used as a phase transfer catalyst See Scheme 3.
Sch em e 3
Sch em e 4. Mech a n ism of th e Rea r r a n gem en t
Rea ction
explained as follows. The epoxide 13 which forms during
the reaction is more reactive due to the two electron-
withdrawing groups, fluorine and sulfonyl, and conse-
quently in the presence of base, acetonitrile attacks the
epoxide 13 as a nucleophile, giving the compound 16
(Scheme 3). Compound 15 forms by the migration of
sulfonyl group and subsequent decarbonylation as shown
in Scheme 4. A similar type of mechanism has also been
described by Durst et al.14 Formation of the compound
11 can be explained by considering the mesomeric effect
of fluorine.15 For this effect, the epoxide ring opens in
the opposite direction and migration of hydride presides
over that of the phenyl group due to steric hindrance.
This is confirmed by the fact that when the reaction was
performed with benzophenone only benzhydril phenyl
sulfone (15c) was obtained and no compound 11 was
isolated. In case of aliphatic aldehyde, only aldol product
17 was obtained in 85% yield. When potassium tert-
butoxide was used as a base, halohydrin sulfone 14 was
also obtained along with 11 and 15. Under this condition,
aliphatic aldehyde gave only halohydrin sulfone 14, and
attempt to make an epoxide by treating potassium
hydroxide failed, but resulted in the retro-products 9 and
12. It was observed that treatment of the compound 14
with several organic bases such as triethylamine, pyri-
dine, DBU, and sodium hexamethyldisilazane in anhy-
drous conditions did not afford the epoxide 13. In most
of the cases, degraded products (11 and 15a ,b) were
obtained, and in some cases starting materials were
recovered. On the other hand, the halohydrin sulfone 14
could be converted to the corresponding epoxide 13 by
treating with sodium hydride in anhydrous THF. The
results were summarized in Table 3. Under this condi-
tion, compounds 14a and 14b were decomposed to
compounds 11 and 15a ,b, whereas compound 14e af-
forded epoxide 13e as a diastereomeric mixture (1:3) in
moderate yield (56%). Exposure of compound 14d to
sodium hydride gave epoxide 13d as a diastereomeric
mixture (2:3) which was contaminated with compound
18d (13d :18d ) 13:7). The mixture of compounds 13d
and 18d was inseparable even by HPLC. The existence
1
of the compound 18d was determined from the H NMR,
1
13C NMR, and IR spectra of the mixture. In the H and
(15) One reviewer’s opinion was that an alternative route of forming
11 from 9 may be due to the reductive properties of aldehydes. But
when the same reaction was carried out with compound 7 neither
compound 9 nor 11 was formed.
13C NMR spectra, the extra peaks at 5.84 and 171.0 ppm
indicated the presence of 18d . It was further confirmed

646 J . Org. Chem., Vol. 66, No. 3, 2001
Saikia and Tsuboi
Ta ble 3. Con ver sion of Ha loh yd r in Su lfon e to Ep oxid e
removed under reduced pressure and purified by column
chromatography to obtain 0.93 g (52%, 72% on the basis of
73% conversion) of the product 2a as an oil; 1H NMR (200
MHz, CDCl3): δ 7.33 (m, 3 H), 7.53 (m, 2 H); 19F NMR (188
MHz, CDCl3, C6F6): δ 141.62 (s, 1 F, CFCl2); GC/MS (EI, 70
eV) m/z 210 (M+), 177, 175, 109, 77, 65.
Red u ction of 2a w ith Zin c in Meth a n ol. A mixture of
2a (0.048 g, 0.23 mmol), and powdered zinc (0.84 g) in
methanol (1.0 mL) was refluxed for 6 h. The solid material
was filtered and the filtrate evaporated to dryness and purified
by column chromatography to give 0.012 g (42%) of the product
as an oil which was identified as methyl phenyl sulfide (3);
1H NMR (200 MHz, CDCl3): δ 2.4 (s, 3 H), 7.27 (m, 5Η); GC/
MS (EI, 70 eV) m/z 124 (M+), 109, 77.
products (% yield)
substrate 14
R1
R2
13
18
Red u ction of 2a w ith Sn Cl2 a n d HCl. A mixture of 2a
(0.11 g, 0.52 mmol), SnCl2‚2H2O (0.09 g, 0.52 mmol) and concd
HCl (0.5 mL) was heated to 90 °C and kept for 12 h. The
mixture was filtered with suction to remove the solid material.
The humus on the filter was washed with water and finally
with ethyl acetate. The aqueous phase was extracted with
ethyl acetate, and the combined filtrate and extract was
washed with sodium bicarbonate and water and then dried
(MgSO4). After evaporation of the solvent, the product was
purified by column chromatography. The compound was
identified as diphenyl disulfide. The spectral data were identi-
cal with the authentic sample.
Red u ction of 2a w ith Al a n d Sn Cl2 in MeOH. A mixture
of 2a (0.14 g, 0.67 mmol), SnCl2‚2H2O (0.13 g, 0.7 mmol), and
Al (0.019 g) was stirred in MeOH at room temperature for 14
h. The mixture was filtered and the residue washed with ethyl
acetate. The combined filtrate and washings were washed with
water and dried (MgSO4). After evaporation of the solvent and
column chromatography, the isolated compound was identified
as diphenyl disulfide.
Red u ction of 2a w ith Sn in HCl a n d EtOH. To a solution
of 2a (0.09 g, 0.43 mmol) in EtOH (1 mL) was added
concentrated HCl (0.1 mL, 1.0 mmol) and granulated tin (0.10
g), and the mixture was refluxed for 4 h. The reaction mixture
was filtered hot, and the residue was washed with ethyl
acetate. The combined filtrate and washings were treated with
sodium bicarbonate solution, dried (MgSO4), and then evapo-
rated to give the crude product, which was further purified
by column chromatography and characterized as ethyl phenyl
thiocarbonate (0.042 g, 54%). Colorless oil; 1H NMR (200 MHz,
CDCl3): δ 1.32 (t, J ) 7.4 Hz, 3 H), 4.30 (q, J ) 7.4 Hz, 2 H),
7.42 (m, 3 H), 7.53 (m, 2 H); GC/MS (EI, 70 eV) m/z 182 (M+),
123, 110, 109, 77, 65.
a
b
d
e
C6H5-
p-CH3C6H5
CH3(CH2)4
H
H
H
H
a
a
34.6
56
19.2b
-
(CH3)2CHCH2
a
b
Decomposed to compounds 11 and 15a ,b. Yield was based
on 1H NMR.
from the IR spectrum where a clear band at 1767 cm-1
was indicative of a carbonyl group.
Reaction of fluoromethyl phenyl sulfone with various
carbonyl compounds has already been studied by In-
basekaran et al.16 to prepare vinyl fluorides. Fluoro-
methyl phenyl sulfone has widely been exploited by
McCarthy’s group in the synthesis of 2′-deoxy-2′-fluoro-
methylene nucleosides as potential inhibitors of ribo-
nucleoside diphosphate reductase.4b
Con clu sion
In summary, we have developed a chlorofluoromethy-
lating agent, chlorofluoromethyl phenyl sulfone, and
studied its Darzens reaction, which differs from the
normal R-halosulfones. Alternatively it is a good method
for the preparation of R-fluoro epoxy sulfone. We have
also developed an alternative method for the synthesis
of fluoromethyl phenyl sulfone which is an important
reagent for introduction of fluoromethyl group in bioac-
tive organic molecules16,4 using relatively cheaper and
easily available starting material CFCl3. It is noteworthy
that there are two known methods for the preparation
of fluoromethyl phenyl sulfone which require costly,
explosive reagents, and exceptional dry conditions.16,17
Red u ction of 2a w ith TBTH (Bu 3Sn H) a n d AIBN. A
mixture of 2a (0.21 g, 1 mmol), tributyltin hydride (0.29 g, 1
mmol), AIBN (0.01 g), and benzene (10 mL) was refluxed under
nitrogen for 3 h. The mixture was evaporated under reduced
pressure and the residue was washed with aqueous NaHCO3
solution, extracted with ethyl acetate, dried (MgSO4), and
evaporated. The product was purified by column chromatog-
raphy to give 0.1 g (56% yield) of the reduced product 4 as an
Exp er im en ta l Section
The melting points are uncorrected. All reactions were
performed under an atmosphere of dry nitrogen, unless
otherwise stated. THF was distilled from sodium/benzophe-
1
oil. H NMR (200 MHz, CDCl3): δ 7.07 (d, J ) 55.8 Hz, 1 H,
-CHFCl), 7.4 (m, 3 H), 7.61 (m, 2 H); 19F NMR (188 MHz,
CDCl3, C6F6): δ 62.6 (d, J ) 55.8 Hz, 1 F, -CHFCl); GC/MS
(EI, 70 eV) m/z 176 (M+), 141, 125, 109, 77.
1
none ketyl. H NMR spectra were recorded in CDCl3 solution
at 200 MHz NMR machine using TMS as internal standard.
19F NMR spectra were recorded at 188 MHz using hexafluo-
robenzene as internal standard.
Oxid a tion of 2a w ith H2O2 a n d AcOH. A mixture of 2a
(0.50 g, 2.38 mmol), 30% H2O2 (2.57 mL, 22.7 mmol), and acetic
acid (2 mL) was stirred at room temperature for 36 h. The
reaction mixture was diluted with water, extracted with ethyl
acetate, washed with 10% sodium bicarbonate solution, dried
(MgSO4), and evaporated. Finally the product was purified by
column chromatography to give sulfone 7 (0.52 g, 90%) as
white solid; mp 32 °C; 1H NMR (200 MHz, CDCl3): δ 7.59 (m,
3 H), 7.83 (m, 2H); 19F NMR (188 MHz, CDCl3, C6F6): δ 99.29
(s, 1 F, -CFCl2); 13C NMR (50 MHz, CDCl3): δ 121.94 (d, J )
335.0 Hz), 129.44, 130.15, 131.79, 136.14; GC/MS (EI, 70 eV)
m/z 242 (M+), 141, 109, 77, 51 and sulfoxide (8) (0.03 g, 5%)
P r ep a r a tion of r-Ha loth ioeth er s: Syn th esis of Dich lo-
r oflu or om eth yl P h en yl Su lfid e (2a ). A mixture of diphenyl
disulfide (1.0 g, 4.58 mmol), sodium hydroxymethanesulfinate
(1.0 g, 8.47 mmol), CFCl3 (1.47 g, 10.8 mmol), DMF (10 mL),
and water (5 mL) was stirred at 4 atm of nitrogen for 48 h in
a pressure bomb. The reaction mixture was diluted with water
and extracted with ethyl acetate. The organic layer was
washed with 5% hydrochloric acid and then with 10% sodium
bicarbonate solution and dried over MgSO4. Solvent was
(16) Inbasekaran, M.; Peet, N. P.; McCarthy, J . R.; LeTourneau, M.
E. J . Chem. Soc., Chem. Commun. 1985, 678.
(17) (a) McCarthy, J . R.; Peet, N. P.; LeTourneau, M. E.; Inbaseka-
ran, M. J . Am. Chem. Soc. 1985, 107, 735. (b) More, K. M.; Wemple, J .
Synthesis 1977, 791.
1
as a gum; H NMR (200 MHz, CDCl3): δ 7.61 (m, 3 H), 7.84
(m, 2 H); 19F NMR (188 MHz, CDCl3, C6F6): δ 99.47 (s, 1 F,
-CFCl2); GC/MS (EI, 70 eV) m/z 226 (M+), 143, 125, 109, 97,
77.

Chemistry of Trichlorofluoromethane
J . Org. Chem., Vol. 66, No. 3, 2001 647
Oxid a tion of 4 w ith H2O2 a n d AcOH. A mixture of 4 (0.5
g, 2.84 mmol), 30% H2O2 (0.52 mL, 5.68 mmol), and acetic acid
(1 mL) was stirred at room temperature for 12 h. The reaction
mixture was diluted with water, extracted with ethyl acetate,
washed with 10% sodium bicarbonate solution, dried (MgSO4),
and evaporated. Finally the product was purified by column
warm to room temperature. After being stirred for 16 h, the
reaction mixture was poured into water, extracted with ethyl
acetate, and purified by column chromatography to give
compound 11 (0.039 g, 31%), and 14a (0.056 g, 25%) as a
diastereomeric mixture (2:3) as determined by 1H NMR
1
analysis; H NMR (200 MHz, CDCl3): δ 3.40 (d, J ) 3.2 Hz,
1
chromatography to give sulfone 9 (0.51 g, 86%) as a gum; H
0.4 H), 3.57 (d, J ) 4.0 Hz, 0.6 H), 5.45 (dd, J ) 20.6 and 3.2
Hz, 0.6 H), 5.58 (br, 0.4 H,), 7.12-7.94 (m, 10 H); 19F NMR
(188 MHz, CDCl3, C6F6): δ -33.8 (d, J ) 20.68 Hz, CClF),
-50.44 (s, CClF); GC/MS (EI, 70 eV) m/z 315 (M+ +1), 107,
79, 77, 51, and the compound 15a (0.05 g, 30%).
NMR (200 MHz, CDCl3): δ 6.54 (d, J ) 49.0 Hz, 1 H, -CHFCl),
7.61-7.80 (m, 3 H), 8.01 (m, 2 H); 13C NMR (50 MHz, CDCl3):
δ 104.4 (d, J ) 282.5 Hz), 129.45, 130.77, 132.01, 135.66; 19F
NMR (188 MHz, CDCl3, C6F6): δ 25.24 (d, J ) 49.1 Hz, 1 F,
CHFCl); GC/MS (EI, 70 eV) m/z 208 (M+), 141, 125, 109, 77,
65; and sulfoxide 10 (diastereomeric mixture (1:2) as deter-
Gen er a l P r oced u r e for th e P r ep a r a tion of Ep oxid e.
To a solution of halohydrine sulfone 14e (0.10 g, 0.34 mmol)
in dry THF (2 mL) was added sodium hydride (60% oil
suspension, 0.20 g, 0.5 mmol) at 0 °C and allowed to warm to
room temperature. After being stirred for 12 h, the reaction
mixture was filtered to remove a small amount of insoluble
material. Evaporation of the filtrate at reduced pressure and
purification of the residue on silica gel column gave 0.20 g
(56%) of the compound 13e as a diastereomeric mixture (1:3)
as determined by 1H NMR analysis; 1H NMR (200 MHz,
CDCl3): δ 0.97 (m, 6 H), 1.5-2.2 (m, 3 H), 4.34 (m, 0.25 H,
CHF), 4.48 (m, 0.75 H, CHF), 7.57-8.0 (m, 5 H); 19F NMR (188
MHz, CDCl3, C6F6): δ 52.26 (s, 0.58 F, OCF), 56.29 (d, J )
5.45, 0.42F, OCF), 13C NMR (50 MHz, CDCl3): δ 22.04, 22.96,
23.19, 24.12, 24.21, 24.36, 40.30, 40.46, 77.79, 77.24, 128.05,
128.99, 129.06, 129.12, 131.31, 135.15.
1
mined by 19F NMR analysis, 0.05 g, 9%) as a gum; H NMR
(200 MHz, CDCl3): δ 6.47 (d, J ) 50.6 Hz, 1 H, CHFCl), 6.46
(d, J ) 50.8 Hz, 1F, CHFCl), 7.53-7.64 (m,3 H), 7.75 (m, 2
H); 19F NMR (188 MHz, CDCl3, C6F6): δ 23.68 (d, J ) 50.19
Hz, 1 F, CHFCl), 23.49 (d, J ) 50.76 Hz, 1 F, CHFCl); GC/MS
(EI, 70 eV) m/z 192 (M+), 109, 77, 65.
Red u ction of 7 w ith Zin c a n d MeOH. A mixture of 7 (1.1
g, 4.54 mmol) and powdered zinc (0.86 g, 13.6 mmol) in
methanol (10 mL) was refluxed for 16 h. The solid material
was filtered and washed with ethyl acetate, and the combined
filtrate and washings were evaporated to dryness and purified
by column chromatography to give 0.60 g (76%) of sulfone 11
1
as a gum; H NMR (200 MHz, CDCl3): δ 5.13 (d, J ) 47.14
Hz, 1 H, -CH2F), 7.57-7.78 (m, 3 H), 7.94-7.98 (m, 2 H); 19
F
NMR (188 MHz, CDCl3, C6F6): δ -48.97 (t, J ) 46.43 Hz, 1
F, CH2F); GC/MS (EI, 70 eV) m/z 174 (M+), 141, 77, 51; and
sulfone 9 (0.15 g, 16%) as a gum.
Ack n ow led gm en t. This work was partially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science and Culture, J apan
(No. 10650834). We thank for the financial support by
Sumitomo Foundation. We are grateful to SC-NMR
Laboratory of Okayama University for the measurement
of NMR spectra. We also thank Miss Kaori Hashimoto
for the preliminary experiments.
Gen er a l P r oced u r e for th e Da r zen s Con d en sa tion
u n d er P h a se-Tr a n sfer Con d ition s. Compound 9 (0.16 g,
0.76 mmol), THF (5 mL), TEBA (0.01 g), 50% NaOH (0.4 mL),
and benzaldehyde (0.08 g, 0.76 mmol) were stirred at room
temperature for 4 h. The product was isolated and purified by
column chromatography to give compound 11 (0.021 g, 15.0%)
and the compound 15a (0.028 g, 15.0%) as a white solid; mp
143 °C (lit.18 144.5-146 °C); 1H NMR (200 MHz, CDCl3): δ
5.21 (s, 2 H), 7.57-7.78 (m, 3 H), 7.94-7.98 (m, 2 H).
Gen er a l P r oced u r e for th e Da r zen s Con d en sa tion
w ith Bu tOK. To a solution of sulfone 9 (0.15 g, 0.72 mmol) in
dry THF (1 mL) was added potassium tert-butoxide (0.11 g,
1.0 mmol) at -30 °C and stirred for 10 min, and then
benzaldehyde (0.07 g, 0.7 mmol) was added and allowed to
Su p p or tin g In for m a tion Ava ila ble: 19F NMR spectra of
compounds 2a -d , 7, 8, 9, 10, 11, 13e, 14a , 14d , 14e; 13C NMR
1
spectra of compounds 7, 9, 13d , 14b, 14d , 14e, 16; H NMR
spectra of compounds 9, 11, 13d , 13e, 14a , 14b, 14d , 14e, 16;
IR spectra of compounds 13d and 18d (as a mixture) and
spectral data of the compounds 2b, 2c, 2d , 13d , 14b, 14d , 14e,
15b, 15c, 16, 17, and 18d (13d and 18d as a mixture). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Squire, J . M.; Waters, W. A. J . Chem. Soc. 1962, 2068.
(19) Bordwell, F. G.; Bares, J . E.; Bartmess, J . E.; McCollum, G. J .;
Puy, M. V. D.; Vanier, N. R.; Matthews, W. S. J . Org. Chem. 1977, 42,
321.
(20) Correa, C. M. M. d. S.; Lindsay, A. S.; Waters, W. A. J . Chem
Soc. (C) 1968, 1872.
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