Synthesis and optical activity of difluoro(organylsulfinyl)acetic acids and their esters

Article abstract of DOI:10.1016/S0040-4039(02)00431-8

Representatives of a new type of optically active sulfur(IV) compound, arylsulfinyldifluoroacetic acids, have been prepared.

Full text of DOI:10.1016/S0040-4039(02)00431-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2949–2952
Synthesis and optical activity of difluoro(organylsulfinyl)acetic
acids and their esters
Andrej V. Matsnev, Nataliya V. Kondratenko, Yurii L. Yagupolskii* and Lev M. Yagupolskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya St., 02094 Kiev, Ukraine
Received 23 July 2001; revised 18 February 2002; accepted 1 March 2002
Abstract—Representatives of a new type of optically active sulfur(IV) compound, arylsulfinyldifluoroacetic acids, have been
prepared. © 2002 Elsevier Science Ltd. All rights reserved.
Optically active sulfoxides comprise an important
group of chiral organosulfur compounds. They are used
in asymmetric synthesis and in stereochemical research
as model compounds.1
use of methyl chlorodifluoroacetate in this reaction led
to alkylation products of the arenethiolates, i.e. to
methylthioarenes.3 Burton obtained ethyl difluoro-
(phenylthio)acetate 1b by reacting ethyl bromodi-
fluoroacetate with sodium benzenethiolate in dimethyl-
formamide.4 We have found that ethyl difluoroiodo-
acetate, like perfluoroalkyl iodides,5 reacts under mild
conditions with alkane-, arene- or heteroarene-
thiolates in dimethylformamide, in the presence of base
to give the corresponding sulfides 1 (Scheme 1).6a
Fluorine-containing, optically active, sulfoxides with a
perfluoroalkyl group immediately bonded to the sulfur
atom are unknown. Meanwhile the synthesis of such
compounds is of great interest. The presence of a
difluoromethylene group at the chiral sulfur atom may
allow one to monitor the optical activity and purity of
the compounds by the NMR spectroscopy. The alkyl or
aryl trifluoromethyl sulfoxides that we have synthesized
earlier,2 are unsuitable for verifying this suggestion as
the fluorine atoms of the trifluoromethyl groups are
equivalent and give only one singlet signal in 19F NMR
Attempts to oxidize sulfide 1c with chlorine in the
presence of SbCl5, as described in Ref. 2c, were not
spectra. The spectra of sulfoxides with
a
difluoromethylene unit, RS(O)CF2R%, should be more
informative in this respect. Their fluorine atoms are
magnetically non-equivalent and this can be used to
check the stereochemical nature of the molecules by 19F
NMR spectroscopy.
In order to reveal the supposed optical asymmetry in
the fluorine-containing sulfoxides, we decided to syn-
thesize the previously unknown arylsulfinylacetic acids
RS(O)CF2COOH.
Scheme 1. Reaction of thiolates with ethyl difluoroiodo-
acetate.
At first we prepared the starting arylthiodifluoroace-
tates by heating the corresponding sodium arenethiol-
ates with phenyl or sodium chlorodifluoroacetates. The
Keywords: synthesis; optically active sulfoxides; difluoro(organylsulfi-
nyl)acetic acids.
* Corresponding author. Tel.: 380(44)5590349; fax: 380(44)5732643;
e-mail: yurii@fluor-ukr.kiev.ua
Scheme 2. Ethyl difluoro(organylsulfinyl)acetates 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00431-8

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A. V. Matsne6 et al. / Tetrahedron Letters 43 (2002) 2949–2952
Scheme 3. Preparation of difluoro(organylsulfinyl)acetic acids 3.
successful. Sulfoxide 2c was obtained by this procedure
in a low 35% yield. The major product of the reaction
was 4-chlorobenzenesulfonyl chloride, even on oxida-
tion at 0°C with a stoichiometric amount of chlorine
gas. We managed to prepare sulfoxides 2a–f in high
yields by oxidation of sulfides 1a–f with meta-chloro-
perbenzoic acid (MCPBA) in dichloromethane (Scheme
2).6b Ethyl arylthiodifluoroacetates are oxidized under
these conditions more easily than the corresponding
aryl trifluoromethyl sulfides. Thus, phenyl trifluoro-
methyl sulfide was oxidized to the sulfoxide with
MCPBA at 0°C. Sulfide 1b is transformed into sulfox-
ide 2b at −5°C while at 0°C the major product is the
corresponding sulfone.
to −85 ppm disappears, giving rise to an AB pattern at
−108 to −112 ppm corresponding to the sulfoxide. The
sulfones display a singlet between −109 and −110 ppm.
To obtain optically active sulfoxides from acids 3b–e,
we prepared their salts 6b–e with (R)-(+)-a-methylben-
zylamine (Scheme 5).6d
Salts 6 were formed as viscous oils in nearly quantita-
tive yields. They possess two chiral centers and are a
mixture of two diastereomers in the ratio of 1:1, as
determined from their 19F NMR spectra which display
two AB patterns.
Salt 6c was separated into two individual crystalline
diastereomers 7c and 8c by fractional crystallization
from anhydrous benzene and benzene/hexane. The 19F
NMR spectra of the diastereomers correspond to par-
ticular AB patterns in the spectrum of the starting salt
6c.
Esters 2a–f were saponified, with sodium trimethylsi-
lanolate in benzene (method A) or with ethanolic
sodium hydroxide (method B), into the corresponding
sodium difluoro(organylsulfinyl)acetates and converted
further into free acids 3a–f by acidification (Scheme
3).6c
Salt 6d was separated by crystallization into pure oily
diastereomer (−,+)-8d and crystalline substance (+,+)-7d
(optical purity of about 60% ee). Salts 6 and their
diastereomers are characterized in Table 1.6d
In order to compare the spectroscopic data, the known
compound, ethyl 4-chlorophenylsulfonyldifluoroacetate
4c and the corresponding acid 5c were prepared
(Scheme 4).3a,4
Table 1. Characterization of salts 6–8 RS(O)CF2COO−
+NH3CH(CH3)Ph
Scheme 4.
Entry
Salt
R
Mp (°C)
The 19F NMR spectra of sulfides 1a–f and sulfones 4c,
5c show singlets due to the magnetically equivalent
fluorine atoms of the difluoromethylene groups,
whereas the spectra of sulfoxides 2a–f and 3a–f present
an AB pattern due to the diastereotopic nature of their
fluorine atoms.
1
2
3
6b
6c
6d
Ph
Oil
Oil
Oil
4-ClC6H4
4-MeOC6H4
4
6e
Oil
5
6
7
8
7c
7d
8c
8d
4-ClC6H4
4-MeOC6H4
4-ClC6H4
135–136
126–128
129–130
Oil
The analysis of the 19F NMR spectra makes it possible
to control the oxidation of sulfides 1 and the purity of
the products. As the oxidation proceeds, the singlet
signal of the CF2 group in the starting sulfides 1 at −79
4-MeOC6H4
Scheme 5. Preparation of amine salts 6.

A. V. Matsne6 et al. / Tetrahedron Letters 43 (2002) 2949–2952
Table 2. Characterization of optically active acids 9 and 10
2951
Entry
Acid
R
Mp (°C)
Specific rotation [h]2D0 (c 0.01, EtOH)
1
2
3
4
9c
9d
10c
10d
4-ClC6H4
4-MeOC6H4
4-ClC6H4
147–148
133–134
145–146
134–135
+142.5
+78.5
−136.2 (eeꢀ95%)
−55.2 (eeꢀ60%)
4-MeOC6H4
The diastereomeric salts 7c,d and 8c,d were trans-
formed, by acidification, into the corresponding free
acids 9 and 10 (Table 2),6e which are the first represen-
6. General procedures. (a) Preparation of sulfides 1: A solu-
tion of ethyl difluoroiodoacetate (0.075 mol) in DMF (5
mL) and triethylamine (0.05 mol) were added to a solution
of the appropriate thiol (0.05 mol) in DMF (7 mL) under
a flow of argon, at 3–5°C. The mixture was treated as
indicated in Scheme 1, poured onto ice, and extracted with
CH2Cl2. The extract was washed with water, dried
(MgSO4), and concentrated in vacuum. Sulfides 1 were
isolated by distillation or crystallization (for 1e). Bp (torr)/
mp (°C): 1a 35 (0.1), 1b 56 (0.01), 1c 82 (0.01), 1d 75
(0.01), 1e 56, 1f 86 (0.01). 19F NMR (CDCl3) l (ppm/
CF3Cl): 1a −81.3 (s, 2F), 1b −79.9 (s, 2F), 1c −82.9 (s, 2F),
1d −81.9 (s, 2F), 1e −82.7 (s, 2F), 1f −85.3 (s, 2F).
tatives of optically active sulfoxides with
a
fluoroalkylene group at the sulfur atom. Therefore, to
prove the optical purity of sulfoxides 9,10 we obtained
the
ing them with
19F NMR spectra of 9c-
L
-menthyl esters of the appropriate acids by react-
-menthol in the presence of DCC.6f The
-menthyl ester showed only
L
L
two doublets, at l (ppm/CF3Cl): −101.7 (d, 2F, J=220
Hz); −105.1 (d, 2F, J=220 Hz), whereas the spectrum
of 10c-L-menthyl ester presented not only signals of the
major diastereomer at l (ppm/CF3Cl): −107.7 (d, 2F,
J=220 Hz); −112.5 (d, 2F, J=220 Hz), but also minor
ones (ꢀ3%).
(b) Preparation of sulfoxides 2: To a cooled solution of
sulfide 1 (5 mmol) in anhydrous CH2Cl2 (7 mL) was added
MCPBA (10 mmol, in a 50% concentration basis). The
reaction conditions are presented in Scheme 2. The reac-
tion mixture was filtered while cold. The filtrate was
washed with a cold saturated solution of NaHCO3 (4×5
mL), water and dried (MgSO4). After removal of the
solvent, the product was purified by silica gel chromatog-
raphy or crystallization. Mp (°C): 2a oil, 2b oil, 2c 20,
2d 26, 2e 53, 2f 43. 19F NMR (CDCl3) l (ppm/CF3Cl):
2a −106.4 (d, 2F, J=234 Hz), −111.5 (d, 2F, J=234 Hz);
2b −110.3 (d, 2F, J=227 Hz), −111.8 (d, 2F, J=227 Hz);
2c −110.6 (d, 2F, J=228 Hz), −112.3 (d, 2F, J=228 Hz);
2d −111.4 (d, 2F, J=229 Hz), −113.5 (d, 2F, J=229 Hz);
2e −105.6 (d, 2F, J=209 Hz), −111.2 (d, 2F, J=209 Hz);
2f −104.5 (d, 2F, J=224 Hz), −110.2 (d, 2F, J=224 Hz).
(c) Preparation of difluoro(organylsulfinyl)acetic acids 3.
Method A: To a solution of ethyl difluoro(organylsulfi-
nyl)acetate 2 (5 mmol) in anhydrous benzene (7 mL) was
added Me3SiONa (5 mmol) and the mixture was heated at
70°C for 2.5 h. After being cooled, the reaction mixture
was filtered, the solid residue was dissolved in a minimum
amount of water and acidified to pH 4–5. The product was
taken up in CH2Cl2 (3×5 mL). The extract was washed
with a small amount of ice-cold water, dried (MgSO4), and
concentrated. The title acids were purified by crystalliza-
tion. Method B: Ester 2 (5 mmol) was added to the
calculated amount of 40% ethanolic NaOH and the mix-
ture was heated at 40°C for 4 h. Ethanol was removed by
vacuum distillation, the residue was dissolved in a small
amount of water and the resulting solution was acidified to
pH 4–5. The product was isolated as in Method A. Mp
(°C): 3a oil, 3b 77–78, 3c 132–134, 3d 147(dec), 3e 150–152,
3f 160(dec). 19F NMR (CDCl3) l (ppm/CF3Cl): 3a −103.6
In summary we have demonstrated a method for the
synthesis of previously unknown difluoro(organylsul-
finyl)acetic acids and their esters. The fluorine atoms of
the difluoromethylene group bonded to the optically
active sulfur atom are magnetically non-equivalent.
Optically active sulfoxides with a fluorinated alkyl sub-
stituent in the a-position with respect to the sulfinyl
group have been obtained for the first time through
separation of the diastereomeric salts of the corre-
sponding arylsulfinyldifluoroacetic acids with (R)-(+)-a-
methylbenzylamine.
References
1. Drabowicz, J.; Kielbasinski, P.; Mikolajczyk, M. In The
Chemistry of Sulphones and Sulphoxides; Patai, S.; Rappo-
port, Z.; Stirling, C. J. M., Eds. Synthesis of sulphoxides.
John Wiley & Sons: Chichester, 1988; pp. 212–423.
2. (a) Yagupolskii, L. M.; Marenets, M. S.; Kondratenko, N.
V. Zh. Obshch. Khim. 1965, 35, 377–387; (b) Yagupolskii,
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Kondratenko, N. V.; Movchun, V. N.; Yagupolskii, L. M.
Zh. Org. Khim. 1989, 25, 1116–1117.
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A. Zh. Obshch. Khim. 1969, 39, 202–205.
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A. V. Matsne6 et al. / Tetrahedron Letters 43 (2002) 2949–2952
(d, 2F, J=237 Hz), −112.8 (d, 2F, J=237 Hz); 3b −104.8
diastereomer were filtered off and the second diastereomer
was precipitated from the filtrate with anhydrous hexane.
(e) Typical procedure for the preparation of acids 9 and 10:
A solution of salt 8c (5 mmol) in a minimum amount of
water was acidified with concentrated HCl to pH 4–5, and
the product was extracted with diethyl ether (3×5 mL).
The extract was washed with a small amount of ice-cold
water, dried (MgSO4), and evaporated to give pure acid
9c.
(d, 2F, J=228 Hz), −111.7 (d, 2F, J=228 Hz); 3c −104.4
(d, 2F, J=226 Hz), −112.5 (d, 2F, J=226 Hz); 3d −105.4
(d, 2F, J=227 Hz); −112.3 (d, 2F, J=227 Hz); 3e −104.7
(d, 2F, J=212 Hz), −112.9 (d, 2F, J=212 Hz); 3f −103.5
(d, 2F, J=232 Hz), −111.4 (d, 2F, J=232 Hz).
(d) Preparation of salts 6–8: To a solution of the appropri-
ate acid 3 (5 mmol) in anhydrous diethyl ether (5 mL) was
added (R)-(+)-a-methylbenzylamine (5 mmol) dissolved in
the same solvent (3 mL). The mixture was allowed to
stand for 4 h, after which time the supernatant liquid layer
was carefully decanted. The oily residue was washed with
a small amount of anhydrous diethyl ether and dried
under oil pump vacuum. The dried residue was mixed with
anhydrous benzene (3 mL) and set aside for 48 h to
crystallize. The precipitated fine crystals of one
(f) A mixture of 9c or 10c, L-menthol and DCC in pyridine
in the presence of p-toluenesulfonic acid was stirred for 24
h, filtered and acetic acid added. After stirring for a
further 12 h, the mixture was filtered, extracted with
CH2Cl2, dried and evaporated to afford the corresponding
ester. Mp (°C) for
L-menthyl ester of acid 9c=108, for
L
-menthyl ester of acid 10c=76.