Synthesis and optical activity of aryl(N-trifluoromethylsulfonylimino) thiodifluoroacetic acids and their derivatives

Article abstract of DOI:10.1016/S0022-1139(03)00158-1

Synthesis and ¹⁹F NMR studies of a new type of optically active sulfur(IV) compounds-aryl(N-trifluoromethylsulfonylimino) thiodifluoroacetic acids and their derivatives are described.

Full text of DOI:10.1016/S0022-1139(03)00158-1

Journal of Fluorine Chemistry 123 (2003) 287–290
Short communication
Synthesis and optical activity of
aryl(N-trifluoromethylsulfonylimino)thiodifluoroacetic
acids and their derivatives
Andrei V. Matsnev1, Natalya V. Kondratenko, Lev M. Yagupolskii*
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya St., 02094 Kiev, Ukraine
Received 7 April 2003; received in revised form 29 May 2003; accepted 4 June 2003
Abstract
Synthesis and 19F NMR studies of a new type of optically active sulfur(IV) compounds—aryl(N-trifluoromethylsulfonylimino)thiodi-
fluoroacetic acids and their derivatives are described.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Synthesis; Aryl(N-trifluoromethylsulfonylimino)thiodifluoroacetic acids; Optical asymmetry; Trifluoromethyl group
1. Introduction
asymmetry of a-fluoroalkyl substituted sulfinylimino deri-
vatives.
In our previous work we described preparation of a new
type of optically active sulfur(IV) derivatives—organylsul-
foxydifluoroacetic acids [1]. These compounds have a
difluoromethylene group attached to the chiral center, and
it was found that their optical purity could be easily con-
The starting compounds were ethyl esters of aryldifluor-
oacetic acids, which were converted to their corresponding
sulfimides using the dichloroimide of trifluoromethanesul-
fonic acid as an imination reagent, as it was shown before on
aryltrifluoromethyl sulfides [5].
However, all attempts to convert the ethyl esters to the
corresponding acids without the destruction of S¼NSO2CF3
bond by hydrolysis in acidic or basic conditions were
unsuccessful.
Therefore, the synthesis of analogous tert-butyl esters was
carried out. However, we were not able to synthesize such
type of compounds by the reaction of thiophenols with tert-
butyl ester of iododifluoroacetic acid as the later one appears
to be hydrolytically and thermally unstable compound.
Arylthiodifluoroacetates (1) were synthesized by the
reaction of acidic chloroanhydrides [1] and tert-butyl alco-
hol in the presence of Et3N as a base (Scheme 1).
Compounds 1a–f were reacted with N,N-dichloroimide
of trifluoromethanesulfonic acid [6] at mild conditions
(0–20 8C) with the formation of derivatives 2a–f in high
yields (Scheme 2). Esters 2a–f given in NMR 19F spectra
signals of AB-system that belongs to difluoromethylene
group with magnetically non-equivalent fluorine atoms.
Thermolyses of esters 2a–f for 10–12 h at 85–97 8C gave
acids 3a–f in high yields (65–70%) (Scheme 3).
In order to investigate the optical asymmetry of synthe-
sized sulfinylimines compounds 3c and e were reacted with
trolled by monitoring of diastereotopic fluorine atoms by 19
F
NMR spectroscopy.
Exchange of the oxygen atom with the more electron
withdrawing ¼NSO2CF3 group commonly leads to the
formation of derivatives with unusual properties [2–4].
Therefore, it was interesting to study the possibility of
preparing the optically active nitrogen analogs of sulfoxides
containing trifluoromethylsulfonylimino group instead of
oxygen atom.
Earlier we described the synthesis of (N-trifluoromethyl-
sulfonyl)aryltrifluoromethylsulfimides [5]. However, these
compounds have chiral sulfur attached to the trifluoromethyl
group with magnetically equivalent fluorine atoms. There-
fore, our aim in this work was to synthesize aryl(N-trifluor-
omethylsulfonylimino)thiodifluoroacetic acids and their
amides as model compounds for investigation of optical
* Corresponding author. Tel.: þ380-44-5590349;
fax: þ380-44-5732643.
E-mail addresses: matsnev@bpci.kiev.ua (A.V. Matsnev),
yurii@fluor-ukr.kiev.ua (L.M. Yagupolskii).
1 Co-corresponding author. Tel.: þ380-44-5510669;
fax: þ380-67-7581863.
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00158-1

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A.V. Matsnev et al. / Journal of Fluorine Chemistry 123 (2003) 287–290
O
benzene
rt
O
+ Et3NHCl
+ t-BuOH + Et3N
ArSCF2C
ArSCF2C
OBu-t
Cl
1 a - f
1a: Ar = Ph
1d: Ar = 4-BrC6H4
1b: Ar = 4-FC6H4 1e: Ar = 4-CH3OC6H4
1c: Ar = 4-ClC6H4 1f: Ar = 4-O2NC6H4
Scheme 1. Synthesis of tert-butyl esters of arylthiodifluoroacetic acids.
NSO2CF3
ArSCF2COOBu-t
2 a-f
The diastereomers were separated by column chromato-
graphy using hexane–iso-propanol mixture as an eluent
giving two individual compounds (6) and (7) with 98%
purity (monitored by 19F NMR spectroscopy).
pentane, 0-20 oC
5 h
1 a-f
+ CF3SO2NCl2
Cl2
+
In the current paper, the synthesis of aryl(N-trifluoro-
methylsulfonylimino)thiodifluoroacetic acids and their deri-
vatives are described. It was shown that fluorine atoms of
difluoromethylene groups in these compounds are magne-
tically non-equivalent and are presented as AB-system in
NMR 19F spectra. The new type of optically active sul-
fur(IV) derivatives—N-trifluoromethylsulfonylimides with
fluorinated group attached to a-position to the chiral center
are described.
Scheme 2. Preparation of tert-butyl esters of aryl(N-trifluoromethylsulfo-
nylimino)thiodifluoroacetic acids (2).
NSO2CF3
H3C
+
2a-f
CH2
ArSCF2COOH
H3C
3a-f
Scheme 3. Preparation of aryl(N-trifluoromethylsulfonylimino)thiodi-
fluoroacetic acids (3).
2. General procedures
(R)(þ)-a-methylbenzylamine; the corresponding salts as a
mixture of diastereomers were prepared. In the NMR
19F spectra of diastereomeric salts, the signals of difluor-
omethylene groups are observed as a single AB-system, that
does not permit to use this salts for isomers separation.
Therefore, the synthesis of the (R)(þ)-a-methylbenzylamide
of aryl(N-trifluoromethylsulfonylimino)thiodifluoroacetic
acid (5) by the imination reaction of the amide (4) was
carried out; the amide (4) was prepared by the reaction of
chloroanhydrides 4-chlorophenylthiodifluoroacetic acid and
(R)(þ)-a-methylbenzylamine (Scheme 4).
2.1. Preparation of tert-butyl esters of
arylthiodifluoroacetic acids (1)
Forty millimoles of thionyl chloride was added to
20 mmol of the corresponding arylthiodifluoroacetic acid
at 0 8C. The reaction mixture was slowly warmed to room
temperature and stirred at 60 8C till gas evolution had
ceased. All volatile compounds were removed in vacuum,
and the residue was dissolved in dry benzene. To this
residue, 20 mmol of Et3N and 40 mmol of dry tert-butanol
were added at 10 8C. The reaction mixture was stirred for
additional 12 h. The volatile compounds were evaporated
away, and the residue was washed with water, extracted
with dichloromethane, and dried over MgSO4. Solvent
was evaporated, and the crude product purified by column
The NMR 19F investigations of amide (5) showed the
formation of two diastereomers in a 1:1 proportion and
which were presented on the spectra as two AB-systems
with J1(FF) coupling constants of 198 and 201 Hz, respec-
tively.
O
O
Et3N
H
4 - ClC6H4SCF2C
+
(+) H2N
C
C6H5
4 - ClC6H4SCF2C
CH3
Cl
NH(CH3)CHC6H5
4
NSO2CF3
O
O
4 - ClC6H4SCF2C
4 - ClC6H4SCF2C
CF3SO2NCl2
+
NH(CH3)CHC6H5
NH(CH3)CHC6H5
4
5
Scheme 4. Preparation of (R)(þ)-a-methylbenzylamide of aryl(N-trifluoromethylsulfonylimino)thiodifluoroacetic acid (5).

A.V. Matsnev et al. / Journal of Fluorine Chemistry 123 (2003) 287–290
289
chromatography using hexane–benzene mixture as an eluent;
mp (8C): 1a (oil), 1b (oil), 1c (oil), 1d (oil), 1e (oil), 1f (46).
2.2.3. (2c) 4-ClC6H4S(NSO2CF3)CF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.60 (s, 9H), 7.66–7.85 (m,
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À78.4 (s, 3F),
2.1.1. (1a) C6H5SCF2COOBu-t
1
À96.4 (d, 2F, JFF ¼ 207 Hz), À103.4 (d, 2F, JFF
¼
NMR H (CDCl3/CCl3F) d: 1.42 (s, 9H), 6.25–6.47 (m,
207 Hz). Analytically calculated for C13H13ClF5NO4S2:
C, 35.34; H 2.97; S 14.51. Found: C, 35.20; H, 3.04; S,
14.54.
5H); NMR 19F (CDCl3) d (ppm/CCl3F): À79.80 (s, 2F).
2.1.2. (1b) 4-FC6H4SCF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.36 (s, 9H), 6.92–7.54 (m,
2.2.4. (2d) 4-BrC6H4S(NSO2CF3)CF2COOBu-t
1
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À80.5 (s, 2F),
À104.73 (s, 1F).
NMR H (CDCl3/CCl3F) d: 1.62 (s, 9H), 7.73–7.85 (m,
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À77.7 (s, 3F), À97.1
(d, 2F, JFF ¼ 206 Hz), À102.7 (d, 2F, JFF ¼ 206 Hz). Ana-
lytically calculated for C13H13BrF5NO4S2: C, 32.11; H, 2.89;
S, 13.19. Found: C, 32.25; H, 2.90; S, 13.16.
2.1.3. (1c) 4-ClC6H4SCF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.49 (s, 9H), 7.58–7.82 (m,
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À80.12 (s, 2F).
2.2.5. (2e) 4-CH3O C6H4S(NSO2CF3)CF2COOBu-t
1
2.1.4. (1d) 4-BrC6H4SCF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.61 (s, 9H), 3.2 (s, 3H),
NMR H (CDCl3/CCl3F) d: 1.51 (s, 9H), 7.71–7.85 (m,
7.70–7.79 (m, 4H); NMR 19F (CDCl3) d (ppm/CCl3F):
À78.1 (s, 3F), À94.2 (d, 2F, JFF ¼ 210 Hz), À102.4 (d,
2F, JFF ¼ 210 Hz). Analytically calculated for C14H16F5-
NO4S2: C, 38.44; H, 3.69; S, 14.66. Found: C, 38.72; H,
3.77; S, 14.65.
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À81.1 (s, 2F).
2.1.5. (1e) 4-CH3O C6H4SCF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.54 (s, 9H), 2.98 (s, 3H),
7.56–7.67 (m, 4H); NMR 19F (CDCl3) d (ppm/CCl3F):
À81.2 (s, 2F).
2.2.6. (2f) 4-O2N C6H4S(NSO2CF3)CF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.60 (s, 9H), 8.12–8.52 (m,
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À78.3 (s, 3F),
2.1.6. (1f) 4-O2N C6H4SCF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.48 (s, 9H), 7.78–8.23 (m,
À95.4 (d, 2F, JFF ¼ 203 Hz), À101.3 (d, 2F, JFF ¼
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À80.92 (s, 2F).
203 Hz). Analytically calculated for C13H13F5 N2O6S2: C,
34.51; H, 2.89; S, 14.17. Found: C, 34.43; H, 2.90; S, 14.40.
2.2. Preparation of tert-butyl esters of aryl(N-
trifluoromethylsulfonyl)thiodifluoroacetic acids (2)
2.3. Preparation of aryl(N-trifluoromethylsulfonyl)-
thiodifluoroacetic acids (3)
To the solution of 5 mmol of tert-butyl ester of arylthiodi-
fluoroacetic acid (1) 5.5 mmol of CF3SO2NCl2 was added at
0 8C. The reaction mixture was slowly warmed to room
temperature and stirred till gas evolution had ceased. After
3–4 h, the oily residue solidifies. The crude product was
filtered off, washed with pentane (5 ml), H2O (2 Â 10 ml),
and, finally, dried over potassium hydroxide. Yield:
95–98%. All the tert-butyl esters are solids, slowly decom-
posing at 60–90 8C with the formation of acids (3).
Ten millimoles of the corresponding tert-butyl ester (2)
was stirred for 10 h at 85–97 8C. At room temperature 5 ml
of H2O was added. The water phase was extracted with
dichloromethane (2 Â 5 ml). The organic fractions were
combined and washed with 5 ml of water. The combined
water fractions were evaporated in vacuum and the residue
washed with dry benzene (2 Â 5 ml). Yields of the acids (3):
55–70%; mp (8C): 3a, 120–121; 3b, 127–128; 3c, 130–132;
3d, 134–135; 3e, 79–80; 3f, 154–155.
2.2.1. (2a) C6H5S(NSO2CF3)CF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.45 (c, 9H), 7.23–7.45 (m,
2.3.1. (3a) C6H5S(NSO2CF3)CF2COOH
1
5H); NMR 19F (CDCl3) d (ppm/CCl3F): À76.9 (s, 3F), À94.1
(d, 2F, JFF ¼ 208 Hz), À103.6 (d, 2F, JFF ¼ 208 Hz). Ana-
lytically calculated for C13H14F5NO4S2: C, 38.32; H, 3.44; S,
15.72. Found: C, 38.44; H, 3.45; S, 15.76.
NMR H (CDCl3/CCl3F) d: 1.45 (s, 9H), 6.23–6.45 (m,
5H); NMR 19F (CDCl3) d (ppm/CCl3F): À76.9 (s, 3F), À94.1
(d, 2F, JFF ¼ 207 Hz), À103.6 (d, 2F, JFF ¼ 207 Hz); IR: nas
ðSO2Þ ¼ 1350, ns ðSO2Þ ¼ 1020, n ðS¼NÞ ¼ 1450, nas
ðC¼OÞ ¼ 1780, nas ðOHÞ ¼ 1230, n ðCF3Þ ¼ 1225. Analy-
tically calculated for C9H6F5NO4S2: C, 30.77; H, 1.71; S,
18.23. Found: C, 30.79; H, 2.20; S, 18.23.
2.2.2. (2b) 4-FC6H4S(NSO2CF3)CF2COOBu-t
1
NMR H (CDCl3/CCl3F) d: 1.48 (s, 9H), 7.37–7.92 (m,
4H); NMR 19F (CDCl3) d (ppm/CCl3F): À79.4 (s, 3F),
À102.45 (s, 1F), À98.9 (d, 2F, JFF ¼ 199 Hz), À99.9 (d,
2F, JFF ¼ 199 Hz). Analytically calculated for C13H13-
F6NO4S2: C, 36.71; H, 3.06; S, 15.06. Found: C, 36.44;
H, 2.89; S, 14.96.
2.3.2. (3b) 4-FC6H4S(NSO2CF3)CF2COOH
1
NMR H (CDCl3/CCl3F) d: 7.39–7.95 (m, 4H); NMR
19F (CDCl3) d (ppm/CCl3F): À79.4 (s, 3F), À98.9 (d, 2F,
JFF ¼ 208 Hz), À104.7 (d, 2F, JFF ¼ 208 Hz), À100.7

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(s, 1F). Analytically calculated for C19H5F6NO4S2:C, 29.27;
H, 1.36; S, 17.34. Found: C, 29.30; H, 1.42; 17.54.
87%; mp (8C): 135–136. NMR 1H (CDCl3) d (ppm/CCl3F):
1.40 (d, 3H), 4.98 (m, 1H), 6.2 (s, 2H), 7.11–7.58 (m, 9H);
NMR 19F (CDCl3) d (ppm/CCl3F): À83.2 (s, 2F). Analyti-
cally calculated for C16H14ClF2NOS: C, 56.30; H, 4.10; N,
4.11. Found: C, 56.41; H, 4.20; N, 3.95.
2.3.3. (3c) 4-ClC6H4S(NSO2CF3)CF2COOH
NMR 1H (CDCl3/CCl3F) d: 8.36–8.64 (m, 4H); NMR 19
F
(CDCl3) d (ppm/CCl3F): À78.3 (s, 3F), À96.4 (d, 2F,
JFF ¼ 209 Hz), À104.2 (d, 2F, JFF ¼ 209 Hz). Analytically
calculated for C9H5ClF5NO4S2: C, 28.02; H 1.30; S 16.60.
Found: C, 28.25; H, 1.27; S, 16.51.
2.5. Reaction of amide (4) with N,N-dichloroamide of
trifluoromethanesulfonic acid
The method of preparation is analogous to (2). The oily
product was obtained as a mixture of two diastereomers. The
NMR 1H (CDCl3/CCl3F) d: NMR 1H (CDCl3) d (ppm/
CCl3F): 1.54 (d, 3H), 4.24 (m, 1H), 6.45 (s, 1H), 7.41–
7.68 (m, 9H); NMR 19F (CDCl3) d (ppm/CCl3F): À78.5 (s,
2.3.4. (3d) 4-BrC6H4S(NSO2CF3)CF2COOH
NMR 1H (CDCl3/CCl3F) d: 8.11 (s, 4H); NMR 19F
(CDCl3) d (ppm/CCl3F): À78.03 (s, 3F), À98.97 (d, 2F,
JFF ¼ 221 Hz), À101.88 (d, 2F, JFF ¼ 221 Hz). Analytically
calculated for C9H5BrF5NO4S2: C, 25.12; H, 1.16; S, 14.88.
Found: C, 24.94; H, 1.13; S, 14.91.
3F), À99.1 (d, 2F, JFF ¼ 198 Hz), À104.1 (d, 2F, JFF
¼
198 Hz); À78.6 (s, 3F), À99.2 (d, 2F, JFF ¼ 201 Hz),
À102.2 (d, 2F, JFF ¼ 201 Hz).
2.3.5. (3e) 4-CH3O C6H4S(NSO2CF3)CF2COOH
NMR 1H (CDCl3/CCl3F) d: 3.4 (s, 3H), 8.14–8.21
(m, 4H); NMR 19F (CDCl3) d (ppm/CCl3F): À78.0
(s, 3F), À98.2 (d, 2F, JFF ¼ 212 Hz), À104.2 (d, 2F,
JFF ¼ 212 Hz); IR: nas ðSO2Þ ¼ 1350, ns ðSO2Þ ¼ 1020, n
ðS¼NÞ ¼ 1490, nas ðC¼OÞ ¼ 1740, nas ðOHÞ ¼ 1190, n
ðCF3Þ ¼ 1140. Analytically calculated for C10H8F5NO4S2:
C, 31.50; H, 2.10; S, 16.80. Found: C, 31.72; H, 2.27; S,
16.65.
2.6. Separation of sulfinimino derivative (5) into the
individual diastereomers
The corresponding diastereomers were separated by col-
umn chromatography using hexane–iso-propanol (2%) mix-
ture as an eluent and taking fractions of 3 ml; mp (8C): 6, 94–
18
96; 7, 106–107. ½aꢀD (c 0.002, CHCl3): 6, þ163; 7, À94. 6,
1
NMR H (CDCl3) d (ppm/CCl3F): 1.53 (d, 3H), 4.21 (m,
1H), 6.44 (s, 1H), 7.41–7.68 (m, 9H); NMR 19F (CDCl3) d
(ppm/CCl3F): À78.5 (s, 3F), À99.1 (d, 2F, JFF ¼ 198 Hz),
À104.1 (d, 2F, JFF ¼ 198 Hz); 7, NMR 1H (CDCl3) d (ppm/
CCl3F): 1.55 (d, 3H), 4.26 (m, 1H), 6.43 (s, 1H), 7.41–7.68
(m, 9H); NMR 19F (CDCl3) d (ppm/CCl3F): À78.6 (s, 3F),
À99.2 (d, 2F, JFF ¼ 201 Hz), À102.2 (d, 2F, JFF ¼ 201 Hz).
Analytically calculated for C17H14ClF5N2O3S2: C, 41.80; H,
2.87; N, 5.74. Found: C, 41.96; H, 2.97; N, 5.86.
2.3.6. (3f) 4-O2N C6H4S(NSO2CF3)CF2COOH
NMR 1H (CDCl3/CCl3F) d: 8.12–8.52 (s, 4H); NMR 19
F
(CDCl3) d (ppm/CCl3F): À78.5 (s, 3F), À94.9 (d, 2F,
JFF ¼ 205 Hz), À100.7 (d, 2F, JFF ¼ 205 Hz). IR: nas
ðNO2Þ ¼ 1660, ns ðNO2Þ ¼ 1420, ns ðSO2Þ ¼ 1050, nas
ðC¼OÞ ¼ 1770, nas ðOHÞ ¼ 1250, n ðCF3Þ ¼ 1225. Analy-
tically calculated for C9H5F5N2O6S2: C, 27.27; H, 1.26; S,
16.16. Found: C, 27.30; H, 1.29; S, 16.40.
2.4. Preparation of aryl(N-trifluoromethylsulfonyl)-
thiodifluoroacetic acid amide (4)
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50 mmol of 4-chlorophenylthiodifluoroacetic acid at room
temperature. The reaction mixture was heated for 3 h at
60 8C (till gas evolution had ceased). All volatile compounds
were removed under vacuum, and the residue was dissolved
in benzene (10 ml). To residue in benzene 50 mmol of
(R)(þ)-a-methylbenzylamine and 50 mmol of Et3N were
added. The reaction mixture was stirred for additional 12 h.
The precipitate was filtered off and washed with dry benzene
(5 ml). The solvent was evaporated, and the crude product
was crystallized from benzene–hexane mixture. Yield of (4):
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