Study of reaction routes in sulfoination of 2-aminothiazoles with chlorosulfonic acid

Article abstract of DOI:10.1007/s11178-005-0073-6

The sulfonation of 4-substituted 2-aminothiazoles with chlorosulfonic acid under mild conditions afforded primarily 2-amino-5-thiazolesulfonic acids that at heating in sulfuric acid rearranged into the corresponding stable 2-thiazolesulfamoylic acids. 200

Full text of DOI:10.1007/s11178-005-0073-6

Russian Journal of Organic Chemistry, Vol. 40, No. 11, 2004, pp. 1647-1650. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 11,
004, pp. 1695-1698.
Original Russian Text Copyright Ó 2004 by Lyashchuk, Enya, Doroshenko, Skrypnik.
2
Study of Reaction Routes in Sulfoination of
-Aminothiazoles with ChlorosulfonicAcid
2
S.N. Lyashchuk, V.I. Enya, T.F. Doroshenko, andYu.G. Skrypnik
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of the Ukraine,
Donetsk, 83114 Ukraine
e-mail: lyaschuk@skif.net
Received June 24, 2003
Abstract-- The sulfonation of 4-substituted 2-aminothiazoles with chlorosulfonic acid under mild conditions afforded
primarily 2-amino-5-thiazolesulfonic acids that at heating in sulfuric acid rearranged into the corresponding stable 2-
thiazolesulfamoylic acids.
According to published data [1–5] two routes are
presumable for sulfonation of 4-substituted 2-amino-
thiazoles: into position 5 of the thiazole ring (electrophilic
substitution in an aromatic ring) (1), and at the amino group
Both Hurd et al. and Poplavskii et al. regarded the
reaction as analogous to the aniline sulfonation where
primarily an unstable benzenesulfamoylic acid arose. They
studied only the sulfonation of 2-aminothiazole and 2-
amino-4-methylthiazole that excluded the possibility to
make any general conclusions. Besides no spectral mea-
surements were performed on the reaction products in
these works preventing unambiguous identification of the
compounds synthesized.
(nucleophilic substitution at a sulfur atom) (2).
5
5
1
;ꢀꢀ62
;
1
(1)
+
1
+ 1
62 +
6
6
The target of this study was the investigation of the
route taken by sulfonation of some 4-substituted 2-
aminothiazoles with chlorosulfonic acid and also evalua-
tion of stability and possible rearrangements of the aris-
ing sulfonic acids.
5
5
1
;ꢀꢀ62
;
1
(2)
+
1
+2 61+
6
6
As objects of the study were chosen 4-substituted 2-
amino-5-thiazolesulfonic acids (I–IV) and 4-substituted
R = CH (I, V, IX), p-ClC H (II,VI, X), p-BrC H (III,VII,
3
6
4
6 4
XI), m-NO C H (IV,VIII, XII).
2
6 4
2-thi-azolesulfamoylic acids V–VIII prepared from the
corresponding 4-substituted 2-aminothiazoles IX–XII.
Besides at R = Ar the sulfonation of the aromatic
substituent can also occur.
5
5
1
1
The formulation of the conditions governing these
competing processes led to ambiguous conclusions [3–
]. For instance, according to [3, 4], the sulfonation of
-aminothiazole with the chlorosulfonic acid and oleum in
the cold gave rise solely to 2-thiazolesulfamic acid whose
high stability against hydrolysis was ascribed to its dipolar
structure.
+
1
62 + +2 61+
6
, ,9
6
5
2
9 9,,,
5
1
+ 1
6
,; ;,,
Later Poplavskii et al. [5] suggested that the sulfona-
tion of 2-aminothiazole with chlorosulfonic acid might in
this case occur in abnormal way into the position 5 of the
thiazole ring.
The sulfonation of 2-aminothiazoles substituted in
position 4 was carried out by adding them at cooling to
excess chlorosulfonic acid.
1070-4280/04/4011-1647Ó2004 MAIK “Nauka/Interperiodica”

1648
LYASHCHUK et al.
To avoid the possibility of sulfonation into the aromatic
Effective charges on atoms of compounds IX–XII
ring of the substituent R we limited the study to compounds
with electron-withdrawing substituents on the phenyl for
+HDWꢀRIꢀ
&
KDUJHꢀRQꢀDWRPꢀꢁ ꢂXꢂꢃꢀ
IRUPDꢄ
WLRQꢅꢀꢀ
N-ꢀ
they prevent the electrophilic substitution. With R = C H5
6
under the reaction conditions a mixture of sulfonation
products was obtained significantly complicating the
observed pattern.
6 ꢀ
& ꢀ
1 ꢀ
& ꢀ
& ꢀ
1
ꢀ
PRO ꢀ
,;ꢀ
ꢀ
ꢀ
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ꢆꢉꢇꢂꢊ ꢀꢈꢂꢍꢉꢎꢀ ±ꢈꢂꢈꢈꢌꢀ±ꢈꢂꢍꢏꢊꢀ ꢈꢂꢈꢆꢊ ꢀ± ꢈꢂꢌꢇꢇꢀ±ꢈꢂꢍꢊꢉꢀ
ꢊꢆꢋꢂꢌ ꢀꢈꢂꢏꢉꢏꢀ ±ꢈꢂꢌꢎꢍꢀ±ꢈꢂꢈꢋꢈꢀ±ꢈꢂꢈꢍꢏ ꢀ± ꢈꢂꢌꢋꢋꢀꢀꢀꢈꢂꢈꢇꢎꢀ
ꢍꢇꢎꢂꢏꢀ ꢈꢂꢌꢊꢎꢀ ±ꢈꢂꢆꢏꢇꢀ±ꢈꢂꢆꢋꢌꢀ±ꢈꢂꢈꢆꢏ ꢀ± ꢈꢂꢌꢏꢍꢀ±ꢈꢂꢍꢊꢍꢀ
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ꢎꢇꢆꢂꢈ ꢀꢈꢂꢏꢉꢍꢀ ±ꢈꢂꢌꢊꢎꢀ±ꢈꢂꢈꢌꢎꢀ ꢈꢂꢈꢍꢌ ꢀ± ꢈꢂꢌꢋꢍꢀꢀꢀꢈꢂꢈꢇꢊꢀ
ꢍꢊꢎꢂꢎꢀ ꢈꢂꢌꢎꢈꢀ ±ꢈꢂꢆꢏꢇꢀ±ꢈꢂꢆꢋꢇꢀ±ꢈꢂꢈꢍꢆ ꢀ± ꢈꢂꢌꢉꢎꢀ±ꢈꢂꢍꢊꢍꢀ
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The analysis of the spectra of the sulfonation prod-
ucts showed that in all cases only the sulfonation of the
position 5 in the thiazole ring occurred, and the corre-
sponding 4-substituted 2-amino-5-thiazolesulfonic acids I–
;ꢀ
ꢀ
ꢀ
1
IV were obtained in good yields. In this case in the H
5
;,ꢀ
ꢀ
ꢀ
NMR spectrum the signal of proton attached to C atom
is lacking. The sulfonic acids obtained are stable to hy-
drolysis: The boiling of their water solution for several
hours did not affect the compounds.
;
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ꢇꢆꢇꢂꢈ ꢀꢈꢂꢌꢇꢎꢀ ±ꢈꢂꢈꢌꢎꢀ±ꢈꢂꢍꢎꢋꢀ ꢈꢂꢈꢆꢇ ꢀ± ꢈꢂꢌꢍꢍꢀ±ꢈꢂꢍꢊꢏꢀ
ꢎꢎꢆꢂꢊ ꢀꢈꢂꢏꢊꢋꢀ ±ꢈꢂꢌꢎꢆꢀ±ꢈꢂꢈꢌꢉꢀ ꢈꢂꢈꢆꢆ ꢀ± ꢈꢂꢌꢌꢊꢀꢀꢀꢈꢂꢈꢇꢊꢀ
At the same time compounds I–IV are capable of
isomerization into the corresponding 4-substituted 2-
thiazolesulfamoylic acids V–VIII at heating in sulfuric
acid (3).
a
ꢀ
Tautomer form of the correcponding compound.
Protonated form of the corresponding compound.
b
be small. In the highly acidic medium the amine group of
the 2-aminothiazoles is virtually completely protonated.
At the same time for the nucleophilic substitution at the
sulfur atom in the chlorosulfonic acid to occur the presence
of nonprotonated form is essential. Under conditions of
acidic medium where in the substrate molecule a
sufficiently strong nucleophilic center (the carbon atom
in position 5) is present obviously the competing route (2)
fails to operate. At the same time the sulfonation of
5
5
1
ꢁꢁꢂ &
62
+2 61+
1
(
3)
+
+
1
62 +
6
6
1
Therewith in the H NMR spectra of the isomeriza-
tion products a signal appeared belonging to the proton at
the C atom of the thiazole ring. The aryl ring of the sub-
stituent did not undergo sulfonation under these condi-
tions.
5
2-aminothiazoles by sulfur trioxide complexes with pyridine
and dioxane when the amino group is not protonated
occurs almost completely along equation (1) [1].
Thus the aniline sulfonation where first occurs nucleo-
philic substitution at the sulfur atom of the chlorosulfonic
acid affording unstable to heating benzenesulfamoylic acid
that then isomerizes at heating into sulfanilic acid cannot
be regarded as similar to the process with 2-aminothi-
azoles. In the 2-aminothiazoles IX–XII that we studied
the process took the opposite route obviously because of
the specific features of their electronic structure.
The heating of 2-aminothiazole-5-sulfonic acid in the
sulfuric acid should intensify the amino group deprotona-
tion, and thus alongside the destabilization of the polar
C–S bond should favor process (3) giving more thermo-
dynamically feasible products, the corresponding 2-thi-
azolesulfamoylic acids. These compounds are fairly stable
and do not appreciably hydrolyze even at prolonged boiling
in water solutions of mineral acids.
For instance, quantum-chemical calculations in the
semiempirical approximationAM1 revealed the presence
of a considerable negative charge on the carbon atom in
the position 5 of all compounds under study, and the
qualitative pattern of the charge distibution remained
unchanged in going to the corresponding protonated and
tautomer forms of 2-aminothiazoles (see table). Note that
the imine tautomers are approximately by 25–34kJmol
less energetically favorable than the amine forms and thus
the fraction of the former in the reaction mixture should
During the aniline sulfonylation with chlorosulfonic acid
the process first occurs at the amino group (the charge on
the nitrogen atom is –0.326 a.u.) since the effective charge
on the carbon atom in the para-position (–0.173 a.u.) is
small, and only the subsequent heating of the reaction
mixture causes a rearrangement of the formed benzene-
sulfamoylic acid into the more thermodynamically stable
sulfanilic acid.
-
1
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

STUDYOF REACTION ROUTES IN SULFOINATION
1649
EXPERIMENTAL
(2H, NH ), 13.6 br.s (1H, SO H). Found, %: C 24.21;
2 3
H 3.15; N 14.52; S 32.92. C H N O S . Calculated, %:
4
6
2
3 2
IR spectra were recorded on spectrophotometer UR-
0 from samples prepared as KBr pellets . H NMR
spectra of compounds synthesized were registered on
spectro-meter Gemini-200 at operating frequency 200
C 24.74; H 3.11; N 14.42; S 33.01.
-Amino-4-(4-bromophenyl)-5-thiazolesulfonic
acida (III). Yield 91%, mp 219–220°C. IR spectrum, n,
1
2
2
–1
cm : 470, 590, 660 (NH ), 845, 1015, 1020, 1075 s (SO ),
2
2
MHz in DMSO-d using TMS as internal reference.
6
1085, 1205 s, 1240 s (SO ), 1490, 1585 (NH ), 1640 s
2 2
(C–H ), 3150, 3320. H NMR spectrum, d, ppm: 7.49 d.d
Ar
1
Quantum-chemical calculations and processing of
results was performed using software Hyper-Chem 5.02
(4H, H arom), 7.60 s (2H, NH ), 13.7 br.s (1H, SO H).
2
3
(
trial) [6] on a computer SINTALCAMEO XL, processor
Found, %: C 26.81; H 2.34; N 9.24; S 20.73.
C H BrN O S . Calculated, %: C 27.02; H 2.27; N 9.00;
Intel Pentium IV 2.4 GHz, 512 Mb DDR SDRAM of
memory. In all cases total geometry optimization of
compounds IX–XII, their protonated and tautomer forms
was carried out.
7
7
2
3 2
S 20.61.
-Amino-4-(3-nitrophenyl)-5-thiazolesulfonic
acida (IV). Yield 85%, mp 262–264°C. IR spectrum, n,
2
–
1
Initial 2-aminothiazoles IX–XII were prepared from
the corresponding phenacyl halides by reaction with
thiourea [4]. Physical constants of compounds obtained
were consistent with the published data.
cm : 565, 600, 665 (NH ), 750, 810, 840, 915, 1020,
2
1075 s (SO ), 1150, 1220 s (SO ), 1365 s (NO ), 1535 s
2
2
2
Ar
1
(NO ), 1580 s (NH ), 1650 s (C–H ), 3150, 3370. H
2
2
NMR spectrum, d, ppm: 7.42 t, 7.83 d, 8.05 d, 8.35 s (4H,
H arom), 7.80 s (2H, NH ), 13.7 br.s (1H, SO H). Found,
The solvents used in the study were purified by known
procedures [7], the chlorosulfonic acid was twice distilled
before use, the middle fraction being collected.
2
3
%
: C 29.84; H 2.61; N 15.36; S 23.37. C H N O S .
7 7 3 5 2
Calculated, %: C 30.32; H 2.54; N 15.15; S 23.13.
-(4-Chlorophenyl)-2-thiazolesulfamoylic acid
VI). To 20 ml of cooled 98% sulfuric acid was added by
4
2
-Amino-4-(4-chlorophenyl)-5-thiazolesulfonic
(
acid (II). To 35 g (0.3 mol) of chlorosulfonic acid cooled
by a bath of ice mixed with salt to –5°C was added by
small portions while stirring within 30 min 21 g (0.1 mol)
of 4-(4-chlorophenyl)-2-aminothiazole X. The solution
turned dark, and the hydrogen chloride evolution was
observed. After adding the substrate the mixture was
stirred at room temperature for 1 h, and then slowly poured
on crushed ice. Then thereto a cooled solution of sodium
hydroxide was added till neutralization while adding ice
to maintain the temperature below 10°C. The precipitate
was filtered off, washed with ethanol, with water, and
recrystallized from a 10-fold amount of water. Yield
portiona at stirring 14.5 g (0.05 mol) of sulfonic acid II.
Then the flask was heated for 3 h on a sand bath
maintaining the temperature at 110 ± 5°C. The dark
solution obtained was cooled and slowly poured on crushed
ice. Then the reaction mixture was neutralized with sodium
hydroxide solution, the precipitate was filtered off, washed
with 2-propanol and water, and recrystallized from water.
Yield 13.3 g (92%), colorless needle-like crystals, mp 222–
–
1
2
1
1
7
24°C. IR spectrum, n, cm : 530, 615, 725, 830, 1020,
040, 1090 s (SO ), 1160 s (SO ), 1490, 1590 (NH),
625 s (C–H ), 3400. H NMR spectrum, d, ppm:
.08 s (1H, C H), 7.54, 7.72 d (4H, H arom), 8.64 s (1H,
2
2
Ar
1
5
2
4.5 g (85%), colorless prismatic crystals, mp 205–206°C.
–
1
NH), 13.5 br.s (1H, SO H). Found, %: C 31.24; H 2.73;
IR spectrum, n, cm : 595, 665 (NH ), 715, 845 Cp, 1020
Cp, 1075 C (SO ), 1095, 1210 C, 1245 C (SO ), 1495,
1
7
3
2
N 10.71; S 24.10. C H ClN O S . Calculated, %: C 31.52;
7
7
2
3 2
2
2
Ar
1
H 2.65; N 10.50; S 24.04.
Likewise were prepared compounds V, VII, and VIII.
-Methyl-2-thiazolesulfamoylic acid (V). Yield
580 (NH ), 1645 C (C–H ), 3150, 3390. H, d, ppm:
.28, 7.48 d (4H, H arom), 7.62 C (2H, NH ), 13.8 br.s
2
2
(1H, SO H). Found, %: C 31.13; H 2.74; N 10.81; S 24.18.
4
3
C H ClN O S . Calculated, %: C 31.52; H 2.65; N 10.50;
–1
8
8
3%, mp 310–312°C. IR spectrum, n, cm : 505, 795,
95, 985, 1025 s (SO ), 1105, 1200 s (SO ), 1250 m, 1365,
1410, 1580 s (NH), 1620, 1650, 3105, 3310. H NMR
spectrum, d, ppm: 3.08 s (CH ), 6.48 s (1H, C H), 8.62 s
1H, NH), 13.3 br.s (1H, SO H). Found, %: C 24.44;
7
7
2
3 2
S 24.04.
Compounds I, III, and IV were prepared in the simi-
lar way.
-Amino-4-methyl-5-thiazolesulfonic acida (I).
2
2
1
5
3
(
2
3
–
1
H 3.19; N 14.57; S 32.97. C H N O S . Calculated, %:
Yield 60%, mp 276–277°C. IR spectrum, n, cm : 475,
4 6 2 3 2
C 24.74; H 3.11; N 14.42; S 33.01.
5
1
3
90, 660 (NH ), 735, 815, 1025 s (SO ), 1110, 1175,
2 2
270 s (SO ), 1380, 1430, 1595 s (NH ), 1640, 1670, 3140,
4-(4-Bromophenyl)-2-thiazolesulfamoylic acid
2
2
1
–1
310. H NMR spectrum, d, ppm: 2.11 s (CH ), 7.54 s
(VII). Yield 66%, mp 280–281°C. IR spectrum, n, cm :
3
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

1650
LYASHCHUK et al.
5
1
3
7
10, 615, 735, 765, 840, 1010 s, 1065 s (SO ), 1120,
REFERENCES
2
Ar
200 s, 1220 s (SO ), 1460, 1575 (NH), 1645 s (C–H ),
2
1. Gilbert, E. E., Sulfonation and Related Reactions, NewYork:
1
5
380. H NMR spectrum, d, ppm: 7.11 s (1H, C H),
Interscience, 1965.
.58 d.d (4H, H arom), 8.65 s (1H, NH), 13.2 br.s (1H,
2
3
4
5
. Kloek, J.A. and Leschinsky, K.L., J. Org. Chem., 1976,
vol. 41, p. 4028.
SO H). Found, %: C 26.89; H 2.29; N 9.14; S 20.75.
C H BrN O S . Calculated, %: C 27.02; H 2.27; N 9.00;
3
7
7
2
3 2
. Hurd, C.D. and Kharasch, N., J. Am. Chem. Soc., 1947,
vol. 69, p. 2113.
S 20.61.
-(3-Nitrophenyl)-2-thiazolesulfamoylic acid
VIII). Yield 92%, mp 195–197°C. IR spectrum, n,
4
. Hurd, C.D. and Kharasch, N., J. Am. Chem. Soc., 1946,
vol. 68, p. 653.
(
–
1
cm : 460, 580, 725, 880, 1040 s, 1055 s (SO ), 1190 s,
2
. Poplavskii, I.Ya. and Mamykina, T.S., Zh. Obshch Khim.,
1953, vol. 23, p. 1765.
1
1
7
210 s (SO ), 1350 s (NO ), 1525 s (NO ), 1560 (NH),
635 s (C–H ), 3130, 3390. H NMR spectrum, d, ppm:
.31 s (1H, C H), 7.76 t, 8.10 d, 8.27 d, 8.53 s (4H, H
2 2 2
Ar
1
5
6. Hyperchem., Release 5.02 trial, Hypercube Inc., 1115 NVV,
4-th Street Gainesville, Florida, 32601 USA.
arom), 8.67 s (1H, NH), 13.2 br.s (1H, SO H). Found, %:
3
C 29.80; H 2.64; N 15.25; S 23.21. C H N O S . Calcu-
lated, %: C 30.32; H 2.54; N 15.15; S 23.13.
7. Laboratorni Technika Organicki Chemie, Keil, B., Ed.,
Prague: Nakladatelstvi CheskoslovenskiAkademie Ved, 1963.
7
7
3
5 2
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004