Synthesis of 3-amino-4,5-dichloroisothiazole

Article abstract of DOI:10.1134/S1070428009040149

4,5-Dichloro-1,2-thiazol-3-amine was synthesized starting from accessible 4,5-dichloro-1,2-thiazole-3-carbonyl azide and -3-carboxamide via Curtius and Hofmann rearrangements, respectively. The procedure involving Curtius rearrangement was found to be mor

Full text of DOI:10.1134/S1070428009040149

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 4, pp. 555–558. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.I. Potkin, Yu.S. Zubenko, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 4, pp. 568–572.
Synthesis of 3-Amino-4,5-dichloroisothiazole
V. I. Potkin and Yu. S. Zubenko
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: potkin@ifoch.bas-net.by
Received June 9, 2008
Abstract—4,5-Dichloro-1,2-thiazol-3-amine was synthesized starting from accessible 4,5-dichloro-1,2-thia-
zole-3-carbonyl azide and -3-carboxamide via Curtius and Hofmann rearrangements, respectively. The proce-
dure involving Curtius rearrangement was found to be more advantageous from the preparative viewpoint.
DOI: 10.1134/S1070428009040149
Aminoisothiazoles and their derivatives possess
versatile biological activity, and they can be used as
effective pesticides in agriculture, kinase inhibitors and
highly selective 5-HT2B receptor antagonists in phar-
macology, as well as biocides for protection of various
materials from biological damage [1–4]. Studies on the
development of convenient methods for preparation of
these compounds and on their biological activity are
extensively progressing [5–7].
Azide III was converted into aminoisothiazole I in
two ways. According to the first of these, heating of
azide III in anhydrous benzene gave the corresponding
isocyanate V, and hydrolysis of the latter in concen-
trated hydrochloric acid afforded 3-amino-4,5-di-
chloroisothiazole (I) in 80% yield (calculated on the
initial azide III; Scheme 1). Intermediate isocyanate V
was not isolated as individual substance. Azide III was
completely converted into isocyanate V during GC–
MS analysis, and compound V was reliably identified
by the mass spectrum. The second version involved
intermediate carbamic acid derivative, ethyl 4,5-di-
chloro-1,2-isothiazol-3-ylcarbamate (VI), which was
obtained in 94% yield by heating azide III in boiling
anhydrous ethanol. Treatment of compound VI with
alkali in boiling ethanol gave amine I. The yield of the
latter was 98% calculated on carbamate VI and 92%
calculated on azide III. Thus the second version en-
sured higher yield of the target product. As in the first
version, azide III can also be converted into amino-
isothiazole I without isolation of intermediate carba-
mate VI.
The goal of the present study was to develop syn-
thetic routes to previously unknown 3-amino-4,5-di-
chloroisothiazole (I) starting from derivatives of
accessible 4,5-dichloroisothiazole-3-carboxylic acid
(II); a convenient procedure for the preparation of acid
II was reported by us previously [8]. Known and
widely used synthetic approaches to amines are based
on the Curtius and Hofmann rearrangements of car-
boxylic acid azides and amides, respectively, with loss
of one carbon atom; also, some modifications of these
methods were reported [9]. We examined two versions
of the Curtius approach. Here, the key starting com-
pound was 4,5-dichloro-1,2-thiazole-3-carbonyl azide
(III) which was prepared in 79% yield by treatment of
4,5-dichloro-1,2-thiazole-3-carbonyl chloride (IV)
with sodium azide and was identified on the basis of its
elemental composition and IR and 13C NMR spectra.
Compound III displayed in the IR spectrum an absorp-
tion band at 2158 cm–1, which is typical of azido
group, and the carbonyl group in III gave a strong
band at 1692 cm–1. The 13C NMR spectrum of azide
III contained four signals at δC 126.53, 152.31, 154.99,
and 166.22 ppm; among these, the first three corre-
spond to the endocyclic carbon atoms, and the latter
belongs to the carbonyl carbon atom.
The structure of amine I and ethyl 4,5-dichloro-1,2-
thiazol-3-ylcarbamate (VI) was determined by elemen-
tal analysis, IR and 1H and 13C NMR spectroscopy, and
mass spectrometry. In the IR spectrum of VI, vibra-
tions of the N–H group were characterized by absorp-
tion bands at 3243 and 1556 cm–1, and stretching
vibrations of the carbonyl group had a frequency of
1
1716 cm–1. In the H NMR spectrum of VI, protons in
the ethoxy group resonated as a triplet (CH3) and
quartet (CH2) at δ 1.33 and 4.29 ppm, respectively. The
NH proton gave a singlet at δ 7.27 ppm. The 13C NMR
spectrum of VI contained signals at δC 15.02 and
555

POTKIN, ZUBENKO
556
Scheme 1.
Cl
NHAc
O
O
Cl
Cl
Cl
NH2
NH3
NaOBr
N
Cl
S
N
N
VIII
Cl
Cl
S
S
IV
VII
AcCl, pyridine
NaN3
O
Cl
NCO
Cl
NH2
N
PhH, Δ
HCl, Δ
N
Cl
Cl
Cl
N3
S
S
V
I
N
Cl
OEt
S
4-AcNHC6H4SO2Cl
pyridine
Cl
HN
N
III
EtOH, Δ
EtOH, KOH
O
Cl
HN
Cl
SO2C6H4NHAc-4
S
VI
N
Cl
S
IX
63.05 ppm from the ethoxy group, signals at δC 148.36
and 113.94 ppm were assigned to two carbon atoms in
the isothiazole ring, and the third carbon atom in the
isothiazole ring and the carbonyl carbon atom gave
only one signal at δC 152.08 ppm.
respectively (hereinafter, m/z values are given for ions
containing 35Cl isotope). The intensity ratio of isotope
peak (100:65:10) is consistent with the presence of
two chlorine atoms in molecules I and VI [10, 11]. The
fragmentation patterns of the molecular ions of I and
VI are typical of isothiazoles [12, 13], and they include
cleavage of the isothiazole ring with formation of ions
A–D (Scheme 2), subsequent decomposition of these
ions, and elimination of substituents.
In the IR spectrum of amine I we observed absorp-
tion bands at 3389 and 3299 cm–1 due to stretching
vibrations of the N–H bonds, which are typical of
primary aromatic amines; bending vibrations of the
amino group were characterized by absorption bands at
1630 and 1616 cm–1. The NH2 protons gave a broad-
In the mass spectrum of amine I, the molecular ion
peak has the maximal intensity (m/z 168, Irel 100%);
next follows ion B with m/z 126 (Irel 33%). The relative
intensities of peaks from ions C (m/z 89) and D
(m/z 79) are 11 and 9%, respectively, while ion A con-
tributes little to the total ion current (m/z 42, Irel 4%).
The relative intensity of the molecular ion peak in the
mass spectrum of VI is 24%, while the most abundant
ion is that with m/z 168 (Irel 100%). The latter corre-
sponds to amine I ion formed as a result of elimination
of the COOEt group from the molecular ion. Also, ions
1
ened singlet at δ 4.88 ppm in the H NMR spectrum.
The 13C NMR spectrum of I contained three signals at
δC 159.82, 146.63, and 111.16 ppm from carbon atoms
in the heteroring, while no signal assignable to exocy-
clic carbon atom was present.
Exhaustive proofs in support of the assumed struc-
ture of compounds I and VI were obtained by mass
spectrometry. The mass spectra of I and VI contained
molecular ion clusters with m/z values of 168 and 240,
Scheme 2.
S
+·
R
C
N
+
Cl
R
Cl
+
Cl
A
B
N
Cl
N
S
Cl
C
S
I, VI
Cl
R
C
D
I, R = NH2; VI, R = EtOC(O)NH.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009

SYNTHESIS OF 3-AMINO-4,5-DICHLOROISOTHIAZOLE
557
B (m/z 126, Irel 17%), C (m/z 161, Irel 3%), and D
(m/z 79, Irel 13%) were detected. No peak of ion A was
observed, but those corresponding to its decomposition
were present.
tions in CDCl3 on a Bruker Avance-500 spectrometer;
the chemical shifts were determined relative to TMS
(1H) or solvent signal (CDCl3, δC 77.0 ppm). The mass
spectra (electron impact, 70 eV) were obtained on
a Hewlett–Packard 5890/5972 GC–MS system (HP-
5MS capillary column, 30 m×0.25 mm, stationary
phase 5% of phenylmethylsilicone, film thickness
0.25 μm; injector temperature 250°C).
With a view to find optimal procedure for the pre-
paration of amine I, we tried to synthesize it via Hof-
mann rearrangement of previously described 4,5-di-
chloro-1,2-thiazole-3-carboxamide (VII) [14]. In fact,
amine I was formed in 78% yield by treatment of
amide VII with a freshly prepared aqueous solution of
sodium hypobromite. The reaction was complete in
0.5 h at 95°C, and the product was identical to that
obtained via Curtius rearrangement. Comparison of the
results showed that the synthesis of 4,5-dichloro-1,2-
thiazol-3-amine (I) from azide III through interme-
diate carbamate VI is more advantageous from the pre-
parative viewpoint, for it ensures the highest yield of
the target product.
4,5-Dichloro-1,2-thiazole-3-carbonyl chloride (IV)
and 4,5-dichloro-1,2-thiazole-3-carboxamide (VII)
were synthesized as described in [14].
4,5-Dichloro-1,2-thiazol-3-amine (I). a. A solution
of 0.67 g (3 mmol) of azide III in 20 ml of anhydrous
benzene was heated for 20 min under reflux, 50 ml of
concentrated hydrochloric acid was added, and the
mixture was heated for 1 h more at the boiling point.
The aqueous phase was separated and neutralized with
potassium hydroxide, and the precipitate was filtered
off, washed with water, and dried under reduced
pressure. Yield 0.40 g (80%), mp 121–122°C (from
hexane). IR spectrum, ν, cm–1: 3389, 3299, 1630, 1616
(NH), 1540, 1466, 1409 (isothiazole), 999, 824 (C–Cl).
1H NMR spectrum: δ 4.88 ppm, br.s (1H, NH).
13C NMR spectrum, δC, ppm: 111.16, 146.63, 159.82.
Found, %: C 21.50; H 1.61; Cl 41.45; N 16.29;
S 18.94. [M]+ 168. C3H2Cl2N2S. Calculated, %: C 21.32;
H 1.19; Cl 41.95; N 16.58; S 18.97. M 169.03.
Aminoisothiazole I was subjected to acylation with
acetyl chloride and 4-acetylaminobenzenesulfonyl
chloride. The reaction of I with acetyl chloride was
carried out in diethyl ether, and it smoothly afforded
87% of N-(4,5-dichloro-1,2-thiazol-3-yl)acetamide
(VIII) (Scheme 1). Treatment of I with 4-acetylamino-
benzenesulfonyl chloride resulted in the formation of
the corresponding sulfonamide, N-[4-(4,5-dichloro1,2-
thiazol-3-ylsulfamoyl)phenyl]acetamide (IX), in 63%
yield. Compounds VIII and IX were identified on the
basis of their elemental compositions and IR and
1H NMR spectra. The presence of a carboxamide moi-
ety in molecule VIII followed from the IR spectrum
which contained amide I band at 1683 cm–1 (νC=O)
and amide II band at 1617 cm–1 (δN–H). Absorption
bands at 1172 and 1312 cm–1 in the IR spectrum of
sulfonamide IX corresponded to vibrations of the S=O
bonds. Broadened absorption bands in the region
3190–3386 cm–1 were assigned to stretching vibrations
of N–H bonds in VIII and IX. Compounds VIII and
b. A mixture of 0.30 g (12 mmol) of azide III and
30 ml of anhydrous ethanol was heated for 3 h under
reflux, a solution of 2.67 g of potassium hydroxide in
30 ml of ethanol was added, and the mixture was
heated for an additional 1 h under reflux. It was then
poured into water, and the precipitate was filtered off,
washed with water, and dried under reduced pressure.
Yield 1.82 (92%). The product was identical to
a sample of amine I prepared as described above in a.
c. A solution of 1.20 g (30 mmol) of sodium
hydroxide in 50 ml of water was cooled to 0°C, 0.3 ml
(6 mmol) of bromine was added, and the mixture was
stirred for 10 min at 0°C. Powdered amide VII, 0.98 g
(5 mmol), was added in one portion, the mixture was
stirred until it turned homogeneous, heated to 95°C,
stirred for 30 min at that temperature, and cooled to
0°C, and the precipitate was filtered off, washed with
water, and dried under reduced pressure. Yield 0.65 g
(78%). The product was identical to samples of amine
I prepared as described above in a and b.
1
IX showed in the H NMR spectra singlets at δ 2.41
and 1.99 ppm, respectively, from the methyl protons in
the acetyl groups, and signals from the NH protons
appeared as broadened singlets in the region δ 8.03–
10.21 ppm. The mass spectrum of VIII contained the
molecular ion peak with m/z 210 (Irel 7%), whereas no
molecular ion peak was present in the mass spectrum
of sulfonamide IX.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Nicolet
Protégé-460 spectrometer with Fourier transform. The
1H and 13C NMR spectra were measured from solu-
4,5-Dichloro-1,2-thiazole-3-carbonyl azide (III).
A solution of 2.16 g (10 mmol) of acid chloride IV in
25 ml of acetone was cooled to 0°C, a solution of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009

POTKIN, ZUBENKO
558
0.97 g (15 mmol) of sodium azide in 3 ml of water was
added dropwise under stirring, the cooling bath was
removed, and the mixture was stirred for 20 min and
diluted with 100 ml of water. The precipitate was
filtered off and dried under reduced pressure over
P2O5. Yield 1.77 g (79%), decomposition point 50°C.
IR spectrum, ν, cm–1: 2158 (N3); 1692 (C=O); 1402,
1349, 1217 (C=C, C=N); 940, 871 (C–Cl). 13C NMR
spectrum, δC, ppm: 126.53, 152.31, 154.99 (4C);
166.22 (C=O). Found, %: C 21.32; Cl 31.57; N 25.19;
S 14.43. C4Cl2N4OS. Calculated, %: C 21.54; Cl 31.79;
N 25.13; S 14.37.
reduced pressure. Yield 1.49 g (63%), mp 156–158°C.
IR spectrum, ν, cm–1: 3260, 3190 (N–H); 1415, 1494,
1582, 1600 (C=C, C=N); 1172, 1312 (S=O); 819
1
(C–Cl). H NMR spectrum, δ, ppm: 1.99 s (3H, CH3),
7.50 d (2H, Harom, 3J = 8.5 Hz), 7.55 d (2H, Harom, 3J =
8.5 Hz), 7.9 br.s (1H, SO2NH), 10.21 br.s (1H, AcNH).
Found, %: C 36.48; H 2.50; Cl 17.67; N 10.96;
S 16.37. C12H9Cl2N3O4S2. Calculated, %: C 36.56;
H 2.30; Cl 17.98; N 10.66; S 16.26.
This study was performed under partial financial
support by the Byelorussian Republican Foundation
for Basic Research (project no. Kh07M-025).
Ethyl 4,5-dichloro-1,2-thiazole-3-ylcarbamate
(VI). A suspension of 0.30 g (12 mmol) of azide III in
30 ml of anhydrous ethanol was heated for 3 h under
reflux. The solvent was removed, and the residue was
purified by recrystallization from hexane. Yield 0.31 g
(94%), mp 70–72°C. IR spectrum, ν, cm–1: 3243, 1556
(N–H); 1716 (C=O); 1518, 1427, 1367 (C=C, C=N);
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009