Synthesis of 3-(6-R-benzothiazol-2-yl)-4-methyl-1,2,5-oxadiazoles

Article abstract of DOI:10.1007/s11178-005-0237-4

The nitrosation of N-aryl-3-oxobutanethioamides afforded 1-(6-R-benzothiasol-2-yl)-1-hydroxyimino-2-propanones that at oximation with hydroxylamine were converted into 1-(6-R-benzothiazol-2-yl)-1,2- dihydroxyiminopropanes. The latter were dehydrated by he

Full text of DOI:10.1007/s11178-005-0237-4

Russian Journal of Organic Chemistry, Vol. 41, No. 5, 2005, pp. 745-747. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005,
pp. 759-761.
Original Russian Text Copyright Ó 2005 by Britsun, Borisevich, Samoilenko, Lozinskii.
.
Synthesis of 3-(6-R-Benzothiazol-2-yl)-4-methyl-1,2,5-oxadiazoles
V.N. Britsun,A.N. Borisevich, L.S. Samoilenko, and M.O. Lozinskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094 Ukraine
e-mail: iochkiev@ukrpack.ne
Received December 6, 2004
Abstract—The nitrosation of N-aryl-3-oxobutanethioamides afforded 1-(6-R-benzothiasol-2-yl)-1-hydroxyimino-
2-propanones that at oximation with hydroxylamine were converted into 1-(6-R-benzothiazol-2-yl)-1,2-dihydroxy-
iminopropanes. The latter were dehydrated by heating with succinic anhydride at 140°C yielding therewith 3-(6-R-
benzothiazol-2-yl)-4-methyl-1,2,5-oxadiazoles.
We formerly demonstrated that N-aryl-3-oxobutane-
thioamides are promising compounds for preparation of
versatile heterocycles: pyrazoles [1], thiazoles [2], 1,2,4-
dithiazolidinesb [3], 6-thioxopiperidin-2-ones, and thio-
pyran-4-ones [4].
of compounds Ia–Ic into a benzothiazole ring. Therefore
the reaction products obtained in 72–84% yields were
1-(6-R-benzothiazol-2-yl)-1-hydroxyimino-2-propanones
(IIa–IIc) (Scheme 1). Note that the oxidative cyclization
of N-aryl-thioamides into benzothiazoles (Jacobson
reaction) occurs under mild conditions in alkaline medium
It is known that quite a number of compounds among
[9] but it is uncommon for acid medium.
1
,2,5-oxadiazole derivatives can be used as pesticides,
1
radioprotectors, analgesics, and anticancer agents [5–8].
The goal of this study was investigation of N-aryl-3-oxo-
butanethioamides nitrosation, oximation of the arising
products followed by cyclization of the latter into 1,2,5-
oxadiazoles.
In the H NMR spectra of compounds IIa–IIc the
singlets from protons of acetyl and hydroxy groups
(d 2.56–2.58 and 13.65–13.97 ppm respectively) are
characteristic. These spectra prove the formation of
benzothiazoles IIa–IIc by the overall integral intensity
and the form of the aromatic protons resonances (7.17–
In the first stage of the study we carried out the
nitrosation of N-aryl-3-oxobutanethioamides Ia–Ic with
sodium nitrite in acetic acid that cleanly occurred at 5°C.
The peculiar feature of the reaction was the replacements
of the hydrogens in the activated methylene group in
compounds Ia–Ic by an isonitroso group and oxidation
of the arylthioamide fragment of the isonitroso derivatives
8
.23 ppm). In the IR spectra of compounds IIa–IIc
appear the absorption bands of groups O–H and C=O
–
1
(
3400 and 1700–1710 cm respectively).
The oximation of propanones IIa–IIc afforded 1-(6-
R-benzothiazol-2-yl)-1,2-dihydroxyiminopropanes­ IIIa–
IIIc in good yields (81–88%). The process was carried
Scheme 1.
5
2
1
6
1
D12 ꢀꢀꢀꢀꢀ&+ &22+
2
6
ꢅ &
+
&
+
&
1
5
+
1
+
2
B
B
,
ꢁꢁꢁ,F
,, ꢁꢁꢁ,,F
2
2
2
2
1
+
1
2
+
&
1
6
1
&
+ 2+ꢀꢀ+&Oꢁ
+ &221Dꢁ
1
6
ꢂꢃꢄ &
+
&
1
2 1
5
5
&
+ 2+
+
B
B
,
,, ꢁꢁꢁ,,,F
,9 ꢁꢁꢁ,9F
R = H (a), OC H (b), CH (c).
2
5
3
1070-4280/05/4105-0745Ó2005 Pleiades Publishing, Inc.

746
BRITSUN et al.
out by heating compounds IIa–IIc with hydroxylamine
1-(6-Ethoxybenzothiazol-2-yl)-1-hydroxyimino-2-
hydrochloride and sodium acetate in ethanol. Formerly a propanone (IIb). Yield 78%, mp 180–182°C. IR
–
1
chelate nickel complex with compound IIIa (prepared
by reaction of o-aminothiophenol with diketone followed
by treating the reaction product with hydroxylamine) was
spectrum, n, cm : 1370, 1430, 1490, 1620, 1710, 3000.
1
H NMR spectrum, d, ppm: 1.38 t (3H, OCH CH ,
J 6.1 Hz), 2.58 s (3H, COCH ), 4.12 q (2H, OCH CH ,
J 6.1 Hz), 7.17 d.d (1H, Harom, J 9.1, J 2.3 Hz), 7.77 d
2
3
3
2
3
1
patented as a light-fast pigment [10, 11]. In the H NMR
1 2
spectra of compounds IIIa–IIIc appear singlet signals
from the protons of two O–H groups (d 11.53–11.60 and
(1H, Harom, J 2.3 Hz), 8.02 d (1H, Harom, J 9.1 Hz),
13.97 br.s (1H, OH). Found, %: C 54.69; H 4.32;
N 10.44. C H N O S. Calculated, %: C 54.53; H 4.58;
12.72–12.81 ppm) and from a methyl group (d 2.12–2.13
12
12
2
3
ppm), and the IR spectra lack the carbonyl absorption
bands.
N 10.60.
-(6-Methylbenzothiazol-2-yl)-1-hydroxyimino-
2-propanone (IIc). Yield 72%, mp 228–230°C. IR
1
Optimum cyclization conditions for 1,2-dihydroxy-
iminopropanes­ IIIa–IIIc proved to be heating with
succinic anhydride at 140°C for 0.5 h: The dehydration
of compounds IIIa–IIIc under these conditions furnished
–1
spectrum, n, cm : 1380, 1420, 1460, 1490, 1590, 1700,
1
2950, 3400. H NMR spectrum, d, ppm: 2.48 s (3H,
CH ), 2.57 s (3H, COCH ), 7.38 d (1H, Harom, J 8.7 Hz),
3
3
3
-(6-R-benzothiazol-2-yl)-4-methyl-1,2,5-oxadiazoles
7.95 m (2H, Harom), 13.65 br.s (1H, OH). Found, %:
C 56.63; H 4.02; N 12.24. C H N O S. Calculated,
%: C 56.40; H 4.30; N 11.96.
1
IVa–IVc in 73–79% yield. The H NMR spectra of 1,2,5-
oxadiazole IVa–IVc contain only signals of methyl group
and aromatic protons (d 2.72–2.79 and 7.22–8.27 ppm
respectively).
11
10
2
2
1
-(6-R-Benzothiazol-2-yl)-1,2-dihydroxyimino-
propanes IIIa–IIIc. General procedure. A mixture
ofü 10 mmol of compound IIa–IIc, 0.754 g (11 mmol) of
hydroxylamine hydrochloride, and 0.913 g (11 mmol) of
anhydrous sodium acetate in 10 ml of ethanol was boiled
for 1 h, filtered from the precipitate, and cooled. The
precipitate separated on cooling was filtered off and
recrystallized from ethanol.
Thus we developed a convenient preparative method
for 3-(6-R-benzothiazol-2-yl)-4-methyl-1,2,5-oxadiazoles
whose structure was confirmed by H NMR and IR
1
spectroscopy, and the composition by elemental analysis.
EXPERIMENTAL
IR spectra of compounds synthesized were recorded
on a spectrophotometer UR-20 from samples pelletized
1-(Benzothiazol-2-yl)-1,2-dihydroxyimino-
propane (IIIa). Yield 88%, mp 185–187°C (mp 184–
1
185°C [10]). IR spectrum, n, cm–1: 1330, 1380, 1430,
with KBr. H NMR spectra of substances dissolved in
1
DMSO-d were registered on spectrometer Varian-300,
1470, 1570, 3000, 3200–3400. H NMR spectrum, d,
6
operating frequency 300 MHz, internal reference TMS.
ppm: 2.13 C (3H, CH3), 7.57 m (2H, Harom), 8.08 d (1H,
Harom, J 7.8 Hz), 8.17 d (1H, Harom
,
J 7.6 Hz), 11.60 s
1
-(6-R-Benzothiazol-2-yl)-1-hydroxyimino-2-
(
4
1H, OH), 12.79 C (1H, OH). Found, %: C 50.84;
H
propanones IIa–IIc. To a solution of 10 mmol of
N-aryl-3-oxobutanethioamide Ia–Ic in 10 ml of acetic
acid was added within 0.5 h dropwise at 5°C while stirring
.07; N 18.08. C H N O S. Calculated, %: C 51.05;
10 9 3 2
H 3.86; N 17.86.
a solution of 1.66 g (24 mmol) of NaNO in 2.5 ml of
1-(6-Ethoxybenzothiazol-2-yl)-1,2-dihydroxy-
2
water. The reaction mixture was stirred for 0.5 h, the
precipitate was filtered off, washed with acetic acid
iminopropane (IIIb). Yield 84%, mp 185–187°C. IR
–1
spectrum, n, cm : 1380, 1410, 1480, 1560, 1615, 3000,
1
(3 ml), with water (5 ml), dried, and recrystallized from
3300, 3500. H NMR spectrum, d, ppm: 1.35 t (3H,
ethanol.
OCH CH , J 6.2 Hz), 2.12 s (3H, CH ), 4.09 q (2H,
2
3
3
OCH CH , J 6.2 Hz), 7.15 d.d (1H, H
J2 2.0 Hz), 7.68 d (1H, Harom, J 2.0 Hz), 7.96 d (1H,
Harom, J 8.9 Hz), 11.53 s (1H, OH), 12.81 s (1H, OH).
, J 8.9,
1
-(Benzothiazol-2-yl)-1-hydroxyimino-2-
2
3
arom
1
propanone (IIa). Yield 84%, mp 143–145°C (publ.:
–1
mp 145°C [10]). IR spectrum, n, cm : 1330, 1380, 1440,
1
Found, %: C 51.85; H 4.42; N 14.81. C H N O S.
1
2
480, 1580, 1700, 3000. H NMR spectrum, d, ppm:
12 13
3
3
Calculated, %: C 51.60; H 4.69; N 15.04.
.56 s (3H, COCH ), 7.58 m (2H, Harom), 8.15 d
3
(
1
1H, Harom, J 8.1 Hz), 8.23 d (1H, Harom, J 8.2 Hz),
3.7 br.s (1H, OH). Found, %: C 54.36; H 3.81; N 13.01.
C H N O S. Calculated, %: C 54.53; H 3.66;
1-(6-Methylbenzothiazol-2-yl)-1,2-dihydroxy-
iminopropane (IIIc). Yield 81%, mp 225–227°C. IR
–1
spectrum, n, cm : 1390, 1440, 1500, 1600, 3000, 3200–
1
0
8
2
2
1
N 12.72.
3400. H NMR spectrum, d, ppm: 2.13 s (3H, CH ),
3
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

SYNTHESIS OF 3-(6-R-BENZOTHIAZOL-2-YL)-4-METHYL-1,2,5-OXADIAZOLES
747
2
.47 s (3H, CH ), 7.39 d (1H, Harom, J 8.8 Hz), 7.93 m
spectrum, d, ppm: 2.49 s (3H, CH ), 2.76 s (3H, CH ),
3 3
3
(2H, Harom), 11.53 (1H, OH), 12.72 C (1H, OH). Found,
7.47 d (1H, Harom, J 8.4 Hz), 8.06 m (2H, Harom). Found,
%
: C 52.83; H 4.72; N 17.12. C H N O S. Calculated,
%: C 56.94; H 4.13; N 18.41. C H N OS. Calculated,
11
11
3
2
11
9
3
%: C 53.00; H 4.45; N 16.86.
%: C 57.13; H 3.92; N 18.17.
3
-(6-R-Benzothiazol-2-yl)-4-methyl-1,2,5-
REFERENCES
oxadiazoles IVa–IVc. General procedure. A mixture
of 5 mmol of compound IIIa–IIIc and 0.55 g (5.5 mmol)
of succinic anhydride was heated at 140°C for 0.5 h,
cooled, and ground with 5 ml of 10% aqueous NaHCO3.
The insoluble residue was filtered off, dried, and
recrystallized from ethanol.
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2
3
4
3
-(Benzothiazol-2-yl)-4-methyl-1,2,5-oxadiazole
1
–1
(
1
IVa). Yield 79%, mp 125–127°C. IR spectrum, n, cm :
320, 1400, 1440, 1470, 1590, 3000. H NMR spectrum,
d, ppm: 2.79 s (3H, CH ), 7.62 m (2H, Harom), 8.27 m
2H, Harom). Found, %: C 55.01; H 3.51; N 19.53.
1
3
(
C H N OS. Calculated, %: C 55.29; H 3.25; N 19.34.
1
0
7
3
3
-(6-Ethoxybenzothiazol-2-yl)-4-methyl-1,2,5-
1
oxadiazole (IVb). Yield 76%, mp 109–111°C. IR
spectrum, n, cm : 1340, 1400, 1480, 1590, 1620, 3000.
NMR spectrum, d, ppm: 1.39 t (3H, OCH CH ,
J 6.5 Hz), 2.72 s (3H, CH ), 4.16 q (2H, OCH CH ,
J 6.5 Hz), 7.22 d.d (1H, Harom, J 8.7, J 2.5 Hz), 7.78 d
1H, Harom, J 2.5 Hz), 8.05 d (1H, Harom, J 8.7 Hz). Found,
: C 54.87; H 3.98; N 16.12. C H N O S. Calculated,
–1
1
H
2 3
8
3
2
3
1
2
(
%
%
9
12 11 3 2
: C 55.16; H 4.24; N 16.08.
-(6-Methylbenzothiazol-2-yl)-4-methyl-1,2,5-
oxadiazole (IVc). Yield 73%, mp 108–111°C. IR spec-
3
10. French Patent 2103 339, 1972; Chem. Abstr., 1973, vol. 78,
17635u.
11. German Patent 2137 372, 1972; Chem. Abstr., 1972, 77, 7279w.
–1
1
trum, n, cm : 1330, 1410, 1450, 1600, 3000. H NMR
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005