Synthesis and intramolecular heterocyclization of β-amino ketone thiosemicarbazones

Article abstract of DOI:10.1134/S1070428012040161

Intramolecular heterocyclization of thiosemicarbazones derived from saturated and conjugated β-amino ketones afforded previously unknown dihydro-1,3,4-thiadiazole derivatives. A probable scheme of the transformation of multicenter intermediate includes ge

Full text of DOI:10.1134/S1070428012040161

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 4, pp. 556–560. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © I.N. Klochkova, A.A. Anis’kov, M.P. Shchekina, E.A. Voronina, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 4, pp. 558–562.
Synthesis and Intramolecular Heterocyclization
of β-Amino Ketone Thiosemicarbazones
I. N. Klochkova, A. A. Anis’kov, M. P. Shchekina, and E. A. Voronina
Chernyshevskii Saratov State University, ul. Astrakhanskaya 83, Saratov, 410012 Russia
e-mail: aniskovaa@mail.ru
Received April 4, 2011
Abstract—Intramolecular heterocyclization of thiosemicarbazones derived from saturated and conjugated
β-amino ketones afforded previously unknown dihydro-1,3,4-thiadiazole derivatives. A probable scheme of the
transformation of multicenter intermediate includes generation and intramolecular cyclization of a thiol thio-
semicarbazone tautomer without participation of conjugated double carbon–carbon bond in the substrate.
DOI: 10.1134/S1070428012040161
Saturated and unsaturated Mannich bases exhibit
antimicrobial [1] and antiviral [2] activity and are
promising as substrates for the design of efficient
agents for cancer therapy [3]. Introduction of various
pharmacophoric fragments into molecules of Mannich
bases could essentially change their activity and extend
their medicinal and biological potential. Thiosemicar-
bazones and their cyclic derivatives, dihydrothiadi-
azoles, are also important as biologically active com-
pounds [4].
which were converted in up to 87% yield into the
corresponding thiosemicarbazone hydrochlorides IIa–
IIf by treatment with thiosemicarbazide in the pres-
ence of a catalytic amount of aqueous HCl (Scheme 1).
The structure of thiosemicarbazones IIa–IIf was
1
confirmed by IR and H and 13C NMR spectra. The
1H NMR spectra of IIa–IIf contained triplets at
δ 2.43–2.56 ppm from protons in the aminomethylene
fragment, while compounds IIc–IIf characteristically
displayed two doublets at δ 6.81–6.87 ppm (J =
16.0 Hz) from the vinylic protons. The C=N and C=S
carbon atoms resonated in the 13C NMR spectra at
δC 143.2–146.2 and 179.2–184.6 ppm, respectively.
The present work was aimed at synthesizing com-
pounds of the thiourea and dihydrothiadiazole series
containing a tertiary aminoalkyl group, including het-
erocyclic amine fragments. As starting compounds we
used saturated and unsaturated β-amino ketones Ia–If
Thiosemicarbazones IIa–IIf were subjected to
heterocyclization by the action of acetic anhydride in
Scheme 1.
'
'
'
R
NR2
NR2
NR2
R
N
R
N
Ac2O
pyridine
Ac2O
pyridine
'
NR2
R
Ac
Ac
N
S
H2NC(=S)NHNH2
· HCl
· HCl
S
S
NH
· HCl
· HCl
N
N
O
NH2
IIa–IIf
NH2
NHAc
Ia–If
IIIa–IIIf
IVa–IVf
'
NR2
R
R
Ac2O, pyridine
S
NHAc
IIa–IIf
N
S
Ac
N
N
Ac
N
NHAc
A
B
R = Ph, R′ = Me (a), R′N = morpholin-4-yl (b); R = (E)-PhCH=CH, R′ = Me (c), R′N = morpholin-4-yl (d);
2
2
R = (E)-2-(2-furyl)ethenyl, R′ = Me (e), R′N = morpholin-4-yl (f).
2
556

SYNTHESIS AND INTRAMOLECULAR HETEROCYCLIZATION OF β-AMINO KETONE
557
Scheme 2.
'
'
'
R
NR2
NR2
NR2
R
N
R
N
Ac+
Ac
Ac2O, pyridine
–AcOH
Ac2O
N
· HCl
· HCl
S
S
IIa–IIf
IVa–IVf
N
· HCl
–AcOH
N
N
H2N
S–
NH2
NH2
IIIa–IIIf
pyridine. This reaction may be expected to produce
several structures, in particular five-membered dihy-
dro-1,3,4-thiadiazole ring (IVa–IVf) via intramolec-
ular heterocyclization, thiadiazepine system A as a re-
sult of elimination of secondary amine and subsequent
cyclization, and acylated thiosemicarbazone B. Anal-
ysis of the product structure, reaction course, and our
previous data [5, 6] showed that heterocyclization of
thiosemicarbazones IIa–IIf is regioselective and that
the products are mono- and bis-acylated dihydro-1,3,4-
thiadiazole derivatives IIIa–IIIf and IVa–IVf, depend-
ing on the reaction time. The IR spectra of IIIa–IIIf
contained two absorption bands in the region 3400–
3300 cm–1 due to stretching vibrations of the primary
thiosemicarbazones and their intramolecular hetero-
cyclization with formation of previously unknown
functionally substituted dihydro-1,3,4-thiadiazoles.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Varian 400 spectrometer at 400 and 100 MHz,
respectively, using DMSO-d6 as solvent and TMS as
internal reference. The IR spectra were measured in
KBr on an FSM-1201 instrument. The progress of
reactions and the purity of products were monitored by
HPLC using a Waters Alliance chromatograph
equipped with a Waters 2996 diode array detector and
a Waters SunFire C18 column (150×2.1 mm, grain
size 3.5 μm); eluent 24% MeCN–58% H2O pH 2.3–
8% MeOH–10% C7H13SO3Na (c = 0.1 M).
1
amino group. The presence in the H NMR spectra of
IIIc–IIIf of doublets at δ 6.52–6.65 ppm (J = 16 Hz)
from vinylic protons indicated trans configuration of
the exocyclic double C=C bond. Diastereotopic
protons in the α-methylene group resonated at δ 2.49–
3.06 ppm as doublets of triplets. The 13C NMR spectra
of IIIa–IIIf contained a signal at δC 82.9–83.1 ppm
from quaternary carbon atom, which rules out forma-
tion of alternative structures A and B.
Thiosemicarbazones IIa–IIf (general procedure).
A solution of 0.05 mol of ketone Ia–If and 0.06 mol of
thiosemicarbazide in 20 ml of propan-2-ol containing
a catalytic amount of hydrochloric acid was heated for
15–120 min under reflux. The mixture was cooled, and
the precipitate was filtered off and recrystallized from
propan-2-ol.
In the IR spectra of IVa–IVf we observed an ab-
sorption band at 3300–3100 cm–1, which corresponded
to stretching vibrations of the amide NH group.
Compounds IVa–IVf displayed in the 1H NMR spectra
two singlets belonging to methyl protons in two acetyl
groups, and the corresponding carbonyl carbon signals
were located at δC 167.2–169.3 ppm in the 13C NMR
spectra.
3-Dimethylamino-1-phenylpropan-1-one thio-
semicarbazone hydrochloride (IIa). Yield 67%,
mp 160–162°C. IR spectrum, ν, cm–1: 3374, 3354
(NH2), 3235 (NH), 2660 (NH+), 1200 (C=S). 1H NMR
spectrum, δ, ppm: 2.71 s (6H, Me), 2.82 t (2H,
CH2CH2N+, J = 10.8 Hz), 3.39 t (2H, CH2N+, J =
10.2 Hz), 7.54 m (5H, Ph), 8.62 s (1H, NH), 10.53 s
(2H, NH2), 11.63 s (1H, NH+). Found, %: C 50.55;
H 6.28; N 20.08. C12H19ClN4S. Calculated, %:
C 50.25; H 6.68; N 19.93.
A probable mechanism of the observed heterocy-
clization is illustrated by Scheme 2. Initial enolization
of thiosemicarbazone II is favored by deprotonation
under the action of acylating agent. Next follows
thiadiazole ring closure as a result of intramolecular
nucleophilic attack by the thiolate ion on the C=N
carbon atom. The cyclic structure is stabilized by
acylation, and the subsequent acylation of III at the
exocyclic amino group yields compounds IV.
3-(Morpholin-4-yl)-1-phenylpropan-1-one thio-
semicarbazone hydrochloride (IIb). Yield 75%,
mp 155–157°C. IR spectrum, ν, cm–1: 3456, 3345
1
(NH2), 3196 (NH), 2557 (NH+), 1191 (C=S). H NMR
spectrum, δ, ppm: 2.85 t (2H, CH2CH2N+, J = 9.5 Hz),
3.41 m (2H, CH2N+, J = 9.8 Hz), 3.91 m (4H,
OCH2CH2), 4.20 t (4H, CH2O, J = 7.8 Hz), 7.56 m
(5H, Ph), 8.75 s (1H, NH), 10.05 s (2H, NH2), 11.26 s
To conclude, we were the first to report on the
synthesis of saturated and unsaturated β-amino ketone
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 4 2012

KLOCHKOVA et al.
558
(1H, NH+). Found, %: C 51.33; H 6.94; N 17.43.
C14H21ClN4OS. Calculated, %: C 51.13; H 6.44;
N 17.04.
mp 174–176°C. IR spectrum, ν, cm–1: 3349, 3276
(NH2), 3178 (NH), 2525 (NH+), 1658 (C=C), 1178
1
(C=S). H NMR spectrum, δ, ppm: 3.02 t (2H,
CH2CH2N+, J = 9.6 Hz), 3.24 t (2H, CH2N+, J =
9.8 Hz), 3.89 m (4H, CH2CH2O), 4.04 m (4H, CH2O),
6.07 d (1H, 2-H, J = 16.0 Hz), 6.19 d (1H, 1-H, J =
16.0 Hz), 6.31–6.39 m (2H, 3′-H, 4′-H), 7.31 d (1H,
5′-H, J = 1.9 Hz), 8.89 s (1H, NH), 11.04 s (2H, NH2),
5-Dimethylamino-1-phenylpent-1-en-3-one thio-
semicarbazone hydrochloride (IIc). Yield 87%,
mp 159–161°C. IR spectrum, ν, cm–1: 3398, 3349
(NH2), 3194 (NH), 2650 (NH+), 1679 (C=C), 1197
1
(C=S). H NMR spectrum, δ, ppm: 2.81 s (6H, Me),
13
11.03 s (1H, NH+). C NMR spectrum, δC, ppm: 26.1
3.01 t (2H, CH2CH2N+, J = 12.3 Hz), 3.43 t (2H,
CH2N+, J = 11.1 Hz), 6.81 d (1H, 2-H, J = 16.0 Hz),
6.87 d (1H, 1-H, J = 16.0 Hz), 7.54 m (5H, Ph), 8.92 s
(1H, NH), 10.56 s (2H, NH2), 11.34 s (1H, NH+).
13C NMR spectrum, δC, ppm: 25.3 (CH2CH2N+), 27.1
(CH2N+), 117.9 (C2), 127.3 (C1); 126.2, 127.4, 127.6,
128.2, 128.4, 137.4 (Carom); 152.5 (C=N), 179.7 (C=S).
Found, %: C 53.92; H 7.14; N 18.04. C14H21ClN4S.
Calculated, %: C 53.75; H 6.77; N 17.91.
(CH2CH2N+), 29.6 (CH2N+), 45.4 (CH2CH2O), 68.7
(CH2O), 112.1 (C2), 118.9 (C1), 117.9 (C4′), 116.1 (C3′),
151.4 (C2′), 154.2 (C5′), 154.7 (C=N), 179.8 (C=S).
Found, %: C 48.43; H 6.41; N 16.14. C14H21ClN4O2S.
Calculated, %: C 48.76; H 6.14; N 16.25.
Dihydro-1,3,4-thiadiazoles IIIa–IIIf (general
procedure). A solution of 0.015 mol of compound IIa–
IIf and 0.06 mol of acetic anhydride in 30 ml of
pyridine was stirred for 25–50 min. The solvent was
distilled off under reduced pressure, and the precipitate
was filtered off, washed with ethanol, and recrystal-
lized from ethanol.
5-(Morpholin-4-yl)-1-phenylpent-1-en-3-one
thiosemicarbazone hydrochloride (IId). Yield 59%,
mp 181–183°C. IR spectrum, ν, cm–1: 3376, 3256
(NH2), 3178 (NH), 2520 (NH+), 1686 (C=C), 1204
1
(C=S). H NMR spectrum, δ, ppm: 2.85 t (2H,
4-Acetyl-5-[2-(dimethylamino)ethyl]-5-phenyl-
4,5-dihydro-1,3,4-thiadiazol-2-amine hydrochloride
(IIIa). Yield 47%, mp 181–182°C. IR spectrum, ν,
cm–1: 3486, 3405 (NH2), 2593 (NH+), 1641 (C=C),
CH2CH2N+, J = 12.8 Hz ), 3.41 m (2H, CH2N+, J =
12.8 Hz), 3.91 m (4H, CH2CH2O), 4.20 m (4H,
CH2O), 6.77 d (1H, 2-H, J = 16.0 Hz), 6.83 d (1H,
1-H, J = 16.0 Hz), 7.54 m (5H, Ph), 8.91 s (1H, NH),
10.14 s (2H, NH2), 10.98 s (1H, NH+). 13C NMR spec-
trum, δC, ppm: 26.3 (CH2CH2N+), 29.1 (CH2N+), 47.1
(CH2CH2O), 69.2 (CH2O), 118.2 (C2) 129.8 (C1);
125.1, 126.3, 124.6, 127.1, 127.9, 137.4 (Carom); 151.3
(C=N), 181.9 (C=S). Found, %: C 54.97; H 6.68;
N 15.51. C16H23ClN4OS. Calculated, %: C 55.11;
H 6.53; N 15.79.
1
1602 (C=N). H NMR spectrum, δ, ppm: 2.12 s (3H,
COMe), 2.74 d.t (2H, 5-CH2, J = 12.1, 4.0 Hz), 2.91 t
(2H, CH2N+, J = 11.9 Hz), 3.18 s (6H, MeN+), 7.49 m
(5H, Ph), 8.90 s (2H, NH2), 10.43 s (1H, NH+). Found,
%: C 51.27; H 6.58; N 16.89. C14H21ClN4OS. Cal-
culated, %: C 51.13; H 6.44; N 17.04.
4-Acetyl-5-[2-(morpholin-4-yl)ethyl]-5-phenyl-
4,5-dihydro-1,3,4-thiadiazol-2-amine hydrochloride
(IIIb). Yield 45%, mp 173–175°C. IR spectrum, ν,
cm–1: 3479, 3412 (NH2), 2636 (NH+), 1668 (C=C),
5-Dimethylamino-1-(2-furyl)pent-1-en-3-one
thiosemicarbazone hydrochloride (IId). Yield 85%,
mp 170–173°C. IR spectrum, ν, cm–1: 3396, 3276
(NH2), 3168 (NH), 2580 (NH+), 1659 (C=C), 1195
1
1609 (C=N), 1538. H NMR spectrum, δ, ppm: 2.13 s
(3H, COMe), 2.76 d.t (2H, 5-CH2, J = 13.6, 4.1 Hz),
3.05 t (2H, CH2N+, J = 12.8 Hz), 3.62 m (4H,
CH2CH2O), 4.02 m (4H, CH2O), 7.59 m (5H, Ph),
8.50 s (2H, NH2), 10.87 s (1H, NH+). Found, %:
C 51.43; H 6.49; N 15.37. C16H23ClN4O2S. Calculated,
%: C 51.18; H 6.25; N 15.11.
1
(C=S). H NMR spectrum, δ, ppm: 2.86 s (6H, Me),
3.15 t (2H, CH2CH2N+, J = 10.3 Hz), 3.39 t (2H,
CH2N+, J = 10.8 Hz), 6.13 d (1H, 2-H, J = 16.0 Hz),
6.21 d (1H, 1-H, J = 16.0 Hz), 6.29–6.41 m (2H, 3′-H,
4′-H), 7.34 d (1H, 5′-H, J = 1.8 Hz), 8.98 s (1H, NH),
10.25 s (2H, NH2), 10.89 s (1H, NH+). 13C NMR spec-
trum, δC, ppm: 25.3 (CH2CH2N+), 27.1 (CH2N+), 111.4
(C2), 117.5 (C1), 117.1 (C4′), 114.3 (C3′), 146.1 (C2′),
153.1 (C5′), 156.1 (C=N), 180.4 (C=S). Found, %:
C 48.03; H 6.35; N 19.01. C12H19ClN4OS. Calculated,
%: C 47.59; H 6.32; N 18.50.
4-Acetyl-5-[2-(dimethylamino)ethyl]-5-(2-phen-
ylethenyl)-4,5-dihydro-1,3,4-thiadiazol-2-amine
hydrochloride (IIIc). Yield 52%, mp 195–196° C. IR
spectrum, ν, cm–1: 3495, 3426 (NH2), 2593 (NH+),
1
1623 (C=C), 1559 (C=N). H NMR spectrum, δ, ppm:
2.08 s (3H, COMe), 2.46 d.t (2H, 5-CH2, J = 13.6,
4.2 Hz), 3.07 t (2H, CH2N+, J = 13.9 Hz), 3.18 s (6H,
MeN+), 6.52 d (1H, 5-CH=, J = 16.0 Hz), 6.78 d (1H,
1-(2-Furyl)-5-(morpholin-4-yl)pent-1-en-3-one
thiosemicarbazone hydrochloride (IIf). Yield 85%,
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SYNTHESIS AND INTRAMOLECULAR HETEROCYCLIZATION OF β-AMINO KETONE
559
13
=CHPh, J = 16.0 Hz), 7.75 m (5H, Ph), 9.30 s (2H,
NH2), 10.51 s (1H, NH+). 13C NMR spectrum, δC, ppm:
25.3 (Me), 31.9 (5-CH2), 54.6 (CH2N), 81.3 (C5),
126.1 (5-CH=), 128.4 (=CHPh); 127.4, 127.9, 128.4,
129.5, 129.8, 135.4 (Carom); 146.5 (C2), 167.9 (C=O).
Found, %: C 54.42; H 6.68; N 16.02. C16H23ClN4OS.
Calculated, %: C 54.15; H 6.53; N 15.79.
8.86 s (2H, NH2), 10.62 s (1H, NH+). C NMR spec-
trum, δC, ppm: 25.6 (Me), 29.1 (5-CH2), 32.1 (CH2N+),
46.8 (CH2CH2O), 67.9 (CH2O), 79.4 (C5), 116.2
(5-CH=), 124.2 (=CHFu), 118.1 (C4′), 119.2 (C3′),
152.3 (C2′), 156.2 (C5′), 148.9 (C2), 168.1 (C=O).
Found, %: C 50.02; H 6.09; N 14.69. C16H23ClN4O3S.
Calculated, %: C 49.67; H 5.99; N 14.48.
4-Acetyl-5-[2-(morpholin-4-yl)ethyl]-5-(2-phen-
ylethenyl)-4,5-dihydro-1,3,4-thiadiazol-2-amine
hydrochloride (IIId). Yield 51%, mp 161–162°C. IR
spectrum, ν, cm–1: 3459, 3436 (NH2), 2606 (NH+),
Dihydro-1,3,4-thiadiazoles IVa–IVf (general
procedure). A solution of 0.015 mol of IIa–IIf or IIIa–
IIIf and 0.06 mol of acetic anhydride in 30 ml of pyri-
dine was stirred for 4–6 h. The solvent was distilled off
under reduced pressure, and the precipitate was filtered
off, washed with ethanol, and recrystallized from
ethanol.
1
1617 (C=C), 1568 (C=N). H NMR spectrum, δ, ppm:
2.11 s (3H, COMe), 2.71 d.t (2H, 5-CH2, J = 13.5,
4.0 Hz), 3.07 t (2H, CH2N+, J = 13.2 Hz), 3.87 m (4H,
CH2CH2O), 4.13 m (4H, CH2O), 6.57 d (1H, 5-CH=,
J = 16.0 Hz), 6.78 d (1H, =CHPh, J = 16.0 Hz), 7.47 m
(5H, Ph), 9.02 s (2H, NH2), 10.41 s (1H, NH+).
13C NMR spectrum, δC, ppm: 24.5 (Me), 31.9 (5-CH2),
53.8 (CH2N+), 46.5 (CH2CH2O), 62.4 (CH2O), 79.4
(C5), 126.8 (5-CH=), 129.5 (=CHPh); 126.4, 126.3,
126.4, 127.3, 128.1, 134.9 (Carom), 151.6 (C2), 168.7
(C=O). Found, %: C 54.16; H 6.24; N 13.96.
C18H25ClN4O2S. Calculated, %: C 54.47; H 6.35;
N 14.11.
N-{4-Acetyl-5-[2-(dimethylamino)ethyl]-5-phen-
yl-4,5-dihydro-1,3,4-thiadiazol-2-yl}acetamide
hydrochloride (IVa). Yield 67%, mp 175–177°C. IR
spectrum, ν, cm–1: 3486 (NH), 2647 (NH+), 1623
1
(C=C), 1590 (C=N), 1540 (amide II). H NMR spec-
trum, δ, ppm: 2.07 s and 2.11 s (3H each, COMe),
2.69 d.t (2H, 5-CH2, J = 15.9, 4.0 Hz), 2.95 t (2H,
CH2N+, J = 15.4 Hz), 3.17 s (6H, Me), 7.61 m (5H,
Ph), 8.91 s (1H, NH), 10.43 s (1H, NH+). Found, %:
C 51.94; H 6.64; N 15.55. C16H23ClN4O2S. Calculated,
%: C 51.81; H 6.25; N 15.11.
4-Acetyl-5-[2-(dimethylamino)ethyl]-5-[2-(2-fu-
ryl)ethenyl]-4,5-dihydro-1,3,4-thiadiazol-2-amine
hydrochloride (IIIe). Yield 61%, mp 184–187°C. IR
spectrum, ν, cm–1: 3419, 3386 (NH2), 2623 (NH+),
N-{4-Acetyl-5-[2-(morpholin-4-yl)ethyl]-5-phen-
yl-4,5-dihydro-1,3,4-thiadiazol-2-yl}acetamide
hydrochloride (IVb). Yield 67%, mp 183–185°C. IR
spectrum, ν, cm–1: 3479 (NH), 2596 (NH+), 1654
1
1618 (C=C), 1585 (C=N). H NMR spectrum, δ, ppm:
1
2.09 s (3H, COMe), 2.45 d.t (2H, 5-CH2, J = 14.1,
3.9 Hz), 3.04 t (2H, CH2N+, J = 14.6 Hz), 3.12 s (6H,
MeN+), 6.02 d (1H, 5-CH=, J = 16.0 Hz), 6.28 d (1H,
=CHFu, J = 16.0 Hz), 6.32–6.37 m (2H, 3′-H, 4′-H),
7.38 d (1H, 5′-H, J = 1.8 Hz), 9.10 s (2H, NH2),
(C=C), 1594 (C=N), 1520 (amide II). H NMR spec-
trum, δ, ppm: 2.11 s and 2.17 s (3H each, COMe),
2.76 d.t (2H, 5-CH2, J = 15.9, 4.1 Hz), 3.05 t (2H,
CH2N+), 3.62 m (4H, CH2CH2O), 4.02 m (4H, CH2O),
7.59 m (5H, Ph), 8.91 s (1H, NH), 10.87 s (1H, NH+).
Found, %: C 52.67; H 6.31; N 13.49. C18H25ClN4O3S.
Calculated, %: C 52.36; H 6.10; N 13.57.
13
10.58 s (1H, NH+). C NMR spectrum, δC, ppm: 25.9
(Me), 27.8 (5-CH2), 29.1 (CH2N+), 87.1 (C5), 114.2
(5-CH=), 124.6 (=CHFu), 117.3 (C4′), 117.9 (C3′),
146.2 (C2′), 159.4 (C5′), 154.1 (C2), 169.4 (C=O).
Found, %: C 49.09; H 6.03; N 16.41. C14H21ClN4O2S.
Calculated, %: C 48.76; H 6.14; N 16.25.
N-{4-Acetyl-5-[2-(dimethylamino)ethyl]-5-
(2-phenylethenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl}-
acetamide hydrochloride (IVc). Yield 78%, mp 195–
196°C. IR spectrum, ν, cm–1: 3495 (NH), 2642 (NH+),
1
4-Acetyl-5-[2-(2-furyl)ethenyl]-5-[2-(morpholin-
4-yl)ethyl]-4,5-dihydro-1,3,4-thiadiazol-2-amine
hydrochloride (IIIe). Yield 57%, mp 168–171°C. IR
spectrum, ν, cm–1: 3426, 3396 (NH2), 2645 (NH+),
1619 (C=C), 1556 (C=N), 1534 (amide II). H NMR
spectrum, δ, ppm: 2.05 s and 2.16 s (3H each, COMe),
2.61 d.t (2H, 5-CH2, J = 15.8, 4.2 Hz), 3.01 t (2H,
CH2N+, J = 15.1 Hz), 3.15 s (6H, Me), 6.54 d (1H,
5-CH=, J = 16.0 Hz), 6.62 d (1H, =CHPh, J =
16.0 Hz), 7.80 m (5H, Ph), 8.58 s (1H, NH) 10.51 s
(1H, NH+). 13C NMR spectrum, δC, ppm: 24.4 and 25.6
(Me), 31.8 (5-CH2), 53.4 (CH2N+), 82.9 (C5), 124.5
(5-CH=), 127.2 (=CHPh); 128.2, 128.3, 128.5, 129.1,
129.9, 136.0 (Carom); 148.7 (C2), 166.4 and 167.3 (C=O).
1
1618 (C=C), 1578 (C=N). H NMR spectrum, δ, ppm:
2.13 s (3H, COMe), 2.45 d.t (2H, 5-CH2, J = 16.1,
3.9 Hz), 3.09 t (2H, CH2N+, J = 15.9 Hz), 3.89 m (4H,
CH2CH2O), 4.12 m (4H, CH2O), 6.21 d (1H, 5-CH=,
J = 16.0 Hz), 6.31 d (1H, =CHFu, J = 16.0 Hz), 6.28–
6.36 m (2H, 3′-H, 4′-H), 7.49 d (1H, 5′-H, J = 1.8 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 4 2012

KLOCHKOVA et al.
560
Found, %: C 54.78; H 6.70; N 14.01. C18H25ClN4O2S.
Calculated, %: C 54.47; H 6.35; N 14.11.
Found, %: C 49.51; H 6.42; N 14.39. C16H23ClN4O3S.
Calculated, %: C 49.67; H 5.99; N 14.48.
N-{4-Acetyl-5-[2-(2-furyl)ethenyl]-5-[2-(morpho-
lin-4-yl)ethyl]-4,5-dihydro-1,3,4-thiadiazol-2-yl}-
acetamide hydrochloride (IVf). Yield 68%, mp 168–
171°C. IR spectrum, ν, cm–1: 3426 (NH), 2656 (NH+),
N-{4-Acetyl-5-[2-(morpholin-4-yl)ethyl]-5-
(2-phenylethenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl}-
acetamide hydrochloride (IVd). Yield 73%, mp 187–
189°C. IR spectrum, ν, cm–1: 3459 (NH), 2634 (NH+),
1
1
1626 (C=C), 1586 (C=N), 1545 (amide II). H NMR
1621 (C=C), 1559 (C=N), 1550 (amide II). H NMR
spectrum, δ, ppm: 2.14 s and 2.16 s (3H each, COMe),
2.41 d.t (2H, 5-CH2, J = 16.2, 3.9 Hz), 3.04 t (2H,
CH2N+, J = 16.0 Hz), 3.68 m (4H, CH2CH2O), 4.13 m
(4H, CH2O), 6.19 d (1H, 5-CH=, J = 16.0 Hz), 6.28 d
(1H, =CHFu, J = 16.0 Hz), 6.29–6.34 m (2H, 3′-H,
4′-H), 7.41 d (1H, 5′-H, J = 1.9 Hz), 9.05 s (1H, NH),
spectrum, δ, ppm: 2.11 s and 2.18 s (3H each, COMe),
2.69 d.t (2H, 5-CH2, J = 16.1, 4.0 Hz), 3.14 t (2H,
CH2N+, J = 15.9 Hz), 3.71 m (4H, CH2CH2O), 4.09 m
(4H, CH2O), 6.53 d (1H, 5-CH=, J = 16.0 Hz), 6.65 d
(1H, =CHPh, J = 16.0 Hz), 7.35 m (5H, Ph), 8.91 s
13
(1H, NH), 10.41 s (1H, NH+). C NMR spectrum, δC,
13
10.59 s (1H, NH+). C NMR spectrum, δC, ppm: 22.7
ppm: 23.7 and 26.4 (Me), 32.5 (5-CH2), 52.9 (CH2N+),
45.9 (CH2CH2O), 63.5 (CH2O), 81.5 (C5), 127.1
(5-CH=), 129.3 (=CHPh); 126.1, 126.5, 126.9, 127.4,
127.6, 135.4 (Carom); 151.2 (C=N), 168.9 and 169.1
(C=O). Found, %: C 55.15; H 6.46; N 12.65.
C20H27ClN4O3S. Calculated, %: C 54.72; H 6.20;
N 12.76.
and 23.4 (Me), 28.4 (5-CH2), 31.6 (CH2N+), 47.1
(CH2CH2O), 68.4 (CH2O), 78.9 (C5), 115.1 (5-CH=),
123.4 (=CHFu), 117.4 (C4′), 118.5 (C3′), 151.2 (C2′),
154.5 (C5′), 149.3 (C=N), 169.2 and 169.7 (C=O).
Found, %: C 50.65; H 5.54; N 13.48. C18H25ClN4O4S.
Calculated, %: C 50.40; H 5.87; N 13.06.
N-{4-Acetyl-5-[2-(dimethylamino)ethyl]-5-[2-(2-
furyl)ethenyl]-4,5-dihydro-1,3,4-thiadiazol-2-yl}-
acetamide hydrochloride (IVe). Yield 78%, mp 184–
187°C. IR spectrum, ν, cm–1: 3419 (NH), 2632 (NH+),
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1
1621 (C=C), 1578 (C=N), 1542 (amide II). H NMR
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 4 2012