Thiosemicarbazides of piperidylacetic acid in the synthesis of bisheterocyclic compounds

Full text of DOI:10.1134/S107036321507035X

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 7, pp. 1775–1778. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © M.A. Dyusebaeva, S.N. Kalugin, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 7, pp. 1214–1216.
LETTERS
TO THE EDITOR
Dedicated to the memory of Sh.S. Akhmedova
Thiosemicarbazides of Piperidylacetic Acid in the Synthesis
of Bisheterocyclic Compounds
M. A. Dyusebaeva and S. N. Kalugin
Al-Farabi Kazakh National University, pr. Al-Farabi 71, Almaty, 050040 Kazakhstan
e-mail: moldyr.dyusebaeva@mail.ru
Received March 17, 2015
Keywords: piperidine, thiosemicarbazide, thiadiazole, triazole, heterocyclization, thione–thiol tautomerism
DOI: 10.1134/S107036321507035X
Among the developed directions to search new
medicines the most attention has been paid to
derivatives of the nitrogen-containing heterocycles and
first all to piperidine derivatives [1, 2].
benzoic acid N-[5-(piperidin-1-ylmethyl)-1,2,4-thiadiazol-
2-yl]amide VI (Scheme 1).
It was found that in the presence of concentrated
alkaline compounds II and III converted to the thiolate
form that was favorable for intramolecular cyclization
[6, 7] due to an attack of the electron-deficient carbon
atom of the carbonyl group by nucleophilic nitrogen
atom with formation of stable compounds VII and
VIII. Based on the spectral characteristics the prepared
compounds occurred to be substituted 1,2,4-triazole-5-
thiones. In the IR spectra of compounds VII and VIII
absorption in the field 2600–2500 (S–H) and 900–
850 cm–1 (C–S–H) was not registered, but there were
two maxima at 1342 and 1320 cm–1 corresponded to
the vibrations of C=S bond of 1,2,4-triazole-5-thione
(Scheme 2).
In the course of the purposeful investigations [3–5]
on the synthesis of biologically active compounds in
the rank of nitrogen-contained heterocycles, the
synthesis of thiosemicarbazides as the main starting
compounds for preparing of biheterocyclic compounds
was per-formed, and some of their reactions were
investigated.
Thus, for preparation of 1,3,4-thiadiazoles IV and V,
cyclization of thiosemicarbazides II and III obtained
from 2-(piperidin-1-yl)acetohydrazine I was performed
in acidic medium.
Acylation of compound IV with benzoyl chloride in
benzene in the presence of trimethylamine afforded
It is known that due to the thione–thiol tautomerism
in the molecule of 1,3,4-triazoel-5-thiones there are
Scheme 1.
H+
C6H5COCl
N
N
N
N
N N
S
N N
S
H2C
NHR
H2C
NHCOC6H5
CH2CNHNHCNHR
CH2CNHNH2
O
S
O
IV, V
VI
II, III
I
R = H (II, IV), Ph (III, V).
1775

1776
DYUSEBAEVA, KALUGIN
temperature followed by alkalization up to pH 6–7.
Scheme 2.
The formed precipitate was filtered and recrystallized
from petroleum ether. Yield 1.38 g (64.0%), mp 226–
228°С. IR spectrum, ν, cm–1: 3305–3240 (NH2), 3210
(СN), 1660 (С=О), 1270 (С=S). Found, %: С 44.42; Н
7.46; N 25.90. C8H16N4OS. Calculated, %: С 44.25; Н
7.29; N 25.63.
N
N NH
−OH
II, III
H2C
S
N
R
N-Phenyl-2-[2-(piperidin-1-yl)acetyl]thiosemi-
carbazide (III). Phenyl isothiocyanate (1.35 g,
0.01 mol) was added to a solution of 2-(piperidin-1-yl)-
acetohydrazine I (1.57 g, 0.01 mol) in 20 mL of
ethanol. The reaction mixture was stirred for 5 h at 60–
65°C. After removing of the solvent, the residue was
recrystallized from petroleum ether. Yield 2.63 g
(90.2%), mp 165–166°С. IR spectrum, ν, cm–1: 3120–
3220 (NH), 3040 (С=С, arom.), 1675 (С=О), 1450–
1605 (С=С, arom.), 1250 (С=S), 690 (С=С, arom.). 1Н
NMR spectrum (DMSO-d6), δ, ppm: 1.41 m (2H,
CH2), 1.63 m (4H, 2-CH2), 2.41 t (4H, 2-CH2, J 4.44
Hz), 3.14 s (2H, NCH2), 7.16–7.51 m (5H, ArH), 10.40
s (1H, NHС=О), 13.72 (1Н, NHC=S). Found, %: С
57.53; Н 6.85; N 19.18. С14Н20N4OS. Calculated, %: С
57.22; Н 6.54; N 19.03.
VII−VIII
R = H (II, VII), Ph (III, VIII).
two reaction sites, NH and SH, that gives an op-
portunity to prepare various derivatives. Alkylation
and acylation of 4-phenyl-3-(piperidin-1-ylmethyl)-
1H-1,2,4-triazole-5(4H)-thione VIII were done by us
(Scheme 3).
Using the procedure elaborated earlier [8] alkyla-
tion of 1,2,4-triazole-5-thione VIII with butyl bromide
and ethyl bromoacetate provided compounds IX and
X. Acylation of compound VIII with benzoyl chloride
led to the formation of phenyl[4-phenyl-3-(piperidin-1-
ylmethyl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]-
ketone XI.
2-[2-(Piperidin-1-yl)acetyl]thiosemicarbazide (II).
A mixture of 2-(piperidin-1-yl)acetohydrazine I (1.57 g,
0.01 mol), potassium rhodanide (1.1 g, 0.015 mol),
1.5 mL of hydrochloric acid, and 20 mL of water was
stirred for 4 h at 95°C, and then left for 24 h at room
The general procedure for the synthesis of 1,3,4-
thiadiazoles (IV, V). Thiosemicarbazide II or III
(0.01 mol) was dissolved in 5.2 mL of conc. sulfuric
acid. The obtained solution was poured into 100 mL of
cooled water. The formed white crystalline solid was
Scheme 3.
N
N
N NH
N N
H2C
S
H2C
SH
N
N
R1
R1
VII−VIII
R2Br
PhCOCl
N
N
N N
N N
COPh
H2C
SR2
H2C
S
N
N
R1
R1
IX, X
XI
R1 = H (VII), Ph (VIII); R2 = C4H9 (IX), CH2COOC2H5 (X).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 7 2015

THIOSEMICARBAZIDES OF PIPERIDYLACETIC ACID
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filtered off, washed with ethanol, and recrystallized
from ethanol.
NCH2), 7.44–7.56 m (5H, ArH), 11.25 s (1H, NH).
Found, %: С 61.31; Н 6.59; N 20.43. С14Н18N4S.
Calculated, %: С 61.16; Н 6.87; N 20.03.
5-(Piperidin-1-ylmethyl)-1,3,4-thiadiazolyl-2-amine
(IV). Yield 1.5 g (75.6%), mp 265–266°С. IR spectrum,
ν, cm–1: 3305–3255 (NH2), 1605 (С=N), 1515–860
(thiadiazole). Found, %: С 48.46; Н 7.12; N 28.26.
C8H14N4S. Calculated, %: С 48.25; Н 7.16; N 28.13.
1-[(5-Butylthio)-4-phenyl-4H-1,2,4-triazol-3-yl-
methyl]piperidine (IX). Butyl bromide (1.37 g,
0.01 mol) was added to a mixture of compound VIII
(2.74 g, 0.01 mol) and triethylamine (1.01 g, 0.01 mol)
in 20 mL of absolute ethanol. The reaction mixture
was heated for 6 h at 70–75°C. After the reaction
completed, ethanol was distilled off. The residue was
washed with diethyl ether and recrystallized from
ethanol. Yield 2.59 g (78.7%), mp 238–240°С. IR
spectrum, ν, cm–1: 3045 (С=С, arom.), 1605 (С=N),
1450–1590 (С=С, arom.). Found, %: С 65.45; Н 7.90;
N 16.97. С18Н26N4S. Calculated, %: С 64.72; Н 7.74;
N 16.82.
N-Phenyl-5-(piperidin-1-ylmethyl)-1,3,4-thiadiazolyl-
2-amine (V). Yield 1.71 g (62.1%), mp 154–155°С. IR
spectrum, ν, cm–1: 3150 (NH), 1670 (С=N), 1440–
1
1660 (С=С, arom.). Н NMR spectrum (DMSO-d6), δ,
ppm: 1.35 m (2H, CH2), 1.50 m (4H, 2-CH2), 2.10 t
(4H, 2-CH2, J 4.44 Hz), 2.44 s (2H, NCH2), 7.10–7.65
m (5H, ArH). Found, %: С 61.06; Н 6.95; N 20.34.
С14Н19N4S. Calculated, %: С 60.82; Н 6.62; N 20.61.
Benzoic acid N-[5-(piperidin-1-ylmethyl)-1,3,4-
thiadiazol-2-yl]amide (VI). Benzoyl chloride (0.7 g,
0.0052 mol) was added to a mixture of 5-(piperidin-1-
ylmethyl)-1,3,4-thiadiazolyl-2-amine IV (1.02 g,
0.005 mol) and triethylamine (0.52 g, 0.0052 mol) in
20 mL of benzene. The reaction mixture was heated
for 2 h at 60–70°C; after the solvent removing, the
residue was recrystallized from petroleum ether. Yield
1.1 g (72.5%), mp 248°С. IR spectrum, ν, cm–1: 3220
(NH), 3030 (С=С, arom.), 1725 (С=О), 1620 (С=N),
1530–1590, (С=С, arom.), 660 (С=С, arom.). Found,
%: С 59.58; Н 6.00; N 18.53. C15H18N4OS. Calculated,
%: С 59.17; Н 6.13; N 18.40.
Ethyl 2-[4-phenyl-5-(piperidin-1-ylmethyl)-4H-
1,2,4-triazol-3-yl]thioacetate (X). Freshly distilled
ethyl bromoacetate (1.8 g, 0.11 mol) was added to a
mixture of compound VIII (2.74 g, 0.01 mol) and
potassium carbonate (2.1 g, 0.015 mol) in 50 mL of
anhydrous acetone. The reaction mixture was heated at
55–60°C for 6 h. The precipitated potassium bromide
was filtered off and washed with acetone. The filtrate
was evaporated; the residue was acidified with solution
of HCl in diethyl ether. The precipitate was filtered off
and recrystallized from ethanol. Yield 2.71 g (68.4%),
mp 254–255°С. IR spectrum, ν, cm–1: 1735 (С=О),
1620 (С=N), 1235 (C–O–C), 940–1450 (С=С, arom.).
Found, %: С 60.00; Н 6.67; N 15.55. С18Н24N4O2S.
Calculated, %: С 59.83; Н 6.85; N 15.32.
The general procedure for the synthesis of sub-
stituted 1,2,4-triazole-5-thiones (VII, VIII). A mix-
ture of thiosemicarbazide II or III (0.01 mol) and 10%
potassium hydroxide (20 mL) was heated for 6 h at
80–85°C. After cooling the reaction mixture was
acidified with hydrochloric acid up to pH 6–7. The
formed precipitate was filtered off and recrystallized
from acetone.
Phenyl[4-phenyl-3-(piperidin-1-ylmethyl)-5-thi-
oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]ketone (XI).
Benzoyl chloride (1.40 g, 0.01 mol) was slowly added
to a mixture of compound VIII (2.74 g, 0.01 mol) and
triethylamine (1.0 g, 0.01 mol) in 25 mL of absolute
benzene. The reaction mixture was heated for 2 h at
60–70°C. After cooling the precipitate was filtered off
and recrystallized from ethanol. Yield 2.36 g (62.6%),
mp 240°С. IR spectrum, ν, cm–1: 3080 (С=С, arom.),
1665 (С=С), 1650 (С=N), 1450–1590 (С=С, arom.),
3-(Piperidin-1-ylmethyl)-1H-1,2,4-triazol-5(4H)-
thione (VII). Yield 1.83 g (92.5%), mp 179–180°С. IR
spectrum, ν, cm–1: 3210 (NH), 1605 (С=N), 1320 (C=S).
Found, %: С 48.16; Н 7.12; N 28.26. C8H14N4S. Cal-
culated, %: С 48.13; Н 7.02; N 28.17.
1
1330 (C=S), 690 (С=С, arom.). Н NMR spectrum
(DMSO-d6), δ, ppm: 1.54 m (2H, CH2), 1.71 m (4H, 3-
CH2), 2.10 t (4H, 2-CH2, J 4.4 Hz), 4.36 s (2H, NCH2),
7.32–7.67 m (10H, ArH). Found, %: С 66.64; Н 5.86;
N 14.80. C21H22N4OS. Calculated, %: С 66.34; Н 5.56;
N 14.35.
4-Phenyl-3-(piperidin-1-ylmethyl)-1H-1,2,4-tri-
azole-5(4H)-thione (VIII). Yield 2.62 g (95.7%), mp
183–184°С. IR spectrum, ν, cm–1: 3100–3300 (NH),
3040 (C=C, arom.), 1590 (CN), 1450–1605 (C=C,
1
arom.), 1380 (C=S), 685 (C=C, arom.). Н NMR
spectrum (DMSO-d6), δ, ppm: 1.30 m (2H, CH2), 1.42
m (4H, 3-CH2), 2.31 m (4H, 2-CH2), 3.30 s (2H,
The reaction progress was monitored by the means
of TLC on Silufol UV-254 plates developing with
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DYUSEBAEVA, KALUGIN
Chem. J., 2004, vol. 1, p. 19. DOI: 10.1023/
B:PHAC.0000027638.24327.bd.
iodine vapors. IR spectra were registered on a Specord
75 IR spectrometer. 1H NMR spectra were recorded on
a Bruker WM 250 and Bruker DRX 500 instruments.
3. Dyusebaeva, M.A., and Akhmedova, Sh.S., Izv. NTO
“KAKHAK,” 2013, no. 4, p. 10.
ACKNOWLEDGMENTS
4. Dyusebaeva, M.A., Akhmedova, Sh.S., and Abilov, Zh.A.,
Vestn. KazNU, 2008, no. 2, p. 87.
This work was financially supported by the
Committee of Science of the Ministry of Education
and Science of the Republic of Kazakhstan (project
no. 2290/GF 4).
5. Nurkenov, O.N., Kulakov, I.V., Satpaeva, Zh.B.,
Zhakina, Zh.B., and Kalugin, S.N., Vestn. KazNU, 2011,
no. 1, p. 322.
6. Kochikyan, T.V., Samvelian, M.A., Arutyunyan, V.S.,
Avetisyan, A.A., Tamazyan, R.A., and Aivazyan, A.G.,
Russ. J. Org. Chem., 2010, vol. 46, no. 4, p. 551. DOI:
10.1134/S1070428010040184.
REFERENCES
7. Mohd, A., and Kumar, S., Eur. J. Med. Chem., 2004,
1. Kurbat, N.M., Praliev, K.D., Salita, T.A., Yu, V.K., and
Verina, L., Pharm. Chem. J., 1991, vol. 25, no. 7,
p. 450. DOI: 10.1007/BF00771998.
vol. 39, p. 535. DOI: 10.1016/j.ejmech.2004.02.008.
8. Kuchukguzel, I., Kuchukguzel, S., Rollas, S., and Kiraz, M.,
Bioorg. Med. Chem. Lett., 2001, vol. 11, p. 1703. DOI:
10.1016/S0960-894X(01)00283-9.
2. Baikenova, G.G., Abdulina, G.A., Gazaliev, A.M.,
Fazylov, S.D., and Kudaibergenova, S.Zh., Pharm.
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