α-Thioureidoalkylation of 4-alkyl- and 4-phenylthiosemicarbazides

Article abstract of DOI:10.1007/s10593-011-0742-z

Previously unknown 1,3-dialkyl-4,5-bis[4-alkyl(phenyl)thiosemicarbazido] imidazolidine-2-thiones and 4,5,7-trialkylperhydroimidazo[4,5-e]-1,2,4-triazine- 3,6-dithiones have been synthesized by the α-thio-ureidoalkylation of 4-alkyl(phenyl)thiosemicarbazides using 1,3-dialkyl-4,5-dihydroxyimidazolidine- 2-thiones.

Full text of DOI:10.1007/s10593-011-0742-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 2, May, 2011 (Russian Original Vol. 47, No. 2, February, 2011)
-THIOUREIDOALKYLATION OF 4-ALKYL-
AND 4-PHENYLTHIOSEMICARBAZIDES
G. A. Gazieva1*, M. I. Struchkova1, and N. G. Kolotyrkina1
Previously unknown 1,3-dialkyl-4,5-bis[4-alkyl(phenyl)thiosemicarbazido]imidazolidine-2-thiones and
4,5,7-trialkylperhydroimidazo[4,5-e]-1,2,4-triazine-3,6-dithiones have been synthesized by the -thio-
ureidoalkylation of 4-alkyl(phenyl)thiosemicarbazides using 1,3-dialkyl-4,5-dihydroxyimidazolidine-
2-thiones.
Keywords: 4-alkyl(phenyl)thiosemicarbazides, 1,3-dialkyl-4,5-bis(4-alkyl(phenyl)thiosemicarbazido)-
imidazolidine-2-thiones, 1,3-dialkyl-4,5-dihydroxyimidazolidine-2-thiones, -thioureidoalkylation.
Thiosemicarbazides have been of considerable interest in synthetic organic chemistry for many years.
They are readily available and, thanks to the presence of several active reaction centers, are widely used as
multipurpose reagents in organic synthesis, especially in the preparation of biologically active thiosemicarbazones
and of nitrogen- and sulfur-containing heterocyclic compounds, e.g. thiazoles, thiadiazoles, triazoles, pyrazoles,
thiadiazines, pyrimidines, etc. [1-6]. Thiosemicarbazide based substances show anticancer [1, 2, 7], antiparasitic [3,
4], and antimicrobial [5, 6] activity.
We have previously studied the -thioureidoalkylation reaction of a thiosemicarbazide to give the
1,3-dialkyl-4,5-bis(thiosemicarbazido)imidazolidine-2-thiones 1a,b and the 5,7-dialkylperhydroimidazo[4,5-e]-
1,2,4-triazine-3,6-dithiones 2a,b [8].
S
H
N
R
R
H
N
NH2
NH2
N
H
N
N
NH
S
S
H
N
N
N
S
N
H
N
H
R
R
S
1a,b
2a,b
1, 2 a R = Me, b R = Et
_______
Dedicated to L. I. Belen'kii on the occasion of his eightieth birthday.
* To whom correspondence should be addressed, e-mail: gaz@ioc.ac.ru.
1N. D. Zelinsky Institute for Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Pr., Moscow
119991, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 266-270, February, 2011. Original
article submitted January 24, 2011.
210
0009-3122/11/4702-0210©2011 Springer Science+Business Media, Inc.

In this work we have now studied the reaction of the 4-alkyl- and 4-phenylthiosemicarbazides 3a-d with the
4,5-dihydroxyimidazolidine-2-thiones 4a,b and the effect of the substituent at position 4 of the thiosemicarbazide 3
on the reaction routes and yields. The -thioureidoalkylation was carried out at 50-90ºC under HCl catalyzed
conditions in water, isopropyl alcohol, or their mixture (depending on the solubility of the thiosemicarbazide). The
highest yields of the 1,3-dialkyl-4,5-bis(4-alkyl(phenyl)thiosemicarbazido)imidazolidine-2-thiones 5a-h (70-82%)
were achieved by carrying out the reaction at 70-80ºC for 2 h. At lower temperature over 24 h the reaction
mixture contains about 40% of the unreacted initial 3a-d and 4a,b materials. At 90ºC the
dihydroxyimidazolidinethiones 4a,b give 30-35% of 1,3-dialkyl-2-thioxoimidazolidin-4-ones (thiohydantoins
[8]) and this leads to a lowering of the yields of compounds 5a-h.
R2
S
R2
R2
H
N
H
N
H
N
R1
R1
OH
NH2
N
N
N
N
N
N
H
N
H
NH
S
+
S
S
S
+
NHR1
N
H
N
N
H
N
H
N
R1
S
OH
N
H
R2
R2
R2
S
4a,b
3a–d
5a–h
6a–f
3a, 5a,b, 6a,b R1 = Me, 3b, 5c,d, 6c,d R1 = Et, 3c, 5e,f, 6e,f R1 = i-Bu, 3d, 5g,h R1 = Ph;
4a, 5a,c,e,g, 6a,c,e R2 = Me, 4b, 5b,d,f,h, 6b,d,f R2 = Et
TABLE 1. Characteristics and High Resolution Mass Spectra* of
Compounds 5a-f and 6a,b
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
(decomp.)
Yield,
%
C
H
N
S
5a
5b
C9H20N8S3
C11H24N8S3
255-257
205-207
77-79
80-82
C11H24N8S3
C13H28N8S3
C15H32N8S3
C17H36N8S3
C19H24N8S3
C21H28N8S3
C7H13N5S2
C9H17N5S2
232-234
225-227
216-218
184-186
186-189
196-198
262-264
230-232
74-76
74-77
71-74
73-76
70-73
71-74
2-5
5c
5d
5e
5f
42.74
42.83
45.66
45.50
49.49
49.54
7.69
7.67
8.13
8.09
5.27
5.25
26.71
26.64
24.91
24.97
24.38
24.33
22.78
22.87
21.37
21.44
20.79
20.88
5g
5h
6a
36.39
36.34
41.62
41.67
5.72
5.66
6.68
6.61
30.23
30.27
27.05
27.00
27.61
27.72
24.60
24.72
6b
2-5
_______
* Mass spectrum:
5a – found, m/z 359.0867 [M+Na]+; calculated, [М+Na]+ 359.0865;
5b – found, m/z 387.1177 [M+Na]+; calculated, [М+Na]+ 387.1178;
5c – found, m/z 387.1182 [M+Na]+; calculated, [М+Na]+ 387.1178;
5d – found, m/z 391.1521 [M–H]–; calculated, [М–H]– 391.1515;
5h – found, m/z 487.1527 [M–H]–; calculated, [М–H]– 487.1515
211

In addition to the derivatives 5a,b the reaction of compounds 4a,b with the thiosemicarbazide 3a also
gives the imidazotriazines 6a,b in 2-5% yields. The 1H NMR spectra of the reaction masses of
imidazolidinethiones 4a,b and thiosemicarbazones 3b,c evaporated to dryness show both signals for compounds
5c-f and also for the 4,5,7-trialkylperhydroimidazo[4,5-e]-1,2,4-triazine-3,6-dithiones 6c-f with low intensity
(typical multiplets for the bridging CH protons at 5.25-5.42 and proton singlets for two NH groups at 5.7-5.8
and 9.4-9.6 ppm being observed).
TABLE 2. 1H NMR Spectra of Compounds 5a-h and 6a,b
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
5a
5b
2.93 (6H, d, J = 4.3, NCH3); 2.98 (6H, s, NCH3); 4.15 (2H, s, CH);
6.04 (2H, s, NH); 8.10 (2H, q, J = 4.3, NH); 8.80 (2H, s, NH)
0.92 (6H, t, J = 6.8, CH3); 2.92 (6H, d, J = 4.0, CH3); 3.19-3.25 (2Н, m, NСН2);
3.86-3.93 (2Н, m, NСН2); 4.27 (2H, s, CH); 6.01 (2H, s, NH);
8.03 (2H, q, J = 3.9, NH); 8.69 (2H, s, NH)
5c
1.08 (6H, t, J = 6.9, CH3); 2.99 (6H, s, NCH3); 3.45-3.55 (4Н, m, NСН2);
4.20 (2H, s, CH); 6.01 (2H, s, NH); 8.08 (2H, br. s, NH); 8.74 (2H, s, NH)
5d
0.95 (6H, t, J = 6.9, CH3); 1.09 (6H, t, J = 7.0, CH3); 3.18-3.28 (2Н, m, NСН2);
3.42-3.59 (4Н, m, 2NСН2); 3.86-3.98 (2Н, m, NСН2); 4.33 (2H, s, CH);
5.97 (2H, s, NH); 7.99 (2H, br. s, NH); 8.55 (2H, s, NH)
5e
5f
0.85 (12H, d, J = 6.5, CH3); 1.87-1.96 (2H, m, CH); 3.00 (6H, s, NCH3);
3.22-3.31 (4Н, m, NСН2); 4.27 (2H, s, CH); 6.05 (2H, s, NH);
7.98 (2H, br. s, NH); 8.77 (2H, s, NH)
0.86 (12H, d, J = 6.5, CH3); 0.95 (6H, t, J = 6.6, CH3); 1.87-1.95 (2H, m, CH);
3.22-3.32 (6Н, m, 3NСН2); 3.87-3.98 (2Н, m, NСН2); 4.38 (2H, s, CH);
6.03 (2H, s, NH); 7.92 (2H, br. s, NH); 8.63 (2H, s, NH)
5g
5h
3.08 (6H, s, NCH3); 4.47 (2H, s, CH); 6.40 (2H, s, NH); 7.15 (2H, t, J = 7.1, H Ph);
7.31 (4H, t, J = 7.5, H Ph); 7.50 (4H, br. s, H Ph); 9.28 (2H, s, NH); 9.83 (2H, s, NH)
0.99-1.05 (6H, m, CH3); 3.27-3.34 (2H, q, J = 7.1, NCH2);
3.96-4.03 (2H, q, J = 7.1, NCH2); 4.55 (2H, s, CH); 6.38 (2H, s, NH);
7.17 (2H, t, J = 6.9, H Ph); 7.33 (4H, t, J = 7.4, H Ph); 7.50 (4H, d, J = 6.4, H Ph);
9.21 (2H, s, NH); 9.80 (2H, s, NH)
6a
6b
2.95 (3H, s, NCH3); 3.07 (3H, s, NCH3); 3.29 (3H, s, NCH3); 5.25-5.36 (2Н, m, CH);
5.83 (1H, s, NH); 9.50 (1H, s, NH)
1.05-1.11 (6H, m, CH3); 3.28 (3H, s, NCH3); 3.31-3.71 (4H, m, NCH2);
5.33-5.42 (2Н, m, CH); 5.77 (1H, s, NH); 9.49 (1H, s, NH)
TABLE 3. 13C NMR Spectra of Compounds 5a-h and 6a,b
Com-
pound
Chemical shifts, δ, ppm
5a
5b
30.6 (NCH3), 32.1 (NCH3), 76.4 (CH), 182.1 (C=S), 183.0 (C=S)
11.4 (CH3), 30.6 (NCH3), 37.6 (NCH2), 73.0 (CH), 180.4 (C=S),
183.1 (C=S)
5c
5d
5e
14.6 (CH3), 32.1 (NCH3), 37.9 (NCH2), 76.6 (CH), 181.9 (C=S), 182.1 (C=S)
11.4 (CH3), 14.7 (CH3), 37.6 (NCH2), 37.8 (NCH2), 73.1 (CH), 180.3 (C=S), 181.9 (C=S)
20.0 (CH3), 27.8 (CH), 32.0 (NCH3), 50.5 (NCH2), 76.7 (CH cycle), 182.1 (C=S),
182.4 (C=S)
5f
12.2 (CH3), 20.6 (CH3), 28.4 (CH), 38.2 (NCH2), 51.1 (NCH2), 74.0 (CH cycle),
180.9 (C=S), 183.1 (C=S)
5g
5h
32.2 (NCH3), 76.6 (CH), 124.9, 125.5, 128.0, 138.9 (all Ph), 181.2 (C=S), 182.3 (C=S)
11.6 (CH3), 37.6 (NCH2), 72.9 (CH), 125.0, 125.5, 128.0, 138.9 (all Ph),
180.5 (C=S), 181.4 (C=S)
6a
6b
31.2 (NCH3), 33.5 (NCH3), 40.1 (NCH3), 72.5 (CH), 75.9 (CH), 182.1 (C=S),
188.8 (C=S)
12.2 (CH3), 12.7 (CH3), 38.3 (NCH2), 39.9 (NCH3), 70.9 (CH), 74.8 (CH),
180.7 (C=S), 189.8 (C=S)
212

Hence the nature of the substituent at position 4 of the thiosemicarbazide does not appear to have a
major effect on the reaction product yields for 5a-h, being little lowered upon lengthening or branching the alkyl
chain at position 4 of the starting thiosemicarbazide (Table 1). We have previously obtained the imidazotriazines
2a,b (unsubstituted on the N(4) atom) in 5-15% yields [8]. The yield of the 4-substitued imidazotriazines 6 is
lower. The 4-methyl derivatives 6a,b are produced in 2-5% yields, the 4-ethyl- (6c,d), and 4-isobutyl derivatives
(6e,f) in trace quantities, but the 4-phenylimidazotriazines are not formed under the conditions studied.
Compound 5b was investigated for cytotoxic activity in the Institute of Technical Chemistry (Ural
Branch, Russian Academy of Sciences) with respect to the cell lines MS (human melanoma) and A549 (human
microcellular lung cancer). The compound studied showed weak cytotoxic activity towards the MS cell line
(IC50 = 238.47 ± 24.19 M/l) but did not show activity towards the A549 line.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker AM 300 spectrometer (300 and 75 MHz
respectively) using DMSO-d6 with TMS as internal standard. High resolution mass spectra were recorded on a
Bruker microTOF II instrument using electrospray ionization [9]. Measurements were carried out on positive
(capillary voltage 4500 V) or negative ions (capillary voltage 3200 V). The mass scanning range was 50-3000 D
with external or internal calibration (Electrospray Calibrant Solution, Fluka). Spray injection of the substances
was used for solutions in methanol with flow rate 3l/min. The gas carrier was nitrogen (4 l/min) and the
interface temperature 180ºC. Melting points were determined on a Gallenkamp apparatus from the Sanyo
Company.
1,3-Dialkyl-4,5-dihydroxyimidazolidine-2-thiones were synthesized by a previously devised method
from 1,3-dialkylureas and glyoxal [10]. The 4-alkyl(phenyl)thiosemicarbazides were prepared from hydrazine
and the corresponding alkyl(phenyl)isothiocyanate [11].
1,3-Dialkyl-4,5-bis[4-alkyl(phenyl)thiosemicarbazido]imidazolidine-2-thiones 5a-h and 4,5,7-Tri-
alkylperhydroimidazo[4,5-e]-1,2,4-triazine-3,6-dithiones 6a,b (General Method). Conc. HCl (2 drops) was
added to a solution of the 4,5-dihydroxyimidazolidine-2-thione 4a or 4b (5 mmol) and the corresponding
thiosemicarbazide 3a-d (10 mmol) in water (10 ml) for compounds 5a-d, in 2-propanol (10 ml) for compounds
5g,h, or in a mixture of water (7 ml) and 2-propanol (3 ml) for compounds 5e,f. The product was stirred for 2 h
at 70-80ºC. After cooling, the precipitated compounds 5c-h and mixtures of compounds 5a,b and 6a,b were
filtered off and recrystallized from methanol. Compounds 5a,b and 6a,b were separated by fractional
crystallization from methanol.
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