Polyfunctional nitriles in the synthesis of derivatives of 1,3,4-thiadiazolo-[3,2-a]pyrimidines

Article abstract of DOI:10.1007/s10593-008-0125-2

A one-pot method has been developed for the synthesis of 2-R-7-methyl-5-oxo-5H-1,3,4-thia-diazolo[3,2-a]pyrimidine by condensation of β-alkylthio(alkoxy)propionitrile, thiosemicarbazide, and ethyl acetoacetate in PPA, and also (7-methyl-5-oxo-5H-1,3,4-thidiazolo[3,2-a]pyrimidin-2-yl)- acetamide from cyanoacetamide, thiosemicarbazide, and ethyl acetoacetate.

Full text of DOI:10.1007/s10593-008-0125-2

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
POLYFUNCTIONAL NITRILES
IN THE SYNTHESIS OF DERIVA-
TIVES OF 1,3,4-THIADIAZOLO-
[3,2-a]PYRIMIDINES
M. A. Kukaniev, M. D. Osimov, Z.G. Sangov,
S. S. Safarov, M. B. Karimov, and T. R. Radjabov
A one-pot method has been developed for the synthesis of 2-R-7-methyl-5-oxo-5H-1,3,4-thia-
diazolo[3,2-a]pyrimidine by condensation of β-alkylthio(alkoxy)propionitrile, thiosemicarbazide, and
ethyl acetoacetate in PPA, and also (7-methyl-5-oxo-5H-1,3,4-thidiazolo[3,2-a]pyrimidin-2-yl)-
acetamide from cyanoacetamide, thiosemicarbazide, and ethyl acetoacetate.
Keywords: alkylthio(alkoxy)propionitrile, (7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)-
acetamide, ethyl acetoacetate, 2-R-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine, PPA,
thiosemicarbazide.
In recent times there has been intense investigation associated the chemistry of derivatives of 5-oxo-5H-
1,3,4-thiadiazolo[3,2-a]pyrimidines (TP) due to their wide range of biological activity. 2R-thio-TPs which have
high anticancer activity are of particular interest [1-4].
The most widely used method for the synthesis of derivatives of 1,3,4-thidiazolo[3,2-a]pyrimidine is the
cyclocondensation of 2-amino-5-R-1,3,4-thiadiazole with ethyl acetoacetate in PPA. It is known that the
reaction of nitrile-containing organic compounds with thiosemicarbazide in PPA gave 2-amino-5R-1,3,4-
thiadiazoles [5-10] and that the ammonia evolved in the reaction formed ammonium polyphosphate.
In the present work we have found that heating 3-alkylthio(alkoxy)propionitriles with thiosemicarbazide
in PPA (95-100°C, 5-6 h) gave 2-aminothiadiazoles 2 in high yield.
This method ensures the more rapid formation of 5-(β-alkylthioethyl)-2-amino-1,3,4-thiadiazole which
leads to the decreasing of the reaction time (4-5 h compared with 15-20 h for known methods [11, 12]) and the
high yield of the end product (78-84%).
When phenoxypropionitrile was used as the starting material we were unable to obtain the expected
2-amino-5-phenoxyethyl-1,3,4-thiadiazole. This is evidently connected with the instability of phenoxypropio-
nitrile under the reaction conditions.
The interaction of thiosemicarbazide with β-alkylthio(alkoxy)propionitriles 1a-f in the presence of ethyl
acetoacetate in a single stage led to 2-R-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidines 3a-f.
__________________________________________________________________________________________
V. I. Nikitin Institute of Chemistry, Tadzhikistan Academy of Sciences, Dushanbe 734063,
Tadzhikistan; e-mail: kukaniev@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7,
1096-1100, July, 2008. Original article submitted July 30, 2007.
882
0009-3122/08/4407-0882©2008 Springer Science+Business Media, Inc.

Evidently the nitriles 1 in a medium of PPA are readily converted to iminoesters of PPA [13], which on
reaction with thiosemicarbazide are converted into amidrazones A, followed by loss of a molecule of ammonia
to give compounds 2a-f.
S
NH
H2N–NH–CS–NH2
RX–CH2–CH2–CN
+
RX–CH2–CH2–C–NH–NH–C–NH2
A
1a–f
O
N
N
AcCH2COOEt
N
N
RXCH2CH2
S
NH2
RXCH2CH2
S
N
Me
2a–f
3a–f
a Х = O, R = Et; b X = O, R = C5H11; c−f X = S; c R = Me, d R = Et, e R = Pr, f R = Bu
In the IR spectra of compounds 3 there are absorption bands of carbonyl groups in the 1690-1720 cm-1
range and C=N and C=C absorptions in the 1590-1640 cm-1 range.
In the 1H NMR spectra there are signals in the 6.17-6.25 ppm range corresponding to protons in position
6 of the rings, and signals in the 2.15-2.20 ppm range (CH3 in position 7).
We have carried out synthesis of (7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)acetamide
by three-step condensation of cyanoacetamide, thiosemicarbazide, and ethyl acetoacetate in PPA (80% yield).
Compound 4 was also obtained by convergent synthesis using the interaction of 2-ethoxy-
carbonylmethyl-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine with ammonia in ethanol solution at
room temperature (2 h), with subsequent boiling for 1 h (83% yield).
Table 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
2a
2b
2c
2d
2e
2f
С6H11N3ОS
41.74
41.60
50.17
50.20
34.20
34.26
38.00
38.07
41.31
41.35
44.13
44.21
50.67
50.19
55.88
55.69
44.51
44.79
47.07
47.04
48.99
49.04
50.88
50.86
6.77
6.40
7.30
7.53
5.11
5.18
5.85
5.86
6.42
6.44
6.85
6.96
5.60
5.48
6.71
6.47
4.18
4.59
5.10
5.13
5.59
5.61
6.01
6.05
128-130
134-136
160-162
158-160
165-167
168-170
130-132
50-54
82
85
76
77
87
91
78
77
47
68
69
65
83
С9H16N3ОS
С5H9N3S2
С6H11N3S2
С7H13N3S2
С8H15N3S2
3a
3b
3c
3d
3e
3f
С10H13N3О2S
С13H18N3О2S
С9H11N3ОS2
С10H13N3ОS2
С11H15N3ОS2
С12H17N3ОS2
С8H8N4О2S
173-175
86-88
59-61
38-0
4
42.39
42.85
3.28
3.60
>250
883

Table 2. Spectroscopic Characteristics of Compounds 2a-f, 3a-f, and 4
Com-
pound
IR spectrum, ν, cm-1
1H NMR spectrum, δ, ppm*
2a
3110 – 3275 (NH2),
2850 – 2960 (alkyl),
3.60 (2Н, t, СН2СН2); 3.05 (2Н, t, СН2СН2);
3.51 (2Н, q, СН2); 1.24 (3Н, t, СН3)
1635 (NH2, def), 1525 (C=N)
2b
3115 – 3325 (NH2),
2850 – 2960 (alkyl),
1635 (NH2, def),
1525 (C=N)
3.62 (2Н, t, СН2СН2); 3.05 (2Н, t, СН2СН2);
2.52 (2Н, t, СН2); 1.44 (6Н, m, (СН2)3);
0.88 (3Н, t, СН3)
2c
2d
2e
3270 – 3120 (NH2),
2960 – 2920 (alkyl),
1640 (NH2, def), 1525 (C=N)
5.50 (2Н, br. s, NH2); 3.06 (2Н, t, СН2СН2);
2.80 (2Н, t, СН2СН2); 2.04 (3Н, s, СН3)
3100 – 3250 (NH),
2870 – 2970 (alkyl),
1630 (NH2, def), 1535 (C=N)
5.35 (2Н, br. s, NH2); 3.00 (2Н, t, СН2СН2);
2.75 (2Н, t, СН2СН2), 2.50 (2Н, q, СН2);
1.15 (3Н, t, СН3)
3120 – 3280 (NH2),
2875 – 2965 (alkyl),
1635 (NH2, def),
1525 (C=N)
4.50 (2Н, br. s, NH2); 3.03 (2Н, t, СН2СН2);
2.80 (2Н, t, СН2СН2); 2.45 (2Н, t, СН2);
1.53 (2Н, sext., СН2); 0.80 (3Н, t, СН3)
2f
3100 – 3270 (NH2),
2873 – 2960 (alkyl),
1625 (NH2, def),
1520 (C=N)
5.45 (2Н, br. s, NH2); 3.00 (2Н, t, СН2СН2);
2.83 (2Н, t, СН2СН2); 2.50 (2Н, t, СН3(СН2)2СН2);
1.44 (4Н, m, (СН2)2); 0.88 (3Н, t, СН3)
3а
3b
3с
3d
3е
2865 – 2965 (alkyl),
1965 (С=О),
1577 (C=N)
6.25 (1Н, s, СН); 3.66 (2Н, t, СН2СН2);
3.03 (2Н, t, СН2СН2); 3.50 (2Н, q, СН2);
2.20 (3Н, s, СН3); 1.27 (3Н, t, СН2СН3)
2867 – 2967 (alkyl),
1695 (С=О),
1576 (C=N)
6.25 (1Н, s, СН); 3.69 (2Н, t, СН2СН2);
3.00 (2Н, t, СН2СН2); 2.50 (2Н, t, СН2);
2.25 (3Н, s, СН3); 1.45 (6Н, m, (СН2)3); 0.85 (3Н, t, СН3)
2865 – 2965 (alkyl),
1690 (С=О), 1570 (C=N),
1400 (С–S–С)
6.25 (1Н, s, СН); 3.20 (2Н, t, СН2СН2);
2.91 (2Н, t, СН2СН2); 2.27 (3Н, s, СН3);
2.21 (3Н, s, СН3)
2865 – 2965 (alkyl),
1690 (С=О), 1570 (C=N),
1400 (С−S−С)
2865 – 2965 (alkyl),
1690 (С=О), 1570 (C=N),
1400 (С–S–С)
6.23 (1Н, s, СН); 3.21 (2Н, t, СН2СН2);
2.93 (2Н, t, СН2СН2); 2.50 (2Н, q, СН2);
2.30 (3Н, s, СН3); 1.23 (3Н, t, СН2СН3)
6.20 (1Н, s, СН); 3.23 (2Н, t, СН2СН2);
2.90 (2Н, t, СН2СН2); 2.50 (2Н, t, СН2);
2.33 (3Н, s, СН3); 1.28 (2Н, m, СН2);
0.83 (3Н, t, СН3)
3f
2865 – 2965 (alkyl),
1690 (С=О), 1570 (C=N),
1400 (С−S−С)
6.20 (1Н, s, СН); 3.19 (2Н, t, СН2СН2);
2.88 (2Н, t, СН2СН2); 2.50 (2Н, t, СН2);
2.30 (3Н, s, СН3); 1.45 (4Н, m, (СН2)2);
0.83 (3Н, t, СН3)
4
3400 (NH2),
7.28 (1H, c, NH2); 6.22 (H, c, CH);
1710 (С=О), 1690 (С=О),
1570 (C=N)
3.97 (2Н, s, СН2); 2.20 (3Н, s, СН3)
_______
1
* In the H NMR spectra coupling through three bonds with standard
values with free rotation around the C-C bond with J = 6-7 Hz were
observed, so these are not noted further in Table 2.
The IR spectrum of amide 4 contains stretching bands corresponding to two carbonyl groups at 1710 and
1
1690 cm-1 and an absorption band of an NH2 in the 3400 cm-1 region. The H NMR spectrum of compound 4
O
O
O
O
N
N
NH3
Me
N
N
O
H2N–NH–CS–NH2
AcCH2COOEt
+
+
H2N
CH2CN
O
S
N
Me
Me
N
S
NH2
4
5
884

contains signals in the form of four singlets at 7.28, 6.22, 3.97, and 2.20 ppm corresponding to protons of the
amide group, a proton at position 6 of the heterocycle, two protons of a methylene group and three protons of
the methyl group.
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions (internal standard HMDS (δ 0.005 ppm) were recorded on a
Tesla BS-58773 C (100 MHz) spectrometer. IR spectra of KBr tablets were recorded on a UR-20 spectrometer.
Melting temperatures were determined with a Boetius microthermal block.
Compound 5 was made by a known method [14].
5-(β-Alkylthioethyl)-2-amino-1,3,4-thiadiazoles 2a,b, 5-(β-Alkoxyethyl)-2-Amino-1,3,4-thiadia-
zoles 2c-f, and 2-R-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidines 3a-f (General Method). A
mixture of the corresponding nitrile 1 (10 mmol), thiosemicarbazide (0.91 g, 10 mmol) and PPA (10 g) was
heated for 5-6 h on a boiling water bath, and, in the case of compounds 3a-f, ethyl acetoacetate (1.05 mmol) was
added and the mixture heated for an additional 3 h. Water (50 ml) was then added and the solution was
neutralized to pH 7-8 with 20% NaOH solution. Crystals were transferred to a filter, washed with water, dried in
the air, and recrystallized from aqueous dioxane.
(7-Methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)acetamide (4). Concentrated ammonia
(2 ml) was added with stirring to a solution of 2-ethoxycarbonylmethyl-7-methyl-5-oxo-5H-1,3,4-thiadia-
zolo[3,2-a]pyrimidine (2.21 g, 11 mmol) in ethanol (15 ml), stirred at room temperature for 2 h, then heated for
1 h. The reaction mixture was poured into water (50 ml). The precipitate was filtered and washed with water and
dried. The product was crystallized from aqueous dioxane (1:1). Yield 1.59 g (83%).
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