Synthesis of 6-[4-(allyl/phenyl)-5-thioxo-1,2,4-triazol-3-yl]pyrimidine-2, 4-diones and their reaction with electrophiles

Article abstract of DOI:10.1007/s10593-006-0163-6

Cyclization of 1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonyl-4-R- thiosemicarbazides in basic medium gave 6-(4-R-5-thioxo-1,2,4-triazol-3-yl) pyrimidine-2,4-diones (R = Allyl, Ph). Alkylation of the latter with iodomethane occurred at the sulphur

Full text of DOI:10.1007/s10593-006-0163-6

Chemistry of Heterocyclic Compounds, Vol. 42, No. 6, 2006
SYNTHESIS OF 6-[4-(ALLYL/PHENYL)-5-THIOXO-
1,2,4-TRIAZOL-3-YL]PYRIMIDINE-2,4-DIONES
AND THEIR REACTION WITH ELECTROPHILES
G. Mekuskiene and P. Vainilavicius
Cyclization of 1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonyl-4-R-thiosemicarbazides in basic
medium gave 6-(4-R-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-diones (R = Allyl, Ph). Alkylation of the
latter with iodomethane occurred at the sulphur atom to give the corresponding methylsulfanyl
derivatives. Acetylation using acetyl chloride occurred at the N(1) atom of the triazole ring to the
corresponding acetyl derivative when R = Ph but for R = Allyl the acetylation did not occur under the
same conditions. In the presence of bromine in refluxing methanol the indicated allyl-substituted
compound
cyclizes
to
6-bromomethyl-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-5,6-
dihydrothiazolo[2,3-c]-1,2,4-triazole. Under Mannich and bromination conditions the methylsulfanyl
derivatives prepared form derivatives at the 5 position of the uracil ring: 5-methylmorpholino-
(piperidino)- and 5-bromo-(4-R-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-diones respectively.
Keywords: 6-[4-(allyl/phenyl)-5-thioxo-1,2,4,-triazol-3-yl]pyrimidine-2,4-diones, 6-bromomethyl-3-(2,4-
dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole,
aminomethylation,
acetylation, bromination, methylation, Mannich reaction products.
Noncondensed bicyclic compounds which contain uracil and 1,2,4-triazole rings are of interest not only
from a chemical viewpoint for their reactions involving the heterocycles but also as potentially biologically
active compounds. It has been shown that some of them increase the activity of phleomycin [1], or have
tuberculostatic [2, 3], anti-inflammatory [4], anticonvulsant [5], antidepresant [6], or nematodacidal and
fungicidal [7, 8] activity. We have previously synthesized 2-(3-thioxo-1,2,4-triazol-5-yl)-4,6-
diphenylpyrimidines which have shown anti-inflammatory action [9, 10].
In continuing our investigation of triazolylpyrimidines we now report the synthesis of 6-(4-R-5-thioxo-
1,2,4-triazol-3-yl)pyrimidine-2,4-diones 2a,b from the 1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonyl-
4-R-thiosemicarbazides 1a,b and their reaction with electrophilic reagents.
Using a known method [11] orotic acid hydrazide and allyl- or phenylisothiocyanates gave the
corresponding thiosemicarbazides 1a,b which underwent cyclization in 10% KOH to give the substituted
pyrimidinediones 2a,b.
It is known that 4-alkyl(aryl)-1,2,4-triazole-3-thiones react with different electrophiles at the S or the N(2)
atom [12, 13]. In the case of compounds 2a,b the formation of products at the N(1), N(3), O, or C(5) atoms might
also be expected.
__________________________________________________________________________________________
Vilnius University, Vilnius 01513, Lithuania; e-mail: giedrute.mekuskiene@chf.vu.lt. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 906-912, June, 2006. Original article submitted October 10,
2004; revision submitted November 22, 2005.
792
0009-3122/06/4206-0792©2006 Springer Science+Business Media, Inc.

N
N
O
N
H
H
N
SMe
O
N
O
N
R
H
R
HN
NH
S
HN
NH
MeI
–
O
O
OH
O
H
N
MeOH
3a,b
1a,b
N
S
N
AcCl,
Et3N
R
HN
NH
(2a)
(2b)
MeCN
O
2a,b
COMe
N
N
O
N
N
S
Br2
O
2a
N
N
S
HN
MeOH
N
Ph
NH
HN
H
O
Br
4
O
5
3a,b
R1R2NH,
CH2O
Br2
AcOH
(3a)
EtOH
Br2
(3b)
3a
MeOH
N
R2R1N
O
N
N
N
Br
N
N
SMe
SMe
O
N
Ph
R
HN
NH
HN
NH
Br
N
SMe
O
O
O
N
.
6
HBr
8a,b, 9a,b
All
HN
NH
O
7
1-3, 8, 9 a R = CH2–CH=CH2, b R = Ph; 8 R1R2N = piperidino; 9 R1R2N = morpholino
Treatment of compounds 2a,b with iodomethane in refluxing methanol in the presence of MeONa gave
the products of alkylation at the sulphur atom as the methylsufanyl derivatives 3a,b. The action of acetyl
chloride in refluxing acetonitrile in the presence of triethylamine occurred only in the case of the phenyl-
substituted 2b to form the product 4 (65%) which is acetylated at atom N(2) in the triazole ring. Under these
conditions the allyl-substituted 2a does not react in acetonitrile. Exchange of solvent and change of reaction
medium temperature did not give a positive result.
Refluxing equimolar amounts of bromine and the thione 2a in methanol gave a 44% yield of the product
of intramolecular cyclization which was the substituted thiazolo[2,3-c]-1,2,4-triazole 5.
Since the triazole ring in compounds 2a,b appeared to be more reactive when reacting with
C-electrophiles, for the reaction involving the pyrimidine we have used the S-methylated derivatives 3a,b. It was
found that bromination and aminomethylation (the Mannich reaction) of the latter occurred at the C(5) atom of
the pyrimidine ring. Thus the action of bromine in glacial acetic acid on the phenyl-substituted 3b at room
temperature gave a 44% yield of the 5-bromo derivative 6. Under the same conditions the allyl-substituted
793

compound 3a did not react with bromine. The bromination product 7 was prepared in overall yield of 18% by
refluxing equimolar amounts of the substituted pyrimidinedione 3a with bromine in methanol. Treatment of
equimolar amounts of the methylsulfanyl-substituted 3a,b with formaldehyde, and piperidine or morpholine in
refluxing ethanol gave the 5-aminomethyl derivatives 8a,b, 9a,b.
The composition and structure of the synthesized compounds were confirmed by the results of elemental
1
analysis (Table 1) and from IR and H NMR spectroscopic data (Table 2). The IR spectra of all of compounds
1-9 show absorption bands in the regions 3030-3381 (NH), 1702-1723 (C(2)=O), and 1616-1691 cm-1 (C(4)=O),
typical of a uracil ring [14, 15]. The spectra of the thiosemicarbazides 1a,b and compound 4 show the presence
of one further absorption band for a C=O group at 1715, 1731, and 1763 cm-1. The absorptions in the spectra of
the thiosemicarbazides 1a,b in the range 1319-1320 cm-1 and in the spectra of thiones 2a,b and 4 at 1324-1348
and 1532-1534 cm-1 are typical for a C=S bond. These bands are absent in the spectra of the S-methyl-
substituted 3, 5-9. The spectra of the bromo derivatives 6, 7 show characteristic absorption bands at
568-580 cm-1 which correspond to the C–Br bond.
In the 1H NMR spectra of all of compounds 1-5 which are not substituted at position 5 of the uracil ring
there is present a signal at 5.2-6.1 ppm for the H-5 proton of this fragment and also signals for the two NH
groups in the uracil at 10.9-11.8 ppm. This signal for the NH group proton of the triazole ring in compounds
2a,b is observed at 13.9-14.5 ppm. In the spectra of compounds 6-9 substituted at uracil ring atom C(5) the H-5
proton signal is absent. The 5-aminomethyl derivatives 8, 9 are typified by a singlet signal for the 5-CH2 at
4.3-5.2 ppm.
TABLE 1. Characteristics of Compounds 1-9
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
(solvent)
Yield,
%
С
Н
N
1а
2а
2b
3a
3b
4
C19H11N5O3S
40.27
40.14
4.31
4.11
25.72
26.00
212-214
(DMF–EtOH)
79
87
66
79
60
65
44
40
18
53
54
31
30
C9H9N5O2S
43.32
43.02
3.58
3.61
27.42
27.87
240-241
(DMF–Н2О)
C12H9N5O2S
C10H11N5O2S
C13H11N5O2S
C14H11N5O3S
C9H8BrN5O2S
C13H10BrN5O2S
49.87
50.16
3.29
3.13
24.58
24.37
300
(DMF)
45.03
45.27
4.19
4.18
26.47
26.39
162-164
(ЕtОH)
51.54
51.77
3.47
3.60
23.17
23.33
299.5-300.5
(DMF)
51.27
51.06
3.42
3.37
21.35
21.26
153-154
(dioxane)
5
33.13
32.74
2.44
2.44
21.26
21.21
236-237
(DMF)
6
41.17
41.07
3.30
2.65
18.32
18.45
242.0-242.5
(ЕtОH–Н2О)
C10H10BrN5O2S HBr
7
·
28.04
28.25
2.37
2.60
16.54
16.46
195-198
(DMF)
8a
8b
9a
9b
C16H22N6O2S
C19H22N6O2S
C15H20N6O3S
C18H20N6O3S
53.36
53.02
6.33
6.12
22.95
23.18
167-170
(ЕtОH)
57.04
57.27
5.80
5.56
20.84
21.08
190 (dec.)
(dioxane)
49.67
49.44
5.71
5.53
23.28
23.06
181-182
(MeОH)
54.09
53.99
5.10
5.03
21.30
20.99
177-179
(Н2О)
794

TABLE 2. Spectroscopic Characteristics of Compounds 1-9
Com-
pound
IR spectrum, ν, сm–1
1Н NMR spectrum, δ, ppm (J, Hz) *
1a
3289, 3170 (NH),
6.12 (1H, s, CHur); 8.39 (1Н, s, NHCH2);
1715 (C=O), 1702 (C(2)=O),
1672 (C(4)=O), 1319 (C=S)
9.53 (1H, NHCS); 10.73 (1H, s, CONH); 10.92 (1H, s,
NHur); 11.36 (1H, s, NHur). Hall: 5.09 (dd); 5.15 (dd);
5.83 (m); 4.13 (d); J = 1.7, J = 10.3, J = 17.3, J = 5.0
1b
2a
2b
3a
3b
4
3184 (NH), 1731 (C=O),
1718 (C(2)=O), 1674 (C(4)=O), 9.86 (2Н, m, NHCSNH); 10.93 (1H, s, CONH);
1320 (C=S)
6.15 (1H, s, CHur); 7.21-7.44 (5Н, m, С6Н5);
10.98 (1H, s, NHur); 11.37 (1H, s, NHur)
3162, 3080 (NH),
5.91 (1H, s, CHur); 11.39 (2H, s, NHur);
1709 (C(2)=O), 1679 (C(4)=O), 13.97 (1H, s, NHthia). Hall: 5.16 (d); 4.92 (d); 5.83 (m);
1532, 1348 (C=S)
4.69 (d); J = 0, J = 10.8, J = 17.1, J = 2.7
3306 (NH),
5.33 (1H, s, CHur); 7.42-7.51 (5Н, m, С6Н5);
1719 (C(2)=O), 1687 (C(4)=O), 11.15-11.27 (2H, m, NHur); 14.47 (1H, s, NHthia
1534, 1340 (C=S)
3156, 3095 (NH),
1710 (С(2)=О), 1668 (С(4)=О), 11.30-11.36 (2Н, s, NHur); Hall: 5.26 (dd); 4.86 (dd);
1309 (С–S–С)
)
2.68 (3Н, s, SCH3); 5.88 (1Н, s, СНur);
5.94 (m); 4.65 (d); J = 0.9, J = 10.5, J = 17.3, J = 4.2
2.65 (3Н, s, SCH3); 5.19 (1Н, s, СНur);
3176, 3030 (NH),
1723 (С(2)=О), 1670 (С(4)=О), 7.51-7.62 (5Н, m, С6Н5); 11.26 (2Н, m, NHur)
1315 (С–S–С)
3154 (NH), 1763 (С=О),
2.73 (3Н, s, СОСН3); 5.41 (1Н, s, СНur);
1708 (С(2)=О), 1667 (С(4)=О), 7.48-7.59 (5Н, m, С6Н5); 11.31-11.40 (2Н, m, NHur)
1532, 1324 (С=S)
5
3163, 3038 (NH),
1706 (С(2)=О), 1663 (С(4)=О)
3.95 (2Н, d, 3J = 6.9, CH2Br); 4.39 (1Н, dd, 2J = 11.7,
3J = 7.5, NCHH); 4.64 (1Н, dd, 2J = 11.7, 3J = 4,
NCHH); 5.05 (1Н, m, 3J = 4, 3J = 6.9, 3J = 7.5, СНтиа);
5.84 (1H, s, СНur); 11.26-11.34 (2H, m, NHur)
6
7
3166 (NH), 1718 (С(2)=О),
1691 (С(4)=О),
1280 (С–S–С), 580 (С–Br)
2.69 (3Н, s, SCH3); 7.39-7.61 (5Н, m, С6Н5);
11.83 (2Н, s, NHur)
3381, 3165 (NH),
2.68 (3Н, s, SCH3); 11.33 (1Н, s, N+Hthia); 11.70 (1Н, s,
NHur); 11.84 (1Н, s, NHur). Hall: 5.23 (d); 5.08 (d);
5.80 (m); 4.55 d; J = 0, J = 10.4, J = 17.3, J = 5.1
2726 (N+H), 1722 (С(2)=О),
1677 (С(4)=О),
1284 (С–S–С), 568 (С–Br)
8a
3054 (NH), 1714 (С(2)=О),
2.08–2.18 (6Н, m, (СH2)3); 3.19 (3Н, s, SCH3);
1633 (С(4)=О), 1306 (С–S–С) 3.22 (2Н, m, 2Jae = 11.4, 3Jae = 9.3, N(СHaHe)2);
3.86 (2Н, d, 2Jae = 11.4, (NСHаНe)2); 4.34 (2H, s,
NCH2). Hall: 5.73 (d); 5.65 (d); 6.03 (m); 5.06 (d);
J = 0, J = 10.6, J = 17.1, J = 6.2
8b
9a
3249 (NH), 1721 (С(2)=О),
1.73–2.18 (6Н, m, (СH2)3); 3.06 (3Н, s, SCH3);
1666 (С(4)=О), 1332 (С–S–С) 3.26 (2Н, m, 2Jae = 11.69, 3Jaa = 12.29, N(СHaHe)2);
3.85 (2Н, d, 2Jae = 11.69, (NСHаНe)2);
4.47 (2H, s, NCH2); 7.61=7.90 (5Н, m, С6H5)
3.67 (3Н, s, SCH3); 4.12 (2Н, m, 2Jae = 12.5, 3Jaa = 13.2,
3260, 3199 (NH),
1717 (С(2)=О), 1680 (С(4)=О), N(СHaHe)2); 4.44 (2Н, d, 2Jae = 12.5, (NСHаНe)2);
1306 (С–S–С)
4.80 (2Н, m, 2Jae = 12.7, 3Jaa = 13.2, O(СHaHe)2);
4.96 (2H, d, 2Jae = 12.7, O(СHaHe)2); 4.99 (2Н, s, NСH2).
Hall: 6.24 (d); 6.16 (d); 6.55 (m); 5.57 (d);
J = 0, J = 10.3, J = 17.1, J = 5.9
9b
3182, 3056 (NH),
3.62 (3Н, s, SCH3); 4.23 (2Н, m, 2Jae = 12.66, 3Jaa = 11.5,
1720 (С(2)=О), 1682 (С(4)=О), N(СHaHe)2); 4.50 (2Н, d, 2Jae = 12.66, NСHаНe)2);
4.86 (2Н, m, 2Jae = 12.5, 3Jaa = 11.5, O(СHaHe)2);
1300 (С–S–С)
5.05 (2H, d, 2Jae = 12.5, O(СHaHe)2); 5.20 (2H, s, NCH2);
8.21-8.47 (5Н, m, C6H5)
_______
* Hur is the proton of the uracil fragment; Htria the proton of the triazole ring;
Hthia the thiazole ring proton; Hall the signals for the protons of the allyl
2
3
3
substituent H', H'', H''', CH2 and spin-spin coupling (J): JH'H'', JH'H''', JH''H'''
,
H'"
H'
3JH'''CH
.
C=C
2
CH2
H"
795

The proton signals of the allyl substituent in the spectra of compounds 1a-3a and 6, 8a, 9a are given in
Table 2. The chemical shifts and spin-spin couplings agree well with literature data for monosubstituted alkenes
[16]. The spectra of the phenyl-substituted compounds 1b-3b, 4, 6, 8b and 9b contain multiplet signals for the
phenyl group protons at 7.2-8.5 ppm.
In the S-methyl derivatives 3, 6-9 the spectra show a typical singlet signal for the SCH3 group at
2.6-3.7 ppm.
In the spectrum of compound 5 there is a signal for the CH2Br substituent as a doublet at 3.9 ppm as well
as signals for the thiazole ring fragments, the CH group (multiplet at 5.1 ppm) and the CH2 group (two double
doublets at 4.4 and 4.6 ppm).
A preliminary study of the anti-inflammatory activity has been made by E. Udrenaite (Vilnius
Univeristy, Medical faculty) which has showed that compounds 2a,b, 3a,b suppresses the inflammatory process
to the same degree as acetylsalicyclic acid.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Unity Inova (300 MHz) spectrometer using DMSO-d6
(compounds 1-7) or CF3COOD (compounds 8a,b, 9a,b) relative to TMS. IR spectra were obtained on a Perkin-
Elmer BX FT-IR spectrometer for a suspension in vaseline oil or for KBr tablets (in the case of compounds 2b,
5, 9a,b). Monitoring of the course of the reaction and the purity of the compounds synthesized was carried out
on Silufol UV-254 plates (Kavalier) with ethyl acetate–methanol (3:1) as eluent.
4-Allyl-1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonylthiosemicarbazide (1a) was prepared
by the method in [1] holding the mixture of orotic acid hydrazide (5.1 g, 30 mmol) and allylisothiocyanate
(5.94 g, 5.84 ml, 60 mmol) for 9 h at 90°C in a mixture of absolute 2-propanol and absolute DMF (4:1) to give
product 1a (6.4 g).
4-Phenyl-1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonylthiosemicarbazide
(1b)
was
synthesized similarly from orotic acid hydrazide and phenylisothiocyanate to give a yield of 82% with mp 221.5-
223°C (DMF) (mp 221.5-223°C [11]).
6-(4-Allyl-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-dione (2a). A mixture of the thiosemicarbazide
1a (5.5 g, 20 mmol) and 10% KOH (40 ml) was refluxed for 4 h. After cooling, the reaction mixture was filtered
and the filtrate was acidified with conc. HCl to a weakly acid reaction. The separated product 2a was filtered,
washed with water and ethanol, dried, and purified by recrystallization.
6-(4-Phenyl-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-dione (2b) was synthesized similarly to
compound 2a.
6-(4-Allyl-5-methylthio-1,2,4-triazol-3-yl)pyrimidine-2,4-dione (3a) and 6-(5-Methylsulfanyl-4-
phenyl-1,2,4-triazol-3-yl)pyrimidine-2,4-dione (3b) (General Method). A solution of sodium methoxide
prepared from sodium (0.18 g, 8 mmol) and methanol (20 ml) was added to a solution of compound 2a,b
(8 mmol) in methanol (100 ml). Iodomethane (1.42 g, 0.62 ml, 10 mmol) was added to the solution obtained (in
the case of 2b a suspension). The mixture was refluxed for 1 h and cooled. The precipitated product 3 was
filtered off, washed with water, dried, and recrystallized.
6-(1-Acetyl-4-phenyl-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-dione (4). Absolute triethylamine
(0.35 g, 0.48 ml, 3.5 mmol) was added to a refluxing suspension of compound 2b (1 g, 3.5 mmol) in absolute
acetonitrile (70 ml). The clear solution obtained was treated with acetyl chloride (0.273 g, 0.25 ml, 3.5 mmol)
and the mixture was refluxed for 2.5 h. After cooling, the precipitated product 4 was filtered off, washed with
methanol and ether, dried, and recrystallized.
796

6-Bromomethyl-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-5,6-dihydrothiazolo[2,3-c]-1,2,4-
triazole (5). A solution of bromine (0.48 g, 0.15 ml, 3 mmol) in absolute methanol (10 ml) was added dropwise
with stirring to a refluxing solution of compound 2a (0.75 g, 3 mmol) in absolute methanol (125 ml). The
mixture was refluxed for 2.5 h and cooled. The precipitated product 5 was filtered off, washed with ether, dried,
and recrystallized.
5-Bromo-6-(5-methylsulfanyl-4-phenyl-1,2,4-triazol-3-yl)pyrimidine-2,4-dione (6). A solution of
bromine (0.29 g, 0.095 ml, 1.85 mmol) in acetic acid (2 ml) was added dropwise to a solution of compound 3b
(0.5 g,1.65 mmol) in acetic acid (3 ml). The product was stirred at room temperature for 45 min and water (5 ml)
and NaOH were added to neutral reaction. The precipitated product 6 was filtered off, washed with water, dried,
and recrystallized.
6-(4-Allyl-5-methylsulfanyl-1,2,4-triazol-3-yl)-5-bromopyrimidine-2,4-dione Hydrobromide (7). A
solution of bromine (0.6 g, 0.19 ml, 3.76 mmol) in absolute methanol (15 ml) was added dropwise over 1 h to a
refluxing solution of compound 3a (1 g, 3.76 mmol) in absolute methanol (60 ml). The mixture obtained was
refluxed with stirring for 15 h. Solvent was distilled off to dryness on a rotary evaporator and the residue was
treated with acetonitrile (10 ml). The precipitated product 7·HBr was filtered off and recrystallized.
6-(4-Allyl-5-methylsulfanyl-1,2,4-triazol-3-yl)-5-[morpholino(piperidino)methyl]pyrimidine-2,4-
diones (8a, 9a) and 6-(5-Methylsulfanyl-4-phenyl-1,2,4-triazol-3-yl)-5-[morpholino(piperidino)methyl]-
pyrimidine-2,4-diones (8b, 9b) (General Method). Piperidine (0.25 g, 0.29 ml, 3 mmol) or morpholine (0.26 g,
0.26 ml, 3 mmol) and a 35% solution of formaldehyde (0.24 ml, 3 mmol) were added to a solution of compound
3a or suspension of 3b (3 mmol) in absolute ethanol (30 ml). The mixture was refluxed for 11 h and cooled. The
precipitated products 8a, 9a were filtered off, dried, and recrystallized. For separation of the products 8b, 9b the
solvent was evaporated on a rotary evaporator and the residue was dried and recrystallized.
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