On the synthesis of pyridinylthiobarbituric acids

Article abstract of DOI:10.1071/CH02050

The reaction of N-(pyridin-3-yl) and -4-yl thiourea derivatives with malonyl dichloride in trifluoroacetic acid is shown to be an efficient synthesis of the corresponding thiobarbituric acids. The pyridin-2-yl analogue cleaved and produced, instead, 2-hyd

Full text of DOI:10.1071/CH02050

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Aust. J. Chem. 2002, 55, 287–289
On the Synthesis of Pyridinylthiobarbituric Acids
Leslie W. Deady,A,B Daniel Ganame, Andrew B. Hughes, Nurul H. Quazi
and Shannon D. Zanatta
A
A
A
A
A
Chemistry Department, La Trobe University, Vic. 3086, Australia.
Author to whom correspondence should be addressed (L.Deady@latrobe.edu.au).
B
The reaction of N-(pyridin-3-yl) and -4-yl thiourea derivatives with malonyl dichloride in trifluoroacetic acid is
shown to be an efficient synthesis of the corresponding thiobarbituric acids. The pyridin-2-yl analogue cleaved and
produced, instead, 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one.
Manuscript received: 5 March 2002.
Final version: 9 April 2002.
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Introduction
hands the reaction of (1a) gave, after quenching with water,
an insoluble product in 28% yield. This was assigned
structure (3) (Scheme 1) from nuclear magnetic resonance
(NMR) and mass spectrometric (MS) data, and by analogy
with (6) (see below); there was no evidence (MS) for the
presence of the target (2a) in the material in the aqueous
filtrate. Clearly, the starting urea cleaved in these conditions
and intramolecular cyclization occurred on the
Thiobarbituric acids have found applications in diverse
fields such as dyes
[
1]
and pharmaceuticals, e.g.
[2]
[3]
anti-convulsant and anti-inflammatory agents, and many
derivatives have been reported. Interestingly though,
N-(pyridin-3-yl) and -4-yl analogues are unknown, and we
are interested in such species as potentially useful
intermediates.
Reactions of the appropriate 1,3-diarylthiourea with
malonic acid/acetic acid/acetic anhydride (method A),
malonic acid/acetyl chloride (method B)
chloride (method C) are standard routes to benzene
derivatives of thiobarbituric acid. However, in our hands,
reaction of pyridinylthioureas by these methods failed to give
the target barbituric acids; complex product mixtures
containing breakdown products of the thiourea were formed
2
-aminopyridine moiety, with subsequent tricycle formation
[1]
through reaction with another malonic acid unit.
[
4–6]
or malonyl
H
[7]
N
O
O
O
[8]*
(i)
+
N
N
NH
O
S
NH
Ph
(A), or unreactive solids (salts) precipitated immediately on
(1a)
(3)
mixing the reagents (C). After some frustrating experiences,
we have now devized conditions for the formation of the
target species.
Scheme1. Reagentsandconditions:(i)CH2(CO2H)2/
CH COCl/80°C/1 h.
3
Reaction of the pyridin-3-yl isomer (1b) under the same
conditions (Scheme 2) gave evidence of the desired reaction
though overreaction occurred. The compound first isolated
was not able to be satisfactorily purified but was presumed
Results and Discussion
[
9]
While 1-(pyridin-2-yl)-3-allyl
and 1-(pyridin-2-yl)-3-
aryl[ derivatives have been reported by method B, in our
10]
O
O
O
N
O
N
CO2Et
N
(i)
(ii)
N
N
N
NH
S
N
O
S
O
OH
S
NH
Ph
Ph
(
1b)
(4)
(5)
Scheme 2. Reagents and conditions: (i) CH (CO H) /CH COCl/80°C/1 h; (ii) ethanol/boil 10 min.
2
2
2
3
*
While this paper was in preparation, a new two-step preparation of 1,3-diphenylthiobarbituric acid, by acylation of 1,3-diphenylthiourea with
methyl malonyl chloride followed by cyclization, was reported to work well (ref. 8).
©
CSIRO 2002
10.1071/CH02050
0004-9425/02/040287

2
88
L. W. Deady et al.
to be (4) by analogy with the known diphenyl analogue,[7]
since attempted recrystallization from ethanol converted it
into a readily handled solid, assigned structure (5).
7 h. The solvent was evaporated under reduced pressure, 5 M
hydrochloric acid (100 mL) was added to the residue, and the mixture
was heated to near boiling and filtered while hot. The filtrate was
cooled and basified with 20% potassium carbonate solution, and the
solid which separated was filtered off to give the white product (3.12 g,
We have, however, succeeded in preparing N-(pyridin-
[11]
3-yl) and -4-yl thiobarbituric acids by modifying method C.
25%), m.p. 154–156°C (lit. 155–156°C).
After some experimenting with different solvents and
conditions, trifluoroacetic acid was found to have the right
properties and any protonated pyridine species remain in
solution throughout the reaction. A room-temperature
reaction with 1.2 molar equivalents of malonyl dichloride
and a simple workup gave the pyridin-3-yl target (2b) in 69%
yield (Scheme 3). In the same way the pyridin-4-yl isomer
1
,3-Di(pyridin-3-yl)thiourea (1d)
To a stirring solution of 3-aminopyridine (1 g, 10.6 mmol) and pyridine
1.68 g, 21.2 mmol) in carbon disulfide (5 mL) was added a solution of
(
iodine (0.67 g, 5.3 mmol) in carbon disulfide (2 mL) and
dichloromethane (2 mL), and the resulting mixture was stirred
vigorously at room temperature for 2 h. The solvent was evaporated
under reduced pressure, the residue was treated with saturated sodium
bicarbonate solution, and the solid was filtered off. This was dissolved
in 5% hydrochloric acid, filtered to remove a little sulfur, and the filtrate
was basified with 10% potassium carbonate solution. The white solid
was filtered off, washed with water and recrystallized from ethanol to
(
2c) (64%) and bis(pyridin-3-yl) analogue (2d) (60%) were
obtained. In our experience, therefore, these conditions
provide the best entry to N-(pyridin-3-yl) and -4-yl
thiobarbituric acids.
[12]
give the thiourea (0.56 g, 23%), m.p. 178–180°C (lit. 183°C).
H
N
O
1-Phenyl-3-(pyridin-3-yl)-2-thiobarbituric acid (2b)
+
N
_
To a solution of 1-phenyl-3-(pyridin-3-yl)thiourea (3.5 g, 15.3 mmol) in
dry trifluoroacetic acid (40 mL) under a nitrogen atmosphere was
added, with stirring, malonyl dichloride (2.58 g, 18.3 mmol) and
stirring was continued for 16 h. The solvent was evaporated under
reduced pressure and the residue was stirred with ethanol (30 mL) and
filtered to give an orange-yellow solid (3.87 g). This was dissolved in
20% potassium carbonate solution (60 mL), filtered and the filtrate was
acidified with concentrated hydrochloric acid to pH 1 to give the
thiobarbituric acid as a yellow powder (3.14 g, 69%), m.p. 254–255°C
(from ethanol) (Found: C, 59.6; H, 3.7; N, 14.2. C H N O S·0.25H O
(6)
O
(
i)
(
a)
O
Ar´
NH
Ar´
(i)
N
S
NH
(b–d)
S
N
O
Ar´´
1
5
11
3
2
2
Ar´´
1
requires C, 59.7; H, 3.8; N, 13.9%). H NMR [(D )DMSO (dimethyl
(
1)
(2)
6
sulfoxide)] δ 7.21, d, 2H, J 7.6 Hz; 7.32–7.38, m, 1H; 7.40–7.47, m, 2H;
7
.68, br s, 1H; 7.98, br s, 1H; 8.62, d, 2H, J 5.5 Hz. ESMS (negative
Ar´
Ar´´
mode): m/z 296 (M – 1).
(
(
(
(
1a/2a) 2-pyr
1b/2b) 3-pyr
1c/2c) 4-pyr
Ph
Ph
Ph
where pyr =
1
-Phenyl-3-(pyridin-4-yl)-2-thiobarbituric acid (2c)
N
This was prepared from 1-phenyl-3-(pyridin-4-yl)thiourea and malonyl
dichloride in trifluoroacetic acid, as for (2b), except that the crude
product was not subjected to the base/acid treatment. Instead,
recrystallization from ethanol gave the product as a yellow solid (64%),
m.p. 156–158°C (Found: C, 59.2; H, 3.7; N, 13.9.
C H N O S·0.3H O requires C, 59.5; H, 3.9; N, 13.9%). H NMR
[(D )DMSO] δ 7.17, d, 2H, J 7.6 Hz; 7.30–7.45, m, 3H; 7.73, br s, 2H;
8.82, d, 2H, J 4.8 Hz.
1d/2d) 3-pyr 3-pyr
Scheme3. Reagentsandconditions:(i)CH (COCl) /
CF CO H/20°C.
2
2
3
2
Again, the pyridin-2-yl thiourea (1a) showed different
behaviour. Cleavage of (1a) occurred in the same way as was
noted with the malonic acid/acetyl chloride method above. In
this case, the compound isolated was the known (6).
1
1
5
11
3
2
2
6
1,3-Di(pyridin-3-yl)thiobarbituric acid (2d)
Experimental
This was prepared from 1,3-di(pyridin-3-yl)thiourea and malonyl
dichloride in trifluoroacetic acid, as for (2b). The pH of the final
acidification was carefully controlled at 5–6, and (2d) slowly
precipitated as a yellow solid (60%), m.p. 278–279°C (from acetic acid)
NMR spectra were recorded on a Bruker AM-300 spectrometer
1
13
operating at 300.13 ( H) and 75.47 MHz ( C) and chemical shifts are
reported as δ values (ppm) relative to tetramethylsilane. Standard
DEPT (distortionless enhancement by polarization transfer)
experiments were used to identify proton-bound carbons in C NMR
spectra. Electrospray (ES) mass spectra were recorded on
(
Found: C, 55.1; H, 3.4; N, 18.4. C H N O S·0.5H O requires C,
14 10 4 2 2
1
1
3
54.7; H, 3.6; N, 18.2%). H NMR [(D )pyridine] δ 6.45, br s, 1H; 6.83,
5
br s, 1H; 7.54, br s, 1H; 7.59, s, 1H.
a
Perkin–Elmer Sciex API-300 triple quadrupole mass spectrometer. The
LSI mode high-resolution mass spectrum was obtained by Dr N.
Davies, University of Tasmania. Microanalyses were carried out at the
Campbell Microanalytical Laboratory, University of Otago, New
Zealand.
2-Hydroxy-1-oxa-9,10a-diazaanthracene-4,10-dione, Inner Salt (3)
A solution of 1-phenyl-3-(pyridin-2-yl)thiourea (0.5 g, 2.2 mmol) and
malonic acid (0.34 g, 3.3 mmol) in acetyl chloride (2 mL) was heated
in an oil bath at 80°C for 1 h. The mixture was cooled and slowly
quenched with ice–water. The dark red-brown solid which separated
was filtered off, washed with ethanol and recrystallized from the same
solvent to give the tricycle (0.14 g, 28%), m.p. 216–217°C. HRMS
1
-Phenyl-3-(pyridin-2-yl)thiourea (1a) and 1-phenyl-3-(pyridin-3-
[
10]
yl)thiourea (1b) were prepared as reported.
1-Phenyl-3-(pyridin-4-yl)thiourea (1c)
+
1
(
LSI), Found: 231.0402. C H N O (M + H ) requires 231.0406. H
11 7 2 4
A
solution of phenylisothiocyanate (7.2 g, 53.25 mmol) and
NMR [(D )DMSO] δ 5.45, s, 1H; 7.51, t, 1H, J 7.0 Hz; 7.75, d, 1H, J
6
13
4
-aminopyridine (5 g, 53.1 mmol) in acetone (200 mL) was refluxed for
8.8 Hz; 8.18, t, 1H, J 7.6 Hz; 8.98, d, 1H, J 7.0 Hz; 11.80, br s, 1H. C

On the Synthesis of Pyridinylthiobarbituric Acids
289
NMR [(D )DMSO] δ 87.9, CH; 90.7, C; 117.5, CH; 125.4, CH; 128.2,
References
6
CH; 141.2, CH; 150.3, C; 157.1, C; 160.7, C; 163.0, C; 168.7, C.
[
[
[
[
[
[
1] R. Yamauchi, Y. Kawashima, N. Kagawa, Jap. Pat. 03223747 A2
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1
5
-[(Ethoxycarbonylmethyl)carbonyl]-1-phenyl-3-(pyridin-3-yl)-2-thio
barbituric Acid (5)
Acetyl chloride (0.79 g, 10 mmol) was added to thiourea (1b) (0.23 g,
1
heated on an oil bath at 80°C for 1 h, and then cooled. Cold water was
added to the yellow paste, with stirring, and the resulting solid was
filtered off and boiled in ethanol for 10 min. The ethyl ester (0.15 g,
mmol) and malonic acid (0.16 g, 1.5 mmol) and the mixture was
3
6%), m.p. 196–198°C, crystallized from the solution on cooling
(Found: C, 58.1; H, 4.1; N, 10.4. C H N O S requires C, 58.4; H, 4.2;
20
17
3
5
1
N, 10.2%). H NMR [(D )DMSO] δ 1.13, t, 3H, J 7.9 Hz, CH CH ;
6
2
3
3
7
8
.73, s, 2H; 4.00, q, 2H, J 7.9 Hz, CH CH ; 7.16–7.19, m, 2H;
.29–7.45, m, 3H; 7.94, br s, 1H; 8.31, d, 1H, J 8.5 Hz; 8.75, br s, 2H;
.88, br s, 1H. ESMS (positive mode): m/z 412 (M + 1).
2 3
[
[
7] H. Schulte, Chem. Ber. 1954, 87, 820.
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Heterocycl. Chem. 1993, 3, 9.
[
2-Hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, Inner Salt (6)
The reaction of 1-phenyl-3-(pyridin-3-yl)thiourea (0.5 g, 2.2 mmol) and
malonyl dichloride (0.37 g, 2.6 mmol) in dry trifluoroacetic acid (10 mL)
was carried out as for the preparation of (2b). The product (0.17 g, 26%)
was obtained from the final acidification, to pH 6–7, as a pale yellow
solid, m.p. 294–296°C (from acetic acid) (lit.[ 295–298°C) (Found: C,
[
[
[
10] A. Dhasmana, J. P. Barthwal, B. R. Pandey, B. Ali, K. P.
Bhargava, S. S. Parmar, J. Heterocycl. Chem. 1981, 18, 635.
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1
2447 1971 (Chem. Abstr. 1971, 75, 20217).
13]
12] J. C. Jochims, Chem. Ber. 1968, 101, 1746.
5
9.0; H, 3.8; N, 17.2. Calc. for C H N O : C, 59.3; H, 3.7; N, 17.3%).
8 6 2 2
[13] A. E. Chichibabin, Ber. Dtsch. Chem. Ges. 1924, 57, 1168.
[14] C. Plüg, B. Wallfisch, H. Gade, H. G. Andersen, P. V. Bernhardt,
L.-J. Baker, G. R. Clark, M. W. Wong, C. Wentrup, J. Chem. Soc.,
Perkin Trans. 2 2000, 2096.
1
13
[14]
H and C NMR [(D )DMSO] were as reported.
6
Acknowledgments
This work was supported by the Cooperative Research Centre
for Diagnostic Technologies. We thank Dr G. Neumann for
recording the electrospray mass spectra.