One-pot synthesis of 5,7,8,9,9a,10-hexahydro-8-thioxotetrahydropyrido[2,3- d: 6,5-d′]dipyrimidine-2,4,6(1H,3H,5aH)-triones via a four-component coupling reaction of aldehydes, amines, barbituric acids, and thiouracil

Article abstract of DOI:10.1002/hlca.201200350

An efficient one-pot approach to the synthesis of 5,7,8,9,9a,10-hexahydro- 8-thioxopyrido[2,3-d: 6,5-d′]dipyrimidine-2,4,6(1H,3H,5aH)-triones 5 via a four-component reaction of an aldehyde 1, an amine 2, a barbituric acid 3, and thiouracil (4) is reported for the first time. This new multicomponent reaction is accomplished in refluxing EtOH in the presence of tungstophosphoric acid (H₃PW₁₂O₄₀) as a catalyst. A variety of hexahydropyrido[2,3-d: 6,5-d′]dipyrimidinetrione derivatives were successfully synthesized in excellent yields with this protocol (Table 2). Copyright

Full text of DOI:10.1002/hlca.201200350

Helvetica Chimica Acta – Vol. 96 (2013)
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One-Pot Synthesis of 5,7,8,9,9a,10-Hexahydro-8-thioxotetrahydropyrido[2,3-
d :6,5-d’]dipyrimidine-2,4,6(1H,3H,5aH)-triones via a Four-Component
Coupling Reaction of Aldehydes, Amines, Barbituric Acids, and Thiouracil
by Ali Khalafi-Nezhad*, Farhad Panahi*, and Bahman Golesorkhi
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
(phone: þ 98-711-2282380; fax: þ 98(711)2280926; e-mail: khalafi@chem.susc.ac.ir,
panahi@shirazu.ac.ir)
An efficient one-pot approach to the synthesis of 5,7,8,9,9a,10-hexahydro-8-thioxopyrido[2,3-d :6,5-
d’]dipyrimidine-2,4,6(1H,3H,5aH)-triones 5 via a four-component reaction of an aldehyde 1, an amine 2,
a barbituric acid 3, and thiouracil (4) is reported for the first time. This new multicomponent reaction is
accomplished in refluxing EtOH in the presence of tungstophosphoric acid (H3PW12O40) as a catalyst. A
variety of hexahydropyrido[2,3-d :6,5-d’]dipyrimidinetrione derivatives were successfully synthesized in
excellent yields with this protocol (Table 2).
Introduction. – Pyrimidines are known as interesting heterocyclic scaffolds which
exhibit various biological and pharmacologic activities [1]. Among them, fused
pyrimidines have been used as a common source for the synthesis of new therapeutic
agents [2]. Recent studies have shown that pyrimidine-fused heterocycles, particularly
their oxo and thioxo derivatives, possess a wide range of biological activity and for this
reason, they are extensively used in the design of new drugs [3]. For example,
pyrimidopyrimidine derivatives have attracted considerable interest due to their
tyrosine kinase inhibitory activity [4], antitumor activity [5], antiviral effect [6], and
antioxidant properties [7]. In this regard, the developments of new methodologies for
the synthesis of these heterocyclic compounds and new pyrimidine-containing hetero-
cycles have received considerable interest in recent years [8 – 13]. The synthesis of
pyrimidine derivatives by a multicomponent reaction (MCR) is an attractive approach
for the construction of this class of compounds [14].
In continuation of our previous works on the synthesis of biologically active
compounds [15], we would like to report a four-component sequence for the synthesis
of a new pyrimidine-fused scaffold, by means of a condensation reaction of an aldehyde
1, an amine 2, a barbituric acid 3, and thiouracil (¼2,3-dihydro-2-thioxopyrimidin-
4(1H)-one; 4). This new strategy allows for the general access to new derivatives 5 of
5,7,8,9,9a,10-hexahydro-8-thioxopyrido[2,3-d :6,5-d’]dipyrimidine-2,4,6(1H,3H,5aH)-
trione. Structureꢀactivity relationship (SAR) studies of 5,6-dihydropyrimidine-
2,4(1H,3H)-dione derivatives showed that their biological activities are highly
dependent on the substituent groups at the saturated pyrimidine moiety [16]. On the
other hand, few methods for the synthesis of multiply substituted tetrahydropyrimidin-
2(1H)-ones have been described [17]. In the present protocol, by choosing different
aldehydes 1 and amines 2, a large structural diversity can be achieved. Accordingly,
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 96 (2013)
from the synthetic perspective, our convenient MCR strategy is a significant advance
for the synthesis of this category of tetrahydropyrimidin-2(1H)-ones. To the best of our
knowledge, this new approach provides the first example of an efficient access to 5.
Results and Discussion. – To achieve proper conditions for the synthesis of
derivatives 5, we tested the reaction of benzaldehyde (1a), aniline (¼ benzenamine;
2a), barbituric acid (¼ pyrimidine-2,4,6(1H,3H,5H)-trione; 3a) and thiouracil (4) in
various solvents and in the presence of an acidic catalyst. The results of the
optimization study (Table 1) revealed that the reaction occurred without any catalyst
in boiling EtOH, but compound 5a was obtained in only 28% yield (Entry 1). The yield
was enhanced to 90% when 2 mol-% of H3PW12O40 were added to the reaction media
(Entry 3). The acid H3PW12O40 is known as an efficient catalyst for many organic
transformations due to its unique properties [18]. The advantages of heteropolyacid
catalysts are the following: high catalytic performance, strong acidity, recyclability,
selectivity to a particular reaction product by selective stabilization of the reaction
intermediate, safety, lower waste, and ease of separation [19]. Thus, we optimized the
reaction conditions with H3PW12O40 as the catalyst. Reducing the amount of catalyst led
to a reduction in yield (Entry 2). Similar results were obtained by increasing the
amount of catalyst to 2.5 mol-% (Entry 4), indicating that a 2.0 mol-% loading of
H3PW12O40 for this reaction was optimal. Refluxing conditions were superior to room
temperature (cf. Entry 5), and EtOH was the best solvent tested (Entries 3 and 4 vs. 6 –
10), establishing boiling EtOH and 2 mol-% of H3PW12O40 as the best conditions.
Table 1. Optimization of the Four-Component Reaction between Benzaldehyde (1a), Aniline (2a),
Barbituric Acid (3a), and Thiouracil (4)a)
Entry
Catalyst
Solvent
Temp. [8]
Time [h]
Yield [%]b)
1
2
3
4
5
6
7
8
9
none
EtOH
EtOH
EtOH
EtOH
EtOH
DMSO
none
MeCN
toluene
H2O
reflux
reflux
reflux
reflux
r.t.
100
80
reflux
100
reflux
12
10
5
5
24
5
12
5
5
28
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
87c)
90
91d)
45
75
42
65
45
61
10
12
a) Amount of materials in all reactions: barbituric acid (3a; 1 mmol), benzaldehyde (1a; 1 mmol),
thiouracil (4; 1 mmol), aniline (2a; 1 mmol), and H3PW12O40 (2 mol-%). b) Yield of isolated 5a. c) 0.03 g
(1.5 mol-%) of catalyst. d) 0.05 g (2.5 mol-%) of catalyst.

Helvetica Chimica Acta – Vol. 96 (2013)
1157
Thus, we selected these optimum conditions for the preparation of other derivatives
of 5 starting from commercially accessible aromatic aldehydes 1 and amines 2,
barbituric acids 3, and thiouracil (4). As shown in Table 2, both electron-poor and
electron-rich aromatic aldehydes 1 furnished excellent yields of products. In addition,
the presence of electron-donating groups at the aromatic amines 2 decreased the
reaction times. Different products 5 with heterocyclic substituting moieties were
synthesized from heterocyclic aldehydes and amines (Entries 3, 10, and 11, and 4 – 6,9,
and 10, resp.). The heterocycle compatibility of the reaction was highlighted by amine
components 2 which are attached to the desired heterocyclic groups by a spacer
(Entries 9 and 10), and the use of 2-thiobarbituric acid resulted in as good results as
with barbituric acid (Entries 2,6, and 8). The practical synthetic efficiency of the
procedure was highlighted by the reaction of terephthaldehyde (¼ benzene-1,4-
dicarboxaldehyde), yielding the structurally complex derivative 5 (Table 2, Entry 7).
The structural diversity of this process was further established with adenosine [20] and
adenine [21] as amine component 2, leading to the formation of the new nucleoside
base derivatives 5f and 5e, respectively (Table 2, Entries 5 and 4). When uracil was used
instead of thiouracil, no significant progress of the reaction was observed. This is most
Table 2. Products of the Four-Component Reaction between Aldehydes 1, and Amines 2, Barbituric Acids
3, and Thiouracil (4)a)
Entry
Ar
R
X
Product
Time [h]
Yield [%]b)
1
2
3
4
5
3-MeꢀC6H4
4-IꢀC6H4
O
S
O
O
O
5b
5c
5d
5e
5f
5
4
4
6
8
87
91
93
84
78
anthracen-9-yl
1H-indol-3-yl
4-NO2ꢀC6H4
4-NO2ꢀC6H4
4-MeOꢀC6H4
4-MeOꢀC6H4
7H-purin-6-yl
6
7
8
4-NO2ꢀC6H4
4-CHOꢀC6H4
3-OH,4-BrꢀC6H3
4-ClꢀC6H4
1H-benzimidazol-2-yl
4-MeOꢀC6H4
S
O
S
O
O
O
O
5g
5h
5i
5j
5k
5l
7
12
7
7
8
86
85
88
90
91
90
89
4-MeOꢀC6H4
9
2-(morpholin-4-yl)ethyl
2-(piperazin-1-yl)ethyl
4-BrꢀC6H4
10
11
12
pyridin-3-yl
2-thienyl
5
6
4-BrꢀC6H4
2-MeOꢀC6H4
5m
a) Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), 4 (1 mmol), H3PW12O40 (0.04 g, 2 mol-%),
and EtOH (5 ml). b) Yield of isolated 5.

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Helvetica Chimica Acta – Vol. 96 (2013)
likely due to the difference of the nucleophilicity of the C(5)-atom in the reaction with
electrophilic reagents [22].
We propose a plausible mechanism for this reaction (Scheme): Presumably,
barbituric acid 3 in its enol form A reacts first with the activated aldehyde to form the
corresponding 5-(arylmethylidene)barbiturate B [23], and then thiouracil (4) adds to
this adduct to produce the intermediate C. The latter can undergo a reaction with the
amine component 2, generating D, which is converted to the desired product 5 by an
intramolecular condensation reaction.
Scheme. Proposed Mechanism for the Four-Component Coupling Reaction of Aldehyde 1, Amine 2,
Barbituric Acid 3, and Thiouracil (4)
Conclusions. – We developed an efficient multicomponent approach for the
preparation of
5,7,8,9,9a,10-hexahydro-8-thioxopyrido[2,3-d :6,5-d’]dipyrimidine-
2,4,6(1H,3H,5aH)-trione derivatives 5. According to this protocol, when an aldehyde,
an amine, and a barbituric acid were treated with thiouracil in the presence of a

Helvetica Chimica Acta – Vol. 96 (2013)
1159
catalytic amount of H3PW12O40 in refluxing EtOH, the products were obtained in
excellent yield. This strategy offers a powerful tool for preparing a new pyrimidine
scaffold which has a high potential for applications in medicinal chemistry. Further
studies on this structure may lead to the exploration of new drugs or biologically active
compounds in the future.
We acknowledge the financial support from the Shiraz University. Also, we are thankful to Dr. Reza
Yousefi for its helpful comments.
Experimental Part
General. Chemicals were purchased from Fluka and Aldrich chemical companies and used without
further purification. TLC: silica gel PolyGram SILG/UV254 plates. M.p.: Barnstead-Electrothermal-
9100-BZ circulating-oil melting-point apparatus; in open capillary tubes. FT-IR Spectra: Shimadzu-FT-
1
IR-8300 spectrophotometer; ˜n in cm-1. H- and 13C-NMR Spectra: Bruker-Avance-250 spectrometer; in
(D6)DMSO; d in ppm rel. to Me4Si as internal standard, J in Hz. GC/MS: Shimadzu-GC/MS-QP-1000-
EX apparatus; in m/z (rel. %).
5,7,8,9,9a,10-Hexahydro-8-thioxopyrido[2,3-d :6,5-d’]dipyrimidine-2,4,6(1H,3H,5aH)-trione Deriva-
tives 5: General Procedure. A mixture of thiouracil (4); 0.128 g, 1 mmol), barbituric acid 3 (0.13 g,
1 mmol), aldehyde 1 (1 mmol), amine 2 (1 mmol), and tungstophosphoric acid (H3PW12O40) (0.04 g,
2 mol-%) in boiling EtOH (5 ml) was stirred for the time specified in Table 2. After completion of the
reaction (TLC (AcOEt/hexane) monitoring), the mixture was cooled to r.t. and the precipitated product
filtered and washed with H2O (20 ml) and EtOH (10 ml): pure 5.
5,7,8,9,9a,10-Hexahydro-5,10-diphenyl-8-thioxopyrido[2,3-d :6,5-d’]dipyrimidine-2,4,6(1H,3H,5aH)-
trione (5a): Yield 90%. Yellow solid. M.p. 240 – 2428. IR (KBr): 3198, 2930, 1763, 17230, 1680, 1591.
1H-NMR (250 MHz): 3.81 (dd, J ¼ 6.5, 3.3, 1 H); 5.04 (d, J ¼ 3.1, 1 H); 5.17 (d, J ¼ 3.2, 1 H); 7.10 – 7.18 (m,
2 H); 7.29 (dd, J ¼ 8.0, 2.9, 4 H); 7.51 (t, J ¼ 4.3, 2 H); 7.76 (d, J ¼ 5.4, 2 H); 9.10 (s, 1 H); 10.08 (s, 1 H);
10.52 (s, 1 H); 11.2 (s, 1 H). 13C-NMR (62.5 MHz): 31.8; 71.0; 86.0; 113.8; 117.4; 130.1; 130.3; 130.7; 140.0;
145.0; 149.9; 152.6; 163.0; 176.1; 183.1. MS: 419.18 (17.9, Mþ). Anal. calc. for C21H17N5O3S (419.46): C
60.13, H 4.09, N 16.70, S 7.64; found: C 60.01, H 3.97, N 16.75, S 7.58.
5,7,8,9,9a,10-Hexahydro-10-(4-iodophenyl)-5-(3-methylphenyl)-8-thioxopyrido[2,3-d :6,5-d’]dipyri-
midine-2,4,6(1H,3H,5aH)-trione (5b): Yield 87%. Violet solid. M.p. 230 – 2328. IR (KBr): 3178, 2926,
1765, 1732, 1677.1, 1581. 1H-NMR (250 MHz): 2.33 (s, 3 H); 3.76 (dd, J ¼ 4.9, 2.0, 1 H); 5.11 (d, J ¼ 3.8,
1 H); 5.33 (d, J ¼ 3.9, 1 H); 6.79 (d, J ¼ 8.3, 2 H); 7.14 (d, J ¼ 5.3, 2 H); 7.41 (dd, J ¼ 6.8, 3.6, 2 H); 7.53 (d,
J ¼ 7.7, 2 H); 9.08 (s, 1 H); 10.12 (s, 1 H); 10.63 (s, 1 H); 11.68 (s, 1 H). 13C-NMR (62.5 MHz): 25.0; 31.2;
50.4; 68.7; 82.2; 83.6; 116.3; 125.1; 126.6; 127.6; 128.6; 129.1; 136.3; 138.0; 140.0; 142.2; 144.3; 150.3; 163.2;
164.5; 176.0; 182.0. MS: 559.02 (14.3, Mþ). Anal. calc. for C22H18IN5O3S (559.38): C 47.24, H 3.24, N 12.52,
S 5.73; found: C 47.29, H 3.21, N 12.58, S, 5.68.
5-(Anthracen-9-yl)-2,3,5,7,8,9,10,10a-octahydro-10-(4-methoxyphenyl)-2,8-dithioxo-pyrido[2,3-
d :6,5-d’]dipyrimidine-4,6(1H,4aH)-dione (5c): Yield 91%. Deep red solid. M.p. > 300 (dec.). IR (KBr):
3217, 3078, 2916, 1763.5, 1674, 1566, 1435, 1381, 1319, 1211, 1165. 1H-NMR (400 MHz): 3.70 (s, 3 H); 4.66
(t, J ¼ 3.8, 1 H); 4.82 (dd, J ¼ 7.6, 1.8, 1 H); 5.19 (dd, J ¼ 7.8, 2.2, 1 H); 7.40 (s, 1 H); 7.49 – 7.95 (m, 6 H);
7.96 (d, J ¼ 8.8, 2 H); 8.13 (d, J ¼ 7.8, 2 H); 8.65 (s, 1 H); 9.00 (s, 1 H); 11.12 (s, 1 H); 11.57 (s, 1 H); 12.30
(br. s, 1 H); 12.48 (br. s, 1 H). 13C-NMR (100 MHz): 27.5; 52.0; 57.7; 68.1; 89.6; 105.2; 125.3; 125.5; 125.5;
126.2; 127.6; 127.7; 128.6; 130.5; 142.1; 150.5; 151.2; 161.0; 162.4; 176.0. MS: 565.29 (15.1, Mþ). Anal. calc.
for C30H23N5O3S2 (565.67): C 63.70, H, 4.10, N 12.38, S 11.34; found: C 63.73, H 4.07, N 12.41, S 11.31.
5,7,8,9,9a,10-Hexahydro-5-(1H-indol-3-yl)-10-(4-methoxyphenyl)-8-thioxopyrido[2,3-d :6,5-d’]dipyr-
imidine-2,4,6(1H,3H,5aH)-trione (5d): Yield 95%. Yellow solid. M.p. 308 – 3128. IR (KBr): 3176, 3002,
1
1770, 1730, 1674, 1586. H-NMR (250 MHz): 3.80 (s, 3 H); 3.98 (d, J ¼ 4.1, 1 H); 5.61 (d, J ¼ 3.3, 1 H);
5.80 (d, J ¼ 3.5, 1 H); 7.31 (dd, J ¼ 10.5, 5.4, 2 H); 7.38 (d, J ¼ 6.6, 2 H); 7.58 (dd, J ¼ 5.9, 2.7, 2 H); 7.85 (t,
J ¼ 2.8, 2 H); 8.29 (d, J ¼ 7.7, 1 H); 11.02 (s, 1 H); 11.1 (s, 1 H); 12.25 (s, 1 H); 12.42 (s, 1 H); 12.72 (s, 1 H).
13C-NMR (62.5 MHz): 31.4; 51.5; 57.8; 70.1; 84.2; 105.2; 108.6; 111.3; 113.1; 117.6; 122.6; 123.6; 129.1;

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Helvetica Chimica Acta – Vol. 96 (2013)
136.3; 139.7; 142.0; 143.6; 150.3; 163.2; 164.5; 176.0. MS: 488.09 (23, Mþ). Anal. calc. for C24H20N6O4S
(488.52): C 59.01, H 4.13, N 17.20, S 6.56; found: C 59.08, H 4.15, N 17.25, S 6.51.
5,7,8,9,9a,10-Hexahydro-5-(4-nitrophenyl)-10-(7H-purin-6-yl)-8-thioxopyrido[2,3-d :6,5-d’]dipyri-
midine-2,4,6(1H,3H,5aH)-trione (5e): Yield 84%. Pale yellow solid. M.p. > 300 (dec.). IR (KBr): 3179,
2974, 1778, 1731, 1680, 1585. 1H-NMR (250 MHz): 3.78 (dd, J ¼ 4.7, 2.5, 1 H); 5.03 (d, J ¼ 2.6, 1 H); 5.57
(d, J ¼ 2.8, 1 H); 7.77 (d, J ¼ 8.7, 2 H); 7.85 (s, 1 H); 8.3 (d, J ¼ 10.0, 2 H); 8.39 (s, 1 H); 9.22 (s, 1 H); 10.16
(s, 1 H); 10.36 (s, 1 H); 11.33 (s, 1 H). 13C-NMR (62.5 MHz): 32.4; 52.4; 67.2; 75.3; 87.3; 122.1; 123.3;
131.0; 137.1; 147.2; 150.0; 151.1; 153.5; 155.6; 157.5; 168.2; 178.5; 181.0. MS: 522.21 (12.5, Mþ). Anal. calc.
for C20H14N10O4S2 (522.52): C 45.97, H 2.70, N 26.81, S 12.27; found: C 46.01, H 2.72, N 26.87, S 12.21.
5,7,8,9,9a,10-Hexahydro-5-(4-nitrophenyl)-10-{9-[(2R,3R,4S,5R)-tetrahydro-3,4-dihydroxy-5-(hy-
droxymethyl)furan-2-yl)-9H-purin-6-yl}-8-thioxopyrido[2,3-d :6,5-d’]dipyrimidine-2,4,6(1H,3H,5aH)-tri-
one (5f): Yield 78%. Yellow solid. M.p. 234 – 2368. IR (KBr): 3530, 3328, 2956, 1745, 1722, 1673, 1571.
1H-NMR (250 MHz): 3.36 – 3.39 (m, 3 H); 4.21 – 4.23 (m, 1 H); 4.42 – 4.44 (m, 1 H); 4.81 – 4.83 (m, 1 H);
5.02 (s, 1 H); 5.53 (s, 1 H); 6.30 (s, 3 H); 7.41 – 7.43 (m, 2 H); 7.67 (dd, J ¼ 6.8, 2.2, 2 H); 7.86 (t, J ¼ 1.5,
1 H); 7.87 (s, 1 H); 7.89 (s, 1 H); 9.14 (s, 1 H); 9.98 (s, 1 H); 11.02 (s, 1 H); 12.40 (s, 1 H). 13C-NMR
(62.5 MHz): 32.7; 50.2; 58.2; 61.0; 73.1; 76.0; 83.1; 85.2; 90.0; 91.9; 118.9; 120.3; 129.0; 140.0; 146.3; 150.4;
151.1; 153.4; 154.7; 155.4; 162.1; 176.3. Anal. calc. for C25H22N10O9S (638.57): C 47.02, H 3.47, N 21.93, S
5.02; found: C 47.08, H 3.49, N 21.99, S 5.00.
10-(1H-Benzimidazol-2-yl)-2,3,4,5,7,8,9,9a,10-octahydro-5-(4-nitrophenyl)-2,8-dithioxopyrido[2,3-
d :6,5-d’]dipyrimidine-4,6(1H,4aH)-dione (5g): Yield 86%. Yellow solid. M.p. 263 – 2658. IR (KBr): 3180,
2970, 1779, 1735, 1676, 1584. 1H-NMR (250 MHz): 3.72 (dd, J ¼ 8.1, 3.6, 1 H); 4.90 (d, J ¼ 7.6, 1 H); 5.87
(d, J ¼ 6.3, 1 H); 6.98 (d, J ¼ 7.5, 2 H); 7.19 (d, J ¼ 2.0, 1 H); 7.22 (d, J ¼ 4.0, 1 H); 7.79 (d, J ¼ 8.1, 2 H);
8.20 (d, J ¼ 5.7, 2 H); 11.68 (s, 1 H); 12.26 (s, 1 H); 12.42 (s, 1 H); 14.02 (s, 2 H). 13C-NMR (62.5 MHz):
31.0; 67.9; 81.0; 116.7; 121.1; 123.0; 130.0; 136.5; 145.6; 150.5; 154.3; 162.8; 174.5; 179.1. MS: 520.12 (21,
Mþ). Anal. calc. for C22H16N8O4S2 (520.54): C 50.76, H 3.10, N 21.53, S 12.32; found: C 50.81, H 3.13, N
21.59, S 12.28.
4-[1,2,3,4,4a,5,6,7,8,9,10,10a-Dodecahydro-10-(4-methoxyphenyl)-4,6-dioxo-2,8-dithioxopyrido[2,3-
d :6,5-d’]dipyrimidin-5-yl]benzaldehyde (5h): Yield 85%. Yellow solid. M.p. > 300 (dec.). IR (KBr):
3190, 2972, 1771, 1728, 1679, 1588. 1H-NMR (250 MHz): 3.88 (s, 6 H); 4.0 (dd, J ¼ 10.0, 4.1, 2 H); 5.78 (d,
J ¼ 7.6, 2 H); 6.05 (s, 2 H); 7.36 (t, J ¼ 10.0, 4 H); 7.78 (d, J ¼ 4.5, 2 H); 7.82 (d, J ¼ 4.0, 2 H); 8.12 (t, J ¼ 4.5,
4 H); 10.87 (s, 2 H); 11.68 (s, 2 H); 12.26 (s, 2 H); 12.42 (s, 2 H). 13C-NMR (62.5 MHz): 31.3; 45.3; 45.7;
66.3; 84.4; 110.5; 128.3; 133.0; 147.3; 150.4; 151.1; 153.5; 155.7; 157.4; 166.2; 168.3; 178.3; 181.2. Anal. calc.
for C38H32N10O8S2 (820.85): C 55.60, H 3.93, N 17.06, S 7.81; found: C 55.64, H 3.95, N 17.12, S 7.78.
2,3,5,7,8,9,10,10a-Octahydro-5-(3-hydroxy-4-methoxyphenyl)-10-(4-methoxyphenyl)-2,8-dithioxo-
pyrido[2,3-d :6,5-d’]dipyrimidine-4,6(1H,4aH)-dione (5i): Yield 85%. Yellow solid. M.p. > 300 (dec.).
IR (KBr): 3182, 2970, 1781, 1739, 1685, 1587. 1H-NMR (250 MHz): 3.75 (s, 3 H); 3.78 (s, 3 H); 4.02 (dd,
J ¼ 4.9, 2.5, 1 H); 4.66 (d, J ¼ 2.4, 1 H); 5.82 (d, J ¼ 7.3, 1 H); 6.86 (d, J ¼ 8.7, 2 H); 7.13 (d, J ¼ 8.1, 1 H);
7.22 (d, J ¼ 8.7, 2 H); 7.36 – 7.41 (m, 2 H); 9.27 (br. s, 1 H); 10.28 (br. s, 1 H); 11.10 (br. s, 1 H); 11.47 (br. s,
1 H). 13C-NMR (62.5 MHz): 33.0; 50.8; 54.9; 68.1; 100.1; 131.2; 132.4; 134.8; 138.4; 149.8; 150.2; 154.4;
163.4; 168.4; 174.2; 179.2. MS: 511.24 (12.8, Mþ). Anal. calc. for C23H21N5O5S2 (511.57): C 54.00, H 4.14,
N 13.69, S 12.54; found: C 54.05, H 4.18, N 13.73, S 12.50.
5-(4-Chlorophenyl)-5,7,8,9,9a,10-hexahydro-10-[2-(morpholin-4-yl)ethyl]-8-thioxopyrido[2,3-d :6,5-
d’]dipyrimidine-2,4,6(1H,3H,5aH)-trione (5j): Yield 91%. Yellow solid. M.p. 258 – 2608. IR (KBr): 3172,
2968, 1783, 1742, 1689, 1587. 1H-NMR (250 MHz): 2.36 – 2.40 (m, 4 H); 2.85 – 2.92 (m, 2 H); 3.37 (d, J ¼
7.1, 2 H); 3.42 (d, J ¼ 5.8, 2 H); 3.50 (d, J ¼ 8.3, 1 H); 3.56 (d, J ¼ 9.5, 2 H); 5.13 (d, J ¼ 13.5, 2 H); 7.41 (d,
J ¼ 3.4, 2 H); 7.65 (d, J ¼ 3.2, 2 H); 9.13 (s, 1 H); 10.10 (s, 1 H); 10.62 (s, 1 H); 11.20 (br. s, 1 H). 13C-NMR
(62.5 MHz): 31.4; 50.0; 51.1; 66.3; 67.1; 79.5; 129.3; 131.0; 137.5; 150.5; 157.4; 162.1; 176.2; 181.6. MS:
500.54 (24, Mþ). Anal. calc. for C21H23ClN6O4S (490.96): C 51.37, H 4.72, N 17.12, S 6.53; found: C 51.41,
H 4.74, N 17.18, S 6.50.
5,7,8,9,9a,10-Hexahydro-10-[2-(piperazin-1-yl)ethyl]-5-(pyridin-3-yl)-8-thioxopyrido[2,3-d :6,5-
d’]dipyrimidine-2,4,6(1H,3H,5aH)-trione (5k): Yield 92%. Yellow solid. M.p. 266 – 2688. IR (KBr): 3378,
3188, 2965, 1786, 1747, 1681, 1583. 1H-NMR (250 MHz): 2.78 (t, J ¼ 1.8, 4 H); 3.23 (t, J ¼ 8.3, 2 H); 3.54 (t,
J ¼ 6.2, 2 H); 3.76 – 3.79 (m, 3 H); 4.14 (s, 2 H); 4.47 (s, 1 H); 5.28 (d, J ¼ 5.2, 1 H); 6.41 (br. s, 2 H); 7.35

Helvetica Chimica Acta – Vol. 96 (2013)
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(dd, J ¼ 4.7, 2.0, 1 H); 7.75 (d, J ¼ 8.0, 1 H); 8.17 (d, J ¼ 9.0, 1 H); 8.39 (s, 1 H); 10.07 (s, 1 H); 11.55 (s,
1 H); 11.72 (s, 1 H). 13C-NMR (62.5 MHz): 32; 37.1; 41.5; 51.2; 55.0; 67.3; 79.5; 123.1; 136.4; 137.1; 147.3;
150.4; 151.1; 158.1; 163.1; 176.1; 182.8. MS: 456 (27, Mþ). Anal. calc. for C20H24N8O3S (456.52): C 52.62, H
5.30, N 24.55, S 7.02; found: C 52.67, H 5.33, N 24.59, S 6.68.
10-(4-Bromophenyl)-5,7,8,9,9a,10-hexahydro-5-(2-thien-yl)-8-thioxopyrido[2,3-d :6,5-d’]dipyri-
midine-2,4,6(1H,3H,5aH)-trione (5l): Yield 89%. Yellow solid. M.p. 235 – 2378. IR (KBr): 3210, 2971,
1790, 1751, 1678, 1579. 1H-NMR (250 MHz): 3.51 – 3.53 (m, 1 H); 4.77 (d, J ¼ 2.7, 1 H); 5.10 (d, J ¼ 2.4,
1 H); 7.02 (d, J ¼ 9.8, 1 H); 7.16 – 7.19 (m, 3 H); 7.38 (d, J ¼ 3.0, 1 H); 7.41 (d, J ¼ 3.1, 1 H); 9.66 (br. s,
1 H); 10.59 (s, 1 H); 11.09 (s, 1 H); 12.04 (br. s, 1 H). 13C-NMR (62.5 MHz): 22.0; 45.7; 71.3; 91.5; 110.9;
116.4; 123.1; 124.0; 125.0; 133.3; 143.5; 146.4; 157.2; 163.1; 176.2; 178.1; 181.8. MS: 504.06 (19, Mþ). Anal.
calc. for C19H14BrN5O3S2 (504.38): C 45.24, H 2.80, N 13.89, S 12.71; found: C 45.29, H 2.83, N 13.93, S
12.68.
5-(4-Bromophenyl)-5,7,8,9,9a,10-hexahydro-10-(2-methoxyphenyl)-8-thioxopyrido[2,3-d :6,5-d’]di-
pyrimidine-2,4,6(1H,3H,5aH)-trione (5m): Yield 90%. Yellow solid. M.p. > 300 (dec.). IR (KBr): 3195,
1
2965, 1787, 1753, 1670, 1573. H-NMR (250 MHz): 3.31 – 3.41 (m, 1 H); 3.72 (s, 3 H); 4.72 (d, J ¼ 11.1,
1 H); 5.27 (d, J ¼ 7.4, 1 H); 5.81 (br. s, 2 H); 7.09 (d, J ¼ 8.2, 2 H); 7.14 – 7.22 (m, 2 H); 7.24 (d, J ¼ 4.2,
1 H); 7.29 – 7.34 (m, 1 H); 7.43 (dd, J ¼ 10.4, 5.4 Hz, 2 H); 9.40 (br. s, 1 H); 9.69 (br. s, 1 H). 13C-NMR
(62.5 MHz): 31.4; 50.0; 55.0; 68.1; 90.0; 105.2; 108.6; 111.3; 117.6; 122.6; 123.6; 128.3; 140.0; 144.4; 150.3;
157.1; 162.2; 173.6; 174.5; 179.6. MS: 528.08 (12, Mþ). Anal. calc. for C22H18BrN5O4S (528.38): C 50.01, H
3.43, N 13.25, S 6.07; found: C 50.07, H 3.47, N 13.29, S 6.02.
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Received July 6, 2012