An efficient three-component synthesis of new barbiturate salts

Article abstract of DOI:10.1016/j.tet.2012.01.069

An efficient synthesis of new barbiturate salts consist of 2-aminopyridinium moiety by an uncatalyzed three-component condensation reaction of C-H acids, pyrimidine-tetraones, and 2-aminopyridines in refluxing chloroform is reported. The reaction of pyrim

Full text of DOI:10.1016/j.tet.2012.01.069

Tetrahedron 68 (2012) 2906e2916
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An efficient three-component synthesis of new barbiturate salts
*
Somayeh Ahadi, Maryam Abaszadeh, Hamid Reza Khavasi, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of new barbiturate salts consist of 2-aminopyridinium moiety by an uncatalyzed
three-component condensation reaction of CeH acids, pyrimidine-tetraones, and 2-aminopyridines in
refluxing chloroform is reported. The reaction of pyrimidine-tetraones and 2-aminopyridines with
ninhydrin in the formation of new barbiturate salts consist of 2-aminopyridinium moiety is also
investigated.
Received 10 October 2011
Received in revised form 2 January 2012
Accepted 23 January 2012
Available online 4 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Barbituric acid
Barbiturate salt
Pyrimidine-tetraones
2-Aminopyridinium
1. Introduction
recently, derivatives of barbituric acids have been reported to ex-
hibit anti-cancer, analeptic, immunomodulating, and anti-AIDS
One of the main challenges in medicinal chemistry is the design
and synthesis of biologically active molecules. Multi-component
reactions (MCRs) play an important role in combinatorial chemis-
try because of its ability to synthesize small drug-like molecules
with several degrees of structural diversity. A MCR is defined as
three or more different starting materials that react to form
a product, where most, if not all of the atoms are incorporated in
the final product. This reaction tool allows compounds to be syn-
thesized in a few steps and usually in a one-pot operation. Another
typical benefit from these reactions is simplified purification, be-
cause all of the reagents are incorporated into the final product.1,2
Barbituric acid derivatives, i.e., phenobarbital,3 mephobarbital,4
are well known drugs, which are used for the treatment of epilepsy.
Although these drugs are very effective in controlling seizures, they
have major side-effects like sedation and hypnosis. Substituted
heterocyclic/substituted aryl systematic variations at the 5-position
of barbituric5e7 or thiobarbituric8,9 acids nucleus remarkably in-
crease the antiepileptic activity. Furthermore, these compounds
been reported to possess a wide spectrum of biologic activities as
sedatives, hypnotics, antitumor agents, antiviral agents, anti-
inflammatory agents, antisclerotics, and bacteriostatics.10e12 In
addition, barbiturates produce changes in mental activity ranging
from mild sedation and sleep, to deep coma and are commonly
used in the treatment of anxiety, insomnia, seizure disorders, mi-
graine headaches, and in surgery as general anesthetics.13 More
activity,14 whilst others are reported to be selective matrix metal-
loproteinase (MMP) inhibitors.15
Aminopyridinium salts show an extensive range of antimicro-
bial activity and potentially interact with certain polymeric fi-
bers.16,17 Moreover, the amino group in the pyridinium ring
interacts via dipoleedipole and hydrogen bonds with wool pro-
teins.18,19 Despite of continuous research for the synthesis of bar-
bituric acid derivatives, only a limited number of barbiturate salts
have been reported.20e23 Therefore, as part of our program aimed
for the preparation of new heterocycles,24e26 guided by the ob-
servation that the presence of two or more different heterocyclic
moieties in a molecule often enhances the biological profile re-
markably, we investigated herein, an efficient synthesis of new
barbiturate salts containing 2-aminopyridinium moiety 4 via the
three-component reaction of 2-aminopyridines 1, pyrimidine-tet-
raones 2, and 1,3-dicarbonyles (Scheme 1). To the best of our
knowledge, this new procedure provides the first example of an
efficient and three-component method for the synthesis of organic
salts incorporating both barbiturate and aminopyridine motifs.
2. Results and discussion
Initially, the three-component reaction of 2-aminopyridine 1a
(1 mmol), pyrimidine-tetraone hydrates 2a (1 mmol), and 4-
hydroxy cumarin 3a (1 mmol) as a model reaction was in-
vestigated in different solvent without any catalyst (Table 1). As
shown in Table 1, the best result was obtained in chloroform at
reflux (entry 7). To study the effect of temperature on the reaction,
* Corresponding author. Fax: þ98 21 22431661; e-mail address: a_bazgir@
sbu.ac.ir (A. Bazgir).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.069

S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
2907
R
H2N
OH
N
N
OH
N
NH
O
R
O
O
O
O
O
or
N
N
N
R1
R1
R1
R1
O
O
O
R
O
O
O
O
CHCl3 (Ref)
+
+
R1
O
N
N
R1
H
O
H2N
N
O
O
O
O
1
2
3
N
N
R1
H
R1
H
N
O
HN
4
R
Scheme 1. Synthesis of barbiturate salt 4.
Table 1
Solvents screen for the synthesis of compound 4a
we also performed the reaction at lower temperature (Table 1). It
was observed that a lower reaction temperature led to a lower yield
(entries 8 and 9).
Subsequently, these optimized conditions were applied for the
conversion of various 2-aminopyridines 1aed, pyrimidine-
tetraones 2a,b, and 1,3-dicarbonyl compounds 3aeh into the cor-
responding barbiturate salts consist of 2-aminopyridinium 4aey
(Scheme 2, Table 2).
O
H
O
OH
O
O
O
N
O
O
O
O
O
+
+
HN
NH
HN
H
NH
H2N
N
O
H
O
O
HN
1a
2a
3a
4a
To further explore the potential of this protocol for new barbi-
turate salts synthesis, we investigated a reaction involving 2,5-
dihydroxycyclohexa-2,5-diene-1,4-dione 5 and obtained bis(2-
Entry
Solvents
EtOH (reflux)
Yielda (%)
1
2
3
4
5
6
7
8
9
54
78
67
53
36
79
99
83
52
CH3CN (reflux)
CH2Cl2 (reflux)
H2O (reflux)
DMF (reflux)
THF (reflux)
CHCl3 (reflux)
CHCl3 (40 ꢀC)
CHCl3 (rt)
aminopyridinium)
(1,4-bis(5-hydroxy-2,4,6-
trioxohexahydropyrimidin-5-yl)-2,3,5,6-tetraoxocyclohexan-1-
ides) 6aee in good yields (Scheme 3).
The products were fully characterized by IR, 1H NMR, and 13C
NMR. The structure of 4a and 4h was confirmed by single-crystal X-
ray analysis27 (Fig. 1).
a
Reaction time, 2 h.
S
Et
O
Et
N
N
3f
O
O
O
O
O
O
O
3c
3e
HN NH
N
N
HN NH
3d
O
O
S
OH
O
O
3b
3g
O
O
O
O
O
OH
O
O
OH
3h
3a
O
1a
O
H2N
N
O
O
2b
O
O
N
N
1b
H
O
R
O
O
H2N
N
O
O
O
N
N
O
R1
R1
O
H2N
N
1c
O
O
N
N
O
R1
R1
H2N
1d
N
H
H
2a
N
HN NH
O
HN
H2N
N
R
Scheme 2. Diversity of reagents.

2908
S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
Table 2
Barbiturate salts consist of 2-aminopyridinium 4
O
H
O
O
O
O
R
O
O
O
CHCl3 (Ref)
+
O
+
N
N
N
N
R1
R1
H2N
N
R1
H
R1
H
N
O
O
O
HN
1a-d
2a,b
3a-h
4a-y
Products
Yield (%)
Time (h)
Products
Yield (%)
Time (h)
99
2
99
3.5
4h
4a
4b
99
92
82
5
10
4.5
99
99
98
3
5
4
4i
4j
4c
4k
4d
97
1
99
1
4e
4l
70
1
98
3
4f
4m

S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
2909
Table 2 (continued )
Products
Yield (%)
Time (h)
Products
Yield (%)
Time (h)
98
20
99
5
4g
4n
99
1
87
20
4u
4o
99
1
86
18
4v
4p
99
3
90
4.5
4w
4q
95
4
84
18
4x
4r
92
1
95
3
4y
4s
98
1
4t

2910
S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
Scheme 3. Synthesis of bis(trioxohexahydropyrimidin-5-yl)-tetraoxocyclohexan-1-ides 6.
We also found that, when 2-amino benzimidazole 7 was used
instead of 2-aminopyridine also successfully reacted under the
same reaction conditions (Scheme 4).
When 2-amino benzimidazole
7
reacted with 2,5-
dihydroxycyclohexa-2,5-diene-1,4-dione 5, it was interesting that
the desired products of 9 were not detected at all, while 2-amino-
benzoimidazolium (5-hydroxy-2,4,6-trioxohexahydropyrimidin-5-
yl)-trioxocyclohex-3-en-1-ide 10 was obtained in 93% yield under
the same reaction conditions (Scheme 5).
Finally, we expected ninhydrin 11 could be used instead of
pyrimidine-tetraones 2 (Scheme 6). The desired reactions were
found to generate the corresponding amino pyridinium (2-hydroxy-
1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-ides 12aee in good yields.
We have not established an exact mechanism for the formation
of barbiturate salts, however, a reasonable possibility is shown in
(Scheme 7).
Due to decreased basicity of aminopyridine with electron with-
drawing group, it is not of surprise that, when 5-bromo or 5-chloro
aminopyridine
was
used,
5-(2,4-dioxochroman-3-yl)-5-
hydroxypyrimidine-trione 13 was obtained in 93% yield (Scheme 8).
It was found, when we used oxindole 14 as CeH acid, desired
barbituric salt has not been obtained and 5-hydroxy-5-(2-
oxoindolin-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione 15 resulted in
92% yield (Scheme 9).
3. Conclusion
In conclusion, an efficient and simple method for the prepara-
tion of new barbiturate salts using readily available starting mate-
rials is reported. Prominent among the advantages of this new
method are novelty, operational simplicity, good yields, and easy
work-up procedures employed.
Fig. 1. X-ray crystal structure of 4a (A) and 4h (B).
Scheme 4. Reaction of 2-amino benzimidazole, pyrimidine-tetraone, and 1,3-dicarbonyles.

S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
2911
Scheme 5. Reaction of 2-amino benzimidazole, pyrimidine-tetraone, and 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione.
Scheme 6. Reaction of aminopyridines, ninhydrin, and 1,3-dicarbonyles.
Scheme 7. Proposed mechanism.
4. Experimental section
4.1. General methods
Scheme 8. Effect of basicity of aminopyridine in the reaction.
Melting points were measured on an Electrothermal 9100 ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recor-
ded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and
75.47 MHz, respectively. 1H and 13C NMR spectra were obtained on
solutions in DMSO-d6. IR spectra were recorded using an FTIR ap-
paratus. Elemental analyses were performed using a Heracus CHN-
O-Rapid analyzer. The chemicals used in this work were obtained
from Fluka and Merck and were used without purification.
4.2. General procedure for preparation of barbiturate salts
consist of 2-aminopyridine
A mixture of 2-aminopyridine (1 mmol), pyrimidine-tetraone
hydrate (1 mmol), and 1,3-dicarbonyl compound (1 mmol) in
refluxing chloroform (5 mL) was stirred for the appropriate time
(Table 2). After completion of the reaction (confirmed by TLC), the

2912
S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
2NH), 11.12 (2H, s, 2NH), 13.21 (1H, br s, OH); dC (75 MHz, DMSO-d6)
74.1, 112.5, 113.8, 136.4, 144.6, 150.7, 154.2, 163.5, 172.4, 174.6.
4.2.6. 2-Aminopyridinium 1,3-diethyl-5-(5-hydroxy-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-4,6-dioxo-2-thioxohexahydropyrimidin-5-
ide (4f). (305.48 g, 70%) as white powder, mp 176e179 ꢀC. [Found:
C, 46.85; H, 4.56; N, 19.17. C17H20N6O6S requires 46.78; H, 4.62; N,
19.26%]; nmax (KBr) 3381, 3197, 3040, 2844, 1745, 1663 cmꢁ1
; dH
Scheme 9. Reaction of aminopyridines, pyrimidine-tetraones, and oxindole.
(300 MHz, DMSO-d6) 1.09 (6H, br s, 2CH3), 4.28e4.30 (2H, br s,
CH2), 6.84e6.97 (2H, m, H-Ar), 7.91(4H, br s, H-Ar and NH2), 10.99
(2H, s, 2NH), 11.29 (1H, s, NH), 11.63 (1H, s, OH); dC (75 MHz, DMSO-
d6) 12.9, 41.38, 74.4, 85.4, 88.0, 112.5, 113.8,136.4, 144.6, 150.7, 154.2,
157.0, 161.7, 169.4, 172.7, 175.5.
reaction mixture was cooled to room temperature. Then, the pre-
cipitate was filtered and washed with ethyl acetate (10 mL) to af-
ford the pure products.
4.2.7. 5-(1,3-Dioxo-2,3-dihydro-1H-inden-2-yl)-5-hydroxypyrimi-
dine-2,4,6 (1H,3H,5H)-trione, 2-aminopyridinium salt (4g).
(375.34 g, 98%) as white powder, mp 224e225 ꢀC. [Found: C, 56.33;
H, 3.85; N, 14.52. C18H15N4O6 requires C, 56.40; H, 3.94; N, 14.62%];
4.2.1. 2-Aminopyridinium 3-(5-hydroxy-2,4,6-trioxohexahydropyri-
midin-5-yl)-2,4-dioxochroman-3-ide (4a). (394.02 g, 99%) as white
powder, mp 195e197 ꢀC. [Found: C, 54.16; H, 3.47; N, 14.16.
C18H14N4O7 requires C, 54.28; H, 3.54; N, 14.07%]; nmax (KBr) 3446,
nmax (KBr) 3412, 3305, 3021, 2826, 1738, 1656, 1618 cmꢁ1
; dH
(300 MHz, DMSO-d6) 6.75e7.22 (4H, m, H-Ar), 7.23e7.51 (br s, NH,
OH and NH2 overlap with solvent), 7.75e7.90 (4H, m, H-Ar), 10.94
(2H, s, 2NH); dC (75 MHz, DMSO-d6) 75.6, 99.1, 112.4, 117.6, 130.2,
139.0, 139.5, 143.0, 150.7, 155.5, 171.9, 188.6.
3212, 3099, 2846, 1709, 1632 cmꢁ1
; dH (300 MHz, DMSO-d6) 3.47
(br s, NH and OH, overlap with solvent), 6.84 (1H, br s, H-Ar),
6.93e6.95 (3H, m, H-Ar), 7.20 (1H, br s, H-Ar), 7.76e7.90 (5H, m, H-
Ar and NH2), 11.05 (2H, s, 2NH); dC (75 MHz, DMSO-d6) 76.0, 94.2,
112.5, 113.8, 116.4, 122.0, 123.3, 124.0, 131.4, 136.5, 144.5, 150.8,
153.7, 154.3, 163.8, 169.4, 172.6, 175.1.
4.2.8. 2-Aminopyridinium 2-(5-hydroxy-2,4,6-trioxohexahydro-
pyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphthalen-2-ide
(4h). (419.86 g, 99%) as orange powder, mp 234e235 ꢀC. [Found: C,
55.50; H, 3.86; N, 13.60. C19H14N4O7 requires C, 55.61; H, 3.44; N,
4.2.2. 2-Aminopyridinium 3-(5-hydroxy-2,4,6-trioxohexahydro-
pyrimidin-5-yl)-6-methyl-2,4-dioxo-3,4-dihydro-2H-pyran-3-ide
(4b). (358.38 g, 99%) as white powder, mp 203e204 ꢀC. [Found: C,
49.65; H, 3.84; N, 15.39. C15H14N4O7 requires C, 49.73; H, 3.89; N,
13.65%]; nmax (KBr) 3346, 3197, 3084, 2837, 1709, 1669 cmꢁ1
; dH
(300 MHz, DMSO-d6) 3.56 (br s, NH and OH, overlap with solvent),
6.80e6.95 (2H, m, H-Ar), 7.57e7.91 (8H, m, H-Ar and NH2), 11.05
(2H, s, 2NH); dC (75 MHz, DMSO-d6) 76.4, 112.5, 113.5, 113.6, 124.9,
125.9, 131.4, 131.8, 134.3, 134.4, 136.8, 136.9, 144.3, 150.9, 154.5,
172.5, 180.3, 181.9, 184.7.
15.46%]; nmax (KBr) 3375, 3209, 3094, 1729, 1663, 1618 cmꢁ1
; dH
(300 MHz, DMSO-d6) 2.01 (3H, s, CH3), 4.57e5.56 (br s, NH and OH
and NH2, overlap with solvent), 5.41 (1H, s, CH), 6.76e6.85 (2H, m,
H-Ar), 7.76e7.89 (2H, m, H-Ar), 11.02 (2H, s, 2NH).
Due to very low solubility of the product 4b, we cannot report
4.2.9. 2-Amino-3-methylpyridinium 3-(5-hydroxy-2,4,6-trioxohexa-
hydropyrimidin-5-yl)-2,4-dioxochroman-3-ide (4i). (407.88 g, 99%)
as white powder, mp 137e139 ꢀC. [Found: C, 55.42; H, 3.98; N,
13.51. C19H16N4O7 requires C, 55.34; H, 3.91; N, 13.59%]; nmax (KBr)
the 13C NMR data for this product.
4.2.3. 2-Aminopyridinium 5-(5-hydroxy-2,4,6-trioxohexahydro-
3407, 3372, 3217, 3068, 2851, 1730, 1725, 1650, 1600 cmꢁ1
; dH
pyrimidin-5-yl)-2,4,6-trioxohexahydropyrimidin-5-ide
(4c).
(334.95 g, 92%) as cream powder, mp 210e212 ꢀC. [Found: C, 42.94;
(300 MHz, DMSO-d6) 2.14 (3H, s, CH3), 3.49 (br s, NH and OH,
overlap with solvent), 6.80 (1H, br s, H-Ar), 7.17 (2H, br s, H-Ar), 7.45
(1H, br s, H-Ar), 7.67 (2H, br s, NH2), 7.78 (3H, br s, H-Ar), 11.01 (2H,
s, 2NH); dC (75 MHz, DMSO-d6) 16.8, 76.1, 79.6, 93.7, 112.7, 116.3,
122.3, 125.5, 123.1, 124.0, 131.2, 134.4, 143.1, 150.8, 153.6, 153.8,
163.9, 172.8, 175.9.
H, 3.25; N, 23.01. C13H12N6O7 requires C, 42.86; H, 3.32; N, 23.07%];
nmax (KBr) 3418, 3330, 3229, 2800, 1669, 1631 cmꢁ1
; dH (300 MHz,
DMSO-d6) 3.45e3.49 (br s, NH and OH, overlap with solvent),
6.82e6.96 (2H, m, H-Ar), 7.90 (4H, br s, H-Ar and NH2), 9.59 (2H, s,
2NH), 10.88 (2H, s, 2NH); dC (75 MHz, DMSO-d6) 74.3, 82.4, 112.4,
112.5, 113.7, 136.5, 144.5, 150.8, 152.2, 154.3, 162.8, 165.4, 173.2.
4.2.10. 2-Amino-3-methylpyridinium 3-(5-hydroxy-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-6-methyl-2,4-dioxo-3,4-dihydro-2H-py-
ran-3-ide (4j). (372.34 g, 99%) as cream powder, mp 203e205 ꢀC.
[Found: C, 50.96; H, 4.21; N, 14.96. C16H16N4O7 requires C, 51.07; H,
4.29; N, 14.89%]; nmax (KBr) 3374, 3324, 3204, 3084, 1726, 1650,
4.2.4. 2-Aminopyridinium 5-(5-hydroxy-2,4,6-trioxohexahydro-
pyrimidin-5-yl)-1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-5-ide
(4d). (321.44 g, 82%) as cream powder, mp 172e173 ꢀC. [Found: C,
45.83; H, 4.04; N, 21.34. C15H16N6O7 requires C, 45.92; H, 4.11; N,
21.42%]; nmax (KBr) 3343, 3229, 3073, 2833, 1723, 1662 cmꢁ1
; dH
1645 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.00 (3H, s, CH3), 2.13 (3H, s,
(300 MHz, DMSO-d6) 3.00 (6H, s, CH3), 3.15e3.39 (br s, NH and
OH, overlap with solvent), 6.82e6.96 (2H, m, H-Ar), 7.90 (4H, br s,
H-Ar and NH2), 10.85 (2H, s, 2NH); dC (75 MHz, DMSO-d6) 26.7,
74.5, 79.6, 112.5, 113.8, 136.4, 144.6, 150.9, 152.6, 154.2, 163.2,
173.3.
CH3), 5.54 (br s, NH and OH, overlap with solvent), 5.54 (1H, s, CH),
6.77 (1H, br s, H-Ar), 7.30e7.44 (2H, br s, NH2), 7.70e7.79 (2H, m, H-
Ar), 11.01 (2H, s, 2NH); dC (75 MHz, DMSO-d6) 16.9, 19.5, 75.5, 93.7,
106.7, 112.7, 121.6, 135.8, 142.2, 142.4, 150.7, 154.2, 159.8, 164.9,
172.4, 178.6.
4.2.5. 2-Aminopyridinium 5-(5-hydroxy-2,4,6-trioxohexahydro-
pyrimidin-5-yl)-4,6-dioxo-2-thioxohexahydropyrimidin-5-ide
(4e). (368.69 g, 97%) as white powder, mp 146e148 ꢀC. [Found: C,
40.94; H, 3.09; N, 22.18. C13H12N6O6S requires C, 41.05; H, 3.18; N,
4.2.11. 2-Amino-3-methylpyridinium 5-(5-hydroxy-2,4,6-trioxohexa-
hydropyrimidin-5-yl)-1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-
5-ide (4k). (397.99 g, 98%) as white powder, mp 164e165 ꢀC.
[Found: C, 47.20; H, 4.59; N, 20.61. C16H18N6O7 requires C, 47.29; H,
4.46; N, 20.68%]; nmax (KBr) 3343, 3229, 3073, 2833, 1723,
22.10%]; nmax (KBr) 3362, 3223, 3096, 2837, 1726, 1650, 1612 cmꢁ1
;
1662 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.16 (3H, s, CH3), 3.00 (6H, s,
dH (300 MHz, DMSO-d6) .67 (br s, NH and OH, overlap with solvent),
6.84e6.96 (2H, m, H-Ar), 7.90 (4H, br s, H-Ar and NH2), 10.98 (2H, s,
2CH3), 6.81 (1H, br s, H-Ar), 7.69 (2H, br s, NH2), 7.80 (2H, br s, H-

S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
2913
Ar), 10.87 (2H, s, 2NH); dC (75 MHz, DMSO-d6) 16.8, 26.6, 74.5, 82.8,
3441, 3218, 3093, 2851, 1712, 1656 cmꢁ1
;
dH (300 MHz, DMSO-d6)
112.7, 122.4, 134.4, 143.1, 143.2, 150.9, 152.7, 153.6, 163.1, 173.3.
2.49 (3H, s, CH3), 3.43 (br s, NH and OH, overlap with solvent),
6.66e6.76 (2H, m, H-Ar), 7.15e7.22 (2H, m, H-Ar), 7.43e7.48 (1H, m,
H-Ar), 7.58 (2H, br s, NH2), 7.75e7.80 (2H, m, H-Ar), 11.01 (2H, s,
2NH); dC (75 MHz, DMSO-d6) 19.3, 76.1, 79.6, 93.7, 110.3, 112.1, 116.3,
122.5, 123.1, 124.0, 131.2, 144.6, 147.4, 150.8, 153.8, 154.6, 163.9,
172.7, 175.8.
4.2.12. 2-Amino-3-methylpyridinium 2-(5-hydroxy-2,4,6-trioxohe-
xahydropyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphthalen-
2-ide (4l). (419.86 g, 99%) as orange powder, mp 233e234 ꢀC.
[Found: C, 56.54; H, 3.72; N, 13.11. C20H16N4O7 requires 56.61; H,
3.80; N, 13.20%]; nmax (KBr) 3437, 3248, 3172, 2818, 1713,
1656 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.15 (3H, s, CH3), 3.41 (br s, NH
4.2.18. 2-Amino-6-methylpyridinium 5-(5-hydroxy-2,4,6-trioxohe-
xahydropyrimidin-5-yl)-1,3-dimethyl-2,4,6-trioxohexahydropyrimi-
din-5-ide (4r). (372.4 g, 95%) as cream powder, mp 179e180 ꢀC.
[Found: C, 47.21; H, 4.52; N, 20.60. C16H18N6O7 requires C, 47.29; H,
4.46; N, 20.68%]; nmax (KBr) 3418, 3336, 3071, 2831, 1719,
and OH, overlap with solvent), 6.81 (1H, br s, H-Ar), 7.59e7.80 (8H,
m, H-Ar and NH2), 11.03 (2H, s, 2NH); dC (75 MHz, DMSO-d6) 16.8,
76.5, 112.7, 113.4, 122.3, 124.9, 125.9, 131.6, 131.7, 134.3, 134.4, 143.1,
150.9, 153.6, 172.5, 172.6, 180.2,184.7.
1658 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.40 (3H, s, CH3), 3.00 (6H, s,
4.2.13. 2-Amino-5-methylpyridinium 3-(5-hydroxy-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-2,4-dioxochroman-3-ide (4m). (403.76 g,
98%) as white powder, mp 209e211 ꢀC. [Found: C, 55.45; H, 3.84; N,
13.52. C19H16N4O7 requires C, 55.34; H, 3.91; N, 13.59%]; nmax (KBr)
2CH3), 6.68e6.78 (2H, m, H-Ar), 7.63 (2H, br s, NH2), 7.78e7.83 (1H,
m, H-Ar), 10.88 (2H, s, 2NH), 13.38 (br s, NH and OH, overlap with
solvent); dC (75 MHz, DMSO-d6) 19.2, 26.6, 74.5, 110.4, 112.1, 144.7,
147.3, 150.9, 152.7, 154.5, 163.1, 173.3.
3391, 3186, 3096, 2828, 1757, 1712, 1604 cmꢁ1
; dH (300 MHz,
DMSO-d6) 2.12 (3H, s, CH3), 3.61e3.64 (br s, NH and OH, overlap
with solvent), 6.86e6.89 (1H, m, H-Ar), 7.15e7.22 (2H, m, H-Ar),
7.43e7.45 (1H, m, H-Ar), 7.71e7.77 (5H, m, H-Ar and NH2), 11.01
(2H, s, 2NH); dC (75 MHz, DMSO-d6) 16.71, 76.1, 93.7, 113.4, 116.3,
121.9, 122.5, 123.1, 124.0, 131.2, 133.3, 134.2, 146.2, 150.8, 152.9,
153.8, 163.9, 172.8, 175.9.
4.2.19. 2-Amino-6-methylpyridinium 1,3-diethyl-5-(5-hydroxy-2,4,
6-trioxohexahydropyrimidin-5-yl)-4,6-dioxo-2-thioxohexahydropyri-
midin-5-ide (4s). Cream powder (414 g, 92%); mp 224e225 ꢀC.
[Found: C, 47.90; H, 4.85; N, 18.61. C18H22N6O6S requires C, 47.99; H,
4.92; N, 18.66%]; nmax (KBr) 3419, 3287, 3162, 2840, 1718, 1656. 1H
NMR (300 MHz, DMSO-d6): dH (ppm) 1.08e1.12 (6H, br s, 6CH3),
2.40 (3H, s, CH3), 4.26e4.33 (4H, m, 2CH2), 6.68e6.78 (2H, m, H-Ar),
7.63 (2H, s, NH2), 7.78e7.83 (1H, m, H-Ar), 8.30 (1H, s, NH), 11.01
(2H, s, 2NH), 13.39 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): dC
(ppm) 12.9, 19.2, 41.3, 74.4, 79.6, 88.0, 110.4, 112.1, 144.7, 147.2, 150.7,
154.5, 161.7, 172.7, 175.5.
4.2.14. 2-Amino-5-methylpyridinium 3-(5-hydroxy-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-6-methyl-2,4-dioxo-3,4-dihydro-2H-py-
ran-3-ide (4n). (372.34 g, 99%) as cream powder, mp 139e140 ꢀC.
[Found: C, 50.96; H, 4.34; N, 14.95. C16H16N4O7 requires C, 51.07; H,
4.29; N, 14.89%]; nmax (KBr) 3381, 3204, 2995, 1726, 1665,
1612 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.02 (3H, s, CH3), 2.14 (3H, s,
4.2.20. 2-Amino-6-methylpyridinium 2-(5-hydroxy-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphtha-
len-2-ide (4t). (415.62 g, 98%) as yellow powder, mp 224e225 ꢀC.
[Found: C, 56.73; H, 3.75; N, 13.11. C20H16N4O7 requires C, 56.61; H,
3.80; N, 13.20%]; nmax (KBr) 3425, 3235, 3185, 2825, 1716, 1738,
CH3), 4.17e4.64 (br s, NH and OH, overlap with solvent), 5.59 (1H, s,
CH), 6.84e6.87 (1H, m, H-Ar), 7.25e7.76 (3H, m, H-Ar and NH2),
8.30 (1H, s, NH), 11.06 (2H, s, 2NH), 11.26 (1H, s, OH); dC (75 MHz,
DMSO-d6) 16.8, 19.5, 75.4, 79.6, 94.0, 106.3, 113.1, 121.8, 134.9, 145.9,
150.7, 153.2, 160.1, 164.9, 172.2, 177.9.
1669 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.38 (3H, s, CH3), 3.45e3.51 (br
s, NH and OH, overlap with solvent), 6.65e6.77 (2H, m, H-Ar),
7.58e7.80 (7H, m, H-Ar and NH2), 11.04 (2H, s, 2NH); dC (75 MHz,
DMSO-d6) 19.2, 76.4, 110.4, 112.0, 113.5, 124.9, 125.9, 131.6, 134.2,
134.3, 144.6, 147.3, 150.9, 154.5, 172.4, 180.3, 184.7.
4.2.15. 5-(1,3-Dioxo-2,3-dihydro-1H-inden-2-yl)-5-hydroxypyrimi-
dine-2,4,6(1H,3H,5H)-trione,
2-amino-5-methylpyridinium
salt
(4o). (393.33 g, 99%) as yellow powder, mp 119e220 ꢀC. [Found: C,
57.52; H, 4.24; N, 14.05. C19H17N4O6 requires C, C, 57.43; H, 4.31; N,
14.10%]; nmax (KBr) 3412, 3311, 3033, 2831, 1726, 1669, 1631,
4.2.21. 2-Aminopyridinium 3-(5-hydroxy-1,3-dimethyl-2,4,6-
1730 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.12 (3H, s, CH3), 3.79e4.22 (br
trioxohexahydropyrimidin-5-yl)-2,4-dioxochroman-3-ide
(4u).
s, NH and OH, overlap with solvent), 6.81e6.84 (1H, br s, H-Ar), 7.05
(2H, br s, H-Ar), 7.23 (2H, br s, H-Ar), 7.69e7.72 (2H, m, H-Ar and
NH2), 7.92 (1H, br s, H-Ar), 10.94 (2H, br s, NH2); dC (75 MHz, DMSO-
d6) 16.8, 75.6, 99.1, 112.8,117.7, 121.7,130.2, 132.3, 135.8, 139.5, 145.3,
150.8, 153.5, 171.9, 188.6.
(370.72 g, 87%) as cream powder, mp 163e165 ꢀC. [Found: C, 56.24;
H, 4.19; N, 13.21. C20H18N4O7 requires C, 56.34; H, 4.26; N, 13.14%];
nmax (KBr) 3425, 3322, 3150, 2683, 1691, 1651 cmꢁ1
; dH (300 MHz,
DMSO-d6) 3.15 (6H, s, 2CH3), 6.82e6.86 (1H, m, H-Ar), 6.93e6.96
(1H, m, H-Ar), 7.16e7.23 (2H, m, H-Ar), 7.44e7.49 (1H, m, H-Ar),
7.76e7.92 (5H, m, H-Ar and NH2), 12.41 (br s, NH and OH, overlap
with solvent); dC (75 MHz, DMSO-d6) 28.7, 76.4, 94.5, 112.5, 113.7,
116.3, 122.4, 123.2, 124.1, 131.3, 136.6, 144.4, 151.6, 153.8, 154.4,
163.9, 171.5, 175.5.
4.2.16. 2-Amino-5-methylpyridinium 2-(5-hydroxy-2,4,6-trioxohe-
xahydropyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphthalen-
2-ide (4p). (419.86 g, 99%) as orange powder, mp 237e239 ꢀC.
[Found: C, 56.50; H, 3.76; N, 13.14. C20H16N4O7 requires C, 56.61; H,
3.80; N, 13.20%]; nmax (KBr) 3355, 3280, 3090, 3040, 2818, 1757,
4.2.22. 2-Aminopyridinium 3-(5-hydroxy-1,3-dimethyl-2,4,6-
trioxohexahydropyrimidin-5-yl)-6-methyl-2,4-dioxo-3,4-dihydro-
2H-pyran-3-ide (4v). (394.02 g, 99%) as cream powder, mp
146e147 ꢀC. [Found: C, 52.24; H, 4.58; N,14.26. C17H18N4O7 requires
C, 52.31; H, 4.65; N, 14.35%]; nmax (KBr) 3299, 3163, 1690,
1720, 1669 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.13 (3H, s, CH3), 3.44 (br
s, NH and OH, overlap with solvent), 6.88e6.91 (1H, m, H-Ar),
7.59e7.61 (1H, m, H-Ar), 7.69e7.83 (1H, m, H-Ar and NH2), 11.04
(2H, s, 2NH); dC (75 MHz, DMSO-d6) 16.78, 76.48, 113.5, 121.9, 124.9,
125.9, 131.6, 133.9, 134.3, 134.4, 146.4, 150.9, 152.8, 172.4, 180.4,
184.7.
1615 cmꢁ1
; dH (300 MHz, DMSO-d6) 1.99 (3H, s, CH3), 3.11 (6H, s,
2CH3), 5.50 (1H, s, CH), 6.78e6.88 (3H, m, H-Ar), 7.79e7.89 (3H, m,
H-Ar and NH2); dC (75 MHz, DMSO-d6) 19.5, 28.7, 76.3, 94.1, 107.2,
112.5, 112.9, 138.3, 143.4, 151.6, 155.2, 159.7, 164.9, 171.4, 179.1.
4.2.17. 2-Amino-6-methylpyridinium 3-(5-hydroxy-2,4,6-trioxohe-
xahydropyrimidin-5-yl)-2,4-dioxochroman-3-ide
(4q). (407.88 g,
99%) as white powder, mp 155e156 ꢀC. [Found: C, 55.24; H, 3.94; N,
13.67. C19H16N4O7 requires C, 55.34; H, 3.91; N, 13.59%]; nmax (KBr)
4.2.23. 2-Aminopyridinium 5-(5-hydroxy-1,3-dimethyl-2,4,6-
trioxohexahydropyrimidin-5-yl)-2,4,6-trioxohexahydropyrimidin-5-

2914
S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
ide (4w). (352.89 g, 90%) as white powder, mp 213e215 ꢀC. [Found:
[Found: C, 48.54; H, 3.84; N,17.55. C26H25N8Oþ12 requires C, 48.68; H,
C, 45.85; H, 4.05; N, 21.55. C15H16N6O7 requires C, 45.92; H, 4.11; N,
3.93; N, 17.47%]; nmax (KBr) 3456, 3141, 3096, 2970, 1726,
21.42%]; nmax (KBr) 3350, 3143, 2842,1691,1619 cmꢁ1
;
dH (300 MHz,
1663 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.35 (6H, s, 2CH3), 3.71 (br s,
DMSO-d6) 3.10 (6H, s, 2CH3), 4.61 (br s, NH and OH, overlap with
solvent), 6.83e6.97 (2H, m, H-Ar), 7.91 (4H, br s, H-Ar and NH2),
9.66 (2H, s, 2NH), 11.13 (1H, br s, OH).
NH, OH and NH2, overlap with solvent), 6.62e6.72 (4H, m, H-Ar),
7.70e7.75 (2H, m, H-Ar), 11.02 (4H, br s, 4NH); dC (75 MHz, DMSO-
d6) 19.6, 75.7, 107.9, 109.9, 111.9, 121.6, 143.9, 148.1, 150.8, 155.3,
172.3, 177.3.
Due to very low solubility of the product 4w, we cannot report
the 13C NMR data for this product.
4.2.30. Bis(2-aminopyridinium) mono(1,4-bis(5-hydroxy-1,3-dime-
thyl-2,4,6-trioxohexahydropyrimidin-5-yl)-2,3,5,6-tetraoxocyclohe-
xan-1-ide) (6e). (602.62 g, 90%) as light pink powder,þ mp
238e240 ꢀC. [Found: C, 50.34; H, 4.29; N, 16.61. C28H29N8O12 re-
quires C, 50.23; H, 4.37; N, 16.74%]; nmax (KBr) 3396, 3326, 3217,
4.2.24. 2-Aminopyridinium5-(5-hydroxy-1,3-dimethyl-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-1,3-dimethyl-2,4,6-trioxohexahydropyri-
midin-5-ide (4x). (352.92 g, 84%) as pink powder, mp 175e177 ꢀC.
[Found: C, 48.65; H, 4.71; N, 19.92. C17H20N6O7 requires C, 48.57; H,
4.80; N, 19.99%]; nmax (KBr) 3428, 3341, 3079, 2969, 1701,
2897, 1688, 1617 cmꢁ1
; dH (300 MHz, DMSO-d6) 3.13 (12H, s, 4CH3),
1660 cmꢁ1
;
dH (300 MHz, DMSO-d6) 3.00 (6H, s, 2CH3), 3.11 (6H, s,
3.4 (br s, NH, OH and NH2, overlap with solvent) 6.79e6.92 (4H, m,
H-Ar), 7.82e7.87 (4H, m, H-Ar); dC (75 MHz, DMSO-d6) 28.7, 76.1,
108.6, 112.5, 113.3, 137.5, 143.7, 151.7, 155.3, 171.2, 177.1.
CH3), 6.80e6.94 (2H, m, H-Ar), 7.85e7.89 (4H, br s, H-Ar and NH2),
10.62e10.81 (br s, NH and OH, overlap with solvent); dC (75 MHz,
DMSO-d6) 26.7, 28.7, 75.0, 83.7, 112.5, 113.5, 137.0, 144.1, 151.7, 152.6,
154.6, 163.1, 172.1.
4.2.31. 2-Amino-1H-benzo[d]imidazol-3-ium 3-(5-hydroxy-2,4,6-tri-
oxohexahydropyrimidin-5-yl)-2,4-dioxochroman-3-ide (8a). (419.62 g,
96%) as cream powder, mp 189e191 ꢀC. [Found: C, 54.84; H, 3.39; N,
16.09. C20H15N5O7 requires C, 54.92; H, 3.46; N, 16.01%]; nmax (KBr)
4.2.25. 2-Aminopyridinium 2-(5-hydroxy-1,3-dimethyl-2,4,6-trioxo-
hexahydropyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphthal-
en-2-ide (4y). (416.47 g, 95%) as orange powder, mp 216e217 ꢀC.
[Found: C, 57.45; H, 4.06; N, 12.69. C21H18N4O7 requires C, 57.53; H,
3284, 3204, 3088, 1745, 1706, 1600 cmꢁ1
; dH (300 MHz, DMSO-d6)
3.27e5.82 (br s, NH and OH, overlap with solvent), 7.18 (4H, br s, H-
Ar), 7.44 (2H, br s, H-Ar), 7.57 (1H, br s, H-Ar), 7.76 (1H, m, H-Ar), 8.37
(2H, s, NH2), 11.02 (2H, s, 2NH), 11.35e11.73 (br s, NH and OH, overlap
with solvent); dC (75 MHz, DMSO-d6) 76.1, 93.6, 111.7, 116.3, 122.6,
123.1, 123.4, 124.0, 130.2, 131.1, 150.9, 153.8, 164.0, 172.8, 176.1.
4.14; N, 12.78%]; nmax (KBr) 3331, 3175, 2963, 1688, 1670 cmꢁ1
; dH
(300 MHz, DMSO-d6) 3.16 (6H, s, 2CH3), 3.4 (br s, NH and OH,
overlap with solvent), 6.80e6.93 (2H, m, H-Ar), 7.59e7.61 (1H, m,
H-Ar), 7.66e7.71 (1H, m, H-Ar), 7.74 (2H, s, NH2), 7.77e7.83 (2H, m,
H-Ar), 7.87e7.92 (2H, m, H-Ar); dC (75 MHz, DMSO-d6) 28.7, 76.9,
112.5, 113.4, 113.9, 125.0, 125.9, 131.6, 134.3, 137.2, 144.1, 151.6, 154.7,
171.3, 172.6, 180.1, 184.6.
4.2.32. 2-Amino-1H-benzo[d]imidazol-3-ium 3-(5-hydroxy-2,4,6-
trioxohexahydropyrimidin-5-yl)-6-methyl-2,4-dioxo-3,4-dihydro-
2H-pyran-3-ide (8b). (369.01 g, 92%) as white powder, mp
219e221 ꢀC. [Found: C, 50.78; H, 3.69; N,17.36. C17H15N5O7 requires
C, 50.88; H, 3.77; N, 17.45%]; nmax (KBr) 3277, 3217, 3080, 2818, 1748,
4.2.26. Bis(2-aminopyridinium)mono(1,4-bis(5-hydroxy-2,4,6-
trioxohexahydropyrimidin-5-yl)-2,3,5,6-tetraoxocyclohexan-1-ide)
(6a). (588.60 g, 96%) as pink powder, mp 246e248 ꢀC. [Found: C,
46.91; H, 3.38; N, 18.20. C24H21N8O12 requires C, 46.99; H, 3.45; N,
1707, 1663 cmꢁ1
; dH (300 MHz, DMSO-d6) 1.98 (3H, s, CH3), 5.47
(1H, s, CH), 7.19e7.32 (4H, m, H-Ar), 8.33 (2H, br s, NH2), 10.90 (2H,
br s, 2NH); dC (75 MHz, DMSO-d6) 19.5, 75.7, 93.1, 107.5, 111.7, 123.4,
130.3, 150.8, 150.9, 159.3, 165.1, 172.7, 179.9.
18.27%]; nmax (KBr) 3431, 3191, 2976,1722, 1667 cmꢁ1
; dH (300 MHz,
DMSO-d6) 4.17e4.57 (br s, NH and OH, overlap with solvent), 6.78
(3H, br s, H-Ar), 6.87e6.90 (3H, m, H-Ar), 7.84e7.93 (6H, br s, H-Ar
and NH2), 11.08 (4H, s, 4NH); dC (75 MHz, DMSO-d6) 75.7, 107.9,
112.5, 113.0, 138.0, 143.4, 150.8, 155.2, 172.3, 172.5, 177.5.
4.2.33. 2-Amino-1H-benzo[d]imidazol-3-ium 2-(5-hydroxy-2,4,6-
trioxohexahydropyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaph-
thalen-2-ide (8c). (431.34 g, 96%) as orange powder, mp
190e192 ꢀC. [Found: C, 56.24; H, 3.25; N, 15.64. C21H15N5O7 re-
quires C, 56.13; H, 3.36; N, 15.58%]; nmax (KBr) 3444, 3324, 3210,
4.2.27. Bis(2-amino-3-methylpyridinium)mono(1,4-bis(5-hydroxy-
2,4,6-trioxohexahydropyrimidin-5-yl)-2,3,5,6-tetraoxocyclohexan-1-
ide) (6b). (589.87 g, 92%) as light pink powder, mp 247e249 ꢀC.
[Found: C, 48.57; H, 3.99; N,17.53. C26H25N8Oþ12 requires C, 48.68; H,
3103, 1732, 1701, 1682 cmꢁ1
; dH (300 MHz, DMSO-d6) 4.54 (2H, br s,
NH and OH), 7.18 (2H, br s, H-Ar), 7.32 (2H, br s, H-Ar), 7.58e7.83
(4H, m, H-Ar), 8.30 (2H, br s, NH2), 11.02 (2H, s, 2NH); dC (75 MHz,
DMSO-d6) 76.5, 111.7, 113.4, 123.3, 124.9, 125.9, 130.4, 131.6, 134.3,
150.9, 151.1, 172.5, 172.6, 180.3, 184.8.
3.93; N, 17.47%]; nmax (KBr) 3431, 3212, 3108, 2846,1721, 1655 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.15 (6H, s, 2CH3), 3.76 (br s, NH, OH and
NH2, overlap with solvent), 6.81 (2H, m, H-Ar), 7.77e7.93 (4H, m, H-
Ar), 11.17 (4H, br s, 4NH); dC (75 MHz, DMSO-d6) 16.8, 75.2, 108.8,
112.7, 122.5, 134.0, 134.1, 143.2, 150.6, 153.5, 171.6, 177.1.
4.2.34. 2-Amino-1H-benzo[d]imidazol-3-ium 3-(5-hydroxy-1,3-
dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)-2,4-dioxochroman-
3-ide (8d). (381.41 g, 82%) as white powder, mp 215e217 ꢀC.
[Found: C, 56.64; H, 4.04; N, 14.93. C22H19N5O7 requires C, 56.77; H,
4.11; N, 15.05%]; nmax (KBr) 3388, 3209, 3069, 2774, 1696,
4.2.28. Bis(2-amino-5-methylpyridinium)mono(1,4-bis(5-hydroxy-
2,4,6-trioxohexahydropyrimidin-5-yl)-2,3,5,6-tetraoxocyclohexan-1-
ide) (6c). (621.92 g, 97%) as light pink powder, mp 249e252 ꢀC.
[Found: C, 48.75; H, 3.85; N,17.36. C26H25N8O12 requires C, 48.68; H,
3.93; N, 17.47%]; nmax (KBr) 3421, 3336, 3216, 3084, 2869, 1721,
1666 cmꢁ1
; dH (300 MHz, DMSO-d6) 3.15 (6H, s, 2CH3), 7.16e7.22
(4H, m, H-Ar), 7.32e7.35 (2H, m, H-Ar), 7.43e7.48 (1H, m, H-Ar),
7.76e7.78 (1H, m, H-Ar), 8.37 (2H, br s, NH2), 11.81e12.24 (br s, NH
and OH, overlap with solvent); dC (75 MHz, DMSO-d6) 28.7, 76.5,
94.3, 111.7, 116.3, 122.6, 123.1, 123.4, 124.1, 130.2, 131.2, 150.9, 151.6,
153.8, 164.0, 171.6, 175.8.
1663 cmꢁ1
; dH (300 MHz, DMSO-d6) 2.14 (6H, s, 2CH3), 4.08e4.154
(br s, NH, OH and NH2, overlap with solvent), 6.87e6.90 (2H, m, H-
Ar), 7.65 (2H, s, H-Ar), 7.74e7.93(2H, m, H-Ar), 11.08 (4H, br s, 4NH);
dC (75 MHz, DMSO-d6) 16.8, 75.7, 108.0, 113.3, 121.8, 122.0, 134.5,
145.9, 150.9, 153.2, 172.5, 177.3.
4.2.35. 2-Amino-1H-benzo[d]imidazol-3-ium 2-(5-hydroxy-1,3-
dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)-1,3,4-trioxo-1,2,3,4-
tetrahydronaphthalen-2-ide (8e). (439.23 g, 92%) as orange powder,
mp 238e239 ꢀC. [Found: C, 57.76; H, 3.95; N, 14.60. C23H19N5O7
4.2.29. Bis(2-amino-6-methylpyridinium)mono(1,4-bis(5-hydroxy-
2,4,6-trioxohexahydropyrimidin-5-yl)-2,3,5,6-tetraoxocyclohexan-1-
ide) (6d). (602.69 g, 94%) as light pink powder, mp 202e203 ꢀC.

S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
2915
requires C, 57.86; H, 4.01; N, 14.67%]; nmax (KBr) 3433, 3343, 2958,
1677, 1594 cmꢁ1
dH (300 MHz, DMSO-d6) 3.16 (6H, s, CH3),
125.9, 131.6, 134.3, 134.4, 136.1, 140.5, 146.1, 153.0, 173.0, 180.2,
184.6, 201.1.
;
7.19e7.22 (2H, m, H-Ar), 7.32e7.35 (2H, m, H-Ar), 7.59e7.83 (4H, m,
H-Ar), 8.39 (2H, s, NH2), 11.44 (1H, br s, NH), 12.41e12.44 (1H, br s,
OH); dC (75 MHz, DMSO-d6) 28.7, 76.9,11.7,113.9,123.4,125.0,125.9,
130.1, 131.6, 134.3, 150.4, 151.6, 171.3, 172.6, 180.1, 184.6.
4.2.42. 5-Hydroxy-5-(2-oxoindolin-3-yl)pyrimidine-2,4,6(1H,3H,5H)-
trione (15). (253.05 g, 91%) as dark red powder, mp 232e234 ꢀC.
[Found: C, 52.26; H, 3.24; N, 15.21. C12H9N3O5 requires C, 52.37; H,
3.30; N, 15.27%]; nmax (KBr) 3336, 3295, 3217, 1730, 1694 cmꢁ1
; dH
4.2.36. 2-Amino-1H-benzo[d]imidazol-3-ium 3-hydroxy-1-(5-
hydroxy-2,4,6-trioxohexahydropyrimidin-5-yl)-2,5,6-trioxocyclohex-
3-en-1-ide (10). (394.02 g, 99%) as light pink powder, mp
201e203 ꢀC. [Found: C, 49.05; H, 3.08; N, 16.73. C17H13N5O8 re-
quires C, 49.16; H, 3.16; N, 16.86%]; nmax (KBr) 3391, 3246, 2983,
(300 MHz, DMSO-d6) 4.20 (1H, s, CH), 6.75e7.39 (5H, m, H-Ar and
NH), 10.54 (1H, s, NH), 11.33 (1H, s, NH), 11.54 (1H, s, OH); dC
(75 MHz, DMSO-d6) 51.2, 73.9, 109.6, 121.7, 126.3, 126.5, 128.3, 143.1,
150.2, 169.0, 171.1, 175.1.
1714, 1675 cmꢁ1
; dH (300 MHz, DMSO-d6) 5.52 (1H, s, CH),
Acknowledgements
6.86e7.56 (4H, m, H-Ar), 7.96 (3H, s, NH2 and OH), 10.61 (1H, s, NH),
10.43e11.08 (2H, br s, 2NH); dC (75 MHz, DMSO-d6) 75.8, 75.9,
102.5, 107.5, 107.7, 111.8, 122.7, 131.8, 150.8, 150.9, 151.9, 172.4, 172.6,
175.6, 178.0.
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti, University.
References and notes
4.2.37. 2-Aminopyridinium 3-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-
inden-2-yl)-2,4-dioxochroman-3-ide (12a). (332.88 g, 80%) as yel-
low powder, mp 170e172 ꢀC. [Found: C, 66.46; H, 3.82; N, 6.79.
C23H16N2O6 requires C, 66.34; H, 3.87; N, 6.73%]; nmax (KBr) 3387,
1. (a) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471e1499; (b) Schreiber, S. L.
Science 2000, 287, 1964e1969; (c) Zhu, J.; Bienayme, H. Multicomponent Re-
ꢀ
actions; Wiley-VCH: Weinheim, Germany, 2005; (d) Domling, A. Chem. Rev.
2006, 106, 17e89; (e) Weber, L. Curr. Med. Chem. 2002, 9, 2085e2093; (f) Bi-
enayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.dEur. J. 2000, 6,
3321e3329; (g) Abboub, F.; Amari, M.; Kolli, B. J. Soc. Alger. Chim. 2001, 11,
223e230; (h) Do_mling, A. Curr. Opin. Chem. Biol. 2002, 6, 306e313.
3090, 1738, 1707, 1637 cmꢁ1
; dH (300 MHz, DMSO-d6) 3.55 (br s, NH
and OH, overlap with solvent), 6.77e6.81 (1H, m, H-Ar), 6.87e6.89
(1H, m, H-Ar), 7.15e7.22 (2H, m, H-Ar), 7.43e7.92 (10H, m, H-Ar and
NH2); dC (75 MHz, DMSO-d6) 78.7, 92.8, 112.5, 113.1, 116.3, 123.1,
123.4, 124.1, 131.2, 136.1, 137.9, 140.5, 143.6, 153.9, 155.0, 163.9, 175.7.
ꢀ
2. (a) Lieby-Muller, F.; Constantieux, T.; Jean Rodriguez, J. J. Am. Chem. Soc. 2005,
127, 17176e17177; (b) Rivera, D. G.; Wessjohann, L. A. J. Am. Chem. Soc. 2006,
128, 7122e7123; (c) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko,
V. N.; Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org. Chem. 2008,
73, 5110e5118; (d) Groenendaal, B.; Vugts, D. J.; Schmitz, R. F.; de Kanter, F. J. J.;
Ruijter, E.; Groen, M. B.; Orru, R. V. A. J. Org. Chem. 2008, 73, 719e722; (e)
Abbiati, G.; Arcadi, A.; Canevari, V.; Capezzuto, L.; Rossi, E. J. Org. Chem. 2005,
70, 6454e6460; (f) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett.
2007, 9, 4223e4226; (g) Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar, V.;
Bindu, S. Org. Lett. 2004, 6, 767e769; (h) Zhang, M.; Jiang, H.; Liu, H.; Zhu, Q.
Org. Lett. 2007, 9, 4111e4113; (i) Heravi, M. M.; Baghernejad, B.; Oskooie, H. A.;
Hekmatshoar, R. Tetrahedron Lett. 2008, 49, 6101e6103; (j) Willy, B.; Mu_ller, T. J.
J. Eur. J. Org. Chem. 2008, 4157e4168; (k) Umkehrer, M.; Kolb, J.; Burdack, C.;
Hiller, W. Synlett 2005, 79e82.
4.2.38. 2-Aminopyridinium 3-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-
inden-2-yl)-6-methyl-2,4-dioxo-3,4-dihydro-2H-pyran-3-ide
(12b). (311.68 g, 82%) as yellow powder, mp 226e227 ꢀC. [Found:
C, C, 63.28; H, 4.33; N, 7.28. C20H16N2O6 requires C, C, 63.16; H, 4.24;
N, 7.37%]; nmax (KBr) 3336, 3167, 3084, 2827, 1709, 1660 cmꢁ1
; dH
(300 MHz, DMSO-d6) 2.29 (3H, s, CH3), 4.97 (1H, s, CH), 6.11 (br s,
NH and OH and NH2, overlap with solvent), 6.48 (2H, m, H-Ar),
7.39e7.94 (6H, m, H-Ar); dC (75 MHz, DMSO-d6) 20.4, 76.7, 86.8,
91.7, 109.0, 112.2, 123.7, 136.6, 138.2, 140.4, 146.6, 159.5, 159.8, 159.9,
163.1, 166.3.
3. Goodman and Gilman’s. In The Pharmacological Basis of Therapeutics, 9th ed.;
McGraw-Hill: New York, 1996; p 471.
4. Archana, S.; Srivastava, V. K.; Kumar, A. Arzneim. Forsch., Drug. Res. 2002, 52,
787e791.
5. Goel, B.; Sharma, S.; Bajaj, K.; Bansal, D.; Singh, T.; Malik, N.; Lata, S.; Tyagi, C.;
Panwar, H.; Agarwal, A.; Kumar, A. Indian J. Pharm. Sci. 2005, 67, 194e199.
6. Osman, A. N.; Kandeel, M. M.; Ahmed, M. Indian J. Chem. 1996, 35B, 1073e1078.
7. Archana, S.; Rani, P.; Bajaj, K.; Chandora, R.; Srivastava, V. K.; Kumar, A. Arzneim.
Forsch., Drug. Res. 2003, 53, 301e306.
8. Sarma, G. V. S. R.; Rao, J. V.; Suresh, B. Indian J. Pharm. Sci. 1999, 61, 105e109.
9. Gupta, K. P.; Gupta, R. C.; Bhargava, K. P.; Ali, B. Eur. J. Med. Chem. 1982, 17,
448e452.
10. Padmavati, V.; Reddy, B. J. M.; Venketa Subbaiah, D. R. C.; Padmaja, A. Indian J.
Chem. 2006, 45B, 808e812.
11. Levina, R. Y.; Velichko, F. K. Russ. Chem. Rev. 1960, 29, 437e438.
12. Sing, P.; Paul, K. Indian J. Chem. 2006, 45B, 247e251.
4.2.39. 2-Aminopyridinium 2-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-
inden-2-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphthalen-2-ide
(12c). (393.82 g, 92%) as orange powder, mp 203e205 ꢀC. [Found:
C, 67.21; H, 3.69; N, 6.46. C24H16N2O6 requires C, 67.29; H, 3.76; N,
6.54%]; nmax (KBr) 3430, 3341, 3216, 2666, 1714, 1672 cmꢁ1
; dH
(300 MHz, DMSO-d6) 3.67 (br s, NH and OH, overlap with solvent),
6.81e7.57 (3H, m, H-Ar), 7.66 (2H, s, NH2), 7.80e7.94 (9H, m, H-Ar);
dC (75 MHz, DMSO-d6) 79.4, 112.5, 112.8, 113.5, 123.5, 125.0, 131.6,
134.3, 136.1, 137.1, 140.5, 144.1, 154.6, 172.9, 180.2, 184.5, 200.9.
13. Olin. B.R., Ed. Central Nervous System Drugs, Sedatives and Hypnotics, Barbi-
turates. In Facts and Comparisons Drug Information, Facts and Comparisons, St.
Louis, MO, 1993, 1398e1413.
4.2.40. 2-Amino-5-methylpyridinium 3-(2-hydroxy-1,3-dioxo-2,3-
dihydro-1H-inden-2-yl)-2,4-dioxochroman-3-ide (12d). (400.74 g,
93%) as yellow powder, mp 190e191 ꢀC. [Found: C, 66.87; H, 4.17; N,
6.61. C24H18N2O6 requires C, 66.97; H, 4.22; N, 6.51%]; nmax (KBr)
14. (a) Naguib, F. N. M.; Levesque, D. L.; Wang, E.-C.; Panzica, R. P.; El kouni, M. H.
Biochem. Pharmacol. 1993, 30, 1273e1283; (b) Levesque, D. L.; Wang, E.-C.; Wei,
D.-C.; Et Kouni, M. H.; Naguib, F. N. M. J. Heterocycl Chem. 1993, 30, 1399e1404;
(c) Oliva, A.; De Cillis, G.; Grams, F.; Livi, V.; Zimmerman, G.; Menta, E.; Krell, H.
W. U.S. Patent 6,335,332, B1, 2002; (d) Ashkinazi, R. I. Int. Patent, WO 99/25699,
1999; (e) Neumann, D. M.; Jursic, B. S.; Morgan, L.-R. Abstracts of Papers, 225th
ACS National Meeting, New Orleans, LA, United States, 2003, 23e27.
15. (a) Puerta, D. T.; Cohen, S. M. Curr. Top. Med. Chem. 2004, 4, 1551e1573; (b)
Skiles, J. W.; Gonnella, N. C; Jeng, A. Y. Curr. Med. Chem. 2004, 11, 2911e2977.
16. Zhao, T.; Sun, G. J. Appl. Microb. 2008, 104, 824e830.
3412, 3305, 1751, 1714, 1675, 1637 cmꢁ1
; dH (300 MHz, DMSO-d6)
2.12 (3H, s, CH3), 3.67 (br s, NH and OH, overlap with solvent),
6.84e7.95 (11H, m, H-Ar and NH2); dC (75 MHz, DMSO-d6) 16.8,
78.7, 92.8, 113.2, 116.3, 121.9, 122.0, 123.1, 124.1, 131.3, 134.5, 136.1,
140.5, 146.1, 153.0, 153.9, 164.0, 175.7.
17. Zhao, T.; Sun, G. J. Surf. Deterg. 2006, 9, 325e330.
18. Zhao, T.; Sun, G. J. Appl. Polymer Sci. 2007, 103, 482e486.
19. Calas, M.; Outtara, M.; Piquet, G.; Ziora, Z.; Bordat, Y.; Ancelin, M. L.; Escale, R.;
4.2.41. 2-Amino-5-methylpyridinium 2-(2-hydroxy-1,3-dioxo-2,3-
dihydro-1H-inden-2-yl)-1,3,4-trioxo-1,2,3,4-tetrahydronaphthalen-
2-ide (12e). (402.33 g, 91%) as dark red powder, mp 232e233 ꢀC.
[Found: C, 67.95; H, 4.17; N, 6.24. C25H18N2O6 requires C, 67.87; H,
Vial, H. J. Med. Chem. 2007, 50, 6307e6315.
20. Wang, Qi-F.; Hui, L.; Hou, H.; Yan, Ch-G. J. Comb. Chem. 2010, 12, 260e265.
21. Han, Y.; Chen, J.; Hui, L.; Yan, Ch-G. Tetrahedron 2010, 66, 7743e7748.
22. Braga, D.; Cadoni, M.; Grepioni, F.; Maini, L.; Streek, J. New J. Chem. 2007, 31,
1935e1940.
23. Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G. New J. Chem. 2001, 25, 408e415.
24. Moafi, L.; Ahadi, S.; Khavasi, H. R.; Bazgir, A. Synthesis 2011, 1399e1402.
25. Moafi, L.; Ahadi, S.; Bazgir, A. Tetrahedron Lett. 2010, 51, 6270e6274.
4.10; N, 6.33%]; nmax (KBr) 3430, 3341, 3216, 2666, 1714, 1672 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.12 (3H, s, CH3), 6.85e7.95 (11H, m, H-Ar);
dC (75 MHz, DMSO-d6) 16.7, 79.4, 112.8, 113.3, 121.8, 123.5, 125.0,

2916
S. Ahadi et al. / Tetrahedron 68 (2012) 2906e2916
26. Ahadi, S.; Yasaei, Z.; Bazgir, A. J. Heterocycl. Chem. 2010, 47, 1090e1094.
27. X-ray data for 4a: C18H14N4O7, M¼398.33 g/mol, triclinic system, space group
dimension of 0.40ꢂ0.35ꢂ0.20 mm. The structure was solved by using
SHELXS. The structure refinement and data reduction were carried out with
SHELXL of the X-Step32 suite of programs.28 The non-hydrogen atoms were
refined anisotropically by full matrix least-squares on F2 values to final R1¼0.
1440, wR2¼0.2948 and S¼1.167 with 283 parameters using 4623 in-
ꢂ
ꢁ
Pı, a¼10.4657(7), b¼13.2774(9), c¼13.6133(9) A,
a
¼102.439(5)
b
¼104.096(13),
3
ꢁ3
g
¼98.860(6) , V¼1737.5(2) A , Z¼4, Dc¼1.523 g cm
,
m
(Mo K
a
)¼0.120 mmꢁ1
,
ꢀ
ꢂ
crystal dimension of 0.40ꢂ0.35ꢂ0.28 mm. The structure was solved by using
SHELXS. The structure refinement and data reduction were carried out with
SHELXL of the X-Step32 suite of programs.28 The non-hydrogen atoms were
refined anisotropically by full matrix least-squares on F2 values to final R1¼0.
1057, wR2¼0.2895 and S¼1.695 with 547 parameters using 9315 independent
dependent reflection (
q
range¼2.26e29.20ꢀ). The hydrogen atoms of NeH2
and OeH groups were located in a difference Fourier map and then refined
isotropically. Other H-atoms were positioned geometrically, with CeH¼0.93
ꢂ
and NeH¼0.86 A and constrained to ride on their parent atoms with Uiso(H)¼
reflection (
q
range¼2.07e29.17ꢀ). The hydrogen atoms of NeH2 and OeH
1.2Ueq. Crystallographic data for 4a and 4h have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data can be obtained,
free of charge, on application to The Director, CCDC 842968 and 842969,
Union Road, Cambridge CB2 1EZ, UK. Fax: þ44 1223 336033 or e-mail: de-
posit@ccdc.cam.ac.uk.
groups were located in a difference Fourier map and then refined isotropi-
cally. Other H-atoms were positioned geometrically, with CeH¼0.93 and
ꢂ
NeH¼0.86 A and constrained to ride on their parent atoms with Uiso(H)¼1.
2Ueq. X-ray data for 4h: C19H14N4O7, M¼410.34 g/mol, monoclinic system,
ꢂ
space group P21/c, a¼10.5672(11), b¼13.1650(13), c¼12.8067(13) A,
b
¼105.
28. X-STEP32 Version 1.07b, X-ray structure Evaluation Package; Stoe & Cie: Darm-
stadt, Germany, 2000.
3
ꢂ
ꢁ3
, m
204(8), V¼1719.3(3) A , Z¼4, Dc¼1.585 g cm
(Mo Ka
)¼0.124 mmꢁ1, crystal