One-pot green synthesis for pyrimido[4,5-d]pyrimidine derivatives

Article abstract of DOI:10.1515/znb-2007-0518

Water has been used efficiently as a solvent for the reaction of barbituric acid, aldehyde and urea or thiourea to yield pyrimido[4,5-d]pyrimidines. This environmentally benign procedure leads to high yields of products of greater purity in a single step using water.

Full text of DOI:10.1515/znb-2007-0518

One-pot Green Synthesis for Pyrimido[4,5-d]pyrimidine Derivatives
Mazaahir Kidwai, Kavita Singhal, and Shuchi Kukreja
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi-10007,
India
Reprint requests to Prof. M. Kidwai. Fax: (+91 11) 27666235. E-mail: kidwai.chemistry@gmail.com
Z. Naturforsch. 2007, 62b, 732 – 736; received November 11, 2006
Water has been used efficiently as a solvent for the reaction of barbituric acid, aldehyde and urea or
thiourea to yield pyrimido[4,5-d]pyrimidines. This environmentally benign procedure leads to high
yields of products of greater purity in a single step using water.
Key words: Barbituric Acid, Pyrimido[4,5-d]pyrimidines, Water, Multicomponent Reaction
Introduction
antiviral [11], antibacterial [12], antioxidant [13]
and hepatoprotective properties [14] of fused pyrim-
idines. The promising methods for the synthesis of
pyrimido[4,5-d]pyrimidines involve multistep synthe-
ses starting from 1,3-disubstituted cyanouracils [15],
polymer bound 2-(alkylsulfanyl)-4-aminopyrimidine-
5-carbonitriles [16], aza-Wittig-type reactions using
iminophosphoranes of 5-aminouracils [17], and react-
ing 6-[(dimethylamino)methylene]aminouracils with
various heterocumulenes [18]. Synthetic alternatives
are many and varied and have resorted to harsh condi-
tions, e. g. the use of PTSA (p-toluenesulfonic acid) as
catalyst, using POCl3 with DMF as a solvent [19]. Ad-
ditionally, reagents for these procedures are not readily
or commercially available which is a key deficiency in
developing conditions for library synthesis.
Moreover, water-mediated single-flask procedures
for the synthesis of pyrimido[4,5-d]pyrimidines avoid-
ing harmful catalysts have not been reported yet.
As part of our ongoing program of developing envi-
ronmentally benign synthetic methods [20] for phar-
macologically important heterocyclic skeletons, we
explored a green multicomponent reaction (MCR) pro-
tocol using water as solvent. Herein, we report a sim-
ple, rapid and one-pot water-mediated procedure for
the synthesis of pyrimido[4,5-d]pyrimidines in high
yield and purity.
For the synthetic chemists, water often appears as
a natural enemy to be kept away from the reaction
mixture until workup. However, recently water [1] has
been reported as a medium in various transformation
reactions with a considerable rate increase [2]. This
has been explained on the basis of its permanent dipole
moment; hence at elevated temperature, water facili-
tates the isolation of products due to the decreased sol-
ubility of organic materials. Further reasons to make
water unique as compared to organic solvents are its
cheapness and non-inflammability, putting water in the
domain of green solvents.
Heterocyclic chemistry is currently experiencing a
renaissance because of the interest in heterocyclic scaf-
folds as templates for combinatorial chemistry [3]. As
heteroaromatic compounds are present in many natural
products [4], and are constituents of numerous thera-
peutic agents [5], they represent ideal drug-like struc-
tures for the elaboration of and increase in molecular
diversity.
Multicomponent reactions (MCRs) have been
proved as simple and convenient ways to produce a
plethora of physiologically active pyrimidinones [6].
Three-component reactions such as the Biginelli re-
action with cyclic 1,3-dicarbonyl compounds, aro-
matic aldehydes and urea/thiourea are well known
microwave-induced reactions (MW) [7]. Pyrimidines
and fused pyrimidine derivatives represent a class
of annulated uracils with biological significance be-
Results and Discussion
Choosing an appropriate solvent is of crucial impor-
cause of their close association with purines and tance for the successful microwave-assisted synthesis.
pteridine systems [8]. Numerous reports have been To search for the optimal solvent, the reaction of bar-
patented [9] and have delineated the antiallergic [10], bituric acid (BA, 1) (0.01 mmol), aromatic aldehydes
0932–0776 / 07 / 0500–0732 $ 06.00 © 2007 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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M. Kidwai et al. · One-pot Green Synthesis for Pyrimido[4,5-d]pyrimidine Derivatives
733
Table 1. Solvent optimization for the synthesis of compound Table 2. Comparison of reaction times and yields of com-
4f under microwave irradiation conditions. pounds 4a – g and 6a – g.
Entry
1.
2.
3.
4.
5.
6.
7.
Solvent
THF
Ethanol
DMF
Acetic acid
Glycol
Water
Power (W)
400
400
400
400
400
400
560
Time (min)
–
Yield (%)
–
Comp.
R
Method A
Time Yield
Method B
Time Yield
(h)
2.0
3.5
4.0
4.0
3.5
3.0
4.5
1.5
4.0
2.0
2.5
2.5
3.5
(%)
80
70
76
72
72
80
76
80
74
75
80
70
76
(min)
2.3
3.3
2.0
3.0
2.0
2.3
3.3
2.3
3.0
2.3
3.0
1.3
2.3
(%)
87
82
85
86
85
92
87
90
80
88
92
88
90
7.0
6.5
6.0
4.5
4.0
2.3
65
71
67
87
88
92
4a
4b
4c
4d
4e
4f
4g
6a
6b
6c
6d
6e
6f
Phenyl
2-Hydroxyphenyl
p-Methoxyphenyl
4-Cl-phenyl
Piperonyl
2-Thienyl
2-Cl-3-Quinolinyl
Phenyl
2-Hydroxyphenyl
p-Methoxyphenyl
4-Cl-phenyl
Piperonyl
Water
2-Thienyl
Scheme 1. One-pot synthesis of pyrimido[4,5-d]pyrimidine-
triones.
2a – g (0.01 mmol) and urea (3a) (0.01 mmol) was ex-
amined using water, glycol, DMF, THF or ethanol as
solvents under MW irradiation conditions. Some of the
reactions were also performed at different powers of
microwaves. As shown in Table 1, the reaction pro-
ceeded efficiently when water was used as solvent re-
sulting in higher yields in comparison to the other sol-
vents used. Inspired by this result, water was then used
as solvent for all further MW-assisted reactions.
Scheme 2. Synthesis of 7-thioxo-pyrimido[4,5-d]pyrimid-
ine-diones.
ents with similar success to provide the correspond-
ing pyrimido[4,5-d]pyrimidine thiones which are also
of interest with respect to their biological activities.
Likewise, 2-thiobarbituric acid (TBA) can also be em-
To optimize the reaction temperature, the synthesis ployed as an alternative under these aqueous condi-
of 4f was performed ◦in water at temperatures rang- tions.
ing from 70 to 130 C, at different powers of mi-
Moreover, for comparison, classical heating condi-
crowaves, i. e. 400, 480, 560, 640, 800 W. At low tions were also applied for the synthesis of all products
powers (400, 480 W), the time taken for the temper- as is summarized in Table 2. It was found that the re-
◦
ature to reach 100 C was too long. Microwave ir- action proceeds efficiently under MW irradiation with
radiation at 560 W in 2 – 3 mL of water furnished a reduction in time from hours to minutes in compari-
the highest yield of 5-thienyl-1,3,5,6,8-pentahydropyr- son to the conventional one with appreciable yield en-
imido[4,5-d]pyrimidine-2,4,7-trione 4f (Scheme 1), hancement. In addition, looking at the success of this
without evaporation of the solvent. Thus, a microwave approach, as no extra catalyst was required for the pro-
power of 560 W was chosen as the optimal one. posed protocol, it was thought worthwhile to attempt
The ease of separation of pyrimido[4,5-d]pyrimidine the reactions without any solvent or catalyst, but no
derivatives from the reaction media is the foremost proper results were obtained; only some charring was
advantage of this process in aqueous media. Simi- observed on prolonged heating. This emphasizes the
larly, thiourea (3b) (0.01 mmol) in place of urea was importance of water which acts as a solvent and pro-
taken (Scheme 2) to get 5-aryl-1,3,5,6,8-pentahydro- vides a media for the transfer of energy. Thus an exam-
7-thioxo-pyrimido[4,5-d]pyrimidine-2,4-diones 6a – f. ple has been established for the condensation reaction
Thus thiourea proved here as one of the ingredi- in water.
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734
M. Kidwai et al. · One-pot Green Synthesis for Pyrimido[4,5-d]pyrimidine Derivatives
The structures of products 4a – g and 6a – f as stirring. The solid obtained was isolated by filtration, washed
with water and dried.
pyrimido[4,5-d]pyrimidinones were assigned on the
basis of the spectral data and the elemental analyses.
In the H NMR spectra, the disappearance of the di-
1
Method B (microwave-assisted synthesis)
agnostic signal due to the methylene protons of barbi-
turic acid at δ = 3.8 ppm indicates the condensation
of the active methylene group with the aromatic alde-
hydes used. Following the mechanism, this intermedi-
ate then condenses with urea/thiourea furnishing the
required products 4a – g and 6a – f, which is confirmed
An Erlenmeyer flask was charged with equimolar
amounts of barbituric acid (1, 0.01 mmol), an aromatic alde-
hyde (2a – g, 0.01 mmol), urea/thiourea (3a/3b, 0.01 mmol),
and 2 – 3 mL of water. The reaction mixture was subjected
to microwave irradiation for a specific time (Table 1) at low
power (560 W). The progress of the reaction was monitored
by the appearance of a singlet at δ = 4.9 ppm assigned at intervals of 30 sec. Upon completion, the reaction mixture
was cooled and the product was isolated by filtration, washed
with cold water and dried.
to 5-H.
In brief, a practically convenient and eco-friendly
synthesis of pyrimido[4,5-d]pyrimidines has been de-
veloped in an aqueous medium without using any cat-
alyst, i. e. completely circumventing the use of haz-
ardous organic solvents and corrosive acids or bases.
Water-insoluble solid products obtained in short time
are found to be essentially pure and in very high yield.
This simple single-step reaction has the ability to with-
stand the variations in the 1,3-diketone and carbonyl
part also. This direct strategy could find broader in-
terest for the synthesis of compound libraries having
in common a heterocyclic pyrimido[4,5-d]pyrimidine
moiety.
5-Phenyl-1,3,5,6,8-pentahydro-pyrimido[4,5-d]pyrimidine-
2,4,7-trione (4a)
White solid; m. p. 244 – 246 ◦C; anal. calcd. for
C12H10N4O3: C 55.81, H 3.87, N 21.70; found: C 55.86,
H 3.79, N 21.75. – IR (nujol): ν = 3480, 3213, 3083,
1749, 1678, 1648, 1583, 1565 cm−1. – 1H NMR (300 MHz,
CDCl3 + [D6]DMSO): δ = 11.27 (s, 1H, NH), 10.99 (s, 2H,
NH), 8.26 (s, 1H, NH), 7.03 – 7.27 (m, 5H, arom. H), 4.88 (s,
1H, 5-H). – MS: m/z = 259 [M+H]+.
5-(2-Hydroxyphenyl)-1,3,5,6,8-pentahydro-pyrimido-
[4,5-d]pyrimidine-2,4,7-trione (4b)
White solid; m. p. 220 – 222 ◦C; anal. calcd. for
C12H10N4O4: C 52.55, H 3.64, N 20.43; found: C 52.49,
H 3.61, N 20.35. – IR (nujol): ν = 3486, 3279, 3220,
3120, 1748, 1695, 1651, 1581 cm−1. – 1H NMR (300 MHz,
CDCl3 + [D6]DMSO): δ = 1.26 (s, 1H, NH), 10.99 (s, 2H,
NH), 8.29 (s, 1H, NH), 7.21 – 7.34 (m, 4H, arom. H), 4.91 (s,
1H, 5-H). – MS: m/z = 274 [M+H]+.
Experimental Section
Melting points were taken on a Thomas Hoover melting
point apparatus and are uncorrected. IR spectra (in nujol)
were recorded on a model Perkin-Elmer FTIR-1710 spec-
1
trophotometer, H NMR spectra on a Bruker Avance Spec-
trospin 300 instrument (300 MHz) using TMS as internal
standard. Elemental analyses were performed on a Heraeus
CHN Rapid Analyzer. Mass spectra were recorded on a
KC455 Waters TOF spectrometer. The purity of the com-
pounds was checked on silica gel-coated aluminum plates
(Merck). A Kenstar microwave oven, Model No. OM9925E
(2450 MHz, 800 W) was used for microwave-assisted re-
actions. The temperature of the reaction mixture was mea-
sured with an AZ, mini gun-type, non-contact IR thermome-
ter, model no. 8868.
5-(4-Methoxyphenyl)-1,3,5,6,8-pentahydro-pyrimido-
[4,5-d]pyrimidine-2,4,7-trione (4c)
White solid; m. p. 284 – 286 ◦C; anal. calcd. for
C13H12N4O4: C 54.16, H 4.16, N 19.44; found: C 54.09,
H 4.22, N 19.40. – IR (nujol): ν = 3468, 3283, 3069, 1756,
1693, 1655, 1548 cm−1. – 1H NMR (300 MHz, CDCl3
+
[D6]DMSO): δ = 11.29 (s, 1H, NH), 10.97 (s, 2H, NH), 8.31
(s, 1H, NH), 7.20 (d, J = 7.0 Hz, 2H, arom. H), 7.14 (d,
J = 7.0 Hz, 2H, arom. H), 4.90 (s, 1H, 5-H), 3.81 (s, 3H,
OCH3). – MS: m/z = 289 [M+H]+.
General procedure for the synthesis of 5-aryl-1,3,5,6,8-
pentahydropyrimido[4,5-d] pyrimidine derivatives
Method A (conventional synthesis)
5-(4-Chlorophenyl)-1,3,5,6,8-pentahydro-pyrimido[4,5-d]-
pyrimidine-2,4,7-trione (4d)
To the mixture of barbituric acid (1, 0.01 mmol), an aro-
matic aldehyde (2a – g, 0.01 mmol) and urea/thiourea (3a/3b,
White solid; m. p. 296 – 298 ◦C; anal. calcd. for
0.01 mmol), 10 mL of water were added. The reaction mix- C12H9N4O3Cl: C 49.23, H 3.07, N 19.14; found: C 49.31,
ture was kept at reflux for an appropriate time with constant H 3.18, N 19.06. – IR (nujol): ν = 3484, 3223, 3090,
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M. Kidwai et al. · One-pot Green Synthesis for Pyrimido[4,5-d]pyrimidine Derivatives
735
1760, 1705, 1673, 1644, 1575 cm−1. – 1H NMR (300 MHz, 1697, 1650, 1582 cm−1. – 1H NMR (300 MHz, CDCl3
+
CDCl3 + [D6]DMSO): δ = 11.27 (s, 1H, NH), 10.98 (s, 2H, [D6]DMSO): δ = 11.26 (s, 1H, NH), 10.97 (s, 2H, NH), 8.29
NH), 8.26 (s, 1H, NH), 7.61 (d, J = 8.0 Hz, 2H, arom. H), (s, 1H, NH) 7.23 – 7.30 (m, 4H, arom. H), 4.89 (s, 1H, 5-H). –
7.26 (d, J = 8.0 Hz, 2H, arom. H), 4.90 (s, 1H, 5-H). – MS: MS: m/z = 291 [M+H]+.
m/z = 292.03 [M]+.
5-(4-Methoxyphenyl)-1,3,5,6,8-pentahydro-7-thioxo-
5-(1,3-Benzodioxol-5-yl)-1,3,5,6,8-pentahydro-pyrimido
[4,5-d]pyrimidine-2,4,7-trione (4e)
pyrimido[4,5-d]pyrimidine-2,4-dione (6c)
Yellow solid; m. p. > 300 ◦C; anal. calcd. for
C13H12N4O3S: C 51.31, H 3.94, N 18.42; found: C 51.37,
H 3.80, N 18.35. – IR (nujol): ν = 3452, 3211, 1720,
Yellow solid; m. p. > 300 ◦C; anal. calcd. for
C13H10N4O5: C 51.65, H 3.31, N 18.54 found: C 51.54,
H 3.38, N 18.61. – IR (nujol): ν = 3480, 3273, 3090, 1760,
1698, 1655, 1560 cm−1. – 1H NMR (300 MHz, CDCl3
+
1696, 1635, 1575 cm−1. – 1H NMR (300 MHz, CDCl3
+
[D6]DMSO): δ = 11.29 (s, 1H, NH), 10.99 (s, 2H, NH),
8.31 (s, 1H, NH), 7.22 (d, J = 7.0 Hz, 2H, arom. H), 7.16
(d, J = 7.0 Hz, 2H, arom. H), 4.88 (s, 1H, 5-H), 3.83 (s, 3H,
OCH3). – MS: m/z = 305 [M+H]+.
[D6]DMSO): δ = 11.27 (s, 1H, NH), 10.98 (s, 2H, NH),
8.30 (s, 1H, NH), 7.11 (s, 1H, arom. H), 6.87 (d, J = 8.0 Hz,
1H, arom. H), 6.71 (d, J = 8.0 Hz, 1H, arom. H), 5.93 (s, 2H,
OCH2O), 4.90 (s, 1H, 5-H). – MS: m/z = 303 [M+H]+.
5-(p-Chlorophenyl)-1,3,5,6,8-pentahydro-7-thioxo-
pyrimido[4,5-d]pyrimidine-2,4-dione (6d)
5-(2-Thienyl)-1,3,5,6,8-pentahydro-pyrimido[4,5-d]-
pyrimidine-2,4,7-trione (4f)
White solid; m. p. 278 ◦C (d); anal. calcd. for
C12H9N4O2SCl: C 42.17, H 3.16, N 19.68; found: C 42.15,
H 3.26, N 19.57. – IR (nujol): ν = 3457, 3201, 1713,
Yellow solid; m. p. > 280 ◦C; anal. calcd. for
C10H8N4O3S: C 45.45, H 3.03, N 21.21; found: C 45.50,
H 3.01, N 21.33. – IR (nujol): ν = 3472, 3146, 3062, 1756,
1700, 1658, 1560 cm−1. – 1H NMR (300 MHz, CDCl3
+
1683, 1655, 1558 cm−1. – 1H NMR (300 MHz, CDCl3
+
[D6]DMSO): δ = 11.29 (s, 1H, NH), 10.98 (s, 2H, NH), 8.26
(s, 1H, NH), 7.59 (d, J = 8.0 Hz, 2H, arom. H), 7.21 (d, J =
8.0 Hz, 2H, arom. H), 4.83 (s, 1H, 5-H). – MS: m/z = 291
[M+H]+.
[D6]DMSO): δ = 11.28 (s, 1H, NH), 10.96 (s, 2H, NH),
8.40 (d, J = 4.6 Hz, 1H, thienyl-H), 8.25 (s, 1H, NH), 8.14
(d, J = 3.0 Hz, 1H, thienyl-H), 7.48 (t, 1H, thienyl-H), 4.90
(s, 1H, 5-H). – MS: m/z = 265 [M+H]+.
5-(1,3-Benzodioxol-5-yl)-1,3,5,6,8-pentahydro-7-thioxo-
pyrimido[4,5-d]pyrimidine-2,4-dione (6e)
5-(2-Chloroquinolinyl)-1,3,5,6,8-pentahydro-pyrimido
[4,5-d]pyrimidine-2,4,7-trione (4g)
Yellow solid; m. p. > 260 ◦C (d); anal. calcd. for
C13H10N4O4S: C 49.05, H 3.14, N 17.61; found: C 49.11,
H 3.23, N 17.54. – IR (nujol): ν = 3480, 3273, 3090, 1760,
Yellow solid; m. p. > 280 ◦C; anal. calcd. for
C10H8N4O3S: C 56.56, H 3.70, N 23.56; found: C 56.63,
H 3.81, N 23.46. – IR (nujol): ν = 3480, 3283, 3094, 1754,
1696, 1635, 1575 cm−1. – 1H NMR (300 MHz, CDCl3
+
1698, 1640, 1563 cm−1. – 1H NMR (300 MHz, CDCl3
+
[D6]DMSO): δ = 11.31 (s, 1H, NH), 10.95 (s, 2H, NH), 8.26
(s, 1H, NH), 7.11 (s, 1H, arom. H), 6.87 (d, J = 8.0 Hz, 1H,
arom. H), 6.69 (d, J = 8.0 Hz, 1H, arom. H), 5.95 (s, 2H,
OCH2O), 4.90 (s, 1H, 5-H). – MS: m/z = 319 [M+H]+.
[D6]DMSO): δ = 11.29 (s, 1H, NH), 10.98 (s, 2H, NH),
8.26 (s, 1H, NH), 7.68 – 7.74 (m, 3H, arom. H), 4.90 (s, 1H,
5-H). – MS: m/z = 298 [M+H]+.
5-Phenyl-1,3,5,6,8-pentahydro-7-thioxo-pyrimido[4,5-d]-
pyrimidine-2,4-dione (6a)
5-(2-Thienyl)-1,3,5,6,8-pentahydro-7-thioxo-pyrimido
[4,5-d]pyrimidine-2,4-dione (6f)
White solid; m. p. 290 – 292 ◦C; anal. calcd. for
C12H10N4O2S: C 48.0, H 4.0, N 22.40; found: C 48.12,
H 3.96, N 22.34. – IR (nujol): ν = 3452, 3195, 1705,
Yellow solid; m. p. 240 – 242 ◦C; anal. calcd. for
C10H8N4O2S2: C 42.85, H 2.85, N 20.00; found: C 42.76,
H 2.88, N 20.08. – IR (nujol): ν = 3472, 3146, 3062, 1756,
1680, 1657, 1564 cm−1. – 1H NMR (300 MHz, CDCl3
+
1683, 1655, 1558 cm−1. – 1H NMR (300 MHz, CDCl3
+
[D6]DMSO): δ = 11.27 (s, 1H, NH), 10.99 (s, 2H, NH),
8.28 (s, 1H, NH), 7.24 – 7.44 (m, 5H, arom. H), 4.88 (s, 1H,
5-H). – MS: m/z = 251 [M+H]+.
[D6]DMSO): δ = 11.28 (s, 1H, NH), 10.91 (s, 2H, NH), 8.42
(d, J = 4.6 Hz, 1H, thienyl-H), 8.31 (s, 1H, NH), 8.18 (d, J =
3.0 Hz, 1H, thienyl-H), 7.48 (t, 1H, thienyl-H), 4.89 (s, 1H,
5-H). – MS: m/z = 304 [M+H]+.
5-(2-Hydroxyphenyl)-1,3,5,6,8-pentahydro-7-thioxo-
pyrimido[4,5-d]pyrimidine-2,4-dione (6b)
Acknowledgement
White solid; m. p. 200 – 202 ◦C; anal. calcd. for
The authors acknowledge the financial assistance by the
C12H10N4O3S: C 49.65, H 3.44, N 19.31; found: C 49.59, Council of Scientific and Industrial Research (CSIR), New
H 3.36, N 19.47. – IR (nujol): ν = 3446, 3222, 3080, Delhi.
Unauthenticated
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736
M. Kidwai et al. · One-pot Green Synthesis for Pyrimido[4,5-d]pyrimidine Derivatives
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