Uncatalyzed synthesis of new substituted dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrimidine-2,4(3H)-dione

Article abstract of DOI:10.1007/s11164-017-2868-9

Abstract: A convenient and new method has been developed for the synthesis of highly substituted dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrimidine-2,4(3H)-dione derivatives by one-pot three-component reactions of barbituric acid, aromatic aldehydes and 2-aminopyrimidine in ethanol under reflux condition without the support of any catalyst. The benefits of this protocol are catalyst-free, clean reaction procedure and providing excellent yields, and the use of ethanol as a solvent, which has been measured to be comparatively environmentally benign. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-017-2868-9

Res Chem Intermed
DOI 10.1007/s11164-017-2868-9
Uncatalyzed synthesis of new substituted dihydro-2H-
dipyrimido[1,2-a,4,5-d]pyrimidine-2,4(3H)-dione
Priyanka T. Patil1 Poojali P. Warekar1
•
•
Kirti T. Patil1 Dattatraya K. Jamale2
Govind B. Kolekar2 Prashant V. Anbhule2
•
•
•
Received: 27 September 2016 / Accepted: 10 January 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract A convenient and new method has been developed for the synthesis of highly
substituted dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrimidine-2,4(3H)-dione derivatives by
one-pot three-component reactions of barbituric acid, aromatic aldehydes and
2-aminopyrimidine in ethanol under reflux condition without the support of any catalyst.
The benefits of this protocol are catalyst-free, clean reaction procedure and providing
excellent yields, and the use of ethanol as a solvent, which has been measured to be
comparatively environmentally benign.
Graphical Abstract
Keywords Multicomponent reaction Á Dipyrimido[1,2-a:4,5-d]pyrimidine
derivatives Á 2-Aminopyrimidine Á Cyclization
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2868-
9) contains supplementary material, which is available to authorized users.
&
Prashant V. Anbhule
pvanbhule@gmail.com
1
2
Department of Agrochemicals and Pest Management, Shivaji University, Kolhapur, India
Medicinal Chemistry Research Lab, Department of Chemistry, Shivaji University, Kolhapur,
MS 416004, India
123

P. T. Patil et al.
Introduction
In recent years, pyrimidopyrimidine moieties have attracted considerable attention
in medicinal chemistry due to their significant biological activities. The pyrim-
ido[4,5-d]pyrimidines are an important group of uracils structurally related to
pteridine and purines [1, 2]. Pyrimido[4,5-d]pyrimidines (Fig. 1) possesses various
pharmacological activities including antitumor [3], anti-allergic [4, 5], anti-oxidant
[6], anti-inflammatory [7], antibacterial [8], hepatoprotective [9], antihypertensive
[10] and antiviral [11]. In addition, they have also effective inhibitory properties
like tyrosine kinase receptor [12], 5-phosphoribosyl-1-pyrophosphate synthetase
[13] and dihydrofolate reductase [14]. Dipyridamole VI (Fig. 1) containing
pyrimidopyrimidine in its core structure is useful to inhibit lower pulmonary
hypertension and phosphodiesterase enzyme, and is also used in electrocardiograms
and echocardiography [15].
Nowadays, numerous methodologies have been reported for the synthesis of
pyrimido[4,5-d]pyrimidine derivatives by using three-component condensation of
aryl aldehydes, amino sources (aminouracils, anilines, ammonium thiocynate or
4-amino-2,6-dichloropyrimidine) and active methylene compounds using acidic or
basic catalysts [16–29]. All these methods have some drawbacks, such as multistep
reaction, drastic reaction conditions, expensive or not readily available starting
materials and complex procedures [30, 31]. Consequently, there is a need to develop
a clean and suitable chemical method for the synthesis of new pyrimido[4,5-
d]pyrimidine derivatives and their analogue compounds to study their applications
in medicinal chemistry research.
NH
N
CH
CH
O
2
3
3
N
N
HN
N
R
N
H N
2
N
O
CH
3
S
N
H
N
H
S
I
II
CH
NH
2
OH
N
N
N
N
N
N
N
N
N
S
HN
OH
HO
NH
N
OH
III
VI
Fig. 1 Some biologically active pyrimidopyrimidine derivatives
123

Uncatalyzed synthesis of new substituted dihydro-2H-dipyrimido…
Multistep reactions make extensive amounts of waste, mostly due to the complex
procedure, frequently involving expensive, toxic and hazardous solvents behind
each step. However, multicomponent reactions (MCRs) [32, 33] have recently
achieved noteworthy interest in organic synthesis, since they involve a one-pot
reaction of more than two starting materials to the desired product in a single step.
MCRs have many advantages including selectivity, minimum waste production, low
energy utilization, high atom economy and occur in a great deal of organic and
medicinal chemistry. MCRs are perfectly appropriate for the synthesis of new drugs
and agrochemicals [34–40].
In the continuation of our research work for the development of new synthetic
methodologies [41, 42], in this article, we wish to report a simple and new
methodology for the synthesis of dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-
2,4(3H)-dione derivatives from barbituric acid, aromatic aldehydes and 2-aminopy-
rimidine under catalyst-free conditions in ethanol (Scheme 1).
Experimental
All the chemicals were purchased from Spectrochem (Mumbai, India) and Alfar
Aesar and used without any further purification. Melting points were determined in
open glass capillary tubes and were used uncorrected. The compounds were
1
confirmed by IR, H NMR and 13C NMR. The IR spectra were recorded on a
1
JASCO FT-IR spectrometer and the values are expressed as Vmax cm-1. The H
13
NMR and
C NMR spectra were recorded on a Bruker Spectrospin Avance II-
300 MHz and a 75-MHz spectrophotometer relative to TMS as an internal standard
using DMSO-d6 as a solvent.
General procedure of 5-phenyl-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrim-
idine-2,4(3H)-dione A mixture of barbituric acid (1 mmol), aromatic aldehydes
(1 mmol) and 2-aminopyrimidine (1 mmol) was stirred under reflux in ethanol
(10 ml) for 1 h. The completion of the reaction was monitored by thin-layer
chromatography (TLC). The solid product was separated, cooled, filtered and
O
CHO
R
N
O
HN
Ethanol
reflux
N
+
+
HN
N
X
N
H
O
N
NH2
R
N
H
N
X
R= -NO2, -Cl, -CN
X= O,S
Scheme 1 Synthesis of dihydro-2H-dipyrimido [1,2-a,4,5d]pyrimidine derivatives
123

P. T. Patil et al.
washed with hot ethanol. The obtained product was recrystalized from ethanol to
afford the pure product in excellent yield.
5-(4-chlorophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d] pyrimidine-2, 4(3H)-
dione. (Entry 1) Pale yellow solid, Mp: 230–235 °C, IRVmax: 3374, 3122, 1867,
1746, 1671, 1647 cm-1. 1H NMR (300 MHz, DMSO-d6): d 6.01 (s, 1H, –CH), 6.78
(s, 1H, Ar–H), 7.30–7.33 (d, J = 9.0 Hz, 2H, Ar–H), 7.99–8.01 (d, J = 6.0 Hz, 2H,
Ar–H), 8.45–8.46 (d, J = 6.0 Hz, 2H, Ar–H), 10.38 (br.s, 2H, –NH). 13C NMR
(75 MHz, DMSO-d6): d 31.79, 91.23, 110.45, 123.06, 124.40, 128.11, 130.93,
145.57, 151.28, 152.94, 157.69, 158.18, 165.42. HRMS: mass calculated for
[C15H10N5O2Cl]: 327.72 [m/z]; Obs. Mass: 327.78 [m/z]. Elemental Anal. Cal. For
C15H10N5O2Cl: C, 54.97; H, 3.08; N, 21.37; Found, C, 55.00; H, 3.05; N, 21.35.
5-(4-nitrophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione.
(Entry 2) Pale yellow solid, Mp: 210–215 °C, IRVmax: 3363, 3125, 1667,
1
1600 cm-1. H NMR (300 MHz, DMSO-d6): d 6.01 (s, 1H, –CH), 6.78–6.80 (d,
J = 6.0 Hz, 1H, Ar–H), 7.30–7.33 (d, J = 9.0 Hz, 2H, Ar–H), 7.99–8.02 (d,
J = 9.0 Hz, 2H, Ar–H), 8.46 (s, 2H, Ar–H), 10.37 (br.s, 2H, –NH). 13C NMR
(75 MHz, DMSO-d6): d 31.82, 91.19, 110.36, 123.00, 124.37, 128.10, 130.88,
145.56, 151.18, 152.81, 157.70, 158.73. Elemental Anal. Cal. For C15H10N6O4: C,
53.26; H, 2.98; N, 24.84; Found, C, 53.23; H, 3.01; N, 24.81.
4-(2,4-dioxo-1,3,4,5-tetrahydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidin-5-yl)benzonitrile.
(Entry 3) Pink solid, Mp: 200 °C, IRVmax: 3131, 2228, 1667, 1601 cm-1. 1H NMR
(300 MHz, DMSO-d6): d 5.95 (s, 1H, –CH), 6.75 (s, 1H, Ar–H), 7.27 (s, 1H, Ar–H),
7.50 (s, 1H, Ar–H), 7.98 (s, 2H, Ar–H), 8.42 (s, 2H, Ar–H), 10.36 (br.s, 2H, –NH).
13C NMR (75 MHz, DMSO-d6): d 31.75, 91.12, 107.99, 110.52, 119.60, 128.08,
131.79, 151.30, 157.72, 165.48. Elemental Anal. Cal. For C16H10N6O2: C, 60.38; H,
3.17; N, 26.40; Found, C, 60.35; H, 3.20; N, 26.37.
5-(4-bromophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione.
1
(Entry 4) Yellow solid, Mp: 180 °C, IRVmax: 3378, 3166, 1670, 1603 cm-1. H
NMR (300 MHz, DMSO-d6): d 5.79 (s, 1H, –CH), 6.59–6.63 (t, 1H, Ar–H),
6.99–7.02 (d, J = 9.0 Hz 1H, Ar–H), 7.19–7.22 (d, J = 9.0 Hz, 1H, Ar–H),
7.48–7.72 (m, 2H, Ar–H), 7.92–7.94 (d, J = 6.0 Hz, 1H, Ar–H), 8.33–8.35(d,
J = 6.0 Hz,1H, Ar–H), 10.45 (br.s, 2H, –NH). 13C NMR (75 MHz, DMSO-d6):
d31.02, 110.32, 118.26, 129.27, 130.61, 131.40, 132.52, 135.17, 151.04, 157.81,
159.32. Elemental Anal. Cal. For C15H10N6O4: C, 48.41; H, 2.71; N, 18.82; Found,
C, 47.98; H, 2.74; N, 18.85.
5-(3-chlorophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione.
(Entry 5) Creamy solid, Mp: 222–224 °C, IRVmax: 3344, 3142, 1687, 1663,
1617 cm-1. 1H NMR (300 MHz, DMSO-d6): d 5.84 (s, 1H, –CH), 6.67–6.70 (t, 1H,
Ar–H), 7.03–7.11 (m, 4H, Ar–H), 8.38–8.40 (d, 2H, Ar–H), 10.45 (br.s, 2H, –NH).
13C NMR (75 MHz, DMSO-d6): d 31.23, 91.10, 110.32, 125.14, 125.76, 126.82,
129.60, 131.82, 133.07, 151.05, 157.81, 158.58, 165.46. Elemental Anal. Cal. For
C15H10N5O2Cl: C, 54.97; H, 3.08; N, 21.37; Found, C, 54.96; H, 3.09; N, 21.39.
123

Uncatalyzed synthesis of new substituted dihydro-2H-dipyrimido…
5-(3-nitrophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione.
(Entry 6) Creamy solid, Mp: 250 °C, IRVmax: 3338, 3139, 1687, 1616, 1527 cm-1
1H NMR (300 MHz, DMSO-d6): d 5.98 (s, 1H, –CH), 6.79 (s, 1H, Ar–H), 7.37 (m,
1H, Ar–H), 7.47–7.49 (d, 1H, Ar–H), 7.83–7.87 (d, 2H, Ar–H), 8.40–8.42 (d, 3H,
Ar–H and 1NH), 10.07 (br.s 1H, NH). 13C NMR (75 MHz, DMSO-d6): d 31.23,
91.17, 110.53, 120.66, 121.41, 129.44, 134.03, 146.30, 148.05, 151.15, 151.42,
157.11, 157.57, 157.71, 165.41. Elemental Anal. Cal. For C15H10N6O4: C, 53.26; H,
2.98; N, 24.84; Found, C, 53.29; H, 2.96; N, 24.87.
.
5-(2-chlorophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione.
1
(Entry 7) Brown solid, Mp: 218–220 °C, IRVmax: 3123, 1690, 1591 cm-1. H
NMR (300 MHz, DMSO-d6): d 5.77 (s, 1H, –CH), 6.69 (s, 1H, –ArH), 7.08–7.18 (s,
1H, –ArH), 7.30 (s, 1H, –ArH), 7.47 (s, 1H, –ArH), 7.73–7.75 (d, 1H, –ArH), 8.34
(s, 2H, –ArH), 10.15 (br.s, 2H, –NH). 13C NMR (75 MHz, DMSO-d6): d 31.44,
110.39, 125.97, 126.45, 127.02, 129.20, 129.55, 130.52, 132.27, 132.39, 133.24,
141.43, 150.51, 151.12, 157.88, 159.91, 161.10, 162.90, 165.18. Elemental Anal.
Cal. For C15H10N5O2Cl: C, 54.97; H, 3.08; N, 21.37; Found, C, 54.99; H, 3.10; N,
21.36.
5-(2-nitrophenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione.
(Entry 8) Pale yellow solid, Mp: 252–254 °C, IRVmax: 3363, 3234, 1743, 1714,
1677 cm-1. 1H NMR (300 MHz, DMSO-d6): d 6.48–6.49 (d, 1H, –CH), 7.47–7.50
(d, 1H, Ar–H), 7.62–7.64 (d, 1H, Ar–H), 7.69–7.71 (d, 1H, Ar–H), 8.16–8.20 (t, 3H,
Ar–H), 8.60 (s, 1H, Ar–H), 11.28 (s, 1H, –NH), 11.53 (s, 1H, –NH). 13C NMR
(75 MHz, DMSO-d6): d 29.15, 90.81, 110.75, 120.24, 124.43, 124.54, 129.78,
130.25, 130.58, 131.52, 134.24, 134.58, 146.40, 150.09, 150.61, 151.37, 153.91,
158.14, 161.12. Elemental Anal. Cal. For C15H10N6O4: C, 53.26; H, 2.98; N, 24.84;
Found, C, 53.24; H, 2.99; N, 24.82.
5-(4-chlorophenyl)-2-thioxo-1,2,3,5-tetrahydro-4H-dipyrimido[1,2-a:40,50-d]pyrim-
idin-4-one. (Entry 9) Faint orange solid, Mp: 216–218 °C, IRVmax: 3374, 3068,
1612, 1536 cm-1. 1H NMR (300 MHz, DMSO-d6): d 5.96 (s, 1H, –H), 6.79–6.81 (t,
1H, Ar–H), 7.01–7.08 (m, 2H, Ar–H), 7.80–7.82 (d, J = 6.0 Hz, 2H, Ar–H),
8.58–8.60 (d, J = 6.0 Hz, 2H, Ar–H), 11.67 (br.s, 2H, –NH). 13C NMR (75 MHz,
DMSO-d6): d 30.71, 96.34, 109.77, 127.78, 128.62, 129.49, 130.38, 157.26, 157.60,
163.99, 173.30. HRMS: mass calculated for [C15H10N5OS]: 343.79 [m/z]; Obs.
Mass: 343.18 [m/z]. Elemental Anal. Cal. For C15H10N5OS: C, 52.40; H, 2.93; N,
20.37; Found, C, 52.44; H, 2.90; N, 20.40.
5-(4-nitrophenyl)-2-thioxo-1,2,3,5-tetrahydro-4H-dipyrimido[1,2-a:40,50-d]pyrim-
idin-4-one. (Entry 10) Creamy solid, Mp: 246–248 °C, IRVmax: 3314, 3100, 1747,
1
1646, 1590, 1540 cm-1. H NMR (300 MHz, DMSO-d6): d 6.07 (s, 1H, –CH),
6.85–6.88 (t, 1H, Ar–H), 7.26–7.29 (d, J = 9.0 Hz, 2H, Ar–H), 7.96–7.99 (d,
J = 9.0 Hz, 2H, Ar–H), 8.54–8.56 (d, J = 6.0 Hz, 2H, Ar–H), 11.72 (br.s, 2H, –
NH). 13C NMR (75 MHz, DMSO-d6): d 31.60, 95.97, 110.04, 123.14, 128.05,
145.76, 156.89, 157.62, 163.99, 173.38. HRMS: mass calculated for [C15H10N6O4]:
123

P. T. Patil et al.
354.34. [m/z]; Obs. Mass, [m/z]: 355.29 [M ? H?]. Elemental Anal. Cal. For
C15H10N6O3S: C, 50.84; H, 2.84; N, 23.72; Found, C, 50.81; H, 2.86; N, 23.75.
4-(4-oxo-2-thioxo-1,3,4,5-tetrahydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidin-5-yl)
benzonitrile. (Entry 11) Light pink solid, Mp: 240–242 °C, IRVmax: 3296, 3119,
1
2200, 1746, 1623, 1592 cm-1. H NMR (300 MHz, DMSO-d6): d 6.03 (s, 1H, –
CH), 6.82–6.85 (t, 1H, Ar–H), 7.20–7.22 (d, J = 6.0 Hz, 2H, Ar–H), 7.46–7.48 (d,
J = 6.0 Hz, 1H, Ar–H), 7.95 (s, 1H, Ar–H), 8.50–8.52 (d, J = 6.0 Hz, 2H, Ar–H),
11.61 (br.s, 2H, –NH). 13C NMR (75 MHz, DMSO-d6): d 31.55, 95.86, 108.41,
110.35, 119.43, 127.99, 131.73, 131.89, 148.95, 157.22, 157.41, 157.61, 163.96,
173.25. Elemental Anal. Cal. For C16H10N6OS: C, 57.48; H, 3.01; N, 25.14; Found,
C, 57.50; H, 2.98; N, 25.16.
5-(3-nitrophenyl)-2-thioxo-1,2,3,5-tetrahydro-4H-dipyrimido[1,2-a:40,50-d]pyrim-
idin-4-one. (Entry 12) Off white solid, Mp: 240–245 °C, IRVmax: 3351, 3064,
1666, 1596 cm-1. 1H NMR (300 MHz, DMSO-d6): d 6.07 (s, 1H, –CH), 6.83–6.87
(t, 1H, Ar–H), 7.39–7.45 (m, 2H, Ar–H), 7.81–7.90 (m, 2H,Ar–H), 8.50–8.52 (d,
2H, Ar–H), 11.64 (br.s, 2H, –NH). 13C NMR (75 MHz, DMSO-d6): d 31.14, 95.65,
110.10, 120.54, 121.54, 129.31, 133.99, 145.88, 148.14, 157.22, 157.71, 163.71,
173.53. Elemental Anal. Cal. For C15H10N6O3S: C, 50.84; H, 2.84; N, 23.72; Found,
C, 50.83; H, 2.80; N, 23.69.
5-phenyl-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione. (En-
try 13) Pale orange solid, Mp: 170 °C IRVmax: 3285, 3180, 1695, 1660, 1601,
1538 cm-1. 1H NMR (300 MHz, DMSO-d6): d 5.90 (s, 1H, –CH), 6.54–6.57 (t, 2H,
Ar–H), 7.08–7.09 (d, 2H, Ar–H), 7.69 (s, 1H, Ar–H), 8.25–8.26 (d, 3H, Ar–H),
10.36 (br.s, 2H, –NH). 13C NMR (75 MHz, DMSO-d6): d 36.03, 110.42, 125.02,
127.03, 127.79, 128.30, 129.27, 129.75, 132.68, 132.80, 133.64, 150.51, 151.02,
156.57, 158.02, 161.90, 167.68. Elemental Anal. Cal. For C15H11N5O2: C, 61.43; H,
3.78; N, 23.88; Found, C, 61.49; H, 3.84; N, 23.70.
5-(3-hydroxyphenyl)-1,5-dihydro-2H-dipyrimido[1,2-a:40,50-d]pyrimidine-2,4(3H)-
dione. (Entry 14) Pale yellow solid, Mp: 240 °C IRVmax: 3503, 3341, 3151, 1698,
1
1648, 1601, 1538 cm-1. H NMR (300 MHz, DMSO-d6): d 5.71 (s, 1H, –CH),
6.55–6.58 (t, 2H, Ar–H), 7.17 (1H, Ar–H), 7.70 (s, 1H, Ar–H), 8.24–8.25 (d, 3H,
Ar–H), 10.36 (br.s, 1H, –NH), 11.10–11.26 (t, 2H, –NH, –OH). Elemental Anal.
Cal. For C15H11N5O3: C, 58.25; H, 3.58; N, 22.64; Found, C, 58.19; H, 3.66; N,
22.59.
Result and discussion
Pyrimido[4,5-d]pyrimidine derivatives are recognized by much bioactivity and are
synthesized by using various methods [43–46], including stereo-controlled synthesis
of bis-pyrimido[4,5-d]pyrimidines as mentioned in the ‘‘Introduction’’. As a result,
these methods have been very useful for the medicinal and industrial chemistry
research areas. Therefore, we decided to develop a new method for the preparation
123

Uncatalyzed synthesis of new substituted dihydro-2H-dipyrimido…
Table 1 optimization of
S. no
Solvents
Time (h)
Yield (%)
reaction conditions for the
synthesis of dihydro-2H-
dipyrimido [1,2-
1
2
3
4
5
Water
12
1
Knoevenagel
Ethanol
Acetonitrile
THF
90
64
–
a,4,5d]pyrimidine
5
Reaction condition: barbituric
acid (1 mmol), aromatic
aldehydes (1 mmol) and
2-aminopyrimidine (1 mmol),
10 ml ethanol
12
3
DMF
50
of pyrimido[4,5-d]pyrimidine derivatives. Initially, we focused our attention on one-
pot three-component condensations of barbituric acid (1 mmol), 4-nitrobenzalde-
hyde (1 mmol) and 2-aminopyrimidine (1 mmol) in 10 ml ethanol, which were
stirred vigorously at room temperature for 12 h. However, the expected results were
not obtained since the reaction did not proceed beyond the Knoevenagel
condensation. The same reaction was carried out under catalyst-free conditions in
ethanol at reflux for 1 h. The progress of the reaction was monitored by TLC and
was completed within 1 h. The solid product was isolated, filtered and thoroughly
washed with hot ethanol. The obtained product was recrystalized from ethanol to
1
afford the pure product and further analyzed by spectroscopic data. The IR, H
NMR, 13C NMR and mass spectra of 5-(4-nitrophenyl)-1,5-dihydro-2H-dipyrim-
ido[1,2-a:40,50-d]pyrimidine-2,4(3H)-dione are in good agreement with the pro-
posed structure.
The choice of an expedient solvent is imperative for successful organic synthesis.
In order to investigate the effect of the solvent, the three-component reaction of
4-nitrobenzaldehyde, barbituric acid and 2-aminopyrimidine was examined using
different solvents such as water, ethanol, acetonitrile, THF and DMF for the
synthesis of 4a. The results are shown in Table 1. These results illustrate that
compound 4a was obtained in good to excellent yield in ethanol, as compared to
other solvents. This result convinced us that ethanol was the appropriate solvent for
this reaction, because it is an easily available, inexpensive, non-toxic and green
solvent (Table 1).
As a result , we chose the optimized reaction condition to examine a series of
different substituted aromatic aldehydes applied in this reaction to afford the
dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrimidine derivative 4. It was pleasing to
report that the majority of the tested substrates exhibited a suitable reactivity profile.
The results are summarized in Table 2.
All the newly synthesized derivatives of the dihydro-2H-dipyrimido[1,2-a:4,5-
1
d]pyrimidine-2,4(3H)-dione (4a–n) were recognized from IR, H NMR, 13C NMR
and mass data. Compound 4a was selected as a representative example. This
compound has the molecular formula C15H10N5O2Cl, interpreted from its HRMS
1
(m/z = 327.7850 [M?H]?. In the H NMR spectra, a peak at d = 6.01 ppm is due
to the –CH proton, the peaks appearing at d = 6.78 to 8.46 ppm are due to the 7
aromatic proton,s while the peak at d = 10.38 ppm is due to the 2 –NH protons. The
123

P. T. Patil et al.
Table 2 Synthesis of dihydro-2H-dipyrimido [1,2-a,4,5-d]pyrimidinea (4a–n)
Entry
Aldehydes
Products
X
O
Time (Min)
60
MP (°C)
230–235
Yieldb %
90
4a
4b
O
50–60
210–215
92
4c
O
50–60
200
88
4d
O
50–60
180
85
4e
O
70–80
222–224
89
4f
O
70–80
250
90
4g
4h
O
O
60–70
60–70
218–220
252–254
88
92
123

Uncatalyzed synthesis of new substituted dihydro-2H-dipyrimido…
Table 2 continued
Entry
Aldehydes
Products
X
S
Time (Min)
50–60
MP (°C)
Yieldb %
91
4i
216–218
4j
S
60
246–248
90
4k
S
60
240–242
85
4l
S
60
60
240–245
88
84
4m
O
170
4n
O
60
240
80
a
Reaction condition: barbituric acid (1 mmol), aromatic aldehydes (1 mmol) and 2-aminopyrimidine
(1 mmol), 10 ml ethanol
b
Isolated yield
IR spectra also show respective absorption bands of the –C=O bonds (1677 and
1746 cm-1) and the –NH groups (3122 and 3374 cm-1).
After successful synthesis of various dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrim-
idine derivatives, the plausible mechanism for the formation of dihydro-2H-
123

P. T. Patil et al.
R
R
O
CHO
O
O
HN
N
+
HN
HN
N
-H2O
R
+
X
N
H
OH
H2N
N
X
N
H
O
X
N
H
N
O
N+
H
1
3
2
5
H
Michael Addition
R
R
R
O
O
O
H
Cyclization
HN
N
HN
N
HN
N
-H2O
Air Oxidation
X
N
H
N
N
X
N
H
N
X
N
H
N
H
N
O
HN
H
7
4a
6
R= - NO2, -Cl, -CN
X= O,S
Scheme 2 Plausible mechanism for the synthesis of dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrimidine
derivatives
dipyrimido[1,2-a,4,5-d]pyrimidine derivatives is given in Scheme 2. In this,
initially, a Knoevenagel condensation of barbituric acid (1) and aromatic aldehydes
(2) form a conjugated enone (5), the Michael-type addition of 2-aminopyrimidine
(3) gives an intermediate (6). It subsequently undergoes cyclization followed by
dehydration giving the desired product, dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrim-
idine derivatives (4a) (Scheme 2).
The successful synthesis of the pyrimido[4,5-d]pyrimidine moieties by using
barbituric acid means that we diversified the replacing the barbituric acid with
thiobarbituric acid (Table 2 entries 4i–4l). Under similar reaction conditions, the
reaction proceeds very well to obtain the desired product in good to excellent yield.
No such effect of O or S is observed on the yield of the desired products.
Conclusion
In conclusion, we have established a new straightforward and efficient protocol for
the synthesis of dihydro-2H-dipyrimido[1,2-a,4,5-d]pyrimidine derivatives via a
three-component condensation reaction of barbituric acid, aromatic aldehydes and
2-aminopyrimidine under catalyst-free conditions in ethanol. The method accepts
many functional groups and leads to the creation of a wide series of novel
derivatives. This methodology is useful for new possibilities in the design and
synthesis of new pyrimido-pyrimidine moieties.
123

Uncatalyzed synthesis of new substituted dihydro-2H-dipyrimido…
Acknowledgement The authors thank the Department of Science and Technology, New Delhi, for
providing thePURSE Fellowship.
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