An expedient synthesis of novel, fused pyrimido[4,5-d]pyrimidine and pyrimido [5,4-e] [1,2,4]triazolo[4,3-c]pyrimidine analogues from 4-amino-2,6-dichloro-pyrimidine

Article abstract of DOI:10.1002/hc.20177

A number of potent pyrimido[4,5-d]pyrimidine have efficiently been synthesized by the condensation of 4-amino-2,6-dichloropyrimidine with various substituted benzaldehyde followed by cyclization with ammonium thiocyanate. Also, these newly synthesized der

Full text of DOI:10.1002/hc.20177

Heteroatom Chemistry
Volume 17, Number 4, 2006
An Expedient Synthesis of Novel, Fused
Pyrimido[4,5-d ]pyrimidine and Pyrimido
[5,4-e] [1,2,4]triazolo[4,3-c]pyrimidine
Analogues from 4-Amino-2,6-dichloro-
pyrimidine
Pratibha Sharma, Ashok Kumar, and Nilesh Rane
School of Chemical Sciences, Devi Ahilya University, Takshila Campus, Khandwa Road,
Indore 452 017, MP, India
Received 24 May 2005; revised 19 September 2005
construction of many pharmacologically important
ABSTRACT: A number of potent pyrimido[4,5-
novel heterocycles [2].
d]pyrimidine have efficiently been synthesized by the
Particularly, pyrimido[4,5-d]pyrimidine fused
condensation of 4-amino-2,6-dichloropyrimidine with
system represents attractive targets owing to diverse
various substituted benzaldehyde followed by cycliza-
pharmacological applications of these molecules
tion with ammonium thiocyanate. Also, these newly
that include modulator of antitumor drug activ-
synthesized derivatives were utilized for the con-
ity [3], antioxidant (as inhibitor of lipid peroxida-
struction of novel pyrimido[5,4-e][1,2,4]triazolo[4,3-
tion) [4], antiviral (as inhibitor of herpes simplex
c]pyrimidine analogues via oxidative cyclization in-
virus reactivation) [5], hepatoprotective [6], potent
volving 1,5-hydrogen abstraction. Structure of all the
inhibitory action on epidermal growth factor recep-
newly constructed derivatives was corroborated by the
tor [7], and 5-phosphoribosyl-1-pyrophosphate syn-
ꢀ
C
elemental and spectral data.
2006 Wiley Periodicals,
thetase [8].
The development of pyrimidopyrimidines as po-
Inc. Heteroatom Chem 17:245–253, 2006; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20177
tential hosts in the enantioselective recognition of
oxo anions in polytopic abiotic receptors [9] and an-
chor modules for oxo anionic functions of molecu-
lar guests species complexed by polytopic artificial
receptors is also well documented [10] and gave an
impetus for the chemistry of such system.
Similarly, a number of compounds with triazolo-
fused pyrimidine ring system exhibiting adenosine
receptor antagonist activity are described as possi-
ble template for adenosine receptor subtype [11],
further providing continuous demand to explore ef-
ficient synthetic routes to gain rapid access to these
functionalized molecules.
INTRODUCTION
The pyrimidine and heterocyclic annulated pyrimi-
dine system undoubtedly belong to the most ubiqui-
tous heterocycles in the nature. They have attracted
considerable attention of both synthetic and medic-
inal chemists by virtue of their interesting biological
activities [1] and immense synthetic potential for the
In this context, as well as to pursue our
interest in developing versatile synthesis of pyrim-
idopyrimidine heteroaromatic ring system [12,13]
Correspondence to: Pratibha Sharma; e-mail: drpratibhasharma
@yahoo.com.
2006 Wiley Periodicals, Inc.
c
ꢀ
245

246 Sharma, Kumar, and Rane
TABLE 1 Characteristics for Newly Synthesized Pyrimido-
[4,5-d]pyrimidines and Pyrimido[5,4-e][1,2,4]triazolo[4,3-c]-
pyrimidines 2–6
Product MP ( ◦C) Reaction Time Yieldsa(%) m/z (M +
)
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
150–152
159–160
142–143
121–123
156–158
210–211
145–147
132–134
128–130
141–142
167–168
197–199
178–180
199–200
219–221
147–148
170–172
132–135
201–202
194–195
161–163
149–151
243–245
219–220
189–190
225–226
3 h
4 h
3 h
3 h
5 h
5 h
4 h
4 h
1 h
94
87
95
88
91
76
85
90
70
77
65
74
83
68
79
82
75
77
74
80
85
79
70
68
66
74
252
286
266
297
311
345
325
356
325
359
339
339
373
353
309
343
323
354
397
431
411
442
395
429
409
440
FIGURE
1 Structure of synthesized pyrimido[4,5-
d]pyrimidine and triazolo-fused pyrimidine derivative.
30 min
30 min
1 h
and other heterocycles [14–16], we herein report
1 h
a
facile new synthesis of structurally diverse
30 min
10 min
15 min
10 min
45 min
4 h
5 h
5 h
4 h
6 h
pyrimido[4,5-d]pyrimidine and pyrimido[5,4-e]
[1,2,4]triazolo[4,3-c]pyrimidine derivatives which
can be envisioned as new lead compounds, us-
ing 4-amino-2,6-dichloropyrimidine as a starting
material.
RESULTS AND DISCUSSION
5 h
4 h
5 h
The most promising methods for the generation of
pyrimidopyrimidine nucleus are multistep synthe-
sis starting from 1,3-disubstituted-5-cyanouracils
[17] or from polymer-bound 2-(alkylsufanyl)-4-
aminopyrimidine-5-carbonitrile [18]. However,
these approaches involve relatively longer synthetic
pathways, lower yields, or the use of stoichiometric
amounts of expensive resin as a polymer support.
Our synthetic plan commences from readily avail-
able 4-amino-2,6-dichloropyrimidine, which offers
large number of annulated heterocycles (Fig. 1) in
efficient yields.
The requisite starting material, i.e., 2,6-dichloro-
4-arylmethylideneamino-pyrimidine 1 was prepared
in excellent yields by Schiff-base [19] type conden-
sation of 4-amino-2,6-dichloropyrimidine with
appropriately substituted benzaldehyde in reflux-
ing ethanol. These 6-aminoarylidine-substituted
aYields refer to isolated pure products.
pyrimidines on subsequent condensation with
ammonium thiocyanate in dioxane generates
the desired products, i.e., 5,7-dichloro-2-aryl-2,-
4a-dihydropyrimido[4,5-d]pyrimidine-4(3H)-thione
2a–d in 87–95% yields (Scheme 1).
The structure of the products was assigned
on the basis of spectroscopic and elemental data
(Table 1). The IR spectrum of 2a exhibited NH
stretching absorption band at 3260 cm−1, whereas
C S and C Cl absorption bands were visible at
1070 and 580 cm−1, respectively. In the 1H NMR
spectrum, the NH proton appeared as a singlet at
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Expedient Synthesis of Novel, Fused Pyrimido[4,5-d ]pyrimidine and Pyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine 247
δ = 10.28, while the 13C NMR spectrum showed the
Likewise, oxidative heterocyclization of hydra-
zones 5a–d by treatment with lead tetraacetate
(1.5 equiv.) in 1,4-dioxane exclusively produces
the 8,10-dichloro-5-aryl-3-phenyl-5,10a-dihydro-py-
rimido[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine 6a–d
(Scheme 2) in good to moderate yields, which was
favored by intramolecular interaction between the
N-3 and the carbon of N CH Ar fragment. The
assignment of the structure of the triazolo[4,3-c]-
pyrimidine derivatives 6a–d thus obtained was
based on spectroscopic data and microanalyses
(Table 1). In 1H NMR spectrum of final product,
the absence of azomethine proton supports the
successful transformation of 5 to triazolo analogues
via oxidative intramolecular cyclization occurring
at azomethine functionality.
We assume that oxidative cyclization, the key
step in the sequence, involves the 1,5-internal hydro-
gen abstraction by the free radical, which is gener-
ated by the attack of lead tetraacetate on 5 followed
by intramolecular addition of nitrogen anion to the
carbonium of azomethine functionality in order to
facilitate the triazolopyrimidine system (Fig. 2).
The N-3 substituted derivatives, i.e., 5,7-
dichloro-3-alkyl-2-aryl-2,4a-dihydro-3H-pyrimido[4,-
5-d]pyrimidine-4-thione, were synthesized by elec-
trophilic replacement of N-3 proton by various alkyl
halides in pyridine under reflux conditions. Also,
the formation of 3a is confirmed by the absence
of signal for NH proton of pyrimidine ring and
presence of N-3 methyl protons at δ = 3.12 in the 1H
NMR spectra.
signal for C S at δ = 199.0.
Consequently, to construct pyrimido[4,5-d]-
pyrimidine skeleton, the pyrimidine nucleus, fused
to the 4-amino-2,6-dichloropyrimidine ring was gen-
erated by cyclocondensation between C C N C
fragment, derived from 1 with N C fragment pro-
vided by ammonium thiocyanate.
In order to extend the synthetic utility of newly
generated compounds, we have also constructed
several N-3 and C-4 substituted pyrimido[4,5-
d]pyrimidines and triazolo-fused pyrimidines using
2 as a starting material.
In this regard, the required key compound 5,7-
dichloro-4-hydrazino-2-aryl-2,4a-dihydropyrimido-
[4,5-d]pyrimidine 4a–c used in the course of reac-
tion was efficiently synthesized by the reaction of 2
with excess hydrazine hydrate (80%) under reflux
condition for 10 min. The subsequent treatment
of 4-hydrazino derivative 4a–d thus obtained, with
benzaldehyde (1.5 equiv.) in glacial AcOH at room
temperature afforded the corresponding 4-aldehyde
hydrazones 5a–d in 74–85% yields, as indicated
1
in Table 1. The H NMR spectrum of 4a displayed
the two broad singlets at δ = 9.11 and 6.22 corre-
sponding to NH and NH2 group, respectively of
hydrazino functionality. Moreover, disappearance
of the signal for C S group at δ = 199.0, in the 13C
NMR spectrum, augment the proposed structure.
The presence of diagnostic signal for the azomethine
1
proton at δ = 8.45 in the H NMR spectra further
confirms the transformation of 4 to 5.
FIGURE 2 Mechanistic details for the transformation of 5 to 6.
Heteroatom Chemistry DOI 10.1002/hc

248 Sharma, Kumar, and Rane
SCHEME 2
In conclusion, we have successfully constructed
a number of highly functionalized N-3, C-4 sub-
stituted pyrimido[4,5-d]pyrimidines, and C-3, C-5
aryl substituted pyrimido[5,4-e][1,2,4]triazolo[4,3-
c]pyrimidines of potential biological significance in
an excellent yields by a new and efficient synthesis
using 4-amino-2,6-dichloropyrimidine. The adopted
protocol is effective and involves simple experimen-
tal procedures and product identification.
Furthermore, the results delineated above have
illustrated that the title compound 2 can be a use-
ful building block for the generation of array of
fused nitrogen heterocycles. The extensive biologi-
cal screening of these newly synthesized compounds
is the subject of further optimization.
EXPERIMENTAL
All the chemicals used were of AR grade purity
from E. Merck. Solvents used for the experiments
were distilled or dried prior to use. IR spectra were
recorded on a Shimadzu 460 FTIR-spectrometer in
KBr disks. Frequencies are reported in cm−1. The
NMR spectra were recorded on a Jeol NMR 200 MHz
(1H) and Bruker DRX 400 MHz (13C) spectrometers
in CDCl3. The chemical shifts are quoted in ppm
value on the δ scale, using TMS as an internal refer-
ence and coupling constants (J) in Hz. Mass spectra
were taken with a Jeol D-300 spectrometer. Melting
points were determined on an electrothermal appa-
ratus by open capillary method and are uncorrected.
Heteroatom Chemistry DOI 10.1002/hc

Expedient Synthesis of Novel, Fused Pyrimido[4,5-d ]pyrimidine and Pyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine 249
Reaction monitoring and purity of all the synthe-
2,6-Dichloro-4-(4-nitrobenzylidineamino)-
sized compounds were ascertained by TLC resolu-
tion studies on silica gel G (E. Merck) using ethyl
acetate–xylene (3:7, v/v) as eluent and HPLC analysis,
performed on Shimadzu LC10AS using L7 phenyl
packing column, a 254 nm UV Shimadzu ASVP de-
tector and acetonitrile/methanol/water (60:30:10) as
eluent with a flow rate of 1 mL/min.
pyrimidine 1d
νmax(KBr)/cm−1: 3020 (CH, sp2), 1660 (C C/C N),
· · ·
1570, 1512, 1485 (C —C, ring str.), 1385 (NO2),
665 (C Cl). δH (CDCl3): 8.60 (s, 1H, N CH), 7.8
(s, 1H, CH), 7.5 (d, 2H, J = 8.0 Hz, ArH), 7.4 (d,
2H, J = 8.0 Hz, ArH). δC (CDCl3): 184.8 (C-2), 168.4
(N CH), 165.1 (C-4), 161.2 (C-6), 132.2, 130.5, 129.0,
128.5 (Ar), 111.0 (C-5). Anal. Calcd for C11H6Cl2N4O2
(297.10): C, 44.47; H, 2.04; N, 18.86. Found C, 44.51;
H, 2.12; N, 18.77.
2,6-Dichloro-4-arylmethylideneamino-
pyrimidine 1
A
mixture of 4-amino-2,6-dichloropyrimidine
(3.28 g, 20 mmol) and corresponding arylaldehyde
(20 mmol) was heated in EtOH (50 mL) under reflux
to the completion of reaction (monitored via TLC).
The solvent was removed in vacuo and the residue
was recrystallized from MeOH to give products
1a–d.
5,7-Dichloro-2-aryl-2,4a-dihydropyrimido[4,5-
d]pyrimidine-4(3H)-thione 2
To a solution of 2,6-dichloro-4-arylmethylidine-
amino-pyrimidine 1 (20 mmol) in dioxane (30 mL),
ammonium thiocyanate (2.736 g, 36 mmol) was
added and dissolved by slow warming with contin-
uous stirring. The reaction mixture was stirred for
30 min at room temperature and subsequently al-
lowed to reflux for required time (Table 1). The sol-
vent was distilled off under reduced pressure and
solid thus obtained was washed repeatedly with wa-
ter, dried in vacuo and recrystallized form EtOH.
2,6-Dichloro-4-benzylideneamino-pyrimidine 1a
νmax(KBr)/cm−1: 3010 (CH, sp2), 1650 (C C/C N),
· · ·
1600, 1525, 1435 (C —C, ring str.), 640 (C Cl). δH
(CDCl3): 8.64 (s, 1H, N CH), 7.8 (s, 1H, CH), 7.4 (s,
5H, Ph). δC (CDCl3): 187.7 (C-2), 163.7 (N CH), 162.2
(C-4), 160.6 (C-6), 132.4, 130.3, 129.1, 128.6 (Ph),
114.4 (C-5). Anal. Calcd for C11H7Cl2N3 (252.10): C,
52.41; H, 2.80; N, 16.67. Found C, 52.35; H, 2.86; N,
16.60.
5,7-Dichloro-2-phenyl-2,4a-dihydropyrimido[4,5-
d]pyrimidine-4(3H)-thione 2a
νmax(KBr)/cm−1: 3260 (NH), 1646 (C C/C N), 1546,
· · ·
1510, 1480 (C —C, ring str.), 1070 (C S), 1017, 947
2,6-Dichloro-4-(4-cholrobenzylidineamino)-
pyrimidine 1b
(CH, in-plane bending), 845, 771 (CH, out-of-plane
bending), 580 (C Cl). δH (CDCl3): 10.28 (br s, 1H,
NH), 7.1 (s, 5H, Ph), 4.11 (s, 1H, H-2), 3.24 (s, 1H, H-
4a). δC (CDCl3): 199.0 (C-4), 164.0 (C-5), 163.0 (C-7),
161.0 (C-8a), 142.4, 128.3, 127.1, 126.5 (Ph), 70.5 (C-
2), 52.7 (C-4a). Anal. Calcd for C12H8Cl2N4S (311.19):
C, 46.32; H, 2.59; N, 18.00. Found C, 46.25; H, 2.62;
N, 17.95.
νmax(KBr)/cm−1: 3000 (CH, sp2), 1640 (C C/C N),
· · ·
1590, 1540, 1412 (C —C, ring str.), 645 (C Cl). δH
(CDCl3): 8.45 (s, 1H, N CH), 7.7 (s, 1H, CH), 7.4 (d,
2H, J = 8.0 Hz, ArH), 7.3 (d, 2H, J = 8.0 Hz, ArH).
δC (CDCl3): 190.4 (C-2), 166.7 (N CH), 163.2 (C-4),
160.1 (C-6), 136.8, 131.4, 129.3, 129.0 (Ar), 112.0 (C-
5). Anal. Calcd for C11H6Cl3N3 (286.54): C, 46.11; H,
2.11; N, 14.66. Found C, 46.05; H, 2.20; N, 14.75.
5,7-Dichloro-2-(4-chlorophenyl)-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine-4(3H)-thione 2b
2,6-Dichloro-4-(4-methylbenzylidineamino)-
pyrimidine 1c
νmax(KBr)/cm−1: 3250 (NH), 1650 (C C/C N), 1610,
· · ·
1585, 1489 (C —C, ring str.), 1072 (C S), 1030,
νmax(KBr)/cm−1: 3010 (CH, sp2), 2935 (CH, sp3), 1630
936 (CH, in-plane bending), 852, 768 (CH, out-of-
plane bending), 684 (C Cl). δH (CDCl3): 10.51 (br s,
1H, NH), 7.0 (d, 2H, J = 8.0 Hz, ArH), 7.4 (d, 2H,
J = 8.0 Hz, ArH), 4.24 (s, 1H, H-2), 3.18 (s, 1H, H-
4a). δC (CDCl3): 198.6 (C-4), 165.0 (C-5), 164.0 (C-7),
160.0 (C-8a), 140.5, 131.8, 128.9, 128.5 (Ar), 72.4 (C-
2), 52.8 (C-4a). Anal. Calcd for C12H7Cl3N4S (345.65):
C, 41.70; H, 2.04; N, 16.21. Found C, 41.62; H, 2.10;
N, 16.26.
· · ·
(C C/C N), 1574, 1540, 1440 (C —C, ring str.), 640
(C Cl). δH (CDCl3): 8.51 (s, 1H, N CH), 7.6 (s,
1H, CH), 7.5 (d, 2H, J = 8.0 Hz, ArH), 7.3 (d, 2H,
J = 8.0 Hz, ArH), 2.46 (s, 3H, CH3). δC (CDCl3): 188.2
(C-2), 164.3 (N CH), 162.9 (C-4), 159.7 (C-6), 140.4,
135.6, 128.7, 126.4 (Ar), 118.1 (C-5), 20.4 (Ar CH3).
Anal. Calcd for C12H9Cl3N3 (266.13): C, 54.16; H,
3.41; N, 15.79. Found C, 54.22; H, 3.34; N, 15.69.
Heteroatom Chemistry DOI 10.1002/hc

250 Sharma, Kumar, and Rane
for C13H10Cl2N4S (325.22): C, 48.01; H, 3.10; N, 17.23.
Found C, 48.10; H, 3.19; N, 17.20.
5,7-Dichloro-2-(4-methylphenyl)-2,4a-dihydro-
pyrimido [4,5-d]pyrimidine-4(3H)-thione 2c
νmax(KBr)/cm−1: 3260 (NH), 2869 (CH, sp3), 1655
(C C/C N), 1590, 1512, 1460 (C —C, ring str.), 1084
· · ·
5,7-Dichloro-3-methyl-2-(4-chlorophenyl)-2,4a-
dihydropyrimido[4,5-d]pyrimidine-4(3H)-thione
3b
(C S), 1034, 921 (CH, in-plane bending), 841, 745
(CH, out-of-plane bending), 645 (C Cl). δH (CDCl3):
9.85 (br s, 1H, NH), 7.20 (d, 2H, J = 8.0 Hz, ArH),
7.36 (d, 2H, J = 8.0 Hz, ArH), 4.43 (s, 1H, H-2), 3.65
(s, 1H, H-4a), 2.34 (s, 3H, CH3). δC (CDCl3): 199.4
(C-4), 162.0 (C-5), 161.0 (C-7), 160.0 (C-8a), 139.7,
135.4, 129.1, 127.2 (Ar), 70.9 (C-2), 51.2 (C-4a), 23.6
(Ar CH3). Anal. Calcd for C13H10Cl2N4S (325.22): C,
48.01; H, 3.10; N, 17.23. Found C, 48.09; H, 3.16; N,
17.16.
νmax(KBr)/cm−1: 2970 (CH, sp3), 1630 (C C/C N),
· · ·
1590, 1524, 1404 (C —C, ring str.), 1060 (C S), 950
(CH, in-plane bending), 854, 761 (CH, out-of-plane
bending), 680 (C Cl). δH (CDCl3): 7.10–7.54 (m, 4H,
ArH), 4.72 (s, 1H, H-2), 3.21 (s, 1H, H-4a), 3.10 (s, 3H,
N CH3). δC (CDCl3): 196.0 (C-4), 162.0 (C-5), 160.0
(C-7), 158.0 (C-8a), 140.2, 135.1, 129.6, 126.4 (Ar),
70.6 (C-2), 52.7 (C-4a), 35.4 (N CH3). Anal. Calcd
for C13H9Cl3N4S (359.66): C, 43.41; H, 2.52; N, 15.58.
Found C, 43.48; H, 2.44; N, 15.50.
5,7-Dichloro-2-(4-nitrophenyl)-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine-4(3H)-thione 2d
νmax(KBr)/cm−1: 3310 (NH), 1636 (C C/C N), 1619,
1547, 1475 (C —C, ring str.), 1361 (NO2), 1050 (C S),
5,7-Dichloro-3-methyl-2-(4-nitrophenyl)-2,4a-
dihydropyrimido[4,5-d]pyrimidine-4(3H)-thione
3c
· · ·
1012, 920 (CH, in-plane bending), 864, 741 (CH, out-
of-plane bending), 680 (C Cl). δH (CDCl3): 10.11 (br
s, 1H, NH), 7.17 (d, 2H, J = 8.0 Hz, ArH), 7.25 (d, 2H,
J = 8.0 Hz, ArH), 4.10 (s, 1H, H-2), 3.56 (s, 1H, H-4a).
δC (CDCl3): 196.0 (C-4), 161.0 (C-5), 160.0 (C-7), 155.0
(C-8a), 148.5, 146.4, 128.0, 123.4 (Ar), 71.9 (C-2), 50.5
(C-4a). Anal. Calcd for C12H7Cl2N5O2S (356.17): C,
40.46; H, 1.98; N, 19.66. Found C, 40.54; H, 2.06; N,
19.60.
νmax(KBr)/cm−1: 2880 (CH, sp3), 1641 (C C/C N),
· · ·
1540, 1467, 1420 (C —C, ring str.), 1340 (NO2), 1065
(C S), 974 (CH, in-plane bending), 862, 755 (CH,
out-of-plane bending), 670 (C Cl). δH (CDCl3): 6.98–
7.36 (m, 4H, ArH), 4.52 (s, 1H, H-2), 3.42 (s, 1H,
H-4a), 3.24 (s, 3H, N CH3). δC (CDCl3): 198.1 (C-4),
165.0 (C-5), 161.0 (C-7), 159.0 (C-8a), 131.2, 130.0,
126.4, 124.5 (Ar), 71.2 (C-2), 51.1 (C-4a), 32.8
(N CH3). Anal. Calcd for C14H12Cl2N4S (339.24): C,
49.57; H, 3.57; N, 16.52. Found C, 49.51; H, 3.63; N,
16.41.
5,7-Dichloro-3-alkyl-2-aryl-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine-4(3H)-thione 3
To a solution of 5,7-dichloro-2-aryl-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine-4(3H)-thione 2 (5 mmol)
in minimum quantity of pyridine (20 mL) at 0˚C,
alkyl chloride (10 mmol) was added dropwise with
constant stirring. The reaction mixture was fur-
ther stirred for 0.5–1.5 h and poured into ice-cold
acidified water. The solid was collected by filtra-
tion, washed repeatedly with water and recrystal-
lized from EtOH.
5,7-Dichloro-3-ethyl-2-phenyl-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine-4(3H)-thione 3d
νmax(KBr)/cm−1: 2970 (CH, sp3), 1630 (C C/C N),
· · ·
1590, 1524, 1435 (CH2/C —C, ring str.), 1052 (C S),
997 (CH, in-plane bending), 821, 758 (CH, out-of-
plane bending), 640 (C Cl). δH (CDCl3): 7.12–7.51
(m, 5H, Ph), 4.89 (s, 1H, H-2), 4.12 (q, 2H, J = 6.0 Hz,
CH2), 3.26 (s, 1H, H-4a), 1.17 (t, 3H, J = 8.0 Hz, CH3).
δC (CDCl3): 210.0 (C-4), 169.0 (C-5), 166.0 (C-7), 160.0
(C-8a), 141.3, 139.4, 127.1, 125.0 (Ph), 74.2 (C-2),
50.9 (C-4a), 40.3 (CH2), 13.5 (CH3). Anal. Calcd for
C14H12Cl2N4S (339.24): C, 49.57; H, 3.57; N, 16.52.
Found C, 49.63; H, 3.50; N, 16.40.
5,7-Dichloro-3-methyl-2-phenyl-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine-4(3H)-thione 3a
νmax(KBr)/cm−1: 2980 (CH, sp3), 1620 (C C/C N),
· · ·
1589, 1500, 1474 (C —C, ring str.), 1087 (C S), 956
(CH, in-plane bending), 862, 740 (CH, out-of-plane
bending), 675 (C Cl). δH (CDCl3): 7.3 (s, 5H, Ph),
4.78 (s, 1H, H-2), 3.69 (s, 1H, H-4a), 3.12 (s, 3H,
N CH3). δC (CDCl3): 197.1 (C-4), 164.0 (C-5), 163.0
(C-7), 160.0 (C-8a), 137.2, 128.3, 128.0, 126.8 (Ph),
70.1 (C-2), 50.2 (C-4a), 32.6 (N CH3). Anal. Calcd
5,7-Dichloro-3-ethyl-2-(4-chlorophenyl)-2,4a-di-
hydropyrimido[4,5-d]pyrimidine-4(3H)-thione
3e
νmax(KBr)/cm−1: 2984 (CH, sp3), 1640 (C C/C N),
· · ·
1584, 1512, 1465 (CH2/C —C, ring str.), 1050 (C S),
Heteroatom Chemistry DOI 10.1002/hc

Expedient Synthesis of Novel, Fused Pyrimido[4,5-d ]pyrimidine and Pyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine 251
945 (CH, in-plane bending), 828, 764 (CH, out-of-
5,7-Dichloro-4-hydrazino-2-(4-chlorophenyl)-
plane bending), 645 (C Cl). δH (CDCl3): 7.14–7.49 (m,
4H, ArH), 4.84 (s, 1H, H-2), 4.15 (q, 2H, J = 6.0 Hz,
CH2), 3.32 (s, 1H, H-4a), 1.10 (t, 3H, J = 8.0 Hz, CH3).
δC (CDCl3): 197.9 (C-4), 168.0 (C-5), 163.0 (C-7), 158.0
(C-8a), 142.7, 140.2, 128.1, 125.2 (Ar), 74.0 (C-2),
50.7 (C-4a), 43.5 (CH2), 15.9 (CH3). Anal. Calcd for
C14H11Cl3N4S (373.69): C, 45.00; H, 2.97; N, 14.99.
Found C, 45.09; H, 2.90; N, 14.93.
2,4a-dihydropyrimido[4,5-d]pyrimidine 4b
νmax(KBr)/cm−1: 3475 (NH2, sym.), 3362 (NH2,
asym.), 3217 (NH), 1623 (C C/C N), 1561, 1510,
· · ·
1412 (C —C, ring str.), 1017, 939 (CH, in-plane
bending), 854, 762 (CH, out-of-plane bending), 662
(C Cl). δH (CDCl3): 9.24 (br s, 1H, NH), 7.18–7.33 (m,
4H, ArH), 6.27 (s, 2H, NH2), 4.69 (s, 1H, H-2), 3.11 (s,
1H, H-4a). δC (CDCl3): 164.0 (C-7), 163.0 (C-4), 160.0
(C-5), 159.0 (C-8a), 139.8, 130.8, 130.6, 128.7 (Ar),
73.4 (C-2), 32.1 (C-4a). Anal. Calcd for C12H9Cl3N6
(343.60): C, 41.95; H, 2.64; N, 24.46. Found C, 42.11;
H, 2.57; N, 24.53.
5,7-Dichloro-3-ethyl-2-(4-nitrophenyl)-2,4a-di-
hydropyrimido[4,5-d]pyrimidine-4(3H)-thione
3f
νmax(KBr)/cm−1: 2880 (CH, sp3), 1620 (C C/C N),
1570, 1517, 1440 (CH2/C —C, ring str.), 1340 (NO2),
5,7-Dichloro-4-hydrazino-2-(4-methylphenyl)-
2,4a-dihydropyrimido[4,5-d]pyrimidine 4c
· · ·
1045 (C S), 936 (CH, in-plane bending), 835, 758
(CH, out-of-plane bending), 640 (C Cl). δH (CDCl3):
7.15–7.56 (m, 4H, ArH), 4.78 (s, 1H, H-2), 4.21 (q,
2H, J = 6.0 Hz, CH2), 3.31 (s, 1H, H-4a), 1.22 (s,
3H, J = 8.0 Hz, CH3). δC (CDCl3): 199.1 (C-4), 167.0
(C-5), 162.0 (C-7), 158.0 (C-8a), 139.1, 128.4, 127.2,
126.3 (Ar), 75.0 (C-2), 53.4 (C-4a), 41.5 (CH2), 13.2
(CH3). Anal. Calcd for C15H14Cl2N4S (353.27): C,
51.00; H, 3.99; N, 15.86. Found C, 49.94; H, 4.11; N,
15.75.
νmax(KBr)/cm−1: 3450 (NH2, sym.), 3374 (NH2,
asym.), 3221 (NH), 2865 (CH, sp3), 1612 (C C/C N),
· · ·
1586, 1534, 1410 (C —C, ring str.), 1021, 926 (CH, in-
plane bending), 832, 750 (CH, out-of-plane bending),
674 (C Cl). δH (CDCl3): 9.15 (br s, 1H, NH), 7.10–7.42
(m, 4H, ArH), 6.75 (s, 2H, NH2), 4.59 (s, 1H, H-2),
3.24 (s, 1H, H-4a), 2.48 (s, 3H, J = 8.0 Hz, CH3). δC
(CDCl3): 167.0 (C-7), 163.0 (C-4), 161.0 (C-5), 160.0
(C-8a), 134.7, 132.1, 129.8, 127.5 (Ar), 72.4 (C-2), 30.4
(C-4a), 20.2 (Ar CH3). Anal. Calcd for C13H12Cl2N6
(323.18): C, 48.31; H, 3.74; N, 26.00. Found C, 48.39;
H, 3.63; N, 26.07.
5,7-Dichloro-4-hydrazino-2-aryl-2,4a-dihydro-
pyrimido[4,5-d]pyrimidine 4
A mixture of 5,7-dichloro-2-aryl-2,4a-dihydropyri-
mido[4,5-d]pyrimidine-4(3H)-thione 2 (20 mmol)
and 80% hydrazine hydrate (10 mL) was heated un-
der reflux for 10 min. After cooling, the precipitated
crystals were collected from filtration under vacuum,
washed with water, dried, and recrystallized from
EtOH to yield corresponding hydrazino derivatives
4a–d.
5,7-Dichloro-4-hydrazino-2-(4-nitrophenyl)-2,4a-
dihydropyrimido[4,5-d]pyrimidine 4d
νmax(KBr)/cm−1: 3446 (NH2, sym.), 3381 (NH2,
asym.), 3246 (NH), 1619 (C C/C N), 1576, 1507,
· · ·
1431 (C —C, ring str.), 1365 (NO2), 1020, 940 (CH,
in-plane bending), 848, 747 (CH, out-of-plane bend-
ing), 691 (C Cl). δH (CDCl3): 9.28 (br s, 1H, NH),
7.11–7.39 (m, 4H, ArH), 6.12 (s, 2H, NH2), 4.55 (s, 1H,
H-2), 3.43 (s, 1H, H-4a). δC (CDCl3): 167.0 (C-7), 165.0
(C-4), 162.0 (C-5), 160.0 (C-8a), 145.4, 142.6, 130.1,
123.4 (Ar), 71.2 (C-2), 31.8 (C-4a). Anal. Calcd for
C12H9Cl2N7O2 (354.15): C, 40.70; H, 2.56; N, 27.69.
Found C, 40.67; H, 2.49; N, 27.78.
5,7-Dichloro-4-hydrazino-2-phenyl-2,4a-dihy-
dropyrimido[4,5-d]pyrimidine 4a
νmax(KBr)/cm−1: 3425 (NH2, sym.), 3340 (NH2,
asym.), 3210 (NH), 1617 (C C/C N), 1558, 1514,
· · ·
1475 (C —C, ring str.), 1012, 920 (CH, in-plane
5,7-Dichloro-4-benzylidenehydrazino-2-aryl-2,4a-
dihydropyrimido[4,5-d]pyrimidine 5
bending), 864, 741 (CH, out-of-plane bending), 680
(C Cl). δH (CDCl3): 9.11 (br s, 1H, NH), 7.11–7.48 (m,
5H, Ph), 6.22 (s, 2H, NH2), 4.62 (s, 1H, H-2), 3.19 (s,
1H, H-4a). δC (CDCl3): 166.0 (C-7), 164.0 (C-4), 163.0
(C-5), 160.0 (C-8a), 137.7, 129.2, 128.4, 125.5 (Ph),
71.1 (C-2), 30.3 (C-4a). Anal. Calcd for C12H10Cl2N6
(309.15): C, 46.62; H, 3.26; N, 27.18. Found C, 46.52;
H, 3.20; N, 27.27.
A mixture of 5,7-dichloro-4-hydrazino-2-aryl-2,4a-
dihydropyrimido[4,5-d]pyrimidine 4 (20 mmol) and
benzaldehyde (3.18 mL, 30 mmol) in glacial AcOH
(30 mL), stirred at room temperature for 4–5 h. After
completion of the reaction, the precipitated solid was
collected by suction filtration, washed with EtOH
Heteroatom Chemistry DOI 10.1002/hc

252 Sharma, Kumar, and Rane
and recrystallized from DMF to give the correspond-
ing hydrazones 5a–d.
(C Cl). δH (CDCl3): 10.24 (br s, 1H, NH), 8.39 (s, 1H,
N CH), 7.19–7.61 (m, 9H, Ph/Ar), 4.89 (s, 1H, H-2),
3.22 (s, 1H, H-4a). δC (CDCl3): 170.0 (C-7), 166.0 (C-
4), 162.0 (C-5), 160.0 (C-8a), 152.7 (N CH), 145.8,
140.2, 131.8, 130.0, 129.4, 128.6, 126.1, 125.8 (Ph/Ar),
71.5 (C-2), 30.4 (C-4a). Anal. Calcd for C19H13Cl2N7O2
(442.26): C, 51.60; H, 2.96; N, 22.17. Found C, 51.55;
H, 3.03; N, 22.12.
5,7-Dichloro-4-benzylidenehydrazino-2-phenyl-
2,4a-dihydropyrimido[4,5-d]pyrimidine 5a
νmax(KBr)/cm−1: 3420 (NH), 3010 (CH, sp2), 1623
· · ·
(C C/C N), 1582, 1523, 1452 (C —C, ring str.), 691
(C Cl). δH (CDCl3): 10.45 (br s, 1H, NH), 8.45 (s,
1H, N CH), 7.10–7.62 (m, 10H, 2 × Ph), 4.82 (s, 1H,
H-2), 3.10 (s, 1H, H-4a). δC (CDCl3): 170.0 (C-7),
168.0 (C-4), 164.0 (C-5), 160.0 (C-8a), 154.7 (N CH),
137.2, 131.5, 130.8, 129.2, 129.0, 128.6, 128.4, 125.5
(2 × Ph), 71.5 (C-2), 30.8 (C-4a). Anal. Calcd for
C19H14Cl2N6 (397.26): C, 57.44; H, 3.55; N, 21.16.
Found C, 57.50; H, 3.45; N, 21.23.
8,10-Dichloro-3-phenyl-5-aryl-5,10a-dihydro-
pyrimido-[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine
6
A mixture of 5,7-dichloro-4-benzylidenehydrazino-
2-aryl-2,4a-dihydropyrimido[4,5-d]pyrimidine 5 (20
mmol) with lead tetraacetate (30 mmol) in 1,4-
dioxane was heated under reflux and stirring for 4–6
h (to the disappearance of starting material). After
the completion of reaction, the residue was removed
by filtration and the filtrate was concentrated under
reduced pressure to leave solid, which was washed
with EtOH and recrystallized from DMF to give the
corresponding triazolopyrimidines.
5,7-Dichloro-4-benzylidenehydrazino-2-(4-
chlorophenyl)-2,4a-dihydropyrimido[4,5-d]-
pyrimidine 5b
νmax(KBr)/cm−1: 3410 (NH), 3025 (CH, sp2), 1618
· · ·
(C C/C N), 1589, 1534, 1465 (C —C, ring str.), 684
(C Cl). δH (CDCl3): 10.32 (br s, 1H, NH), 8.23 (s, 1H,
N CH), 7.11–7.58 (m, 9H, Ph/Ar), 5.21 (s, 1H, H-2),
3.28 (s, 1H, H-4a). δC (CDCl3): 172.0 (C-7), 168.0
(C-4), 165.0 (C-5), 161.0 (C-8a), 152.1 (N CH), 140.2,
136.7, 132.8, 130.6, 128.8, 128.1, 125.4, 121.3 (Ph/Ar),
70.7 (C-2), 30.2 (C-4a). Anal. Calcd for C19H13Cl3N6
(431.71): C, 52.86; H, 3.04; N, 19.47. Found C, 52.79;
H, 3.12; N, 19.40.
8,10-Dichloro-3,5-diphenyl-5,10a-dihydro-
pyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine
6a
νmax(KBr)/cm−1: 1632 (C C/C N), 1584, 1535, 1400
· · ·
(C —C, ring str.), 1015 (CH, in-plane bending),
852 (out-of-plane bending), 662 (C Cl). δH (CDCl3):
6.98 7.56 (m, 10H, 2 × Ph), 4.62 (s, 1H, H-5), 3.11
(s, 1H, H-10a). δC (CDCl3): 165.0 (C-8), 163.0 (C-10),
162.0 (C-10b), 160.0 (C-6a), 151.0 (C-3), 137.6, 136.5,
129.2, 129.0, 128.5, 128.4, 127.0, 125.4 (2 × Ph),
71.4 (C-5), 33.1 (C-10a). Anal. Calcd for C19H12Cl2N6
(395.24): C, 57.74; H, 3.06; N, 21.26. Found C, 57.68;
H, 3.00; N, 21.38.
5,7-Dichloro-4-benzylidenehydrazino-2-(4-
methylphenyl)-2,4a-dihydropyrimido[4,5-
d]pyrimidine 5c
νmax(KBr)/cm−1: 3425 (NH), 3040 (CH, sp2), 2864
(CH, sp3), 1640 (C C/C N), 1581, 1500, 1460
· · ·
(C —C, ring str.), 680 (C Cl). δH (CDCl3): 10.62
(br s, 1H, NH), 8.26 (s, 1H, N CH), 7.14–7.63
(m, 9H, Ph/Ar), 5.17 (s, 1H, H-2), 3.49 (s, 1H,
H-4a), 2.45 (s, 3H, CH3). δC (CDCl3): 169.0 (C-
7), 164.0 (C-4), 162.0 (C-5), 160.0 (C-8a), 154.0
(N CH), 138.8, 137.5, 129.1, 129.0, 127.6, 127.2,
124.1, 124.0 (Ph/Ar), 72.4 (C-2), 32.6 (C-4a), 20.2
(Ar CH3). Anal. Calcd for C20H16Cl2N6 (411.29): C,
58.41; H, 3.92; N, 20.43. Found C, 58.35; H, 4.01; N,
20.37.
8,10-Dichloro-3-phenyl-5-(4-chlorophenyl)-5,10-
a-dihydropyrimido[5,4-e][1,2,4]triazolo[4,3-
c]pyrimidine 6b
νmax(KBr)/cm−1: 1622 (C C/C N), 1600, 1567, 1423
· · ·
(C —C, ring str.), 1021 (CH, in-plane bending), 850
(out-of-plane bending), 665 (C Cl). δH (CDCl3): 7.18–
7.62 (m, 9H, Ph/Ar), 4.98 (s, 1H, H-5), 3.26 (s, 1H,
H-10a). δC (CDCl3): 169.0 (C-8), 167.0 (C-10), 164.0
(C-10b), 161.0 (C-6a), 154.2 (C-3), 138.9, 134.2, 128.6,
128.5, 126.0, 125.2, 124.0, 122.1 (Ph/Ar), 74.2 (C-5),
32.0 (C-10a). Anal. Calcd for C19H11Cl3N6 (429.69): C,
53.11; H, 2.58; N, 19.56. Found C, 53.23; H, 2.51; N,
19.61.
5,7-Dichloro-4-benzylidenehydrazino-2-(4-nitro-
phenyl)-2,4a-dihydropyrimido[4,5-d]pyrimidine
5d
νmax(KBr)/cm−1: 3484 (NH), 3050 (CH, sp2), 1621
· · ·
(C C/C N), 1591, 1514, 1434 (C —C, ring str.), 681
Heteroatom Chemistry DOI 10.1002/hc

Expedient Synthesis of Novel, Fused Pyrimido[4,5-d ]pyrimidine and Pyrimido[5,4-e][1,2,4]triazolo[4,3-c]pyrimidine 253
[2] Brown, J. D. In Comprehensive Heterocyclic
8,10-Dichloro-3-phenyl-5-(4-methylphenyl)-5,
10a-dihydropyrimido[5,4-e][1,2,4]triazolo[4,3-
c]pyrimidine 6c
Chemistry; Katritzky, A. R.; Rees, C. W. (Eds.);
Pergamon: Oxford, 1984; Vol. 3.
[3] Curtin, N. J.; Barlow, H. C.; Bowman, K. J.;
Calvert, A. H.; Richard Davison, R.; Golding, B. T.;
Huang, B.; Loughlin, P. J.; Newell, D. R.; Smith,
νmax(KBr)/cm−1: 2960 (CH, sp3), 1643 (C C/C N),
· · ·
1589, 1475, 1412 (C —C, ring str.), 1024 (CH, in-plane
P. G.; Griffin, R. J.
4905.
J Med Chem 2004, 47,
bending), 845 (out-of-plane bending), 665 (C Cl). δH
(CDCl3): 7.05–7.60 (m, 9H, Ph/Ar), 4.75 (s, 1H, H-
5), 3.35 (s, 1H, H-10a), 2.47 (s, 3H, CH3). δC (CDCl3):
166.0 (C-8), 163.0 (C-10), 162.0 (C-10b), 161.0 (C-6a),
152.0 (C-3), 134.7, 130.2, 128.7, 128.5, 126.6, 125.4,
124.9, 124.2 (Ph/Ar), 71.2 (C-5), 30.4 (C-10a), 24.3
(Ar CH3). Anal. Calcd for C20H14Cl2N6 (409.27): C,
58.69; H, 3.45; N, 20.53. Found C, 58.79; H, 3.36; N,
20.60.
[4] De la Cruz, J. P.; Carrasco, T.; Ortega, G.; Sanchez, De
la Cuesta, F. Lipid 1992, 27, 192.
[5] Sanghvi, Y. S.; Larson, S. B.; Matsumoto, S. S.;
Nord, L. D.; Smee, D. F.; Willis, R. C.; Avery, T. H.;
Robins, R. K.; Revankar, G. R. J Med Chem 1989, 32,
629.
[6] Ram, V. J.; Goel, A.; Sarkhel, S.; Maulik, P. R. Bioorg
Med Chem 2002, 10, 1275.
[7] Rewcastle, G. W.; Bridges, A. J.; Fry, D. W.;
Rubin, J. R.; Denny, W. A. J Med Chem 1997, 40,
1820.
[8] Fry, D. W.; Becker, M. A.; Switzer, R. L. Mol Pharmacol
1995, 47, 810.
[9] Kurzmeier, H.; Schmidtehen, F. P. J Org Chem 1990,
55, 3749.
[10] Kosasayama, A.; Ishikawa, F. Chem Pharm Bull 1979,
72, 1596.
[11] Baraldi, P. G.; Cacciari, B.; Borea, P. A.; Varani, K.;
Pastorin, G.; Da Ros, T.; Tabrizi, M. A.; Fruttarolo,
F.; Spalluto, G. Curr Pharm Des 2002, 8,
2299.
8,10-Dichloro-3-phenyl-5-(4-nitrophenyl)-5,10a-
dihydropyrimido[5,4-e][1,2,4]triazolo[4,3-c]-
pyrimidine 6d
νmax(KBr)/cm−1: 1622 (C C/C N), 1575, 1460, 1410
· · ·
(C —C, ring str.), 1019 (CH, in-plane bending), 832
(out-of-plane bending), 670 (C Cl). δH (CDCl3): 7.00–
7.52 (m, 9H, Ph/Ar), 4.84 (s, 1H, H-5), 3.26 (s, 1H,
H-10a). δC (CDCl3): 167.0 (C-8), 165.0 (C-10), 163.0
(C-10b), 162.0 (C-6a), 154.7 (C-3), 142.6, 139.2, 130.1,
129.7, 128.4, 128.0, 126.5, 125.9 (Ph/Ar), 75.4 (C-5),
32.6 (C-10a). Anal. Calcd for C19H11Cl2N7O2 (440.24):
C, 51.84; H, 2.52; N, 22.27. Found C, 51.79; H, 2.61;
N, 22.35.
[12] Sharma, P.; Kumar, A.; Rane, N.; Gurram, V. K.
Tetrahedron 2005, 61, 4237.
[13] Sharma, P.; Rane, N.; Gurram, V. K. Bioorg Med
Chem Lett 2004, 14, 4185.
[14] Sharma, P.; Kumar, A.; Sharma, S.; Rane, N. Bioorg
Med Chem Lett 2005, 15, 937.
[15] Sharma, P.; Sharma, S.; Rane, N. Bioorg Med Chem
2004, 12, 3135.
[16] Sharma, P.; Kumar, A.; Mandloi, A. Synth Comm
2003, 33, 373.
[17] (a) Hirota, K.; Kitade, Y.; Sajiki, M.; Maki, Y. Synthe-
sis 1984, 589. (b) Hirota, K.; Kitade, Y.; Sajiki, H.;
Maki, Y. J Chem Soc, Perkin Trans 1, 1990, 1,
123.
ACKNOWLEDGMENTS
We are thankful to Director, Indian Institute of Tech-
nology, Chennai and Central Drug Research Insti-
tute, Lucknow for providing the spectroanalytical
facilities.
[18] Srivastava, S. W.; Haq, W.; Chauhan, P. M. S. Bioorg
Med Chem Lett 1999, 9, 965.
[19] Furniss, B. S.; Hannaford, A. J.; Smith, P. W.
G.; Tatchell, A. R. Vogel’s Text Book of Practi-
cal Organic Chemistry, 5th ed.; Addison Wesley,
Longman: England, 1989.
REFERENCES
[1] Lunt, E. In Comprehensive Organic Chemistry;
Barton, D.; Ollis, W. D. (Eds.); Pergamon: Oxford,
1979; Vol. 4.
Heteroatom Chemistry DOI 10.1002/hc