Design, two-directional synthesis, DFT study of new pyrimido[5,4-d]pyrimidine-2,8-dione derivatives

Article abstract of DOI:10.1016/j.tet.2018.12.057

A facile two-directional synthesis of new pyrimido[5,4-d]pyrimidine-2,8-dione was reported via an efficient reaction of premade bis-aldehydes and 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea in the presence of triethylamine as the base and Cu (II) as catalys

Full text of DOI:10.1016/j.tet.2018.12.057

Accepted Manuscript
Design, two-directional synthesis, DFT study of new pyrimido[5,4-d]pyrimidine-2,8-
dione derivatives
Ammar Sheykhi-Estalkhjani, Nosrat O. Mahmoodi, Asieh Yahyazadeh, Meysam
Pasandideh Nadamani, Hossein Taherpour Nahzomi
PII:
S0040-4020(18)31547-3
https://doi.org/10.1016/j.tet.2018.12.057
TET 30043
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 November 2018
Revised Date: 24 December 2018
Accepted Date: 26 December 2018
Please cite this article as: Sheykhi-Estalkhjani A, Mahmoodi NO, Yahyazadeh A, Nadamani MP,
Nahzomi HT, Design, two-directional synthesis, DFT study of new pyrimido[5,4-d]pyrimidine-2,8-dione
derivatives, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2018.12.057.
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Design, two-directional synthesis, DFT study of new
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pyrimido[5,4-d]pyrimidine-2,8-dione derivatives
Ammar Sheykhi-Estalkhjani, Nosrat O. Mahmoodi, Asieh Yahyazadeh, Meysam Pasandideh Nadamani,
Hossein Taherpour Nahzomi
Department of Chemistry, Faculty of Science, University of Guilan, P.O. Box 41335-1914, Rasht, Iran

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Design, two-directional synthesis, DFT study of new pyrimido[5,4-d]pyrimidine-2,8-
dione derivatives
a
a,∗
a,
*
Ammar Sheykhi-Estalkhjani , Nosrat O. Mahmoodi , Asieh Yahyazadeh and Meysam Pasandideh
a
b
Nadamani and Hossein Taherpour Nahzomi
a
Department of Chemistry, Faculty of Science, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran
a
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile two-directional synthesis of new pyrimido[5,4-d]pyrimidine-2,8-dione was reported via
an efficient reaction of premade bis-aldehydes and 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea
in the presence of triethylamine as the base and Cu (II) as catalyst. As there is controversy about
the formation of two types of products, that is, purine or pyrimidine ring containing compounds
in the reaction of diaminomaleonitrile with isocyanates and aldehydes, the computational model
chemistry has been employed to obtain new insight about this reaction and determining the
dominant pathway of the process. Using DFT model, two alternative pathways have been
explored and geometrical isomerization of central double bond has been considered.
Accordingly, the evaluated energy barriers affirm the formation of six-membered pyrimidine
Available online
Keywords:
Pyrimido[5,4-d]pyrimidine
Catalyst
ring as the major product in the presence of CuCl
2
as the catalyst and MeOH as solvent.
DFT study
Pyrimidine
2018 Elsevier Ltd. All rights reserved
.
1
. Introduction
cellular reuptake of adenosine, furthermore, it is currently
prescribed as a medication to prevent excessive blood
clotting and is also used in electrocardiogram and
Heterocycles containing nitrogen atoms in their ring
structure have occupied tremendous importance in the field
of chemistry. The ring systems of pyrimidine welded with
other rings or the derivatives of pyrimidine are found
abundantly in nature, 1 including nucleotide, thiamine
15
echocardiography.
In general, there are two methods for the synthesis of
pyrimidopyrimidines, the first method is the use of multi-
16
component reactions1 and the second method is the use of
(vitamin B ) and alloxan. Pyrimidines, along with purines,
1
7
are organic ingredients that are involved in the nucleotide
cyclization reactions. Several approaches have been reported to
2
,3
structure of DNA and RNA. It is well known that
pyrimidine and fused heterocyclic pyrimidine derivatives
play an essential role in the field of drugs and medicinal
chemistry, especially as antitumor, antiviral, antioxidant,
antimicrobial, anti-HIV and antifungal agents.
generate this drug like scaffolds by the use of multi-component
reactions (MCRs), but so far insignificant research has been done
on cyclization reactions and its products. In one of these few
studies, pyrimido[5,4-d]Pyrimidine-2,8-dione was synthesized
4
,5
6
7
18
8
9,10
11
for the first time by Ohtsuka in 1978, via condensation of
diaminomaleonitrile (DAMN) with phenyl isocyanate and
subsequently, interactions with various aldehydes in the presence
of triethylamine (TEA) as a base (Scheme 1, Path A). In 2001,
Booth et al. in a reinvestigation announced that the products of
these reactions are not pyrimidino[5,4-d]pyrimidines as
Pyrimidopyrimidines such as pyrimido[5,4- ]pyrimidines
d
due to their structural similarity to Purines, a lot of attention
has been paid to their various pharmacological andbiological
activities like their antitumor, antiviral, antiallergic,
vasodilatory and diuretic effects,
promising structural units in the field of medicinal
chemistry. For example, dipyridamole (DP), a 2,4,6,8-
1
2–15
and have been raised as
previously
reported,
but
8-oxo-6-carboxamido-1,2-
dihydropurines are produced as intermediate of these reactions
which rapidly are oxidized to the corresponding 6-
tetrasubstituted
pyrimido[5,4-
d
]pyrimidine,
shows
19
carboxamidopurines in air (Scheme 1, Path B).
This
antithrombotic and cardiovascular activity. Dipyridamole
functions as an indirect purinergic agonist by inhibiting the
—
contradiction attracted our attention, so we focused on this issue
and carry out research in this field.
——
∗
Corresponding authors. E-mail addresses: mahmoodi@guilan.ac.ir (N. O. Mahmoodi), Tel: +981333320912; yahyazadeh@guilan.ac.ir (A.
Yahyazadeh)

2
Tetrahedron
ACCEPTED MAIn
NU
c
on
S
si
C
de
R
rat
I
i
P
on of these characteristics and in continuation
T
20–22
to our previous synthesis of heterocyclic compounds
2
3–26
with dimeric, trimeric and tetrameric linkers,
the first time we investigated a two-directional synthesis
between phenylurea ( ) and premade bis-aldehydes (10a
0g) in the presence of TEA and Cu (II) as catalyst. A
comprehensive investigation of the spectroscopic data
here for
2
-
1
1
13
including FT-IR, H NMR, C NMR, HRMS spectrometer
and elemental analysis, indicated that the obtained products
are
pyrimido[5,4-
d]pyrimidine-2,8-dione
(11a-11g)
(Scheme 2).
2
. Results and discussion
.1. Synthesis and Spectral studies
In the first step of our approach, bis-aldehydes (10a-10g) were
2
synthesized through an S 2 reaction of 2 equiv. hydroxy
N
aldehyde with 1 equiv. dihaloalkane in DMF using K CO as
2
3
catalyst, as shown in Scheme 2. Then, DAMN was condensed
with phenyl isocyanate to give the 1-(2-amino-1,2-dicyanovinyl)-
3
-phenylurea (2) in excellent yields as expected (Scheme 2).
Subsequently, in order to optimize the reaction conditions, we
carried out the reaction of bis-aldehyde (10g) and 1-(2-amino-
1
,2-dicyanovinyl)-3-phenylurea (2) in the presence of TEA
0.1mL) as a model reaction and studied the reaction in different
solvents including MeOH, EtOH, CH CN, DMF and CH Cl .
(
3
2
2
The results are summarized in Table 1. At the onset, we explored
preparation of (11g) in EtOH at room temperature (entry 1),
which after 1h afforded the desired product in 45 % yield. In the
presence of MeOH as solvent, the yield of (11g) increased to 63
%
(entry 2). The reaction efficiency in CH CN was 55 % (entry
3
3
). When the solvent was replaced by DMF or CH Cl the
2 2
reaction yields decreased to 54% and 30%, respectively (Table 1,
entries 4 and 5). Then, the scope of the reaction was investigated
under reflux conditions. In general, as shown in Table 1, the
results showed that the reaction efficiency in the MeOH as
solvent is higher at both reflux and room temperature than the
other solvents. But in the absence of the TEA, the corresponding
product was not produced. In continuance, in order to further
improve the efficiency of the reaction, the effects of different
Lewis acids were investigated. To reach this goal, different Lewis
acids (5 mol%) were added to the phenylurea (2) precursor
solution to be more active, and then the solution containing the
active phenylurea precursor was added to the solution containing
the bis-aldehyde (10g) and TEA. As shown in Table 1, Addition
of Lewis acids improved the yields (entries 10-18). As a result,
Scheme 1. The possible synthetic routes: path A)
pyrimido[5,4-
d]pyrimidine-2,8-dione (5), path B) 6-
carboxamidopurine (
9
)
CuCl in the presence of TEA as the base in MeOH at room
2
temperature for 30 min was found to be the best reaction
conditions to give (11g) in an 83% yield (Table 1, entry 13).
Table 1 Optimization of two-directional synthesis of bis-
aldehyde (10g) with phenylurea 2 for the synthesis of (11g)
Temp Time
Entry Base Catalyst solvent
Yield%
(°C)
(min)
1
2
3
4
5
6
7
8
9
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
-
-
-
-
-
-
-
-
-
-
EtOH
r.t
r.t
r.t
r.t
r.t
60
60
60
60
60
60
60
60
60
30
30
45
63
55
54
30
60
56
54
-
CH OH
3
CH CN
3
DMF
CH Cl2
2
CH OH reflux
3
CH CN reflux
3
DMF
reflux
r.t
r.t
CH OH
3
Scheme 2. Synthesis of bis-pyrimido[5,4-
,8-diones
d
]pyrimidine-
10
11
TEA
TEA
ZnCl
FeCl
2
CH
CH
3
OH
OH
77
76
2
3
3
r.t

3
1
1
1
1
1
1
1
2
3
4
5
6
7
8
TEA
TEA
TEA
TEA
TEA
TEA
TEA
NiCl2
CuCl2
CoCl2
AlCl3
CuCl2
CuCl2
CuCl2
CH OH
r.t
r.t
r.t
r.t
30
76
3
ACCEPTED MANUSCRIPT
CH OH
30
30
30
30
30
30
83
72
75
81
74
70
3
CH OH
3
1
1f
290-293
292-294
80
83
CH OH
3
CH OH reflux
3
CH CN
r.t
r.t
3
DMF
In order to evaluate the generality of a two-directional
process, different bis-aldehydes (10a-10g) were used in the
1
1g
synthesis of pyrimido[5,4-
d]pyrimidine-2,8-diones (11a-
1
1g) under optimized reaction condition (Table 2). As
shown in Table 2, the expected products were obtained in a
short reaction time (2-30 min) with high yields. Bis-
aldehydes 10a-10g were compared for the effect of the
length of the linkers on yield of formation of pyrimido[5,4-
The main evidence for structure (11) rather than (12
)
1
confirmed by investigation of the H NMR spectroscopic
1
data (Scheme 3 and Fig. 1). The H NMR spectra of
d]pyrimidine-2,8-dione derivatives. With regard to the effect
compounds (11a-11g) were recorded in DMSO-d at 25 °C.
6
1
of entropy, it seems that with the increase in the length of
the chains, yields of product 11a-11g should be reduced.
However, the products studied in this research, do not
follow a specific process. Nevertheless, the lowest yield was
observed for compounds with 5 carbons. It seems that with
decreasing steric strain, from orto to meta and para, yield of
As shown in Fig. 1, the H NMR spectra of (11g) showed
three signals in 11.78, 8.08 and 8.00 ppm due to the NH
protons each with an integration intensity equal to one H-
atom. The singlet at 11.78 ppm (1H) is typical of the NH
proton of the pyrimidin-4(3H)-one ring (Fig. 1, ring 1).
Two other singlet signals at 8.08 and 8.00 ppm are
2
7–29
products have increased (e.g. 11a (para) 90%, 11d (meta
)
corresponding to NH protons of 3,4-dihydropyrimidin-
1
8
9% and 11f (orto) 80%). The results show that p'-alkoxy-
p
,
2(1
H)-one ring (Fig. 1, ring 2). As shown in Fig. 1b, the H
linked products have the highest yield. The structures of
NMR signals due to the NH protons were completely
disappeared by addition of D O, which confirms the
pyrimidopyramidine structure for (11g)
1
prepared compounds were confirmed by FT-IR, H NMR,
2
1
3
CNMR, HRMS spectrometer and elemental analysis. The
.
FT-IR spectra of compounds (11a-11g) revealed the
presence of stretching vibration for NH bands at 3185–3455
-
1
-1
cm . Two different absorption bands in the 1688–1743 cm
region are corresponding to two C=O stretching bands. The
-
1
NH
NH
absorption bands in the 1598–1604 cm region indicate the
presence of C=N stretching bands, and absorption bands in
the 1222–1248 cm region are related to C–O stretching
bands. It should be noted that the absence of the C≡N groups
is consistent with cyclization.
before D O
2
NH
-
1
a
Table 2 The physical properties of target bis-pyrimido[5,4
]pyrimidine-2,8-dione (11a-11g
-
d
)
after D O
2
Entry
Product
mp (°C) Yield%
b
1
1a
1b
234-237
216-218
90
83
85
1
Fig. 1. H NMR spectra of compound 11g in DMSO-d6 a)
before and b) after D O exchange
2
On the other hand, the absence of an NH signal
absorption in the FT-IR and H NMR indicates the reaction
doesn’t proceed from scheme 3, pathB. The protons on the
aromatic rings and aliphatic linkages (CH ) were observed
within the expected ppm regions and exhibited the
anticipated integral values. These spectra data confirms that
the structure of the existing compounds is pyrimido[5,4-
]pyrimidine-2,8-dione (11a
not 6-carboxamidopurine (12).
2
1
1
2
1
1c
225-227
>300
d
-11g) scheme 3, path Aand is
1
1d
89
82
1
1e
2
50-253

4
Tetrahedron
ACCEPTED MAN
T
U
he
relative energies and energy barriers are collected in Table
. The DAMN has two CN groups with cis configuration,
S
l
C
oc
RI
PTstructures are represented in Fig. 4 and their
ate
d
3
however in the final product the configuration changed to
trans. It seems likely to consider the rotation of C1=C2
double bond in DAMN. The main point that should be
determined is that whether this rotation occurs in the initial
step of the reaction (i.e. before any reaction between DAMN
and aldehyde occurs) or requires an approximate progression
to be performed at further steps via providing the necessary
conditions. TSct1 is the transition state involving the
rotation of C1=C2 double bond in DAMN for cis to trans
isomerization with overcoming an energy barrier of amount
Scheme 3. A two-directional synthetic route to bis-
pyrimido[5,4-
d]pyrimidine-2,8-diones
-
1
46.6 Kcal mol in MeOH. Accordingly, this barrier is high
The bis-pyrimido[5,4-d]pyrimidine-2,8-dione
formation are proceed by nucleophilic addition of Cu-coordinated
-(2-amino-1,2-dicyanovinyl)-3-phenylurea (2)(2 equiv.) to bis-
aldehydes (10) (1 equiv.), and subsequently cyclocondensation of
intermediate (13) lead to intermediate (14), which in turn
rearranges to intermediate (15) via H shift. Then oxidative
cyclization leads to the target compounds (11a-11g) (Scheme 4).
(11a-11g)
enough to inhibit the initial rotation of C1=C2 double bond
in DAMN and this proposal should be discarded. This result
leads to the conclusion that the rotation occurs after
performing some steps in a reaction sequence (Scheme 4).
To obtain more information two pathways will be followed:
one initiated from cis DAMN and the other from trans
DAMN. However, these two pathways share the same
features in common such as the two steps resulting from the
reactions between DAMN with isocyanate and aldehyde
respectively (Scheme 1). Thus, MIN1c, the compound that
produced by the reaction of cis DAMN with isocyanate and
aldehyde, considered as the starting point of the calculations.
There are some noteworthy features in this structure that
need more comments. The H45 atom previously bonded to
O44 as a part of hydroxyl group (O44-H45) is transferred to
the nitrogen atom of TEA but still there is a stabilizing
hydrogen bonding and indicating that this hydroxyl group
doesn’t intact in the presence of TEA. This proton exchange
leads to an increase in the charge density at O44 center and
subsequently makes it a more efficient and stronger
nucleophile. The two Cu(II) cations definitively play a
crucial role in various aspects either from stereochemical or
stereoelectronic points of view (Scheme 4). Each Cu(II)
cation is coordinated to nitrogen of CN group from one side
and with an effective π-interaction of aromatic ring from the
other side. Such chelation significantly reduces the
rotational and vibrational degrees of freedom and yields
conformation therein, interacting atoms such as O44, C3
pair and also N23, C5 pair, place in appropriate positions
and orientations to prepare for further reactions. Remember
that each of these steps would lead to a five-membered ring.
It should be pointed out that in the absence of Cu(II) cations,
such conformation no longer would be available.
Coordination, in turn, enhances the electrophilicity of the
carbon atom of CN groups and is expected to decrease the
energy barrier of the corresponding cyclization. In order to
make the computations more feasible the methoxy group
attached to one of the aromatic rings replaced the other half
of the whole structure. MIN1c evolves to INT2c by passing
1
Scheme 4. Proposed mechanism in presence of CuCl /TEA for
the synthesis of bis-pyrimido[5,4-d]pyrimidine-2,8-diones (11a-
1g)
2
1
2
.2. Computational
Computational
details.
Quantum
mechanical
calculations were carried out by employing the Gaussian 16
30
program. The located geometries of all structures obtained by
31–34
B3LYP model chemistry
in combination with the 6-31+G(d)
basis sets for C, H, O and N atoms, and in the case of Cu atom,
the effective core potential (ECP), LANL2DZ, was used together
with the accompanying basis set to describe the valence electron
density. The solvation effects examined by using the integral
35
equation formalism model (IEFPCM).
2
.2.1. Computational assessment
Potential Energy Surface (PES) of the reaction.
From the experimental data, it is conceivable that the formation
of the substituted pyrimidino[5,4-d]pyrimidine (11) is favored
rather than 1,2-dihydropurine-6-carboxamide (12) as the sole
product of the reaction under study, but as pointed before 1,2-
dihydropurine-6-carboxamide (12) might also be formed in
preferential depending on the different employed reaction
conditions. However, to obtain more information about this type
of reaction the stereochemical aspects e.g. regioselectivity,
formation of six membered versus five membered ring and
electronic effects has been launched. For example, the role of
catalyst, complex formation and pi interaction investigated in a
computational study involving the exploring of the Potential
Energy Surface (PES) of the reaction (Fig. 2 and 3).
-
1
through TS1c by an energy barrier of about 6.7 Kcal mol .
TS1c represents the attack of O44 to C3 to afford a five-
membered ring that after the C8-O44 bond cleavage via
-
1
TS2c by a barrier of 6.6 Kcal mol and then hydrolysis
gives INT3c the precursor of purine ring containing
substance 12 Scheme 3. The next step involves approaching
of N23 toward C5 via TS3c via energy barrier amount to
-
1
1
5.6 Kcal mol to give MIN4c as the product of five-
membered purine ring (Fig. 2). To determine that in which
step the rotation around the C1=C2 double bond might
occur, DAMNc and MIN1c are compared structurally, the
bond length of C1=C2 in DAMNc and MIN1c is 1.37 and
1.38 A° respectively, also the conjugated systems around

5
this bond seems to be similar in two struc
A
tu
C
res
C
a
E
ndPTsh
ED MANUSCRIPT
ow
s
more localized forms. Therefore, considering such little
changes, a significant decrease in energy barrier of rotation
in MIN1c is not expected. On the other hand, MIN1ct, a
structure derived from the reaction of cis DAMN with
isocyanate and aldehyde just before treatment of hydroxyl
group (O44-H45) and TEA, presumably lead to solution of
the problem. The calculated C1=C2 bond length of about
1.43 A° (6 pm longer than that of DAMNc) in combination
with extended conjugated system around C1=C2. Altogether
are pointing to a noticeable decrease in bond order and
double bond character that indeed is confirmed by
calculation. However, the energy barrier for rotation via
-
1
-1
TSct2 is 14.3 Kcal mol , that is, about 32.3 Kcal mol less
than that of TSct1, even less than the calculated energy
barrier for TS3c. This finding indicates that the alternative
pathway initiated after rotation of double bond of MIN1ct
should be seriously considered. Treatment of MIN1ct with
TEA leads to MIN1t in which H45 bonded to the nitrogen
atom of TEA and is interacting with O44 through a
hydrogen bonding type of interaction and leads two cyanide
groups as trans configuration. Following the new reaction
pathway, TS1t is the transition state that converts MIN1t to
INT2t through movement of the O44 and C5 atoms toward
Fig. 3. Reaction profile of trans path
Table 3. Calculated energies obtained at the B3LYP/6-31+G
(d) /LANL2DZ level of theory.
a
Structure
Energy
(
Rel. Energy
(Kcal mol ) (Kcal mol )
Ea
-
1
-1
hartree)
DAMNc
TSct1
DAMNt
MIN1c
TS1c
INT2c
TS2c
INT3c
TS3c
MIN4c
MIN1ct
TSct2
MIN1t
TS1t
INT2t
TS2t
INT3t
TS3t
-373.730259
-373.655946
-373.727003
-1916.731599
-1916.720895
-1916.742380
-1916.731921
-1428.772013
-1428.747070
-1428.771508
-1624.488323
-1624.465466
-1916.732100
-1916.726987
-1916.738549
-1916.735921
-1428.772660
-1428.765289
-1428.789121
0.0
46.6
46.6
-
1
each other by an activation energy of 3.2 Kcal mol , which
is less than half of the value that of TS1c (Fig. 3). After C8-
O44 bond fission via TS2t by activation energy of 1.6 Kcal
2.0
0.0
6.7
6.7
-6.8
-0.2
0.0
15.6
0.3
0.0
14.3
0.0
-
1
mol , followed by hydrolysis INT3t, the precursor of
pyrimidine ring containing substance, is obtained. TS2t
seems likely to be an electrocyclic 6π disrotatory ring
opening transition state. The next transition state that leads
to the formation of a compound involving the pyrimidine
ring, MIN4t (compound 11 Scheme 3 & Fig. 3), is TS3t by
6
.6
1
5.6
-
1
14.3
an energy barrier of 4.6 Kcal mol that displays the addition
of N23 to C3 carbon atom of the CN group activated by
Cu(II) cation. Comparison of the energy barriers of these
two competing pathways A & B and observing that the route
with trans CN groups relative to each other follows a lower
energy pathway leaves us with this conclusion that trans
pathway A is favored over cis pathway B and preferentially
would lead to the formation of 11 (Fig. 2 & 3).
3
1
4
.2
.6
.6
3.2
-4.0
-2.4
0.0
4.6
-10.3
MIN4t
E
a
0
elec+ZPVE
Fig. 2. Reaction profile of cis path

6
Tetrahedron
ACCEPTED MAFi
N
g.
MIN1t obtained with QTAIM analysis of B3LYP/6-
1+G(d)/LANL2DZ electron density functions. Bond critical
U
5.
S
C
C
om
R
p
I
le
P
te
T
molecular graphs (MGs) of the MIN1c and the
3
points: brown circles.
The low size of ρ values and simultaneously the presence of
b
2
TS1t
INT3t
positive values of Laplacian, ∇ , lead to conclusion that the
ρ
covalent characters of these interactions are negligible. By taking
into account the calculated values of |V |/G that are very close to
b
b
one, the presence of entirely electrostatic interactions is logical.
Table 4. The obtained mathematical properties of some selected
BCPs in the MIN1c and MIN1t via QTAIM analysis of the
B3LYP/6-31+G(d)/LANL2DZ calculated wave function of
electron density.
TS3t
MIN4t
Bonded
atoms of
BCPs
2
ρb
∇
Gb
Vb
Hb
|V |/G
b b
ρb
MIN1ct
MIN1ct
MIN1c
Fig. 4. Optimized geometries obtained at B3LYP/6-31+G
d)/LANL2DZ level of theory
Cu40-N4 0.0647 0.4004 0.0963 -0.0925 0.0038 0.9605
Cu40-C12 0.0504 0.2145 0.0532 -0.0528 0.0004 0.9925
Cu41-N6 0.0795 0.5067 0.1288 -0.1309 -0.0021 1.0163
Cu41-C25 0.0535 0.2340 0.0577 -0.0569 0.0008 0.9861
MIN1t
(
2
.2.2. Topology analysis
Cu40-N4 0.0799 0.5207 0.1320 -0.1338 -0.0018 1.0136
Cu40-C26 0.0542 0.2175 0.0555 -0.0566 -0.0011 1.0198
Cu41-N6 0.0772 0.5047 0.1266 -0.1271 -0.0005 1.0039
Cu41-C12 0.0518 0.2237 0.0556 -0.0554 0.0003 0.9964
To confirm the incorporation of phenyl ring and cyanide group in
the coordination sphere of Cu cations in MIN1c and MIN1t, the
topology analysis based on QTAIM method has been carried out
36
employing the Multiwfn program package. The resulted
molecular graphs of MIN1c and MIN1t displaying some Bond
Critical Points (BCPs) and their associated bond paths are
depicted in Fig. 5. From these graphs the chemical interactions
between Cu cations and neighbor cyanide group and also two
carbon atoms of each phenyl ring are qualitatively realized. To
discuss more quantitatively the related parameters of BCPs
collected in Table 4 should be considered.
3. Conclusion
Here, some new bis-pyrimido[5,4-d]pyrimidine-2,8-dione
derivatives 11a-11g were successfully synthesized in good yields
via a simple reaction between bis-aldehydes and phenylurea
precursors in the presence of TEA as the base and CuCl as
2
catalyst. The simplicity, easy execution, simple workup, and
good yields, together with the use of easily accessible starting
materials are characters of this process. Cu(II) cations through
coordination by cyanide groups and also π-interaction with
aromatic rings conveniently incorporate in the reaction and
essentially through reducing the energy barrier of C1=C2
rotation, change the configuration and conformational
distribution favoring MIN1ct form and dominantly afford
compound involving pyrimidine ring.
4
. Experimental section
4
.1. Materials and apparatus
DAMN (1) was purchased from Merck and used without
further purification. Bis-aldehydes (10a-10g) used as a precursor
3
7
were synthesized according to previously reported procedure.
MIN1c
Melting points were measured by electrothermal 9100s apparatus
and were uncorrected. The FT-IR spectra were recorded on a
−1
Bruker Vector 22 in the region of 400–4000 cm in KBr pellets.
1
The structure of all synthesized compounds was confirmed by H
13
and C NMR spectra, recorded on Bruker Avance 400 MHz
spectrometer using DMSO-d as solvent. The CHN analyses were
6
performed on a Vario-ELIII elemental analyzer. High resolution
mass spectra (HRMS) were obtained on a Finnigan MAT 95, EI:
7
0 eV, R:10000.
4
.2. Synthesis of 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea 2
DAMN (1) (1.081 g, 10 mmol) was dissolved in acetonitrile
(
5
10 ml) in an ice bath and the solution was stirred vigorously for
min. Then phenyl isocyanate (1.092 ml, 10 mmol) was added
and the mixture stirred at 0 °C for 10 min. The reaction was
MIN1t

-7
then stirred for a further 24 h at room tempe
phenylurea derivative (2). The product was collected by filtration
A
rat
C
ur
C
e t
E
o
P
g
T
ive
E
t
D
he MAN
Y
U
ie
S
ld
C
: 8
R
5%IP
,
T
mp 225-227 °C; brown; FT-IR (KBr, υ/cm
1
): 3453 (N–H stretch), 3218 (N–H stretch), 3069 (aromatic
and washed with acetonitrile. Yield: 90%, mp 182-185 °C
C–H stretch), 2937 (aliphatic C–H stretch), 2861 (aliphatic
C–H stretch), 1738 (C=O stretch), 1689 (C=O stretch), 1601
38
-1
(
reported 180-210); FT-IR (KBr, υ/cm ): 3452 and 3354 (NH2
stretch), 3262 (N–H stretch), 3017 (aromatic C–H stretch), 2219
C≡N stretch), 1689 (C=O stretch), 1604, 1550, 1512 (C=C
(C=N stretch), 1508 (C=C stretch), 1391 (CH bend), 1248
2
1
(
(C–O stretch), 768 (aromatic C–H out-of-plane bend). H
stretch), 752 (aromatic C–Hout-of-plane bend). Anal. Calcd for
C H N O (%): C, 58.14; H, 3.99; N, 30.82. Found: C, 58.19; H,
NMR (400 MHz, DMSO- 6
1H, NH), 7.99 (s, 1H, NH), 7.85 (d,
d ) δ 11.72 (s, 1H, NH), 8.51 (s,
J
= 8.5 Hz, 2H, Hg),
= 7.7 Hz, 2H, Hb),
= 2.2 Hz, 1H, Hh),
l1
9
5
3
.95; N, 30.87.
7.74 (d,
J
= 7.9 Hz, 2H, H ), 7.62 (t,
J
J
c
7.50 (t,
J
= 7.4 Hz, 1H, H ), 6.98 (d,
a
4
.3. General procedure for a two-directional synthesis of bis-
4
.03 (t,
k
J = 6.5 Hz, 2H, H ), 1.77 (s, 2H, H ), 1.49 (s, 2H,
i
j
pyrimido[5,4-d]pyrimidine-2,8-diones 11a-11g
13
H ). C NMR (100 MHz, DMSO-d6, ppm): δ 166.2, 164.1,
1
1
60.9, 155.2, 153.3, 133.4, 133.2, 132.3, 129.7, 129.4,
28.3, 126.8, 115.4, 114.6, 68.4, 29.1, 25.8. Anal. Calcd.
In a 25 mL round bottom flask, bis-aldehyde (10a-10g) (1
mmol) was dissolved in 5 mL of MeOH and TEA(0.1 mL) were
added, the mixture was stirred at room temperature for 5 min,
then the solution of phenylurea (2) (0.454 g, 2 mmol) in MeOH
For C H N O (%): C, 64.94; H, 4.67; N, 18.03. Found: C,
6
C H N O [M + H] 777.2892, found 777.2899.
42 36 10
6
5.01; H, 4.71; N, 18.08. HRMS-ESI (m/z) calcd. for
+
+
(
5 mL) containing CuCl (5mol %) was added and the mixture
42 37 10
6
2
stirred for 30 min. Thin layer chromatography (TLC) was used to
monitor the progress of the reaction (EtOAc:n-hexane 1:2). After
completion of the reaction, the product was collected by
filtration, washed with MeOH and recrystallized from DMF.
4
.3.4.
6,6'-((butane-1,4-diylbis(oxy))bis(3,1-
phenylene))bis(4-imino-3-phenyl-1,3,4,7-tetrahydro
pyrimido[5,4-d]pyrimidine-2,8-dione) (11d)
-
Yield: 89%, mp >300 °C; light brown; FT-IR (KBr, cm
: 3451 (N–H stretch), 3216 (N–H stretch), 2948 (aliphatic
4
.3.1.
6,6'-((butane-1,4-diylbis(oxy))bis(4,1-
1
)
phenylene))bis(4-imino-3-phenyl-1,3,4,7-tetrahydro
C–H stretch), 2871 (aliphatic C–H stretch), 1735 (C=O
stretch), 1686 (C=O stretch), 1604 (C=N stretch), 1503
(C=C stretch), 1451 (CH
pyrimido[5,4-d]pyrimidine-2,8-dione) (11a)
-
Yield: 90%, mp 234-237 °C; brown; FT-IR (KBr, υ/cm
bend), 1389 (CH bend), 1222 (C–
3 2
1
1
): 3452 (N–H stretch), 3317 (N–H stretch), 3243 (N–H
O stretch), 767 (aromatic C–H out-of-plane bend). H NMR
stretch), 2953, 2875 (aliphatic C–H stretch), 1731, 1681
C=O stretch), 1600 (C=N stretch), 1508 (C=C stretch),
393, 1246 (C–O stretch), 837, 768 (aromatic C–H out-of-
(400 MHz, DMSO-
NH), 8.01 (s, 3H, H
d ) δ 11.82 (s, 1H, NH), 8.56 (s, 1H,
6
(
1
d
, H
j
, H
g
), 7.75 (d,
), 7.48 (t,
), 7.08 (d1, J = 8.2 Hz, 1H, H
h
3
J
J
= 8.0 Hz, 2H, H
c
),
),
),
7.62 (t,
J
= 7.7 Hz, 2H, H
= 8.1 Hz, 1H, H
), 1.93 (s, 2H, H
, ppm): δ 166.1, 159.4, 154.9, 153.3, 153.2, 138.8,
133.4, 133.1, 130.0, 129.4, 129.1, 128.4, 126.8, 120.4,
116.5, 114.1, 67.7, 26.0. Anal. Calcd. For C40 (%):
C, 64.16; H, 4.31; N, 18.71. Found: C, 64.19; H, 4.36; N,
= 8.1 Hz, 1H, H
b
a
1
plane bend). H NMR (400 MHz, DMSO-d ) δ 11.73 (s, 1H,
7.38 (t,
J
i
6
NH), 8.51 (s, 1H, NH), 7.99 (s, 1H, NH), 7.87 (d,
J
= 8.5
4.14 (s, 2H, H
DMSO-
k
). C NMR (100 MHz,
l
Hz, 2H, H ), 7.74 (d,
J
= 7.8 Hz, 2H, H ), 7.62 (t,
J
= 7.8 Hz,
H, H ), 7.50 (t, J = 7.5 Hz, 1H, H ), 7.02 (d, J = 8.8 Hz,
b a
13
d
6
g
c
2
2
H, H ), 4.12 (s, 2H, H ), 1.93 (s, 2H, H ). C NMR (100
H N O
32 10 6
h
i
j
MHz, DMSO-d , ppm): δ 166.2, 164.1, 160.8, 155.2, 153.3,
6
+
+
1
1
6
1
7
33.4, 133.2, 132.3, 129.7, 129.4, 128.3, 126.8, 115.4,
14.7, 68.2, 25.7. Anal. Calcd. For C H N O (%): C,
18.67
. HRMS-ESI (m/z) calcd. for C40H N O [M + H]
33 10 6
749.2579, found 749.2585.
4
0
32 10
6
4.16; H, 4.31; N, 18.71. Found: C, 64.23; H, 4.37; N,
+
6
+
4.3.5. 6,6'-((pentane-1,5-diylbis(oxy))bis(3,1-
phenylene))bis(4-imino-3-phenyl-1,3,4,7-tetrahydro
pyrimido[5,4-d]pyrimidine-2,8-dione) (11e)
8.67. HRMS-ESI (m/z) calcd. for C H N O [M + H]
4
0
33 10
49.2579, found 749.2585.
4
.3.2. 6,6'-((pentane-1,5-diylbis(oxy))bis(4,1-
-
Yield: 82%, mp 250-253 °C; light brown; FT-IR (KBr, cm
)
phenylene))bis(4-imino-3-phenyl-1,3,4,7-tetrahydro
pyrimido[5,4-d]pyrimidine-2,8-dione) (11b)
1
: 3450 (N–H stretch), 3218 (N–H stretch), 2940 (aliphatic
C–H stretch), 2868 (aliphatic C–H stretch), 1737 (C=O
stretch), 1687 (C=O stretch), 1604 (C=N stretch), 1502
(C=C stretch), 1450 (CH bend), 1390 (CH bend), 1223 (C–
-
1
Yield: 83%, mp 216-218 °C; brown; FT-IR (KBr, υ/cm ):
455 (N–H stretch), 3282 (N–H stretch), 3221 (N–H stretch),
942 (aliphatic C–H stretch), 2866 (aliphatic C–H stretch), 1740
3
2
3
2
1
O stretch), 766 (aromatic C–H out-of-plane bend). H NMR
(400 MHz, DMSO- 6) δ 11.80 (s, 1H, NH), 8.55 (s, 1H,
NH), 8.02-8.00 (m, 3H, H , H , H ), 7.74 (d, = 7.9 Hz, 2H,
= 8.6 Hz, 1H, Ha),
= 9.1 Hz, 1H, Hh),
= 7.1 Hz, 2H, Hl),
= 6.2 Hz, 1H, Hm). C NMR (100 MHz,
, ppm): δ 166.1, 159.4, 154.9, 153.4, 153.2, 138.8,
(
(
C=O stretch), 1690 (C=O stretch), 1601 (C=N stretch), 1508
C=C stretch), 1465 (CH bend), 1392 (CH bend), 1248 (C–O
d
3
2
d
j
g
J
1
stretch), 770 (aromatic C–H out-of-plane bend). H NMR (500
MHz, DMSO-d ) δ 11.70 (s, 1H, NH), 8.50 (s, 1H, NH), 7.97 (s,
1
H ), 7.62 (t, J = 7.8 Hz, 2H, H ), 7.50 (t, J
c b
6
7.37 (t,
4.10 (t, J = 5.9 Hz, 2H, H ), 1.84 (quint, J
k
13
J = 8.0 Hz, 1H, H ), 7.04 (d, J
i
H, NH), 7.85 (d, J = 6.9 Hz, 2H, H ), 7.72 (d, J = 7.9 Hz, 2H,
g
H ), 7.61 (t, J = 7.7 Hz, 2H, H ), 7.49 (t, J = 7.4 Hz, 1H, H ), 7.00
1.63 (quint,
DMSO- 6
J
c
b
a
(d, J = 8.6 Hz, 2H, H ), 4.06 (t, J = 6.4 Hz, 2H, H ), 1.81 (quint, J
d
h
i
13
=
6.8, 2H, H ), 1.59 (quint, J = 4.9, 2H, H ). C NMR (125 MHz,
133.4, 133.2, 130.0, 129.4, 129.0, 128.4, 126.8, 120.5,
116.5, 114.1, 68.0, 29.0, 22.7. Anal. Calcd. For C H N O
6
j
k
DMSO-d , ppm): δ 166.2, 164.1, 160.9, 155.2, 153.2, 133.4,
6
41 34 10
1
2
1
7
33.2, 132.3, 129.7, 129.4, 128.3, 126.8, 115.4, 114.7, 68.4, 28.7,
2.6. Anal. Calcd. For C H N O (%): C, 64.56; H, 4.49; N,
(%): C, 64.56; H, 4.49; N, 18.36. Found: C, 64.52; H, 4.53;
+
+
41
34 10
6
N, 18.43. HRMS-ESI (
m/z) calcd. for C H N O [M + H]
41 35 10 6
+
+
8.36. HRMS-ESI (m/z) calcd. for C H N O [M + H]
763.2736, found 763.2741.
41
35 10
6
63.2736, found 763.2741.
4
.3.6. 6,6'-((butane-1,4-diylbis(oxy))bis(2,1-
4
.3.3. 6,6'-((hexane-1,6-diylbis(oxy))bis(4,1-
phenylene))bis(4-imino-3-phenyl-1,3,4,7-tetrahydro
phenylene))bis(4-imino 3-phenyl-1,3,4,7-tetrahydro
pyrimido[5,4-d]pyrimidine-2,8-dione) (11f)
pyrimido[5,4-d]pyrimidine-2,8 dione) (11c)
Yield: 80%, mp 290-293 °C; light brown; FT-IR (KBr,
υ/cm ): 3439 (N–H stretch), 3194 (N–H stretch), 2944
-
1

8
Tetrahedron
9
.
Kubota Y, Kaneda Y, Haraguchi K, et al. Synthesis of novel 4′-C-
(
aliphatic C–H stretch), 1734 (C=O stret
A
ch
C
),
C
16
E
8
P
8
T
(C
ED MANUSCRIPT
methyl-1′, 3′-dioxolane pyrimidine nucleosides and evaluation of its
3
=
O
stretch), 1600 (C=N stretch), 1501 (C=C stretch), 1456 (CH
bend), 1394 (CH bend), 1246 (C–O stretch), 756 (aromatic
C–H out-of-plane bend). H NMR (400 MHz, DMSO-d6) δ
anti-HIV-1 activity. Tetrahedron. 2013;69(51):10884-10892.
Mizuhara T, Oishi S, Ohno H, Shimura K, Matsuoka M, Fujii N.
Concise synthesis and anti-HIV activity of pyrimido [1, 2-c][1, 3]
benzothiazin-6-imines and related tricyclic heterocycles. Org
Biomol Chem. 2012;10(33):6792-6802.
Gholap AR, Toti KS, Shirazi F, Deshpande M V, Srinivasan K V.
Efficient synthesis of antifungal pyrimidines via palladium
catalyzed Suzuki/Sonogashira cross-coupling reaction from
Biginelli 3, 4-dihydropyrimidin-2 (1H)-ones. Tetrahedron.
2008;64(44):10214-10223.
2
1
1
0.
1.
1
11.77 (s, 1H, NH), 8.11 (s, 1H, NH), 7.99 (s, 1H, NH), 7.69
(d, = 6.1 Hz, 1H, H ), 7.64 (d, = 7.9 Hz, 2H, H ), 7.50 (t,
J
J
j
c
J
7
= 7.7 Hz, 2H, H ), 7.41 – 7.35 (m, 2H, H , H ), 7.01 (t,
J
=
b
a
h
.5 Hz, 1H, H ), 6.96 (d,
J = 8.3 Hz, 1H, H ), 3.82 (s, 2H,
i
g
1
3
H ), 1.56 (s, 2H, H ). C NMR (100 MHz, DMSO-d6, ppm):
δ 166.0, 157.2, 156.3, 153.3, 152.6, 133.4, 133.1, 132.0,
k
l
1
2
30.9, 129.3, 128.4, 128.3, 126.9, 120.6, 119.5, 113.5, 68.1,
5.7. Anal. Calcd. For C H N O (%): C, 64.16; H, 4.31;
12.
13.
Fang Y, Xu J, Li Z, et al. Design and synthesis of novel pyrimido
[
5, 4-d] pyrimidine derivatives as GPR119 agonist for treatment of
4
0
32 10
6
type 2 diabetes. Bioorg Med Chem. 2018;26(14):4080-4087.
Solca FF, Baum A, Langkopf E, et al. Inhibition of epidermal
growth factor receptor activity by two pyrimidopyrimidine
derivatives. J Pharmacol Exp Ther. 2004;311(2):502-509.
Northen JS, Boyle FT, Clegg W, et al. Controlled stepwise
conversion of 2, 4, 6, 8-tetrachloropyrimido [5, 4-d] pyrimidine into
2, 4, 6, 8-tetrasubstituted pyrimido [5, 4-d] pyrimidines. J Chem
Soc Perkin Trans 1. 2002;(1):108-115.
Curtin NJ, Barlow HC, Bowman KJ, et al. Resistance-Modifying
Agents. 11. Pyrimido [5, 4-d] pyrimidine Modulators of Antitumor
Drug Activity. Synthesis and Structure− Activity Relationships for
Nucleoside Transport Inhibition and Binding to α1-Acid
Glycoprotein. J Med Chem. 2004;47(20):4905-4922.
Badvel S, Gopireddy RR, Shaik TB, Hasti S, Tummaluru VR,
Chamarthi NR. An efficient one-pot three-component synthesis of
pyrimido [4, 5-d] pyrimidine derivatives in aqueous medium. Chem
Heterocycl Compd. 2015;51(8):749-753.
Moghaddam FM, Khodabakhshi MR, Aminaee M. Highly efficient
synthesis of pyrimido [4, 5-d] pyrimidine-2, 4-dione derivatives
catalyzed by iodine. Tetrahedron Lett. 2014;55(34):4720-4723.
Ohtsuka Y. Chemistry of diaminomaleonitrile. 3. Reaction with
isocyanate: a novel pyrimidine synthesis. J Org Chem.
1978;43(16):3231-3234.
N, 18.71. Found: C, 64.20; H, 4.34; N, 18.76. HRMS-ESI
(m/z) calcd. for C H N O [M + H] 749.2579, found
+
+
40 33 10 6
748.2584.
1
1
4.
5.
4
.3.7.
6,6'-((hexane-1,6-diylbis(oxy))bis(2,1-
phenylene))bis(4-imino-3-phenyl-1,3,4,7-tetrahydro
pyrimido[5,4-d]pyrimidine-2,8-dione) (11g)
-
1
Yield: 83%, mp 292-294 °C; light brown; FT-IR (KBr, cm ):
435 (N–H stretch), 3186 (N–H stretch), 2938 (aliphatic C–H
3
stretch), 2862 (aliphatic C–H stretch), 1737 (C=O stretch), 1689
(
(
C=O stretch), 1599 (C=N stretch), 1501 (C=C stretch), 1455
CH bend), 1392 (CH bend), 1241 (C–O stretch), 756 (aromatic
1
1
6.
7.
3
2
1
C–H out-of-plane bend). H NMR (400 MHz, DMSO-d ) δ 11.78
6
(s, 1H, NH), 8.08 (s, 1H, NH), 8.00 (s, 1H, NH), 7.70 – 7.65 (m,
3
H, H , H ), 7.51 (t, J = 7.7 Hz, 2H, H ), 7.41 – 7.38 (m, 2H, H ,
c
j
b
a
H ), 7.08 (d, J = 8.3 Hz, 1H, H ), 7.02 (t, J = 7.5 Hz, 1H, H ),
h
g
i
1
3
3
.91 (t, J = 6.4 Hz, 2H, H ), 1.51 (s, 2H, H ), 1.20 (s, 2H, H ). C
k l m
18.
NMR (100 MHz, DMSO-d , ppm) δ 166.0, 157.4, 156.3, 153.3,
6
1
1
52.7, 133.3, 133.1, 131.9, 131.0, 129.3, 128.6, 128.3, 126.9,
20.6, 119.5, 114.0, 68.7, 29.0, 25.5. Anal. Calcd. For
1
9.
Booth BL, Dias AM, Proença MF, Zaki MEA. The reactions of
diaminomaleonitrile with isocyanates and either aldehydes or
ketones revisited. J Org Chem. 2001;66(25):8436-8441.
Pirbasti FG, Mahmoodi NO. Facile synthesis and biological assays
of novel 2, 4-disubstituted hydrazinyl-thiazoles analogs. Mol
Divers. 2016;20(2):497-506.
C H N O (%): C, 64.94; H, 4.67; N, 18.03. Found: C, 64.97;
H, 4.69; N, 18.06. HRMS-ESI (m/z) calcd. for C H N O [M +
H] 777.2892, found 776.2897.
42
36 10
6
+
6
42
37 10
20.
+
2
1.
Khodaee Z, Yahyazadeh A, Mahmoodi NO. One‐ Pot Synthesis
and Characterization of Some New Types of 5, 5′‐ Disubstituted
Bis (imidazolidine‐ 2, 4‐ diones). J Heterocycl Chem.
Acknowledgments
We thank the Research Committee of the University of Guilan
for the partial support given to this study.
2
013;50(2):288-292.
22.
Mahmoodi NO, Parvizi J, Sharifzadeh B, Rassa M. Facile
Regioselective Synthesis of Novel bis‐ Thiazole Derivatives and
Their Antimicrobial Activity. Arch Pharm (Weinheim).
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