TBHP-mediated oxidative synthesis of substituted pyrimido[4,5-: D] pyrimidines from N -uracil amidines and methylarenes under metal free conditions

Article abstract of DOI:10.1039/c9ra06625j

An efficient and operationally simple protocol has been demonstrated for the synthesis of 1,3,5,7-tetrasubstituted pyrimido[4,5-d]pyrimidines via TBHP-mediated direct oxidative coupling of N-uracil amidines and methylarenes under metal-free conditions. Du

Full text of DOI:10.1039/c9ra06625j

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PAPER
TBHP-mediated oxidative synthesis of substituted
pyrimido[4,5-d]pyrimidines from N-uracil amidines
and methylarenes under metal free conditions†
Cite this: RSC Adv., 2019, 9, 29831
*
Pradip Debnath
An efficient and operationally simple protocol has been demonstrated for the synthesis of 1,3,5,7-
tetrasubstituted pyrimido[4,5-d]pyrimidines via TBHP-mediated direct oxidative coupling of N-uracil
amidines and methylarenes under metal-free conditions. Due to the inherent stability of methylarenes
compared to aldehydes, the presented synthetic protocol is adaptable to a broad substrate scope, is
operationally simple, has no need for stringent protection in the whole preparation process, and has the
potential to prepare valuable products that are currently inaccessible or challenging to prepare using
conventional methods. It is a significantly important complement to the conventional synthetic methods.
The reaction possesses an efficient tandem oxidation–imination–cyclization process.
Received 22nd August 2019
Accepted 10th September 2019
DOI: 10.1039/c9ra06625j
rsc.li/rsc-advances
compounds still remain scarce.15,16 According to the literature
survey, the previously reported methods for the preparation of
Introduction
pyrimido[4,5-d]pyrimidines are highlighted in Scheme 1. The
most frequent routes to pyrimido[4,5-d]pyrimidines typically
involve three-component reactions involving 6-aminouracils15
or by the cycloaddition reactions16 between 6-methyl-
ideneaminouracils and electron-decient substrates. The latter
method is restricted to electron decient substrates and does
not offer unrestricted scope for the synthesis of products. Other
promising methods for the synthesis of pyrimido[4,5-d]pyrimi-
dines involve multistep syntheses starting from 1,3-disubsti-
tuted cyanouracils,17 polymer bounded 2-(alkylsulfanyl)-4-
aminopyrimidine-5-carbonitrile etc. A new approach to the
synthesis of pyrimido[4,5-d]pyrimidines reported by Wamhoff
et al.18 is the aza-Wittig type reaction of iminophosphoranes of
5-aminouracils leading to functionalised pyrimido[4,5-d]
pyrimidines. Wang and co-workers reported a protocol for the
synthesis of tetrasubstituted pyrimido[4,5-d]-pyrimidine deriv-
atives by sequential reactions of 6-aminouracil with hydrazine
involving 6 steps.19 Tummaluru and co-workers also developed
a one-pot protocol for the synthesis of 5,6-dihydropyrimido[4,5-
d]pyrimidines involving 6-amino-N,N-dimethyluracil, phenyl-
isocyanate, and aromatic aldehydes in water solvent.20 In
another approach, Ghorbani-Vaghei and Sarmast employed
a magnetic nanoparticle Fe3O4@SiO2 as catalyst in water solvent
for the synthesis of substituted pyrimido[4,5-d]pyrimidines.21
Nevertheless, these methods are associated with few short-
comings such as – harsh reaction conditions (high temperature,
microwave),16a,b use of toxic solvents, use of metal catalysts, or
use of complex synthetic pathways,19 and less-environmentally
benign, or not readily available substrates.22a,23 So, there is
a necessity to develop more effective and sustainable chemical
procedures for the synthesis of pyrimido[4,5-d]pyrimidines.
Nitrogen containing heterocycles play leading roles in the eld
of biological and medicinal chemistry.1 These molecules have
also been extensively used in the elds of agrochemicals,
pesticides and pharmaceuticals, and in industry.2 Over the past
few decades, great efforts have been made to develop novel and
efficient methods for the construction of nitrogen containing
heterocycles.3 Pyrimidines are one of the most important
nitrogen heterocycles, exhibiting remarkable pharmaceutical
activities.4 Among them, pyrimido[4,5-d]pyrimidines are very
important scaffolds found in many natural products and
synthetic drugs or drug candidates exhibiting a wide range of
biological activities.5 These compounds have attracted consid-
erable attention in medicinal chemistry due to their signicant
and diverse biological activities, including anticancer,6 anti-
viral,7 antifungal,8a antioxidant,8b antitumor,9 and hep-
atoprotective.10 Some of their derivatives are also useful as
bronchodilators,6 vasodilators,11 antiallergic,12 antihyperten-
sive13 agents. Dipyridamole,
a pyrimidopyrimidine based
heterocycles, is a medicine that inhibits the phosphodiesterase
enzyme, lowers pulmonary hypertension,13b and is also used in
electro-cardiogram and echocardiography. Recently, pyrimido
[4,5-d]pyrimidine analogues of folic acid have also been
screened for antitumor activity.14 Despite these enormous
applications, the approaches for the preparation of this type of
Department of Chemistry, Maharaja Bir Bikram College, Agartala, Tripura-799004,
India.
E-mail:
pradipchem78@gmail.com;
pdn0099@yahoo.co.in;
Fax:
+3812516728; Tel: +3812526607
† Electronic supplementary information (ESI) available: Detailed of experimental
procedure and analytical data for starting materials, and copies of 1H NMR and
13C NMR for all synthesized compounds. See DOI: 10.1039/c9ra06625j
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More viable and efficient approaches are being tried to alleviate
Herein, we wish to develop a new method for the synthesis of N1,
the shortcomings. Recently, Deb and co-workers have devel- N3, C5 and C7 tetrasubstituted pyrimido[4,5-d]pyrimidines directly
oped a new strategy for the synthesis of 5,6-dihydropyrimido from N-uracil amidine and methylarenes under meta-free condi-
[4,5-d]pyrimidines based on a cascade 3-component reaction tions. SNAE of the C6 halogen of 6-chlorouracil by an amidine leads
involving 6-aminouracil, aldehydes and tetrahydroisoquino- to an N-uracil amidine (1),34 which can be converted to the corre-
lines under solvent free reaction conditions.24 Very recently, we sponding pyrimido[4,5-d]pyrimidines (3) by the oxidative coupling
have shown that pyrimido[4,5-d]pyrimidines could be achieved with methylarenes (2) using TBHP as a green oxidant (Scheme 1).
by the direct annulation of N-uracil amidines with benzalde- The reaction possesses an efficient oxidation–imination–cyclization
hydes under transition metal free conditions.25 Although, this tandem process. The requisite amidine substrates can be easily
method is highly efficient but the use of aldehydes as the prepared using a Pinner approach,35 starting from the correspond-
coupling partners could frequently meet some problems such ing nitriles and ammonia, and allowing installation of R at C7
as – (i) the active aldehyde groups may suffer from an oxidation position. To the best of our knowledge, such a synthetic protocol
reaction leading to the formation of undesirable by-products, has not been reported.
and hence necessitating the requirement for inert condi-
tions;26 (ii) aldehydes could undergo a decarbonylation reaction
under harsh reaction conditions resulting in lower yields of the
products;27 (iii) cost of some aldehydes are high or not readily
Results and discussion
At the outset, we began our study by investigating the TBHP
mediated oxidative coupling of N-uracil amidine 1a and toluene 2a
under basic medium. We are pleased to obtain the desired product
of pyrimido[4,5-d]pyrimidine 3a in 52% isolated yield when the
reaction was performed using K2CO3 as base in the presence of 70%
available. On the basis of these facts, the search for readily
available, in expensive and stable alternatives of aldehydes
would provide a new avenue for the synthesis of pyrimido[4,5-d]
pyrimidines and is of high importance.
In recent years, the use of abundant and sustainable meth-
ylarenes for carbon–carbon (C–C) and carbon–nitrogen (C–N)
bond formations have received considerable attentions.28,29
Methylarenes are cheap, stable, less toxic, commercially avail-
able, and easy to handle, thus making it advantageous to be
used as ideal starting materials. By exploring suitable oxidant
systems, the oxidation of methylarenes leading to in situ
formation of aldehydes is considered to be the key step for the
formation of desired products.30,31 Based on these elegant
contributions, we believed that methylarenes could be applied
as latent aldehydes32 for the synthesis of aryl substituted pyr-
imido[4,5-d]pyrimidines. Compared to aldehydes, methylarenes
have a variety of advantages such as cost-effectiveness, ther-
modynamic stability, abundance and sustainability. On the
other hand, burgeoning metal-free organo-catalyst C–H func-
tionalization strategies have attracted much attention in recent
years in many oxidation processes with TBHP as an oxidant,
which have outstanding performances and advantages such as
inexpensive, safe, environmentally benign, mild conditions,
and ease of purication.32,33
ꢀ
TBHP (3.0 equiv.) in toluene (2a) at 100 C (Table 1, entry 1). For
optimizing the reaction conditions, the effect of oxidants was
Table 1 Optimization of the reaction conditions for the synthesis of
pyrimido[4,5-d]pyrimidine (3a)a
Entry
Oxidant
Base
Yieldb (%)
1
2
3
4
5
6
7
8
70% TBHP
TBHP
PhI(OAc)2
H2O2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
Et3N
DBU
KOAc
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
52
37
21
Tracec
0
45
82
0
O2
70% TBHP
70% TBHP
70% TBHP
70% TBHP
70% TBHP
70% TBHP
—
70% TBHP
70% TBHP
70% TBHP
70% TBHP
70% TBHP
9
0
25
0
10
11
12
13d
14e
15f
16f
17g
0
28
40
79
64
57
a
Reaction conditions: all reactions were performed with 1a (0.5 mmol,
1.0 equiv.), oxidant (3.0 equiv.) and base (1.0 mmol, 2.0 equiv.) in 1 mL
b
c
toluene (2a) at 100 ꢀC, 15 h. Isolated yield of 3a. 1a was recovered.
d
f
e
1.5 equiv. of 70% TBHP was used. 1.5 equiv. of Cs2CO3 was used.
Reaction was carried out at 110 ꢀC (entry 15) and at 90 ꢀC (entry 16).
Reaction was performed with a mixture of 0.5 mL toluene and
g
Scheme 1 Selected methods for the synthesis of pyrimido[4,5-d]
0.5 mL chlorobenzene (entry 17).
pyrimidines from 6-substituted uracil.
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investigated, and we found that oxidant plays an important role in
this oxidation process. 70% TBHP was found to be superior to TBHP
and PhI(OAc)2. Other oxidant such as H2O2, O2 were proved
completely ineffective (Table 1, entries 4 and 5). Various bases such
as K3PO4, Cs2CO3, KOAc, Et3N, and DBU were also screened (Table
1, entries 6–10). Cs2CO3 was found to be the optimum choice and
provided 82% yield of the desired product (Table 1, entry 7). The
reaction did not take place in the presence of organic bases such as
Et3N and DBU (entries 8 and 9). No products were obtained in the
absence of base or oxidant (Table 1, entries 11 and 12). When the
amount of oxidant or base were decreased, dramatic lowering of
yields was observed (Table 1, entries 13 and 14). Next, the effect of
ꢀ
temperature was studied, and it was observed that 100 C is the
optimum reaction temperature. Increase in the reaction tempera-
ture did not have any noticeable effect on this transformation,
however, the yield of 3a decreased considerably when the reaction
was performed at 90 ꢀC (entries 15 and 16). Moreover, the yield of 3a
dropped to 57% when the reaction was performed with a mixture
0.5 mL of toluene and 0.5 mL chlorobenzene (entry 17). Thus, the
optimized reaction conditions are summarized as follows: N-uracil
benzamidine (1a, 0.5 mmol), toluene (2a, 1 mL), Cs2CO3 (1.0 mmol,
2.0 equiv.), 70% TBHP (3.0 equiv.) at 100 ꢀC for 15 h under air (Table
1, entry 7).
With the optimized conditions in hand, we then tested the
generality and limitations of this synthetic protocol. Firstly, the
effect of substitution on methylarene was investigated using N-
uracil benzamidine 1a as reaction partner and the results are listed
in Scheme 2. As shown in Scheme 2, all the reactions using meth-
ylarenes proceeded smoothly and furnished desired products in
good to excellent isolated yields. It was observed that methylarenes
with electron-donating substituents such as OMe, Me, SMe, OH
produced respective pyrimido[4,5-d]-pyrimidines 3b–f and 3m in
very good yields (69–90%) while methylarenes having strong
electron-withdrawing substituents such as F, CN furnished slightly
lower yield of the products 3j and 3k. It was also observed that
methylarenes having para-substituents afforded the products in
higher yields than those with ortho-substituents. We reasoned that
steric hindrance by a group at the ortho-position of methylarenes
might be playing a major role in lowering the yield (3d, 3i). It is
pertinent to mention that when the toluene derivatives were
substituted with more than one methyl group, the reaction took
place on one methyl group only and the other methyl group
remained unreacted (3c,d). This result might be attributed to that,
once one of the methyl groups on the aromatic ring was involved in
the reaction and its electron-withdrawing property was unfav-
ourable to the subsequent oxidation of other methyl group.31,32 a-
Methylnaphthalene could also be employed to react with N-uracil
amidine under the optimal reaction conditions giving 3l in 85%
yield. Even oxidation-sensitive functional groups such as a thio-
methyl group (3e) was compatible with the reaction conditions.
Upon a thorough literature investigation, it was found that the
synthesis of heteroaryl substituted pyrimido[4,5-d]pyrimidines has
not been explored with the conventional methods. Herein, we wish
to prepare this type of compounds by employing our synthetic
protocol. Representative heterocyclic methylarenes such as 2-
methylthiophene and 2-methylpyridine were selected as coupling
patterns for the oxidative coupling with N-uracil amidine (1a).
Scheme 2 Scope of the arylmethanes (2) in the reaction with N-uracil
benzamidine (1a).a,b aReaction conditions: substrate 1a (0.5 mmol), 2 (1
mL), 70% TBHP (3.0 equiv.), and Cs2CO3 (1.0 mmol, 2.0 equiv.), were
stirred at 100 ꢀC for 15 h under air. bYield of the isolated product.
Delightfully, both the reactions proceeded smoothly producing the
corresponding pyrimido[4,5-d]pyrimidines 3n and 3o in 70% and
63% yields, respectively.
To extend the scope of the reaction, we also explored the
reactions of different N-uracil benzimidamides (1b–h) with
toluene (1a) under the standard reaction conditions (Scheme 3).
The protocol tolerated a variety of substituents on the aryl ring
of the N-uracil benzimidamide, with both electron-donating
and electron-withdrawing groups (3p–u, Scheme 3). Only an
exception was observed in case of less stable alkyl amidines
such as acetamidine bearing a methyl at the R3 position (1h). No
1h was recovered and its decomposition mechanism is not
clear. Notably, the para-bromo substituted pyrimido[4,5-d]
pyrimidines 3g and 3s, which can be used for further cross
coupling reactions, were obtained in very good yields. As uo-
rine can have a major inuence on the pharmacological prop-
erties of a drug,36 we were delighted to see that this protocol is
also compatible with this halogen (3j and 3q). Finally, it is also
possible to work with N-protected uracil substrates such as N-(1-
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Scheme 5 Plausible mechanism for the formation of pyrimido[4,5-d]
pyrimidines.
Scheme 3 Scope of various N-uracil amidine substrates in the reac-
tion with toluene 2a.a,b aReaction conditions: substrate 1 (0.5 mmol),
2a (1 mL), 70% TBHP (3.0 equiv.), and Cs2CO3 (1.0 mmol, 2.0 equiv.),
were stirred at 100 ꢀC for 15 h under air. bYield of the isolated product.
performed and trace amount of 3a was observed along with 67%
of 3a0 (Scheme 4c). These reactions conrm that oxygen is
essential for the oxidation of 3a0 into 3a, however, an external
supply of oxygen is not required.
On the basis of the previous reports on the progresses about
TBHP mediated methylarenes oxidation30–32 and based on our
control experiments a plausible mechanism for the formation
of 3 is proposed in Scheme 5. Initially, the reaction may
proceeds with the formation of an aldehyde (A) by TBHP
mediated oxidation of toluene.31,32 Then, in situ generated
aldehyde A condensed with N-uracil amidine 1a to give azadiene
4.38 The intramolecular [4+2] cycloaddition reaction of 4 fol-
lowed by a [1,5]-hydrogen shi to form the intermediate 5,6-
dihydropyrimido[4,5-d]pyrimidine 3a0, which on oxidation by
aerial oxygen affords the desired product 3a.
benzyl-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)
benzimidamide (1f) and N-(1,3-dibenzyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-yl)benz-imidamide (1g) under the opti-
mized reaction conditions. Delightfully, both the reactions
proceeded smoothly producing the corresponding pyrimido
[4,5-d]pyrimidines 3t and 3u in 88% and 92% yields, respec-
tively. Deprotection of these substrates37 may allowed post-
decoration of the uracil moiety, via N-alkylation/arylation or
dehydroxychlorination and subsequent consecutive SNAr which
is particularly interesting for medicinal chemistry purposes.
To study the mechanism of the formation of 3, we performed
some control experiments (Scheme 4). We isolated compound
3a0 along with 3a when the reaction was stopped aer 5 h
(Scheme 4a). When compound 3a0 was heated at 100 ꢀC, it
Conclusions
produced 3a in excellent yield (Scheme 4b). Therefore, we In summary, we have developed an efficient and straightforward
believed that the reaction proceeded through the formation of method for the synthesis of 1,3,5,7-tetrasubstituted pyrimido
3a0. As our reactions were performed in open air, we thought [4,5-d]pyrimidines from inexpensive and easily available meth-
aerial oxygen might play some crucial role in the cyclization. In ylarenes and N-uracil amidines employing a green oxidant
order to conrm the possibility of O2 being involved in the under metal-free conditions. Methylarenes are performed as
oxidation step, a control reaction under N2 atmosphere was effective aldehyde precursors in the oxidation–imination–cycli-
zation transformation. Compared to other methods, the present
protocol has a number of advantages such as – inherent stability
of methylarenes compared to aldehydes, operational simplicity,
use of green oxidant, avoidance of metal catalysts, and easy
accessibility of the starting materials, making it a highly prac-
tical approach to access various pyrimido[4,5-d]pyrimidines of
biological interest. Hence, it is a signicantly superior to the
existing methodologies. On the basis of importance of pyrimido
[4,5-d]pyrimidines in pharmacological science, this protocol
has the potential for applications in both drug discovery and
chemical development projects.
Experimental
General information
All the chemicals and reagents were purchased from commer-
cial suppliers (Sigma-Aldrich, Alfa-Aesar, Spectrochem, TCI
Scheme
mechanism.
4 Some control experiments to establish the reaction
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Chemicals) and were used without further purication. Silica 136.2, 151.4, 158.1, 159.9, 161.5, 164.9, 169.7. HRMS (ESI): m/z
gel [(60–120, 230–400 mesh), Spectrochem, India] was used for calcd for C21H18N4O3Na [M+ + Na]: 397.1271; found: 397.1263.
chromatographic separation. Thin-layer chromatography (TLC)
was performed on TLC plates purchase from Merck. Solvents
used in extraction and purication were distilled prior to use.
Melting points were determined by silicon oil bath in open
capillaries and are uncorrected. 1H (13C) NMR spectra were
recorded at 400 (100) MHz on a Brucker (Ascend 400 MHz)
spectrometer using CDCl3 or DMSO-d6 solvent with tetrame-
thylsilane as internal standard. Chemical shis were reported
in parts per million (ppm, d) and coupling constants are given in
Hertz. Proton coupling patterns are described as singlet (s),
doublet (d), triplet (t), multiplet (m). Due to the existence of
tautomers, in some cases the amidine NH proton signals in the
1H spectrum and amidine carbon in 13C spectrum was not
detected. Only distinct signals are reported. High resolution
mass spectra (HRMS) [Make: Waters; Model: Xevo XS QTof mass
spectrometer] were obtained by using positive electrospray
ionization (ESI) by Time of Flight (TOF) method.
1,3-Dimethyl-5-(4-methylphenyl)-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3c)25
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 5 : 95); yield:
83% (149 mg, 0.415 mmol), mp 226–228 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 2.45 (s, 3H), 3.41 (s, 3H), 3.85 (s, 3H), 7.30 (d, J ¼
8.0 Hz, 2H) 7.48–7.58 (m, 5H), 8.57 (dd, J ¼ 1.6 Hz, 8.4 Hz, 2H).
13C NMR (100 MHz, CDCl3): d ¼ 21.6, 28.6, 29.9, 103.5, 128.5,
128.6, 129.3, 132.2, 135.5, 136.1, 140.3, 151.3, 157.9, 159.7,
165.1, 170.4. HRMS (ESI): m/z calcd for C21H18N4O2Na [M+ + Na]:
381.1322; found: 381.1316.
1,3-Dimethyl-5-(2-methylphenyl)-7-phenylpyrimido[4,5-
d]pyrimidine-2,4(1H,3H)-dione (3d)
White solid; Rf ¼ 0.45 (SiO2, hexane/ethyl acetate ¼ 5 : 95); yield:
69% (123 mg, 0.345 mmol), mp 246 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 2.19 (s, 3H), 3.38 (s, 3H), 3.87 (s, 3H), 7.20 (d, J ¼
7.6 Hz, 1H), 7.32 (t, J ¼ 7.2 Hz, 2H), 7.39–7.42 (m, 1H) 7.48–7.58
(m, 3H), 8.56 (t, J ¼ 1.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼
19.7, 28.5, 29.8, 104.7, 125.5, 127.4, 128.7, 129.0, 129.4, 130.0,
132.3, 134.8, 136.2, 138.9, 151.4, 157.5, 159.3, 165.8, 171.1.
HRMS (ESI): m/z calcd for C21H19N4O2 [M+ + H]: 359.1508;
found: 359.1492.
General procedure for the TBHP-mediated oxidative synthesis
of pyrimido[4,5-d]pyrimidines from N-uracil amidines and
methylarenes
An oven-dried microwave vial (10 mL) equipped with a magnetic
stirring bar was charged with N-uracil amidine (0.5 mmol, 1.0
equiv.), toluene (1 mL), 70% TBHP (192 mg, 3 equiv.), Cs2CO3
(325 mg, 1.0 mmol, 2.0 equiv.). The reaction mixture was placed
in a pre-heated oil bath at 100 ꢀC and stirred for 15 hours with
magnetic stirrer. Aer completion of 15 h reaction time, the
mixture was allowed to reach room temperature and extracted
with ethyl acetate (2 ꢁ 10 mL). The combined organic layers
were washed with water and then brine. The organic layer was
dried over anhydrous Na2SO4, ltered, and concentrated under
reduced pressure. The resulting residue was puried by column
chromatography on silica gel (60–120 mesh) using hexane–ethyl
acetate mixture as eluent to give the title compounds.
1,3-Dimethyl-5-(4-thiomethylphenyl)-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3e)
Off-white solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 20 : 80);
yield: 76% (148 mg, 0.38 mmol), mp 270 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 2.55 (s, 3H), 3.42 (s, 3H), 3.85 (s, 3H), 7.34 (d, J ¼
8.4 Hz, 2H), 7.49–7.56 (m, 3H) 7.63 (d, J ¼ 8.4 Hz, 2H), 8.56 (t, J ¼
1.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 15.2, 28.6, 29.9,
103.4, 124.9, 128.6, 129.3, 130.0, 132.3, 134.5, 136.1, 141.9,
151.3, 158.0, 159.8, 165.1, 169.6. HRMS (ESI): m/z calcd for
C
21H18N4O2SNa [M+ + Na]: 413.1043; found: 413.1036.
1,3-Dimethyl-5,7-diphenylpyrimido[4,5-d]pyrimidine-2,4(1H,3H)-
dione (3a)22a,25
5-(4-Hydroxyphenyl)-1,3-dimethyl-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3f)25
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield:
82% (141 mg, 0.41 mmol), mp 210–211 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 3.41 (s, 3H), 3.85 (s, 3H), 7.48–7.57 (m, 6H), 7.64 (dd,
J ¼ 2.0 Hz, 8.4 Hz, 2H), 8.57 (d, J ¼ 8.4 Hz, 2H). 13C NMR (100
MHz, CDCl3): d ¼ 28.6, 29.9, 103.7, 127.7, 128.6, 129.1, 129.3,
130.0, 132.3, 136.1, 138.4, 151.3, 157.9, 159.6, 165.2, 170.4.
HRMS (ESI): m/z calcd for C20H16N4O2Na [M+ + Na]: 367.1165;
found: 367.1158.
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 20 : 80); yield:
71% (128 mg, 0.355 mmol), mp 246–248 ꢀC. 1H NMR (400 MHz,
DMSO): d ¼ 3.22 (s, 3H), 3.66 (s, 3H), 6.84 (d, J ¼ 8.8 Hz, 2H),
7.54–7.62 (m, 5H), 8.47 (d, J ¼ 6.8 Hz, 2H), 10.0 (br s, 1H, OH).
13C NMR (100 MHz, DMSO): d ¼ 28.7, 30.0, 103.8, 114.7, 129.0,
129.2, 129.3, 132.3, 132.6, 136.4, 151.4, 158.3, 160.0, 163.6,
168.8. HRMS (ESI): m/z calcd for C20H17N4O3 [M+ + H]: 361.1301;
found: 361.1294.
5-(4-Methoxyphenyl)-1,3-dimethyl-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3b)25
5-(4-Bromophenyl)-1,3-dimethyl-7-phenylpyrimido[4,5-
d]pyrimidine-2,4(1H,3H)-dione (3g)25
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield:
88% (164 mg, 0.44 mmol), mp 235–236 ꢀC. 1H NMR (400 MHz, White solid; Rf ¼ 0.45 (SiO2, hexane/ethyl acetate ¼ 5 : 95); yield:
CDCl3): d ¼ 3.43 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 7.01 (dd, J ¼ 85% (179 mg, 0.425 mmol), mp 258 ꢀC. 1H NMR (400 MHz,
2.0 Hz, 6.8 Hz, 2H), 7.49–7.58 (m, 3H), 7.69–7.72 (m, 2H), 8.58 CDCl3): d ¼ 3.41 (s, 3H), 3.86 (s, 3H), 7.49–7.59 (m, 6H), 7.63 (d, J
(dd, J ¼ 1.6 Hz, 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ ¼ 8.4 Hz, 1H), 8.58 (d, J ¼ 7.2 Hz, 2H). 13C NMR (100 MHz,
28.7, 29.9, 55.4, 103.2, 113.1, 128.6, 129.2, 130.4, 131.6, 132.2, CDCl3): d ¼ 28.6, 30.0, 103.6, 124.7, 128.7, 129.3, 130.9, 131.0,
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132.5, 135.9, 137.2, 151.2, 157.9, 159.6, 165.4, 169.3. HRMS 129.3, 129.5, 130.8, 132.4, 133.3, 136.1, 136.8, 151.3, 157.6,
(ESI): m/z calcd for C20H16BrN4O2 [M+ + H]: 423.0457; found: 159.0, 165.9, 170.2. HRMS (ESI): m/z calcd for C24H18N4O2Na
423.0477.
[M+ + Na]: 417.1322; found: 417.1315.
5-(4-Chlorophenyl)-1,3-dimethyl-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3h)25
1,3-Dimethyl-7-phenyl-5-(3,4,5-trimethoxyphenyl)pyrimido
[4,5-d]pyrimidine-2,4(1H,3H)-dione (3m)
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield: White solid; Rf ¼ 0.35 (SiO2, hexane/ethyl acetate ¼ 20 : 80);
70% (132 mg, 0.35 mmol), mp 242 ꢀC. 1H NMR (400 MHz, yield: 90% (195 mg, 0.45 mmol), mp 208–209 ꢀC. 1H NMR (400
CDCl3): d ¼ 3.41 (s, 3H), 3.86 (s, 3H), 7.46–7.61 (m, 7H), 8.55 (t, J MHz, CDCl3): d ¼ 3.45 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H), 3.97 (s,
¼ 1.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 28.6, 30.0, 103.6, 3H), 6.92 (s, 2H), 7.52–7.61 (m, 3H), 8.60 (t, J ¼ 1.6 Hz, 2H). 13
C
128.0, 128.7, 129.3, 130.7, 132.5, 136.0, 136.3, 136.7, 151.2, NMR (100 MHz, CDCl3): d ¼ 28.7, 30.0, 56.3, 61.0, 103.6, 106.9,
157.9, 159.6, 165.4, 169.2. HRMS (ESI): m/z calcd for C20H15
-
128.7, 129.3, 132.4, 133.6, 136.0, 139.7, 151.3, 152.6, 158.0,
159.5, 165.1, 170.0. HRMS (ESI): m/z calcd for C23H23N4O5 [M+ +
H]: 435.1663; found: 435.1658.
ClN4O2Na [M+ + Na]: 401.0776; found: 401.0766.
1,3-Dimethyl-5-(2-chlorophenyl)-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3i)
1,3-Dimethyl-7-phenyl-5-(thiophen-2-yl)pyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3n)
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield:
66% (125 mg, 0.33 mmol), mp 258–259 ꢀC. 1H NMR (400 MHz, Pale yellow solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90);
CDCl3): d ¼ 3.39 (s, 3H), 3.87 (s, 3H), 7.37–7.58 (m, 7H), 8.56 (t, J yield: 70% (122 mg, 0.35 mmol), mp 260–261 ꢀC. 1H NMR (400
¼ 1.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 28.5, 29.8, 105.0, MHz, CDCl3): d ¼ 3.48 (s, 3H), 3.79 (s, 3H), 7.21 (t, J ¼ 4.0 Hz,
126.8, 128.7, 128.9, 129.2, 129.4, 130.2, 132.0, 132.4, 136.1, 1H), 7.53–7.58 (m, 3H), 7.66 (d, J ¼ 4.4 Hz, 1H), 8.54 (d, J ¼
138.2, 151.3, 157.3, 159.3, 166.2, 167.9. HRMS (ESI): m/z calcd 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 28.8, 30.2, 101.8,
for C20H16ClN4O2 [M+ + H]: 379.0962; found: 379.0971.
128.2, 128.6, 129.0, 132.3, 132.9, 135.0, 135.9, 141.8, 151.0,
158.4, 160.0, 161.3, 164.3. HRMS (ESI): m/z calcd for C18H14
-
N4O2SNa [M+ + Na]: 373.0730; found: 373.0723.
5-(4-Fluorophenyl)-1,3-dimethyl-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3j)25
1,3-Dimethyl-7-phenyl-5-(pyridin-2-yl)pyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3o)
White solid; Rf ¼ 0.45 (SiO2, hexane/ethyl acetate ¼ 10 : 90);
yield: 67% (121 mg, 0.335 mmol), mp 233 ꢀC. 1H NMR (400
MHz, CDCl3): d ¼ 3.41 (s, 3H), 3.85 (s, 3H), 7.18 (t, J ¼ 8.8 Hz, Pale yellow solid; Rf ¼ 0.45 (SiO2, hexane/ethyl acetate ¼
2H), 7.50–7.56 (m, 3H), 7.66–7.69 (m, 2H), 8.55 (t, J ¼ 1.6 Hz, 50 : 50); yield: 63% (109 mg, 0.315 mmol), mp 254 ꢀC. 1H NMR
2H). 13C NMR (100 MHz, CDCl3): d ¼ 28.6, 29.5, 103.6, 114.8 (d, J (400 MHz, CDCl3): d ¼ 3.38 (s, 3H), 3.86 (s, 3H), 7.48–7.56 (m,
¼ 22.0 Hz), 128.7, 129.3, 131.6 (d, J ¼ 8.0 Hz), 132.4, 134.22, 4H), 7.63 (d, J ¼ 8.0 Hz, 1H), 7.89 (d, J ¼ 7.6 Hz, 1H), 8.56 (d, J ¼
134.25, 136.0, 151.2, 158.0, 159.7, 164.0 (d, J ¼ 250 Hz), 169.2. 7.2 Hz, 2H), 8.73 (d, J ¼ 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
HRMS (ESI): m/z calcd for C20H16FN4O2 [M+ + H]: 363.1257; d ¼ 28.5, 29.8, 104.3, 122.8, 124.0, 128.7, 129.4, 132.4, 136.0,
found: 363.1268.
136.5, 149.0, 151.3, 156.7, 157.6, 159.3, 165.9, 168.5. HRMS
(ESI): m/z calcd for C19H16N5O2 [M+ + H]: 346.1298; found:
346.1293.
1,3-Dimethyl-5-(4-cyanophenyl)-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3k)
1,3-Dimethyl-5-phenyl-7-(p-tolyl)pyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (3p)25
Off-white solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90);
yield: 72% (133 mg, 0.36 mmol), mp 252 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 3.41 (s, 3H), 3.87 (s, 3H), 7.52 (t, J ¼ 6.8 Hz, 2H), 7.65 White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield:
(d, J ¼ 8.4 Hz, 1H), 7.71 (d, J ¼ 8.4 Hz, 2H), 7.79 (d, J ¼ 8.0 Hz, 83% (148 mg, 0.415 mmol), mp 247 ꢀC. 1H NMR (400 MHz,
2H), 8.55 (d, J ¼ 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ CDCl3): d ¼ 2.44 (s, 3H), 3.40 (s, 3H), 3.84 (s, 3H), 7.30 (d, J ¼
28.6, 30.0, 103.7, 118.7, 127.0, 128.8, 129.4, 129.8, 131.5, 132.3, 8.4 Hz, 2H), 7.47–7.53 (m, 3H), 7.64 (dd, J ¼ 2.0 Hz, 8.0 Hz, 2H),
132.7, 135.7, 142.9, 151.1, 157.9, 159.5, 165.8. HRMS (ESI): m/z 8.46 (t, J ¼ 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 21.7,
calcd for C21H15N5O2Na [M+ + Na]: 392.1118; found: 392.1111.
28.6, 29.9, 103.4, 127.7, 128.6, 129.1, 129.3, 129.4, 129.9, 133.5,
138.5, 143.0, 157.8, 159.7, 165.3, 170.3. HRMS (ESI): m/z calcd
for C21H19N4O2 [M+ + H]: 359.1508; found: 359.1492.
1,3-Dimethyl-5-(naphthalen-1-yl)-7-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3l)
7-(4-Fluorophenyl)-1,3-dimethyl-5-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3q)25
Pale yellow solid; Rf ¼ 0.35 (SiO2, hexane/ethyl acetate ¼
10 : 90); yield: 85% (167 mg, 0.425 mmol), mp 264 ꢀC. 1H NMR
(400 MHz, CDCl3): d ¼ 3.29 (s, 3H), 3.91 (s, 3H), 7.36–7.40 (m, White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield:
2H) 7.44–7.62 (m, 7H), 7.94 (d, J ¼ 8.4 Hz, 1H), 8.0 (d, J ¼ 8.4 Hz, 77% (139 mg, 0.385 mmol), mp 243–245 ꢀC. 1H NMR (400 MHz,
1H), 8.56 (t, J ¼ 1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d ¼ CDCl3): d ¼ 3.41 (s, 3H), 3.85 (s, 3H), 7.18 (t, J ¼ 8.8 Hz, 2H),
28.5, 29.8, 105.5, 124.6, 125.1, 125.4, 126.0, 126.5, 128.7, 129.1, 7.48–7.54 (m, 3H), 7.63 (dd, J ¼ 1.6 Hz, 8.0 Hz, 2H), 8.60 (dd, J ¼
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5.6 Hz, 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 28.6, 29.9, d ¼ 3.28 (s, 3H), 3.68 (s, 3H), 5.80 (d, J ¼ 2.8 Hz, 1H), 6.81
103.6, 115.7 (d, J ¼ 21.0 Hz), 127.7, 129.1, 130.0, 131.7 (d, J ¼ (br s, 1H, NH), 7.30–7.37 (m, 3H), 7.46–7.53 (m, 4H), 7.61 (t, J
10.0 Hz), 132.4, 138.3, 151.3, 157.9, 159.6, 164.4, 165.6 (d, J ¼ ¼ 7.6 Hz, 1H), 7.89 (t, J ¼ 1.2 Hz, 2H). 13C NMR (100 MHz,
161.0 Hz), 170.5. HRMS (ESI): m/z calcd for C20H15FN4O2Na [M+ CDCl3): d ¼ 27.8, 29.4, 53.4, 89.8, 126.7, 127.2, 128.5, 128.96,
+ Na]: 385.1071; found: 385.1063.
129.0, 132.6, 133.0, 144.2, 150.6, 152.3, 159.4, 161.4.
7-(4-Chlorophenyl)-1,3-dimethyl-5-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3r)25
Conflicts of interest
The author declares no conicts of nancial interest.
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 10 : 90); yield:
80% (151 mg, 0.40 mmol), mp 259–260 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 3.41 (s, 3H), 3.85 (s, 3H), 7.46–7.54 (m, 5H), 7.62 (t, J
¼ 1.6 Hz, 2H), 8.52 (d, J ¼ 8.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d ¼ 28.6, 29.9, 103.8, 127.8, 128.9, 129.1, 130.1, 130.6,
134.6, 138.3, 138.7, 151.3, 157.9, 159.5, 164.3, 170.5. HRMS
(ESI): m/z calcd for C20H15ClN4O2Na [M+ + Na]: 401.0776; found:
401.0766.
Acknowledgements
The author P. Debnath is thankful to DST (New Delhi) for
nancial assistance (Grant no. YSS/2015/001554).
Notes and references
˚
¨
1 (a) T. C. Kuhler, J. Fryklund, N.-A. Bergman, J. Weilitz, A. Lee
7-(4-Bromophenyl)-1,3-dimethyl-5-phenylpyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3s)25
and H. Larsson, J. Med. Chem., 1995, 38, 4906; (b) P. Madsen,
L. B. Knudsen, F. C. Wiberg and R. D. Carr, J. Med. Chem.,
1998, 41, 5150; (c) L. Llauger, H. He, J. Kim, J. Aguirre,
N. Rosen, U. Peters, P. Davies and G. Chiosis, J. Med.
Chem., 2005, 48, 2892; (d) N. Pietrancosta, A. Moumen,
Off-white solid; Rf ¼ 0.45 (SiO2, hexane/ethyl acetate ¼ 10 : 90);
yield: 80% (169 mg, 0.40 mmol), mp 255–256 ꢀC. 1H NMR (400
MHz, CDCl3): d ¼ 3.41 (s, 3H), 3.85 (s, 3H), 7.48–7.54 (m, 3H),
7.61–7.64 (m, 4H), 8.44 (dd, J ¼ 1.6 Hz, J ¼ 6.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d ¼ 28.7, 30.0, 103.9, 127.4, 127.8, 129.1,
130.1, 130.8, 131.9, 135.1, 138.2, 151.3, 157.9, 159.5, 164.4,
170.6. HRMS (ESI): m/z calcd for C20H16BrN4O2 [M+ + H]:
423.0451; found: 423.0441.
¨
R. Dono, P. Lingor, V. Planchamp, F. Lamballe, M. Bahr,
J.-L. Kraus and F. Maina, J. Med. Chem., 2006, 49, 3645; (e)
A. T. Mavrova, D. Vuchev, K. Anichina and N. Vassilev, Eur.
J. Med. Chem., 2010, 45, 5856.
2 For review: (a) M. Asif, Int. J. Bioorg. Chem., 2017, 2, 146; (b)
H. A. Al-Khamees, S. M. Bayomi, H. A. Kandil and K. E. H. El-
Tahir, Eur. J. Med. Chem., 1990, 25, 103; (c) A. T. Chaviara,
P. J. Cox, K. H. Repana, R. M. Papi, K. T. Papazisis,
D. Zambouli, A. H. Kortsaris, D. A. Kyriakidis and
C. A. J. Bolos, Inorg. Biochem., 2004, 98, 1271; (d)
G. Deepika, P. Gopinath, G. Kranthi, C. Nagamani,
Y. V. Jayasree, N. V. Naidu and S. Enaganti, J. Pharm. Res.,
2012, 5, 1105.
3 For review on synthesis of nitrogen heterocycles:(a) L. Yu,
R. Qian, X. Deng, F. Wang and Q. Xu, Sci. Bull., 2018, 63,
1010; (b) L. Yu, M. Liu, F. Chen and Q. Xu, Org. Biomol.
Chem., 2015, 13, 8379; (c) K. C. Majumdar, P. Debnath,
N. De and B. Roy, Curr. Org. Chem., 2011, 15, 1760; (d)
K. C. Majumdar, B. Roy, P. Debnath and A. Taher, Curr.
Org. Chem., 2010, 14, 846; (e) C. Allais, J.-M. Grassot,
J. Rodriguez and T. Constantieux, Chem. Rev., 2014,
114, 10829; (f) Y. Yamamoto, Chem. Soc. Rev., 2014, 43,
1575; (g) B. Zhang and A. Studer, Chem. Soc. Rev., 2015,
44, 3505.
4 (a) G. M. Ziarani, N. H. Nasaba and N. Lashgarib, RSC Adv.,
2016, 6, 38827; (b) T. P. Selvam, C. R. James,
P. V. Dniandev and S. K. Valzita, Res. Pharm., 2012, 4, 01.
5 (a) J. D. Brown, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katrizky and C. W. Rees, Pergamon, Oxford, 1984, vol.
3, p. 57; (b) E. D. Clercq and R. Beraaerts, J. Biol. Chem.,
1987, 262, 14905–14911; (c) V. S. Dinakaran, B. Bomma and
K. K. Srinivasan, Pharma Chem., 2012, 4, 255; (d)
A. Y. Aksinenko, T. V. Goreva, T. A. Epishina, S. V. Trepalin
and V. B. Sokolov, J. Fluorine Chem., 2016, 188, 191.
1-Benzyl-3-methyl-5,7-diphenylpyrimido[4,5-d]pyrimidine-
2,4(1H,3H)-dione (3t)25
White solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 5 : 95); yield:
88% (185 mg, 0.44 mmol), mp 211–212 ꢀC. 1H NMR (400 MHz,
CDCl3): d ¼ 3.41 (s, 3H), 5.71 (s, 2H), 7.28–7.36 (m, 3H), 7.48–
7.57 (m, 6H), 7.60–7.65 (m, 4H), 8.58 (t, J ¼ 6.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d ¼ 28.7, 45.9, 103.7, 127.7, 128.0, 128.70,
128.74, 128.8, 129.1, 129.4, 130.0, 132.4, 136.2, 136.6, 138.4,
151.2, 157.6, 159.5, 165.3, 170.7. HRMS (ESI): m/z calcd for
C
26H20N4O2Na [M+ + Na]: 443.1478; found: 443.1471.
1,3-Dibenzyl-5,7-diphenylpyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione
(3u)25
White solid; Rf ¼ 0.5 (SiO2, hexane/ethyl acetate ¼ 5 : 95);
yield: 92% (228 mg, 0.46 mmol), mp 215 ꢀC. 1H NMR (400
MHz, CDCl3): d ¼ 4.70 (s, 2H), 5.21 (s, 2H), 7.26–7.38 (m,
6H), 7.46–7.60 (m, 10H), 7.65 (t, J ¼ 1.6 Hz, 2H), 8.56 (t, J ¼
2.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): d ¼ 45.0, 46.0,
103.9, 127.8, 127.9, 128.5, 128.68, 128.7, 129.1, 129.4, 130.2,
132.3, 136.2, 136.5, 136.6, 138.3, 151.1, 157.7, 159.4, 165.2,
170.7. HRMS (ESI): m/z calcd for C32H24N4O2Na [M+ + Na]:
519.1791; found: 519.1782.
1,3-Dimethyl-5,7-diphenyl-5,6-dihydropyrimido[4,5-d]
pyrimidine-2,4(1H,3H)-dione (3a0)
Yellow solid; Rf ¼ 0.4 (SiO2, hexane/ethyl acetate ¼ 50 : 50);
1
yield: 42% (73 mg, 0.21 mmol), H NMR (400 MHz, CDCl3):
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6 (a) W. J. Coates, Eur. Pat., 351058, 1990Chem. Abstr., 1990, 24 M. L. Deb, P. J. Borpatra and P. K. Baruah, Green Chem.,
113, 40711; (b) A. A. Ramsey, US Pat., 3830812, FMC Corp.,
1974Chem. Abstr., 1974, 81, 136174.
7 Y. S. Sanghvi, S. B. Larson, S. S. Matsumoto, L. D. Nord,
2019, 21, 69.
25 P. Debnath, G. Sahu and U. C. De, ChemistrySelect, 2019,
4, 2327.
D. F. Smee, R. C. Willis, T. L. Avery, R. K. Robins and 26 G. V. R. Sharama and A. Robert, Res. Chem. Intermed., 2013,
G. R. Revankar, J. Med. Chem., 1989, 32, 629. 39, 3251.
8 (a) P. Sharma, N. Rane and V. Gurram, Bioorg. Med. Chem. 27 (a) A. Modak, A. Deb, S. Patra, S. Rana, S. Maity and
Lett., 2004, 14, 4185; (b) J. De La Cruz, T. Carrasco,
G. Ortega and G. F. S. De La Cuesta, Lipids, 1992, 27, 192.
D. Maiti, Chem. Commun., 2012, 4253; (b) T. Iwai,
T. Fujihara and Y. Tsuji, Chem. Commun., 2008, 6215.
9 (a) D. W. Fry, M. A. Becker and R. L. Switzer, Mol. Pharmacol., 28 (a) S. Michlik and R. Kempe, Nat. Chem., 2013, 5, 140; (b)
1995, 47, 810; (b) P. Sharma, N. Rane and P. Pandey, Arch.
Pharm., 2006, 339, 572; (c) H. Wang, C. Yang, J. R. Doherty,
W. R. Roush, J. L. Cleveland and T. D. Bannister, J. Med.
Chem., 2014, 57, 7317.
S. Michlik and R. Kempe, Angew. Chem., Int. Ed., 2013, 52,
6326; (c) D. Srimani, Y. Ben-David and D. Milstein, Angew.
Chem., Int. Ed., 2013, 52, 4012; (d) M. Zhang, H. Neumann
and M. Beller, Angew. Chem., Int. Ed., 2013, 52, 597; (e)
M. Zhang, X. Fang, H. Neumann and M. Beller, J. Am.
Chem. Soc., 2013, 135, 11384; (f) R. H. Crabtree,
Organometallics, 2011, 30, 17; (g) T. D. Nixon,
M. K. Whittlesey and J. M. J. Williams, Dalton Trans.,
10 V. J. Ram, A. Goel, S. Sarkhel and P. R. Maulik, Bioorg. Med.
Chem., 2002, 10, 1275.
11 J. D. Figueroa-Villar, C. L. Carneiro and E. R. Cruz,
Heterocycles, 1992, 34, 891.
´
12 N. Kitamura and A. Onishi, Eur. Pat., 163599, 1984Chem.
Abstr., 1984, 104, 186439.
13 (a) P. Raddatz and R. Bergmann, Ger. Pat., 360731,
1988Chem. Abstr., 1988, 109, 54786; (b) R. C. Dukarm,
2009, 753; (h) G. Guillena, D. J. Ramon and M. Yus,
Chem. Rev., 2009, 110, 1611; (i) M. H. S. A. Hamid,
P. A. Slatford and J. M. J. Williams, Adv. Synth. Catal.,
2007, 349, 1555.
¨
F. C. Morin, J. A. Russell and R. H. Steinhorn, Pediatr. Res., 29 (a) M. Zhang, S. Imm, S. Bahn, H. Neumann and
1998, 44, 831.
M. Beller, Angew. Chem., Int. Ed., 2011, 50, 11197; (b)
¨
14 T. J. Delia, M. Baumann and A. Bunker, Heterocycles, 1993,
35, 1397.
S. Imm, S. Bahn, M. Zhang, L. Neubert, H. Neumann,
F. Klasovsky, J. Pfeffer, T. Haas and M. Beller, Angew.
¨
15 Synthesis of 5,6-dihydropyrimido[4,5-d]pyrimidine by three
component reactions:(a) M. Dabiri, H. Arvin-Nezhad,
H. R. Khavasi and A. Bazgir, Tetrahedron, 2007, 63, 1770;
(b) S. Majumder, P. Borah and P. J. Bhuyan, Tetrahedron
Lett., 2014, 55, 1168; (c) M. Kidwai, K. Singhal and
S. Kukreja, Z. Naturforsch., 2007, 62b, 732.
16 Synthesis of 5,6-dihydropyrimido[4,5-d]pyrimidine by [4+2]
cycloaddition reactions:(a) D. Prajapati, M. Gohain and
A. Thakur, Bioorg. Med. Chem. Lett., 2006, 16, 3537; (b)
I. Devi, H. N. Borah and P. J. Bhuyan, Tetrahedron Lett.,
Chem., Int. Ed., 2011, 50, 7599; (c) S. Bahn, S. Imm,
L. Neubert, M. Zhang, H. Neumann and M. Beller,
ChemCatChem, 2011, 3, 1853; (d) G. Guillena,
D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2007,
46, 2358–2364; (e) F.-X. Yan, M. Zhang, X.-T. Wang,
F. Xie, M.-M. Chen and H.-F. Jiang, Tetrahedron, 2014,
70, 1193; (f) X.-T. Wang, M.-M. Chen, F. Xie and
M. Zhang, RSC Adv., 2014, 4, 14744; (g) M. Zhang,
F. Xie, X.-T. Wang, F.-X. Yan, T. Wang, M.-M. Chen and
Y.-Q. Ding, RSC Adv., 2013, 3, 6022.
´
2004, 45, 2405; (c) M. Gohain, D. Prajapati, B. J. Gogoi and 30 Y. Wu, P. Y. Choy, F. Mao and F. Y. Kwong, Chem. Commun.,
J. S. Sandhu, Synlett, 2004, 1179; (d) M. El-Moghazy, 2013, 49, 689.
D. A. Ibrahim, N. M. Abdelgawad, N. A. H. Farag and 31 W. Guo, K. Huang, F. Ji, W. Wu and H. Jiang, Chem.
A. S. El-Khouly, Sci. Pharm., 2011, 79, 429; (e) D. Prajapati
and A. J. Thakur, Tetrahedron Lett., 2005, 46, 1433.
17 K. Hirota, Y. Kitade, H. Sajiki and Y. Maki, J. Chem. Soc.,
Perkin Trans. 1, 1990, 123.
Commun., 2015, 51, 8857.
32 (a) W. Guo, Org. Biomol. Chem., 2015, 13, 10285; (b) Z. Yin
and P. Sun, J. Org. Chem., 2012, 77, 11339; (c) F. Xie,
M. Chen, X. Wang, H. Jiang and M. Zhang, Org. Biomol.
Chem., 2014, 12, 2761.
18 H. Wamhoff and J. Muhr, Synthesis, 1998, 919.
19 H. Wang, C. Wang and T. D. Bannister, Tetrahedron Lett., 33 (a) X.-F. Wu, J.-L. Gong and X. Qi, Org. Biomol. Chem.,
2015, 56, 1949–1952.
2014, 12, 5807; (b) Y. F. Li, Synlett, 2007, 2922; (c)
T. K. Achar and P. Mal, J. Org. Chem., 2015, 80, 666; (d)
X. Zhang, M. Wang, P. Li and L. Wang, Chem. Commun.,
2014, 50, 8006; (e) L. Gao, H. Tang and Z. Wang, Chem.
Commun., 2014, 50, 4085; (f) W.-P. Mai, H.-H. Wang,
Z.-C. Li, J.-W. Yuan, Y.-M. Xiao, L.-R. Yang, P. Mao and
L.-B. Qu, Chem. Commun., 2012, 48, 10117.
20 S. Badvel, R. R. Gopireddy, T. B. Shaik, S. Hasti,
V. R. Tummaluru and N. R. Chamarthi, Chem. Heterocycl.
Compd., 2015, 51, 749.
21 R. Ghorbani-Vaghei and N. Sarmast, Appl. Organomet. Chem.,
2018, 32, e4003.
22 (a) M. F. Moghaddam, M. R. Khodabakhshi and M. Aminaee,
Tetrahedron Lett., 2014, 55, 4720; (b) A. Hamed, Synthesis, 34 B. Morel, P. Franck, J. Bidange, S. Sergeyev, D. Smith,
1992, 591.
J. Moseley and B. U. W. Maes, ChemSusChem, 2017, 10,
624.
35 M. Noe, A. Perosa and M. Selva, Green Chem., 2013, 15, 2252.
23 S. K. Srivastava, W. Haq and P. M. S. Chauhan, Bioorg. Med.
Chem. Lett., 1999, 9, 965.
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RSC Advances
36 S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem.
Soc. Rev., 2008, 37, 320.
M. Diekmann, K. A. Jacobson, W. L. Padgett and
J. W. Daly, J. Med. Chem., 2002, 45, 3440.
37 (a) M. Cernova, I. Cerna, R. Pohl and M. Hocek, J. Org. Chem., 38 (a) M. Wang, Y. Meng, W. Wei, J. Wu, W. Yu and J. Changa,
2011, 76, 5309; (b) C. E. Muller, M. Thorand, R. Qurishi,
Adv. Synth. Catal., 2018, 360, 86; (b) A. R. Tiwari and
B. M. Bhanage, ChemistrySelect, 2016, 3, 343.
This journal is © The Royal Society of Chemistry 2019
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