Convenient One-Pot Four-Component Synthesis of 6,8-Disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]-pyrimidin-4(3H)-ones via a Triple Mannich Reaction

Article abstract of DOI:10.1071/CH19088

An efficient and simple one-pot four-component protocol has been developed and performed for the synthesis of 6,8-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones, involving a triple Mannich reaction of 6-amino-2-(ethylthio)pyrimidin-4(3H)-one, formaldehyde, primary amines, and alcohols. Secondary amines were also utilised instead of alcohols as Mannich nucleophiles, and a variety of functional groups and electronically varied reaction partners were tolerated. This one-pot reaction facilitated the generation of a library of pyrimido[4,5-d]pyrimidin-4(3H)-ones in very good to excellent yields. The regioselectivity of this reaction was investigated using atomic charge calculations, and spectroscopic data confirmed that the triple Mannich products were 6,8-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones rather than the isomeric 3,6-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones. The structures of all compounds synthesised using the triple Mannich reaction were confirmed via spectroscopic and elemental analyses. The reaction mechanism was studied and confirmed by isolation of the intermediate.

Full text of DOI:10.1071/CH19088

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
https://doi.org/10.1071/CH19088
Convenient One-Pot Four-Component Synthesis of
6,8-Disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]-
pyrimidin-4(3H)-ones via a Triple Mannich Reaction
A B C
, ,
A C
,
Ahmed F. M. EL-Mahdy,
Zainab A. Hozien
Hassan A. H. El-Sherief,
and
A
A
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt.
Department of Materials and Optoelectronic Science, National Sun Yat-Sen University,
Kaohsiung 80424, Taiwan.
B
C
Corresponding authors. Email: ahmedelmahdy@mail.nsysu.edu.tw;
hassan.elsherief@science.au.edu.eg
An efficient and simple one-pot four-component protocol has been developed and performed for the synthesis of
6,8-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones, involving a triple Mannich reaction of
6-amino-2-(ethylthio)pyrimidin-4(3H)-one, formaldehyde, primary amines, and alcohols. Secondary amines were also
utilised instead of alcohols as Mannich nucleophiles, and a variety of functional groups and electronically varied reaction
partners were tolerated. This one-pot reaction facilitated the generation of a library of pyrimido[4,5-d]pyrimidin-4(3H)-
ones in very good to excellent yields. The regioselectivity of this reaction was investigated using atomic charge
calculations, and spectroscopic data confirmed that the triple Mannich products were 6,8-disubstituted-5,6,7,8-tetrahy-
dropyrimido[4,5-d]pyrimidin-4(3H)-ones rather than the isomeric 3,6-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]
pyrimidin-4(3H)-ones. The structures of all compounds synthesised using the triple Mannich reaction were confirmed
via spectroscopic and elemental analyses. The reaction mechanism was studied and confirmed by isolation of the
intermediate.
Manuscript received: 22 February 2019.
Manuscript accepted: 15 April 2019.
Published online: 21 May 2019.
Introduction
are accompanied by high cost, lower yields, and complex product
isolation. MCRs greatly contribute to the possibility of efficiently
generating a highly complex molecule in a single step, which
would lead to shorter reaction times, higher yield, greater step-
efficiency, and simpler purification procedures.[17,18] Accord-
ingly, MCRs have attracted considerable attention in combinato-
rial synthesis,[19,20] medicinal chemistry, the pharmaceutical
industry,[21,22], and modern drug discovery.[23–25] The Mannich
reaction, one of the MCRs, is considered useful because of its
effectiveness in the generation of carbon–carbon and carbon–
nitrogen single bonds.[26] A condensation Mannich reaction is
usually utilised in the amino-alkylation of various compounds
with one or more active hydrogen atoms. On the other hand, a
double Mannich reaction could occur when the starting com-
pounds already have two adjacent active hydrogen atoms.[27–30]
Recently, we established a new efficient strategy for the synthesis
of triazolothiadiazine,[27] pyrimidothiadiazine,[28] pyrazolopyri-
midine,[29] and thiadiazinobenzimidazole[30] derivatives in rela-
tively high yields via double Mannich reactions. In addition, we
reportedanefficient quadruple Mannich reactionfor the synthesis
of 2,5,7,9,11-pentaazaphenalenes in excellent yields.[31]
Pyrimidopyrimidine derivatives represent an important class of
annelated uracils that have received significant attention from
researchers in the field of medicinal chemistry because of their
close relation to purines and pteridine systems.[1–3] Most of them
possess a diverse range of biological activities, such as anti-
tumour,[4] antioxidant,[5] antiviral,[4,6] antibacterial,[7] antifun-
gal,[8] and hepatoprotective activities.[9] The pyrimidopyrimidine
derivatives have a wide range of pharmacological activities,
such as vasodilation, bronchodilation, and antiallergic
activities. Moreover, this type of heterocyclic compound exhibits
potent inhibitory properties towards the 5-phosphoribosyl-1-
pyrophosphate synthetase,[10] dihydrofolate reductase,[11] and
tyrosine kinase domain.[12] Due to the aforementioned biological
activities and medicinal utilities of pyrimidopyrimidines, these
moieties have a significant contribution to drug discovery and
medicinal applications.
In recent years, the goal of organic chemists has been to
discover new biologically active moieties with minimum syn-
thetic steps.[13–16] in addition, chemists aim to develop new
methods that are rapid, efficient, high yielding, and environmen-
tally benign. To achieve this goal, multi-component reactions
(MCRs)—with at least three components interacting simulta-
neously in a one-pot synthetic step—have become the modern
approachinplaceofmorecomplicatedmulti-stepreactions,which
To the best of our knowledge, there are few methods available
for the synthesis of pyrimido[4,5-d]pyrimidinones via the double
Mannich reaction of 6-aminouracil (R1 ¼ H) or its corresponding
N-1 substituted derivatives (R1 ¼ H) with primary amines and
Journal compilation ꢀ CSIRO 2019
www.publish.csiro.au/journals/ajc

B
A. F. M. EL-Mahdy, H. A. H. El-Sherief, and Z. A. Hozien
(a)
O
O
R2
5
8
4
HN
HN
N
3
2
6
7
HCHO, R2-NH2
1
N
EtOH or MeOH/AcOH
NH2
X
N
X
N
H
R1
R1
X ϭ O, S
R1 ϭ H, alkyl, aryl, benzyl, phenylethyl
R2 ϭ alkyl, aryl
O
O
4
(b)
R2
5
N
N
N
3
6
7
HCHO, R2-NH2
2
8
1
N
EtOH, 3 days
O
N
NH2
O
N
R2 ϭ aryl
OH
Fig. 1. Background for the synthesis of pyrimido[4,5-d]pyrimidinones via Mannich reaction.
O
R1
HN
N
O
S
N
N
O
4
4a–p
R2
HCHO
HN
3
2
5
6
R1
NH2
ϩ
ϩ
R2
OH
Δ, 2 h
O
1
S
N
NH2
R1
R2
O
N
N
1
2
3
S
N
N
H
5a–p
4a–i, R2 ϭ CH3 (a: R1 ϭ CH2CH2CH2CH3, b: R1 ϭ CH2CH(CH3)2, c: R1 ϭ CH2C6H5, d: R1 ϭ C6H5, e: R1 ϭ C6H4OCH3-p, f: R1 ϭ C6H4CH3-p,
g: R1 ϭ C6H4OH-P, h: R1 = C6H4Cl-p, i: R1 = C6H4Br-p).
4j–p, R2 ϭ H (j: R ϭ CH2CH(CH3)2, k: R1 ϭ CH2C6H5, l: R1 ϭ C6H5, m: R1 ϭ C6H4OCH3-p, n: R1 ϭ C6H4CH3-p, o: R1 ϭ C6H4Cl-p, p: R1 ϭ C6H4Br-p).
Scheme 1. Triple Mannich reaction of 6-amino-2-(ethylthio)pyrimidin-4(3H)-one in alcoholic solvent.
formaldehyde (Fig. 1a).[32–35] Furthermore, the 8-hydroxymethyl
derivative of pyrimido[4,5-d]pyrimidinone was once prepared
by reacting 6-amino-1,3-dimethyluracil with primary aromatic
amines and formaldehyde in ethanol for 3 days (Fig. 1b).[36]
Interestingly, there are no reported methods for the synthesis
of the 8-alkoxymethyl derivatives of pyrimido[4,5-d]pyrimidi-
none by either the Mannich reaction or other methods. There-
fore, as part of our continued interest in the preparation of
various heterocyclic compounds with pharmacological and
biological activities, herein we report an efficacious and
facile four-component protocol for the preparation of various
8-(alkoxymethyl)pyrimido[4,5-d]pyrimidinones (4 and 8) in-
volving the triple Mannich reaction of 6-amino-2-(ethylthio)
pyrimidin-4(3H)-one (1) with formaldehyde, primary amines 2,
and alcohols 3 or 7 under reflux for 2 h.
our efforts were directed to studying the behaviour of 6-amino-
2-(ethylthio)pyrimidin-4(3H)-one (1) as a trifunctional nucleo-
phile with both primary aliphatic and aromatic amines under
Mannich reaction conditions. When compound 1 was treated
with one equivalent of primary amine 2 and an excess of aqueous
formaldehyde (35 %) in ethanol or methanol for 2 h, a single
product with an undetermined structure was formed. Further
analyses—NMR and mass spectrometry—as well as elemental
analysis determined that the structure of this new product might
have been either 4a–p or 5a–p (Scheme 1). The IR spectrum of
the product obtained using isobutylamine in methanol lacked the
amino (NH2) absorption band and showed absorption bands at
3380 cmꢀ1 for NH, 2975–2930 cmꢀ1 for C–H aliphatic
stretching, 1632 cmꢀ1 for C=O stretching, 1567 cmꢀ1 for C=N
stretching, and 1488 cmꢀ1 for C=C stretching. Surprisingly,
1
the H NMR (Fig. 2a) and 13C NMR spectra (Fig. 2b) of the
Results and Discussion
product indicated that one molecule of isobutylamine, three
molecules of formaldehyde, and one molecule of methanol had
reacted, confirming a triple Mannich reaction. Consequently,
In the course of our on-going research on the synthesis of
innovative heterocyclic scaffolds using the Mannich reaction,

One-Pot Synthesis via a Triple Mannich Reaction
C
(a)
3.0
2.5
2.0
1.5
1.0
f1 [ppm]
13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
f1 [ppm]
0 Ϫ0.5
(b)
220 210 200 190 180 170 160 150 140 130 120 110 100 90
f1 [ppm]
80
70
60
50
40
30
20
10
0
Fig. 2. 1H NMR (a) and 13C NMR (b) spectra of the triple Mannich product of isobutylamine in methanol.
the 1H NMR spectrum of the new product was singularised by
the appearance of a singlet signal at 12.50 ppm, which dis-
appeared on deuteration and three single signals at 5.00, 4.21,
and 3.73 ppm corresponding to the three methylene groups, in
addition to the other protons for isobutyl, methoxy, and ethyl
groups ((CH3)2CHCH2, OCH3, and SCH2CH3). On the other
hand, its 13C NMR spectrum was characterised by the presence
of three signals for the methylene groups at 75.53, 66.89, and
48.89 ppm, as well as signals for the rest of the carbon atoms at
the expected chemical shifts. The mass spectrum of the obtained
product revealed a molecular ion peak at the m/z value of 313.56
[M þ 1] and elemental analysis was found to be consistent with
the theoretical values of the suggested structure 4a or 5a.
Formation of 4a–p rather than 5a–p isomers could be attrib-
uted to the following. First, the S-alkylated-6-aminouracil 1 is
shown to exist in solution largely in the lactam form, and the

D
A. F. M. EL-Mahdy, H. A. H. El-Sherief, and Z. A. Hozien
, HCHO
R
3
OH
2
Δ, 2 h
O
N
O
4
O
N
R1
R1
5
8
N
H
HN
N
HCHO, Dioxane
HN
N
HCHO
HN
3
2
R2
OH
6
3
ϩ
4a–p
R1
NH2
Δ, 2 h
7
1
N
S
N
S
S
NH2
OH
O
1
2
6
O
N
O
O
N
HN
N
HN
N
HN
N
HN
N
S
N
H
S
N
N
S
N
H
S
N
N
H
H
6a, 78 %
6b, 86 %
6c, 79 %
6d, 73 %
Cl
Br
O
O
O
O
O
HN
N
HN
N
HN
N
HN
N
S
N
N
H
S
N
N
H
S
N
N
S
N
N
H
H
6e, 82 %
6f, 80 %
6g, 75 %
6h, 74 %
Scheme 2. The formation of the intermediates 6a–h via a double Mannich reaction.
tautomeric hydrogen was found to be in position 3, as indicated
byspectroscopicstudies.[37–40] Second, theappearance ofNH(3)
at 12.89–11.92 ppm[41] supported the formation of 4a–p rather
than that of 5a–p. Third, the differences in electron densities of
the nitrogen atoms, N-3 and N-8, of the expected intermediate
6a–h control the regioselectivity of the third Mannich step
(Scheme 2). As per the atomic charge calculations of the
intermediate 6a (Fig. 3 and Table 1), the highest electron density
value is located on N-8 (ꢀ0.64343) rather than N-3 (ꢀ0.63955).
Furthermore, we observed that the obtained products completely
dissolved in 5 % KOH alcoholic solution and completely repre-
cipitated upon addition of dilute acetic acid, in agreement with
the suggested structure of the isomeric products 4a–p. Conse-
quently, based on the above data, the formation of products 5a–p
was ruled out, and the structures of the reaction products were
assigned as the isomeric products 4a–p (Scheme 2).
26
14
27
25
24
21
4
12
23
13
7
5
20
11
9
19
1
3
15
6
10
2
22
28
18
16
8
17
31
29
35
34
30
32
33
Finally, as reported, the double condensation Mannich reac-
tion of 6-aminouracils with primary amines and formaldehyde
occurred on the CH and NH2 groups to provide the correspond-
ing pyrimido[4,5-d]pyrimidin-4-ones.[32–35] These reported
results support our hypothesis that the formed intermediates of
this triple Mannich products are 2-(ethylthio)-6-substituted-
pyrimido[4,5-d]pyrimidin-4-ones 6a–h (Scheme 2), which
could be easily transformed to their 8-hydroxymethyl deriva-
tives followed by condensation with the solvent to afford the
final isomeric products 4a–p via a third Mannich step. This
hypothesis is also supported by isolation of intermediates 6a–h
in 80–90 % yield upon refluxing a mixture of 6-amino-2-
(ethylthio)pyrimidin-4(3H)-one (1), formaldehyde, and primary
amines in dioxane as the aprotic solvent. Subsequently, the
isolated intermediates 6a–h were subjected to the third Mannich
reaction with formaldehyde and a variety of alcohols to give
4a–p in 73–86 % yield (Scheme 2). The IR and NMR spectra,
melting points, and mixed melting points of the products were
the same as those of products obtained from the direct inter-
action of 6-amino-2-(ethylthio)pyrimidin-4(3H)-one (1) with
Fig. 3. The geometry structure of 6a: grey (carbon), blue (nitrogen), red
(oxygen), yellow (sulfur) and white (hydrogen).
formaldehyde and primary amines in alcohol. However, the
8-hydroxymethyl derivative could not be isolated.
Encouraged by these results, we focussed on evaluating
the substrate scope of various aromatic or aliphatic amines 2
with regards to the triple Mannich reaction using ethanol as
both reactant and solvent. The reaction was effective and
produced the corresponding 6-substituted-8-(ethoxymethyl)-2-
(ethylthio)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-
ones 4a–i in good-to-excellent yields (Scheme 3). It was noted
that aliphatic amines (Scheme 3, 4a and 4b) gave higher yields
than the aromatic amines (especially those with electron-
withdrawing groups). Steric hindrance did not affect the yield
when isobutylamine was utilised (Scheme 3, 4b). Benzylamine
also successfully generated the corresponding product in excel-
lent yields (Scheme 3, 4c). When aniline was reacted, the

One-Pot Synthesis via a Triple Mannich Reaction
E
Table 1. The atomic charge values of 6a
Atom
Number
Charge
Atom
Number
Charge
C
1
2
0.30968
0.41801
N(3)
H
O
H
H
C
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
20.63955
0.45568
ꢀ0.65030
0.19928
0.27053
ꢀ0.69903
0.23376
0.24725
0.23616
0.27097
ꢀ0.60002
0.26909
0.27133
ꢀ0.71543
0.25582
0.24886
0.24948
C
C
3
ꢀ0.26064
0.63705
C
4
C
5
ꢀ0.26582
ꢀ0.06695
0.22220
C
6
H
H
C
7
H
H
H
S
8
0.24706
9
ꢀ0.25879
0.23542
H
H
C
10
11
12
13
14
15
16
17
18
0.20631
C
ꢀ0.49163
0.24726
H
H
C
H
H
N
N(8)
H
N
0.24142
ꢀ0.54763
20.64343
0.43708
H
H
H
ꢀ0.57050
corresponding product was obtained in good yield (Scheme 3,
4d). We further noted that reaction of aromatic amines having
electron-donating substituents generated products in higher
yields than those with electron-withdrawing substituents. For
example, p-methoxyaniline, p-methylaniline, and p-hydroxy-
aniline exhibited very good-to-excellent yields (Scheme 3,
4e–g), whereas, p-chloroaniline and p-bromoaniline exhibited
good yields (Scheme 3, 4h and 4i).
piperidine or morpholine was reacted with 1, formaldehyde, and
various primary amines under the same reaction conditions, the
corresponding products 2-(ethylthio)-8-(piperidin-1-yl/morpho-
lin-4-ylmethyl)-6-substituted-5,6,7,8-tetrapyrimido[4,5-d]pyr-
imidin-4(3H)-ones 10a–d were obtained in high yields
(Scheme 4).
The structure of isolated compounds 8a–d and 10a–d were
deduced based on the IR, NMR, and mass spectroscopic data,
taking compounds 8a and 10a as examples. In the case of 8a, the
IR spectrum revealed massive absorption bands at 3050 cmꢀ1
for C–H aromatic stretching, 2970–2951 cmꢀ1 for C–H aliphatic
stretching, 1633 cmꢀ1 for C=O stretching, 1569 cmꢀ1 for C=N
Furthermore, variation of the alcoholic solvent was also
investigated under the same reaction conditions. 6-Amino-2-
(ethylthio)pyrimidin-4(3H)-one (1) was subjected to a triple
Mannich reaction with various primary aliphatic and aromatic
amines 2b–i and formaldehyde in methanol, and the results are
summarised in Scheme 3. As expected, methanol took part in the
reaction and the corresponding 6-substituted-8-(methoxy-
methyl)-2-(ethylthio)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimi-
din-4(3H)-ones 4j–p were obtained in very good-to-excellent
yields (Scheme 3). The substrate scope study of various amines in
methanol indicated that the bulky aliphatic amine, isobutylamine,
generated the product in an excellent yield (Scheme 3, 4j).
Similarly,benzylaminegeneratedanexcellentyieldoftheproduct
(Scheme 3, 4k). Furthermore, as observed with ethanol as the
solvent, aromatic amines such as aniline generated the product in
yields lower than aliphatic amines (Scheme 3, 4l). We also
observed that aromatic amines with electron-donating substitu-
ents gave products in higher yields than those having electron-
withdrawing substituents. p-Methoxyaniline and p-methylaniline
exhibited very good-to-excellent yields (Scheme 3, 4m and 4n),
while p-chloroaniline and p-bromoaniline showed good yields
(Scheme 3, 4o and 4p). In general, the reaction proceeded with
high efficiency and was completed within a short reaction time.
Moreover, to study the behaviour of the 6-amino-2-(ethylthio)
pyrimidin-4(3H)-one (1) in terms of the triple Mannich reaction,
we examined the utilisation of benzyl alcohol, piperidine, and
morpholine as Mannich nucleophiles instead of ethanol or
methanol (Scheme 4). The reaction of 1 with various primary
amines, excess of formaldehyde (37 %), and benzyl alcohol in
dioxane for 2 h directly generated 8-(benzyloxymethyl)-2-
(ethylthio)-6-substituted-5,6,7,8-tetrapyrimido[4,5-d]pyrimidin-
4(3H)-ones 8a–d in very high yields (Scheme 4). Similarly, when
1
stretching, and 1489 cmꢀ1 for C=C stretching. The H NMR
spectrum was distinguished by the appearance of singlet signals
at 5.05, 4.47, 4.14, and 3.63 ppm ascribed to the four methylene
groups as well as the aromatic protons at the anticipated
chemical shifts—which indicated the performance of the triple
Mannich reaction. In addition, its 13C NMR spectrum revealed
the four methylene groups at 75.56, 69.86, 67.68, and
47.65 ppm. The mass spectrum of 8a revealed the molecular
ion peak at m/z 389.29 [M þ 1]. While in the case of 10a, the IR
spectrum revealed massive absorption bands at 3052 cmꢀ1 for
C–H aromatic stretching, 2929–2853 cmꢀ1 for C–H aliphatic
stretching, 1635 cmꢀ1 for C=O stretching, 1569 cmꢀ1 for C=N
1
stretching, and 1472 cmꢀ1 for C=C stretching. The H NMR
spectrum revealed three singlet signals at 4.75, 4.18, and
4.13 ppm associated with the three methylene groups, in addi-
tion to peaks at 2.68–2.51 and 1.80–1.50 ppm for the piperidine
moiety. The 13C NMR spectrum of 10a was distinguished by the
appearance of peaks at 67.65, 66.84, and 65.42 ppm for the three
methylene groups and other carbons for the piperidine moiety.
The mass spectrum of 10a revealed the molecular ion peak at
m/z 416.67 [M þ 1].
Proposed Mechanism
Based on the experimental findings, a possible mechanism for
the obtained compounds 4a–p, 6a–h, 8a–d, and 10a–d is
illustrated in Scheme 5. In the first stage, the double conden-
sation Mannich reaction proceeded through a typical conden-
sation reaction between the primary amines with formaldehyde

F
A. F. M. EL-Mahdy, H. A. H. El-Sherief, and Z. A. Hozien
O
O
N
R1
HCHO
HN
N
HN
ϩ
ϩ R1
NH2
NH2
R2
OH
Δ, 2 h
N
N
S
S
1
2
3
4
O
R2
O
N
O
N
O
N
O
HN
N
O
HN
N
HN
N
O
HN
N
N
S
S
N
S
N
N
S
N
O
O
4a, 93 %
4b, 94 %
4c, 90 %
4d, 85 %
H
O
Cl
O
O
O
O
O
N
HN
N
O
HN
HN
HN
HN
N
HN
N
O
N
S
N
N
N
N
S
S
S
N
N
N
O
O
4e, 91 %
4f, 89 %
4g, 87 %
4h, 70 %
Br
O
O
N
O
O
N
HN
N
HN
N
HN
N
O
N
O
N
N
S
N
N
N
N
S
S
S
O
O
4i, 71 %
4j, 95 %
4k, 89 %
4l, 80 %
Br
Cl
O
O
O
O
O
HN
N
O
HN
N
O
N
HN
N
O
N
N
S
N
N
N
N
N
N
S
S
S
O
4m, 90 %
4n, 89 %
4o, 70 %
4p, 71 %
Scheme 3. Synthesis of 8-(ethoxymethyl)-2-(ethylthio)pyrimido[4,5-d]pyrimidin-4(3H)-ones 4a–i and 8-(methoxymethyl)-2-(ethylthio)pyrimido[4,5-d]
pyrimidin-4(3H)-ones 4j–p under triple Mannich reaction.
to form imines 11a–h. The active centre (CH-3) of the starting
compound 1 nucleophilically attacked the formed imines to
provide the uncyclised intermediates 12a–h. These inter-
mediates then underwent a nucleophilic addition reaction with
another formaldehyde molecule followed by an acid-catalysed
dehydration and intramolecular cyclisation to generate the
cyclised intermediates 6a–h. Attack of the active nucleophilic
centre (NH-8) with a third molecule of formaldehyde and then
with ethanol, methanol, benzyl alcohol, or secondary amines
resulted in the corresponding products 4a–i, 4j–p, 8a–d, and
10a–d, respectively.
and reactants in the reaction process. The substrate scope for
the various aromatic or aliphatic amines was investigated, and
benzyl alcohol and secondary amines were utilised as Mannich
nucleophiles instead of ethanol or methanol. Based on the
atomic charge calculations and spectroscopic data, the reaction
products were identified as 6,8-disubstituted-5,6,7,8-tetra-
hydropyrimido[4,5-d]pyrimidin-4(3H)-ones rather than the
isomeric 3,6-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]
pyrimidin-4(3H)-ones. The products formed were easily iso-
lated by filtration and then purified through recrystallisation
using a suitable solvent. Further transformations of these func-
tional pyrimido[4,5-d]pyrimidin-4(3H)-ones could be utilised
to construct a library of biologically active compounds for
medicinal and pharmaceutical applications.
Conclusion
We have demonstrated a novel, regioselective, and highly
effective one-pot four-component synthesis of 6,8-disubsti-
tuted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones,
involving a triple Mannich reaction of 6-amino-2-(ethylthio)
pyrimidin-4(3H)-one, formaldehyde, primary amines, and
alcohols. Ethanol and methanol were utilised as both solvents
Experimental
Materials
All reagents and solvents were used directly from commercial
sources.

One-Pot Synthesis via a Triple Mannich Reaction
G
O
N
OH
R1
HN
N
O
7
HCHO, dioxane, Δ, 2 h
N
S
O
8
HN
ϩ
R1
NH2
S
N
NH2
O
N
R1
1
2
X
NH
HN
N
N
9
HCHO, dioxane, Δ, 2 h
S
N
10
X
Br
O
N
O
N
O
N
O
HN
N
HN
N
O
HN
N
O
HN
N
N
N
S
S
N
N
N
S
S
O
O
8a, 84 %
8b, 78 %
8c, 75 %
8d, 80 %
OCH3
OCH3
O
N
O
O
N
O
N
HN
N
N
HN
N
N
HN
N
N
HN
N
N
S
N
S
S
S
N
N
N
N
O
O
10a, 82 %
10b, 84 %
10c, 77 %
10d, 79 %
Scheme 4. Synthesis of 8-(benzyloxymethyl)-2-(ethylthio)pyrimido[4,5-d]pyrimidin-4(3H)-ones 8a–d and 2-(ethylthio)-8-(piperidin-1-yl/morpholin-4-
ylmethyl)pyrimido[4,5-d]pyrimidin-4(3H)-ones 10a–d under triple Mannich reaction.
Instrumentation
solid product was sufficiently pure to be used in the subsequent
reactions without further purification. Yield: 85 %, white crys-
tals (EtOH), mp 220–2228C (Lit.[41] 218–2198C). nmax/cmꢀ1
3465 (NH), 3275–3260 (NH2), 2926 (C–H aliphatic), 1659
(C=O), 1571 (C=N stretching), 1453 (C=C stretching). dH
(90 MHz, DMSO-d6) 11.80 (s, 1H, NH(3)), 6.45 (s, 2H, NH2),
5.00 (s, 1H), 3.10 (q, J 18.0, 2H), 1.30 (t, J 18.0, 3H).
The melting points were measured on a Gallencamp melting
point apparatus in open capillary tubes. The FT-IR spectra of the
products were recorded on a Perkin–Elmer 1430 FT-IR spec-
trometer using KBr discs. The H and 13C NMR spectra were
recorded on a Bruker Advance 400 NMR spectrometer or a
Varian EM-390 90 MHz spectrometer using TMS as the internal
standard and DMSO-d6 or CDCl3 as the solvent. The chemical
shifts and coupling constants (J) were denoted as parts per
million (ppm) and hertz (Hz), respectively. Elemental analyses
were performed on a Perkin–Elmer 240-C analyser. Mass
spectra of the products were measured on a JEOL JMS-600 mass
spectrometer using a direct inlet system.
1
6,8-Disubstituted-2-(ethylthio)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones 4a–p
General procedure: A solution of 6-amino-2-(ethylthio)
pyrimidin-4(3H)-one (1) (3 mmol) in the corresponding alcohol
3 (5 mL) was added dropwise to a stirred solution of formalde-
hyde (35 wt-% in H2O, 1 mL) and primary amines 2 (3 mmol) in
alcohol 3 (20 mL) and the resulting reaction mixture stirred
under reflux for 2 h. The reaction was monitored by thin-layer
chromatography. After starting materials had been consumed,
the reaction mixture was cooled and the separated precipitate
was isolated by filtration, washed with alcohol, and then dried.
The solid product was recrystallised from alcohol to afford the
desired products 4a–p in very good-to-excellent yields.
Synthetic Procedures
6-Amino-2-(ethylthio)pyrimidin-4(3H)-one (1)[41]
Ethyl iodide (12 mmol) was added dropwise into a solution
of6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(6mmol)
in KOH (6.2 mmol) and then the reaction mixture was stirred at
room temperature overnight. The obtained solid was collected
by filtration, washed with petroleum ether, and then dried. The

H
A. F. M. EL-Mahdy, H. A. H. El-Sherief, and Z. A. Hozien
O
N
O
H
R1
NH
O
HN
N
H
H
H
H
H
R-NH2 (2)
ϩ
H
R1
N
..
O
H2N
S
N
NH
..
2
S
11a–h
1
12a–h
O
O
O
O
N
5
R1
R1
4
R
H
1
R1
HN3
2
6 N
HN
N
ϩHϩ
ϪHϩ
HN
N
..
HN
ϪH2O
Nϩ
ϩ
1
N
8
7
N
S
N
S
N
O
NH
N
S
NH
2
..
NH
2
S
O
..
..
O
-
2
H
ϩ
H
H
S
6a–h
O
O
H
H
R1
R1
HN
O
HN
N
(a)
..
N
ϩ
N
..
N
N
S
(a)
(i)
HO
R2
..
ϩ
(ii)
ϪH
H
H
R2
4a–i, R2 ϭ CH3
4j–p, R2 ϭ H
8a–d, R2 ϭ C6H5
O
(b)
X
(b)
(i)
..
HN
R1
N
ϩ
(ii) ϪH
HN
S
N
N
N
10a–d
X
Scheme 5. Possible mechanism for the triple Mannich reaction of 6-amino-2-(ethylthio)pyrimidin-4(3H)-one (1).
8-(Ethoxymethyl)-2-(ethylthio)-6-propyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4a)
Yield: 93 %, white crystals (EtOH), mp 1408C. nmax/cmꢀ1
aliphatic), 1685 (C=O), 1555 (C=N stretching), 1499 (C=C
stretching). dH (400 MHz, DMSO-d6) 12.32 (s, 1H, NH(3)),
7.62–7.46 (m, 5H), 5.01 (s, 2H), 4.35 (s, 2H), 3.84 (s, 2H), 3.81
(s, 2H), 3.42 (q, J 8.0, 5.7, 2H), 3.13 (q, J 8.0, 2H), 1.31 (t, J 8.1,
3H), 1.06 (t, J 8.1, 3H). dC (100 MHz, DMSO-d6) 163.35,
159.08, 156.96, 138.02, 129.10, 128.43, 127.35, 89.92, 75.56,
66.36, 63.34, 57.20, 47.75, 24.94, 14.95, 14.43. m/z (EI, 70 eV)
361.26 [M þ 1], 360.38 [M]. Anal. Calc. for C18H24N4O2S
(360.47): C 59.97, H 6.71, N 15.54, S 8.90. Found: C 59.88,
H 6.80, N 15.48, S 8.99 %.
3400 (NH), 2959–2931 (C–H aliphatic), 1633 (C=O), 1570
(C=N stretching), 1489 (C=C stretching). dH (400 MHz, CDCl3)
11.92 (s, 1H, NH(3)), 5.03 (s, 2H), 4.22 (s, 2H), 3.73 (s, 2H), 3.51
(q, J 7.0, 2H), 3.11 (q, J 7.3, 2H), 2.50 (t, J 7.0, 2H), 1.60
(m, J 7.0, 2H), 1.37 (t, J 7.0, 3H), 1.20 (t, J 7.0, 3H), 0.93 (t, J 7.0,
3H). dC (100 MHz, CDCl3) 163.25, 158.78, 156.87, 89.70,
75.62, 66.97, 63.35, 54.85, 47.36, 24.88, 21.00, 15.11, 14.44,
11.72. m/z (EI, 70 eV) 313.26 [M þ 1], 312.12 [M]. Anal. Calc.
for C14H24N4O2S (312.43): C 53.82, H 7.74, N 17.93, S 10.26.
Found: C 53.01, H 7.92, N 18.11, S 10.14 %.
8-(Ethoxymethyl)-2-(ethylthio)-6-phenyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4d)
Yield: 85 %, white crystals (EtOH), mp 176–1788C. nmax
/
cmꢀ1 3446 (NH), 3052 (C–H aromatic), 2972–2925 (C–H
aliphatic), 1645 (C=O), 1568 (C=N stretching), 1489 (C=C
stretching). dH (90 MHz, DMSO-d6) 12.10 (s, 1H, NH(3)),
7.40–6.80 (m, 5H), 5.05 (s, 2H), 4.95 (s, 2H), 4.15 (s, 2H), 3.30
(q, J 9.0, 2H), 3.10 (q, J 9.1, 2H), 1.20 (t, J 9.2, 3H), 1.00 (t, J 9.0,
3H). Anal. Calc. for C17H22N4O2S (346.45): C 58.94, H 6.40,
N 16.17, S 9.26. Found: C 58.69, H 5.46, N 16.30, S 9.57 %.
8-(Ethoxymethyl)-2-(ethylthio)-6-isobutyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4b)
Yield: 94 %, white crystals (EtOH), mp 186–1888C. nmax
/
cmꢀ1 3410 (NH), 2951–2928 (C–H aliphatic), 1633 (C=O),
1569 (C=N stretching), 1490 (C=C stretching). dH (400 MHz,
CDCl3) 12.64 (s, 1H, NH(3)), 4.95 (s, 2H), 4.11 (s, 2H), 3.62
(s, 2H), 3.44 (q, J 6.8, 2H), 3.05 (q, J 7.1, 2H), 2.21 (d, J 7.1, 2H),
1.75 (m, 1H), 1.31 (t, J 7.2, 3H), 1.11 (t, J 6.9, 3H), 0.86 (d, J 6.8,
6H). dC (100 MHz, CDCl3) 163.26, 158.69, 156.97, 89.82,
75.54, 67.51, 63.32, 61.17, 47.77, 26.49, 24.88, 20.71, 15.12,
14.45. m/z (EI, 70 eV) 327.31 [M þ 1], 326.34 [M]. Anal. Calc.
for C15H26N4O2S (326.46): C 55.19, H 8.03, N 17.16, S 9.82.
Found: C 55.31, H 8.12, N 17.04, S 9.73 %.
8-(Ethoxymethyl)-2-(ethylthio)-6-(4-methoxyphenyl)-
5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one(4e)
Yield: 91 %, white crystals (EtOH), mp 170–1728C. nmax
/
cmꢀ1 3390 (NH), 3048 (C–H aromatic), 2971–2928 (C–H
aliphatic), 1643 (C=O), 1568 (C=N stretching), 1513 (C=C
stretching). dH (400 MHz, CDCl3) 12.30 (s, 1H, NH(3)), 7.03
(d, J 8.5, 2H), 6.85 (d, J 7.9, 2H), 5.06 (s, 2H), 4.79 (s, 2H), 4.33
(s, 2H), 3.77 (s, 3H), 3.38 (q, J 6.9, 2H), 3.13 (q, J 7.4, 2H), 1.41
(t, J 7.4, 3H), 1.13 (t, J 6.9, 3H). dC (100 MHz, CDCl3) 162.53,
158.96, 157.39, 154.51, 142.43, 119.61, 114.57, 90.43, 75.42,
6-Benzyl-8-(ethoxymethyl)-2-(ethylthio)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4c)
Yield: 90 %, white crystals (EtOH), mp 182–1848C. nmax
/
cmꢀ1 3380 (NH), 3069 (C–H aromatic), 2974–2932 (C–H

One-Pot Synthesis via a Triple Mannich Reaction
I
65.90, 63.34, 55.53, 45.97, 24.98, 15.00, 14.78. m/z (EI, 70 eV)
377.17 [M þ 1], 376.32 [M].
(s, 2H), 3.33 (s, 3H), 3.16 (q, J 7.3, 2H), 2.34 (d, J 7.1, 2H), 1.85
(m, J 13.2, 6.6, 1H), 1.41 (t, J 7.3, 3H), 0.96 (d, J 6.5, 6H). dC
(100 MHz, CDCl3) 163.23, 158.76, 156.85, 89.67, 75.53, 66.89,
61.77, 56.54, 48.89, 26.48, 24.85, 20.70, 14.47. m/z (EI, 70 eV)
313.56 [M þ 1], 312.25 [M]. Anal. Calc. for C14H24N4O2S
(312.43): C 53.82, H 7.74, N 17.93, S 10.26. Found: C 53.90,
H 7.81, N 17.85, S 10.17 %.
8-(Ethoxymethyl)-2-(ethylthio)-6-p-tolyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4f)
Yield: 89 %, white crystals (EtOH), mp 172–1748C. nmax
/
cmꢀ1 3380 (NH), 3047 (C–H aromatic), 2971–2924 (C–H
aliphatic), 1636 (C=O), 1567 (C=N stretching), 1515 (C=C
stretching). dH (400 MHz, CDCl3) 12.10 (s, 1H, NH(3)), 6.94
(d, J 8, 2H), 6.68 (d, J 8, 2H), 4.91 (s, 2H), 4.69 (s, 2H), 4.24
(s, 2H), 3.30 (q, J 7.0, 2H), 3.05 (q, J 7.1, 2H), 2.19 (s, 3H), 1.34
(t, J 7.2, 3H), 1.07 (t, J 7.0, 3H). m/z (EI, 70 eV) 361.16 [M þ 1],
360.14 [M]. Anal. Calc. for C18H24N4O2S (360.47): C 59.97,
H 6.71, N 15.54, S 8.90. Found: C 59.26, H 5.83, N 15.68,
S 9.33 %.
6-Benzyl-2-(ethylthio)-8-(methoxymethyl)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4k)
Yield: 89 %, white crystals (MeOH), mp 160–1628C. nmax
/
cmꢀ1 3400 (NH), 3042 (C–H aromatic), 2974–2930 (C–H
aliphatic), 1629 (C=O), 1559 (C=N stretching), 1487 (C=C
stretching). dH (400 MHz, CDCl3) 12.89 (s, 1H, NH(3)), 7.37–
7.29 (m, 5H), 4.96 (s, 2H), 4.20 (s, 2H), 3.85 (s, 2H), 3.74 (s, 2H),
3.33 (s, 3H), 3.15 (q, J 7.1, 2H), 1.42 (t, J 6.9, 3H). dC (100 MHz,
CDCl3) 163.38, 159.05, 156.98, 138.00, 129.06, 128.42, 127.37,
89.83, 66.34, 57.14, 55.65, 47.64, 24.95, 14.44.
8-(Ethoxymethyl)-2-(ethylthio)-6-(4-hydroxyphenyl)-
5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one(4g)
Yield: 87 %, brown crystals (EtOH), mp 200–2028C. nmax
/
cmꢀ1 3370 (NH), 3349 (OH), 3051 (C–H aromatic), 2966–2928
(C–H aliphatic), 1643 (C=O), 1584 (C=N stretching), 1496
(C=C stretching). dH (400 MHz, DMSO-d6) 11.97 (s, 1H, NH
(3)), 8.84 (s, 1H), 6.86 (d, J 8.1, 2H), 6.66 (d, J 7.9, 2H), 4.97
(s, 2H), 4.73 (s, 2H), 4.09 (s, 2H), 3.33 (q, J 8.0, 2H), 3.06
(q, J 8.2, 2H), 1.28 (t, J 8.2, 3H), 1.04 (t, J 8.2, 3H). dC (100 MHz,
DMSO-d6) 161.38, 159.48, 156.88, 151.97, 141.46, 119.40,
116.01, 89.96, 75.27, 65.45, 63.00, 46.09, 24.63, 15.44, 15.00.
Anal. Calc. for C17H22N4O3S (362.45): C 56.33, H 6.12,
N 15.46, S 8.85. Found: C 56.30, H 6.48, N 15.19, S 8.94 %.
2-(Ethylthio)-8-(methoxymethyl)-6-phenyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4l)
Yield: 80 %, white crystals (MeOH), mp 204–2068C. nmax
/
cmꢀ1 3410 (NH), 3051 (C–H aromatic), 2976–2926 (C–H
aliphatic), 1640 (C=O stretching), 1566 (C=N stretching),
1489 (C=C). dH (400 MHz, DMSO-d6) 12.07 (s, 1H, NH(3)),
7.25 (t, J 7.9, 2H), 7.03 (d, J 8.1, 2H), 6.83 (t, J 7.9, 1H), 4.97
(s, 2H), 4.88 (s, 2H), 4.22 (s, 2H), 3.12 (s, 3H), 3.06 (q, J 7.2,
2H), 1.28 (t, J 7.4, 3H). m/z (EI, 70 eV) 333.24 [M þ 1], 332.26
[M]. Anal. Calc. for C16H20N4O2S (332.42): C 57.81, H 6.06,
N 16.85, S 9.65. Found: C 57.75, H 6.13, N 16.78, S 9.76 %.
6-(4-Chlorophenyl)-8-(ethoxymethyl)-2-(ethylthio)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4h)
2-(Ethylthio)-8-(methoxymethyl)-6-(4-
methoxyphenyl)-5,6,7,8-tetrahydropyrimido[4,5-d]
pyrimidin-4(3H)-one (4m)
Yield: 70 %, pale yellow crystals (EtOH), mp 188–1908C.
max/cmꢀ1 3310 (NH), 3049 (C–H aromatic), 2970–2923 (C–H
n
aliphatic), 1632 (C=O), 1567 (C=N stretching), 1493 (C=C
stretching). dH (90 MHz, DMSO-d6) 12.30 (s, 1H, NH(3)),
7.60 (d, J 9.0, 2H), 7.20 (d, J 9.0, 2H), 5.10 (s, 2H), 4.95
(s, 2H), 4.20 (s, 2H), 3.40 (q, J 7.0, 2H), 3.10 (q, J 7.0, 2H), 1.20
(t, J 7.1, 3H), 1.05 (t, J 7.1, 3H).
Yield: 90 %, white crystals (MeOH), mp 188–1908C. nmax
/
cmꢀ1 3410 (NH), 3048 (C–H aromatic), 2975–2930 (C–H
aliphatic), 1640 (C=O), 1569 (C=N stretching), 1488 (C=C
stretching). dH (400 MHz, CDCl3) 11.95 (s, 1H, NH(3)), 7.02
(d, J 8.4, 2H), 6.85 (d, J 8.5, 2H), 5.01 (s, 2H), 4.79 (s, 2H), 4.34
(s, 2H), 3.78 (s, 3H), 3.19–3.12 (m, 5H), 1.40 (t, J 7.2, 3H).
dH (100 MHz, CDCl3) 162.23, 158.84, 156.68, 154.50, 142.33,
119.60, 114.55, 90.62, 75.45, 66.04, 55.51, 45.96, 25.07, 14.40.
m/z 363.18 [M þ 1], 362.26 [M].
6-(4-Bromophenyl)-8-(ethoxymethyl)-2-(ethylthio)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4i)
Yield: 71 %, pale yellow (EtOH), mp 174–1768C. nmax/cmꢀ1
3250 (NH), 3051 (C–H aromatic), 2972–2926 (C–H aliphatic),
1624 (C=O), 1574 (C=N stretching), 1490 (C=C stretching).
dH (400 MHz, DMSO-d6) 12.01 (s, 1H, NH(3)), 7.36 (d, J 7.1,
2H), 6.98 (d, J 7.1, 2H), 4.99 (s, 2H), 4.87 (s, 2H), 4.21 (s, 2H),
3.34 (q, J 7.0, 2H), 3.05 (q, J 7.0, 2H), 1.27 (t, J 7.0, 3H), 1.05
(t, J 7.0, 3H). dC (100 MHz, DMSO-d6) 161.36, 159.74, 156.84,
148.27, 132.10, 119.43, 111.82, 89.81, 75.24, 63.93, 63.09,
45.28, 24.64, 15.40, 14.97. m/z (EI, 70 eV) 426.98 [Br81,
M þ 1], 424.98 [Br79, M þ 1]. Anal. Calc. for C17H21BrN4O2S
(426.05): C 48.00, H 4.98, N 13.17, S 7.54. Found: C 48.11,
H 4.89, N 13.22, S 7.47 %.
2-(Ethylthio)-8-(methoxymethyl)-6-p-tolyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4n)
Yield: 89 %, white crystals (MeOH), mp 182–1848C. nmax
/
cmꢀ1 3390 (NH), 3051 (C–H aromatic), 2969–2922 (C–H
aliphatic), 1644 (C=O), 1568 (C=N stretching), 1487 (C=C
stretching). dH (90 MHz, DMSO-d6) 12.20 (s, 1H, NH(3)),
7.00 (s, 4H), 4.99 (s, 2H), 4.81 (s, 2H), 4.20 (s, 2H), 3.30–3.00
(m, 5H), 2.20 (s, 3H), 1.30 (t, J 7.0, 3H). m/z (EI, 70 eV) 347.11
[M þ 1], 346.12 [M]. Anal. Calc. for C17H22N4O2S (346.45):
C 58.94, H 6.40, N 16.17, S 9.26. Found: C 57.49, H 5.72,
N 16.27, S 9.51 %.
2-(Ethylthio)-6-isobutyl-8-(methoxymethyl)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (4j)
6-(4-Chlorophenyl)-2-(ethylthio)-8-(methoxymethyl)-
5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-
one (4o)
Yield: 95 %, white crystals (MeOH), mp 176–1788C. nmax
/
cmꢀ1 3380 (NH), 2975–2930 (C–H aliphatic), 1632 (C=O),
1567 (C=N stretching), 1488 (C=C stretching). dH (400 MHz,
CDCl3) 12.50 (s, 1H, NH(3)), 5.00 (s, 2H), 4.21 (s, 2H), 3.73
Yield: 70 %, pale yellow crystals (MeOH), mp 208–2108C.
max/cmꢀ1 3300 (NH), 3049 (C–H aromatic), 2971–2928
n

J
A. F. M. EL-Mahdy, H. A. H. El-Sherief, and Z. A. Hozien
(C–H aliphatic), 1644 (C=O), 1567 (C=N stretching), 1495
(C=C stretching). dH (400 MHz, DMSO-d6) 12.10 (s, 1H, NH
(3)), 7.27 (d, J 7.4, 2H), 7.05 (d, J 7.6, 2H), 4.96 (s, 2H), 4.88
(s, 2H), 4.21 (s, 2H), 3.25–3.05 (m, 5H), 1.30 (t, J 7.0, 3H). dC
(100 MHz, DMSO-d6) 161.39, 159.66, 156.90, 147.83, 129.26,
124.12, 118.94, 90.02, 76.97, 64.14, 55.45, 45.35, 24.68, 14.98.
m/z (EI, 70 eV) 368.35 [Cl37, M þ 1], 366.27 [Cl35, M þ 1].
Anal. Calc. for C16H19ClN4O2S (366.09): C 52.38, H 5.22,
N 15.27, S 8.74. Found: C 52.43, H 5.14, N 15.19, S 8.81 %.
C12H20N4OS (268.38): C 53.70, H 7.51, N 20.88, S 11.95.
Found: C 53.81, H 7.43, N 20.95, S 11.88 %.
6-Benzyl-2-(ethylthio)-5,6,7,8-tetrahydropyrimido
[4,5-d]pyrimidin-4(3H)-one (6c)
Yield: 79 %, white crystals (benzene/cyclohexane), mp 122–
1248C. nmax/cmꢀ1 3412–3180 (2 ꢁ NH), 3051 (C–H aromatic),
2951–2927 (C–H aliphatic), 1628 (C=O), 1570 (C=N stretch-
ing), 1490 (C=C stretching). dH (400 MHz, CDCl3) 12.08 (s, 1H,
NH(3)), 7.55–7.47 (m, 5H), 5.25 (s, 1H, NH(8)), 4.25 (s, 2H),
3.85 (s, 2H), 3.70 (s, 2H), 3.14 (q, J 7.0, 2H), 1.32 (t, J 7.0, 3H).
dC (100 MHz, CDCl3) 162.12, 159.05, 154.48, 138.02, 129.09,
128.38, 127.29, 87.40, 64.90, 59.84, 48.46, 24.93, 14.54.
6-(4-Bromophenyl)-2-(ethylthio)-8-(methoxymethyl)-
5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-
one (4p)
Yield: 71 %, pale yellow crystals (MeOH), mp 222–2248C.
max/cmꢀ1 3272 (NH), 3050 (C–H aromatic), 2972–2929 (C–H
n
2-(Ethylthio)-6-phenyl-5,6,7,8-tetrahydropyrimido
aliphatic), 1621 (C=O), 1574 (C=N stretching), 1491 (C=C
stretching). dH (90 MHz, DMSO-d6) 12.20 (s, 1H, NH(3)),
7.30 (d, J 7.0, 2H), 6.95 (d, J 7.0, 2H), 4.90 (s, 2H), 4.85
(s, 2H), 4.20 (s, 2H), 3.20 (s, 3H), 3.15 (q, J 7.0, 2H), 1.30 (t, J 7.0,
3H). Anal. Calc. for C16H19BrN4O2S (412.04): C 46.72, H 4.66,
N 13.62, S 7.80. Found: C 46.10, H 4.33, N 14.50, S 8.67%.
[4,5-d]pyrimidin-4(3H)-one (6d)
Yield: 73 %, white crystals (dioxane), mp 168–1708C. nmax
/
cmꢀ1 3410–3200 (2 ꢁ NH), 3049 (C–H aromatic), 2952–2926
(C–H aliphatic), 1628 (C=O), 1559 (C=N stretching), 1496
(C=C stretching). dH (90 MHz, DMSO-d6) 12.05 (s, 1H,
NH(3)), 7.50–7.00 (m, 5H), 5.65 (s, 1H, NH(8)), 4.75 (s, 2H),
4.25 (s, 2H), 3.25 (q, J 7.0, 2H), 1.30 (t, J 7.2, 3H). Anal. Calc.
for C14H16N4OS (288.37): C 58.31, H 5.59, N 19.43, S 11.12.
Found: C 58.41, H 5.51, N 19.50, S 11.03 %.
2-(Ethylthio)-6-substituted-5,6,7,8-tetrahydropyrimido
[4,5-d]pyrimidin-4(3H)-ones (6a–h)
General procedure: A solution of 6-amino-2-(ethylthio)
pyrimidin-4(3H)-one (1) (3 mmol) in dioxane (5 mL) was added
dropwise to a stirred solution of formaldehyde (35 wt-% in H2O,
1 mL) and primary amines 2 (3 mmol) in dioxane (20 mL) and
then the reaction mixture was stirred under reflux for 2 h. The
reaction was monitored by thin-layer chromatography. After
starting materials had been consumed, the reaction mixture was
cooled, concentrated under vacuum, and poured into ice-cold
water. The precipitate that separated was isolated by filtration,
washed with water, and then dried. The solid product was
recrystallised from an appropriate solvent to generate the
desired products 6a–h in very good-to-excellent yields.
2-(Ethylthio)-6-(4-methoxyphenyl)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (6e)
Yield: 82 %, white crystals (dioxane), mp 144–1468C. nmax
/
cmꢀ1 3415–3210 (2 ꢁ NH), 3052 (C–H aromatic), 2951–2929
(C–H aliphatic), 1632 (C=O), 1566 (C=N stretching), 1509
(C=C stretching). dH (90 MHz, DMSO-d6) 12.03 (s, 1H,
NH(3)), 7.15–6.9 (dd, J 7.1, 4H), 5.50 (s, 1H, NH(8)), 4.95
(s, 2H), 4.25 (s, 2H), 3.75 (s, 3H), 3.20 (q, J 7.2, 2H), 1.35
(t, J 7.2, 3H). dC (100 MHz, DMSO-d6) 162.26, 158.42, 154.28,
142.25, 119.95, 114.65, 94.29, 68.04, 55.76, 45.17, 25.28,
14.60. m/z (EI, 70 eV) 419.67 [M þ 1], 418.34 [M].
2-(Ethylthio)-6-propyl-5,6,7,8-tetrahydropyrimido
[4,5-d]pyrimidin-4(3H)-one (6a)
2-(Ethylthio)-6-p-tolyl-5,6,7,8-tetrahydropyrimido
[4,5-d]pyrimidin-4(3H)-one (6f)
Yield: 78 %, white crystals (benzene/cyclohexane), mp 180–
1828C. nmax/cmꢀ1 3400–3260 (2 ꢁ NH), 2950–2867 (C–H ali-
phatic), 1632 (C=O), 1566 (C=N stretching), 1515 (C=C
stretching). dH (400 MHz, CDCl3) 12.01 (s, 1H, NH(3)), 5.42
(s, 1H, NH(8)), 4.42 (s, 2H), 3.92 (s, 2H), 3.10 (q, J 7.1, 2H), 2.50
(t, J 7.1, 2H), 71H), 1.60 (m, J 7.1, 2H), 1.39 (t, J 7.1, 3H), 0.93
(t, J 7.1, 3H). dC (100 MHz, CDCl3) 162.92, 158.85, 152.92,
86.51, 65.04, 55.94, 47.43, 25.94, 21.04, 14.50, 11.79. Anal.
Calc. for C11H18N4OS (254.35): C 51.94, H 7.13, N 22.03,
S 12.61. Found: C 52.03, H 7.21, N 21.94, S 12.54 %.
Yield: 80 %, white crystals (dioxane), mp 280–2848C. nmax
/
cmꢀ1 3431–3200 (2 ꢁ NH), 3051 (C–H aromatic), 29525–2928
(C–H aliphatic), 1635 (C=O), 1563 (C=N stretching), 1512
(C=C stretching). dH (400 MHz, DMSO-d6) 12.01 (s, 1H,
NH(3)), 6.96 (d, J 7.3, 2H), 6.72 (d, J 7.3, 2H), 5.41 (s, 1H,
NH(8)), 4.55 (s, 2H), 4.03 (s, 2H), 3.13 (q, J 7.3, 2H), 2.17
(s, 3H), 1.29 (t, J 7.3, 3H). dC (100 MHz, DMSO-d6) 161.25,
159.99, 156.72, 146.65, 129.95, 129.76, 117.81, 89.77, 64.70,
45.28, 24.62, 20.49, 15.00. Anal. Calc. for C15H18N4OS
(302.39): C 59.58, H 6.00, N 18.53, S 10.60. Found: C 59.69,
H 5.92, N 18.60, S 10.51 %.
2-(Ethylthio)-6-isobutyl-5,6,7,8-tetrahydropyrimido
[4,5-d]pyrimidin-4(3H)-one (6b)
6-(4-Chlorophenyl)-2-(ethylthio)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (6g)
Yield: 86 %, white crystals (benzene/cyclohexane), mp 210–
2128C. nmax/cmꢀ1 3411–3200 (2 ꢁ NH), 2954–2927 (C–H ali-
phatic), 1630 (C=O), 1566 (C=N stretching), 1485 (C=C
stretching). dH (400 MHz, CDCl3) 12.41 (s, 1H, NH(3)), 5.50
(s, 1H, NH(8)), 4.23 (s, 2H), 3.70 (s, 2H), 3.17 (q, J 6.9, 2H), 2.29
(d, J 6.9, 2H), 1.77 (m, J 13.2, 6.5, 1H), 1.43 (t, J 6.9, 3H), 0.93
(d, J 6.5, 3H). dC (100 MHz, CDCl3) 162.67, 159.04, 156.80,
89.75, 67.45, 61.43, 47.51, 26.57, 24.94, 20.74, 14.40. m/z
(EI, 70 eV) 289.49 [M þ 1], 286.14 [M]. Anal. Calc. for
Yield: 75 %, pale yellow crystals (dioxane), mp 244–2468C.
n
max/cmꢀ1 3411–3205 (2 ꢁ NH), 3049 (C–H aromatic), 2951–
2928 (C–H aliphatic), 1631 (C=O), 1566 (C=N stretching), 1493
(C=C stretching). dH (400 MHz, DMSO-d6) 12.04 (s, 1H,
NH(3)), 7.25–6.83 (dd, J 7.1, 4H), 5.42 (s, 1H, NH(8)), 4.64
(s, 2H), 4.14 (s, 2H), 3.12 (q, J 7.1, 2H), 1.27 (t, J 7.2, 3H). Anal.
Calc. for C14H15ClN4OS (322.07): C 52.09, H 4.68, N 17.36,
S 9.93. Found: C 52.21, H 4.75, N 17.27, S 9.85 %.

One-Pot Synthesis via a Triple Mannich Reaction
K
6-(4-Bromophenyl)-2-(ethylthio)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (6h)
7.35–7.24 (m, 5H), 7.04–6.90 (m, 4H), 5.12 (s, 2H), 4.87 (s, 2H),
4.40 (s, 2H), 4.17 (s, 2H), 2.95 (q, J 7.4, 2H), 2.18 (s, 3H), 1.21
(t, J 7.3, 3H). dC (100 MHz, DMSO-d6) 161.41, 159.68, 156.81,
146.68, 138.74, 129.97, 129.34, 128.59, 128.00, 127.73, 117.58,
90.27, 75.57, 69.51, 64.69, 45.43, 24.58, 20.48, 14.89. m/z (EI,
70 eV) 423.42 [M þ 1], 422.34 [M]. Anal. Calc. for
C23H26N4O2S (422.54): C 65.38, H 6.20, N 13.26, S 7.59.
Found: C 65.27, H 6.29, N 13.35, S 7.67 %.
Yield: 74 %, pale yellow (dioxane), mp 238–2408C. nmax
/
cmꢀ1 3407–3200 (2NH), 3051 (C–H aromatic), 2951–2926
(C–H aliphatic), 1630 (C=O), 1566 (C=N stretching), 1492
(C=C stretching). dH (400 MHz, DMSO-d6) 12.05 (s, 1H,
NH(3)), 7.28 (d, J 8.8, 2H), 6.79 (d, J 8.9, 2H), 5.42 (s, 1H, NH
(8)), 4.64 (s, 2H), 4.10 (s, 2H), 3.11 (q, J 7.3, 2H), 1.28 (t, J 7.3,
3H). dC (100 MHz, DMSO-d6) 161.24, 160.40, 156.75, 148.21,
132.14, 119.55, 112.23, 89.77, 64.08, 45.19, 24.66, 14.95. m/z
(EI, 70 eV) 367.45 [Br79, M þ 1], 369.56 [Br81, M þ 1].
8-(Benzyloxymethyl)-6-(4-bromophenyl)-2-(ethylthio)-
5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-
one (8d)
Yield: 80 %, white crystals (dioxane), mp 204–2068C. nmax
/
Synthesis of 8-(Benzyloxymethyl)-2-(ethylthio)-6-
substituted-5,6,7,8-tetrapyrimido[4,5-d]pyrimidin-
4(3H)-ones (8a–d)
cmꢀ1 3428 (NH), 3052 (C–H aromatic), 2972–2923 (C–H
aliphatic), 1633 (C=O), 1563 (C=N stretching), 1488 (C=C
stretching). dH (90 MHz, DMSO-d6) 12.15 (s, 1H, NH(3)),
7.20 (m, 5H), 6.95 (m, 4H), 5.10 (s, 2H), 4.85 (s, 2H), 4.35
(s, 2H), 4.15 (s, 2H), 2.95 (q, J 7.0, 2H), 1.25 (t, J 7.0, 3H). Anal.
Calc. for C22H23BrN4O2S (487.41): C 54.21, H 4.76, N 11.49,
S 6.58. Found: C 54.16, H 4.68, N 11.56, S 6.65 %.
General procedure: A solution of 6-amino-2-(ethylthio)pyr-
imidin-4(3H)-one (1) (3 mmol) in dioxane (5 mL) was added
dropwise to a stirred solution of formaldehyde (35 wt-% in H2O,
1 mL), primary amines 2 (3 mmol), and benzyl alcohol (7)
(3 mmol) in dioxane (20 mL) and then the reaction mixture was
stirred under reflux for 2 h. The reaction was monitored by thin-
layer chromatography. After starting materials had been con-
sumed, the reaction mixture was cooled, and the separated
precipitate was isolated by filtration, washed with dioxane,
and then dried. The solid product was recrystallised from
dioxane to afford the desired products 8a–d in very good-to-
distinguished yields.
2-(Ethylthio)-8-(piperidin-1-yl/morpholin-4-ylmethyl)-
6-substituted-5,6,7,8-tetrapyrimido[4,5-d]pyrimidin-
4(3H)-ones 10a–d
General procedure: A solution of 6-amino-2-(ethylthio)pyr-
imidin-4(3H)-one (1) (3 mmol) in dioxane (5 mL) was added
dropwise to a stirred solution of formaldehyde (35 wt-% in H2O,
1 mL), primary amines 2 (3 mmol), and piperidine or morpho-
line (7) (3 mmol) in dioxane (20 mL) and then the reaction
mixture was stirred under refluxed for 2 h. The reaction was
monitored by thin-layer chromatography. After starting materi-
als had been consumed, the reaction mixture was cooled, and the
separated precipitate was isolated by filtration, washed with
dioxane, and then dried. The solid product was recrystallised
from dioxane to afford the desired products 10a–d in very good-
to-distinguished yields.
8-(Benzyloxymethyl)-2-(ethylthio)-6-isobutyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (8a)
Yield: 84 %, white crystals (dioxane), mp 154–1568C. nmax
/
cmꢀ1 3410 (NH), 3050 (C–H aromatic), 2970–2951 (C–H
aliphatic), 1633 (C=O), 1569 (C=N stretching), 1489 (C=C
stretching). dH (400 MHz, CDCl3) 12.28 (s, 1H, NH(3)), 7.29–
7.18 (m, 5H), 5.05 (s, 2H), 4.47 (s, 2H), 4.14 (s, 2H), 3.63 (s, 2H),
2.92 (q, J 7.3, 2H), 2.27 (d, J 7.1, 2H), 1.77 (m, 1H), 1.24 (t, J 7.3,
3H), 0.85 (d, J 7.1, 6H). dC (100 MHz, CDCl3) 162.98, 158.88,
156.82, 138.03, 128.39, 127.64, 127.45, 126.94, 89.98, 75.56,
69.86, 67.68, 61.21, 47.65, 26.46, 24.91, 20.72, 14.29. m/z (EI,
70 eV) 389.29 [M þ 1], 388.30 [M]. Anal. Calc. for
C20H28N4O2S (388.53): C 61.83, H 7.26, N 14.42, S 8.25.
Found: C 61.92, H 7.18, N 14.51, S 8.17 %.
2-(Ethylthio)-6-(4-methoxyphenyl)-8-(piperidin-1-
ylmethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-
4(3H)-one (10a)
Yield: 82 %, white crystals (dioxane), mp 194–1968C. nmax
/
cmꢀ1 3350 (NH), 3052 (C–H aromatic), 2929–2853 (C–H
aliphatic), 1635 (C=O), 1569 (C=N stretching), 1472 (C=C
stretching). dH (400 MHz, DMSO-d6) 11.80 (s, 1H, NH(3)),
6.99 (d, J 9.0, 2H), 6.82 (d, J 8.9, 2H), 4.75 (s, 2H), 4.18 (s, 2H),
4.13 (s, 2H), 3.68 (s, 3H), 3.05 (q, J 8.9, 2H), 2.36 (t, J 9.0, 4H),
1.46–1.30 (m, 6H), 1.26 (t, J 8.9, 3H). dC (100 MHz, DMSO-d6)
161.19, 159.29, 157.29, 153.91, 142.92, 119.12, 114.84, 88.65,
67.65, 66.84, 65.42, 55.71, 51.93, 46.14, 25.92, 24.51, 15.19.
m/z (EI, 70 eV) 416.67 [M þ 1], 415.34 [M].
8-(Benzyloxymethyl)-2-(ethylthio)-6-phenyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (8b)
Yield: 78 %, white crystals (dioxane), mp 198–2008C. nmax
/
cmꢀ1 3400 (NH), 2975–2927 (C–H aliphatic), 1632 (C=O),
1567 (C=N stretching), 1454 (C=C stretching). dH (400 MHz,
DMSO-d6) 12.05 (s, 1H, NH(3)), 7.25–7.17 (m, 5H), 7.02
(m, 2H), 6.55 (m, 3H), 5.18 (s, 2H), 4.91 (s, 2H), 4.62 (s, 2H),
4.18 (s, 2H), 3.08 (q, J 8.7, 2H), 1.32 (t, J 8.7, 3H). dC (100 MHz,
DMSO-d6) 162.97, 158.68, 156.72, 150.21, 138.13, 129.62,
128.28, 127.53, 127.36, 126.84, 122.62, 115.52, 89.97, 75.65,
61.21, 59.85, 47.55, 25.01, 14.28.
2-(Ethylthio)-6-(4-methoxyphenyl)-8-(morpholin-4-
ylmethyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-
4(3H)-one (10b)
Yield: 84 %, white crystals (dioxane), mp 208–2108C. nmax
/
cmꢀ1 3407 (NH), 3050 (C–H aromatic), 2920–2860 (C–H
aliphatic), 1628 (C=O), 1560 (C=N stretching), 1496 (C=C
stretching). dH (400 MHz, DMSO-d6) 11.83 (s, 1H, NH(3)),
6.99 (d, J 8.5, 2H), 6.83 (d, J 8.5, 2H), 4.77 (s, 2H), 4.20 (s, 2H),
4.13 (s, 2H), 3.68 (s, 3H), 3.53 (t, J 7.0, 4H), 3.04 (q, J 7.2, 2H),
2.36 (t, J 7.0, 4H), 1.29 (t, J 7.2, 3H). dC (100 MHz, DMSO-d6)
161.23, 159.43, 157.25, 153.95, 142.83, 119.15, 114.86, 88.81,
8-(Benzyloxymethyl)-2-(ethylthio)-6-p-tolyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (8c)
Yield: 75 %, white crystals (dioxane), mp 188–1908C. nmax
/
cmꢀ1 3400 (NH), 3051 (C–H aromatic), 2972–2923 (C–H
aliphatic), 1633 (C=O), 1570 (C=N stretching), 1489 (C=C
stretching). dH (400 MHz, DMSO-d6) 12.02 (s, 1H, NH(3)),

L
A. F. M. EL-Mahdy, H. A. H. El-Sherief, and Z. A. Hozien
67.08, 66.84, 66.57, 65.54, 55.72, 51.21, 45.95, 24.57, 15.13.
Anal. Calc. for C20H27N5O3S (417.53): C 57.53, H 6.52,
N 16.77, S 7.68. Found: C 57.64, H 6.45, N 16.68, S 7.72 %.
[9] V. J. Ram, A. Goel, S. Sarkhel, P. R. Maulik, Bioorg. Med. Chem.
2002, 10, 1275. doi:10.1016/S0968-0896(01)00423-0
[10] D. W. Fry, M. A. Becker, R. L. Switzer, Mol. Pharm. 1995, 47, 810.
[11] M. G. Gebauer, C. McKinlay, J. E. Gready, Eur. J. Med. Chem. 2003,
38, 719. doi:10.1016/S0223-5234(03)00140-5
[12] G. W. Rewcastle, A. J. Bridge, D. W. Fry, J. R. Rubin, W. A. Denny,
J. Med. Chem. 1997, 40, 1820. doi:10.1021/JM960879M
[13] A. Kaur, M. Kaur, B. Singh, J. Heterocycl. Chem. 2015, 52, 827.
doi:10.1002/JHET.2199
[14] D. J. Ramon, M. Yus, Angew. Chem. 2005, 117, 1628. [Angew. Chem.
Int. Ed. 2005, 44, 1602] doi:10.1002/ANGE.200460548
[15] H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, A. A. O. Sarhan,
Synthesis 2010, 2636. doi:10.1055/S-0030-1258153
[16] H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, A. A. O. Sarhan,
ARKIVOC 2011, X, 71.
[17] H. Bienayme, C. Hulme, G. Oddon, P. Schmitt, Chem. – Eur. J.
2000, 6, 3321. doi:10.1002/1521-3765(20000915)6:18,3321::
AID-CHEM3321. 3.0.CO;2-A
2-(Ethylthio)-8-(piperidin-1-ylmethyl)-6-p-tolyl-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one (10c)
Yield: 77 %, white crystals (dioxane), mp 200–2028C. nmax
/
cmꢀ1 3400 (NH), 3051 (C–H aromatic), 2923–2890 (C–H
aliphatic), 1628 (C=O), 1567 (C=N stretching), 1494 (C=C
stretching). dH (400 MHz, DMSO-d6) 11.95 (s, 1H, NH(3)),
7.00 (d, J 8.7, 2H), 6.92 (d, J 8.7, 2H), 4.49 (s, 2H), 4.14 (s, 4H),
2.99 (q, J 8.9, 2H), 2.32 (t, J 9.0, 4H), 2.15 (s, 3H), 1.43–1.34
(m, 6H), 1.24 (t, J 8.9, 3H). Anal. Calc. for C21H29N5OS
(399.55): C 63.13, H 7.32, N 17.53, S 8.03. Found: C 63.05,
H 7.40, N 17.46, S 8.12 %.
2-(Ethylthio)-8-(morpholin-4-ylmethyl)-6-p-tolyl-
5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-one
(10d)
[18] B. Ganem, Acc. Chem. Res. 2009, 42, 463. doi:10.1021/AR800214S
[19] B. Alcaide, P. Almendros, C. Aragoncillo, R. Callejo, M. P. Ruiz,
M. R. Torres, Eur. J. Org. Chem. 2012, 2359. doi:10.1002/EJOC.
201101625
[20] N. K. Terrett, M. Gardner, D. W. Gordon, R. J. Kobylecki, J. Steel,
Tetrahedron 1995, 51, 8135. doi:10.1016/0040-4020(95)00467-M
[21] G. H. Posner, Chem. Rev. 1986, 86, 831. doi:10.1021/CR00075A007
[22] L. F. Tietze, U. Beifuss, Angew. Chem. Int. Ed. Engl. 1993, 32, 131.
doi:10.1002/ANIE.199301313
Yield: 79 %, white crystals (dioxane), mp 214–2168C. nmax
/
cmꢀ1 3395 (NH), 3052 (C–H aromatic), 2972–2922 (C–H
aliphatic), 1629 (C=O), 1563 (C=N stretching), 1493 (C=C
stretching). dH (400 MHz, DMSO-d6) 11.88 (s, 1H, NH(3)),
7.00 (d, J 8.5, 2H), 6.91 (d, J 8.5, 2H), 4.79 (s, 2H), 4.16 (s, 2H),
4.13 (s, 2H), 3.50 (t, J 7.3, 4H), 2.98 (q, J 7.3, 2H), 2.32 (t, J 7.3,
4H), 2.15 (s, 3H), 1.21 (t, J 7.3, 3H). dC (100 MHz, DMSO-d6)
161.21, 159.44, 157.25, 146.69, 129.97, 129.21, 117.55, 88.76,
67.03, 66.86, 66.60, 51.23, 45.55, 24.59, 20.56, 15.24. m/z (EI,
70 eV) 402.30 [M þ 1], 401.29 [M].
[23] V. Este´vez, M. Villacampa, J. C. Men’endez, Chem. Soc. Rev. 2010,
39, 4402. doi:10.1039/B917644F
[24] C. Hulme, V. Gore, Curr. Med. Chem. 2003, 10, 51. doi:10.2174/
0929867033368600
[25] F. Lieby-Muller, T. Constantieux, J. Rodriguez, J. Am. Chem. Soc.
2005, 127, 17176. doi:10.1021/JA055885Z
[26] M. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110, 1096.
doi:10.1002/(SICI)1521-3757(19980420)110:8,1096::AID-ANGE1096.
3.0.CO;2-Z
[27] A. M. Mahmoud, H. A. H. El-Sherief, O. M. A. Habib, A. A. O. Sarhan,
Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 1757. doi:10.1080/
10426500701313920
[28] H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, A. A. O. Sarhan,
J. Heterocycl. Chem. 2010, 47, 1294. doi:10.1002/JHET.471
[29] Z. A. Hozien, A. A. O. Sarhan, H. A. H. El-Sherief, A. M. Mahmoud,
Z. Naturforsch. B: J. Chem. Sci. 1997, 52, 1401. doi:10.1515/ZNB-
1997-1119
Atomic Charge Calculations
The computational calculations of atomic charges were mea-
sured by using the natural population analysis method. The
Gaussian 09 software package with B3LYP functional and
6–31þG(d,p) basis set was used.[42]
Supplementary Material
FTIR, 1H and 13C NMR spectra of the synthesised compounds
are available on the Journal’s website.
[30] A. A. O. Sarhan, S. H. Abdel-Hafez, H. A. H. El-Sherief,
T. Aboel-Fadl, Synth. Commun. 2006, 36, 987. doi:10.1080/
00397910500501243
[31] A. F. M. El-Mahdy, H. A. H. El-Sherief, RSC Adv. 2016, 6, 92134.
doi:10.1039/C6RA20689A
Conflicts of Interest
The authors declare no conflicts of interest.
[32] M. S. Mohamed, S. M. Awad, A. I. Sayed, Molecules 2010, 15, 1882.
doi:10.3390/MOLECULES15031882
[33] S. Youssif, J. Chem. Res. 2004, 2004, 341. doi:10.3184/
0308234041639683
[34] H. Sladowska, M. Sieklucka-Dziuba, G. Rajtar, R. Wydro, Z.
Kleinrok, Acta Pol. Pharm. (Engl. Transl) 1996, 53, 39.
[35] J. J. Marugan, W. Zheng, O. Motabar, N. Southall, E. Goldin,
E. Sidransky, R. A. Aungst, K. Liu, S. K. Sadhukhan, C. P. Austin,
Eur. J. Med. Chem. 2010, 45, 1880. doi:10.1016/J.EJMECH.2010.01.
027
[36] W. S. Hamama, Z. Naturforsch. B: J. Chem. Sci. 2000, 55, 443. doi:10.
1515/ZNB-2000-0515
[37] D. Brown, E. Hoerger, S. Mason, J. Chem. Soc. 1955, 211. doi:10.
1039/JR9550000211
[38] H. F. Andrew, C. K. Bradsher, J. Heterocycl. Chem. 1967, 4, 577.
doi:10.1002/JHET.5570040419
[39] H. T. Abdel-Mohsen, J. R. Conrad, U. Beifuss, J. Org. Chem. 2013, 78,
7986. doi:10.1021/JO401193E
Acknowledgement
This research did not receive any specific funding.
References
[1] E. Lunt, in Comprehensive Organic Chemistry (Eds D. Barton, W. D.
Ollis) 1974, Vol. 4, p. 493 (Pergamon Press: Oxford).
[2] J. D. Brown, Comprehensive Heterocyclic Chemistry (Eds A. R.
Katritzky, C. W. Rees) 1984, Vol. 4, p. 57 (Pergamon Press: Oxford).
[3] E. D. Clercq, R. Beraaerts, J. Biol. Chem. 1987, 262, 14905.
[4] Y. S. Sanghvi, S. B. Larson, S. S. Matsumoto, L. D. Nord, D. F. Smee,
R. C. Willis, T. H. Avery, R. K. Robins, G. R. Revankar, J. Med. Chem.
1989, 32, 629. doi:10.1021/JM00123A022
[5] J. P. de la Cruz, T. Carrasco, G. Ortega, F. Sanchez De la Cuesta, Lipids
1992, 27, 192. doi:10.1007/BF02536177
[6] R. B. Tenser, A. K. Gaydos, A. Hay, Antimicrob. Agents Chemother.
2001, 45, 3657. doi:10.1128/AAC.45.12.3657-3659.2001
[7] J. Cieplik, J. Pluta, O. Gubrynowicz, Boll. Chim. Farm. 2003, 142, 146.
[8] P. Sharma, N. Rane, V. K. Gurram, Bioorg. Med. Chem. Lett. 2004, 14,
4185. doi:10.1016/J.BMCL.2004.06.014
[40] M. Mizutani, Y. Sanemitsu, Y. Tamaru, Z. Yoshida, J. Org. Chem.
1985, 50, 764. doi:10.1021/JO00206A007

One-Pot Synthesis via a Triple Mannich Reaction
M
[41] B. Cosimelli, G. Greco, M. Ehlardo, E. Novellino, F. D. Settimo,
S. Taliani, C. L. Motta, M. Bellandi, T. Tuccinardi, A. Martinelli,
O. Ciampi, M. L. Trincavelli, C. Martini, J. Med. Chem. 2008, 51,
1764. doi:10.1021/JM701159T
[42] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci,
G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
Revision D.01 2009 (Gaussian, Inc.: Wallingford, CT).