Microwave irradiation assists the synthesis of a novel series of bis-arm s-triazine oxy-schiff base and oxybenzylidene barbiturate derivatives

Article abstract of DOI:10.3390/molecules23112976

A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde was prepared and fully characterized. The reaction was carried out via stepwise nucleophilic aromatic substitution of chlorine atoms in cyanuric chloride. The first chlorine was substituted by different amines (morpholine, piperidine, or diethylamine) to afford 2,4-dichloro-6-substituted-1,3,5-triazine. The second and third chlorines were substituted by benzaldehyde derivatives in the presence of Na₂CO₃ as a HCl scavenger to afford the target products: s-triazine oxyaldehyde derivatives (dipodal). The dipodal derivatives were reacted with acid hydrazide, hydralazine, barbituric, or thiobarbituric acid derivatives using conventional heating or microwave irradiation to afford the di-arm s-triazine oxy-Schiff base and oxybenzylidene barbiturate derivatives in good yields. Microwave irradiation done in less solvent afforded the target product in less reaction time with good yield and purity. These types of derivatives might have special interest in coordination and medicinal chemistry.

Full text of DOI:10.3390/molecules23112976

molecules
Article
Microwave Irradiation Assists the Synthesis
of a Novel Series of bis-Arm s-Triazine Oxy-Schiff
Base and Oxybenzylidene Barbiturate Derivatives
1
1
1
Kholood A. Dahlous , Zainab Almarhoon , Ahmed-Yacine Badjah-Hadj-Ahmed ,
1
1,2,
Zeid A. AL Othman and Ayman El-Faham
*
1
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455,
Riyadh 11451, Saudi Arabia; kdahloos@ksu.edu.sa (K.A.D.); zalmarhoon@ksu.edu.sa (Z.A.);
ybadjah@ksu.edu.sa (A.-Y.B.-H.-A.); zaothman@ksu.edu.sa (Z.A.A.O.)
2
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia,
1
2321 Alexandria, Egypt
*
Correspondence: aelfaham@ksu.edu.sa; Tel.: +966-1146-73195
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 13 October 2018; Accepted: 10 November 2018; Published: 14 November 2018
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3-
methoxybenzaldehyde was prepared and fully characterized. The reaction was carried out via stepwise
nucleophilic aromatic substitution of chlorine atoms in cyanuric chloride. The first chlorine
was substituted by different amines (morpholine, piperidine, or diethylamine) to afford
2,4-dichloro-6-substituted-1,3,5-triazine. The second and third chlorines were substituted by
benzaldehyde derivatives in the presence of Na CO as a HCl scavenger to afford the target
2
3
products: s-triazine oxyaldehyde derivatives (dipodal). The dipodal derivatives were reacted with acid
hydrazide, hydralazine, barbituric, or thiobarbituric acid derivatives using conventional heating or
microwave irradiation to afford the di-arm s-triazine oxy-Schiff base and oxybenzylidene barbiturate
derivatives in good yields. Microwave irradiation done in less solvent afforded the target product in
less reaction time with good yield and purity. These types of derivatives might have special interest in
coordination and medicinal chemistry.
Keywords: s-Triazine; dipodal; oxy-Schiff base; oxybenzylidene
1
. Introduction
In the past few years, the applications of microwaves have been increasing in use and become more
interesting in various fields since the first published reports on the use of microwave irradiation to carry
out organic reactions by Gedye et al. in 1986 [ ]. Recently, microwave-assisted organic synthesis (MAOS)
1
has grown dramatically because it reduces reaction times and increases the yield and purity of the product
by reducing the undesirable side reactions associated with conventional heating [2–7].
In addition, 1,3,5-triazine (s-triazine) has drawn significant interest as a perfect example for
combinatorial library scaffold. The use of 1,3,5-triazine derivatives in various applications is well
documented [
on the use of the inexpensive and readily commercially available reagent 2,4,6-trichloro-1,3,5-triazine
cyanuric chloride) as the starting material. The ease of the stepwise substitution of the three chlorine
atoms and the chemoselective reactivity with a variety of nucleophiles under temperature control has
drawn significant interest for the synthesis of hyperbranched polymers [ 13 18 20], dendrimers [21],
8–17]. The most convenient method for the synthesis of 1,3,5-triazine derivatives is based
(
9
,
,
–
and tri-arm star-shaped molecules with applications in organic light-emitting diodes [22].
The reaction of cyanuric chloride with three equivalents of 4-hydroxybenzaldehyde that afforded
the tri-oxyaldehyde (tripodal) derivatives in a single step has been reported in the literature [23–26],
Molecules 2018, 23, 2976; doi:10.3390/molecules23112976
www.mdpi.com/journal/molecules

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2,4,6-Tris(4-formylphenoxy)-1,3,5-triazine, with three reactive peripheral aldehyde groups makes
it a useful reagent for the preparation of star-shaped molecules. Gingrast et al. [23] reported the
preparation of some star-shaped thiosemicarbazones containing the s-triazine ring as a new class of
biologically active compounds. Later, tripodal was reported as a useful imprinting material on silica,
which provides a site of three organized amino groups that can be further modified with various
functional groups [23]. Recently, Koc et al. [25] reported the use of tri-oxyaldehyde derivatives for
the preparation of several oxy-Schiff bases, which were used as tripodal-trinuclear systems formed
by the 1,3,5-tricarboxylate bridge for complexation with iron (III). Later, the same author reported
the synthesis, electrochemical behavior, and antimicrobial activity of four tripodal–benzimidazole
derivatives based on the reaction of tris(4-oxyaldehyde)-1,3,5-triazone with different o-phenylene
diamine derivatives [26]. Recently, Celikbilek and Koc [27] reported the dipodal oxy-Schiff base
derived from the methoxy-s-triazine and their salen and salophen complexes.
Due to the presence of the azomethine (R-NH-N=C-R) in Schiff bases moiety, these compounds
have gained great importance in medicinal chemistry as well as coordination chemistry [28
In addition, barbiturate derivatives have shown remarkable biological activity [35 36] and are
considered as important intermediates for the synthesis of several heterocyclic compounds [37 38].
–34].
,
,
Herein, we report the synthesis and characterization of a novel series of bis-arm s-triazine oxy-Schiff
bases and oxybenzylidene barbiturate derivatives using conventional heating and microwave
irradiation as a new template, which might be important in coordination and medicinal chemistry for
researchers in this field.
2
. Results and Discussion
Due to the different reactivities of the three chlorine atoms in cyanuric chloride, these chlorine atoms
could be replaced using different nucleophiles by controlling the temperature, i.e., temperature-controlled
selectivity. Moreover, cyanuric chloride also shows good selectivity toward nucleophilic substitution by the
amino-to-hydroxyl group, which is called functional group selectivity [39
this advantage for the preparation of di-arm derivatives. First, cyanuric chloride
amines—morpholine, piperidine, and diethylamine—to afford 2,4-dichloro-6-substituted-s-triazine 2a
In the second step, compounds 2a were reacted with two equiv. of 4-hydroxybenzaldehyde derivatives to
afford dipodal derivatives 3–8 with high yield and purity as observed from their spectral data (Scheme 1).
,40]. In the present work, we took
1
was reacted with different
–c.
–c
Scheme 1. Synthetic pathway for dipodal of s-triazine derivatives.
For preparation of di-arm derivatives
9–11, compounds 3–8 were reacted with acid hydrazide
or hydralazine in ethanol as a solvent to afford the target products 9a
yields (Scheme 2). The reaction was repeated using microwave irradiation (60 C, 600 W, 4–6 min
for the hydrazide reaction; 4 min for the hydralazine reaction). Microwave irradiation afforded the
–
c
,
10a
–
c
, and 11a
–
c
with good
◦

Molecules 2018, 23, 2976
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products in shorter reaction times with higher yields and purities, as observed from their spectral data
and UPLC-MS data (see experimental section).
Scheme 2. Synthesis of dipodal oxy-Schiff base s-triazine derivatives.
The Infrared (IR) spectra for the hydralazine series 10a–c and 11a–c were verified by the
–
1
appearance of very characteristic
ν
ν
(C=N ) vibrations in the region 1531 cm . The amide
ν
(N-H) and
T
(C=O) bands were observed in the regions 3210 cm–1 and 1669 cm , respectively, and these triazine
derivatives showed another important infrared band in the region 1384 cm that was attributed to
CT-O-Ar stretching. The -C=N-imine stretching vibrations that were observed in the region 1594 cm–1
–1
−
1
bands are the distinguishing feature of triazine.
1
The H-NMR spectrum of 11c (Figure 1) as a prototype showed triplet and multiplet peaks at
δ
0.97
and
δ 3.32 ppm related to the ethyl residue (CH and CH , respectively), a doublet peak at δ 7.28 ppm
3 2

Molecules 2018, 23, 2976
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for 4H related to the H3,3’, and a multiplet peak in the range
δ
7.72–7.77 ppm for 6H corresponding to
the aromatic protons H9,10,11. In addition, two doublets appeared at
and the peak at 8.28 ppm represented H . The proton related to the HC=N appeared as a singlet
at 8.46 ppm. Due to the possibility of the tautomeric structure of compound 11c, as indicated in
Figure 1, the NH appeared at 12.15 ppm, which indicated the high acidic character and agreed with
the proposed structure more than , and this observation agreed with the recently reported data
by our group [41]. The 13C-NMR spectrum of 11c exhibited two peaks for the diethylamino residue
at 12.6 and 41.5 ppm related to CH and CH , respectively, and absorption peaks at 165.8 and
71.5 ppm related to (2-C=N-O–Ar) and (C=N-diethyl amino), respectively, besides peaks at 121.8
C11a), 123.6 (C ), 126.1 (C , ), 126.4 (C ), 127.0 (C ), 128.9 (C ), 131.7 (C ), 132.9 (C ), 137.6 (C ),
δ 8.09 representing 4H2,2’ and 2H8,
δ
7
δ
δ
B
A
δ
δ
3
2
1
δ
(
11
2 2’
7a
8
3,3’
1
10
9
1
48.5 (C ), 152.3 (C ), and 152.9 (C ) ppm.
7 5 1
Figure 1. Structure of compound 11c.
The UPLC-MS m/z for compound 11c showed the exact molar mass (found m/z: 677.5 [M + 1])
calculated for C H N O (676.75) using direct infusion to the UPLC-MS instrument with electrospray
37
32 12
2
positive ionization (see Supplementary Materials).
The results obtained from the synthesis of oxy-Schiff base derivatives encouraged us to try the reaction
of the dipodal with barbituric acid derivative 12 (1,3-dimethylpyrimidine- 2,4,6(1H,3H,5H)-trione) under
mild conditions (Scheme 3).
As a first attempt, we tried the reaction of dipodal
ethanol as a solvent in the presence of piperidine as a catalyst [42]. From the thin layer chromatography
TLC) observation, the starting material had almost completely disappeared after 2–3 h at room
3 with barbituric acid derivatives 12 using
(
temperature, while three more spots were observed. After the workup and separation of the crude
product, the NMR spectrum showed more than one product that failed to be isolated or purified.
As a second attempt, we tried other conditions using dichloromethane (DCM) or water as a solvent
in the presence of diethylamine as a catalyst [43,44]; the same problem was observed, where more than
one product was formed. Finally, we followed the method described by Jursic [45], in which ethanol
was used without any catalyst. Better results were obtained, but the starting material was observed
even after stirring at room temperature for 24 h or refluxing for 6 h, as observed from following the
reaction by TLC (ethylacetate-hexane, 4:6). Using microwave irradiation improved the yield of the
product and the reaction was completed in 4 min, where TLC observed none of the starting material.
Accordingly, for the reaction using dipodal
Scheme 3), complete conversion was observed after 4 h, as observed by TLC (ethylacetate-hexane; 4:6).
The solvent was removed under reduced pressure and the crude yellow product was recrystallized
from CHCl –hexane (1:1) to afford pure product 14.
6 with compound 12 in ethanol and refluxed for 4–6 h
(
3

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By repeating the reaction using microwave irradiation in ethanol as a solvent, the reaction afforded
the target product in 4 min with higher yield and purity (see experimental section).
Scheme 3. Synthesis of dipodal oxybenzylidene barbiturate derivatives.
3
. Materials and Methods
3
.1. General
Cyanuric chloride, 4-hydroxybenzaldehyde, and 4-hydroxy-3-methoxybenzaldehyde were
purchased from Sigma-Aldrich (Chemie GmbH, Taufkirchen, Germany). Melting points were recorded
in open capillary tubes and were uncorrected (Sigma–Aldrich Chemie GmbH, Taufkirchen, Germany).
–1
IR spectra (KBr in cm ) were recorded on a Shimadzu 8201 PC FTIR spectrophotometer (Shimadzu,
1
13
Ltd., Tokyo, Japan). H and C-NMR spectra were recorded using on a JEOL-NMR spectrometer (JEOL,
Ltd., Tokyo, Japan) (400, 850 MHz), and the chemical shifts were reported in ppm. The purity of the
δ
compounds was monitored by TLC silica (Type 60 GF254, Merck) and visualized by UV light at 254 nm.
Elemental analyses were performed on a Perkin-Elmer 2400 elemental analyzer (PerkinElmer, Inc.,
Waltham, MA, USA), and the values found were within
±
0.3% of the theoretical values. Microwave
irradiation was performed in a multimode reactor with a 1400 W maximum magnetron (Synthos 3000,
Aton Paar GmbH, Ostfildern, Germany). UPLC-MS conditions were as follows: The instruments
used were a Waters Acquity UPLC system (Waters Corp., Milford, MA, USA) and a triple quadrupole

Molecules 2018, 23, 2976
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(
TQD) mass spectrometer equipped with a Z-electrospray interface. The parameters of the electrospray
ionization source were as follows: capillary voltage 3.0 kV; cone voltage 28 V; desolvation gas was
nitrogen with a flow of 800 L/h; cone gas was nitrogen with a flow of 70 L/h; source temperature
◦ ◦
20 C; and desolvation temperature 300 C. Analysis was done in full scan mode with positive
1
ionization in the mass range 50–850 Da. Data acquisition and processing were done using Waters
MassLynx software.
3
.2. General Method for Synthesis of Dipodal 3–8
The synthesis of dipodal was performed in two steps. First, cyanuric chloride was reacted
with different amines—morpholine, piperidine, benzylamine, or diethylamine—following the reported
methods [41] to afford 2,4-dichloro-6-substituted s-triazine 2a with good yields and purity. The spectral data
were in good agreement with the reported data [41].
Second, compounds 2a were reacted with the 4-hydroxybenzaldehyde derivatives as follows:
,4-Dichloro-6-substituted-1,3,5-triazine 2a (10 mmol) were added portionwise to a suspended
solution of 4-hydroxybenzaldehyde or 4-hydroxy-3-methoxybenzaldehyde (22 mmol) and Na CO
3–8
–c
–c
2
–c
2
3
(
50 mmol) in 100 mL of benzene at room temperature. The reaction mixture was refluxed for 24 h and
then cooled to room temperature. Water (100 mL) was added, and the mixture was extracted with
ethylacetate (2 100 mL). The organic layer was collected and washed twice with a 10% solution of
Na CO , dried over MgSO , and filtered, and then the solvent was removed under vacuum to afford
×
2
3
4
an off-white solid, which crystallized from ethylacetate–hexane to afford the pure products
a yield of 80–88%.
3–8 at
0
◦
;
4
,4 -((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))dibenzaldehyde
3
. White powder in yield 88%; mp 157–158 C
1
H-NMR (CDCl ):
H, Hald) ppm; C-NMR (CDCl ):
δ
3.63 (brs, 8H, 4CH ), 7.29 (d, 4H, J = 8.4 Hz), 7.88 (dd, 4H, J = 8.0 Hz
,
J = 2.0 Hz), 9.96 (s,
44.0, 66.3, 122.4, 131.1, 133.8, 156.5, 166.5, 171.7, 190.8 ppm. Anal. Calcd
3
2
1
3
2
δ
3
for C H N O (406.40): C, 62.07; H, 4.46; N, 13.79; found: C, 62.26; H, 4.59; N, 13.91.
21
18
4
5
0
4
,4 -((6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(oxy))dibenzaldehyde
4
[
46]. White powder in yield 86%;
◦
1
mp 125–127 C. H-NMR (CDCl ):
N-CH ), 7.29 (d, 4H, J = 8.8 Hz), 7.88 (d, 4H, J = 8.8Hz), 9.95 (s, 2H, Hald) ppm; 3C-NMR (CDCl3):
δ 1.49 (brs, 4H, 2CH ), 1.59 (brs, 2H, CH ), 3.59 (t, 4H, J = 6.0 Hz,
2 2
3
1
2
δ
2
2
4.1, 25.3, 44.6, 122.2, 130.8, 133.4, 156.5, 165.7, 171.4, 190.7 ppm. Anal. Calcd for C H N O (404.43):
22 20 4 4
C, 65.34; H, 4.98; N, 13.85; found: C, 65.54; H, 5.04; N, 14.09.
0
4
,4 -((6-(Diethylamino)-1,3,5-triazine-2,4-diyl)bis(oxy))dibenzaldehyde
5
[
47]. White powder in yield 86%;
◦
1
mp 127–129 C. H-NMR (CDCl ):
CH ), 7.26 (d, 4H, J = 8.8 Hz), 7.81 (d, 4H, J = 8.8 Hz), 9.89 (s, 2H, Hald) ppm; 13C-NMR (CDCl3):
δ
0.97 (t, 6H, J = 6.4 Hz, 2CH ), 3.32 (q, 4H, J = 9.6 Hz, J = 7.6 Hz,
3
3
2
δ
2
1
3.2, 42.6, 122.9, 131.4, 134.1, 157.2, 166.4, 171.9, 191.4, 191.4 ppm. Anal. Calcd for C H N O (392.42):
21 20 4 4
C; 64.28; H, 5.14; N, 14.28; found: C, 64.41; H, 5.28; N, 14.51.
0
4
8
7
,4 -((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxybenzaldehyde)
6
. White powder in yield
◦
1
1%; mp 192–195 C. H-NMR (CDCl ):
.41(d, 4H, J= 8.0 Hz, Ar-H), 9.9 (s, 2H, Hald) ppm; 13C-NMR (CDCl3):
δ
3.62 (s, 8H, CH ), 3.81 (s, 6H, 2OCH ), 7.24 (d, 2H, J = 8.8 Hz),
3
2
3
δ 43.9, 55.9, 110.7, 123.1, 124.6,
1
34.9, 146.0, 152.1, 166.8, 171.7, 190.9 ppm. Anal. Calcd for C H N O : C, 59.22; H, 4.75; N, 12.01;
23
22
4
7
found: C, 59.45; H, 4.92; N, 12.28.
0
4
,4 -((6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxybenzaldehyde)
7
[
47]. White powder in
◦
1
yield 90%; mp 152–153 C. H-NMR (CDCl ):
δ 1.49 (brs, 4H, 2CH ), 1.61 (brs, 2H, CH ), 3.58 (t, 4H,
3
2
2
J = 5.2 Hz, 2CH ), 3.82 (s, 6H, 2O-CH ), 7.24–7.27 (m, 2H, Ar-H), 7.41–7.43 (m, 4H, Ar-H), 9.92 (s, 2H,
2
3
Hald) ppm; 13C-NMR (CDCl3):
δ
24.4, 25.6, 44.8, 56.0, 110.7, 123.2, 124.7, 134.8, 146.3, 152.2, 166.2, 171.6,
1
91.1 ppm. Anal. Calcd for C H N O (464.48): C, 62.06; H, 5.21; N, 12.06; found: C, 62.28; H, 5.39;
24 24 4 6
N, 12.32.

Molecules 2018, 23, 2976
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0
4
,4 -((6-(Diethylamino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxybenzaldehyde)
8
[
48]. White powder
◦
1
in yield 91%; mp 118–119 C. H-NMR (CDCl ):
δ 0.96 (t, 6H, J = 7.6, 2CH ), 3.32 (q, 4H, J = 6.8 Hz,
3
3
J = 7.2 Hz, 2CH ), 3.82 (s, 6H, 2O-CH ), 7.26 (d, 2H, J = 8.0 Hz, Ar-H), 7.41–7.42 (m, 4H, Ar-H), 9.91 (s,
2
3
H, Hald); 1 C-NMR (CDCl3):
3
δ
12.7, 42.1, 56.0, 110.5, 123.3, 124.7, 134.8, 146.3, 152.3, 171.4, 191.1 ppm;
2
Anal. Calcd for C H N O (452.47): C, 61.05; H, 5.35; N, 12.38; found: C, 61.29; H, 5.47; N, 12.63.
23
24
4
6
3
.3. General Procedure for Preparation of Bis-Arm s-Triazine oxy-Schiff Base Derivatives 9a–c, 10a–c, and 11a–c
Method A: Conventional heating
A suspension of the dipodal derivatives 3–8 (10 mmol) in 30 mL of absolute ethanol was added to
a solution of 4-chlorobenzohydrazide (20 mmol) or hydralazine hydrochloride (20 mmol) in 10 mL of
ethanol containing 1–3 drops of concentrated HCl (for the reaction with hydralazine, an equivalent
amount of NaOAc was used). The reaction mixture was refluxed for 4–12 h (with hydrazide) or 4–6 h
(
with hydralazine) until the reaction was completed (TLC:ethyl acetate–hexane, 6:4; CHCl :EtOH, 8:2).
3
After cooling, the resulting solid was filtered and washed with ethanol, dried, and then recrystallized
from ethylacetate.
Method B: Microwave irradiation
A mixture of the dipodal derivatives 3–8 (10 mmol), 4-chlorobenzohydrazide (20 mmol),
or hydralazine hydrochloride (20 mmol) in 10 mL of ethanol containing 1 drop of concentrated
HCl or sodium acetate (20 mmol) in the case of hydralazine were mixed at room temperature.
The reaction mixture was then irradiated in a microwave using a multimode reactor (Synthos 3000,
◦
Aton Paar GmbH) at 60 C and 600 W for 4–6 min (6 min for 4-chlorobenzohydrazide and 4 min for
hydralazine). After cooling, the resulting solid was washed with ethanol, dried, and then recrystallized
from ethylacetate.
0
000
0
N ,N -((1Z,1 Z)-(((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis
(
8
methanylylidene))bis(4-chlorobenzohydrazide) 9a. Yellow powder in yield 67% (A; reaction time 8 h),
9% (B, 6 min); mp 279–280 C. IR (KBr): 3192 (NH), 1650 (C=O), 1594, 1550 (C=N) cm . H-NMR
◦
−1
1
(
(
2
1
DMSO-d6):
dd, 2H, J = 7.65 Hz, J = 0.9 Hz), 7.48 (s, 2H, Ar-H), 7.28 (d, 4H, Ar-H), 7.93 (d, 4H, Ar-H), 7.94 (s,
Hald), 11.95 (s, 2H) ppm; 13C-NMR (DMSO-d6):
43.6, 55.9, 65.5, 109.9, 120.7, 123.0, 128.6, 129.4, 132.9,
35.3, 136.9, 141.9, 147.6, 151.3, 162.2, 171.5 ppm. Anal. Calcd for C H Cl N O (771.61): C, 57.59;
δ
3.53 (s, 4H, 2CH ), 3.56 (s, 4H, 2CH ), 3.81 (s, 6H, 2O-CH ), 7.25 (d, 2H, J = 7.7 Hz), 7.48
2
2
3
δ
37
32
2
8
7
H, 4.18; N, 14.52; found: C, 57.84; H, 4.33; N, 14.79. UPLC-MS: calc. m/z: 771.61 (M); found: 773.37
M + 2), 775.39 (M + 4).
(
0
000
0
N ,N -((1Z,1 Z)-(((6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis
(
8
methanylylidene))bis(4-chlorobenzohydrazide) 9b. White powder in yield 76% (A, reaction time 12 h),
9% (B, 6 min); mp 280–283 C. IR (KBr): 3202 (NH), 1654 (C=O), 1594, 1531 (C=N) cm . H-NMR
◦
−1
1
(DMSO-d6):
δ
1.43 (s, 4H, 2CH ), 1.56 (s, 2H, CH ), 3.41 (s, 4H, 2CH ), 3.82 (s, 6H, 2O-CH ), 7.25 (d,
2
2
2
3
2
8
H, J = 7.7 Hz), 7.30 (dd, 2H, J = 7.7 Hz), 7.48 (s, 2H), 7.61 (d, 4H, J = 8.5 Hz), 7.93 (d, 4H, J = 7.65 Hz),
.45 (s, 2H, NH), 11.95 (s, 2H) ppm; 13C-NMR (DMSO-d6):
δ
23.8, 25.1, 44.0, 55.9, 109.8, 120.7, 123.0,
1
32.0, 132.8, 136.6, 142.1, 147.7, 151.4, 162.2, 165.6, 171.4 ppm. Anal. Calcd for C H Cl N O (769.76):
38 34 2 8 6
C, 59.30; H, 4.45; N, 14.56; found: C, 59.53; H, 4.61; N, 14.78. UPLC-MS: calc. m/z: 769.76 (M); found
71.49 (M + 2).
7
0
000
0
N ,N -((1Z,1 Z)-(((6-(Diethylamino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis
(
8
(
methanylylidene))bis(4-chlorobenzo hydrazide) 9c. White powder in yield 78% (A, reaction time 12 h),
◦
−1
1
7% (B, 6 min), mp 276–279 C. IR (KBr): 3210 (NH), 1696 (C=O), 1594, 1531 (C=N), cm . H-NMR
1.05 (s, 6H, 2CH ), 3.40 (s, 4H, 2CH ), 3.82 (s, 6H, CH ), 7.27 (d, 2H, J = 7.65 Hz), 7.31 (d,
DMSO-d6):
δ
3
2
3
2
H, J = 6.8 Hz), 7.49 (s, 2H), 7.60 (s, 4H), 7.94 (d, 4H, J = 8.5 Hz), 8.45 (s, 2H, NH), 11.69 (s, 2H) ppm;
1
3
C-NMR (DMSO-d6):
δ 12.6, 41.6, 55.8, 109.7, 120.7, 123.1, 128.6, 129.6, 132.8, 136.8, 142.1, 147.7, 151.5,

Molecules 2018, 23, 2976
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162.2, 165.7, 171.4 ppm. Anal. Calcd for C H Cl N O (757.63): C, 58.66; H, 4.52; N, 14.79; found: C,
37 34 2 8 6
5
8.81; H, 4.69; N, 14.99. UPLC-MS: calc. m/z: 757.63 (M); found 758 (M + 1).
4
-(4,6-bis(4-((E)-(2-(Phthalazin-1-yl)hydrazono)methyl)phenoxy)-1,3,5-triazin-2-yl)morpholine 10a. Yellow
◦
powder in yield 78% (A, reaction time 4 h), 91% (B, 4 min); mp 238–241 C. IR (KBr): 3398 (NH), 1582,
−
528 (C=N) cm . H-NMR (DMSO-d ): δ 3.57 (brs, 8H, 4CH ), 7.27 (d, 4H, J = 8.8 Hz), 7.68–7.76 (m,
6 2
1 1
1
13
6
(
1
6
H), 8.10 (m, 6H, J = 8.4 Hz), 8.26 (d, 2H, J = 7.2 Hz), 8.45 (s, 2H), 12.15 (s, 2H, NH) ppm; C-NMR
DMSO-d6): 43.6, 65.5, 121.7, 123.6, 126.1, 126.4, 127.0, 129.1, 131.7, 132.3, 132.9, 137.6, 148.5, 152.2,
52.7, 166.2, 171.7 ppm. Anal. Calcd for C H N O (690.26): C, 64.34; H, 4.38; N, 24.33; found: C,
δ
37
30 12
3
4.56; H, 4.55; N, 24.61.
0
0
1
,1 -(((1E,1 E)-(((6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))bis(methanylylidene))bis
(
hydrazin-1-yl-2-ylidene))diphthalazine 10b. Yellow powder in yield 76% (A, reaction time 6 h), 90% (B, 4
◦
−1
1
min); mp 236–238 C. IR (KBr): 3291 (NH), 1613, 1528 (C=N), cm . H-NMR (DMSO-d ):
δ
1.44 (brs,
6
4
H, 2CH ), 1.59 (brs, 2H, CH ), 3.57 (brs, 4H, 2N-CH ), 7.29 (d, 4H, J = 8.8 Hz), 7.65–7.82 (m, 6H), 8.10
2
2
2
13
(
d, 6H, J = 9.6 Hz), 8.26 (d, 2H, J = 7.2 Hz), 8.45 (s, 2H), 12.15 (s, 2H, NH) ppm; C-NMR (DMSO-d6):
3.9, 25.1, 44.1, 121.7, 123.6, 126.1, 126.4, 127.0, 129.0, 131.7, 132.3, 132.9, 137.6, 148.5, 152.2, 152.8, 160.1,
65.7, 171.7 ppm. Anal. Calcd for C H N O (688.28): C, 66.27; H, 4.68; N, 24.40; found: C, 66.41; H,
δ
2
1
4
38
32 12
2
.89; N, 24.65. UPLC-MS: calc. m/z: 689.53 (M + 1); found 690.56 (M + 2).
N,N-Diethyl-4,6-bis(4-((E)-(2-(phthalazin-1-yl)hydrazono)methyl)phenoxy)-1,3,5-triazin-2-amine 10c. Yellow
◦
powder in yield 75% (A, reaction time 5 h), 88% (B, 4 min); mp 217–220 C; IR (KBr): 3404 (NH), 1615,
1
−
1 1
526 (C=N) cm ; H-NMR (DMSO-d6):
H, J = 8.8 Hz), 7.72–7.77 (m, 6H), 8.08 (d, 6H, J = 8.8 Hz), 8.27 (d, 2H, J = 7.6 Hz), 8.46 (s, 2H), 12.15 (s,
H, NH) ppm; 13C-NMR (DMSO-d6):
12.6, 41.5, 121.8, 123.6, 126.1, 126.4, 127.0, 128.9, 131.7, 132.9,
δ 0.97 (t, 6H, J = 6.8 Hz, 2CH ), 3.32 (m, 4H, 2CH ), 7.28 (d,
3 2
4
2
δ
137.6, 148.5, 152.3, 152.9, 165.8, 171.5 ppm; Anal. Calcd for C H N O (676.75): C, 65.67; H, 4.77; N,
37 32 12 2
2
4.84; found: C, 65.91; H, 4.89; N, 25.05. UPLC-MS: calc. m/z: 677.75; found: 679.76 (M + 2).
4
-(4,6-bis(2-Methoxy-4-((E)-(2-(phthalazin-1-yl)hydrazono)methyl)phenoxy)-1,3,5-triazin-2-yl)morpholine 11a
.
◦
Yellow powder in yield 77% (A, reaction time 5 h), 92% (B, 4 min); mp 245–247 C. IR (KBr): 3309
−
NH), 1603 (C=O), 1589, 1532 (C=N) cm ; H-NMR (DMSO-d6): δ 3.34–3.54 (m, 8H, 4CH ), 3.88 (s, 6H,
2
1 1
(
2
8
5
O-CH ), 7.19 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 6.4 Hz, Ar-H), 7.72–7.77 (m, 6H), 7.97 (s, 2H, Ar-H),
3
13
.11 (s, 2H), 8.28 (d, 2H, J = 7.6 Hz), 8.43 (s, 2H), 12.24 (s, 2H, NH) ppm; C-NMR (DMSO-d6):
6.1, 65.5, 110.7, 122.5, 123.7, 126.1, 126.5, 127.0, 131.8, 132.3, 134.2, 137.7, 141.7, 148.5, 151.6, 152.5, 165.8,
71.6 ppm. Anal. Calcd for C H N O (750.28): C, 62.39; H, 4.56; N, 22.39; found: C, 62.64; H, 4.76;
δ 43.5,
1
39
34 12
5
N, 22.68.
0
0
1
,1 -(((1E,1 E)-(((6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis
(
methanylylidene))bis(hydrazin-1-yl-2-ylidene))diphthalazine 11b. Yellow powder in yield 79% (A, reaction
◦
−1
time 6 h), 89% (B, 4 min); mp 215–216 C. IR (KBr): 3202 (NH), 1654 (C=O), 1584, 1528 (C=N) cm
.
1
H-NMR (DMSO-d6):
δ 1.41 (brs, 4H, 2CH ), 1.53 (brs, 2H, CH ), 3.57 (brs, 4H, 2N-CH ), 3.88 (s, 6H,
2 2 2
2
8
5
O-CH ), 7.19 (d, 2H, J = 8.0 Hz), 7.39 (d, 2H, J = 6.4Hz), 7.69–7.77 (m, 6H), 7.91 (s, 2H), 8.11 (s, 2H),
3
13
.27 (d, 2H, J = 8.0 Hz,), 8.43 (s, 2H), 12.25 (s, 2H, NH) ppm; C-NMR (DMSO-d6):
6.2, 108.4, 110.6, 115.6, 121.9, 123.7, 126.1, 126.4, 127.0, 131.8, 134.2, 137.7, 141.8, 148.5, 151.3, 152.6,
65.7, 171.6 ppm. Anal. Calcd for C H N O (748.30): C, 64.16; H, 4.85; N, 22.45; found: C, 64.35; H,
δ 24.1, 25.1, 40.1,
1
5
40
36 12
4
.02; N, 22.21. UPLC-MS: calcd. m/z: 748.30; found: 749.91 (M + 1).
N,N-Diethyl-4,6-bis(2-methoxy-4-((E)-(2-(phthalazin-1-yl)hydrazono)methyl)phenoxy)-1,3,5-triazin-2-amine
◦
1
3
3
(
(
1c. Yellow powder in yield 74% (A, reaction time 4 h), 89% (B, 4 min); mp 228–230 C. IR (KBr):
−
1
1
301(NH), 1644 (C=O), 1588 (C=N) cm
.
H-NMR (DMSO-d6): δ 0.93(t, 6H, J = 6.4Hz, 2CH3),
.28–3.50 (m, 4H, 2CH ), 3.88 (s, 6H, 2O-CH ), 7.21 (d, 2H, J = 8.0 Hz), 7.41 (d, 2H, J = 6.8 Hz), 7.72–7.77
m, 6H), 7.97 (s, 2H), 8.12 (s, 2H), 8.28 (d, 2H, J = 8.0 Hz), 8.44 (s, 2H), 12.25 (s, 2H, NH) ppm; C-NMR
DMSO-d6): 12.5, 40.1, 56.1, 110.5, 121.8, 122.6, 123.7, 126.1, 126.5, 127.1, 131.8, 132.3, 134.2, 137.7,
41.8, 148.5, 151.3, 152.6, 165.7, 171.5 ppm. Anal. Calcd for C H N O (736.30): C, 63.58; H, 4.93; N,
2
3
13
δ
1
39
36 12
4

Molecules 2018, 23, 2976
9 of 13
22.81; found: C, 63.77; H, 5.16; N, 23.06. UPLC-MS: calcd. m/z: 736.30; found: 737.91 (M + 1), 738.85
(M + 2).
3
.4. General Method for the Reaction of Dipodal 3–8 with Barbiturate Derivatives
Method A: Conventional heating
The barbituric acid derivative 12 or 13 (4 mmol) was added to a solution of dipodal derivatives 3–8
(
2 mmol) in 10 mL of absolute ethanol, mixed well at room temperature for 5 min, and then refluxed for
4
–6 h until the reaction was completed (TLC:ethyl acetate hexane, 6:4; CHCl :MeOH, 9:1). The solvent
3
was evaporated under reduced pressure and the crude solid crystallized from DCM–hexane to afford
the pure product.
Method B: Microwave irradiation
The dipodal derivatives 3–8 (2 mmol) and barbituric acid derivative 12 or 13 (4 mmol) in 5 mL
of EtOH were mixed at room temperature and then irradiated in a microwave oven for 4 min.
After cooling, the resulting solid was recrystallized from DCM–hexane to afford the pure product.
0
5
,5 -((((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))bis(methanylylidene))bis(1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) 14. Yellow powder in yield 81% (A, 5 h). 90% (B, 4 min),
◦
1
mp 204–206 C. H-NMR (CDCl ):
7
δ
3.35 (brs, 4H, N-CH ), 3.45 (brs, 4H, O-CH ), 3.67 (s, 12H, 4CH ),
3
2
2
3
13
.21 (d, 4H, J = 7.6 Hz); 8.17 (d, 4H), 8.47 (s, 2H, CH=C) ppm; C-NMR (CDCl3):
δ
29.1, 44.1, 66.4,
1
16.9, 121.6, 129.8, 135.7, 151.1, 155.4, 157.8, 160.0, 166.7, 171.2 ppm. Anal. Calcd for C H N O
33 30 8 9
(682.21): C, 58.06; H, 4.43; N, 16.4; found: C, 58.29; H, 4.63; N, 16.69.
0
5
,5 -((((6-(Diethylamino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))bis(methanylylidene))bis(1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) 15. Yellow powder in yield 82% (A, 4 h), 92% (B, 4 min);
◦
1
mp 224–245 C. H-NMR (CDCl ):
δ 1.10–1.13 (m, 6H, 2CH , ethyl residue), 3.38–3.41 (m, 12H,
3
3
4
N-CH ), 4.49 (s, 4H, 2N-CH , ethyl residue), 7.26 (d, 4H, J = 8 Hz); 8.2 (d, 4H, J = 8.8 Hz), 8.49 (s, 2H,
3 2
13
CH=C) ppm; C-NMR (CDCl3):
δ 12.8, 29.1, 42.2, 116.8, 121.8, 129.7, 135.7, 155.7, 158.0, 160.5, 162.6,
1
66.2, 171.4 ppm. Anal. Calcd for C H N O (668.23): C, 59.28; H, 4.82; N, 16.76, found: C, 59.55; H,
33
32
8
8
4
.96; N, 16.98.
0
5
,5 -((((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis(methanylylidene))bis
(
1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) 16. Yellow powder in yield 79% (A, 6 h), 91% (B, 4 min),
◦
1
mp 252–253 C. H-NMR (CDCl ):
δ 3.36 (s, 12H, 4N-CH ), 3.69 (brs, 4H, 2N-CH ), 3.77 (brs, 10H,
3 2
3
2
O-CH , 2O-CH ), 7.05 (d, 2H, J = 8.0 Hz); 7.54 (s, 2H), 7.97 (d, 2H, J = 1.6 Hz), 8.30 (s, 2H, CH=C) ppm;
2 3
1
3
C-NMR (CDCl3):
δ 29.0, 44.1, 55.9, 66.5, 116.6, 117.5, 122.2, 128.7, 130.8, 145.0, 150.9, 151.1, 158.0,
1
60.0, 162.6, 167.7, 171.2 ppm. Anal. Calcd for C H N O (742.23): C, 58.66; H, 4.61; N, 15.09; found:
35
34
8
11
C, 58.49; H, 4.86; N, 15.28.
0
5
,5 -((((6-(Diethylamino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis(methanylylidene))
bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) 17. The product obtained as a yellow powder in yield
◦
3% (A, 5 h), 92% (B, 4 min), mp 249–251 C. H-NMR (CDCl ): δ 1.07–1.10 (m, 6H, 2CH ), 3.37 (m,
3 3
1
8
1
2
2
2H, 4N-CH ), 3.45–3.48 (m, 4H, 2N-CH ), 3.79–3.82 (m, 6H, 2O-CH ), 7.13 (d, 2H, J = 8.4 Hz); 7.60 (dd,
3 2 3
13
H, J = 2 Hz, J = 8.8 Hz), 8.04 (d, 2H, J = 1.6 Hz), 8.36(s, 2H, CH=C) ppm; C-NMR (CDCl3):
δ 12.8,
9.0, 42.0, 55.9, 116.5, 117.5, 122.5, 128.9, 130.7, 145.4, 151.2, 158.2, 160.5, 162.6, 166.5, 171.2 ppm. Anal.
Calcd for C H N O (728.26): C, 57.69; H, 4.98; N, 15.38; found: C, 57.90; H, 5.16; N, 15.56.
35
36
8
10
0
5
,5 -((((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))bis(methanylylidene))bis(1,3-diethyl-
2
-thioxodihydropyrimidine-4,6(1H,5H)-dione) 18. Yellow powder in yield 86% (A, 5 h), 92% (B, 4 min);
◦
1
mp 221–223 C. H-NMR (CDCl ):
δ 1.28–1.32 (m, 12H, 4CH ), 3.68–3.73 (m, 8H, 2N-CH CH -O
3 2 2
3
morpholine residue), 4.57 (m, 8H, 4N-CH ), 7.26 (d, 4H, J = 8.8 Hz); 8.23 (d, 4H, J = 8.8 Hz), 8.47 (s, 2H,
2
CH=C) ppm; 13C-NMR (CDCl3):
δ 12.3, 43.6, 44.1, 66.4, 117.6, 121.7, 130.1, 135.98, 155.6, 158.8, 160.6,

Molecules 2018, 23, 2976
10 of 13
166.6, 171.6, 178.7 ppm. Anal. Calcd for C H N O S (770.23): C, 57.65; H, 4.97; N, 14.54; found: C,
37 38 8 7 2
5
7.93; H, 5.12; N, 14.77.
0
5
,5 -((((6-Morpholino-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis(methanylylidene))bis
(
(
1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione) 19. Yellow powder in yield 73% (A, 5 h), 90%
◦
B 4 min); mp 195–196 C. H-NMR (CDCl ): δ 1.22–1.29 (m, 12H, 4CH ), 3.67 (m, 6H, 2O-CH ), 3.77
3 3 3
1
(
2
m, 8H, 4N-CH ), 4.55 (m, 8H, 2N-CH CH -O), 7.1 (d, 2H, J = 8.8 Hz); 7.62 (d, 2H, J = 8.4 Hz), 7.99 (s,
2 2 2
H), 8.34 (s, 2H, CH=C) ppm; C-NMR (CDCl3): δ 12.3, 43.6, 44.2, 55.9, 66.5, 117.5, 122.4, 128.7, 131.1,
13
145.1, 150.9, 151.1, 158.5, 160.0, 166.9, 171.5, 178.8 ppm. Anal. Calcd for C H N O S (830.23): C,
39 42 8 9 2
5
6.37; H, 5.09; N, 13.49; found: C, 56.61; H, 5.28; N, 13.16.
0
5
,5 -((((6-(Piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(3-methoxy-4,1-phenylene))bis(methanylylidene))
bis(1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione) 20. Yellow powder in yield 80% (A, 4 h),
◦
9% (B, 4 min); mp 197–198 C. H-NMR (CDCl ): δ 1.28 (t, 12H, J = 6.4 Hz, 4CH ), 1.48 (brs, 4H,
3 3
1
8
2
2
1
1
CH ), 1.62 (brs, 2H, CH ), 3.69 (brs, 4H, 2N-CH ), 1.82 (s, 6H, 2O-CH ), 4.55 (m, 8H, 4CH ), 7.1 (d,
2
2
2
3
2
13
H, J = 8.8 Hz); 7.62 (d, 2H, J = 8.4 Hz), 8.01 (s, 2H), 8.35 (s, 2H, CH=C) ppm; C-NMR (CDCl3):
2.4, 24.5, 25.7, 43.6, 44.2, 45.0, 55.9, 117.6, 122.5, 128.9, 131.1, 145.4, 151.0, 158.6, 159.1, 160.9, 171.2,
78.8 ppm. Anal. Calcd for C H N O S (828.96): C, 57.96; H, 5.35; N, 13.52; found: C, 57.74; H, 5.21;
δ
40
44
8
8 2
N, 13.78.
0
5
,5 -((((6-(Diethylamino)-1,3,5-triazine-2,4-diyl)bis(oxy))bis(4,1-phenylene))bis(methanylylidene))bis(1,3-
diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione) 21. Yellow powder in yield 82% (A, 6 h), 89% (B,
◦
min); mp 215–217 C. H-NMR (CDCl ): δ 1.04–1.08 (m, 6H, 2CH ), 3.41–3.45 (m, 12H, 4N-CH ),
3 3 3
1
4
3
7
5
.45–3.48 (m, 4H, 2N-CH ), 3.81 (s, 6H, 2O-CH ), 4.49–4.54 (s, 8H, 4N-CH ), 7.13 (d, 2H, J = 8.8 Hz);
2
3
2
13
.60 (d, 2H, J = 10 Hz), 8.06 (d, 2H, J = 2.0 Hz), 8.38 (s, 2H) ppm; C-NMR (CDCl3):
δ 12.7, 42.1, 44.2,
6.0, 116.5, 117.5, 122.6, 129.0, 131.0, 145.5, 151.1, 158.5, 161.0, 162.6, 171.2, 179.8 ppm. Anal. Calcd for
C H N O S (816.27): C, 57.34; H, 5.43; N, 13.72; found: C, 58.57; H, 5.56; N, 14.00.
39
44
8
8 2
4
. Conclusions
Due to the different reactivities of the three chlorine atoms in cyanuric chloride, these chlorine
atoms could be replaced using different nucleophiles by controlling the temperature. Moreover, cyanuric
chloride also showed good selectivity toward substitution by the amino-to-hydroxyl group. We used this
advantage for the preparation of a novel series of di-arm s-triazine derivatives (dipodal). These di-arm
aldehyde derivatives were used for the preparation of a new series of oxy-Schiff bases, oxybenzylidene
barbituric and thiobarbituric acid derivatives, using conventional heating or microwave irradiation.
Microwave irradiation was usually done in less solvent and afforded the target products in shorter
1
13
reaction time, with higher yields and purities. NMR ( H and C), elemental analyses and UPLC-MS
confirmed the structures of the prepared compounds.
Efforts made on the synthesis and characterization of higher generation of s-triazine derivatives
are in progress in our lab, which might be of special interest in medicinal chemistry and coordination
chemistry for other researchers.
Supplementary Materials: Spectral data are available online: H-NMR, 13C-NMR, and UPLC-MS.
1
Author Contributions: The chemistry was carried out by K.A.D. and the novel series was designed and supervised
by Z.A.M., Z.A.A.O., and A.E.-F. All authors contributed to the explanation of the results and discussion. K.A.D.
prepared the first draft of the manuscript, and the final version included contributions from all authors.
Funding: This research received no external funding.
Acknowledgments: The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding this work through research group RGP-234, Saudi Arabia.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2018, 23, 2976
11 of 13
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α,β-conjugated and aromatic aldehydes with
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Sample Availability: Samples of the compounds are available from the authors.
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