A one-pot synthesis of: N 2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines and systematic evaluation of their ability to host ethanol in crystals

Article abstract of DOI:10.1039/c9ra08795h

A convenient one-pot method for the preparation of N²,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines was developed using a three-component synthesis of 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines followed by their Dimroth rearrangement

Full text of DOI:10.1039/c9ra08795h

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A one-pot synthesis of N2,6-diaryl-5,6-dihydro-
1,3,5-triazine-2,4-diamines and systematic
evaluation of their ability to host ethanol in
crystals†
Cite this: RSC Adv., 2019, 9, 37660
b
Ahmad Junaid,ad Yee Seng Tan,b Edward R. T. Tiekink
ac
*
and Anton V. Dolzhenko
A convenient one-pot method for the preparation of N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines
was developed using a three-component synthesis of 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines
followed by their Dimroth rearrangement to the desired products. The prepared compounds crystallized
from ethanol as ethanol clathrates (1 : 1). X-ray crystallography on several products confirmed the
adoption of 5,6-dihydro-tautomer. The thermal analysis and powder X-ray diffraction experiments on
selected compounds suggested that thermal desolvation of crystals was irreversible.
Received 26th October 2019
Accepted 13th November 2019
DOI: 10.1039/c9ra08795h
rsc.li/rsc-advances
multicomponent synthesis of bioactive 1,3,5-triazines,4,5 we
report herein a one-pot synthesis of N2,6-diaryl-5,6-dihydro-
1,3,5-triazine-2,4-diamines, including 1a and 1b. The yield
of 1a in the rearrangement of 2a described by Modest and
Levine1 was not reported, but the fact that 2a could be effec-
tively prepared via a three-component reaction of cyanogua-
nidine, aniline and benzaldehyde6 prompted us to combine
these two reactions in a one-pot procedure.
Introduction
The rst synthesis of N2,6-diphenyl-5,6-dihydro-1,3,5-triazine-
2,4-diamine (1a) was reported in 1956 by Modest and Levine.1
They prepared 1a using a piperidine-catalyzed condensation of
N-phenylbiguanide with benzaldehyde and alternatively, by
a Dimroth rearrangement of 1,6-diphenyl-1,6-dihydro-1,3,5-
triazine-2,4-diamine hydrochloride (2a) upon its heating with
a base (Scheme 1).
Despite a signicant interest in 1,3,5-triazine derivatives as
bioactive compounds, particularly due to their anticancer
properties,2 since that time no reports on N2,6-diphenyl-5,6-
dihydro-1,3,5-triazine-2,4-diamine (1a) and its analogues
had appeared until recently. In 2019, a Japanese patent3
mentioned another N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-
diamine, compound 1b, as an agent against esophageal
squamous cell carcinoma. However, the preparation of this
compound was not described. With our interest towards
development of new practical methods for the
Modest and Levine reported1 that recrystallization of N2,6-
diphenyl-5,6-dihydro-1,3,5-triazine-2,4-diamine
(1a)
from
aSchool of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar
Sunway, Selangor Darul Ehsan 47500, Malaysia. E-mail: anton.dolzhenko@monash.
edu
bResearch Centre for Crystalline Materials, School of Science and Technology, 5 Jalan
Universiti, Sunway University, Bandar Sunway, Selangor Darul Ehsan 47500,
Malaysia
cSchool of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research
Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987 Perth,
Western Australia 6845, Australia
ethanol resulted in the formation of an ethanol solvate (1 : 1). In
our study, we attempted to explore whether this ability to host
ethanol is common for analogues of 1a substituted at the
phenyl rings. We also solved crystal structures of several of
these ethanol clathrates and assessed their stability.
Results and discussion
dDepartment of Chemistry, Prairie View A&M University, P.O. Box 519, Prairie View,
Texas 77446, USA
The synthesis of N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-
diamines (2) was performed using a one-pot methodology
combining two steps: (1) a three-component condensation of
† Electronic supplementary information (ESI) available. CCDC 1961317–1961319.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra08795h
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Scheme 1 Reported1 syntheses of N2,6-diphenyl-5,6-dihydro-1,3,5-triazine-2,4-diamine (1a).
cyanoguanidine, an aniline and a benzaldehyde in the presence it was critical for the success of the reaction to maintain pH at
in hydrochloric acid and (2) a base-promoted Dimroth rear- 10–11. Further increase of the pH resulted in the partial dehy-
rangement of the intermediate 1,6-diaryl-1,6-dihydro-1,3,5- drogenation of the product and aromatization of the dihydro-
triazine-2,4-diamine hydrochlorides (2) (Scheme 2).
triazine in a process similar to the one we reported earlier.5
Variations of substituents on aniline (1c–j) benzaldehyde
The products were isolated as a racemic mixture of R- and S-
(1k), and their combinations (1b) were tolerated in the reaction. stereoisomers in the form of ethanol solvates aer recrystalli-
The structure of the prepared compounds 1 was conrmed by zation from this solvent. The integration of signals at 1.06, 3.44–
NMR spectroscopic data. The signals of the sp3-hydridized 3.45, and 4.34–4.37 ppm, attributed to ethanol, in the 1H NMR
carbon atom in 13C NMR spectra at 67.5–68.4 ppm and the spectra of samples dried in air at room temperature indicated
corresponding proton in 1H NMR spectra at 5.70–5.77 ppm that all prepared solvates of N2,6-diaryl-5,6-dihydro-1,3,5-
conrmed formation of the dihydrotriazine ring. We found that triazine-2,4-diamines (1) contained one molecule of ethanol
Scheme 2 One-pot synthesis N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines (1).
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per heterocycle molecule. This was further conrmed by X-ray
crystallographic studies as described below. We did not
observe formation of stable clathrates with methanol and des-
olvated compounds 1 can be obtained by the recrystallization
from this solvent. The NMR spectra of a representative des-
olvated sample of 1a can be found in ESI.†
In principle, three tautomeric forms of the prepared
compounds are possible due to annular prototropic tautom-
1
erism in the dihydrotriazine ring (Scheme 3). In the H NMR
spectra of compounds 1, signals of the annular NH and the NH
link between the triazine and benzene rings were very broad and
not always detectable. This can be attributed to the tautom-
erism, proton exchange with ethanol, or both processes taking
place together. X-ray crystallography (vide infra) revealed that
the compounds crystallized as the 5,6-dihydro-tautomer, A.
The molecular structures of 1b, 1e and 1f were established by
single crystal X-ray crystallography as their ethanol solvates
(1 : 1) and found to be isostructural. The discussion will focus
on 1e$EtOH with details of 1b$EtOH and 1f$EtOH available in
the ESI. Crystals of 1e$EtOH adopt the non-centrosymmetric
space group P21 with two independent molecules each of 1e
and ethanol comprising the asymmetric unit of 1e$EtOH, Fig. 1;
the molecular structure diagrams for 1b$EtOH and 1f$EtOH are
given in ESI Fig. S1 and S2,† respectively.
The independent molecules of 1e are related by a non-
crystallographic centre of inversion with the congurations at
the C1 and C16 atoms being R and S, respectively; this therefore,
an example of kyptoracemic behaviour.7 Key geometric param-
eters are collated in Table 1 for 1e$EtOH and ESI Table S1† for
1b$EtOH and 1f$EtOH. The parameters describing chemically
equivalent bonds and angles follow the same trends across the
series. At least three key parameters point to the adoption of 5,6-
dihydro-tautomer, A, shown in Scheme 3. These are the short
C2–N1 bond, consistent with signicant double bond character,
the wider angle subtended at the N3 atom compared with those
at the N1 and N2 atoms, consistent with protonation at N3, and
the participation of the N3-bound proton in signicant
hydrogen bonding interactions with the N7 atom of the second
independent molecule and conversely, the N8-bound proton to
the N2 atom. Based on the closeness of the C3–N2 and C3–N3
bond lengths, there is some evidence of delocalization of the p-
electron density over these atoms.
Fig. 1 The molecular structures of the two independent organic
molecules comprising the asymmetric unit of 1e, showing atom
labelling scheme and displacement ellipsoids at the 70% probability
level: (a) N1-containing molecule and (b) N6-containing molecule. (c)
An overlay diagram of 1b (N1-molecule, blue image), 1b (inverted N6-
molecule, aqua), 1e (N1-molecule, red), 1e (inverted N6-molecule,
green), 1f (inverted N1-molecule, pink) and 1f (N6-molecule, yellow).
The molecules have been overlapped so the N1, N2 and N3 atoms are
coincident. Solvent ethanol molecules are omitted.
The N1-triazine ring adopts an envelope conformation
˚
whereby the C1 atom lies 0.442(3) A out of the plane dened by
Scheme 3 Annular tautomerism in N2,6-diaryl-X,6-dihydro-1,3,5-triazine-2,4-diamines.
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Table 1 Key geometric parameters (A˚, ꢀ) for 1e$EtOH
the c-axis are of the type primary amine-N–H/p(chlorophenyl),
again occurring between the different 1e molecules of the
asymmetric unit. Links between layers along the a-axis are of
the type phenyl-C–H/p(phenyl). Here, the donor and acceptor
molecules are the N1- and N6-containing molecules, respec-
tively. As there is no reciprocal contact, i.e. having the N6- and
N- molecules as the donor and acceptor, this interaction
distinguishes the two independent molecules. Each of the
independent ethanol molecules participates in analogous
hydrogen-bonding with the 1e molecules dening the host
structure. The donor interactions are of the type ethanol–O–H/
N6(triazine), where the nitrogen acceptor is adjacent to the
methine-carbon atom. The ethanol molecules each accept two
hydrogen bonds, one from each of the exocyclic amines.
Subtle differences in the molecular packing are apparent in
the crystal of 1b$EtOH; see ESI Table S3 and Fig. S3.† Crucially,
the intra-layer O–H/N, N–H/O and N–H/N hydrogen-
bonding remains the same. However, the connections
between layers are chlorophenyl-C–H/O(methoxy) interac-
tions. Additional intra-layer methoxyphenyl-C–H/p(chlor-
ophenyl) and ethanol–methylene–C–H/Cl interactions are
noted, which contribute to the stability of the layer. The
molecular packing of the bromo analogue of 1e$EtOH, i.e.
1f$EtOH, mimics that described above with the addition of
inter-layer phenyl-C–H/Br contacts; see ESI Table S4 and
Fig. S4.†
Additional investigations were conducted on the three crys-
tallographically characterised compounds, i.e. simultaneous
thermal analysis (STA) and powder X-ray diffraction (PXRD)
studies. The original STA traces and data are given in ESI Fig. S5.†
For 1b$EtOH, the results of the thermogravimetric analyses
showed a single-step between 90 and 162 ꢀC corresponding to the
loss of one ethanol molecule per molecule of 1b. Similar features
were noted for each of 1e$EtOH and 1f$EtOH although the onset
temperatures were higher and the process was completed at lower
temperatures. For 1e$EtOH and 1f$EtOH, a second exothermic
event corresponding to melting was also observed. This was not
seen in the STA of 1b$EtOH and visual inspection showed the
sample to be a paste aer desolvation in contrast to the powders
generated aer the desolvation of the other samples. In order to
ascertain whether desolvation altered the crystal structures of
1e$EtOH and 1f$EtOH, PXRD measurements were conducted. As
C1–N1
C1–N3
C2–N1
C2–N2
C3–N2
C3–N3
C1–N1–C2
C2–N2–C3
C1–N3–C3
N1–C1–N3
N1–C2–N2
N2–C3–N3
1.449(3)
1.469(3)
1.305(3)
1.383(3)
1.337(3)
1.329(3)
115.67(19)
114.0(2)
118.5(2)
110.70(19)
127.6(2)
122.9(2)
C16–N6
C16–N8
C17–N6
C17–N7
C18–N7
C18–N8
C16–N6–C18
C17–N7–C18
C16–N8–C18
N6–C16–N8
N6–C17–N7
N7–C18–N8
1.458(3)
1.456(3)
1.300(3)
1.378(3)
1.330(3)
1.339(3)
114.63(19)
114.4(2)
118.1(2)
110.92(19)
127.5(2)
122.6(2)
˚
the ve remaining atoms, r.m.s. deviation ¼ 0.033 A; the
equivalent parameters for the N6-ring/C16 atom are 0.471(3)
˚
and 0.034 A, respectively. There are some conformational
differences evident between the two independent molecules as
highlighted in the overlay diagram of Fig. 1(c). These relate
primarily to the relative orientation of the phenyl rings. The
dihedral angles between the best plane through the triazine ring
and the phenyl and chlorophenyl rings are 89.59(8) and
17.74(12)ꢀ, respectively for the N1-molecule; the equivalent
angles for the N6-molecule are 72.76(9) and 19.24(14)ꢀ, respec-
tively. For the N1- and N6-molecules, the dihedral angle
between the peripheral rings are 77.95(8) and 57.86(9)ꢀ,
respectively. Very similar trends are evident in the molecules
comprising the methoxy (1b) and bromo (1f) analogues; see ESI
Table S2† for data.
An interesting feature of the crystal structure determinations
of 1b$EtOH, 1e$EtOH and 1f$EtOH is that each has occluded
solvent in their structures so the ratio of organic molecule to
ethanol was 1 : 1. A description of the molecular packing of
1e$EtOH ensues; details of the intermolecular interactions are
gathered in Table 2. Fig. 2(a) shows a view of the molecular
packing for 1e$EtOH showing only contacts occurring between
the organic molecules, i.e. 1e only. The two 1e molecules in the
asymmetric unit are connected into helical supramolecular
chains via ring amine-N–H/N(imine) hydrogen-bonding. The
chains are aligned along the b-axis direction, being propagated
by screw (21) symmetry. The connections between chains along
Table 2 Geometric parameters (A˚, ꢀ) characterizing the intermolecular interactions occurring in the crystal of 1e$EtOH
A
H
B
A–H
H/B
A/B
A–H/B
Symmetry operation
N3
N8
N4
N9
C22
O1
O2
N4
N10
N5
N9
H3n
H8n
H4na
H9na
H22
H1o
H2o
H4nb
H10n
H5n
N7
N2
0.87(2)
0.87(2)
0.88(2)
0.87(2)
0.95
0.84(2)
0.84(2)
0.88(3)
0.88(2)
0.88(2)
0.88(3)
2.11(2)
2.12(2)
2.60(3)
2.63(4)
2.71
1.88(2)
1.89(2)
1.99(3)
2.05(3)
2.04(2)
2.00(3)
2.931(3)
2.939(3)
135(2)
156(2)
156(2)
3.279(2)
3.236(3)
152
169(3)
172(3)
176(3)
165(2)
169(2)
177(3)
1 ꢁ x, 1/2 + y, 1 ꢁ z
1 ꢁ x, 1/2 + y, 1 ꢁ z
x, y, z
x, y, 1 + z
1 + x, y, 1 + z
x, y, z
x, y, 1 + z
x, y, z
1 ꢁ x, ꢁ1/2 + y, 1 ꢁ z
1 ꢁ x, ꢁ1/2 + y, 1 ꢁ z
x, y, z
Cg(C10–C15)
Cg(C25–C30)
Cg(C4–C9)
N6
N1
O1
O1
O2
O2
128(3)
3.577(3)
2.706(3)
2.726(3)
2.865(3)
2.913(3)
2.907(3)
2.874(3)
H9nb
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Fig. 2 Molecular packing in the crystal of 1e$EtOH: (a) a view of the unit cell contents in projection down the b-axis. The N–H/N, N–H/p and
C–H/p interactions are shown as blue, purple and pink dashed lines, respectively. (b) A side-on view of a supramolecular layer highlighting the
encapsulation of the solvent ethanol molecules and (c) a plan view of the layer shown in (b). Hydrogen-bonding interactions involving ethanol are
indicated by orange dashed lines. For (b) and (c), non-participating hydrogen atoms are omitted for reasons of clarity.
seen from ESI Fig. S6,† the desolvated forms did not retain the which was in turn placed in a larger container containing ethanol,
original crystal structures. Attempts at re-solvation of 1e and 1f capped and allow to stand overnight. Subsequent PXRD
were performed. Thus, powders were placed in a sample vial measurements showed no evidence of re-solvation.
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Table 3 Crystallographic data and refinement details for 1b$EtOH, 1e$EtOH, and 1f$EtOH
Compound
1b$EtOH
16H16ClN5O$C2H6O
1e$EtOH
1f$EtOH
Formula
C
C15H14ClN5$C2H6O
345.83
0.03 ꢂ 0.06 ꢂ 0.06
Colourless
Monoclinic
P21
12.6684(2)
9.81230(10)
15.0780(2)
109.8020(10)
1763.46(4)
4
C15H14BrN5$C2H6O
390.29
0.02 ꢂ 0.08 ꢂ 0.11
Colourless
Monoclinic
P21
12.7568(4)
9.7768(3)
15.1645(4)
109.622(3)
1781.49(10)
4
Molecular weight
Crystal size/mm3
Colour
375.85
0.04 ꢂ 0.07 ꢂ 0.13
Colourless
Monoclinic
P21
13.2045(2)
9.7903(2)
14.8676(2)
93.816(2)
1917.76(6)
4
Crystal system
Space group
˚
a/A
˚
b/A
˚
c/A
b/ꢀ
3
˚
V/A
Z
Dc/g cmꢁ3
1.302
1.949
1.303
2.030
1.455
3.258
m/mmꢁ1
Measured data
24 367
3.0–67.1
6693
42 215
3.1–67.1
6286
22 035
3.1–67.1
5907
q range/ꢀ
Unique data
Observed data (I $ 2.0s(I))
No. parameters
R, obs. data; all data
a; b in weighting scheme
Rw, obs. data; all data
Range of residual electron
6456
503
0.053; 0.145
0.071; 3.036
0.055; 0.146
6062
465
0.029; 0.072
0.041; 0.308
0.031; 0.073
5554
465
0.037; 0.093
0.058; 0.019
0.040; 0.096
ꢁ3
˚
Density peaks/eA
ꢁ0.46 to 0.60
ꢁ0.27 to 0.18
ꢁ0.74 to 0.74
doublet of doublets (ddd), or multiplet (m). Thermogravimetric
analyses were performed on a PerkinElmer STA 6000 Ther-
mogravimetric Analyzer in the range 25–600 ꢀC at the rate of
10 ꢀC minꢁ1 under a nitrogen purge. The data was manipulated
by PerkinElmer thermal analysis proprietary soware Pyris®.
Powder X-ray diffraction (PXRD) patterns were measured on
a Rigaku SmartLab X-ray diffractometer using Cu-Ka (l ¼ 1.5406
Conclusions
An efficient one-pot protocol for the synthesis of N2,6-diaryl-5,6-
dihydro-1,3,5-triazine-2,4-diamines (1) from simple, readily
available reagents i.e. cyanoguanidine, anilines and benzalde-
hydes was developed. Aer the initial three-component
condensation of these building blocks, the intermediate 1,6-
diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines (2) were iso-
merized to the targeted products via the base-promoted Dim-
roth rearrangement. The X-ray crystallographic study
established the tautomeric form as the 5,6-dihydro-tautomer. It
was found that N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-
diamines (1) crystallised from ethanol trapping one molecule
of this solvent per molecule of 1 in the crystals, giving 1$EtOH.
The STA and PXRD data for selected compounds suggested that
desolvation irreversibly change crystal structure.
ꢀ
ꢀ
˚
A) radiation in the 2q range 10 to 60 with step size 0.01 .
General procedure for the preparation of N2,6-diaryl-5,6-
dihydro-1,3,5-triazine-2,4-diamines (1)
To a solution of cyanoguanidine (0.84 g, 10 mmol), a (un)
substituted benzaldehyde (10 mmol) and a (un)substituted
aniline (10 mmol) in EtOH (5 mL), conc. HCl (0.84 mL, 10
mmol) was added and the reaction mixture was heated under
reux for 24 h. The reaction mixture was cooled to rt and diluted
with 50% aq. EtOH (5 mL). Then, aq. NaOH solution (5 N) was
added drop-wise to the solution until the pH increased to 10–11.
The mixture was heated under reux for another 5 h. Aer
cooling at 0 ꢀC, the resulting precipitate was ltered, washed
Experimental
General information
All the chemicals and reagents were purchased from commer- with water and recrystallized from EtOH.
cial suppliers (Sigma-Aldrich, Merck, and Alfa-Aesar) and were
N2,6-Diphenyl-5,6-dihydro-1,3,5-triazine-2,4-diamine etha-
ꢀ
used without additional purication. Melting points (uncor- nolate (1a/EtOH). Yield: 1.4 g, 53%; mp: 154–156 C (EtOH).
rected) were determined on a Stuart™ SMP40 automatic 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼ 7.0 Hz, CH3),
1
melting point apparatus. H and 13C NMR spectra were recor- 3.44 (2H, q, J ¼ 7.0 Hz, CH2), 4.37 (1H, brs, OH), 5.75 (1H, s, CH),
ded on a Bruker Fourier NMR spectrometer (300 MHz) using 5.84 (2H, brs, NH2), 6.73 (1H, t, J ¼ 7.3 Hz, H-400), 7.10 (2H, t, J ¼
DMSO-d6 as a solvent and TMS as an internal reference. The 7.4 Hz, H-300 and H-500), 7.27–7.44 (5H, m, H-20, H-30, H-40, H-50
chemical shis are reported in parts per million (ppm, d) and and H-60), 7.73 (2H, d, J ¼ 7.6 Hz, H-200 and H-600); 13C NMR (75
coupling constants are reported in Hertz with the splitting MHz, DMSO-d6): d 18.5 (CH3), 55.9 (CH2), 68.2 (C-6), 117.9 (C-200
pattern described as singlet (s), broad signal (brs), doublet (d), and C-600), 119.3 (C-400), 126.1 (C-30 and C-50), 127.2 (C-40), 127.9
triplet (t), quartet (q), doublet of doublets (dd), double of (C-300 and C-500), 128.1 (C-20 and C-60), 142.3 (C-10), 145.7 (C-100),
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N2-(4-Bromophenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1f/EtOH). Yield: 2.7 g, 79%; mp: 227–
228 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 3.44 (2H, q, J ¼ 7.0 Hz, CH2), 4.34 (1H, brs, OH),
5.75 (1H, s, CH), 5.82 (2H, brs, NH2), 6.98 (1H, brs, NH), 7.24
(2H, d, J ¼ 9.0 Hz, H-300 and H-500), 7.27–7.43 (5H, m, H-20, H-30,
H-40, H-50 and H-60), 7.74 (2H, d, J ¼ 8.9 Hz, H-200 and H-600), 8.03
(H, brs, NH); 13C NMR (75 MHz, DMSO-d6): d 18.5 (CH3), 56.0
(CH2), 68.3 (C-6), 110.4 (C-400), 119.7 (C-200 and C-600), 126.1 (C-30
and C-50), 127.3 (C-40), 128.1 (C-20 and C-60), 130.5 (C-300 and C-
500), 141.9 (C-100), 145.6 (C-10), 155.4 (C-2), 157.9 (C-4). Anal. calcd
for C17H20BrN5O: C, 52.32; H, 5.17; N, 17.94. Found: C, 52.20; H,
5.05; N, 18.06.
155.4 (C-2), 157.9 (C-4). Anal. calcd for C17H21N5O: C, 65.57; H,
6.80; N, 22.49. Found: C, 65.44; H, 6.67; N, 22.55.
N2-(4-Chlorophenyl)-6-(4-methoxyphenyl)-5,6-dihydro-1,3,5-
triazine-2,4-diamine ethanolate (1b/EtOH). Yield: 2.0 g, 61%;
1
ꢀ
mp: 128–130 C (EtOH). H NMR (300 MHz, DMSO-d6): d 1.06
(3H, t, J ¼ 7.0 Hz, CH3), 3.44 (2H, q, J ¼ 7.0 Hz, CH2), 3.74 (3H, s,
OCH3), 4.36 (1H, brs, OH), 5.70 (1H, s, CH), 5.81 (2H, brs, NH2),
6.91 (2H, d, J ¼ 8.8 Hz, H-30 and H-50), 7.12 (2H, d, J ¼ 9.0 Hz, H-
300 and H-500), 7.32 (2H, d, J ¼ 8.6 Hz, H-20 and H-60), 7.78 (2H, d, J
¼ 8.9 Hz, H-200 and H-600); 13C NMR (75 MHz, DMSO-d6): d 18.5
(CH3), 55.0 (OCH3), 55.9 (CH2), 67.7 (C-6), 113.4 (C-30 and C-50),
119.2 (C-200 and C-600), 122.5 (C-400), 127.3 (C-20 and C-60), 127.6
(C-300 and C-500), 137.8 (C-10), 141.5 (C-100), 155.4 (C-2), 157.9 (C-
4), 158.5 (C-40). Anal. calcd for C18H22ClN5O2: C, 57.52; H,
5.90; N, 18.63. Found: C, 57.29; H, 5.76; N, 18.75.
N2-(4-Methoxyphenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-
2,4-diamine ethanolate (1g/EtOH). Yield: 2.0 g, 68%; mp: 135–
136 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 3.44 (2H, q, J ¼ 7.0 Hz, CH2), 3.65 (3H, s, OCH3),
4.34 (1H, brs, OH), 5.72 (1H, s, CH), 5.74 (2H, brs, NH2), 6.70
(2H, d, J ¼ 9.1 Hz, H-300 and H-500), 7.24–7.43 (5H, m, H-20, H-30,
H-40, H-50 and H-60), 7.64 (2H, d, J ¼ 9.0 Hz, H-200 and H-600); 13C
NMR (75 MHz, DMSO-d6): d 18.5 (CH3), 55.0 (OCH3), 55.9 (CH2),
68.4 (C-6), 113.2 (C-300 and C-500), 119.1 (C-200 and C-600), 126.2 (C-
30 and C-50), 127.1 (C-40), 128.0 (C-20 and C-60), 135.8 (C-100), 145.9
(C-10), 152.6 (C-400), 155.3 (C-2), 157.8 (C-4). Anal. calcd for
N2-(4-Fluorophenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1c/EtOH). Yield: 2.0 g, 71%; mp: 202–
204 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 3.45 (2H, q, J ¼ 7.0 Hz, CH2), 4.35 (1H, brs, OH),
5.74 (1H, s, CH), 5.80 (2H, brs, NH2), 6.92 (2H, dd, 3JHF ¼ 9.0 Hz,
3JHH ¼ 9.0 Hz, H-300 and H-500), 7.25–7.30 (1H, m, H-40), 7.33–7.43
4
(4H, m, H-20, H-30, H-50 and H-60), 7.76 (2H, dd, JHF ¼ 5.1 Hz,
3JHH ¼ 9.1 Hz, H-200 and H-600); 13C NMR (75 MHz, DMSO-d6):
d 18.5 (CH3), 56.0 (CH2), 68.3 (C-6), 114.2 (d, 2JCF ¼ 21.6 Hz, C-300
and C-500), 119.0 (d, 3JCF ¼ 7.1 Hz, C-200 and C-600), 126.2 (C-30 and
C-50), 127.2 (C-40), 128.1 (C-20 and C-60), 139.0 (d, 4JCF ¼ 1.5 Hz,
C
18H23N5O2: C, 63.32; H, 6.79; N, 20.51. Found: C, 63.11; H,
6.63; N, 20.72.
1
N2-(3-Methylphenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1h/EtOH). Yield: 1.7 g, 61%; mp: 155–
157 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 2.18 (3H, s, CH3), 3.45 (2H, q, J ¼ 7.0 Hz, CH2),
4.37 (1H, brs, OH), 5.76 (1H, s, CH), 5.85 (2H, brs, NH2), 6.56
(1H, d, J ¼ 9.0 Hz, H-400), 6.98 (1H, dd, J ¼ 7.8 Hz, J ¼ 7.8 Hz,
H-300), 7.27 (1H, t, J ¼ 7.1 Hz, H-40), 7.36 (2H, dd, J ¼ 7.3 Hz, J ¼
7.3 Hz, H-30 and H-50), 7.42 (2H, dd, J ¼ 1.2 Hz, J ¼ 8.1 Hz, H-20
and H-60), 7.48 (1H, s, H-600), 7.60 (1H, d, J ¼ 8.1 Hz, H-200),
6.5–8.03 (2H, brs, 2(NH)); 13C NMR (75 MHz, DMSO-d6):
d 18.5 (CH3), 21.3 (CH3), 55.9 (CH2), 68.2 (C-6), 115.2 (C-600),
118.4 (C-200), 120.1 (C-400), 126.1 (C-30 and C-50), 127.2 (C-40),
127.7 (C-300), 128.0 (C-20 and C-60), 136.7 (C-500), 142.2 (C-100),
145.7 (C-10), 155.4 (C-2), 157.8 (C-4). Anal. calcd for
C-100), 145.8 (C-10), 155.8 (d, JCF ¼ 235.5 Hz, C-400), 155.4 (C-2),
157.9 (C-4). Anal. calcd for C17H20FN5O: C, 61.99; H, 6.12; N,
21.26. Found: C, 61.86; H, 5.98; N, 21.40.
N2-(3-Chlorophenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1d/EtOH). Yield: 2.1 g, 70%; mp: 154–
156 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 3.45 (2H, q, J ¼ 7.0 Hz, CH2), 4.34 (1H, brs, OH),
5.78 (1H, s, CH), 5.85 (2H, brs, NH2), 6.75 (1H, ddd, J ¼ 0.8 Hz, J
¼ 2.0 Hz, J ¼ 7.9 Hz, H-400), 7.01 (1H, brs, NH), 7.10 (1H, dd, J ¼
8.1 Hz, J ¼ 8.1 Hz, H-300), 7.26–7.44 (5H, m, H-20, H-30, H-40, H-50
and H-60), 7.58 (1H, ddd, J ¼ 0.9 Hz, J ¼ 1.6 Hz, J ¼ 8.6 Hz, H-200),
8.04 (1H, s, H-600), 8.11 (1H, brs, NH); 13C NMR (75 MHz, DMSO-
d6): d 18.5 (CH3), 56.0 (CH2), 68.2 (C-6), 116.2 (C-600), 117.0 (C-200),
118.6 (C-400), 126.1 (C-30 and C-50), 127.3 (C-40), 128.1 (C-20 and C-
60), 129.3 (C-300), 132.4 (C-500), 144.1 (C-100), 145.6 (C-10), 155.5 (C-
2), 157.9 (C-4). Anal. calcd for C17H20ClN5O: C, 59.04; H, 5.83; N,
20.25. Found: C, 58.89; H, 5.67; N, 20.42.
C
18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C, 66.29; H,
6.98; N, 21.69.
N2-(4-Methylphenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1i/EtOH). Yield: 1.8 g, 63%; mp: 206–
208 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 2.17 (3H, s, CH3), 3.44 (2H, q, J ¼ 7.0 Hz, CH2),
4.37 (1H, brs, OH), 5.74 (1H, s, CH), 5.91 (2H, brs, NH2), 6.91
(2H, d, J ¼ 8.3 Hz, H-300 and H-500), 7.24–7.43 (4H, m, H-20, H-30,
H-40, H-50 and H-60), 7.60 (2H, d, J ¼ 8.4 Hz, H-200 and H-600); 13C
NMR (75 MHz, DMSO-d6): d 18.5 (CH3), 20.2 (CH3), 55.9 (CH2),
68.3 (C-6), 117.9 (C-200 and C-600), 126.1 (C-30 and C-50), 127.2 (C-
40), 127.8 (C-400), 127.9 (C-20 and C-60), 128.0 (C-300 and C-500),
139.8 (C-10), 145.8 (C-100), 155.4 (C-2), 157.8 (C-4). Anal. calcd
for C18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C, 66.28; H,
6.95; N, 21.74.
N2-(4-Chlorophenyl)-6-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1e/EtOH). Yield: 0.8 g, 27%; mp: 213–
215 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 3.44 (2H, q, J ¼ 7.0 Hz, CH2), 4.34 (1H, brs, OH),
5.76 (1H, s, CH), 5.81 (2H, brs, NH2), 6.98 (1H, brs, NH), 7.12
(2H, d, J ¼ 9.0 Hz, H-300 and H-500), 7.24–7.43 (5H, m, H-20, H-30,
H-40, H-50 and H-60), 7.78 (2H, d, J ¼ 8.9 Hz, H-200 and H-600), 8.04
(1H, brs, NH); 13C NMR (75 MHz, DMSO-d6): d 18.5 (CH3), 55.9
(CH2), 68.3 (C-6), 119.2 (C-200 and C-600), 122.5 (C-400), 126.1 (C-30
and C-50), 127.2 (C-40), 127.6 (C-300 and C-500), 128.1 (C-20 and C-
60), 141.5 (C-100), 145.6 (C-10), 155.4 (C-2), 157.9 (C-4). Anal. calcd
for C17H20ClN5O: C, 59.04; H, 5.83; N, 20.25. Found: C, 58.92; H,
5.72; N, 20.32.
37666 | RSC Adv., 2019, 9, 37660–37667
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6-Phenyl-N2-(4-(triuoromethoxy)phenyl)-5,6-dihydro-1,3,5-
RSC Advances
Conflicts of interest
triazine-2,4-diamine ethanolate (1j/EtOH). Yield: 2.3 g, 66%;
1
ꢀ
mp: 205–208 C (EtOH). H NMR (300 MHz, DMSO-d6): d 1.06 There are no conicts to declare.
(3H, t, J ¼ 7.0 Hz, CH3), 3.45 (2H, q, J ¼ 7.0 Hz, CH2), 4.36 (1H,
brs, OH), 5.77 (1H, s, CH), 5.85 (2H, brs, NH2), 7.09 (2H, d, J ¼
Acknowledgements
8.4 Hz, H-300 and H-500), 7.25–7.44 (5H, m, H-20, H-30, H-40, H-50
and H-60), 7.85 (2H, d, J ¼ 9.1 Hz, H-200 and H-600), 7.00–8.03 (2H,
brs, 2(NH)); 13C NMR (75 MHz, DMSO-d6): d 18.5 (CH3), 56.0
(CH2), 68.3 (C-6), 118.6 (C-300 and C-500), 120.2 (q, J ¼ 254.6 Hz,
OCF3), 120.8 (C-200 and C-600), 126.2 (C-30 and C-50), 127.3 (C-40),
128.1 (C-20 and C-60), 140.7 (q, J ¼ 1.5 Hz, C-400), 141.9 (C-100),
145.7 (C-10), 155.5 (C-2), 158.0 (C-4). Anal. calcd for
This work is supported by the Ministry of Higher Education,
Malaysia under Fundamental Research Grant Scheme, grant
number FRGS/1/2015/SG01/MUSM/03/1. The authors thank
Sunway University Sdn Bhd (grant number STR-RCTR-RCCM-
001-2019) for support of crystallographic studies.
C
18H20F3N5O2: C, 54.68; H, 5.10; N, 17.71. Found: C, 54.51; H,
References
4.97; N, 17.88.
6-(4-Chlorophenyl)-N2-phenyl-5,6-dihydro-1,3,5-triazine-2,4-
diamine ethanolate (1k/EtOH). Yield: 2.0 g, 67%; mp: 182–
185 ꢀC (EtOH). 1H NMR (300 MHz, DMSO-d6): d 1.06 (3H, t, J ¼
7.0 Hz, CH3), 3.44 (2H, q, J ¼ 7.0 Hz, CH2), 4.35 (1H, brs, OH),
5.76 (1H, s, CH), 5.91 (2H, brs, NH2), 6.74 (1H, t, J ¼ 7.3 Hz, H-
400), 7.10 (2H, t, J ¼ 7.9 Hz, H-300 and H-500), 7.43 (4H, m, H-20, H-
30, H-50 and H-60), 7.72 (2H, d, J ¼ 7.6 Hz, H-200 and H-600), 6.50–
8.00 (2H, brs, 2(NH)); 13C NMR (75 MHz, DMSO-d6): d 18.5
(CH3), 55.9 (CH2), 67.5 (C-6), 117.9 (C-200 and C-600), 119.4 (C-400),
127.9 (C-300 and C-500), 128.1 (C-20 and C-60), 128.0 (C-30 and C-50),
131.7 (C-40), 142.2 (C-10), 144.6 (C-100), 155.4 (C-2), 157.7 (C-4).
Anal. calcd for C17H20ClN5O: C, 59.04; H, 5.83; N, 20.25.
Found: C, 58.92; H, 5.69; N, 20.38.
1 E. J. Modest and P. Levine, J. Org. Chem., 1956, 21, 14.
2 S. Cascioferro, B. Parrino, V. Spano, A. Carbone,
A. Montalbano, P. Barraja, P. Diana and G. Cirrincione,
Eur. J. Med. Chem., 2017, 142, 523.
3 S. Tsuchiya, H. Murayama and Y. Sugimoto, Japan Patent, JP
2019064976, 2019.
4 F. P. L. Lim, K. C. Tan, G. Luna, E. R. T. Tiekink and
A. V. Dolzhenko, Tetrahedron, 2019, 75, 2322; F. P. L. Lim,
L. Y. Tan, E. R. T. Tiekink and A. V. Dolzhenko, RSC Adv.,
2018, 8, 21495; F. P. L. Lim, N. R. Halcovitch,
E. R. T. Tiekink and A. V. Dolzhenko, Tetrahedron, 2018,
74, 1868; F. P. L. Lim, S. T. Low, E. L. K. Ho,
N. R. Halcovitch, E. R. T. Tiekink and A. V. Dolzhenko, RSC
Adv., 2017, 7, 51062; F. P. L. Lim, G. Luna and
A. V. Dolzhenko, Tetrahedron Lett., 2015, 56, 7016;
F. P. L. Lim, G. Luna and A. V. Dolzhenko, Tetrahedron
Lett., 2015, 56, 521; F. P. L. Lim, G. Luna and
A. V. Dolzhenko, Tetrahedron Lett., 2014, 55, 5159;
S. A. Kalinina, D. V. Kalinin and A. V. Dolzhenko,
Tetrahedron Lett., 2013, 54, 5537; A. V. Dolzhenko,
S. A. Kalinina and D. V. Kalinin, RSC Adv., 2013, 3, 15850.
5 A. Junaid, F. P. L. Lim, E. R. T. Tiekink and A. V. Dolzhenko,
ACS Comb. Sci., 2019, 21, 548.
X-ray crystallographic analysis
X-ray intensity data for 1b$EtOH, 1e$EtOH and 1f$EtOH were
measured at T ¼ 100 K on Rigaku/Oxford Diffraction XtaLAB
Synergy diffractometer (Dualex, AtlasS2) tted with Cu-Ka
radiation (l ¼ 1.54178 A) so that qmax ¼ 67.1ꢀ. Data reduction,
˚
including absorption correction, was accomplished with
CrysAlisPro.8 The structures were solved by direct-methods9
and rened (anisotropic displacement parameters and C-
bound H atoms in the riding model approximation) on F2.10
The O- and N-bound H atoms were rened with O–H and N–H
6 E. J. Modest, J. Org. Chem., 1956, 21, 1.
˚
´
´
constrained to 0.84 ꢃ 0.01 and 0.88 ꢃ 0.01 A, respectively,
7 L. Fabian and C. P. Brock, Acta Crystallogr., Sect. B: Struct.
and with Uiso(H) ¼ 1.2Ueq(O, N). A weighting scheme of the
Sci., 2010, 66, 94.
8 Rigaku Oxford Diffraction, CrysAlis PRO, Yarnton,
Oxfordshire, England, 2017.
9 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr.,
2008, 64, 112.
2
form w ¼ 1/[s2(Fo2) + (aP)2 + bP] where P ¼ (Fo + 2Fc2)/3 was
introduced in each case. The absolute structures were
determined based on differences in Friedel pairs included in
the respective data sets. In 1b$EtOH, two reections, i.e. (3–5
8) and (3 5 8), were omitted from the nal cycles of rene- 10 L. J. Farrugia, J. Appl. Crystallogr., 2012, 45, 849.
ment owing to poor agreement. The molecular structure 11 G. M. Sheldrick, Acta Crystallogr., Sect. B: Struct. Sci., 2015,
diagrams were generated with ORTEP for Windows11 with
71, 3.
50% displacement ellipsoids, and the packing diagrams were 12 K. Brandenburg, Diamond, Crystal Impact GbR, Bonn,
drawn with DIAMOND.12 Additional data analysis was made
Germany, 2006.
with PLATON.13 Crystal data and renement details are given 13 A. L. Spek, Acta Crystallogr., Sect. D: Biol. Crystallogr., 2009,
in Table 3.
65, 148.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 37660–37667 | 37667