An optimized synthesis, molecular structure and characterization of benzylic derivatives of 1,2,4-Triazin-3,5(2H,4H)-dione

Article abstract of DOI:10.3390/molecules22111924

4-Benzyl-1,2,4-triazin-3,5(2H,4H)-dione (3-benzyl-6-azauracil, 2), and 2,4-dibenzyl-1,2,4-triazin-3,5(2H,4H)-dione (1,3-dibenzyl-6-azauracil, 3) were synthesized by the reaction of 1,2,4-triazin-3,5(2H,4H)-dione (6-azauracil, 1) with benzyl bromide and potassium carbonate in dry acetone via the 18-crown-6-ether catalysis. In these reaction methods, we developed more convenient and efficient methodologies to afford compounds 2 and 3 in good yields. These compounds were characterized by¹H- and¹³C-NMR, MS spectrum, IR spectroscopy and elemental analysis. The structure of 2 was verified by 2D-NMR measurements, including gHSQC and gHMBC measurements. A single-crystal X-ray diffraction experiment indicated that compound 3, with the molecular formula C₁₇H₁₅N₃O₂, crystallized from a CH₃OH/CH₂Cl₂ diffusion solvent system in a monoclinic space group P2₁/c with a = 13.7844(13), b = 8.5691(8), c = 13.0527(12), β = 105.961(2)^?, V = 1482.3(2)³, Z = 4, resulting in a density D_calc of 1.314 g/cm³. The crystal structure of compound 3 is tightly stabilized by contact with five other molecules from the six short contacts formed by intermolecular C?O···H?Car, C?H···Car, and weakly π···π stacking interactions. The dihedral angle 31.90^? is formed by the mean planes of the benzene rings of the N-2 and N-4 benzyl groups.

Full text of DOI:10.3390/molecules22111924

molecules
Article
An Optimized Synthesis, Molecular Structure
and Characterization of Benzylic Derivatives
of 1,2,4-Triazin-3,5(2H,4H)-dione
Long-Chih Hwang 1,2,*, Shiun-Yau Yang 1, Chung-Lin Chuang 1 and Gene-Hsiang Lee 3
1
Department of Medicinal and Applied Chemistry, College of Life Sciences, Kaohsiung Medical University,
Kaohsiung 807, Taiwan; hangtenyang@gmail.com (S.-Y.Y.); jojodick1215@gmail.com (C.-L.C.)
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Instrumentation Center, College of Science, National Taiwan University, Taipei 106, Taiwan;
2
3
ghlee@ntu.edu.tw
*
Correspondence: lnchhw@kmu.edu.tw; Tel.: +886-7-312-1101 (ext. 2276)
Received: 21 September 2017; Accepted: 3 November 2017; Published: 8 November 2017
Abstract: 4-Benzyl-1,2,4-triazin-3,5(2H,4H)-dione (3-benzyl-6-azauracil,
triazin-3,5(2H,4H)-dione (1,3-dibenzyl-6-azauracil, ) were synthesized by the reaction of
1,2,4-triazin-3,5(2H,4H)-dione (6-azauracil, ) with benzyl bromide and potassium carbonate in dry
acetone via the 18-crown-6-ether catalysis. In these reaction methods, we developed more convenient
2), and 2,4-dibenzyl-1,2,4-
3
1
and efficient methodologies to afford compounds
2 and 3 in good yields. These compounds
1
were characterized by H- and 13C-NMR, MS spectrum, IR spectroscopy and elemental analysis.
The structure of
measurements. A single-crystal X-ray diffraction experiment indicated that compound
molecular formula C17H15N3O2, crystallized from a CH3OH/CH2Cl2 diffusion solvent system in a
monoclinic space group P21/c with a = 13.7844(13), b = 8.5691(8), c = 13.0527(12) Å,
= 105.961(2)◦,
V = 1482.3(2) Å3, Z = 4, resulting in a density Dcalc of 1.314 g/cm3. The crystal structure of compound
is tightly stabilized by contact with five other molecules from the six short contacts formed by
2
was verified by 2D-NMR measurements, including gHSQC and gHMBC
3, with the
β
3
intermolecular C
−
O
···
H
−
Car, C
− ···Car, and weakly π···π stacking interactions. The dihedral
H
angle 31.90◦ is formed by the mean planes of the benzene rings of the N-2 and N-4 benzyl groups.
Keywords: 1,2,4-triazine; 1,2,4-triazin-3,5(2H,4H)-dione; 6-azauracil; X-ray crystal structure; short
contacts; synthesis
1. Introduction
Many aza/deaza analogues of purine have been found to display interesting biological activities.
The 1,2,4-triazine ring system had been suggested for study because of various interesting biological
activities [1]. Until now, the 1,2,4-triazine and/or fused 1,2,4-triazine moiety have been two of the most
popular heterocycles in heterocyclic chemistry. They have been reported to possess a broad spectrum
of biological properties and are used in medicine. In the last decade numerous compounds with the
1,2,4-triazine moiety have been synthesized, along with numerous biological tests, thus revealing their
varied bioactivity, such as benzodiazepine receptor inhibition [
neuroprotective [ ], antifungals [ ], anti-inflammatory [ ], antiparasitic [10], antiparkinson [11],
and anticancer [12–15] activities.
The starting material of the title compound 1,2,4-triazin-3,5(2H,4H)-dione (6-azauracil;
2], antimicrobial [3,4], anxiolytic [5,6],
7
8
6,9
1),
an azapyrimidine analogue of uracil, has been known for over 60 years [16] to inhibit the growth
of various species of microorganisms. 6-Azauridine, the ribonucleoside of 6-azauracil, has been
proved to display a range of biological effects which include antiviral [17,18], antitumor [19,20],
Molecules 2017, 22, 1924; doi:10.3390/molecules22111924
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and antifungal [21] activities. The major effect has been ascribed to the in vivo formation of
6-azauridine-50-phosphate (6-azaUMP), a competitive inhibitor of orotidine-50-phosphate (OMP)
decarboxylase. OMP decarboxylase catalyzes the decarboxylation of orotidine-50-phosphate to
uridine-50-phosphate, an essential step in the de novo biosynthesis of pyrimidine nucleoside [22
,23].
Meanwhile, 6-azaUMP is also a strong inhibitor of inosine-50-monophosphate dehydrogenase (IMP
dehydrogenase), which catalyzes the rate-limiting reaction of de novo GTP biosynthesis [24].
6-Azauracil and its derivatives form an important class of heteroaromatic compounds with
various interesting biochemical properties [1]. Among these derivatives the 2-benzyl-1,2,4-triazin-
3,5(2H,4H)-dione has showed anticoccidial activity [25] and property of aldose reductase inhibitor [26].
Banavara [25] reported the product yields were in 10–40% range in synthesis 2-substituted,
4-substituted, or symmetrically 2,4-disubstituted 1,2,4-triazin-3,5(2H,4H)-dione compounds, and the
yield of synthesis of unsymmetrically 2,4-disubstituted compounds were showed in 20–60%. In our
past studies on acyclonucleosides synthesis the site of glycosylation was established at the N-2 position
of the 2-substituted products of 1,2,4-triazin-3,5(2H,4H)-dione, based on the comparison of the UV
1
spectra and identified by H-13C heteronuclear correlation (HETCOR) NMR experiments [27
–
29].
Meanwhile, our studies increased the 2-substituted products yield more than 70% by modifying the
silyl-Hilbert-Johnson (SHJ or Vorbrüggen) reaction [30]. In this work, we investigated the preparation
methods of 4-substituted and symmetrically 2,4-disubstituted of 1,2,4-triazin-3,5(2H,4H)-dione.
Furthermore, we report advanced information about the structure of 4-substituted molecule
spectral analysis, mainly 2D-NMR. In addition, the full characterization by X-ray structural analysis
of the molecule is also reported. These improved synthesis methods and structure character will
2 by
3
facilitate our preparation and identification of 2-, 4-substituted, and symmetrically, unsymmetrically
2,4-disubstituted compounds of 1,2,4-triazin-3,5(2H,4H)-dione as potential bioactive molecules in our
ongoing program.
2. Results and Discussion
2.1. Chemistry
The preparation of 4-benzyl-1,2,4-triazin-3,5(2H,4H)-dione (
3,5(2H,4H)-dione ( ) are illustrated in Scheme 1. The starting material 1,2,4-triazin-3,5(2H,4H)-dione
(6-azauracil; ) was prepared according to the method described by Novacek [31]. Scheme 1 presents
the IUPAC numbering system of compound reacted with potassium carbonate and benzyl bromide
in dry acetone at room temperature for 16 h, under 18-crown-6-ether catalysis, to afford a 2.3:1 ratio of
major product (49%; Rf = 0.42, chloroform:methanol = 18:1) and minor product (21%; Rf = 0.63)
(Method A). Keeping the same amount of each reagent and solvent volume, we refluxed the mixture
for 6 h, affording compounds (45%) and (26%) (Method B). The same condition as Method A,
except the anhydrous potassium carbonate with two equivalents, would afford compounds (46%)
and (23%) (Method C). Moreover, the same condition as Method B, except the anhydrous potassium
carbonate with two equivalents, gave compounds (35%) and (30%) (Method D). With a modified
2) and 2,4-dibenzyl-1,2,4-triazin-
3
1
1
2
3
2
3
2
3
2
3
Method A (i.e., under the same amount of each reagent, using a pressure-equalizing dropping funnel
with the benzyl bromide in dry acetone, which was introduced drop by drop into a round-bottomed
flask, the total solvent volume increase 33%, reacted at room temperature for 20 h), we obtained
compounds
and decreased the yield of
with compound make the yield of the N-4 benzylated much higher than the N-2,N-4 dibenzylated,
which implies N-4 nucleophile have more opportunity to react with benzyl bromide. In other words,
the evidence showed the dissociation rate of N-4-H is quicker than N-2-H of compound under basic
2
(59%) and
3
(13%) (Method E). This reaction method increased the yield of
2 significantly
3. In method E, the lower concentration of benzyl bromide added to react
1
1
conditions. In another modified reaction of Method A, we increased potassium carbonate and benzyl
bromide to double amount and refluxed the mixture for 6 h to give the only product 2,4-disubstituted

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compound
3 in good yield (93%) (Method F). All reaction times of the above methods were monitored
by TLC. The improvement of this synthetic method was derived from our previous research [32].
Scheme 1.
The IUPAC numbering system of compound 1,2,4-triazin-3,5(2H,4H)-dione
(6-azauracil;
triazin-3,5(2H,4H)-dione (
1
), synthesis of the 4-benzyl-1,2,4-triazin-3,5(2H,4H)-dione (
2
) and 2,4-dibenzyl-1,2,4-
a
3
) to afford different yield ratios by different methods. Benzyl bromide in
dry acetone (15 mL), which was added to the flask five times, each time with 3 mL drop by drop in
20 min for 2 h, stirred at room temperature for a total of 20 h.
The structures of
and EA. In NMR spectroscopy the presence of a benzyl group and eight carbon signals were
observed in compound . The thirteen carbon signals showed two benzyl groups of compound 3.
2 and 3
were completely assigned by 1H- and 13C-NMR, MS and IR spectra
2
A detailed 2D-NMR study, including gHSQC and gHMBC measurements was necessary to confirm
1
the benzylation sites of
2
. The long-range gHMBC H-13C correlations showed the attachment of
the benzyl group on N-4 for structure
2, since the methylene protons (δH 5.07 ppm) of benzyl group
showed a 3J (H,C) coupling to the C-3 (δC 149.35 ppm) and the C-5 (δC 155.86 ppm) carbonyl carbon
atom. Meanwhile, the fact that the proton of the H-6 (δH 7.41 ppm) have a 2J (H,C) coupling to the C-5
carbon atom and certification the carbon chemical shifts of C-5 is higher than the C-3 carbon in the
1,2,4-triazin-3,5(2H,4H)-dione moiety. The standard range gHSQC 1H-13C experiments showed the
methylene protons (δH 5.07 ppm) of the benzyl group with a 1J (H,C) coupling to the methylene (δC
43.35 ppm) carbon atom and H-6 proton have a coupling to the C-6 (δC 135.07 ppm) carbon atom.
Scheme 2 presents the complete assignment of 1H- and 13C-NMR signals for compounds
together with the corresponding long-range (pink dashed arrow) and short-range (black color) 1H-13C
correlations. The
values of 1H- and 13C-NMR of 1,2,4-triazin-3,5(2H,4H)-dione moiety were similar in
and . In compound , the
values of the 1H-NMR spectra were very similar between the methylene
proton on N-2 benzyl and N-4 benzyl group showed values of 5.10 and 5.07 ppm, respectively. On the
other hand, the clearly different
values of the 13C-NMR spectra between the methylene carbon on
N-2 and N-4 benzyl groups showed values of 55.40 and 43.94 ppm, respectively. Taken together,
the
values of the 1H- and 13C-NMR spectra display the methylene group on N-2 showed significant
downfield shifts than the N-4 benzyl group of molecule 3.
2 and 3,
δ
2
3
3
δ
δ
δ
δ
δ

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Scheme 2. The gHSQC and gHMBC measurements of compound
assignment of 1H- and 13C-NMR for 2 and 3.
2 and the chemical shift (δ)
2.2. Analysis of the X-ray Crystallographic Structure
An ORTEP drawing for the molecular
3 is depicted in Figure 1. From this X-ray analysis of the
Compound , revealing the 1,2,4-triazine ring is slightly distorted. Obviously, the benzyl groups are
3
located at N2 (i.e., N-2) and N1 (i.e., N-4). The location of benzyl group are compatible with tautomeric
proton 2-H located at N-2 and 4-H located at N-4 of the starting material 1,2,4-triazin-3,5(2H,4H)-dione
(1). The bond lengths and angles for compound 3 are shown in Table S1 (see Supplemental Material).
Figure 1. An ORTEP drawing of compound
3 with atom labelling; thermal ellipsoids are drawn at the
50% probability level.
In the crystal structure of
3 of the 1,2,4-triazin-3,5(2H,4H)-dione moiety, the shorter bond 1.273(6)
Å of N3–C3 has an appreciable double-bond character and the longest bond 1.441(7) Å is C2–C3.
The bond length 1.211(4) Å of C1–O1 and 1.211(5) Å of C2–O2 are shorter than the bond length 1.240 Å
of Csp2=O in
δ-lactams [33], due to the strong electron withdraw by these nitrogen atoms in the
1,2,4-triazine ring. Additionally, the sum of these three angles, O2–C2–N1, O2–C2–C3, and N1–C2–C3,
◦
as well as the sum of O1–C1–N2, O1–C1–N1, and N2–C1–N1, both reach 360 , thus confirming the sp2
hybridization bonding. Meanwhile, the bond angle 123.0(4)◦ of N1–C1–O1 is wider than N1–C2–O2
and N2–C1–O1. This evidence suggests that the lone electron pair of the two nitrogen atoms N1 and N2
strongly resonates with O2 and O1, respectively. Additionally, the angles 112.6(3)◦ of N1–C4–C5 and
◦
113.3(3) of N2–C11–C12 are similar through the N-4 and N-2 benzyl group, respectively. The dihedral
angles of 66.52◦ and 68.53◦ forms from mean plane of the central ring (defined by atoms N1, N2, N3,
C1, C2, and C3) with mean planes of the benzene rings C5–C10 and C12–C17 of the N-4 and N-2 benzyl

Molecules 2017, 22, 1924
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groups, respectively (Figure S1) (see Supplemental Material). Meanwhile, another dihedral angle
31.90◦ is formed by mean planes of the benzene rings of the N-2 and N-4 benzyl groups (Figure S1).
2.3. Analysis of the Molecular Packing
The molecular packing of compound
in the unit cell reveals that there are neither classic hydrogen bond nor molecule disorder in the
crystal structure of . The intermolecular short contacts in the molecular graphic were all obtained
3 is shown in Figure 2. An analysis of the molecular packing
3
using the Mercury program (version 2.3, CCDC, Cambridge, UK). We note that in the unit cell each
molecule is linked to five other molecules with six short contacts (Figure 3). These short contacts
include weak hydrogen bond interactions (Figure 3 notation (a, b, c, d)) and C-sp2···s-sp3 interactions
(Figure 3 notation (e, f)) which stabilized the crystal structure. The title molecule (i = x, y, z) atom
C1–O1i linked with H16–Carii at (ii = 1
identical short contacts distance of 2.656(3) Å (Figure 3 notation (a, b)). Meanwhile, the Oxygen atom
C2–O2i linked with H8 Cariii at (iii = 2 z) and Car–H8i linked with O2–C2iv at
x, 1/2 + y, 1/2
iv = 2 − x 1/2 + y, 1/2 z) have a same short contacts distance of 2.566(5) Å (Figure 3 notation (c,
d)). Another type of short contact involves interactions between layer and layer via O1–C1i linked
with H11A–C11v at (v = 1 z) and H11A–C11i linked with C1–O1vi at (vi = 1
x, 1/2 + y, 1/2 x,
1/2 + y, 1/2 z) with an identical contact distance of 2.771(4) Å (Figure 3 notation (e, f)). The bonding
environment of carbon C1i is in a -deficient 1,2,4-triazinone ring and also attaches with oxygen O1i,
−
x,
−
y, 1
−
z) and Car–H16i linked with O1–C1ii with an
−
−
−
−
(
,
−
−
−
−
−
−
π
resulting more positive charge in the C1i (C-sp2), which forms a short contact with H11A C11v (s-sp3).
−
Another possible interpretation is that the C11–H11A···C1 involves an sp3 C atom and likely exhibits
the observed motif because of close packing principles rather than some cohesive interaction.
Figure 2. A perspective drawing of the packing arrangement of compound 3, showing the molecules’
direction along the a, b, and c axis.

Molecules 2017, 22, 1924
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Figure 3. Intermolecular short contacts in compound
codes see the text.
3 along the c axis. For the notation and symmetry
In addition to the above three types of short contacts, it is worth noting that the crystal structure
is further stabilized by weakly π···π stacking interactions (see Figure 4). The centroid 1i (defined
by atoms N1N2N3C1C2C3 of the molecule 3
, i = x, y, z), contacts with the centroid 4v (defined by
atoms C12–C17 of the upper layer molecule, v = 1
interactions distance 4.756 Å. Meanwhile, the centroid 2i (atoms C12–C17) contacts with centroid
5vi (atoms N1N2N3C1C2C3, vi = 1
x, 1/2 + y, 1/2 z) of the lower layer molecule with the
−
x,
−
1/2 + y, 1/2
− z) with a π···π stacking
−
−
same contact distance 4.756 Å. Another π···π stacking interactions with contact distance of 3.967 Å
are centroid 1i contacts with centroid 6vi (atoms C12–C17) and centroid 2i contacts with centroid 3v
(atoms N1N2N3C1C2C3).
Figure 4. A view of π···π stacking interactions contact running parallel to the [010] direction in
compound 3 along the c axis. For the symmetry codes see the text.

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3. Materials and Methods
3.1. General Techniques
Melting points were measured on a Yanaco MP-500D micromelting point apparatus (Yanaco
Technical Science Co., Ltd., Kyoto, Japan) and were uncorrected. The Infrared spectra were recorded as
KBr discs on a Perkin-Elmer FTIR 1650 instrument (PerkinElmer, Waltham, MA, USA). The 1H-NMR
and 13C-NMR spectra were obtained in CDCl3 on a Varian Mercury-plus 400 (400 MHz) spectrometer
(Varian Inc., Palo Alto, CA, USA). Chemical shifts are expressed in ppm (
δ
) with tetramethylsilane
(TMS) as an internal standard. For the assignments of signals, standard and long-range H-13C
1
heteronuclear chemical shift correlation 2D-NMR experiments (gHSQC and gHMBC) were used.
Thin layer chromatography (TLC) analyses were performed on silica gel plates (Merck 60 F254
,
0.2 mm thickness; Merck KGaA, Darmstadt, Germany), and the components were detected by UV
light (254 nm). Mass spectra were obtained on a gas chromatography mass spectrometer (GC-MS)
Thermo Finnigan PolarisQ quadrupole ion trap (Thermo electron corporation, Austin, TX, USA).
Elemental analyses were performed on a Heraeus CHN-O-Rapid elemental analyzer (Heraeus GmbH,
Hanau, Germany). All the solvents used were dried and distilled under argon prior to use.
3.2. Syntheses
3.2.1. Syntheses of 4-Benzyl-1,2,4-triazin-3,5(2H,4H)-dione (2) and 2,4-Dibenzyl-1,2,4-triazin-
3,5(2H,4H)-dione (3)
Method A: A solution of 1 (0.57 g, 5 mmol) in dry acetone (30 mL) was mixed with anhydrous
potassium carbonate (0.69 g, 5 mmol) and a catalytic amount of 18-crown-6-ether (0.13 g, 0.5 mmol).
Then benzyl bromide (0.86 g, 5 mmol) was added and the mixture stirred at room temperature for 16 h
(monitored by TLC). The solvent was evaporated to afford a crude product which was then applied to
a silica gel (230–400 mesh) column. The column was eluted with a mixture of chloroform and methanol
(80:1) and the appropriate fractions were combined and evaporated.
The Rf value of the major adduct was 0.42 (chloroform:methanol = 18:1). The residue thus obtained
was recrystallized from dichloromethane and methanol (20:1) which afforded white crystals 2 in 49%
yield (0.50 g). m.p. = 118–119 ◦C; IR (cm−1),
δ
max: 3213, 3170, 3092, 2920, 1727 (C=O), 1662 (C=N),
1496, 1442, 1411, 1353, 1210, 1160, 937, 890; 1H-NMR (400 MHz, CDCl3)
= 5.07 (s, 2H, CH2), 7.41 (s,
1H, 6-H), 10.00 (brs, 1H, NH), 7.29–7.35 (m, 3H, Ar-H), 7.46–7.49 (dd, 2H, Ar-H); 13C-NMR (400 MHz,
δ
CDCl3) δ = 43.35 (CH2), 128.26, 128.63, 129.36, 135.53 (Ar-C), 135.07 (C-6), 149.35 (C-3), 155.86 (C-5);
MS, m/z (%): 203 (M+, 53), 147 (100), 132 (9), 104 (28), 91 (32), 77 (17), 65 (17), 51 (15); Anal. Calcd. for
C10H9N3O2 (203.20): C, 59.11; H, 4.46; N, 20.68; Found: C, 58.89; H, 4.48; N, 20.38.
The Rf value for the minor product was 0.63 (chloroform:methanol = 18:1). The residue thus
obtained was recrystallized from dichloromethane and methanol (30:1) to give
crystals in 21% yield (0.31 g). m.p. = 95–96 ◦C; IR (cm−1),
max: 1714 (C=O), 1668 (C=N), 1583, 1493,
1432, 1421, 1366, 1331, 1244, 1204, 1062, 907, 866; 1H-NMR (400 MHz, CDCl3)
= 5.07 (s, 2H, CH2), 5.10
(s, 2H, CH2), 7.40 (s, 1H, 6-H), 7.28–7.40 (m, 3H 2, Ar-H), 7.46–7.48 (dd, 2H
2, Ar-H); 13C-NMR
(400 MHz, CDCl3) = 43.94 (CH2), 55.40 (CH2), 128.13, 128.35, 128.57, 128.68, 128.76, 129.37, 134.49,
135.35 (Ar-C
2), 135.33 (C-6), 148.63 (C-3), 155.83 (C-5); MS, m/z (%): 293 (M+, 28), 265 (7), 238
3 as bright white
δ
δ
×
×
δ
×
(11), 202 (4), 175 (12), 161 (53), 132 (59), 106 (52), 91 (100), 77 (33), 65 (47), 51 (21); Anal. Calcd. for
C17H15N3O2 (293.32): C, 69.61; H, 5.15; N, 14.33; Found: C, 69.43; H, 5.17; N, 14.27
Method B: A solution of
1 (0.57 g, 5 mmol) in dry acetone (30 mL) was mixed with anhydrous
potassium carbonate (0.69 g, 5 mmol) and a catalytic amount of 18-crown-6-ether (0.13 g, 0.5 mmol).
Then benzyl bromide (0.86 g, 5 mmol) was added and the mixture refluxed for 6 h (monitored by TLC).
The separation and recrystallization was treated as described in Method A to afford compounds
2
(0.46 g; 45%) and 3 (0.38 g; 26%).

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Method C: The same condition as Method A except the anhydrous potassium carbonate with
two equivalent (1.38 g, 10 mmol) was applied. The separation and recrystallization was treated as
described in Method A to afford compounds 2 (0.47 g; 46%) and 3 (0.34 g; 23%).
Method D: The reacted condition was the same with Method B except the anhydrous potassium
carbonate with two equivalent (1.38 g, 10 mmol). The separation and recrystallization was treated as
described in Method A to afford Compounds 2 (0.36 g; 35%) and 3 (0.44 g; 30%).
Method E: Equip a dry 150 mL round-bottomed flask at the top arm attached with a
pressure-equalizing dropping funnel. Place a solution of
1 (0.57 g, 5 mmol) in dry acetone (25 mL)
mix with anhydrous potassium carbonate (0.69 g, 5 mmol) and a catalytic amount of 18-crown-6-ether
(0.13 g, 0.5 mmol) in the round-bottomed flask, and fill the dropping funnel with a solution of benzyl
bromide (0.86 g, 5 mmol) in dry acetone (15 mL), which was added to the flask five times, each
time with 3 mL drop by drop in 20 min for 2 h, and stirred at room temperature for a total of 20 h
(monitored by TLC). The separation and recrystallization was treated as described in Method A to
afford compounds 2 (0.60 g; 59%) and 3 (0.19 g; 13%).
3.2.2. 2,4-Dibenzyl-1,2,4-triazin-3,5(2H,4H)-dione (3)
Method F: A solution of
1 (0.57 g, 5 mmol) in dry acetone (30 mL) was mixed with anhydrous
potassium carbonate (0.69 g, 10 mmol) and a catalytic amount of 18-crown-6-ether (0.13 g, 0.5 mmol).
Then benzyl bromide (1.71 g, 10 mmol) was added and the mixture refluxed for 6 h (monitored by TLC).
The solvent was evaporated to afford a crude product which was recrystallized from dichloromethane
and methanol (25:1) to give bright white crystals (1.36 g, 93%) identical in every respect with compound
3, which was afforded by Method A above.
3.3. X-ray Diffraction
A plate colorless crystal
recrystallization from a CH3OH/CH2Cl2 diffusion solvent system and suitable for single-crystal X-ray
diffraction measurements. The data were collected on a Bruker Smart APEXCCD diffractometer (Bruker
3
having dimensions of 0.48
×
0.27
×
0.04 mm was obtained by
AXS GmbH, Karlsruhe, Germany) with a graphite-monochromated Mo K
at 295(2) K. A total of 8796 reflections and 2612 independent reflections (Rint = 0.0509) were collected
within the range of 2.83 < scan technique, of which 1758 observed reflections
< 25.00◦ by using
α radiation (λ = 0.71073 Å)
θ
ω
with I > 2
σ
(I) were used in the structural analysis. The crystal and experimental data are given in
Table 1.
Table 1. Crystallographic data of fcompound 3.
Empirical Formula
C17H15N3O2
Formula weight
Temperature
Wavelength
293.32
295(2) K
0.71073 Å
Crystal system
Space group
Monoclinic
P21/c
a = 13.7844(13) Å
b = 8.5691(8) Å, β = 105.961(2)
c = 13.0527(12) Å
1482.3(2) Å3
4
◦
Unit cell dimensions
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
1.314 Mg/m3
−1
0.089 mm
616
◦
Theta range for data collection
Index ranges
2.831 to 24.999
-16 ≤ h ≤ 16, −9 ≤ k ≤ 10, −15 ≤ l ≤ 15

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Table 1. Cont.
Empirical Formula
C17H15N3O2
Reflections collected
8796
2612 (Rint = 0.0509)
99.90%
Independent reflections
Completeness to θ = 24.999
Absorption correction
◦
Semi-empirical from equivalents
0.756 and 0.659
Max. and min. transmission
Full-matrix least-squares on F2
2612/0/199
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
1.085
Final R indices (I > 2σ(I))
R indices (all data)
Largest difference peak and hole
R1 = 0.0851, wR2 = 0.1922
R1 = 0.1281, wR2 = 0.2139
0.566 and −0.189 eÅ
−3
The crystal structure was solved by direct methods using SHELXS-97 [34] and refined by
full-matrix least-squares methods on F2 using SHELXL-2014/7 [35]. All of the non-hydrogen atoms
were refined anisotropically. All hydrogen atom positions were calculated and included in the
calculation using the riding atom model. The final cycle of full-matrix least-squares refinement gave
R1 = 0.0851, wR2 = 0.1922 incorporating the weighting scheme w = 1/[σ2(F2o) + (0.0756P)2 + 1.3197P]
where P = (F2o + 2F2c)/3. S = 1.085 and (
max = < 0.001. The maximum peak on the final difference
Fourier map is 0.556 and the minimum peak
0.189 eÅ−3. The final positional parameters for all
non-hydrogen atoms are given in Table S2 (see Supplementary material).
The supplementary crystallographic data for were deposited at the Cambridge Crystallographic
,
∆/σ)
−
3
Data Centre (CCDC) as CCDC-1565082. These data can be obtained free of charge from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-336033; www:http://www.ccdc.cam.ac.uk/
conts/retrieving.html or e-mail: deposit@ccdc.cam.ac.uk).
4. Conclusions
In summary, we have reported the simple, convenient, safe, and high yield synthesis methods
and molecular structure characterization of N-4 benzylic
spectral analysis allowed identification of the benzylated position and complete assignments of various
carbons of the molecules N-4 benzylic . Meanwhile, obviously different
values in 1H- and 13C-NMR
spectra between and were found. A single X-ray crystal structure analysis of supplied the crystal
structure data and the analysis of the molecular packing showed evidence that the compound was
2 and N-2,N-4 dibenzylic 3. The 2D-NMR
2
δ
2
3
3
3
tightly stabilized by contact with five other molecules from six short contacts formed by intermolecular
◦
C–O···H–Car, C–H···Car, and weakly π···π stacking interactions. The dihedral angle 31.90 was formed
by the mean planes of the benzene rings of the N-2 and N-4 benzyl groups.
Supplementary Materials: Supplementary Materials are available online. Table S1: Bond lengths (Å) and
bond angles (◦) in compound
3
. Table S2: Atomic coordinates (
103) for compound
4-Benzyl-1,2,4-triazin-3,5(2H,4H)-dione (
×
104) and equivalent isotropic displacement
◦
parameters (Å2
×
3
. Figure S1: A view of the dihedral angles ( ) of the compound
3. Figure S2:
2
), (a) 1H-NMR spectrum, (b) 13C-NMR spectrum, (c) gHSQC spectrum,
(d) gHMBC spectrum, (e) MS spectrum, and (f) IR spectrum. Figure S3: 2,4-Dibenzyl-1,2,4-triazin-3,5(2H,4H)-dione
(3), (a) 1H-NMR spectrum, (b) 13C-NMR spectrum, (c) MS spectrum, and (d) IR spectrum.
Acknowledgments: The authors would like to thank the Kaohsiung Medical University for support under
grant KMU-M098030.
Author Contributions: Long-Chih Hwang developed the concept of the work, synthesized the starting material
compound, crystal growth, data analysis and wrote the paper. Shiun-Yau Yang and Chung-Lin Chuang carried
out the synthetic work, NMR spectra, IR spectra, and determined the melting point. Gene-Hsiang Lee performed
the X-ray diffraction. All authors have given approval to the final version of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2017, 22, 1924
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Sample Availability: Samples of the compounds are not available from the authors.
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2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).