Synthesis of new substituted 1,2,4-triazines from isonitrosoketones and terephthalaldehydedihydrazone

Article abstract of DOI:10.1002/jhet.819

This study describes a novel method for the synthesis of 1,2,4-triazines. Firstly, isonitrosoacetophenone, p-methylisonitrosoacetophenone, and isonitroso-1-acetylnaphthalene were synthesized from the reaction of butylnitrite with acetophenone, p-methylisonitrosoacetophenone, and 1-acetylnaphthalene, respectively. Then, symmetric derivatives of 1,2,4-triazines were prepared from the condensation reaction of keto oximes with terephthalohydrazone. However, the heteroaromatic closure was not observed in the condensation reaction of pyruvic-aldehyde-1-oxime(keto oxime) with terephthalohydrazone. Structures of the obtained products were confirmed by FTIR, ¹H-NMR, and elemental analyses techniques.

Full text of DOI:10.1002/jhet.819

576
Synthesis of New Substituted 1,2,4-Triazines from
Isonitrosoketones and Terephthalaldehydedihydrazone
Vol 49
*
Onder Alici and Ibrahim Karatas
Department of Chemistry, Faculty of Science, Selcuk University, 42075 Konya, Turkey
*
E-mail: ikaratas@selcuk.edu.tr
Received November 26, 2010
DOI 10.1002/jhet.819
View this article online at wileyonlinelibrary.com.
This study describes a novel method for the synthesis of 1,2,4-triazines. Firstly, isonitrosoacetophenone,
p-methylisonitrosoacetophenone, and isonitroso-1-acetylnaphthalene were synthesized from the reaction
of butylnitrite with acetophenone, p-methylisonitrosoacetophenone, and 1-acetylnaphthalene, respectively.
Then, symmetric derivatives of 1,2,4-triazines were prepared from the condensation reaction of keto
oximes with terephthalohydrazone. However, the heteroaromatic closure was not observed in the
condensation reaction of pyruvic-aldehyde-1-oxime(keto oxime) with terephthalohydrazone. Structures
of the obtained products were confirmed by FTIR, 1H-NMR, and elemental analyses techniques.
J. Heterocyclic Chem., 49, 576 (2012).
INTRODUCTION
acetate–acetic acid for 6–24 h [10]. In addition to this,
the different synthetic methods are reported as follows.
(a) Condensation of acid hydrazides with benzil in a
solution of acetic acid–ammonium acetate to give 5,6-
diphenyl-1,2,4-triazines containing various aromatic and
heterocyclic groups attached at position 3 [11]. (b) Cycliza-
tion of aliphatic, aromatic, and heterocyclic acid hydrazide
with 1,2-diketone monoacylhydrazones in alcoholic am-
monia under pressure [12]. (c) Condensation of aromatic
monohydrazones (but not aliphatic) with 1,2-diketones to
give 5,6-disubstituted 1,2,4-triazines [13]. (d) Condensa-
tion reaction of acid hydrazide and b-halo acetophenone
in the presence of NaOAc or AgOAc [14,15]. (e) Reaction
of b-diketones with amidrazones and S-methylthiosemicar-
bazide were also reported in the literature [16,17].
As it is seen from the above-reported methods, many
synthetic ways for the synthesis of substituted 1,2,4-
triazines are available. However, according to our knowledge,
a keto oxime and a hydrazone have been not used as
starting materials for this purpose. We have presented a
new pathway for the synthesis of substituted-1,2,4-
triazines by using terephthalaldehyde dihydrazone and
isonitrosoketones.
1,2,4-Triazines are well-known compounds, and substituted
triazines represent an important class of nitrogen-containing
heterocycles. A wide variety of synthetic methods for the prep-
aration of them and their substituted derivatives are available.
Some of 1,2,4-triazine compounds are yellow in color, and
their nonsubstituted or alkyl-bonded derivatives have lower
melting points. Moreover, lots of 1,2,4-triazine compounds
are liquids. Nevertheless, it is stated in literature that aryl or het-
erocyclic substituted compounds of 1,2,4-triazines are solid,
crystalline, and soluble in many organic solvents [1].
Compounds containing the 1,2,4-triazine moiety are found in
natural materials. Also, a large of number of synthetic 1,2,
4-triazines have biological activity and have been used for
various purposes. While only a few of these heterocyclic
compounds are found in nature, a number of substituted
1,2,4-triazines have been prepared and tested as potentially ac-
tive building blocks in agrochemical and medicinal fields [2].
The 1,2,4-triazine core is a versatile synthetic platform to
access a wide range of condensed heterocyclic ring systems
via intramolecular Diels–Alder reactions with a vast array of
dienophiles. In addition, the triazine ring system is a significant
component of commercial dyes, herbicides, insecticides, and
more recently, pharmaceutical compositions [3–9].
RESULTS AND DISCUSSION
The traditional thermal conditions for the synthesis of
1,2,4-triazines involve refluxing of a 1,2-diketone and an
acyl hydrazide, in a 1:1 ratio, in a solution of ammonium
In this study, the isonitrosoacetophenone (I), isonitroso-
1-acetylnaphtalene (II), p-methyl isonitrosoacetophenone
© 2012 HeteroCorporation

May 2012
Synthesis of New Substituted 1,2,4-Triazines from Isonitrosoketones and
Terephthalaldehydedihydrazone
577
(III), and terephthalaldehydedihydrazone (V) were synthe-
sized according to the known procedure. The melting
points and other properties of those compounds were
compatible with the literature knowledge [18–21]. Many
synthesis methods of 1,2,4-triazine compounds are avail-
able in studies that have been performed since 1950 [1].
However, the synthesis of 1,2,4-triazine compound
derivatives by using keto oxime and hydrazone com-
pounds were not seen in the literature investigations.
For this reason, a new synthetic procedure to 1,2,4-triazine
derivatives is reported using different starting materials.
In our previous study, five-membered heterocyclic
compounds were prepared by the heteroaromatic closing
reaction [22].
In the study, three symmetrical 1,2,4-triazine compounds
were prepared by the condensation of four keto oxime
compounds with terephthalohydrazone. The alkyl and
aryl groups in keto oxime derivatives were efficient on
synthesizing the 1,2,4-triazine derivatives. When the R
group of keto oxime was phenyl, p-tolyl, and naphtyl,
the triazine compound was formed (Scheme 1), but
when the R group was methyl, the triazine compound
was not formed (Scheme 2). Moreover, when the R
group was naphtyl, it was seen that the reaction time
would be shorter. When the R group was methyl, the
ring closure was not observed, and this reaction was
realized as normal condensation reaction. Characterization
of the synthesized compounds was made by 1H-NMR,
FT-IR and elemental analysis.
derivatives have lower melting points. Moreover, lots
of 1,2,4-triazine compounds are liquids. Nevertheless,
it is stated in literature that aryl or heterocyclic substi-
tuted compounds of 1,2,4-triazine compounds are solid,
crystalline, very stable, and have ability to dissolve in
much organic solvents [1].
By 1H-NMR evaluation of synthesized compound VI, it
is observed that —NOH peak of oxime is at 12.08 ppm
(s,2H); —CH peak of oxime is at 8.52 ppm (d,2H,
J = 6.32 Hz); —CH peak of benzene ring is at 8.11 ppm
(d,4H, J = 12.30 Hz); —CH peak which is neighbor to
benzene ring is at 7.9 ppm (s,2H), and proton peaks of
methyl groups are at 2.31 ppm (s,6H). For compound
VII, it is observed that —CH peaks of triazine ring is at
8.74 ppm (s,2H); the phenyl rings which are neighbor to
triazines have —CH peaks at 7.90 ppm (d,4H, J = 8.3 Hz),
7.77 ppm (s,2H), 7.66 ppm (d,4H, J = 8.3 Hz) and —CH
peaks of central phenyl ring is at 7.17 ppm (s,4H). Also, for
compound VIII, it is observed that the —CH peak of (s,2H)
triazine compound is at 8.70 ppm and both naphthalene
rings which are neighbors to triazine have —CH peaks at
8.10 ppm (s,4H), 7.90 ppm (t,4H, J = 10.0 Hz), 7.76 ppm
(s,2H), 7.65 ppm (t,4H, J = 8.3 Hz). In addition, the
benzene ring, which is central phenyl ring, has —CH peak
at 7.18 ppm (d,4H, J = 10.35 Hz). In the 1H-NMR analysis
of synthesized compound IX, the —CH peak of (s,2H)
triazine compound is at 8.65 ppm and both p-tolyl rings,
which are neighbors to triazine, have —CH peaks at
7.80 ppm (d, 4H, J = 8.41 Hz), 7.65 ppm (d, 4H, J = 8.34 Hz).
In addition, the benzene ring, which is neighbor to both
triazines, has —CH peak at 7.70 ppm (s, 4H). It is observed
Some of 1,2,4-triazine compounds are generally yellow
in color and their nonsubstituted or alkyl-bonded
Scheme 1. The ring closure reaction mechanism.
Scheme 2. The condensation reaction without ring closing.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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O. Alici and I. Karatas
Vol 49
carried out in the Laboratories of the Scientific and Technical
Research Council of Turkey (TUBITAK). 1H-NMR spectra
were recorded in DMSO-d6 solutions on a Bruker 400 MHz
spectrometer using TMS as an internal reference. Infrared spectra
were recorded on a Perkin Elmer Model 1605 FT-IR spec-
trophotometer as KBr pellets in the region of 500–4000 cm.ꢀ1
that —CH3 peak of p-tolyl is at 2.45 ppm (s, 6H). These
values are compatible with literature values the one-sided
triazine derivative [2].
The compound (VI) has yellow color and crystalline
structure, can partly dissolve only in hot DMSO. The same
results were obtained for corresponding compounds (VII,
VIII, and IX).
The FTIR spectrum data of 1,2,4-triazine are mentioned
in lots of studies. The characteristic IR peaks of 1,2,4-
triazine compounds have C—H stretching frequency in
3090–3030 cmꢀ1 interval. Moreover, C¼N and C¼C
frequencies are in 1560–1295 cmꢀ1 interval. Again, it is
observed that the vibration peaks of (C—H, N—N) which
is of triazine ring are in 1050–995 cmꢀ1 [2].
With the evaluation of FT-IR spectrum of compound
VI, —OH stretching vibration peak of oxime group is seen
at 3159 cmꢀ1. C¼N and N—O vibration peaks are observed
at 1618 and 986 cmꢀ1, respectively.
General procedure for the preparation of VII-XI. A solu-
tion of 2.40 mmol of compound (I–IV) in ethanol (20 mL) was
added dropwise to a solution of 0.162 g (1.0 mmol) of compound
(V) in ethanol (20 mL). After completion of dropping, the mixture
was stirred until the temperature is up to room temperature. The
mixture was allowed to stand to crystallize for 2 days. The formed
yellow solid was filtered and washed with ethanol and ether.
2-((4-(((1-(Hydroxyimino)propan-2-ylidene)hydrazono)
methyl)benzylidene)hydrazono) propanal oxime (VI). This
compound was obtained as yellow color crystal. Yield 0.108 g
(52%); mp >300ꢁC (decomp); IR: OH 3159 cmꢀ1, CH (aromatic)
3065 cmꢀ1, C¼N 1618 cmꢀ1, N—O 986 cmꢀ1
.
1H NMR:
d 12.08 (s, 2H, NOH), 8.52 (d, 2H, CH, J = 6.32 Hz), 8.11
(d, 4H, J = 12.30 Hz, aromatic CH), 7.9 (s, 2H, CH), 2.31 ppm
(s, 6H, CH3); Anal. Calcd. for C14H16N6O2: C, 56.00; H, 5.33;
N, 28.00. Found: C, 57.40; H, 5.62; N, 27.60.
For compound VII, —CH groups peaks of triazine and
aromatic ring are observed at 3331 and 3182 cmꢀ1
,
respectively. Moreover, C¼C and C¼N groups of triazine
1,4-Bis(6-phenyl-1,2,4-triazin-3-yl)benzene (VII). This com-
pound was obtained as yellow color crystal. Yield 0.21 g (64%);
mp >300ꢁC (decomp.); IR: CH (triazine) 3331 cmꢀ1; CH
ring have specific peaks in the region of 1597–1215 cmꢀ1
.
For the isonitroso-1-acetylnaphtalene compound, —NO
peak is observed at 971 cmꢀ1 but is not observed for com-
pound VIII. At 1670 cmꢀ1, decreased strength of —CN
stretching frequency peak is observed. —OH peak, which
is seen at 3287 cmꢀ1 of isonitroso-1-acetylnaphtalene, is
not seen for the compound VIII. —NH peak, which
appeared at 3360 cmꢀ1 of terephthalodihydrazone, disap-
peared in the spectrum of compound VIII. In addition,
C¼C and C¼N groups of triazine ring are observed in
(aromatic) 3182 cmꢀ1; C¼C 1597 cmꢀ1; C¼N 1215 cmꢀ1
.
1H-NMR: d 8.74 (s, 2H, triazine ring); 7.90 (d, 4H, J = 8.3 Hz);
7.77 (s, 2H); 7.66 (d, 4H, J = 8.3 Hz); 7.17 ppm (s, 4H); Anal.
Calcd. for C24H16N6: C, 78.60; H, 4.10; N, 18.80. Found: C, 76.71;
H, 4.53; N, 18.80.
1,4-Bis(6-(naphthalen-1-yl)-1,2,4-triazin-3-yl)benzene
(VIII).
This compound was obtained as yellow color crystal.
Yield 0.24 g (%55); mp > 300ꢁC (decomp.); IR: CH (triazine)
3333 cmꢀ1; CH (aromatic) 2908 cmꢀ1; C¼C 1559, 1529, 1430,
1380, 1290 cmꢀ1; C¼N 1215 cmꢀ1
.
1H-NMR: d 8.7 (s, 2H,
the region of 1529–1215 cmꢀ1
.
triazine ring), 8.10 (s, 4H), 7.90 (t, 4H, J = 10.0 Hz), 7.76 (s, 2H),
7.65 (t, 4H, J = 8.3 Hz), 7.18 ppm (d, 4H, J = 10.35 Hz); Anal.
Calcd. for C32H20N6: C, 74.20; H, 4.20; N, 21.60. Found: C, 73.10;
H, 6.70; N, 20.20.
For the p-methyl isonitrosoacetophenone, —NO peak is
observed at 971 cmꢀ1 but is not observed for compound
IX. At 1670 cmꢀ1, decreased strength of —CN stretching
frequency peak is observed. —OH peak, which is seen at
3150 cmꢀ1 of p-methyl isonitrosoacetophenone, is not
seen for the compound IX. —NH peak, which appeared
at 3360 cmꢀ1 of terephthalodihydrazone, disappeared in
the spectrum of compound IX. The specific peak of
triazine (C¼C and C¼N) framework is observed in
1540–1215 cmꢀ1 interval. In addition, aliphatic —CH
1,4-Bis(6-p-tolyl-1,2,4-triazin-3-yl)benzene (IX). This com-
pound was obtained as yellow color crystal. Yield 0.29 g (%69);
mp >300ꢁC (decomp.); IR: CH (triazine) 3333 cmꢀ1; CH
(aromatic) 2915 cmꢀ1; C¼C 1565, 1540, 1450, 1350, 1270 cmꢀ1
;
1
C¼N 1215 cmꢀ1; CH (aliphatic) 1079 cmꢀ1. H NMR: d 8.65
(s, 2H, triazine ring), 7.70 (s, 4H), 7.80 (d, 4H, J = 8.41 Hz),
7.65 (d, 4H, J = 8.34 Hz), 2.45 ppm (s, 6H); Anal. Calcd. for
C26H20N6: C, 74.98; H, 4.84; N, 20.18. Found: C, 73.62; H,
5.60; N, 20.88.
peak is observed in 1079 cmꢀ1
.
EXPERIMENTAL
Acknowledgments. We thank the Scientific Research Projects
Foundation of Selcuk University (SUBAP-Grant Number 2005-
05201014) for financial support of this work produced from a
part of Onder Alici’s MSc Thesis.
Materials and measurements. Pyruvic aldehyde 1-oxime
(98%) (IV), terephthalaldehyde (99%), hydrazine hydrate (80%),
2-acetonaphthalen (99%), 40-methylacetophenone (95%), and
4-acetylbiphenyl (98%) were purchased from Merck. The
starting materials, isonitrosoacetophenone (I), isonitroso-1-
acetylnaphtalene (II), p-methylisonitrosoacetophenone (III), and
terephthalaldehydedihydrazone (V) were synthesized according to
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of New Substituted 1,2,4-Triazines from Isonitrosoketones and
Terephthalaldehydedihydrazone
579
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