Reinvestigation of the reaction of 3-substituted 1,2,4-triazines with nitronate anions: unexpected behavior of 3-(2-ethoxyphenyl)-1,2,4-triazine in the reaction with anions of nitroalkanes

Article abstract of DOI:10.1007/s10593-019-02564-9

[Figure not available: see fulltext.] 3-Substituted 1,2,4-triazines easily react with nitronate anions to replace hydrogen atom in the position C-5 according to nucleophilic substitution mechanism and form appropriate oximes of 5-formyl- or 5-acyl-1,2,4-t

Full text of DOI:10.1007/s10593-019-02564-9

DOI 10.1007/s10593-019-02564-9
Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
Dedicated to Professor Andrzej Rykowski on the occasion of his 77th birthday
Reinvestigation of the reaction of 3-substituted 1,2,4-triazines
with nitronate anions: unexpected behavior
of 3-(2-ethoxyphenyl)-1,2,4-triazine in the reaction
with anions of nitroalkanes
Mariusz Mojzych1*, Zofia Bernat1, Zbigniew Karczmarzyk1
1 Department of Chemistry, Siedlce University of Natural Sciences and Humanities,
54 3-go Maja St., 08-110 Siedlce, Poland; e-mail: mmojzych@yahoo.com
Submitted May 10, 2019
Accepted June 10, 2019
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(10), 968–977
3-Substituted 1,2,4-triazines easily react with nitronate anions to replace hydrogen atom in the position C-5 according to nucleophilic
substitution mechanism and form appropriate oximes of 5-formyl- or 5-acyl-1,2,4-triazines. Present study has shown that the course of
the reaction strongly depends on the structure of the substituent in the position C-3 of 1,2,4-triazine ring. Thus, 2-ethoxyphenyl substitu-
ent in 1,2,4-triazine allowed to form, besides appropriate oximes, also new nitronic acid derivatives stabilized by intramolecular hydro-
gen bonds. The synthesis pathway and molecular structures of oximes were confirmed by X-ray analysis performed for model compound
1-[3-(2-ethoxyphenyl)-1,2,4-triazin-5-yl]ethanone oxime. The presence of the new nitronic acid derivatives in the reaction mixture and
the theoretical calculations at DFT/B3LYP/6-311++G(d,p) level strongly suggest that intermediate stabilized by bifurcated intramolecu-
lar hydrogen bond is a common intermediate for the construction of appropriate oximes.
Keywords: nitroalkanes, nitronate anions, oximes, 1,2,4-triazine, nucleophilic substitution reaction.
Hydrogen nucleophilic substitution reactions are
excellent tools for the synthesis and functionalization of
heterocyclic systems.1 Due to the strong electron-deficient
nature, 1,2,4-triazine derivatives readily undergo addition
of nucleophilic agents. These processes may also include
the reaction of 1,2,4-triazine with nitronate discovered by
Rykowski and Mąkosza, in the mid 80's.2 This reaction
leads to the substitution of hydrogen atom at the C-5
position of 1,2,4-triazine by hydroxyiminoalkyl group
(Scheme 1).
1,2,4-triazines obtained in this way are used widely in the
synthesis of new heterocyclic derivatives. They have been
used in the preparation of 5-acyl-1,2,4-triazines,2,3 chiral
1,2,4-triazine alcohols,4 2-acylpyridines,5 cyanotriazines,6
pyrazolo[4,3-e][1,2,4]triazines,7 and 3-aryl-5,6,7,8-tetra-
hydroisoquinolines which are valuable precursors for the
synthesis of alkaloid sempervirine and its analogs.8
Due to the fact that the synthesis of oximes has a wide
range of applications in organic chemistry, it became of
interest to reinvestigate their formation mechanism proposed
for the first time by Rykowski and Mąkosza2 (Scheme 2).
The proposed mechanism involves the attachment of
carbanion to the carbon atom at the position C-5 of 1,2,4-tri-
azine ring to form the anionic σH-adduct I. This adduct is in
equilibrium with the aci-nitro form II, wherein the proton
of the methine group is transferred to the nitrogen atom N-2
of 1,2,4-triazine ring. Detachment of proton from the
position C-5 of 1,2,4-triazine ring through an oxygen atom
of the nitro group followed by elimination of OH group
(compound III) gives nitroso compound IV. Isomerization
of the latter leads to the corresponding oxime. This scheme
Scheme 1
N
N
N
N
RCH2NO2
N
R2
N
R1
KOH, DMSO
R1
NOH
2
1
R1 = H, Me, OMe, SMe, Si-Pr, Ph
R2 = H, Me, Et, n-Pr, n-Bu
In this process, nitroalkanes play a role of masked
acylating agents giving in a first stage oximes of 5-formyl-
or 5-acyl-1,2,4-triazines.2,3 Oximes of 5-formyl- and 5-acyl-
0009-3122/19/55(10)-0968©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
Scheme 2
byproducts 3a–c which did not precipitate after pouring the
reaction mixture into ice water and acidification with
AcOH. The latter compounds were isolated by extraction
with Et2O from the filtrate after separation of the oximes.
The Rf value of compounds 3a–c were always higher than
the Rf value of the corresponding oximes. Products 3a–c
were purified by column chromatography using a mixture
of CH2Cl2–EtOH, 50:1. The structures of the obtained new
1
oximes 2a–c and compounds 3a–c were established by H
and 13C NMR spectroscopy, elemental analysis, and mass
spectrometry. In the 1H NMR spectra for compounds 2a–c,
we could see characteristic signals in the range of 7.06–
7.86 ppm corresponding to the protons of the aromatic ring
in the C-3 position of 1,2,4-triazine and coupled signals for
the ethoxy group as a triplet at 1.38 ppm and quartet at
4.15 ppm. The NMR spectra for derivatives 3a–c were very
similar to the spectra of the corresponding oximes 2a–c.
There was only a small difference in the chemical shifts of
the corresponding signals.
is only a hypothetical assumption because so far it has not
been possible to prove the formation of intermediate
products, except for the σH-adduct which is formed in the
first step, and its presence was documented by spectro-
scopic methods.9
In this work, we have attempted to obtain and identify
the intermediates proposed by Rykowski and Mąkosza
using specific 3-substituted 1,2,4-triazines in the reaction
with carbanions generated from nitroalkanes.
Recently, oximes of 5-acyl-1,2,4-triazine were used in
the synthesis of sildenafil analogs with pyrazolo[4,3-e]-
[1,2,4]triazine core.10 A key feature of this synthesis was
introduction of the 2-ethoxyphenyl substituent into the
heterocyclic system in the place of the methylsulfanyl
group.10,11 This may be achieved in two ways. One way
involved Suzuki coupling reaction of the appropriate
derivatives of the pyrazolo[4,3-e][1,2,4]triazine with 2-ethoxy-
phenylboronic acid.11 The second synthesis method of
sildenafil analogs could be initiated by reaction of 3-methyl-
sulfanyl-1,2,4-triazine (1a) with 2-ethoxyphenylboronic
acid which leads to 3-(2-ethoxyphenyl)-1,2,4-triazine (1b)
in 65% yield. The latter can easily react with nitronate
anions generated from nitroethane, nitropropane, or nitro-
butane (Scheme 3). However, besides of the expected
oximes 2a–c, byproducts 3a–c were found in the reaction
mixture, which so far have not been observed in the
reaction of 3-phenyl-, 3-methyl, 3-methoxy-1,2,4-triazines,
etc. with nitroalkanes.2
The presence of compounds 3a–c in the reaction
mixtures encouraged us to investigate the conditions of
their formation and the possibility of transformation into
the corresponding oximes 2a–c. Thus, the first problem
that had to be solved was determination of influence of the
substituent structure present in the position C-3 of the 1,2,4-
triazine ring on the course of the reaction. Therefore, in the
next step of our study, we have prepared 3-aryl-1,2,4-
triazines 1c–e in the Suzuki reaction of compound 1a with
appropriate available arylboronic acids using procedure
described in the literature (Scheme 3).11 3-Aryl-1,2,4-
triazines 1c–e were obtained in good yields. The chemical
structures of the obtained 3-aryl-1,2,4-triazines were
confirmed by 1H and 13C NMR spectra.
Next, we have decided to react obtained 3-aryl-1,2,4-
triazine derivatives 1c–e with nitroethane using literature
procedure (Scheme 3).2 In all performed reactions, only
oximes 2d–f were isolated and no corresponding structures
similar to derivatives 3a–c were observed. The structures
of oximes 2d–f were confirmed by 1H and 13C NMR
spectra. These experiments show that the formation of
derivatives 3a–c strongly depends on the presence of the
alkoxy group in position C-2' of the phenyl ring attached to
the carbon C-3 of 1,2,4-triazine. This can probably be
explained by the possibility of hydrogen bond formation
between the OH group of aci-nitro group and triazine
nitrogen atom N-4 (O–H···N(4)) (Fig. 1, structure A). It
could be facilitated by the presence of electron-donating
alkoxy group at the ortho position of the phenyl ring which
can increase the electron density on the triazine nitrogen
In all cases, the TLC control of the reactions of
compound 1b with nitronate anions revealed the presence
in the reaction mixture of expected oximes 2a–c and
Scheme 3
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Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
obtained in 69% total yield. Since the stereochemistry of the
adduct does not affect subsequent steps in the synthesis of
oximes, exact configuration of diastereoisomers was not deter-
mined. The structure of the major and minor adducts was
confirmed using NMR spectroscopy and mass spectrometry.
Scheme 4
Figure 1. Plausible intramolecular hydrogen bonds in the struc-
ture of compounds 3a–c.
atom N-4. Moreover, it should be mentioned that the basicity
of the nitrogen atoms in the 1,2,4-triazine and its 3-sub-
stituted derivatives decrease in the order of N-4 > N-2 > N-1,
which means that electron density in the 1,2,4-triazine
molecule is the highest around nitrogen atom N-4 and the
atom readily accepts electrons.12 On the other hand, the
formation of another hydrogen bond between the OH group
and an ethoxy substituent is also possible (O–H···O–Et)
giving structure B (Fig. 1) stabilized by a double intra-
molecular interaction.
The lack of appropriate nitronic acid form 3 in the
reaction of triazines 1c–e with nitroethane may confirm the
occurrence of intramolecular hydrogen bonds in derivatives
3a–c. These bonds have a significant effect on the stability
of structures 3a–c and allow their isolation from the
reaction mixture, while in the reaction of triazines 1c–e
with nitromethane the less stable nitronic acid forms
without additional O–H···O intramolecular hydrogen bond
probably are completely transformed into final oximes 2d–f.
As can be seen in Scheme 2, the reaction of 1,2,4-
triazine with nitronate anions involves in the first step the
addition of a nucleophilic agent and formation of σH-adduct
which undergoes dehydration to yield final oxime.
Detection of the σH-adducts as key intermediates in the
nucleophilic substitution reaction is possible by nuclear
magnetic resonance methods.13 In the adduct, signals of
hydrogen attached to carbon atom C-5 are shifted (Fig. 2).
The chemical shift of the proton in the range of 3.5–4.0 ppm is
a result of a change of hybridization of the C-5 carbon
atom from sp2 to sp3. The formation of the σH-adduct is a
very fast process, and the adduct has the highest stability
due to energetically preferred p-quinone structure12 with
negative charge on the nitrogen atom N-2 (Fig. 2).
In order to investigate chemical transformations of the
σH-adduct we have performed its synthesis starting from
1,2,4-triazine 1b and nitroethane in the presence of K2CO3
in DMSO according to the method described previously
(Scheme 4).9 The reaction was carried out at room
temperature for 2.5 h. After this time, the reaction mixture
was poured into ice water. Diastereoisomers 4a were
extracted with Et2O and then purified by column chromato-
graphy using EtOAc–hexane, 1:1 mixture to give products
in 32% total yield. To increase the yield, the reaction time
was prolonged to 3.5 h. In this case compounds 4a were
1H NMR spectra of compound 4a (major diastereomer)
showed the characteristic doublet of doublet for the proton
at C-5 in the range of 4.00–4.02 ppm while the proton in
3-(2-ethoxyphenyl)-1,2,4-triazine (1b) was observed with
the chemical shift of 8.67 ppm. Moreover, the proton in the
C-6 position of triazine 4a was observed as doublet at
6.82 ppm while in the NMR spectra of compound 1b the
proton was present as doublet at 9.14 ppm. Signal at 10.69 ppm
1
in the H NMR spectra for compound 4a is derived from
the N(2)–H proton whereas signals in the range of 6.90–
7.40 ppm belong to the ethoxyphenyl ring. Characteristic
doublet of quartets in the range of 4.90–4.94 ppm derived
from the proton linked to the carbon with nitro group NO2
(CH3CHNO2). Quartet at 4.07 and triplet at 1.32 ppm were
provided by ethoxy group. Doublet present at 1.61 ppm
derived from the methyl group of CH3CHNO2 moiety.
Continuing our research the obtained adduct 4a was
subjected to oxidation at room temperature using a variety
of oxidizing agents, namely, DDQ, p-chloranil, KMnO4,
Br2, O2 (Scheme 4, Table 1).
The first experiment was conducted for 1 h at room
temperature in CDCl3 using DDQ as an oxidant (Table 1,
entry 1). The use of the deuterated solvent enabled the
control of the reaction progress by NMR. As a result of this
transformation, compound 3a was obtained with 50%
1
yield. Its structure was established by H NMR spectrum
Table 1. Conditions and yields of the oxidation of compound 4a
Entry
Oxidant
Product
Yield, %
1
2
3
4
5
DDQ
p-Chloranil
KMnO4
Br2
50
3a
3a
–
71
N
1
2N–
Decomposition of the adduct
Decomposition of the adduct
Only adduct recovered
6
5
3
H
Nu
4
N
–
R
O2
4a
Figure 2. Structure of the σH-adduct.
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Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
Scheme 5
and was compared with the spectrum obtained for com-
pound 3a from the reaction of triazine 1b with nitroethane
in suspension of KOH in DMSO (Scheme 3). The
Taking into account that the reaction of nitroalkanes
with 1,2,4-triazines can be considered as nucleophilic
substitution reaction of hydrogen and in part as Nef-type
reaction, the formation of structures 3a–c is reasonable and
could be a result of two mentioned above reaction mecha-
nisms. Therefore a plausible mechanism for the formation
of triazines 3a–c is presented in Scheme 6. However, it
should be noted that nitronic acid forms 3a–c were not
observed so far and not isolated from reactions of 3-methyl-,
3-phenyl-, 3-methylsulfanyl-, or 3-methoxy-1,2,4-triazine
with nitroalkanes. This result can confirm our previous
suggestion that 2-ethoxyphenyl substituent in 1,2,4-triazine
allows to form nitronic acids 3a–c stabilized by intra-
molecular hydrogen bonds.
1
comparison of H NMR and mass spectra confirmed that
compound 3a can form upon oxidation of adduct 4a. The
next oxidation process was performed at room temperature
in CDCl3 in the presence of p-chloranil as the oxidizing
agent (Table 1, entry 2). In this case, after 1 h product 3a
1
was obtained in 71% yield, and its H NMR spectrum was
identical with the spectrum of product obtained in the
reaction with DDQ. Oxidation of adduct 4a in the presence
of KMnO4, Br2, and O2 failed (Table 1, entries 3–5).
Considering the experimental results and the fact that
adduct 4a is intermediate in the synthesis of the corres-
ponding oxime 2a, derivative 4a was mixed in suspension
of KOH in DMSO (Scheme 4) under typical reaction
conditions used for preparation of oxime. The reaction
mixture was stirred at room temperature for 2 h till
substrate 4a disappeared. After that, the reaction mixture
was poured into ice water and neutralize with AcOH to pH 7.
Two products were formed and isolated by extraction with
Et2O from an aqueous solution followed by column
chromatography. Product 3a was formed in 42% yield, and
oxime 2a was isolated in 11% yield. The reaction was
repeated under the same conditions, but the reaction
mixture was poured into ice water without neutralization
with AcOH. As a result of this change, only one product 3a
was obtained in 71% yield.
Scheme 6
These results prompted us to synthesize other adducts
with different substituents at the C-3 position of the 1,2,4-tri-
azine ring. Therefore, 3-phenyl- and 3-(1-naphthyl)-1,2,4-tri-
azines were reacted with nitroethane in the presence of
K2CO3 in DMSO at room temperature. The reactions were
carried out for 2.5 h (Scheme 5). Adducts 4b,c were
isolated in the same way as diastereomers 4a, and NMR
spectra were recorded. It should be noted that it is not
possible to prepare the appropriate σH-adduct of 3-methyl-
sulfanyl-1,2,4-triazine (1a) in this way. The adduct with
methylsulfanyl group could be only obtained in the
presence of KOH in liquid ammonia.9
In the next stage of our study, the obtained adducts 4b,c
were subjected to oxidation using DDQ in CDCl3. The
oxidation process was carried out in a small scale (0.1 mmol)
at room temperature for 1 h. The NMR spectra performed
for the reaction mixtures confirmed structures 5a,b. We
have also investigated transformation of adducts 4b,c in a
suspension of KOH in DMSO. As a result of these
transformations we have obtained respective products 5a,b.
Their structures were different from compound 3a obtained
from compound 4a under KOH/DMSO conditions or using
DDQ in CDCl3.
Oximes of 5-acyl-1,2,4-triazine 2a–f are valuable
starting materials for the synthesis of carbonyl compounds
useful in organic synthesis.3,4,8,10,14,15 Therefore, using
Pojer's method16 for reduction of oximes to the cor-
responding carbonyl compounds, we have converted
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Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
Table 2. The hydrogen bond lengths (Å) observed in crystal
Scheme 7
N
N
N
and obtained using DFT/B3LYP/6-311++G(d,p) calculations
N
N
Na2S2O4
for compound 2a
R
R
N
Ar
Ar
1,4-dioxane, H2O
rt, 24 h
D–H···A
D–H
H···A
D···A
D–H···A
O
NOH
2a (X-ray)
2a–f
6a–f
C(10)–H(102)···O(9)
O(9)–H(9)···N(1)*
O(9)–H(9)···N(2)*
0.96
2.25
2.664(4)
3.152(3)
2.797(4)
105
130(3)
163(3)
6 a Ar = 2-EtOC6H4, R = Me (52%); b Ar = 2-EtOC6H4, R = Et (58%);
c Ar = 2-EtOC6H4, R = n-Pr(52%); d Ar = 4-EtOC6H4, R = Me (56%);
e Ar = Ph, R = Me (64%); f Ar = 1-Naphth, R = Me (53%)
0.96(4)
0.96(4)
2.45(3)
1.86(4)
2a (DFT)
O(9)–H(9)···N(4)
O(9)–H(9)···O(17)
0.995
0.995
3a (DFT)
1.030
1.030
3d (DFT)
1.024
3e (DFT)
1.020
3f (DFT)
1.019
1.704
2.515
2.590
3.261
146.0
131.5
oximes 2a–f into corresponding ketones 6a–f (Scheme 7).
The structures of the obtained compounds 6a–f were
established by NMR spectroscopy.
In order to confirm the synthesis pathway, the proposed
molecular structures, and conformational preferences
associated with the possible formation of intramolecular
hydrogen bonds, the X-ray analysis of triazine 2a as the
model compound was performed. View of molecule 2a in
conformation observed in crystal with numbering of atoms
is shown in Figure 3.
O–H···N(4)
O–H···O(Et)
1.547
2.461
2.497
3.140
150.7
122.7
O–H···N(4)
O–H···N(4)
O–H···N(4)
1.553
2.508
2.519
2.522
152.9
152.9
151.2
1.568
1.581
* Symmetry code i = 1 – x, 1/2 + y, 1/2 – z.
The oxime substituent adopts the trans-trans confor-
mation in relation to the 1,2,4-triazine ring with the methyl
group in the cis position with respect to N(4)–C(5) bond, which
is confirmed by the torsion angles N(4)–C(5)–C(7)–N(8),
C(5)–C(7)–N(8)–O(9) and N(4)–C(5)–C(7)–C(10) of
–173.0(3), 179.1(3) and 5.3(4)°, respectively. This confor-
mation is stabilized by C(10)–H(102)···N(4) intramole-
cular hydrogen bond (Table 2), but in this conformation the
intramolecular hydrogen bond between O–H group and
N-4 atom of the 1,2,4-triazine ring is not observed. The
same conformation of the oxime group with respect to the
triazine and pyridine rings is observed in closely related
structure of (E)-1-(3-methylsulfanyl-1,2,4-triazin-5-yl)-
ethanone O-acryloyl oxime17 and (E)-1-(pyridin-2-yl)-
ethanone O-acryloyl oxime,18 respectively. The theoretical
calculations at DFT/B3LYP/6-311++G(d,p) level showed,
that the alternative cis–cis conformation of the oxime group
with calculated torsion angles N(4)–C(5)–C(7)–N(8) of
3.28° and C(5)–C(7)–N(8)–O(9) of –0.11° and the possi-
bility to form O(9)–H(9)···N(4) intramolecular hydrogen
bond (Table 2; Supplementary information file, Table S1,
Fig. S1) is less energetically stable than that observed in
the crystal with the difference of energy of 2.399 kcal/mol.
This value of energy does not exclude the coexistence of
these two conformations with the population of 0.98:0.02
in favor of that observed in the crystal at room temperature
calculated from non-degenerate Boltzmann distribution. It
should be noted, that this calculation was performed for
isolated molecule (gaseous phase), while the X-ray analysis
unambiguously showed that compound 2a occurs in one
trans–trans conformation in the crystalline state.
The benzene ring of the ethoxyphenyl substituent is
twisted with respect to 1,2,4-triazine ring with the torsion
angle N(2)–C(3)–C(11)–C(16) of –30.3(4)°. This mutual
position of the rings is forced by the electrostatic repulsion
of the lone pairs of N-4 and O-17 atoms. The 2-ethoxy
group in the phenyl substituent lies practically in the plane
of the benzene ring with the trans-trans conformation as
shown by the torsion angles C(11)–C(12)–O(17)–C(18) of
–174.5(3)° and C(12)–O(17)–C(18)–C(19) of 177.0(3)°.
In the crystal structure, the molecules related by 21 axes
are linked into chains parallel to Y direction via bifurcated
intermolecular O–H···N hydrogen bonds (Fig. 4, Table 2).
It should be noted that the trans–trans conformation of the
oxime group with respect to 1,2,4-triazine ring favors the
formation of structural motif observed in crystal of triazine 2a.
Figure 4. The molecular motif formed by molecules via O–H···N
intermolecular hydrogen bonds (symmetry code i = 1 – x, 1/2 + y,
1/2 – z) in crystal of compound 2a.
Figure 3. Molecular structure of compound 2a with atoms repre-
sented as thermal vibration ellipsoids of 30% probability.
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Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
Figure 5. The structure of compound 3a and hypothetical structures of compounds 3d–f obtained after theoretical calculations
at DFT/B3LYP/6-311++G(d,p) level.
Moreover, the 1,2,4-triazine rings belonging to the inver-
sion-related molecules overlap each other with a centroid-
to-centroid separation of 4.0016(19) Å (1 – x, –y, 1 – z) and
the slippage of 1.156 Å.
acid form 3 in the reaction of triazines 1c–e with nitro-
ethane may be due to the lack of intramolecular O–H···O
hydrogen bond stabilizing molecular structures of triazines
3a–c.
As mentioned earlier, the experiments carried out
suggest that the formation of derivatives 3a–c strongly
depends on the presence of the alkoxy group in position 2'
of the phenyl ring attached to the carbon C-3 of 1,2,4-tri-
azine ring. This may be due to the occurrence of O–H···N(4)
hydrogen bond between the OH group of aci-nitro group
and triazine nitrogen atom N(4) (Fig. 1, structure A) or
O–H···N(4) and O–H···O hydrogen bonds, where the atom
O from ethoxy substituent is additional acceptor of proton
(Fig. 1, structure B). It could be facilitated by presence of
electron-donating alkoxy group at the ortho position of the
phenyl ring which may increase the electron density on the
triazine nitrogen atom N-4. Unfortunately, attempts to
crystallize compounds 3a–c with nitro-aci group and
adducts 4a–c from different solvents were unsuccessful
giving residues unsuitable for X-ray analysis. However,
theoretical calculations at DFT/B3LYP/6-311++G(d,p)
level performed for compound 3a and hypothetical
structures 3d–f do not confirm correlation between the
possibility to formation of derivatives 3a–c and 3d–f and
the net charge on N-4 atom of the 1,2,4-triazine ring. The
geometry and conformation calculated using DFT method
for molecules 3a,d–f are presented in Figure 5.
One can see the strong intramolecular hydrogen bond
O–H···N(4) with the clear shift of the H atom from
O atom in the direction of N-4 atom; the respective O···H
and H···N distances are 1.030 and 1.547 Å in compound
3a, 1.024 and 1.553 Å in compound 3d, 1.020 and 1.568 Å
in compound 3e, and 1.019 and 1.581 Å in compound 3f
(Table 2). Moreover, the weak intramolecular hydrogen
bond O–H···O between O atoms of aci-nitro and ethoxy
groups in compound 3a is observed with H···O distance of
2.461 Å (Table 2) being shorter than the sum of van der
Waals radii of H (1.20 Å) and O (1.52 Å) atoms. It is also
noted, that the calculated NBO net charge on N-4 atom is
–0.534 e for compound 3a and –0.554 e, –0.551 e, and
–0.555 e for compounds 3d, 3e, and 3f, respectively, and
this charge does not depend on the presence of additional
proton acceptor atom in the ortho-substituent of the phenyl
group (Supplementary information file, Table S2).
The results presented in this paper indicate that
3-methylsulfanyl-1,2,4-triazine easily react with various
boronic acids according to methodology of Suzuki-type
reaction and provided 3-aryl-1,2,4-triazines in very good
yield. 3-(2-Ethoxyphenyl)-1,2,4-triazine in the reaction
with nitroalkanes yielded appropriate oximes and new
nitronic acid forms stabilized by intramolecular hydrogen
bonds. Reaction of 3-aryl derivatives of 1,2,4-triazine with
nitroalkanes in a suspension of K2CO3 in DMSO leads to
the corresponding σH-adducts isolated in good yield. The
structures of the σH-adducts were clearly confirmed by
spectroscopic methods. Adducts can be oxidized, and the
course of these reactions depends on their structures. If the
adduct contained 2-ethoxyphenyl substituent at the C-3
position of the 1,2,4-triazine ring we have observed only
3-(2-etoxyphenyl)-5-(1-aci-nitroethyl)-1,2,4-triazine inter-
mediate identical to the product of the reaction with KOH
in DMSO. However, if at the C-3 position of the adduct, an
aryl substituent is other than 2-ethoxyphenyl, only nitro
product was obtained. Introduction of 2-ethoxyphenyl
moiety in the C-3 position of the 1,2,4-triazine ring allows
to form compounds with nitronic acid structure which have
never been observed during the synthesis of oximes
starting from 3-methyl-, 3-phenyl, 3-methylsulfanyl-, or
3-methoxy-1,2,4-triazine and applying described herein
procedure. We have not obtained or have not even detected
by spectroscopic methods the presence of other inter-
mediates proposed by Rykowski and Mąkosza in the
mechanism of the synthesis of oximes from 1,2,4-triazines
and nitroalkanes. However, our studies can indirectly
confirm the formation of key structure as essential
intermediate for the construction of both oximes and new
nitronic acid forms.
Experimental
IR spectra were recorded in CCl4 on a Nicolet Magna
1
760 FTIR spectrometer in thin films. H and 13C NMR
spectra were recorded on a Varian 400 MR spectrometer
(400 and 100 MHz, respectively), TMS used as internal
standard. Mass spectra were recorded on an Agilent
Technologies 6538 UHD Accurate Mass Q-TOF LC/MS
spectrometer with electrospray ionization (ESI/MS). Mass
spectra of compounds 3, 4 a were recorded on a DFS High
Resolution GC/MS spectrometer (EI, 70 eV). Elemental
Theoretical calculations show, that the electronic nature
of the substituent in position 2' of the phenyl ring is
probably not associated with the formation of derivatives
3a–c. The impossibility of isolation of appropriate nitronic
973

Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
analysis was performed on a LECO 628 series elemental
suspension of powdered KOH (8.0 g, 0.14 mol) in dry
DMSO (20 ml) at room temperature. The mixture was
stirred at room temperature for 2 h, then poured into ice
water (200 ml) and neutralized with AcOH to pH 7.0. The
precipitated oxime was filtered off and washed with H2O.
The crude oxime was purified by chromatography on silica
gel, eluent CH2Cl2–EtOH, 50:1, to afford products 2a–f as
yellowish powders. After filtration of the oxime, the
solution was extracted with Et2O. After evaporation of the
Et2O, the residue was purified by column chromatography
using silica gel and CH2Cl2–EtOH, 50:1, to yield bypro-
ducts 3a–c as yellow solids.
analyzer. Melting points were determined on a Mel-Temp
apparatus and are uncorrected.
Triazine 1a19 and Cu(I) 3-methylsalicylate (MeSalCu)20
were prepared by methods described in the literature.
Synthesis of 3-aryl-1,2,4-triazines 1b–e (General method).
Pd(PPh3)4 (1.15 g, 1 mmol, 0.1 equiv) was added to a
mixture of 3-methylsulfanyl-1,2,4-triazine (1а) (1.27 g,
10 mmol, 1.0 equiv), MeSalCu (4.7 g, 22 mmol, 2.2 equiv),
arylboronic acid (22 mmol, 2.2 eqiuv) in dry THF (50 ml)
under argon atmosphere. The reaction mixture was stirred
overnight at reflux. The reaction was quenched with a
saturated Na2CO3 solution and extracted with CH2Cl2. The
combined organic phases were dried over MgSO4 and
concentrated under reduced pressure. After purification by
column chromatography on silica gel, eluent hexane–
CH2Cl2, 3:1, the desired products were obtained.
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]ethanone oxime
(2a). Yield 1.21 g (47%), mp 154–156°C. IR spectrum,
1
ν, cm–1: 3120, 2937, 1583, 1274, 751. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.38 (3H, t, J = 6.8, CH3); 2.37
(3H, s, CH3); 4.15 (2H, q, J = 6.8, CH2); 7.06–7.13 (2H, m,
H Ar); 7.46–7.49 (1H, m, H Ar); 7.87 (1H, dd, J = 7.6,
J = 1.6, H Ar); 9.66 (1H, s, H triazine); 10.20 (1H, br. s,
OH). 13C NMR spectrum (CDCl3), δ, ppm: 9.0; 14.7; 64.4;
113.2; 120.7; 125.0; 131.9; 132.2; 143.2; 153.7; 154.1;
157.7; 164.9. Found, m/z: 259.1188 [M+H]+. C13H14N4O2.
Calculated, m/z: 259.1190.. Found, %: C 60.51; H 5.63;
N 21.55. C13H14N4O2. Calculated, %: C 60.46; H 5.46;
N 21.69.
3-(2-Ethoxyphenyl)-1,2,4-triazine (1b).21 Yield 1.96 g
(98%), yellowish oil. IR spectrum, ν, cm–1: 2927, 1600,
1452, 1236, 1037, 750. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.31 (3H, t, J = 5.8, CH3); 4.10 (2H, q, J = 5.8,
CH2); 7.02–7.09 (2H, m, H Ar); 7.42–7.46 (1H, m, H Ar);
7.75 (1H, dd, 1J = 7.6, 2J = 2.0, H Ar); 8.67 (1H, d, J = 2.0,
H Ar); 9.14 (1H, d, J = 2.0, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 14.5; 64.5; 113.2; 120.6; 125.6; 131.6;
131.9; 147.0; 148.0; 157.3; 165.9.
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]propanone
oxime (2b). Yield 1.0 g (37%), mp 121°C. IR spectrum,
3-(4-Ethoxyphenyl)-1,2,4-triazine (1c). Yield 1.60 g
(80%), yellow solid, mp 104–105°C. IR spectrum, ν, cm–1:
2983, 1608, 1517, 1402, 1390, 1354, 1257, 1174, 1116,
1041, 844, 792. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.45 (3H, t, J = 7.0, CH3), 4.13 (q, 2H, J = 7.0,
CH2); 7.01–7.03 (2H, m, H Ar); 8.46–8.49 (2H, m, H Ar);
8.59 (1H, s, H triazine); 9.07 (1H, s, H triazine). 13C NMR
spectrum (CDCl3), δ, ppm: 14.7; 63.6; 114.7; 126.9; 130.0;
146.9; 148.5; 162.1; 164.0. Found, %: C 65.70; H 5.64;
N 20.64. C11H11N3O. Calculated, %: C 65.66; H 5.51; N 20.88.
3-Phenyl-1,2,4-triazine (1d). Yield 1.28 g (82%), yellow
solid, mp 35–38°C. IR spectrum, ν, cm–1: 1523, 1398,
1355, 748, 686. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.51–7.57 (3H, m, H Ph); 8.51 (2H, d, J = 1.6,
H Ph); 8.68 (1H, s, H triazine); 9.17 (1H, s, H triazine).
13C NMR spectrum (CDCl3), δ, ppm: 115.4; 128.1; 128.7;
129.4; 131.7; 134.5; 147.6. Found, %: C 68.90; H 4.60;
N 26.49. C9H7N3. Calculated, %: C 68.78; H 4.49; N 26.73.
3-(Naphthalen-1-yl)-1,2,4-triazine (1e). Yield 1.45 g
(70%), yellow solid, mp 53–55°C. IR spectrum, ν, cm–1:
1
ν, cm–1: 3123, 2940, 1589, 1268, 755. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.19 (3H, t, J = 7.6, CH3); 1.38
(3H, t, J = 7.2, CH3); 2.97 (2H, q, J = 7.6, CH2); 4.16 (2H,
q, J = 6.8, CH2); 7.06–7.13 (2H, m, H Ar); 7.47–7.49 (1H,
m, H Ar); 7.49–7.87 (1H, m, H Ar); 9.64 (1H, s, H triazine).
13C NMR spectrum (CDCl3), δ, ppm: 10.4; 14.6; 16.6; 64.4;
113.0; 120.6; 125.0; 131.9; 132.2; 143.5; 157.6; 158.7; 166.1.
Found, m/z: 273.1346 [M+H]+. C14H17N4O2. Calculated, m/z:
273.1268. Found, %: C 61.53; H 6.03; N 20.48.
C14H16N4O2. Calculated, %: C 61.75; H 5.92; N 20.57.
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]butan-1-one
oxime (2c). Yield 1.28 g (45%), mp 124–126°C. IR spectrum,
1
ν, cm–1: 3130, 2947, 1571, 1260, 752. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 0.98 (3H, t, J = 7.2, CH3); 1.38
(3H, t, J = 6.8, CH3); 1.63–1.70 (2H, m, CH2); 2.94 (2H, t,
J = 7.2, CH2); 4.15 (2H, q, J = 6.8, CH2); 7.06–7.12 (2H,
m, H Ar); 7.48 (1H, t, J = 7.2, H Ar); 7.82 (1H, d, J = 7.2,
H Ar); 9.65 (1H, s, H triazine); 9.84 (1H, br. s, OH).
13C NMR spectrum (CDCl3), δ, ppm: 14.4; 14.8; 19.5; 25.2;
64.5; 113.3; 120.7; 125.6; 132.1; 132.2; 143.7; 153.4; 157.8;
157.9; 165.2. Found, m/z: 287.1502 [M+H]+. C15H19N4O2.
Calculated, m/z: 287.1503. Found, %: C 62.88; H 6.40;
N 19.40. C15H18N4O2. Calculated, %: C 62.92; H 6.34;
N 19.57.
1
1506, 1338, 1305, 1041, 767. H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.52–7.63 (2H, m, H Ar); 7.93 (2H, d,
J = 7.6, H Ar); 8.02 (1H, d, J = 8.4, H Ar); 8.20 (1H, d,
J = 7.2, H Ar); 8.70 (1H, d, J = 8.0, H Ar); 8.70 (1H, d,
J = 1.6, H Ar); 9.20 (1H, d, J = 1.6, H Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 125.0; 125.2; 126.1; 127.3;
128.5; 130.2; 130.7; 131.6; 132.5; 133.9; 147.1; 148.3;
166.9. Found, %: C 75.39; H 4.51; N 20.08. C13H9N3.
Calculated, %: C 75.35; H 4.38; N 20.28.
1-[3-(4-Ethoxyphenyl)-1,2,4-triazin-5-yl]ethanone oxime
(2d). Yield 0.36 g (14%), mp 228–229°C. IR spectrum,
1
ν, cm–1: 3211, 2943, 1543, 1354, 1257, 844, 792. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.36 (3H, t, J = 6.8,
CH3); 2.25 (3H, s, CH3); 4.11 (2H, q, J = 6.8, CH2); 7.08
(2H, d, J = 8.8, H Ar); 8.37 (2H, d, J = 8.8, H Ar); 9.51
(1H, s, H triazine); 12.61 (1H, s, OH). 13C NMR spectrum
(CDCl3), δ, ppm: 8.9; 14.5; 63.3; 114.8; 126.6; 129.4;
Reaction of 3-aryl-1,2,4-triazines with nitroalkanes
(General method). A solution of the appropriate 1,2,4-tri-
azine 1b–e (10 mmol) and nitroalkane (25 mmol) in
DMSO (2 ml) was added in one portion to a stirred
974

Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
1
2
143.1; 152.5; 153.1; 157.5; 161.5. Found, m/z: 259.1190
[M+H]+. C13H15N4O2. Calculated, m/z: 259.1190. Found,
%: C 60.38; H 5.80; N 21.49. C13H14N4O2. Calculated, %:
C 60.46; H 5.46; N 21.69.
(1H, dd, J = 8.0, J = 1.6, H Ar); 9.19 (1H, s, H triazine).
13C NMR spectrum (CDCl3), δ, ppm: 14.4; 15.4; 19.7; 25.5;
65.0; 114.5; 121.4; 125.7; 132.4; 133.3; 143.9; 149.1; 158.1;
165.8; 202.1. Found, m/z: 303.1451 [M–H]. C15H20N4O3.
Calculated, m/z: 303.1452.
1-(3-Phenyl-1,2,4-triazin-5-yl)ethanone oxime (2e). Yield
0.87 g (41%), mp 198°C. IR spectrum, ν, cm–1: 3145, 2827,
Synthesis of σH-adducts (General method). A solution
of the appropriate 1,2,4-triazine 1b,d,e (1 mmol) and nitro-
ethane (0.225 g, 3 mmol) in DMSO (1 ml) was added in
one portion to a vigorously stirred suspension of powdered
K2CO3 (0.414 g, 3 mmol ) in dry DMSO (1 ml) at room
temperature. The mixture was stirred at room temperature
for 2.5 h, then poured into ice water (20 ml) and extracted
with Et2O. After evaporation of the solvent, the residue was
purified by column chromatography on silica gel, eluent
EtOAc–hexane, 1:1, to yield product as yellow crystals.
3-(2-Ethoxyphenyl)-5-(1-nitroethyl)-2,5-dihydro-1,2,4-
triazine (4a), mixture of diastereomers 1.3:1. Yield 0.19 g
(69%). Major diastereomer: Rf 0.78. IR spectrum, ν, cm–1:
1
1539, 1517, 1363, 1354, 1029, 756, 686. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.30 (3H, s, CH3); 7.60–7.62 (3H,
m, H Ph); 8.48 (2H, d, J = 8.0, H Ph); 9.62 (1H, s, H triazine);
12.67 (1H, s, OH). 13C NMR spectrum (CDCl3), δ, ppm: 9.0;
127.7; 129.0; 131.8; 134.5; 143.9; 152.5; 153.4; 162.1.
Found, m/z: 215.2747 [M+H]+. C12H14N4O. Calculated, m/z:
214.2749. Found, %: C 61.51; H 4.80; N 26.29. C11H10N4O.
Calculated, %: C 61.67; H 4.71; N 26.15.
1-[3-(Naphthalen-1-yl)-1,2,4-triazin-5-yl]ethanone oxime
(2f). Yield 1.34 g (51%), mp 196°C. IR spectrum, ν, cm–1:
3134, 3053, 2812, 1506, 1338, 1305, 1041, 1028, 767.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.42 (3H, s,
CH3); 7.52 –7.67 (3H, m, H Ar); 7.95–7.97 (1H, m, H Ar);
8.05–8.08 (1H, t, J = 7.2, H Ar); 8.24 (1H, d, J = 7.2,
H Ar); 8.71 (1H, d, J = 8.0, H Ar); 9.80 (1H, s, H triazine).
13C NMR spectrum (CDCl3), δ, ppm: 25.5; 124.8; 125.1;
125.2; 126.4; 127.6; 128.0; 128.8; 128.9; 130.8; 131.8;
132.3; 133.0; 134.1; 169.4. Found, m/z: 264.3310 [M+H]+.
C15H12N4O. Calculated, m/z: 264.3306. Found, %: C 68.42;
H 5.71; N 21.00. C15H12N4O. Calculated, %: C 68.17;
H 4.58; N 21.20.
1
3407, 2926, 1600, 1544, 1454, 1236, 1033, 750. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.32 (3H, t, J = 7.2,
1
CH3); 1.61 (3H, d, J = 6.8, CH3); 4.01 (1H, dd, J = 7.2,
2J = 2.0, CH); 4.07 (2H, q, J = 7.2, CH2); 4.92 (1H, p,
J = 6.8, CH); 6.82 (1H, d, J = 2.0, H triazine); 6.98 (1H, t,
J = 8.0, H Ar); 7.08 (1H, d, J = 8.0, H Ar); 7.36–7.44 (2H,
m, H Ar); 10.69 (1H, br. s, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 15.3; 55.5; 83.1; 112.6; 119.8; 121.5; 131.4; 132.4;
133.7; 154.5; 156.9. Mass spectrum, m/z (Irel, %): 276 [M]+
(1), 229 (48), 202 (100), 174 (44), 148 (6), 120 (28), 91
(10), 39 (5). Minor diastereomer: Rf 0.69. IR spectrum,
ν, cm–1: 3409, 2920, 1602, 1546, 1451, 1230, 1028, 758.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.32 (3H, t,
J = 7.2, CH3); 1.54 (3H, d, J = 6.8, CH3); 4.07 (2H, q, J = 7.2,
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]-N-hydroxy-
ethanimine oxide (3a). Yield 0.16 g (6%), mp 138–140°C.
IR spectrum, ν, cm–1: 3331, 2981, 1587, 1537, 1463, 1222,
1
1029, 734, 682. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 1.27 (3H, t, J = 6.8, CH3); 3.30 (3H, s, CH3); 4.13
(2H, q, 1J = 6.8, CH2); 7.14–7.26 (2H, m, H Ar); 7.54–7.56
(1H, m, H Ar); 7.76–7.86 (1H, m, H Ar); 9.62 (1H, s,
H triazine). 13C NMR spectrum (DMSO-d6), δ, ppm: 14.5;
25.3; 64.0; 113.7; 120.5; 124.8; 131.5; 132.3; 142.9; 148.3;
157.1; 164.9; 199.2. Mass spectrum, m/z (Irel, %): 274 [M]+
(4), 228 (8), 200 (5), 148 (13), 119 (100), 53 (16).
1
2
CH2); 4.20 (1H, dd, J = 3.6, J = 2.0, CH); 5.00 (1H, p,
J = 5.6, CH); 6.78 (1H, d, J = 1.6, H triazine); 6.98 (1H, t,
J = 8.0, H Ar); 7.08 (1H, d, J = 8.0, H Ar); 7.36–7.44 (2H, m,
H Ar); 10.60 (1H, br. s, NH). 13C NMR spectrum (CDCl3),
δ, ppm: 15.5; 55.3; 82.9; 112.7; 119.8; 121.4; 131.2; 132.4;
134.3; 154.5; 156.9. Mass spectrum (EI, 70 eV) m/z (Irel, %):
276 [M]+ (1), 229 (38), 202 (100), 174 (55), 148 (8), 120
(25), 91 (16), 39 (8).
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]-N-hydroxy-
propanimine oxide (3b). Yield 0.29 g (10%), mp 130–
132°C. IR spectrum, ν, cm–1: 3278, 2956, 1583, 1465,
5-(1-Nitroethyl)-3-phenyl-2,5-dihydro-1,2,4-triazine (4b),
mixture of diastereomers 1.5:1. Yield 0.09 g (40%). Major
diastereomer: Rf 0.70. IR spectrum, ν, cm–1: 3390, 2937,
1602, 1548, 1355, 692. 1H NMR spectrum (CDCl3), δ, ppm
1
1230, 1029, 750. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 1.02 (3H, t, J = 7.6, CH3); 1.34 (3H, t, J = 6.8,
CH3); 2.81 (2H, q, J = 7.6, CH2); 4.15 (2H, q, J = 6.8,
CH2); 7.12 (1H, t, J = 7.6, H Ar); 7.21 (1H, d, J = 8.0,
1
(J, Hz): 1.70 (3H, d, J = 6.8, CH3); 4.31 (1H, dd, J = 6.4,
1
2
H Ar); 7.57 (1H, td, J = 8.0, J = 1.6, H Ar); 7.69 (1H, t,
J = 7.2, H Ar); 9.19 (1H, s, H triazine); 13.30 (1H, s, OH).
13C NMR spectrum (DMSO-d6), δ, ppm: 14.4; 16.2; 30.6;
64.0; 113.4; 120.5; 124.8; 130.7; 131.5; 132.3; 143.2;
156.9; 157.1. Found, m/z: 289.1295 [M–H]. C14H18N4O3.
Calculated, m/z: 289.1217.
2J = 2.4, CH); 4.90 (1H, q, J = 6.8, CH); 6.82 (1H, d,
J = 1.6, H triazine); 7.43–7.51 (4H, m, H Ph); 7.71 (1H, t,
J = 7.2, H Ph); 8.71 (1H, br. s, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 15.3; 55.4; 83.0; 126.5; 128.4; 131.4;
131.8; 132.0; 134.8. Minor diastereomer: Rf 0.62. IR spectrum,
ν, cm–1: 3396, 2933, 1610, 1552, 1356, 700. H NMR
1
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]-N-hydroxy-
butanimine oxide (3c). Yield 0.39 g (13%), mp 85–86°C.
IR spectrum, ν, cm–1: 3315, 2920, 1436, 1234, 1375, 750.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.88 (3H, t,
J = 7.2, CH3); 1.34 (3H, t, J = 6.8, CH3); 1.47 (2H, dq,
J = 7.2, CH2); 2.78 (2H, t, J = 7.2, CH2); 4.15 (2H, q,
J = 7.2, CH2); 7.12 (1H, t, J = 7.6, H Ar); 7.21 (1H, d,
J = 8.4, H Ar); 7.57 (1H, td, 1J = 8.4, 2J = 1.6, H Ar); 7.63
spectrum (CDCl3), δ, ppm (J, Hz): 1.77 (3H, d, J = 6.8,
1
2
CH3); 4.22 (1H, dd, J = 6.4, J = 2.4, CH); 4.86 (1H, p,
J = 6.8, CH); 6.77 (1H, d, J = 1.2, H triazine); 7.43–7.51
(4H, m, H Ph); 7.71 (1H, t, J = 7.2, H Ph); 8.71 (1H, br. s,
NH). 13C NMR spectrum (CDCl3), δ, ppm: 15.6; 55.4;
83.2; 126.4; 128.5; 131.4; 131.9; 132.1; 134.8.
3-(Naphthalen-1-yl)-5-(1-nitroethyl)-2,5-dihydro-1,2,4-
triazine (4c), mixture of diastereomers 4:1. Yield 0.16 g
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Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
(55%), mp 126–127°C. Major diastereomer: Rf 0.72.
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]ethan-1-one (6a).
Yield 1.26 g (52%), yellow solid, mp 65°C. IR spectrum,
ν, cm–1: 2981, 1705, 1600, 1516, 1454, 1386, 1276, 1246,
IR spectrum, ν, cm–1: 3380, 2920, 1587, 1537, 1463, 1228,
1
1031, 754, 738, 690. H NMR spectrum (CDCl3), δ, ppm
1
1
(J, Hz): 1.77 (3H, d, J = 6.8, CH3); 4.40 (1H, dd, J = 6.0,
1037, 754. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2J = 2.0, CH); 5.03 (1H, p, J = 6.8, CH); 6.90 (1H, d,
1J = 2.0, H triazine); 7.40–7.62 (4H, m, H Ar); 7.89 (1H, d,
J = 7.6, H Ar); 7.96 (1H, d, J = 8.4, H Ar); 8.00 (1H, d,
J = 7.6, H Ar); 8.66 (1H, br. s, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 15.8; 55.5; 83.3; 124.2; 125.0; 126.5;
126.8; 126.9; 127.3; 128.5; 130.1; 130.4; 130.9; 133.6;
134.6. Minor diastereomer: Rf 0.65. IR spectrum, ν, cm–1:
3387, 2927, 1582, 1542, 1469, 1219, 1037, 759, 732, 698.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.84 (3H, d,
1.27 (3H, t, J = 6.8, CH3); 2.68 (3H, s, CH3); 4.14 (2H, q,
J = 6.8, CH2); 7.15 (2H, t, J = 7.6, H Ar); 7.25 (1H, d,
J = 8.8, H Ar); 7.55–7.57 (1H, m, H Ar); 7.78 (1H, dd,
1J = 7.6, 2J = 1.6, H Ar); 9.62 (1H, s, H triazine). 13C NMR
spectrum (CDCl3), δ, ppm: 14.8; 25.4; 64.4; 113.2; 120.8;
124.7; 132.1; 132.6; 142.3; 147.7; 157.8; 165.9; 199.7.
Found, m/z: 244.0925 [M+H]+. C13H14N3O2. Calculated, m/z:
244.1003. Found, %: C 64.13; H 5.53; N 17.20. C13H13N3O2.
Calculated, %: C 64.19; H 5.39; N 17.27.
1
2
J = 6.8, CH3); 4.23 (1H, dd, J = 6.4, J = 1.6, CH); 4.99
(1H, p, J = 6.8, CH); 6.87 (1H, d, 1J = 1.2, H triazine); 7.40–
7.62 (4H, m, H Ar); 7.89 (1H, d, J = 7.6, H Ar); 7.96 (1H,
d, J = 8.4, H Ar); 8.00 (1H, d, J = 7.6, H Ar); 8.63 (1H, br.
s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 15.3; 55.4;
82.8; 124.3; 124.9; 126.5; 126.8; 126.9; 127.3; 128.5;
130.2; 130.3; 130.9; 133.7; 134.9.
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]propan-1-one
(6b). Yield 1.49 g (58%), yellow solid, mp 65°C. IR spectrum,
ν, cm–1: 2982, 1714, 1603, 1510, 1460, 1391, 1268, 1245,
1
1039, 750. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
1.17 (3H, t, J = 7.6, CH3); 1.38 (3H, t, J = 7.2, CH3); 3.00
(2H, q, J = 7.6, CH2); 4.16 (2H, q, J = 7.2, CH2); 7.07 (1H,
1
2
d, J = 7.6, H Ar); 7.10 (1H, td, J = 7.2, J = 0.8, H Ar);
1
2
Conversion of adducts 4a–c. Oxidation. Adduct 4a–c
(0.1 mmol) was dissolved in CDCl3 (2 ml), and DDQ
(56 mg, 0.25 mmol) was added. The reaction mixture was
stirred at room temperature for 1 h, then quenched with
brine (NaCl in D2O, 1 ml). The organic layer was sepa-
rated, dried with anhydrous MgSO4, and filtered. The
resultant organic solution containing crude product was
used to run NMR spectra.
7.47–7.51 (1H, m, H Ar); 7.86 (1H, dd, J = 7.6, J = 1.6,
H Ar); 9.64 (1H, s, H triazine). 13C NMR spectrum (CDCl3),
δ, ppm: 13.3; 15.0; 16.9; 64.4; 113.1; 120.6; 124.9; 132.0;
132.5; 142.5; 147.6; 157.9; 164.8; 199.8. Found, m/z:
258.2821 [M+H]+. C14H16N3O2. Calculated, m/z: 258.2802.
Found, %: C 65.43; H 6.03; N 16.21. C14H15N3O2. Calcu-
lated, %: C 65.36; H 5.88; N 16.33.
1-[3-(2-Ethoxyphenyl)-1,2,4-triazin-5-yl]butan-1-one
(6c). Yield 1.40 g (52%), yellow oil. IR spectrum, ν, cm–1:
2962, 1707, 1597, 1510, 1454, 1382, 1246, 1016, 752.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.02 (3H, t,
J = 7.6, CH3); 1.38 (3H, t, J = 6.8, CH3); 1.77–1.84 (2H, m,
CH2); 3.23 (2H, t, J = 7.2, CH2); 4.16 (2H, q, J = 6.8, CH2);
7.08–7.15 (2H, m, H Ar); 7.49–7.54 (1H, m, H Ar); 7.91
Transformation in KOH–DMSO. Appropriate adduct
4b,c (0.1 mmol) was added in one portion to a stirred
suspension of powdered KOH (80 mg, 1.4 mmol) in dry
DMSO (1 ml) at room temperature. The mixture was
stirred at room temperature for 1 h, then poured into ice
water and neutralized with AcOH to pH 7.0. The preci-
pitated product was filtered off and washed with H2O. The
crude product was investigated by NMR.
1
2
(1H, dd, J = 7.6, J = 2.0, H Ar); 9.62 (1H, s, H triazine).
13C NMR spectrum (CDCl3), δ, ppm: 13.7; 14.7; 16.9; 39.6;
64.4; 113.2; 120.7; 124.8; 132.0; 132.5; 142.4; 147.7; 157.8;
165.8; 201.8. Found, m/z: 272.1394 [M+H]+. C15H18N3O2.
Calculated, m/z: 272.1399. Found, %: C 66.45; H 6.44;
N 15.30. C15H17N3O2. Calculated, %: C 66.40; H 6.32;
N 15.49.
5-(1-Nitroethyl)-3-phenyl-1,2,4-triazine (5a). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 2.07 (3H, d, J = 6.8,
CH3); 5.79 (1H, q, J = 6.8, CH); 8.08 (2H, s, H Ph); 8.56
(2H, d, J = 7.2, H Ph); 8.62 (1H, d, J = 6.4, H Ph); 9.32
(1H, s, H triazine).
3-(Naphthalen-1-yl)-5-(1-nitroethyl)-1,2,4-triazine (5b).
1-[3-(4-Ethoxyphenyl)-1,2,4-triazin-5-yl]ethan-1-one (6d).
Yield 1.36 g (56%), yellow oil. IR spectrum, ν, cm–1: 2981,
2941, 1707, 1604, 1516, 1361, 1251, 1174, 1116, 1039,
850, 796. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.47
(3H, t, J = 6.8, CH3); 2.82 (3H, s, CH3); 4.15 (2H, q,
J = 6.8, CH2); 7.05 (2H, d, J = 8.8, H Ar); 8.54 (2H, d,
J = 8.8, H Ar); 9.53 (1H, s, H triazine). 13C NMR spectrum
(CDCl3), δ, ppm: 14.7; 25.3; 63.7; 114.9; 126.2; 130.2;
142.2; 148.0; 162.5; 163.9; 199.6. Found, %: C 63.98;
H 5.60; N 17.10. C13H13N3O2. Calculated, %: C 64.19;
H 5.39; N 17.27.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.09 (3H, d,
1
J = 6.8, CH3); 5.85 (1H, q, J = 6.8, CH); 7.66–7.49 (3H,
m, H Ar); 7.96 (1H, d, J = 7.6, H Ar); 8.07 (1H, d, J = 7.6,
H Ar); 8.25 (1H, d, J = 7.2, H Ar); 8.68 (1H, d, J = 8.0,
H Ar); 9.42 (1H, s, H triazine).
Synthesis of ketones 6a–f (General method). The cor-
responding oxime 2a–f (10 mmol) was dissolved in
1,4-dioxane (40 ml) and treated with a solution of Na2S2O4
(4.6 g, 26.4 mmol) in H2O (40 ml). The resulting mixture
was stirred at room temperature for 24 h. 1,4-Dioxane was
removed under reduced pressure, and the residue was
treated with 10% HCl (pH ~3) and bubbled by air for
10 min. Then the mixture was made neutral (pH ~7.0) by
addition of solid NaHCO3 and extracted with CH2Cl2.
Evaporation of the organic solvent gave a crude product,
which was purified by chromatography on silica gel, eluent
CH2Cl2–hexane, 1:2.
1-(3-Phenyl-1,2,4-triazin-5-yl)ethan-1-one (6e). Yield
1.27 g (64%), yellow solid, mp 133–134°C. IR spectrum,
1
ν, cm–1: 3068, 1707, 1531, 1350, 1122, 761, 698. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 2.85 (3H, s, CH3); 7.55–
7.61 (3H, m, H Ar); 8.60–8.62 (2H, m, H Ar); 9.63 (1H, s,
H triazine). 13C NMR spectrum (CDCl3), δ, ppm: 25.3;
128.4; 129.0; 132.3; 133.9; 143.0; 148.1; 164.1; 199.4.
976

Chemistry of Heterocyclic Compounds 2019, 55(10), 968–977
Tetrahedron Lett. 2016, 57, 2665. (d) Chupakhin, O. N.;
Found, %: C 66.22; H 4.68; N 20.92. C11H9N3O. Calcu-
lated, %: C 66.32; H 4.55; N 21.09.
Charushin, V. N. Pure Appl. Chem. 2017, 89, 1195.
2. Rykowski, A.; Mąkosza, M. Tetrahedron Lett. 1984, 25,
4795.
1-[3-(Naphthalen-1-yl)-1,2,4-triazin-5-yl]ethan-1-one (6f).
Yield 1.32 g (53%), yellow solid, mp 192–195°C. IR spectrum,
ν, cm–1: 3049, 2922, 1708, 1525, 1508, 1367, 1346, 783.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.84 (3H, s,
CH3); 7.56–7.63 (2H, m, H Ar); 7.67 (1H, t, J = 8.0, H Ar);
7.98 (1H, d, J = 7.2, H Ar); 8.09 (1H, d, J = 8.4, H Ar);
8.29 (1H, d, J = 7.2, H Ar); 8.73 (1H, d, J = 8.0, H Ar);
9.74 (1H, s, H triazine). 13C NMR spectrum (CDCl3),
δ, ppm: 25.5; 125.1; 125.2; 126.4; 127.6; 128.8; 130.8;
131.8; 132.3; 134.1; 142.6; 147.8; 166.8; 199.3. Found, %:
C 72.39; H 4.53; N 16.64. C15H11N3O. Calculated, %:
C 72.28; H 4.45; N 16.86.
3. Rykowski, A.; Lipińska, T. Synth. Commun. 1996, 26, 4409.
4. Rykowski, A.; Lipińska, T.; Guzik, E.; Adamiuk, M.;
Olender, E. Polish J. Chem. 1997, 71, 69.
5. Rykowski, A.; Olender, E.; Branowska, D.; van der Plas, H.
C. Org. Prep. Proced. Int. 2001, 33, 501.
6. Rykowski, A.; Branowska, D.; Mąkosza, M.; van Ly, P. J.
Heterocycl. Chem. 1996, 33, 1567.
7. Rykowski, A.; Mojzych, M.; Karczmarzyk, Z. Heterocycles
2000, 53, 2175.
8. Lipińska, T. M. Tetrahedron 2006, 62, 5736.
9. Guzik E. Ph.D. Dissertation, Medical University, Poznan,
1993.
X-ray analysis of compound 2a was performed on a Kuma
KM4 diffractometer; crystal size 0.50 × 0.15 × 0.10 mm,
MoKα (λ 0.71073 Å) radiation, ω-2θ scans, 293(2) K,
10. Mojzych, M.; Bielawska, A.; Bielawski, K.; Ceruso, M.;
Supuran, C. T. Bioorg. Med. Chem. 2014, 22, 2643.
11. Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Synlett 2002, 447.
absorption correction: refdelf,22
Tmin/Tmax = 0.416/0.677. The
structure was solved by direct methods using SHELXS9722
program and refined by full-matrix least-squares method
with SHELXL-2014/7 program.23 The O-bound H atom
was located by difference Fourier synthesis and refined
freely. The remaining H atoms were positioned geo-
metrically and treated as riding on their parent C atoms
with C–H distances of 0.97 Å (CH2), 0.96 Å (CH3), and
0.93 Å (Ar). All H atoms were refined with isotropic
displacement parameters taken as 1.5 times those of the
respective parent atoms. All calculations were performed
using the WINGX version 2014.1 package.24 Crystal data
of compound 2a (C13H14N4O2, M 258.28): monoclinic;
space group P21/c; a 10.281(2), b 16.098(3), c 7.914(2) Å;
β 100.38(3)°; V 1288.3(5) Å3; Z 4; dcalc 1.332 g·cm–3;
F(000) 544; μ(KoKα) 0.094 mm–1; 4632 measured reflec-
tions (θ range 2.01–30.08°), 3783 unique reflections, final
R 0.059, wR 0.182, S 0.824 for 1060 reflections with I > 2σ(I).
Crystallographic data of compound 2a was deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
1877568).
12. Charushin, V. N.; Alexeev, S. G.; Chupakhin, O. N.;
van der Plas, H. C. Adv. Heterocycl. Chem. 1989, 46, 73.
13. Rykowski, A.; Guzik, E.; Mąkosza, M.; Holzer, W. J.
Heterocycl. Chem. 1993, 30, 413.
14. Rykowski, A.; Lipińska, T. Polish J. Chem. 1997, 71, 83.
15. Mojzych, M.; Rykowski, A. Heterocycles 2004, 63, 1829.
16. Pojer, P. M. Aust. J. Chem. 1979, 32, 201.
17. Mojzych, M.; Karczmarzyk, Z.; Fruziński, A. Anal. Sci.:
X-ray Struct. Anal. Online 2007, 23, x205.
18. Mojzych, M.; Karczmarzyk, Z.; Fruziński, A. Acta
Crystallogr., Sect. E: Struct. Rep. Online 2008, E64, o653.
19. Poudler, W. W.; Chen, T.–K. J. Heterocycl. Chem. 1970, 7, 767.
20. Saravin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4,
4309.
21. Mojzych, M.; Karczmarzyk, Z.; Wysocki, W.; Ceruso, M.;
Supuran, C. T.; Kryštof, V.; Urbanczyk-Lipkowska, Z.;
Kalicki, P. Bioorg. Med. Chem. 2015, 23, 1421.
22. Parkin, S.; Moezzi, B.; Hope, H. J. Appl. Crystallogr. 1995,
28, 53.
23. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, A64, 112.
24. Farrugia, L. J. Appl. Crystallogr. 2012, 45, 849.
25. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;
Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; . Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision E.01; Gaussian, Inc.: Wallingford,
2004.
Theoretical calculations at the DFT/B3LYP level with
6-311++G(d,p) basis set implemented in GAUSSIAN 0325
were carried out to investigate the conformational prefe-
rences of compounds 2a, 3a–c and hypothetical structures
of compounds 3d–f. All structures were fully optimized
without any symmetry constraint and the initial geometries
were built from crystallographic data of compound 2a.
Supplementary information file containing crystallo-
graphic data of compound 2a and DFT calculations of
compounds 2a, 3a,d–f is available at the journal website at
http://link.springer.com/journal/10593.
References
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Nucleophilic Displacement of Hydrogen; Charushin, V. N.;
Chupakhin, O. N., Eds.; Springer: Heidelberg, New York,
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977