Effect of substituent in pyridine-2-carbaldehydes on their heterocyclization to 1,2,4-triazines and 1,2,4-triazine 4-oxides

Article abstract of DOI:10.1134/S1070428017070016

A series of substituted pyridine-2-carbaldehydes were brought into heterocyclization with isonitrosoacetophenone hydrazones, followed by aromatization by the action of oxidants or by dehydration in boiling acetic acid. As a result, substituted 3-(pyridin-2-yl)-1,2,4-triazines or 3-(pyridin-2-yl)-1,2,4-triazine 4-oxides were formed. 6-Formylpyridine-2-carbonitrile failed to undergo heterocyclization, 6-methylpyridine-2-carbaldehyde and methyl 6-formylpyridine-3-carboxylate can be converted to both 1,2,4-triazine and 1,2,4-triazine 4-oxide derivative, and only 1,2,4-triazine 4 oxides were obtained from 6-bromopyridine-2-carbaldehyde and 6-formyl-3-phenylpyridine-2-carbonitrile. Convenient procedures were proposed for the synthesis of some initial pyridinecarbaldehydes.

Full text of DOI:10.1134/S1070428017070016

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 7, pp. 963–970. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © A.P. Krinochkin, D.S. Kopchuk, N.V. Chepchugov, I.S. Kovalev, G.V. Zyryanov, V.L. Rusinov, O.N. Chupakhin, 2017, published in
Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 7, pp. 951–958.
Effect of Substituent in Pyridine-2-carbaldehydes on Their
Heterocyclization to 1,2,4-Triazines and 1,2,4-Triazine 4-Oxides
A. P. Krinochkina, D. S. Kopchuka, b, N. V. Chepchugova, I. S. Kovaleva, G. V. Zyryanova, b,*
V. L. Rusinova, b, and O. N. Chupakhina, b
a Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
*e-mail: gvzyryanov@gmail.com
b Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620990 Russia
Received October 26, 2016
Abstract—A series of substituted pyridine-2-carbaldehydes were brought into heterocyclization with iso-
nitrosoacetophenone hydrazones, followed by aromatization by the action of oxidants or by dehydration in
boiling acetic acid. As a result, substituted 3-(pyridin-2-yl)-1,2,4-triazines or 3-(pyridin-2-yl)-1,2,4-triazine
4-oxides were formed. 6-Formylpyridine-2-carbonitrile failed to undergo heterocyclization, 6-methylpyridine-
2-carbaldehyde and methyl 6-formylpyridine-3-carboxylate can be converted to both 1,2,4-triazine and
1,2,4-triazine 4-oxide derivative, and only 1,2,4-triazine 4 oxides were obtained from 6-bromopyridine-
2-carbaldehyde and 6-formyl-3-phenylpyridine-2-carbonitrile. Convenient procedures were proposed for the
synthesis of some initial pyridinecarbaldehydes.
DOI: 10.1134/S1070428017070016
3-(Pyridin-2-yl)-1,2,4-triazines and their fused
derivatives constitute an important class of hetero-
cyclic compounds which offer a wide potential for use
in practice for various purposes. In particular, 3-(pyri-
din-2-yl)-1,2,4-triazines are intermediate products in
the synthesis of bipyridines [1–3] (including cyclo-
alkene-fused derivatives [4–6]), 1-(pyridin-2-yl)iso-
quinolines [7], (pyridin-2-yl)azatriphenylenes [8], and
10-(1,2,3-triazol-1-yl)pyrido[1,2-a]indoles [9–11] via
recently discovered rearrangement with aryne inter-
mediates. 1,2,4-Triazines can be successfully function-
alized by nucleophilic substitution of hydrogen (SNH),
and successive SNH and aza-Diels–Alder reactions give
rise to 2,2′-bipyridines with a variety of substituents
(e.g., carborane and acetylene residues, etc.), which are
difficult to obtain by other methods [12–14]. 3-(Pyri-
din-2-yl)-1,2,4-triazines can be used as reagents for
spectrophotometric determination of metal cations
[15], gene expression promoters [16], and selective
extractants for lanthanides and actinides [17].
mediate product with formation of 1,2,4-triazine
4-oxides [18] and its dehydration in boiling acetic acid
to produce just 3-(pyridin-2-yl)-1,2,4-triazines [1].
Following this approach, heterocyclizations of pyri-
dine-2-carbaldehyde and its 6-methyl [19], 6-hydroxy-
methyl [20], and 5- [1] and 6-methoxycarbonyl deriv-
atives [19, 21] have been reported, though the potential
of functionalization of pyridine-2-carbaldehyde is
much wider.
In this work we studied the behavior of 3-methyl-,
6-methyl-, and 6-bromopyridine-2-carbaldehydes,
methyl 6-formylpyridine-3-carboxylate, 6-formylpyri-
dine-2-carbonitrile, and 6-formyl-3-phenylpyridine-2-
carbonitrile in analogous heterocyclizations with the
goal of obtaining 3-(pyridin-2-yl)-1,2,4-triazines or
3-(pyridin-2-yl)-1,2,4-triazine 4-oxides. 6-Bromopyri-
dine-2-carbaldehyde (1a) is a commercially available
reagent, while the other aldehydes were prepared from
readily accessible initial compounds according to
procedures optimized by us.
3-(Pyridin-2-yl)-1,2,4-triazines are generally syn-
thesized by condensation of isonitrosoacetophenone
hydrazones with pyridine-2-carbaldehydes. This reac-
tion can involve both oxidative aromatization of inter-
3- and 6-Methylpyridine-2-carbaldehydes 1b and
1c were previously synthesized from 2,3-dimethyl-
pyridine [22] and 2,6-dimethylpyridine [23], respec-
tively (Scheme 1). N-Oxides 2a and 2b were treated
963

KRINOCHKIN et al.
964
Scheme 1.
H2SeO3 (3a) or MnO2 (3b)
Me
Me
Me
OH
N
Me
N
N
CHO
O
2a, 2b
3a, 3b
1b (75%), 1c (80%)
1b, 2a, 3a, 6-Me; 1c, 2b, 3b, 3-Me.
Scheme 2.
NBS, (BzO)2
NaOAc
Br
OAc
N
NC
N
Me
NC
N
NC
4
5
6
K2CO3
MnO2
OH
NC
N
NC
N
CHO
7, 75%
1d
with acetic anhydride, and subsequent hydrolysis of
the resulting (pyridin-2-yl)methyl acetates gave 3- and
6-methylpyridin-2-ylmethanols 3a and 3b which were
oxidized to aldehydes 1b and 1c, respectively.
6-Methylpyridine-2-carbaldehyde (1b) was also pre-
pared according to a simplified procedure (compared
to [23]) with the use of selenous acid. It was found that
the reaction with selenium dioxide is accompanied by
partial oxidation of the α-methyl group. 3-Methyl-
pyridine-2-carbaldehyde (1c) cannot be obtained by
oxidation of 3b with selenous acid or selenium diox-
ide; therefore, aldehyde 1c was synthesized according
to simplified procedure [24] using activated manga-
nese dioxide as oxidant.
forded aldehyde 1d. 6-Formyl-3-phenylpyridine-2-car-
bonitrile (1e) was synthesized as shown in Scheme 3,
starting from 3-(furan-2-yl)-6-phenyl-1,2,4-triazine
4-oxide (8) [26]. Nucleophilic substitution of hydrogen
in the triazine ring of 8 by cyano group [27], trans-
formation of the 1,2,4-triazine ring to pyridine by the
aza-Diels–Alder reaction [18], oxidation of the furyl
substituent to carboxy group, and subsequent esteri-
fication, reduction of the ester group to hydroxy-
methyl, and oxidation afforded aldehyde 1e.
Methyl 6-formylpyridine-3-carboxylate 1f was
obtained according to the procedure described previ-
ously [1] from dimethyl pyridine-2,5-dicarboxylate
(14) via selective reduction of the ester group in the
2-position and subsequent oxidation of alcohol 15 with
selenium dioxide (Scheme 4).
6-Formylpyridine-2-carbonitrile (1d) was prepared
from 6-methylpyridine-2-carbonitrile (4) [25]
(Scheme 2). Radical bromination of 4 with N-bromo-
succinimide (according to optimized procedure [25]),
followed by nucleophilic substitution of bromine by
acetoxy group, alkaline hydrolysis, and oxidation af-
Aldehydes 1a–1f were brought into hetero-
cyclization with isonitrosoacetophenone hydrazones
(Scheme 5; for R1, R2, R3, see table). As we showed
previously, aldehydes 1b and 1f can be converted to
Scheme 3.
Ph
N
Ph
N
Ph
Me2C(OH)CN
Et3N
N
N
N
O
NC
N
NC
N
O
O
O
8
9
10
MnO2
NaOH
KMnO4
MeOH
SOCl2
Ph
Ph
Ph
Ph
NaBH4
OH
NC
N
COOH
NC
N
COOMe
NC
N
NC
N
CHO
11
12
13
1e
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 7 2017

EFFECT OF SUBSTITUENT IN PYRIDINE-2-CARBALDEHYDE
965
Scheme 4.
MeOC(O)
MeOC(O)
MeOC(O)
NaBH4
SeO2
OH
N
COOMe
N
N
CHO
14
15, 57%
1f, 75%
Scheme 5.
R2
R1
R2
R1
Ar
N
NH2
N
R3
N
N
+
R3
N
CHO
N
N
HO
Ar
OH
1a–1f
17a–17g
4
4
R2
R1
N
R2
R3
R1
5
5
O
3
2
3
2
6
6
Pb3O4 (a–f) or MnO2 (g)
Me2C(OH)CN, NEt3
N
N
N
CN
5′
R3
N
N
N
19a–19f
N
Ar
Ar
16a–16g
R2
R3
R1
AcOH
N
N
N
N
Ar
18a–18c
the corresponding 1,2,4-triazines in up to 62 [19] and
55% yield [1], respectively. In this work we found that
the same aldehydes can also be used to synthesize
triazine 4-oxides 16. 1,2,4-Triazine 4-oxides 16b and
16c were readily obtained from 6-methylpyridine-2-
carbaldehyde (1b) according to the procedure de-
scribed in [18] by oxidative aromatization of interme-
diates 17b and 17c with red lead oxide (Pb3O4). The
oxidation under the same conditions of intermediate
17g derived from methyl 6-formylpyridine-3-carbox-
ylate (1f) gave no 1,2,4-triazine 4-oxide 16g, so that
the procedure needed to be modified. By using ac-
tivated manganese dioxide as oxidant we succeeded in
obtaining 1,2,4-triazine 4-oxide 16g in 52% yield.
The reactions with the other pyridine-2-carbalde-
hydes revealed some essential limitations. Neither
1,2,4-triazine 18 nor 4-oxide 16 was obtained from
compound 1d regardless of the conditions, and a com-
Heterocyclization of pyridine-2-carbaldehydes 1a–1f
Initial aldehyde (1),
Yield, %
R1
R2
R3
Ar
intermediate (17)
18
16
19
1a, 17a
1b, 17b
1b, 17c
1c, 17d
1d, –
H
H
Br
Ph
–
16a, 57
16b, 40
16c, 35
16d, 50
–
19a, 83
19b, 70
19c, 76
19d, 50
–
H
H
Me
Me
H
Ph
18a, 50 [18]
H
H
4-MeOC6H4
18b, 62 [18]
Me
H
H
Ph
–
H
CN
CN
CN
H
Ph
–
1e, 17e
1e, 17f
1f, 17g
H
Ph
Ph
Ph
–
–
16e, 64
16f, 60
16g, 52
H
4-MeC6H4
Ph
19e, 73
19f, 65
H
COOMe
18c, 48 [1]
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 7 2017

KRINOCHKIN et al.
966
plex mixture of unidentified products was formed,
presumably due to side reactions involving the cyano
group. Introduction of an additional phenyl substituent
(compound 1e) is likely to induce electron density
redistribution in the pyridine ring and/or shielding of
the cyano group, so that the latter becomes consider-
ably less reactive. As a result, we isolated 1,2,4-tri-
azine 4-oxides 16e and 16f, but the corresponding
intermediates 17e and 17f did not undergo dehydration
to 1,2,4-triazines 18. Likewise, 3-methyl- and
6-bromopyridine-2-carbaldehydes 1a and 1c were
converted to only 1,2,4-triazine 4-oxides 16a and 16d,
whereas no 1,2,4-triazines 18 were obtained therefrom.
Initial isonitrosoacetophenone hydrazones [28],
6-methylpyridine-2-carbonitrile (4) [25], 3-(furan-2-
yl)-6-phenyl-1,2,4-triazine 4-oxide (8) [26], methyl
6-formylpyridine-3-carboxylate (1f) [1], and 6-(hy-
droxymethyl)pyridine-2-carbonitrile (7) [29] were syn-
thesized according to known methods.
6-Methylpyridine-2-carbaldehyde (1b). A solu-
tion of 10.47 g (0.081 mol) of selenous acid in 30 mL
of water was added with stirring to a solution of 20 g
(0.162 mol) of (6-methylpyridin-2-yl)methanol (3a) in
150 mL of 1,4-dioxane, and the mixture was stirred for
6 h at 100°C. Metallic selenium was filtered off, the
solvent was distilled off from the filtrate under reduced
pressure, and the residue was treated with hot hexane
(3×150 mL). The solvent was distilled off from the
combined extracts under reduced pressure, and the
product was not purified additionally. Yield 14.76 g
In the final stage of our study, we examined the
possibility of further functionalization of triazine
4-oxides 16 by nucleophilic substitution of hydrogen
with acetone cyanohydrin and triethylamine [27]. In all
cases, the corresponding 1,2,4-triazine-5-carbonitriles
19 were formed, but the reactions with 6-bromo- and
3-methyl-1,2,4-triazine 4-oxides 16a and 16d required
more severe conditions to achieve complete conversion
(the reactions were carried out in boiling 1,2-dichloro-
ethane under reflux rather than at 50°C, and the reac-
tion time was longer).
1
(0.121 mol, 75%), mp 31‒33°C. H NMR spectrum
(DMSO-d6), δ, ppm: 2.61 s (3H, Me), 7.49 d (1H, 5-H,
J = 7.5 Hz), 7.71 d (1H, 3-H, J = 7.5 Hz), 7.86 d.d
(1H, 4-H, J = 7.5, 7.5 Hz), 9.93 s (1H, CHO). Mass
spectrum: m/z 122.06 (Irel 100%) [M + H]+. Calculated:
M 122.06.
Radical bromination of 6-methylpyridine-2-car-
bonitrile (4). Compound 4, 1 g (8.46 mmol), was
dissolved in 50 mL of anhydrous carbon tetrachloride,
1.51 g (8.46 mmol) of N-bromosuccinimide and
a catalytic amount of benzoyl peroxide were added,
and the mixture was refluxed for 10 h under irradiation
with bright light. The precipitate was filtered off, the
filtrate was evaporated under reduced pressure, and
the residue was subjected to column chromatography
using methylene chloride–ethyl acetate (100 :1) as
eluent to isolate 6-(bromomethyl)pyridine-2-carbo-
nitrile (5) and minor 6-(dibromomethyl)pyridine-2-
carbonitrile.
In summary, substituted pyridine-2-carbaldehydes
react with isonitrosoacetophenone hydrazones to give
the corresponding 1,2,4-triazine 4-oxides or 1,2,4-tri-
azines as a result of oxidative aromatization or thermal
dehydration (in boiling acetic acid). 1,2,4-Triazine
4-oxides were formed in most cases, regardless of the
substituent in the pyridine ring (except for 6-formyl-
pyridine-2-carbonitrile). 3-(Pyridin-2-yl)-1,2,4-tri-
azines were obtained by dehydration in boiling acetic
acid only from 6-methylpyridine-2-carbaldehyde and
methyl 6-formylpyridine-3-carboxylate. 3-Methyl- and
6-bromopyridine-2-carbaldehydes and 3-phenyl-6-
formylpyridine-2-carbonitrile were not converted to
corresponding 1,2,4-triazines.
6-(Bromomethyl)pyridine-2-carbonitrile (5).
Yield 590 mg (2.99 mmol, 35%), mp 79‒81°C,
Rf 0.45. 1H NMR spectrum (DMSO-d6), δ, ppm: 4.66 s
(2H, CH2Br), 7.82‒7.89 m (2H, 3-H, 5-H), 8.03 d.d
(1H, 4-H, J = 7.8, 7.8 Hz). Mass spectrum: m/z 196.97
(Irel 100%) [M + H]+. Calculated: M 196.97.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
6-(Dibromomethyl)pyridine-2-carbonitrile. Yield
150 mg (0.54 mmol, 6%), mp 114‒116°C, Rf 0.75.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.22 s (1H,
CHBr2), 7.95 m (1H), 8.10‒8.17 m (2H). Mass spec-
trum: m/z 274.88 (Irel 100%) [M + H]+. Calculated:
M 274.88.
Avance-400 spectrometer at 400 MHz using tetra-
methylsilane as internal standard. The melting points
were measured on a Boetius melting point apparatus.
The mass spectra (electrospray ionization) were ob-
tained on a Bruker Daltonics MicrOTOF-Q II instru-
ment (Bremen, Germany). The elemental compositions
were determined with a Perkin Elmer 2400 Series II
CHN analyzer.
(6-Cyanopyridin-2-yl)methyl acetate (6). A mix-
ture of 820 mg (4.16 mmol) of compound 5 and 3.41 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 7 2017

EFFECT OF SUBSTITUENT IN PYRIDINE-2-CARBALDEHYDE
967
(41.6 mmol) of sodium acetate was dispersed in 40 mL
of anhydrous DMF, and the mixture was stirred for
10 h at 130°C. The solvent was distilled off under
reduced pressure, the residue was treated with 10 mL
of water and extracted with methylene chloride (3×
20 mL), the combined extracts were evaporated, and
the residue was used in the next stage without addi-
tional purification. Yield 670 mg (3.79 mmol, 91%),
perature while gradually adding 3.21 g (20.3 mmol) of
potassium permanganate. It was then refluxed for
10 min, diluted with 20 mL of water, and heated until
it became colorless. The precipitate of manganese
dioxide was filtered off and washed with water, the
filtrate was evaporated under reduced pressure, 30 mL
of water was added to the residue, and the mixture was
heated to the boiling point. The undissolved material
was filtered off, the filtrate was cooled to room tem-
perature, 5 N aqueous HCl was added to pH 2, and the
precipitate was filtered off, washed with water, dried,
and used in the next step without additional purifica-
tion. Yield 600 mg (2.68 mmol, 66%), mp 188‒190°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.52‒7.63 m
(3H, Ph), 7.64‒7.70 m (2H, Ph), 8.22 d (1H, Py, J =
7.7 Hz), 8.34 d (1H, Py, J = 7.7 Hz), 13.54 br.s (1H,
COOH). Mass spectrum: m/z 223.05 (Irel 100%)
[M – H]‒. Calculated: M 223.05.
1
light oily material. H NMR spectrum (DMSO-d6), δ,
ppm: 2.14 s (3H, Me), 5.17 s (2H, CH2), 7.70 d and
7.86 d (1H each, 3-H, 5-H, J = 7.7 Hz), 8.03 d.d (1H,
4-H, J = 7.7, 7.7 Hz). Mass spectrum: m/z 177.07
(Irel 100%) [M + H]+. Calculated: M 177.07.
3-(Furan-2-yl)-6-phenyl-1,2,4-triazine-5-car-
bonitrile (9). 1,2,4-Triazine 4-oxide 8, 5.5 g
(22.99 mmol), was dispersed in 50 mL of 1,2-dichloro-
ethane, 3.19 mL (34.48 mmol) of acetone cyanohydrin
and 1.6 mL (11.49 mmol) of triethylamine were added,
and the mixture was heated for 30 min at 50°C with
stirring. The solvent was distilled off under reduced
pressure, and the residue was purified by flash chroma-
tography using chloroform as eluent. Yield 3.3 g
Methyl 6-cyano-5-phenylpyridine-2-carboxylate
(12). Thionyl chloride, 1 mL, was added to a suspen-
sion of 0.96 g (4.28 mmol) of acid 11 in 25 mL of
methanol, and the mixture was refluxed for 20 h. The
solvent was distilled off under reduced pressure, and
the residue was used in the next step without additional
purification. Yield 1.02 g (4.28 mmol, 100%), mp 118‒
1
(13.29 mmol, 58%), mp 128‒130°C. H NMR spec-
trum (DMSO-d6), δ, ppm: 6.79 d.d (1H, Fu, J = 3.6,
2.0 Hz), 7.62‒7.68 m (4H, Ph, Fu), 8.04 m (3H, Ph,
Fu). Mass spectrum: m/z 249.08 (Irel 100%) [M + H]+.
Calculated: M 249.08.
1
120°C. H NMR spectrum (DMSO-d6), δ, ppm: 3.98 s
(3H, OMe), 7.55‒7.61 m (3H, Ph), 7.65‒7.70 m (2H,
Ph), 8.26 d (1H, Py, J = 8.0 Hz), 8.37 d (1H, Py,
J = 8.0 Hz). Mass spectrum: m/z 239.08 (Irel 100%)
[M + H]+. Calculated: M 239.08.
6-(Furan-2-yl)-3-phenylpyridine-2-carbonitrile
(10). 2,5-Norbornadiene, 4.92 mL (48.33 mmol), was
added to a suspension of 4 g (16.11 mmol) of com-
pound 9 in 45 mL of o-xylene, and the mixture was
refluxed for 10 h. An additional 2.46 mL (24.17 mmol)
of 2,5-norbornadiene was then added, and the mixture
was refluxed for 8 h more. The solvent was distilled
off under reduced pressure, and the residue was puri-
fied by flash chromatography using chloroform as
eluent. An analytical sample was obtained by recrys-
tallization from acetonitrile. Yield 2.78 g (11.28 mmol,
70%), mp 128‒130°C. 1H NMR spectrum (DMSO-d6),
δ, ppm: 6.65 d.d (1H, Fu, J = 3.6, 2.0 Hz), 7.25 d (1H,
Fu, J = 3.6 Hz), 7.50‒7.59 m (3H, Ph), 7.62 m (2H,
Ph), 7.79 d (1H, Fu, J = 2.0 Hz), 8.04 d (1H, Py, J =
8.0 Hz), 8.08 d (1H, Py, J = 8.0 Hz). Mass spectrum:
m/z 247.09 (Irel 100%) [M + H]+. Found, %: C 77.93;
H 4.02; N 11.22. C16H10N2O. Calculated, %: C 78.03;
H 4.09; N 11.38. M 247.09.
6-(Hydroxymethyl)-3-phenylpyridine-2-carbo-
nitrile (13). Ester 12, 700 mg (2.94 mmol), was
dispersed in 20 mL of ethanol, 0.56 g (14.7 mmol) of
sodium tetrahydridoborate was added, and the mixture
was stirred for 1 h at 40°C. An additional portion of
NaBH4 (0.28 g, 7.35 mmol) was added, and the mix-
ture was stirred at 40°C for 1 h more. The mixture was
diluted with 20 mL of water and extracted with
methylene chloride (3×25 mL). The extract was dried
over anhydrous sodium sulfate and evaporated under
reduced pressure, and the residue was used in the next
step without additional purification. Yield 400 mg
(1.91 mmol, 65%), mp 110‒112°C. 1H NMR spectrum
(DMSO-d6), δ, ppm: 4.64 d (2H, CH2OH, J = 5.5 Hz),
5.50 t (1H, CH2OH, J = 5.5 Hz), 7.47‒7.62 m (5H,
Ph), 7.85 d (1H, Py, J = 8.0 Hz), 8.01 d (1H, Py,
J = 8.0 Hz). Mass spectrum: m/z 211.09 (Irel 100%)
[M + H]+. Calculated: M 211.09.
6-Cyano-5-phenylpyridine-2-carboxylic acid
(11). A solution of 0.81 g (20.3 mmol) of sodium
hydroxide in 5 mL of water was added to a suspension
of 1 g (4.06 mmol) of compound 10 in 17 mL of
pyridine. The mixture was stirred for 2 h at room tem-
Aldehydes 1c–1e (general procedure). Hydroxy-
methylpyridine 3b, 7, or 13, 1.9 mmol, was dissolved
in 25 mL of 1,2-dichloroethane, 1.65 g (19 mmol) of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 7 2017

KRINOCHKIN et al.
968
activated manganese dioxide was added, and the mix-
ture was stirred for 6 h at 50°C. The precipitate was
filtered off, the filtrate was evaporated under reduced
pressure, and the residue was used in the next step
without additional purification.
3-(6-Methylpyridin-2-yl)-6-phenyl-1,2,4-triazine
4-oxide (16b). Yield 106 mg (0.4 mmol, 40%),
1
mp 206‒208°C. H NMR spectrum (DMSO-d6), δ,
ppm: 2.61 s (3H, Me), 7.41 d (1H, 5-H, J = 7.8 Hz),
7.54–7.62 m (3H, Ph), 7.79 d (1H, 3-H, J = 7.8 Hz),
7.86 d.d (1H, 4-H, J = 7.8, 7.8 Hz), 8.22 m (2H, Ph),
9.32 s (1H, 5′-H). Mass spectrum: m/z 265.11
(Irel 100%) [M + H]+. Found, %: C 68.22; H 4.51;
N 21.06. C15H12N4O. Calculated, %: C 68.17; H 4.58;
N 21.20. M 265.11.
6-(4-Methoxyphenyl)-3-(6-methylpyridin-2-yl)-
1,2,4-triazine 4-oxide (16c). Yield 103 mg
(0.35 mmol, 35%), mp 206‒208°C. 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.61 s (3H, Me), 3.88 s (3H,
OMe), 7.09 m (2H, Harom), 7.41 d (1H, 5-H, J =
7.8 Hz), 7.81 m (2H, 3-H, 4-H), 8.19 m (2H, Harom),
9.24 s (1H, 5′-H). Mass spectrum: m/z 295.12
(Irel 100%) [M + H]+. Found, %: C 65.12; H 4.82;
N 19.08. C16H14N4O2. Calculated, %: C 65.30; H 4.79;
N 19.04. M 295.12.
3-Methylpyridine-2-carbaldehyde (1c). Yield
185 mg (1.52 mmol, 80%), light oily material.
1H NMR spectrum (CDCl3), δ, ppm: 2.66 s (3H, Me),
7.39 d.d (1H, 5-H, J = 7.8, 4.6 Hz), 7.62 d (1H, 4-H,
J = 7.8 Hz), 8.66 d (1H, 6-H, J = 4.6 Hz), 10.20 s
(1H, CHO). Mass spectrum, m/z 122.06 (Irel 100%)
[M + H]+. Calculated: M 122.06.
6-Formylpyridine-2-carbonitrile (1d). Yield
1
160 mg (1.235 mmol, 65%), mp 80‒82°C. H NMR
spectrum (CDCl3), δ, ppm: 8.06 d.d (1H, 4-H, J = 7.7,
7.7 Hz), 8.16 d.d and 8.36 d.d (1H each, 3-H, 5-H,
J = 7.7, 1.0 Hz), 10.20 s (1H, CHO). Mass spectrum:
m/z 133.04 (Irel 100%) [M + H]+. Calculated: M 133.04.
6-Formyl-3-phenylpyridine-2-carbonitrile (1e).
Yield 240 mg (1.14 mmol, 60%), mp 146‒148°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.56‒7.63 m
(3H, Ph), 7.70 m (2H, Ph), 8.24 d (1H, Py, J = 8.2 Hz),
8.32 d (1H, Py, J = 8.0 Hz), 10.03 s (1H, CHO). Mass
spectrum: m/z 209.07 (Irel 100%) [M + H]+. Calculated:
M 209.07.
3-(3-Methylpyridin-2-yl)-6-phenyl-1,2,4-triazine
4-oxide (16d). Yield 132 mg (0.5 mmol, 50%),
1
mp 194‒196°C. H NMR spectrum (DMSO-d6), δ,
ppm: 2.25 s (3H, Me), 7.49 d.d (1H, 5-H, J = 7.8,
4.8 Hz), 7.56‒7.62 m (3H, Ph), 7.80 d.d (1H, 4-H, J =
7.8, 1.0 Hz), 8.21‒8.29 m (2H, Ph), 8.55 d.d (1H, 6-H,
J = 4.8, 1.0 Hz), 9.39 s (1H, 5′-H). Mass spectrum:
m/z 265.11 (Irel 100%) [M + H]+. Found, %: C 68.11;
H 4.45; N 21.02. C15H12N4O. Calculated, %: C 68.17;
H 4.58; N 21.20. M 265.11.
1,2,4-Triazine-4-oxides 16 (general procedure).
Aldehyde 1a–1f, 1 mmol, was dissolved in 15 mL of
ethanol, a solution of 1 mmol of the corresponding
isonitrosoacetophenone hydrazone in 25 mL of ethanol
was added, and the mixture was stirred for 10 h at
room temperature. The solvent was distilled off under
reduced pressure, the residue was dispersed in 5 mL of
acetic acid, and the mixture was stirred for 1 h on
cooling with a water bath while gradually adding
0.685 g (1 mmol) of red lead oxide. The mixture was
then stirred for 30 min on cooling and diluted with
50 mL of water with stirring, and the precipitate was
filtered off, washed with water, and dried. Analytical
samples were obtained by recrystallization from
ethanol.
6-(4-Oxido-6-phenyl-1,2,4-triazin-3-yl)-3-phenyl-
pyridine-2-carbonitrile (16e). Yield 225 mg
1
(0.64 mmol, 64%), mp >250°C. H NMR spectrum
(DMSO-d6), δ, ppm: 7.56‒7.66 m (6H, Ph), 7.77 m
(2H, Ph), 8.26‒8.35 m (3H, Ph, Py), 8.49 d (1H, Py,
J = 8.0 Hz), 9.46 s (1H, 5′-H). Mass spectrum:
m/z 352.12 (Irel 100%) [M + H]+. Found, %: C 71.59;
H 3.83; N 20.04. C21H13N5O. Calculated, %: C 71.79;
H 3.73; N 19.93. M 352.12.
6-[6-(4-Methylphenyl)-4-oxido-1,2,4-triazin-
3-yl]-3-phenylpyridine-2-carbonitrile (16f). Yield
1
219 mg (0.6 mmol, 60%), mp >250°C. H NMR spec-
3-(6-Bromopyridin-2-yl)-6-phenyl-1,2,4-triazine
trum (DMSO-d6), δ, ppm: 2.46 s (3H, Me), 7.40 m
(2H, C6H4), 7.55‒7.65 m (3H, Ph), 7.74 m (2H, Ph),
8.17 m (2H, C6H4), 8.28 d (1H, Py, J = 8.4 Hz), 8.46 d
(1H, Py, J = 8.4 Hz), 9.38 s (1H, 5′-H). Mass spectrum:
m/z 366.14 (Irel 100%) [M + H]+. Found, %: C 72.17;
H 4.11; N 18.94. C22H15N5O. Calculated, %: C 72.32;
H 4.14; N 19.07. M 366.14.
4-oxide (16a). Yield 187 mg (0.57 mmol, 57%),
mp 218‒220°C. H NMR spectrum (DMSO-d6), δ,
1
ppm: 7.55‒7.64 m (3H, Ph), 7.80 d (1H, 5-H, J =
7.9 Hz), 7.96 d.d (1H, 4-H, J = 7.9, 7.9 Hz), 8.14 d
(1H, 3-H, J = 7.9 Hz), 8.21‒8.27 m (2H, Ph), 9.37 s
(1H, 5′-H). Mass spectrum: m/z 329.00 (Irel 100%)
[M + H]+. Found, %: C 50.90; H 2.59; N 16.87.
C14H9BrN4O. Calculated, %: C 51.09; H 2.76;
N 17.02. M 329.00.
Methyl 6-(4-oxido-6-phenyl-1,2,4-triazin-3-yl)-
pyridine-3-carboxylate (16g). A solution of 270 mg
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EFFECT OF SUBSTITUENT IN PYRIDINE-2-CARBALDEHYDE
969
(1.65 mmol) of aldehyde 1f in ethanol was added to
a solution of 270 mg (1.65 mmol) of isonitroso-
acetophenone hydrazone in 15 mL of ethanol, and the
mixture was kept for 10 h at room temperature. The
precipitate was filtered off, washed with ethanol, and
dried. We thus isolated 0.41 g (1.32 mmol) of com-
pound 17g which was dissolved in 40 mL of 1,2-di-
chloroethane, 1.16 g (13.2 mmol) of activated manga-
nese dioxide was added, and the mixture was stirred
for 15 h at room temperature. The inorganic precipitate
was filtered off, the filtrate was evaporated under
reduced pressure, and the residue was recrystallized
from acetonitrile. Yield 210 mg (0.7 mmol, 52%),
(DMSO-d6), δ, ppm: 2.68 s (3H, Me), 3.93 s (3H,
OMe), 7.20 m (2H, Harom), 7.46 d (1H, 5-H, J =
8.0 Hz), 7.92 d.d (1H, 4-H, J = 8.0, 8.0 Hz), 8.11 m
(2H, Harom), 8.35 d (1H, 3-H, J = 8.0 Hz). Mass spec-
trum: m/z 304.12 (Irel 100%) [M + H]+. Found, %:
C 67.43; H 4.22; N 22.99. C17H13N5O. Calculated, %:
C 67.32; H 4.32; N 23.09. M 304.12.
3-(3-Methylpyridin-2-yl)-6-phenyl-1,2,4-triazine-
5-carbonitrile (19d). Yield 55 mg (0.2 mmol, 50%),
1
mp 116‒118°C. H NMR spectrum (CDCl3), δ, ppm:
2.66 s (3H, Me), 7.43 d.d (1H, 5-H, J = 7.8, 4.8 Hz),
7.61‒7.69 m (3H, Ph), 7.76 d.d (1H, 4-H, J = 7.8,
1.0 Hz), 8.13‒8.19 m (2H, Ph), 8.72 d.d (1H, 6-H, J =
4.8, 1.0 Hz). Mass spectrum: m/z 274.11 (Irel 100%)
[M + H]+. Found, %: C 70.17; H 3.87; N 25.69.
C16H11N5. Calculated, %: C 70.32; H 4.06; N 25.63.
M 274.11.
1
mp 208‒210°C. H NMR spectrum (DMSO-d6), δ,
ppm: 3.98 s (3H, OMe), 7.60 m (3H, Ph), 8.23 m (3H,
Ph, 5-H), 8.50 d.d (1H, 4-H, J = 8.0, 1.5 Hz), 9.29 d
(1H, 2-H, J = 1.5 Hz), 9.36 s (1H, 5′-H). Mass spec-
trum: m/z 309.10 (Irel 100%) [M + H]+. Found, %:
C 62.27; H 3.91; N 18.04. C16H12N4O3. Calculated, %:
C 62.33; H 3.92; N 18.17. M 309.10.
3-(6-Cyano-5-phenylpyridin-2-yl)-6-(4-methyl-
phenyl)-1,2,4-triazine-5-carbonitrile (19e). Yield
1
108 mg (0.29 mmol, 73%), mp 228‒230°C. H NMR
1,2,4-Triazine-5-carbonitriles 19 (general proce-
dure). 1,2,4-Triazine 4-oxide 16a–16g, 0.4 mmol, was
dispersed in 15 mL of 1,2-dichloroethane, 55 μL
(0.6 mmol) of acetone cyanohydrin and 28 μL
(0.2 mmol) of triethylamine were added, and the mix-
ture was stirred for 30 min at 50°C. In the synthesis of
19a and 19d the reaction mixture was refluxed for 2 h.
The solvent was distilled off under reduced pressure,
and the product was isolated by flash chromatography
using chloroform as eluent.
spectrum (DMSO-d6), δ, ppm: 2.51 s (3H, Me), 7.50 m
(2H, C6H4), 7.60 m (3H, Ph), 7.76 m (2H, Ph), 8.04 m
(2H, C6H4), 8.38 d (1H, Py, J = 8.4 Hz), 8.89 d (1H,
Py, J = 8.4 Hz). Mass spectrum: m/z 375.14 (Irel 100%)
[M + H]+. Found, %: C 73.59; H 3.61; N 22.32.
C23H14N6. Calculated, %: C 73.78; H 3.77; N 22.45.
M 375.14.
Methyl 6-(5-cyano-6-phenyl-1,2,4-triazin-3-yl)-
pyridine-3-carboxylate (19f). Yield 82 mg
(0.26 mmol, 65%), mp 182‒184°C. 1H NMR spectrum
(CDCl3), δ, ppm: 4.04 s (3H, OMe), 7.68 m (3H, Ph),
8.19 m (2H, Ph), 8.60 d.d (1H, 4-H, J = 8.0, 2.0 Hz),
8.81 d (1H, 5-H, J = 8.0 Hz), 9.51 d (1H, 2-H, J =
2.0 Hz). Mass spectrum: m/z 318.10 (Irel 100%)
[M + H]+. Found, %: C 64.23; H 3.30; N 21.88.
C17H11N5O2. Calculated, %: C 64.35; H 3.49; N 22.07.
M 318.10.
3-(6-Bromopyridin-2-yl)-6-phenyl-1,2,4-triazine-
5-carbonitrile (19a). Yield 111 mg (0.33 mmol, 83%),
1
mp 158‒160°C. H NMR spectrum (DMSO-d6), δ,
ppm: 7.65‒7.72 m (3H, Ph), 7.87 d (1H, 5-H, J =
7.9 Hz), 8.05 d.d (1H, 4-H, J = 7.9, 7.9 Hz), 8.09‒
8.13 m (2H, Ph), 8.61 d (1H, 3-H, J = 7.9 Hz). Mass
spectrum: m/z 338.00 (Irel 100%) [M + H]+. Found, %:
C 53.20; H 2.31; N 20.66. C15H8BrN5. Calculated, %:
C 53.28; H 2.38; N 20.71. M 338.00.
This study was performed under financial support
by the Russian Science Foundation (project no. 15-13-
10 033), by the Council for Grants at the President of
the Russian Federation (project no. MK-644.2017.3),
and by the Government of the Russian Federation
(Program no. 211, contract no. 02.A03.21.0006).
3-(6-Methylpyridin-2-yl)-6-phenyl-1,2,4-triazine-
5-carbonitrile (19b). Yield 76 mg (0.28 mmol, 70%),
1
mp 132‒134°C. H NMR spectrum (DMSO-d6), δ,
ppm: 2.69 s (3H, Me), 7.48 d (1H, 5-H, J = 8.0 Hz),
7.65‒7.71 m (3H, Ph), 7.94 d.d (1H, 4-H, J = 8.0,
8.0 Hz), 8.11 m (2H, Ph), 8.39 d (1H, 3-H, J = 8.0 Hz).
Mass spectrum: m/z 274.11 (Irel 100%) [M + H]+.
Found, %: C 70.23; H 3.90; N 25.48. C16H11N5. Cal-
culated, %: C 70.32; H 4.06; N 25.63. M 274.11.
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