Efficient one-step synthesis of 3-aryl-2-pyridones from 6-aryl-1,2,4-triazin-5-ones

Article abstract of DOI:10.1007/s10593-019-02566-7

[Figure not available: see fulltext.] An efficient method for the synthesis of substituted 2-pyridones based on the aza-Diels–Alder reaction of 1,2,4-triazin-5-ones and dienophiles, 2,5-norbornadiene and 4-(cyclopent-1-en-1-yl)morpholine, is proposed.

Full text of DOI:10.1007/s10593-019-02566-7

DOI 10.1007/s10593-019-02566-7
Chemistry of Heterocyclic Compounds 2019, 55(10), 985–988
Efficient one-step synthesis of
3-aryl-2-pyridones from 6-aryl-1,2,4-triazin-5-ones
Maria I. Savchuk1, Yaroslav K. Shtaitz1, Dmitry S. Kopchuk1,2,
Grigory V. Zyryanov1,2*, Oleg S. Eltsov1, Tatiana А. Pospelova1,
Vladimir L. Rusinov1,2, Oleg N. Chupakhin1,2
1 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; e-mail: gvzyryanov@gmail.com
2 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
21 S. Kovalevskoi /20 Akademicheskaya St., Yekaterinburg 620219, Russia
Submitted April 15, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
Accepted after revision June 19, 2019
2019, 55(10), 985–988
An efficient method for the synthesis of substituted 2-pyridones based on the aza-Diels–Alder reaction of 1,2,4-triazin-5-ones and dieno-
philes, 2,5-norbornadiene and 4-(cyclopent-1-en-1-yl)morpholine, is proposed.
Keywords: 2,2'-bipyridine, 2-pyridone, 1,2,4-triazin-5-one, autoclave, aza-Diels–Alder reaction, nucleophilic ipso-substitution.
Derivatives of 2-pyridones are of interest due to their
biological activity,1 in particular anticonvulsant
(perampanel),2 antifungal, and antimicrobial (cyclopirox)3
properties, together with the ability to inhibit phospho-
diesterase,3 which is used in the treatment of heart failure
(milrinone).4 In addition, the 2-pyridone ring is part of
natural compounds (trichodin A, B and pyridoxatin,
Fig. 1), including alkaloids.5 Derivatives of 2-pyridones are
used as herbicides, insecticides,6 and luminophores.7
6-(Pyridin-2-yl)-2-pyridones are of interest as ligands and
fluorescent sensors of zinc cations in the composition of
living cells,8 and also have promising photophysical
properties.9
8-(pyridin-2-yl)coumarins16 via the aza-Diels–Alder
reaction under conditions of elevated pressure and
temperature in an autoclave. In the present work,
2-pyridones, including new derivatives with a pyridin-2-yl
substituent at position 6 (2,2'-bipyridines), using easily
accessible precursors, 1,2,4-triazin-5-ones, were obtained
in a similar manner.
To date, a variety of synthetic approaches to 2-pyridones
are presented in the literature, summarized in several
reviews.10 However, the method based on the use of 1,2,4-tri-
azines as dienes, well-established in the synthesis of bi- and
oligopyridines,11 is limited to only a few examples of
intramolecular reactions of 1,2,4-triazines with terminal
acetylene for the preparation of 2-pyridones.12 Moreover,
the formation of a mixture of products is noted in a number
of cases.13
Earlier, we reported the possibility of synthesizing 5-aryl-
2,2'-bipyridines with a methoxy, pyrrolidine,14 or phenyl-
(cyano)methyl15 substituent at position 6, as well as
Figure 1. Structures of biologically active 2-pyridones.
0009-3122/19/55(10)-0985©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(10), 985–988
Experimental
The precursors 1,2,4-triazin-5-ones 1a–d were obtained
from readily available 5-cyano-1,2,4-triazines 2a–d.17 Of
the described procedures for performing this transfor-
mation,17b,18 we chose the most convenient18d (Scheme 1).
The subsequent aza-Diels–Alder reaction of the
synthesized 1,2,4-triazin-5-ones 1a–d with 2,5-nor-
bornadiene as dienophile was carried out in an autoclave in
1,2-dichlorobenzene at 215°C for 20 h, as a result of which
2-pyridones 3a–d were obtained with high yields. Use of
6-(4-fluorophenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-one
(1b) and another dienophile, 4-(cyclopent-1-en-1-yl)-
morpholine, allowed to obtain 2-pyridone 4 with an
annulated cyclopentene ring in one step. This reaction was
carried out also according to the previously described
method19 without solvent, but in this case it took more time
to complete it. In all cases, the formation of a single
product was recorded and flash chromatography was used
for its final purification.
1H and 13C NMR spectra were acquired on a Bruker
Avance II 400 spectrometer (400 and 100 MHz,
respectively) in DMSO-d6, with TMS as internal standard.
Mass spectra were recorded on a Bruker Daltonics
MicrOTOF-Q II instrument, electrospray ionization.
Elemental analysis was performed on a Perkin Elmer 2400
CHN-analyzer. Melting points were determined on a
Boetius heating bench. Monitoring of the reaction progress
and assessment of the purity of synthesized compounds
were done by TLC on Sigma-Aldrich SiO2 plates with a
fluorescent indicator (254 nm). Products were purified by
column chromatography on SiO2 (230–400 mesh).
5-Cyano-1,2,4-triazines 2a–d were synthesized accord-
ing to a literature method.17a 1,2,4-Triazin-5-ones 1a–d
were obtained from the respective 5-cyano-1,2,4-triazines
2a–d according to the previously described procedure for
similar compounds.18d
6-Phenyl-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-one (1а).
Yield 193 mg (77%), yellow crystals, mp 177–179°C (mp 174–
176°C21). 1H NMR spectrum, δ, ppm (J, Hz): 7.49–7.52 (3H,
m, H Ph); 7.73–7.76 (1Н, m, H-5 Py); 8.11–8.17 (3Н, m, Н-4
Py, H Ph); 8.35 (1Н, d, J = 8.0, Н-3 Py); 8.84 (1Н, d,
J = 4.8, Н-6 Py); 14.60 (1H, br. s, NH). Mass spectrum,
m/z (Irel, %): 251 [M+H]+ (100). Found, %: C 67.09;
H 3.99; N 22.31. С14Н10N4O. Calculated, %: C 67.19;
H 4.03; N 22.39.
Scheme 1
6-(4-Fluorophenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-
one (1b). Yield 196 mg (73%), yellow crystals, mp 171–
1
173°C. H NMR spectrum, δ, ppm (J, Hz): 7.17–7.21 (2H,
m, H Ar); 7.60–7.68 (1Н, m, H-5 Py); 8.08 (1Н, ddd,
J = 7.9, J = 7.9, J = 1.0, Н-4 Py); 8.31–8.42 (3Н, m, H Ar,
Н-3 Py); 8.79 (1Н, d, J = 4.8, Н-6 Py); 14.44 (1H, br. s,
NH). Mass spectrum, m/z (Irel, %): 269 [M+H]+ (100).
Found, %: C 62.60; H 3.29; N 20.80. С14Н9FN4O.
Calculated, %: C 62.69; H 3.38; N 20.89.
6-(4-Methoxyphenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-
one (1c). Yield 210 mg (75%), yellow crystals, mp 183–
1
185°C. H NMR spectrum, δ, ppm (J, Hz): 3.84 (3Н, s,
OСН3); 7.05–7.08 (2H, m, H Ar); 7.71–7.75 (1Н, m, H-5
Py); 8.13 (1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4 Py); 8.21–
8.24 (2Н, m, H Ar); 8.34 (1Н, d, J = 8.0, Н-3 Py); 8.83
(1Н, d, J = 4.8, Н-6 Py); 14.50 (1H, br. s, NH). Mass
spectrum, m/z (Irel, %): 281 [M+H]+ (100). Found, %:
C 64.19; H 4.28; N 19.90. С15Н12N4O2. Calculated, %:
C 64.28; H 4.32; N 19.99.
6-(4-Chlorophenyl)-1,2,4-triazin-5(4H)-one (1d). Yield
160 mg (78%), light-yellow crystals, mp 190–192°C. 1H NMR
spectrum, δ, ppm: 7.48–7.50 (2H, m, H Ar); 8.16–8.25 (2H,
m, H Ar); 8.65 (1Н, br. s, Н-3); 13.99 (1H, br. s, NH). Mass
spectrum, m/z (Irel, %): 208 [M+H]+ (100). Found, %:
C 52.00; H 2.85; N 20.16. С9Н6ClN3O. Calculated, %:
C 52.07; H 2.91; N 20.24.
Synthesis of pyridones 3а–d (General method).
2,5-Norbornadiene (0.41 ml, 4 mmol) was added to a
suspension of 1,2,4-triazin-5-one 1a–d (0.5 mmol) in 1,2-di-
chlorobenzene (15 ml). The resulting mixture was stirred
under an argon atmosphere in an autoclave at 215°С for 20 h.
The solvent was evaporated under reduced pressure, and
The structures of products 3a–d and 4 were proved on
the basis of 1H and 13C NMR spectroscopy, mass
spectrometry, and elemental analysis data. In particular,
upon conversion of 1,2,4-triazin-5-ones 1a–d to 2-pyrido-
nes 3a–d, the 1H NMR spectra show an upfield shift of the
signals of the protons of the pyridine ring and the proton of
the NH group from 13.99–14.60 to 10.98–11.79 ppm. In
1
addition, the H NMR spectroscopy data of product 3d
correlate with previously published data when compound
3d was obtained by an alternative method.20 In case of
product 4, the characteristic signals of the annulated
cyclopentene ring appear in the resonance region of
aliphatic protons.
To conclude, we have proposed an efficient synthetic
approach to novel 2-pyridones containing a pyridin-2-yl
substituent using readily available precursors 5-cyano-1,2,4-
triazines and 1,2,4-triazin-5-ones. The products were
obtained in high yields.
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Chemistry of Heterocyclic Compounds 2019, 55(10), 985–988
the residue was purified by flash chromatography (SiO2,
eluent CH2Cl2–EtOAc, 10:1). An analytical sample was
obtained by recrystallization from MeCN.
combined fractions containing product 4, and the residue
was treated with EtOH (20 ml). The formed precipitate was
filtered off, washed with EtOH (20 ml), and dried. Yield
172 mg (75%), light-yellow crystals, mp 124–126°C
(MeCN), Rf 0.40 (CH2Cl2–EtOAc, 10:1). 1H NMR
spectrum, δ, ppm (J, Hz): 2.02–2.05 (2H, m, 6-CH2); 2.80
(2H, t, J = 7.6, 7-CH2); 3.11 (2H, t, J = 7.6, 5-CH2); 7.08–
7.12 (2Н, m, H Ar); 7.43–7.47 (3Н, m, H-5 Py, H Ar); 7.86
(1Н, d, J = 7.6, Н-3 Py); 7.93 (1Н, ddd, J = 7.9, J = 7.9,
J = 1.0, Н-4 Py); 8.71 (1Н, d, J = 4.8, Н-6 Py); 10.60 (1H,
br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 26.3; 31.8;
33.0; 115.0 (d, J = 21.8); 121.9; 122.3; 123.8; 127.1; 131.3
(d, J = 3.2); 131.5; 134.0; 137.1; 148.8; 149.5; 158.2;
161.8; 162.1 (d, J = 246.4). Mass spectrum, m/z (Irel, %):
307 [M+H]+ (100). Found, %: C 74.42; H 4.89; N 9.05.
С19Н15FN2O. Calculated, %: C 74.50; H 4.94; N 9.14.
5-Phenyl-2,2′-bipyridin-6(1H)-one (3a). Yield 87 mg
(70%), light-yellow crystals, mp 166–168°C. 1H NMR
spectrum, δ, ppm (J, Hz): 7.23 (1Н, d, J = 8.0, H-3); 7.31–
7.35 (1Н, m, H Ph); 7.37–7.43 (2Н, m, H Ph); 7.46–7.48
(1H, m, Н-5'); 7.73–7.81 (3Н, m, H Ph, H-4); 7.95 (1Н,
ddd, J = 7.9, J = 7.9, J = 1.0, Н-4'); 8.17 (1Н, d, J = 8.0,
Н-3'); 8.70 (1Н, d, J = 4.8, Н-6'); 11.00 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 103.2; 119.6; 124.4; 128.0;
128.3; 128.5; 132.9; 136.3; 137.3; 138.4; 140.7; 147.9;
149.3; 161.5. Mass spectrum, m/z (Irel, %): 249 [M+H]+
(100). Found, %: C 77.18; H 4.73; N 11.01. С16Н12N2O.
Calculated, %: C 77.40; H 4.87; N 11.28.
5-(4-Fluorophenyl)-2,2′-bipyridin-6(1H)-one (3b).
Yield 98 mg (74%), light-yellow crystals, mp 181–183°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.09–7.13 (2Н, m,
H Ar); 7.18 (1Н, d, J = 8.0, H-3); 7.41–7.44 (1H, m, Н-5');
7.72 (1Н, d, J = 8.0, H-4); 7.80–7.84 (2H, m, H Ar); 7.91
(1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4'); 8.12 (1Н, d,
J-= 8.0, Н-3'); 8.67 (1Н, d, J = 4.8, Н-6'); 10.98 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm (J, Hz): 103.3; 115.2 (d,
J = 21.6); 119.6; 124.5; 130.2; 130.3; 131.9; 132.2 (d,
J = 3.4); 137.4; 138.2; 140.6; 147.8; 149.4; 161.5; 162.6 (d,
J = 247.8). Mass spectrum, m/z (Irel, %): 267 [M+H]+ (100).
Found, %: C 72.08; H 4.01; N 10.45. С16Н11FN2O.
Calculated, %: C 72.17; H 4.16; N 10.52.
This work was supported by the Russian Science
Foundation (grant 18-13-00365).
Elemental analysis was performed by an elemental
analysis group of the Postovsky Institute of Organic
Synthesis of the Russian Academy of Sciences.
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