Synthesis and some chemical properties of 2-cyano-4-pyrone

Article abstract of DOI:10.1007/s10593-020-02642-3

[Figure not available: see fulltext.] 2-Cyano-4-pyrone obtained from comanic acid ethyl ester reacts with amines and hydrazines with the opening of the pyrone ring and substitution of the cyano group to form carbamoylated aminoenones (yields 62–87%) and p

Full text of DOI:10.1007/s10593-020-02642-3

DOI 10.1007/s10593-020-02642-3
Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
Synthesis and some chemical properties of 2-cyano-4-pyrone
Dmitrii L. Obydennov1*, Aleksandra I. Suslova1,
Vyacheslav Ya. Sosnovskikh1
1 Institute of Natural Sciences and Mathematics of
the Ural Federal University named after the first President of Russia B. N. Yeltsin,
51 Lenina Ave., Yekaterinburg 620000, Russia; е-mail: dobydennov@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(2), 173–179
Submitted October 14, 2019
Accepted December 13, 2019
2-Cyano-4-pyrone obtained from comanic acid ethyl ester reacts with amines and hydrazines with the opening of the pyrone ring and
substitution of the cyano group to form carbamoylated aminoenones (yields 62–87%) and pyrazolylacetic acid hydrazides. The reactions
of 2-cyano-4-pyrone with hydroxylamine or sodium azide involve exclusively the cyano group, which makes it possible to obtain
2-heteroaryl-4-pyrones and 2-heteroaryl-4-hydroxypyridines.
Keywords: carbamoylated enaminones, 2-cyano-4-pyrones, 2-heteroaryl-4-hydroxypyridines, 2-heteroaryl-4-pyrones, 4-oxo-1,4-di-
hydropyridine-3-carboxamides, pyrazoles.
The search for novel molecules possessing low
molecular weight and diverse reactivity is an important task
of modern organic synthesis and is of great importance for
medicinal chemistry and materials chemistry.1 Pyrones
containing a cyano group belong to polyelectrophilic
substrates and are of interest for obtaining more complex
heterocyclic structures.2 Only substituted 2-cyano-4-pyrones
are known in the literature, although the transformations
described on their basis are limited to a small number of
examples.3,4 Thus it was previously shown that 6-aryl-
2-cyano-4-pyrones react with NaN3 at the cyano group to
form tetrazolylpyrones exhibiting antiallergic activity.4 We
obtained also 2-cyano-6-(trifluoromethyl)-4-pyrone, which
was subsequently in high demand for the construction of
various fluorine-containing heterocycles.5
fragment and with the simultaneous substitution of the
cyano group or as a synthetic equivalent of still not
described 4-hydroxy-2-pyrone (b) (Scheme 1).
Scheme 1
This work is devoted to unsubstituted 2-cyano-4-pyrone
(3), which was described in our preliminary report6 without
carrying out a systematic study of its properties. This
compound has four electrophilic centers (C-2, C-4, C-6
atoms, and CN group) and can be considered as a hidden
triketo cyanide a, capable of reacting by the diketone
As starting material for the preparation of 2-cyano-
4-pyrone (3), comanic acid ethyl ester (1) was used which
was first converted to amide 2.7 It must be taken into
account that the pyrone ring is easily opened by the action
0009-3122/20/56(2)-0173©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
Scheme 2
of ammonia with the formation of 4-pyridone. Despite this,
we were able to find the reaction conditions allowing to
access 2-cyano-4-pyrone from comanic acid ethyl ester in
moderate yield: the reaction of ethyl comanate (1) under
heterogeneous conditions with 20% aqueous NH3 upon
cooling (–10°С) hinders the opening the pyrone ring and
affords 2-carbamoyl-4-pyrone (2) in 82% yield (Scheme 1).
Subsequent treatment of amide 2 with (CF3CO)2O in the
presence of pyridine in absolute THF at –10°С leads to
dehydration and the formation of 2-cyano-4-pyrone (3) in
48% yield. It should be noted that carrying out the reaction
at room temperature, 2-cyano-4-pyrone (3) is obtained in
trace amounts.
MeSO3H, although such a cyclization reaction was
previously observed for 5-substituted enaminones.9
The reaction of 2-cyano-4-pyrone (3) with hydrazine
hydrate proceeds in anhydrous MeOH at 0°С via the
opening of the pyrone ring and the formation of pyrazole 7
in 65% yield (Scheme 3). Carrying out the reaction in
EtOH gives the target product, but in a lower yield (26%).
By analogy with amines, pyrazolylacetyl cyanide C is
formed during the reaction, which reacts with hydrazine to
replace the cyano group (Scheme 3).
Scheme 3
We further investigated the reaction of 2-cyano-
4-pyrone (3) with various nucleophilic reagents. It was
found that the reaction of 2-cyano-4-pyrone (3) with
primary aliphatic and aromatic amines in anhydrous MeOH
at –20°С for 7 days results in the opening of the pyrone
ring and the formation of carbamoylated enaminones 4a–f
in 62–87% yields (Scheme 2). It follows from the structure
of the resulting product that the attack of the amine
molecule occurs at position С-6 of the pyrone ring. A
possible intermediate of this reaction is acyl cyanide A,
which is able to react with a second amine molecule
resulting in substitution of the cyano group. The structure
of the employed amine practically does not affect the
course of the reaction, and even in the case of sterically
hindered o-toluidine, the yield of enaminone 4e decreases
only slightly (62%). When this reaction is carried out in
EtOH, the yields are reduced by about 20%, which is
explained by the competing reaction of intermediate A with
water present in EtOH.
Enaminones are polyfunctional substrates, which allows
us to consider them as precursors for the synthesis of
various compounds.5,6,8,9 Thus, they undergo cyclization
with the formation of 4-oxo-1,4-dihydropyridine-3-carb-
oxamides 5a–c in 74–87% yields under the action of
DMA-DMF in dry PhMe for 24 h at room temperature
(Scheme 2). We assume that this reaction proceeds with the
formation of intermediate B, which then cyclizes to
pyridones 5a–c. The reaction of enaminone 4d with
4-bromobenzaldehyde in the presence of piperidine at room
temperature leads to the Mannich reaction product 6
(Scheme 2). The resulting product 6 does not form the
corresponding dihydropyridone in the presence of
The reaction of 2-cyano-4-pyrone 3 with phenylhydra-
zine in MeOH proceeds nonselectively forming a mixture
of pyrazoles 8 and 9. Probably, the nucleophilic attack of
phenylhydrazine occurs not only at the position C-6 of
2-cyano-4-pyrone, but also at its carbonyl group.
Optimization of the reaction conditions showed that the
temperature and nature of the solvent affect the regio-
selectivity of the process (Scheme 4). Thus, polar protic
solvents favor the formation of the 1,4-addition product at
the C-6 atom (intermediate D, pyrazole 8). In PhMe, the
main isomer was the product of the 1,2-addition
(intermediate E, pyrazole 9). The obtained result is
consistent with the data on the reaction of 2,6-disubstituted
4-pyrones with hydrazines.10 By recrystallization of the
mixture of regioisomers from EtOH, pyrazole 9 was
isolated in pure form in 46% yield.
The structures of pyrazoles 8 and 9 were established
using the spin-spin coupling constants and the values of
chemical shifts of protons. In the case of regioisomer 8,
the pyrazole protons H-3 and H-4 appear at 7.62 and
6.42 ppm, respectively. A characteristic signal of pyrazole
9 is the downfield doublet of the H-5 proton at 8.43 ppm,
which is a consequence of the deshielding effect of the
phenyl substituent (Scheme 4). It is known from the
literature that, for 3-substituted pyrazoles, the spin-spin
coupling constant of the H-3 and H-4 protons is greater
than for 5-substituted pyrazoles.10 Thus, it was found that
174

Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
Scheme 4
for pyrazole 9 JH4,H5 = 2.6 Hz, and for pyrazole 8
JH3,H4 = 1.2 Hz, which is consistent with the proposed
structures.
structures.11 It was found that pyrones 10, 12, 13 react
with NH3 via opening of the pyrone ring and subsequent
closure to previously unknown pyridines 14–16 at room
temperature for 4 days (Scheme 5). In the 1H NMR
spectra of compounds 14–16, the signals of the protons
of the pyridine ring are shifted downfield in comparison
with similar protons of the pyrones, which indicates
that the obtained products are found in the 4-hydroxy-
pyridine rather than 4-pyridone form. The largest value
∆δ = δН(pyridine) – δН(pyrone) was found for protons H-3
and H-5 – 0.5–1.0 ppm, while for proton H-6, the value ∆δ
lies in the range of 0.05–0.36 ppm.
To conclude, the synthesis of 2-cyano-4-pyrone, which
is the active substrate in reactions with N-nucleophiles for
the construction of diverse azaheterocycles, was carried
out. Depending on the nature of the nucleophile, reactions
proceed either with the opening of the pyrone ring and
substitution of the cyano group or selectively at the cyano
group. In the latter case, it becomes possible to access such
important classes of heterocycles as 2-heteroaryl-4-pyrones
and 2-heteroaryl-4-hydroxypyridines.
It should be noted that the reaction of 2-cyano-4-pyrone
(3) with hydroxylamine, in contrast to the reaction with
hydrazines, does not lead to the product of ring opening,
but proceeds with the participation of the cyano group to
form amidoxime 10 (yield 72%). The observed change in
the course of the reaction is probably a consequence of the
coordination of the OH and CN groups (intermediate F),
which leads to an attack at the cyano group. As a result of
acylation of amidoxime 10 with (CF3CO)2O in the presence
of pyridine, oxadiazolylpyrone 11 is formed in 41% yield
(Scheme 5).
2-Cyano-4-pyrone (3) also enters the [3+2] cycloaddition
reaction with NaN3 in the presence of NH4Cl in aqueous
THF solution to form 2-tetrazolyl-4-pyrone (12) in 65%
yield (Scheme 5). The reaction proceeds selectively at the
cyano group, without affecting the pyrone ring. When
heating under reflux in Ac2O, tetrazolylpyrone 12 undergoes
the Huisgen rearrangement, which leads to the formation of
oxadiazolylpyrone 13 in 66% yield (Scheme 5).
Experimental
Next, we investigated the possibility of obtaining the
corresponding 2-substituted pyridines starting from
pyrones 10, 12, and 13 that are of interest as coordination
IR spectra were registered on a Shimadzu IRSpirit-T
spectrometer with the ATR. 1H and 13C NMR spectra were
Scheme 5
175

Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
acquired on Bruker Avance II (400 and 101 MHz,
(1H, br. s, NH). 13C NMR spectrum (101 MHz, DMSO-d6),
δ, ppm: 13.5; 13.7; 19.5; 31.4; 38.2; 42.3; 47.7; 50.0; 92.0;
167.2; 189.8; 191.3 (1C not detected). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 13.6; 13.7; 19.6; 20.1; 31.5;
32.9; 39.1; 47.8; 49.0; 93.4; 154.4; 167.6; 193.1. Found, %:
С 64.57; H 10.08; N 11.93. C13H24N2O2. Calculated, %:
С 64.97; Н 10.07; N 11.66.
respectively) or Bruker Avance-500 (500 and 126 MHz,
respectively) spectrometers in pulse Fourier transform
mode in CDCl3 or DMSO-d6. TMS or the residual solvent
1
signals (CDCl3 – 7.26 ppm, DMSO-d6 – 2.50 ppm for Н
nuclei; DMSO-d6 – 39.5 ppm, CDCl3 – 77.1 ppm for 13С
nuclei). High-resolution mass spectra were recorded on a
Waters Xevo Qtof mass spectrometer, electrospray
ionization. Elemental analysis was performed on a Perkin
Elmer Series II 2400 elemental analyzer. Melting points
were determined on an SMP40 apparatus. Ethyl comanate
(1) was obtained according to a literature method.12
(Z)-N-Octyl-5-(octylamino)-3-oxopent-4-enamide (4b).
The precipitated crystals were filtered off and washed with
cold EtOH. Yield 0.233 g (80%), gray crystals, mp 73–74°С.
IR spectrum, ν, cm–1: 2920, 2849, 1658, 1618, 1549, 1282,
1
1218, 959, 872. H NMR spectrum (500 MHz, CDCl3),
4-Oxo-4H-pyran-2-carboxamide (2). Ethyl comanate (1)
(2.50 g. 0.015 mol) was added to a 50-ml flask containing
20% aqueous NH3 (25 ml) with cooling in a NaCl/ice bath.
The obtained suspension was stirred at –10°C for 30 min.
The formed precipitate was filtered off on a Buchner funnel
and washed with H2O (10 ml). Yield 1.53 g (82%),
colorless powder, mp 250°С (subl.). IR spectrum, ν, cm–1:
δ, ppm (J, Hz): 0.81–1.79 (26H, m, СН3 octyl, СН2 octyl);
3.08–3.36 (10H, m, СН2 octyl, CH2); 5.03 (1H, d, J = 7.1,
=CH); 6.76 (1H, dd, J = 13.1, J = 7.1, =CHN); 7.48 (1H,
br. s, NHC=O); 9.92 (1H, br. s, NH). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm: 14.0 (2C); 22.5; 22.6; 26.5;
26.9; 29.1 (2C); 29.2 (2C); 29.4 (2C); 30.9; 31.7; 31.8;
93.4; 154.4; 167.6; 193.2 (2С not detected). Found, %:
С 71.49; Н 11.53; N 7.93. C21H40N2O2. Calculated, %:
C 71.54; H 11.44; N 7.95.
(Z)-N-Benzyl-5-(benzylamino)-3-oxopent-4-enamide (4с).
MeOH was evaporated at room temperature, and the
residue was recrystallized from a mixture of PhMe–hexane.
Yield 0.188 g (74%), colorless crystals, mp 106–107°С
(mp 113–114°С6). IR spectrum, ν, cm–1: 3369, 3262, 3030,
2919, 1649, 1629, 1562, 1249, 951, 771. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 3.14 (2H,
s, CH2); 4.27 (2H, d, J = 5.8, СН2Ph); 4.41 (2H, d, J = 5.8,
СН2Ph); 5.04 (1H, d, J = 7.4, =СН); 7.07 (1H, dd, J = 13.1,
J = 7.4, =CHN); 7.17–7.43 (10Н, m, H Ph); 8.42 (1H, t,
J = 5.8, NHC=O); 9.88 (1Н, dt, J = 13.1, J = 5.8, NH).
1H NMR spectrum (500 MHz, CDCl3), δ, ppm (J, Hz): 3.33
(2H, s, CH2); 4.39 (2H, d, J = 6.1, СН2Ph); 4.46 (2H, d,
J = 5.8, СН2Ph); 5.10 (1H, d, J = 7.3, =СН); 6.83 (1H, dd,
J = 13.0, J = 7.3, =CHN); 7.21–7.38 (10Н, m, H Ph); 7.85
(1H, br. s, NHC=O); 9.88 (1Н, br. s, NH). 13C NMR
spectrum (126 MHz, CDCl3), δ, ppm: 43.3; 47.7; 52.8;
94.2; 127.2; 127.6; 127.9; 128.5; 128.9; 137.1; 138.4;
154.2; 167.5; 193.4 (1C not detected). Found, %: С 74.20;
Н 6.45; N 9.29. C19H20N2O2. Calculated, %: C 74.00;
H 6.54; N 9.08.
(Z)-3-Oxo-N-phenyl-5-(phenylamino)pent-4-enamide (4d).
The precipitated crystals were filtered off and washed with
cold EtOH. Yield 0.153 g (66%), yellow crystals, mp 138–
139°С. IR spectrum, ν, cm–1: 3263, 3058, 3034, 1674,
1648, 1597, 1544, 1475, 1268, 987, 887, 837, 802. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 3.46 (2H, s,
CH2); 5.42 (1H, d, J = 7.9, =СН); 7.00–7.09 (2H, m, H Ph);
7.22–7.38 (6Н, m, H Ph); 7.60 (2H, d, J = 7.9, H-2,6 Ph);
7.73 (1H, dd, J = 12.5, J = 7.9, =СНN); 10.12 (1Н, s,
NHC=O); 11.42 (1Н, d, J = 12.5, NH). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 49.2; 96.5; 115.5; 119.0;
122.2; 123.2; 128.7; 129.5; 139.2; 140.9; 144.5; 166.2;
190.8. Found, %: С 72.85; Н 5.61; N 9.99. C17H16N2O2.
Calculated, %: C 72.84; H 5.75; N 9.99.
1
3352, 3152, 3051, 1702, 1638, 1696. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 6.41 (1H, dd, J = 5.7,
J = 2.3, H-5); 6.80 (1H, d, J = 2.3, H-3); 8.06 (1H, s, NHH);
8.20 (1H, d, J = 5.7, H-6); 8.30 (1H, s, NHH). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 115.8; 117.4; 156.1; 156.5;
160.4; 178.0. Found, %: C 51.89; H 3.51; N 10.23.
C6H5NO3. Calculated, %: C 51.80; H 3.62; N 10.07.
4-Oxo-4H-pyran-2-carbonitrile (3). (CF3CO)2O (2.5 ml)
was added to a mixture of carefully ground amide 2
(1.21 g, 8.70 mmol) and pyridine (1.73 ml) in anhydrous
THF (16 ml), cooled in a NaCl/ice bath. The mixture was
then stirred at –10°С for 3 h. The formed solution was
diluted with H2O (30 ml), the product was extracted with
CHCl3 (3×10 ml). The combined extracts were concent-
rated under reduced pressure, and the residue was
recrystallized from hexane–PhMe. Yield 0.50 g (48%),
yellowish crystals, mp 90–91°С (mp 89–90°С6). IR spect-
rum, ν, cm–1: 1705, 1621, 1599, 1502, 1483, 1474.
1H NMR spectrum corresponds to that described in the
literature.6 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 6.53 (1H, dd, J = 6.0, J = 2.6, H-5); 7.32
(1H, d, J = 2.6, H-3); 8.26 (1H, d, J = 6.0, H-6). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm: 111.9; 118.3;
125.2; 138.1; 157.9; 175.7.
Synthesis of enaminones 4a–f (General method). The
corresponding amine (1.82 mmol; 2.48 mmol amine for
products 4a,b) in cooled MeOH (1 ml) was added to a
solution of 2-cyano-4-pyrone (3) (0.100 g, 0.826 mmol) in
cold anhydrous MeOH (1 ml). The resulting reaction
mixture was kept at –20°С for 7 days.
(Z)-N-Butyl-5-(butylamino)-3-oxopent-4-enamide (4а).
MeOH was evaporated, the product was isolated by column
chromatography, eluent EtOAc. Yield 0.137 g (69%), dark-
yellow liquid. IR spectrum, ν, cm–1: 3277, 2957, 2872,
1637, 1537, 1286, 1115, 738. 1H NMR spectrum (400 MHz,
CDCl3), δ, ppm (J, Hz): 0.94 (3H, t, J = 7.1, СН3); 0.96
(3H, t, J = 7.1, СН3); 1.32–1.45 (4H, m, 2CH2 butyl); 1.46–
1.63 (4H, m, 2CH2 butyl); 3.21–3.32 (4H, m, 2CH2 butyl);
3.25 (2H, s, CH2); 5.03 (1H, d, J = 7.1, =CH); 6.78 (1H,
dd, J = 13.1, J = 7.1, CHN); 7.48 (1H, br. s, NHC=O); 9.94
(Z)-3-Oxo-N-(o-tolyl)-5-(o-tolylamino)pent-4-enamide
(4e). The precipitated crystals were filtered off and washed
with cold EtOH. The filtrate was evaporated, and the
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Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
residue was recrystallized from a mixture of PhMe–hexane.
130.1; 138.4; 141.0; 142.6; 144.0; 161.7; 176.9. Found, %:
C 74.22; H 4.86; N 9.89. C18H14N2O2. Calculated, %:
C 74.47; H 4.86; N 9.65.
Combined yield 0.158 g (62%), colorless crystals, mp 126–
127°С. IR spectrum, ν, cm–1: 3253, 3030, 1642, 1587,
1565, 1524, 1470, 1456, 1276, 1115, 967. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 2.39 (3H,
s, CH3); 2.41 (3H, s, CH3); 3.60 (2H, s, CH2); 5.47 (1H, d,
J = 7.4, =СН); 7.03–7.12 (2H, m, H Ar); 7.16–7.34 (6Н, m,
H Ar); 7.48 (1H, dd, J = 12.5, J = 7.4, =СНN); 10.12 (1Н,
s, NH); 11.42 (1Н, d, J = 12.5, NH). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 17.0; 17.8; 50.3; 96.9;
113.7; 123.2; 124.4; 124.9; 125.0; 125.9; 127.3; 130.3;
130.9; 131.1; 136.2; 138.2; 145.1; 165.7; 193.9. Found, %:
С 73.93; Н 6.47; N 9.24. C19H20N2O2. Calculated, %:
C 74.00; H 6.54; N 9.08.
N,1-Bis(4-methoxyphenyl)-4-oxo-1,4-dihydropyridine-
3-carboxamide (5c). Yield 0.084 g (74%), yellow powder,
mp 201–202°С (mp 201–202°С6). IR spectrum, ν, cm–1:
3074, 2902, 2835, 1677, 1608, 1552, 1504, 1236, 1018,
822. 1H and 13C NMR spectra correspond to those
described in the literature.6 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 3.75 (3H, s, OCH3); 3.84 (3H, s,
OCH3); 6.65 (1H, d, J = 7.4, 5-СH); 6.88 (2H, d, J = 8.8, Н-3,5
ArNHC=О); 7.14 (2H, d, J = 8.9, Н-3,5 ArN); 7.56–7.67 (4H,
m, H Ar); 8.17 (1H, dd, J = 7.4, J = 2.4, 6-CH); 8.62 (1Н, d,
J = 2.4, 2-CH); 12.50 (1H, s, CONH).
(Z)-N-(4-Methoxyphenyl)-5-(4-methoxyphenylamino)-
3-oxopent-4-enamide (4f). The precipitated crystals were
filtered off. The product was recrystallized from a mixture
of PhMe–hexane. Yield 0.245 g (87%), yellow crystals,
mp 149–151°С (mp 152–153°С6). IR spectrum, ν, cm–1:
3301, 3009, 2832, 1636, 1568, 1025, 751. 1H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 3.38 (2H,
s, CH2); 3.72 (3H, s, OCH3); 3.73 (3H, s, OCH3); 5.36 (1H,
d, J = 7.7, =CH); 6.88 (2H, d, J = 8.9, Н-3,5 ArNHC=C);
6.92 (2H, d, J = 8.9, Н-3,5 ArNHC=O); 7.21 (2H, d,
J = 8.9, Н-2,6 ArNHC=C); 7.51 (2H, d, J = 8.9, Н-2,6
ArNHC=O); 7.62 (1Н, dd, J = 12.7, J = 7.7, =СН); 9.96
(1H, s, CONH); 11.46 (1H, d, J = 12.7, NH). Found, %:
C 67.08; H 6.05; N 8.09. C19H20N2O4. Calculated, %:
C 67.05; H 5.92; N 8.23.
Synthesis of 4-oxo-1,4-dihydropyridine-3-carbox-
amides 5а–с (General method). Enaminone 4c,d,f
(0.325 mmol) and N,N-dimethylformamide dimethyl acetal
(0.078 g, 0.65 mmol) in anhydrous PhMe (1 ml) were
stirred at room temperature for 24 h. The formed
precipitate was filtered off and washed with hexane.
(Z)-2-[(4-Bromophenyl)(piperidin-1-yl)methyl]-3-oxo-
N-phenyl-5-(phenylamino)pent-4-enamide (6). Enaminone
4d (100 mg, 0.357 mmol), p-bromobenzaldehyde (72.6 mg,
0.393 mmol), and piperidine (36.5 mg, 0.428 mmol) in
anhydrous MeCN (2 ml) were stirred at room temperature
for 2 days. The formed precipitate was filtered off. Yield
0.144 g (76%), yellow powder, mp 145–146°С. IR spect-
rum, ν, cm–1: 3273, 2939, 2809, 2756, 1678, 1627, 1598,
1
1479, 1274, 1128, 973. H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm (J, Hz): 1.10–1.21 (2H, m, CH2); 1.25–
1.43 (4H, m, CH2); 2.01–2.19 (2H, m, CH2); 2.42–2.52
(2H, m, CH2); 4.43 (1Н, d, J = 11.9, CH); 4.52 (1Н, d,
J = 11.9, CH); 5.47 (1Н, d, J = 7.7, =CH); 7.01 (1H, t,
J = 7.3, Н-4 Ph); 7.07 (1H, t, J = 7.4, Н-4 Ph); 7.14 (2H, d,
J = 8.3, H Ph, H Ar); 7.16 (2H, d, J = 8.1, H Ph, H Ar); 7.28
(2H, t, J = 8.0, Н-3,5 Ph); 7.33 (2H, t, J = 7.9, Н-3,5 Ph);
7.53 (2H, d, J = 8.3, H Ph, H Ar); 7.59 (1H, dd, J = 12.7,
J = 7.7, =CH); 7.61 (2H, d, J = 7.8, H Ph, H Ar); 10.26
(1H, s, NH); 11.13 (1H, d, J = 12.7, NH). 13C NMR
spectrum (126 MHz, DMSO-d6) (selected signals), δ, ppm:
24.1; 26.1; 50.1; 60.7; 61.5; 96.7; 115.5; 119.0; 122.2;
123.7; 128.8; 129.5; 130.4; 130.5; 130.7; 134.6; 139.2;
140.8; 144.5; 166.9; 189.8. Found, %: C 65.67; H 5.86;
N 8.03. C29H30BrN3O2. Calculated, %: C 65.41; H 5.68;
N 7.89.
N,1-Dibenzyl-4-oxo-1,4-dihydropyridine-3-carbox-
amide (5a). Yield 0.083 g (80%), gray powder, mp 125–
127°С (mp 129–130°С6). IR spectrum, ν, cm–1: 3088, 3074,
1
1662, 1622, 1547, 1489, 1187, 839. H NMR spectrum
(400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.51 (2Н, d, J = 6.0,
PhCH2NH); 5.31 (2H, s, PhCH2N); 6.47 (1Н, d, J = 7.6,
5-CH); 7.20–7.43 (10Н, m, H Ph); 7.96 (1Н, dd, J = 7.6,
J = 2.4, 6-CH); 8.67 (1Н, d, J = 2.4, 2-CH); 10.65 (1Н, t,
J = 6.0, NH). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 42.0; 59.0; 118.5; 120.2; 127.3; 127.8; 128.4 (2C);
129.0; 136.2; 139.3; 141.4; 144.8; 163.8; 176.5 (1C not
detected). Found, %: C 75.39; H 5.69; N 8.91. C20H18N2O2.
Calculated, %: C 75.45; H 5.70; N 8.80.
4-Oxo-N,1-diphenyl-1,4-dihydropyridine-3-carbox-
amide (5b). Yield 0.082 g (87%), yellow powder, mp 134–
135°С. IR spectrum, ν, cm–1: 3098, 2961, 1686, 1629, 1598,
1544, 1488, 1294, 1230, 833. 1H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm (J, Hz): 6.69 (1H, d, J = 7.5, 5-CH);
7.11 (1H, t, J = 7.4, Н-4 Ph); 7.37 (2H, t, J = 7.9, Н-3,5
Ph); 7.56 (1H, tt, J = 7.4, J = 1.1, Н-4 Ph); 7.63 (2H, t,
J = 8.1, Н-3,5 Ph); 7.67–7.73 (4Н, m, H Ph); 8.27 (1Н, dd,
J = 7.5, J = 2.5, 6-CH); 8.71 (1Н, d, J = 2.5, 2-CH); 12.62
(1H, s, CONH). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 118.5; 119.7; 120.2; 123.3; 123.8; 128.9; 129.1;
(Pyrazol-3-yl)acethydrazide (7). Hydrazine hydrate
(0.330 g, 6.60 mmol) in MeOH (1 ml) was added with
stirring to a solution of 2-cyano-4-pyrone (3) (0.200 g,
1.65 mmol) in MeOH (1 ml) with cooling in ice bath. The
reaction mixture was stirred with cooling for 1 h and at
room temperature for 12 h. The precipitate was filtered off
and washed with cold EtOH. Yield 0.151 g (65%),
colorless powder, mp 181–182°С (mp 181–183°С13).
IR spectrum, ν, cm–1: 3276, 3133, 2881, 1649, 1620, 1533,
1171, 757. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm: 3.35 (2Н, s, CH2); 4.20 (2H, br. s, NH2); 6.10 (1H,
br. s, H-4 pyrazole); 7.24–7.65 (1H, br. s, H-5 pyrazole);
9.09 (1H, br. s, NHNH2); 12.51 (1H, br. s, NH). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm: major NH-tauto-
mer: 33.7; 103.9; 128.7; 146.0; 169.0; minor NH-tautomer:
30.8; 136.5; 168.1.
N'-Phenyl-2-(1-phenyl-1H-pyrazol-5-yl)acethydrazide (8)
was not isolated as an individual substance. 2-Cyano-
4-pyrone (3) (0.100 g, 0.83 mmol) and phenylhydrazine
(0.196 g, 1.82 mmol) were mixed in MeOH (1 ml) in ice
177

Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
bath, and the mixture was kept at room temperature for
(СF3CO)2O (0.400 g, 1.95 mmol), pyridine (0.150 g,
1.95 mmol) in anhydrous CH2Cl2 (2 ml) were stirred in ice
bath for 1 h, then the mixture was kept at room temperature
overnight. The solvent was evaporated under reduced
pressure, and H2O was added to the residue. The precipitate
was filtered off and recrystallized from a mixture of PhMe–
hexane. Yield 0.062 g (41%), gray crystals, mp 123–125°С.
IR spectrum, ν, cm–1: 3081, 1723, 1655, 1312, 1180, 1149,
2 days. The formed precipitate was filtered off. Yield
0.138 g (57%), gray powder, the crude product is a mixture
of regioisomers 8:9 = 67:33. Compound 8 in DMSO-d6
solution exists as a mixture of rotamers sin:anti = 83:17.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
sin-8 (83%): 3.70 (2H, s, CH2); 6.42 (1H, d, J = 1.2, H-4);
6.59 (2H, d, J = 7.9, Н-2,6 Ph); 6.68 (1H, t, J = 7.3, Н-4
Ph); 7.10 (2H, t, J = 7.8, Н-3,5 Ph); 7.52–7.56 (5H, m,
H Ph); 7.62 (1H, d, J = 1.2, Н-3); 7.74 (1H, d, J = 2.4,
PhNHNH); 9.83 (1H, d, J = 2.4, PhNHNH); anti-8 (17%)
(selected signals): 3.73 (2H, s, CH2); 6.34 (1H, d, J = 1.2,
H-4); 7.95 (1H, s, PhNHNH); 9.19 (1H, s, PhNHNH).
Found, m/z: 293.1390 [M+Н]+. C17H17N4O. Calculated,
m/z: 293.1402.
1
847. H NMR spectrum (400 MHz, DMSO-d6), δ, ppm
(J, Hz): 6.47 (1Н, dd, J = 5.9, J = 2.6, 5-CH); 7.05 (1Н, d,
J = 2.6, 3-CH); 8.30 (1Н, d, J = 5.9, 6-CH). 13C NMR
spectrum (101 MHz, DMSO-d6), δ, ppm (J, Hz): 115.4 (q,
J = 273.4, CF3); 117.8; 118.0; 151.1; 157.1 (q, J = 18.1,
C-2); 163.3; 165.6 (q, J = 44.5, CCF3); 176.6. Found, %:
C 41.43; H 1.47; N 11.70. C8H3F3N2O3. Calculated, %:
C 41.40; H 1.30; N 12.07.
N'-Phenyl-2-(1-phenyl-1H-pyrazol-3-yl)acethydrazide
(9). 2-Cyano-4-pyrone (3) (0.100 g, 0.83 mmol) and phenyl-
hydrazine (0.196 g, 1.82 mmol) in PhMe (2 ml) were kept
at room temperature for 2 days. The formed precipitate was
filtered off. Yield 0.215 g (89%), gray powder, mp 154–
155°С, the crude product is a mixture of regioisomers 8:9 =
15:85. After recrystallization from EtOH, compound 9 was
obtainned in pure form. Yield 0.115 g (46%), yellow
crystals, mp 164–165°С. IR spectrum, ν, cm–1: 3361, 3229,
3046, 1683, 1651, 1595, 1492, 1384, 1242, 1046, 838.
Compound 9 in DMSO-d61solution exists as a mixture of
rotamers sin:anti = 93:7. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): sin-9 (93%): 3.60 (2H, s, CH2);
6.46 (1H, d, J = 2.6, Н-4); 6.69 (1H, t, J = 7.3, Н-4 Ph);
6.75 (2H, d, J = 7.7, Н-2,6 Ph); 7.12 (2H, t, J = 7.8, Н-3,5
Ph); 7.29 (1H, t, J = 7.4, Н-4 Ph); 7.50 (2H, t, J = 8.0,
H-3,5 Ph); 7.78 (1H, d, J = 2.5, PhNHNH); 7.83 (2H, d,
J = 7.7, H-2,6 Ph); 8.43 (1H, d, J = 2.6, Н-5); 9.89 (1H, d,
J = 2.5, PhNHNH); anti-9 (7%) (selected signals): 3.67
(2H, s, CH2); 6.39 (1H, d, J = 2.4, Н-4); 8.06 (1H, s,
PhNHNH); 8.37 (1H, d, J = 2.4, Н-5); 9.15 (1H, s,
PhNHNH). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 33.8; 107.8; 112.1; 117.9; 118.4; 125.9; 128.3; 128.6;
129.5; 139.6; 148.4; 149.2; 168.8. Found, %: C 69.91; H 5.63;
N 19.13. C17H16N4O. Calculated, %: C 69.85; H 5.52; N 19.17.
4-Oxo-4H-pyran-2-carboxylic acid amidoxime (10).
KOH (0.200 g, 3.57 mmol) and NH2OH·HCl (0.270 g,
3.89 mmol) were stirred in MeOH (4 ml) for 10 min, the
formed precipitate of KCl was filtered. The filtrate was
added from the dropping funnel to a cooled solution of
2-cyano-4-pyrone (3) (0.400 g, 3.30 mmol) in МеОН
(4 ml). The reaction mixture was stirred with cooling for
further 2 h, the resulting product was filtered off. Yield
0.367 g (72%), gray powder, mp 235–237°С. IR spectrum,
2-(Tetrazol-5-yl)-4H-pyran-4-one (12). 2-Cyano-4-py-
rone (3) (0.400 g, 3.30 mmol), NH4Cl (0.265 g, 4.95 mmol),
NaN3 (0.322 g, 4.95 mmol), and THF–Н2O, 1:1 (8 ml)
were heated under reflux for 1.5 h (until phase separation
disappears). Then, THF was evaporated, and the residue
was treated with 4 M aqueous HCl to pН 1. The precipitate
from H2O was filtered off and washed with Н2O. Yield
0.352 g (65%), colorless powder, mp 215–216°C (decomp.).
IR spectrum, ν, cm–1: 3084, 1654, 1618, 1420, 932.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
6.23 (1H, dd, J = 5.8, J = 2.6, 5-CH); 6.77 (1H, d, J = 2.6,
3-CH); 8.12 (1H, d, J = 5.8, 6-CH). 13C NMR spectrum
(101 MHz, DMSO-d6), δ, ppm: 115.5; 117.5; 152.2; 152.6;
156.7; 176.9. Found, %: C 43.70; H 2.25; N 34.21.
C6H4N4O2. Calculated, %: C 43.91; H 2.46; N 34.14.
2-(5-Methyl-1,3,4-oxadiazol-2-yl)-4H-pyran-4-one (13).
Tetrazolylpyrone 12 (0.300 g, 1.73 mmol) in Ac2O (12 ml)
was heated under reflux for 24 h. After that, the solvent
was evaporated in an evaporating dish at room temperature,
and the residue was recrystallized from a PhMe–hexane
mixture. Yield 0.204 g (66%), colorless crystals, mp 164–
165°С. IR spectrum, ν, cm–1: 3076, 3049, 1655, 1625,
1
1343, 1217, 909. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 2.65 (3Н, s, CH3); 6.42 (1H, dd, J = 5.9,
J = 2.5, H-5); 6.93 (1H, d, J = 2.5, H-3); 8.26 (1H, d,
J = 5.9, Н-6). 13C NMR spectrum (101 MHz, DMSO-d6),
δ, ppm: 10.6; 115.9; 117.6; 149.6; 156.8; 158.1; 165.6;
176.6. Found, m/z: 179.0457 [M+Н]+. C6H8N3O2. Calculated,
m/z: 179.0457.
4-Hydroxypicolinic acid amidoxime (14). Amidoxime 10
(0.100 g, 0.65 mmol) and 20% aqueous NH3 (2 ml) were
stirred for 4 days. The solvent was evaporated in an
evaporating dish at room temperature, the solid residue was
washed with PhMe and dried at 120°C. Yield 0.087 g
(88%), beige powder, mp 235–236°С. IR spectrum, ν, cm–1:
3253, 3034, 2784, 1655, 1594, 1386, 1218, 966, 863.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 5.78
(2H, s, NH2); 6.73 (1H, br. s, Н-5); 7.19 (1H, br. s, Н-3);
8.17 (1H, br. s, Н-6); 9.83 (1H, br. s, OH); 10.18–11.05
(1Н, br. s, OH). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 106.4; 112.6; 149.4; 151.4; 164.2 (1С not detected).
Found, m/z: 154.0621 [M+Н]+. C6H8N3O2. Calculated, m/z:
154.0617.
1
ν, cm–1: 3399, 3151, 1680, 1606, 1253, 906, 796. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 5.77 (2Н,
s, NH2); 6.26 (1H, dd, J = 5.8, J = 2.5, 5-CH); 6.63 (1H, d,
J = 2.5, 3-CH); 8.04 (1H, d, J = 5.8, 6-CH); 10.33 (1H, s,
OH). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm
(J, Hz): 112.4; 116.9; 145.3; 156.1; 157.6; 177.5. Found,
%: С 46.37; Н 3.80; N 17.93. C6H6N2O3. Calculated, %:
С 46.76; Н 3.92; N 18.18.
2-[5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl]-4H-pyran-
4-one (11). Amidoxime 10 (0.100 g, 0.649 mmol),
178

Chemistry of Heterocyclic Compounds 2020, 56(2), 173–179
Wu, B.; Zhu, D.; Zhang, C.; Zheng, B.; Wang, D.; Guo, H.
4-Hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine
(15). Pyrone 13 (0.070 g, 0.39 mmol) in 15% NH3/EtOH
(2 ml) was stirred at 0°С for 1 h, then the stirring was
continued for 4 days. The starting pyrone dissolved over
time. The excess solvent was evaporated in an evaporating
dish at room temperature, the solid residue was washed
with PhMe and dried at 120°С. Yield 0.052 g (75%), gray
crystals, mp 190–191°С. IR spectrum, ν, cm–1: 3312, 2851,
ACS Catal. 2019, 9, 1645. (c) Liu, K.; Teng, H.-L.; Wang, C.-J.
Org. Lett. 2014, 16, 4508.
3. (a) Politanskaya, L. V.; Selivanova, G. A.; Panteleeva, E. V.;
Tretyakov, E. V.; Platonov, V. E.; Nikulshin, P. V.;
Vinogradov, A. S.; Zonov, Ya. V.; Karpov, V. M.;
Mezhenkova, T. V.; Vasilyev, A. V.; Koldobskii, A. B.;
Shilova, O. S.; Morozova, S. M.; Burgart, Ya. V.;
Shchegolkov, E. V.; Saloutin, V. I.; Sokolov, V. B.;
Aksinenko, A. Yu.; Nenajdenko, V. G.; Moskalik, M. Yu.;
Astakhova, V. V.; Shainyan, B. A.; Tabolin, A. A.; Ioffe, S. L.;
Muzalevskiy, V. M.; Balenkova, E. S.; Shastin, A. V.;
Tyutyunov, A. A.; Boiko, V. E.; Igumnov, S. M.; Dilman, A. D.;
Adonin, N. Yu.; Bardin, V. V.; Masoud, S. M.; Vorobyeva, D. V.;
Osipov, S. N.; Nosova, E. V.; Lipunova, G. N.; Charushin, V. N.;
Prima, D. O.; Makarov, A. G.; Zibarev, A. V.; Trofimov, B. A.;
Sobenina, L. N.; Belyaeva, K. V.; Sosnovskikh, V. Ya.;
Obydennov, D. L.; Usachev, S. A. Russ. Chem. Rev. 2019, 88,
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Fluorine Chem. 2015, 172, 80. (c) Młochowski, J.; Giurg, M.;
Uher, M.; Korenova, A.; Vegh, D. J. Prakt. Chem. 1996, 338,
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1975, 12, 219. (e) Masanobu, I.; Atsuko, N.; Hideo, E.;
Shosuke, Y. Chem. Lett. 1980, 9, 1323. (f) Huynh-Dinh, T.;
Gouyette, C.; Igolen, J. Tetrahedron Lett. 1980, 21, 4499.
4. (a) Honma, Y.; Sekine, Y.; Hashiyama, T.; Takeda, M.; Ono, Y.;
Tsuzurahara, K. Chem. Pharm. Bull. 1982, 30, 4314.
(b) Shahrisa, A.; Hemmati, S. Indian J. Chem. 2000, 39B,
190.
1
1677, 1634, 1524, 1196, 1095, 992, 869, 815. H NMR
spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 2.60 (3Н,
s, CH3); 6.85 (1H, dd, J = 5.6, J = 2.3, H-5); 7.44 (1H, d,
J = 2.3, H-3); 8.31 (1H, d, J = 5.6, H-6); ОН proton not
detected. 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 10.6; 110.4; 114.0; 144.0; 151.1; 163.6; 164.6; 165.5.
Found, m/z: 178.0622 [M+Н]+. C8H8N3O2. Calculated, m/z:
178.0617.
2-(1H-Tetrazol-5-yl)-4-hydroxypyridine (16). Tetra-
zolylpyrone 12 (0.100 g, 0.58 mmol) in 20% aqueous NH3
(2 ml) was kept for 4 day. Ammonia was evaporated under
reduced pressure, 4 M aqueous HCl (4 ml) was added to
the residue, the formed precipitate was filtered off and
dried at 120°С. Yield 0.068 g (68%), colorless crystals,
mp >318°С. IR spectrum, ν, cm–1: 3096, 2897, 1618, 1463,
1
1315, 1230, 865. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 7.18 (1H, dd, J = 6.1, J = 2.3, Н-5); 7.81
(1H, d, J = 2.3, H-3); 8.46 (1H, d, J = 6.1, H-6); 8.50 (2Н,
br. s, OH, NH). 13C NMR spectrum (101 MHz, DMSO-d6),
δ, ppm: 110.1; 113.6; 114.6; 149.4; 154.9; 166.7. Found,
%: С 44.17; Н 3.21; N 42.83. C6H5N5O. Calculated, %:
С 44.17; Н 3.09; N 42.93.
5. Usachev, B. I.; Obydennov, D. L.; Röschenthaler, G.-V.;
Sosnovskikh, V. Ya. J. Fluorine Chem. 2012, 137, 22.
6. Obydennov, D. L.; Sidorova, E. S.; Usachev, B. I.;
Sosnovskikh, V. Ya. Tetrahedron Lett. 2013, 54, 3085.
7. (a) Zhou, J.; Wang, D.; Luo, X. H.; Jia, X.; Li, M. X.;
Laudon, M.; Zhang, R. X.; Jia, Z. P. J. Pharmacol. Exp. Ther.
2018, 364, 55. (b) Glenn, M. P.; Kahnberg, P.; Boyle, G. M.;
Hansford, K. A.; Hans, D.; Martyn, A. C.; Parsons, P. G.;
Fairlie, D. P. J. Med. Chem. 2004, 47, 2984.
8. (a) Obydennov, D. L.; El-Tantawy, A. I.; Kornev, M. Yu.;
Sosnovskikh, V. Ya. Mendeleev Commun. 2019, 29, 234.
(b) Obydennov, D. L.; El-Tantawy, A. I.; Sosnovskikh, V. Ya.
New J. Chem. 2018, 42, 8943.
9. Obydennov, D. L.; El-Tantawy, A. I.; Sosnovskikh, V. Ya.
J. Org. Chem. 2018, 83, 13776.
10. Obydennov, D. L.; Usachev, B. I.; Sosnovskikh, V. Ya. Chem.
Heterocycl. Compd. 2015, 50, 1388. [Khim. Geterotsikl. Soedin.
2014, 1510.]
11. Lu, C.-W.; Wang, Y.; Chi, Y. Chem.–Eur. J. 2016, 22, 17892.
12. Attenburrow, J.; Elks, J.; Elliott, D. F.; Hems, B. A.; Harris, J. O.;
Brodrick, C. I. J. Chem. Soc. 1945, 571.
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44, 1205. [Zh. Org. Khim. 2008, 44, 1218.]
This work was supported by the Russian Science
Foundation (grant 18-13-00186).
1
Elemental analysis was performed and H, 13C NMR
spectra were recorded on equipment of the Center for
collective use ''Spectroscopy and analysis of organic
compounds'' of the Institute of Organic Synthesis, Ural
Branch of the Russian Academy of Sciences and
''Laboratory of comprehensive examination and expert
evaluation of organic materials'' of Ural Federal
University.
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