Interaction of 5-acetyl(alkoxycarbonyl)-3-alkoxycarbonyl-6-methylpyridin- 2(1H)-ones with primary aromatic amines and hydrazine hydrate

Article abstract of DOI:10.1023/B:COHC.0000048288.74767.6f

5-Acetyl(alkoxycarbonyl)-3-alkoxycarbonyl-6-methylpyridin-2(1H)-ones have been obtained from enaminocarbonyl compounds. Their interactions with benzylamine, α-phenylethylamine, and hydrazine hydrate have been studied, as a result of which a series of amid

Full text of DOI:10.1023/B:COHC.0000048288.74767.6f

Chemistry of Heterocyclic Compounds, Vol. 40, No. 9, 2004
INTERACTION OF 5-ACETYL-
(ALKOXYCARBONYL)- 3-ALKOXYCARBONYL-
6-METHYLPYRIDIN-2(1H)-ONES WITH PRIMARY
AROMATIC AMINES AND HYDRAZINE HYDRATE
Zh. A. Krasnaya
5-Acetyl(alkoxycarbonyl)-3-alkoxycarbonyl-6-methylpyridin-2(1H)-ones have been obtained from
enaminocarbonyl compounds. Their interactions with benzylamine, α-phenylethylamine, and hydrazine
hydrate have been studied, as a result of which a series of amides, hydrazides, and hydrazones of 2(1H)-
pyridones has been synthesized.
Keywords: amides, hydrazides, hydrazones, 2(1H)-pyridones.
The considerable attention paid to the synthesis and investigation of 2(1H)-pyridones is linked primarily
with the broad spectrum of their biological activity. Among them are highly effective cardiotonics, tranquilizers,
fungicides, antimicrobial preparations, etc. [1-4]. Certain functionally substituted pyridones proved to be
inhibitors of the reverse transcriptase of HIV-1 [5], which opened new prospects for using them.
The introduction of such "pharmacophoric" fragments as hydrazide, hydrazone, and amide functions
proved to have a significant effect on the biological activity of pyridones [2, 6]. The hydrazide of isonicotinic
acid and its derivatives display high antitubercular activity [6]. Compounds have been discovered among the
hydrazones of heterocyclic ketones, which possess high antitumor, antimicrobial, antitubercular, and other forms
of activity [7].
In the present work the interaction has been studied of 3-alkoxycarbonyl-6-methylpyridin-2(1H)-ones,
functionally substituted at position 5, with aromatic primary amines (benzylamine, α-phenylethylamine) and
hydrazine hydrate, with the aim of synthesizing new derivatives of 2(1H)-pyridone, which are of interest as
potential biologically active compounds.
The initial substituted pyridin-2(1H)-ones were obtained by reacting enaminocarbonyl compounds with
cyanoacetic esters. We discovered previously that the substituted pyridones 2a,b are formed on interacting
ketone 1a and keto ester 1b with alkyl cyanoacetates [8].
Me
O
Me
R
NCCH2COOR1
R1
O
N
O
Me
R
Me
N
H
2a–e
O
1a–d
1, 2 a R = Me, b R = COOEt, c R = COOMe, d R = COMe;
2 e R = COMe; 2 a,c,d R1 = Me, b,e R1 = Et
__________________________________________________________________________________________
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913; e-mail:
kra@cacr.ioc.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1336-1342, September,
2004. Original article submitted January 16, 2002.
0009-3122/04/4009-1155©2004 Springer Science+Business Media, Inc.
1155

Using this method we obtained in high yield and under mild conditions (40°C, 1 h) pyridone 2c from
keto ester 1c and methyl cyanoacetate, and pyridones 2d,e from diketone 1d and alkyl cyanoacetates.
On heating (160-165°C, 30 min) pyridone 2a with an excess of benzylamine amide 3a is formed in 80%
yield. In the case of pyridones 2b,c, containing two alkoxycarbonyl groups in positions 3 and 5, only one group
(that located at position 3) reacts with benzylamine or α-phenylethylamine under the same conditions, leading to
the formation of amides 3b-e.
The structures of products 3a-e were confirmed by the results of elemental analysis (Table 1) and by
1
data of H NMR and UV spectra (Table 2), and the structure of amide 3c by the 13C NMR spectrum as well
(Table 2). The fact that the ester group in position 5 did not react was established, using amide 3c as an example,
with the aid of a 2D NOESY CH3/CH3O experiment.
On interacting a large excess of hydrazine hydrate with pyridones 2b,c (80°C, 30 min, i-PrOH) the
monohydrazides 4a,b were formed in 90% yield. Bishydrazides were not obtained on more extended heating
(10 h) of the reactants.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
2a
2b
С9Н11NО3
—
—
—
—
—
—
215-216 [8]
185-187 [8]
70
73
C12H15NO5
C10H11NO5
C10H11NO4
C11H13NO4
C15H16N2O2
C16H16N2O4
C17H18N2O4
C17H18N2O4
C18H20N2O4
C9H11N3O4
C10H13N3O4
C17H18N2O3
C18H20N2O3
С23H23N3O2
C9H11N3O3
C9H13N5O2
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
5a
5b
6
53.02
53.33
57.27
57.41
58.84
59.18
69.97
70.29
63.85
64.00
65.30
64.95
65.02
64.95
65.76
65.84
47.77
48.00
49.82
50.20
64.58
64.70
65.33
65.44
73.78
73.97
51.74
51.67
48.64
48.42
4.78
4.92
5.18
5.30
5.99
5.87
6.31
6.29
5.14
5.34
5.80
5.77
5.69
5.77
6.13
6.14
4.91
4.92
5.76
5.48
6.51
6.34
6.70
6.71
6.43
6.21
5.32
5.30
6.00
5.87
6.31
6.22
6.78
6.70
6.38
6.28
10.86
10.93
9.21
9.34
8.98
8.91
9.01
8.91
8.84
8.53
19.06
18.66
17.58
17.57
8.92
8.89
8.97
8.48
11.51
11.25
19.90
20.09
31.29
31.38
199-201
208-209
170-171
212-213
258-260
253-255
255-256
198-200
>260
80
74
76
81
90
80
89
80
90
90
87
90
65
86
85
>260
203-204
169-170
165-166
246-247
260-261
·
H2O
H2O
·
7
8
1156

TABLE 2. Spectral Characteristics of the Synthesized Compounds
Y
X
5
3
1
Me
N
O
H
2–8
1H NMR spectrum, δ, ppm*
UV spectrum
(EtOH), λmax, nm (ε)
Com-
pound
Н-1
Н-4
6-СН3
(3Н, s)
5
X
6
Y
7
(1Н, br. s) (1Н, s)
1
2
3
4
2a
2b
208 (9300), 243 (7760) 345 (9100)
13.40
13.05
8.10
8.80
2.55
2.82
3.90 (3H, s, CH3)
2.15 (3H, s, CH3)
210 (15200), 263 (16700),
330 (8450)
4.38 (2H, q, CH2); 1.40 (3H, t, CH3)
4.38 (2H, q, CH2); 1.40 (3H, t, CH3)
2c
2d
2е
3a
3b
210 (14050), 263 (16850),
330 (8450)
12.50
12.95
13.10
12.10
12.70
8.50
8.75
8.70
8.20
8.76
2.60
2.85
2.85
2.30
2.68
3.78 (3H, s, CH3)
3.80 (3H, s, CH3)
212 (18200), 280 (21800),
335 (11800)
3.95 (3H, s, CH3)
2.55 (3Н, s, CH3)
212 (18500), 283 (21400),
338 (11900)
4.40 (2H, q, CH2); 1.40 (3H, t, CH3)
2.55 (3Н, s, CH3)
208 (21800), 240 (12800),
335 (16800)
10.20 (1H, t, NH); 4.55 (2H, d, CH2);
7.20-7.40 (5H, m, C6H5)
2.10 (3Н, s, CH3)
208 (29400), 260 (16200),
325 (11100)
9.73 (1H, t, NH); 4.55 (2H, d, CH2);
7.20-7.40 (5H, m, C6H5)
3.85 (3Н, s, CH3)

TABLE 2 (continued)
1
2
3
4
5
6
7
3c*2
210 (33000), 263 (16000),
328 (12950)
12.65
8.70
2.65
9.80 (1H, d, NH); 5.10 (1Н, m, СН);
1.45 (3H, d, CH3);
3.80 (3H, s, CH3)
7.20-7.40 (5H, m, C6H5)
3d
3e
4a
4b
5a
5b
210 (28600), 260 (18900),
324 (12800)
12.75
12.75
8.75
8.70
8.68
8.70
8.48
8.45
2.65
2.65
2.62
2.65
2.58
2.60
9.75 (1H, t, NH); 4.52 (2H, d, CH2);
7.20-7.40 (5H, m, C6H5)
4.28 (2H, q, CH2); 1.30 (3H, t, CH3)
4.25 (2H, q, CH2); 1.30 (3H, t, CH3)
3.80 (3H, s, CH3)
210 (33200), 262 (19300),
325 (13100)
210 (17300), 263 (14100),
325 (10000)
9.80 (1H, d, NH); 5.15 (1Н, m, СН);
1.50 (3H, d, CH3); 7.20-7.40 (5H, m, C6H5)
10.15 (1Н, s, NH)
210 (21800), 260 (17900),
325 (12800)
4.25 (2H, q, CH2); 1.30 (3H, t, CH3)
210 (18900), 275 (20200),
330 (10750)
210 (18800), 275 (20700),
328 (11300)
3.80 (3H, s, CH3)
2.45 (3H, s, CH3); 3.75 (2H, s, СН2);
7.10-7.30 (5Н, m, C6H5)
2.35 (3Н, s, CH3); 3.75 (2H, s, CH2);
7.10-7.40 (5H, m, C6H5)
4.22 (2Н, m, СН2); 1.25 (3H, d, CH3)
6
210 (82000), 255 (41000),
335 (36000)
12.45
12.10
8.40
2.50
10.00 (1H, br. s, NH);
7.10-7.40 (10H, m, 2 C6H5)*3;
4.55 (2Н, d, СН2)
4.60 (2Н, s, СН2); 2.25 (3Н, s, CH3)
7
8
210 (17200), 270 (16200),
325 (11300)
8.70
8.17
2.6
10.20 (1Н, br. s, NHNH2)
2.45 (3Н, s, CH3)
208 (11400), 255 (13400),
340 (8950)
2.30
5.70 (2Н, br. s, NН2); 10.40 (1Н, br. s, NHNН2)
1.95 (3Н, s, CH3); 4.80 (2Н, br. s, NH2)
_______
* Spectra were taken in CDCl3 (compounds 2a,b,d,e) and DMSO-d6 (compounds 2s, 3a-e, 4a,b, 5a,b, 6-8). In all cases
when the signal was d, t, or q, J ~7 Hz.
2
*
13C NMR spectrum (DMSO-d6): 18.80 (CH3-C(6)); 22.57 (CH3–CH); 48.11 (CH–NH); 51.80 (CH3); 107.64 (C(5));
116.81 (C(3)); 125.84 (o-CPh); 126.84 (p-CPh); 128.43 (m-CPh); 143.94 (C6H5); 144.04 (C(4)); 156.82 (C(6)); 161.62
(CONH); 162.55 (C(2)); 164.33 (COCH3).
*3 Signals of the C6H5 group protons in substituents X and Y were superimposed, forming an aggregate multiplet.

R2
O
R
N
Ph
H
2a–c
+
+
H2NCH(R2)Ph
Me
N
H
O
O
3a–e
R
NHNH2
.
NH2NH2 H2O
2b,c
Me
N
H
O
4a,b
3 a R = Me, R2 = H, b R = COOMe, R2 = H, c R = COOMe, R2 = Me,
d R = COOEt, R2 = H, e R = COOEt, R2 = Me, 4 a R = COOMe, b R = COOEt
We discovered that the structure of the products of the interaction of benzylamine and hydrazine hydrate
with pyridones 2d,e, containing an acetyl group in position 5, depends on the reaction conditions when
interacting equivalent quantities of pyridones 2d,e and benzylamine. At 20°C azomethines 5a,b are formed in
87-90% yield.
Me
O
O
O
2 : PhCH2NH2,
1 : 1
PhCH2N
Me
OR
Me
OR
20 oC
N
H
O
Me
N
H
O
5a,b
2d,e
Me
O
2 : PhCH2NH2,
1 : 3
PhCH2N
Me
NHCH2Ph
160 oC
N
O
O
H
6
O
.
2 : H2NNH2 H2O,
Me
NHNH2
1 : 1
80 oC
Me
N
H
O
7
NNH2
O
O
.
2 : H2NNH2 H2O,
Me
NHNH2
1 : 17
80 oC
Me
N
H
8
5 a R = Me, b R = Et
1159

On heating pyridone 2d with an excess of benzylamine (160°C, 20 min) the reaction proceeds at both the
acetyl and ester groups and leads to amide 6 in 65% yield. From equimolar quantities of hydrazine hydrate and
pyridone 2d or 2e hydrazide 7 is formed in 86% yield on boiling in i-PrOH solution (1 h). Under the same
conditions, but using a large excess of hydrazine hydrate, the hydrazidohydrazone 8 is formed in 85% yield.
1
The structures of products 5-8 were confirmed by data of elemental analysis (Table 1) and of H NMR
and UV spectra (Table 2).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker WM-250 (250 MHz) instrument, and the 13C NMR
spectrum (62 MHz) and the 2D NOESY experiment on a Bruker DRX-500 instrument. The UV spectra were
taken on a Specord UV-vis instrument in ethanol.
Esters 2a,b were obtained by the known method of [8].
3,5-Dimethoxycarbonyl-6-methylpyridin-2(1H)-one
(2c).
A
mixture
of
2-acetyl-3-
dimethylaminoacrylic acid methyl ester (1c) (10 g, 5.9 mmol) and methyl cyanoacetate (5.8 g, 5.9 mmol) was
maintained for 1 h 30 min at 40°C and 1 day at room temperature. Dry ether was then added to the copious
yellow precipitate, the solid was filtered off, washed with ether, and recrystallized from methanol. Product 2c
(10.5 g) was obtained.
5-Acetyl-3-methoxycarbonyl-6-methylpyridin-2(1H)-one (2d). A mixture of 3-(dimethylamino-
methylene)pentane-2,4-dione (1d) (3 g, 2 mmol), methyl cyanoacetate (2.8 g, 2.8 mmol), and absolute methanol
(7 ml) was maintained for 1 h at 40°C, then for 1 day at room temperature. The bright-yellow solid (3.5 g) was
filtered off, washed with methanol, and recrystallized from methanol. Product 2d (3.1 g) was obtained as a
snow-white solid.
5-Acetyl-3-ethoxycarbonyl-6-methylpyridin-2(1H)-one (2e) was obtained analogously to pyridone 2d
from diketone 1d (2 g, 1.3 mmol), ethyl cyanoacetate (2 g, 1.8 mmol), and absolute ethanol (5 ml). Compound
2e was recrystallized from ethanol.
3-Benzylcarbamoyl-5-ethoxycarbonyl-6-methylpyridin-2(1H)-one (3d). A mixture of pyridone 2b
(1 g, 4 mmol) and benzylamine (1.3 g, 12 mmol) was heated on an oil bath. At 130-140°C the reaction mixture
became homogeneous, it was heated to 160-170°C and maintained at this temperature for 15 min. After cooling,
absolute ether was added to the copious colorless solid, the solid was filtered off, and washed thoroughly with
absolute ether, and with methanol. Amide 3d (1.1 g) was obtained.
3-Benzylcarbamoyl-5-methoxycarbonyl-6-methylpyridin-2(1H)-one (3b) was obtained analogously
to amide 3d from diester 2c (0.9 g, 4 mmol) and benzylamine (1.3 g, 12 mmol) with a yield of 1.05 g.
3-Benzylcarbamoyl-5,6-dimethylpyridin-2(1H)-one (3a) was obtained analogously to compounds
3b,d from pyridone 2a (0.3 g, 1.7 mmol) and benzylamine (0.27 g, 2.5 mmol) with a yield of 0.34 g.
5-Methoxycarbonyl-6-methyl-3-(1-phenylethyl)carbamoylpyridin-2(1H)-one (3c). A mixture of
pyridone 2c (3 g, 12 mmol) and α-phenylethylamine (4.4 g, 36 mmol) was maintained at 160-165°C for 20 min.
After cooling, the solid was filtered off, and washed with ether. Methanol was added to it, the mixture was
boiled for 5-10 min, and cooled. The solid was filtered off, washed with methanol, and with dry ether. Amide 3c
(3 g) was obtained.
5-Ethoxycarbonyl-6-methyl-3-(1-phenylethyl)carbamoylpyridin-2(1H)-one (3e). A mixture of
pyridone 2b (1 g, 4 mmol) and α-phenylethylamine (1.5 g, 12 mmol) was maintained at 160-165°C for 35 min,
then cooled, absolute ether was added, and the solid separated. Absolute ethanol was added to the solid, and the
mixture boiled for 5-10 min. The solid was separated, washed with absolute ether, and amide 3e (1.05 g) was
obtained.
1160

3-Carbazoyl-5-methoxycarbonyl-6-methylpyridin-2(1H)-one (4a). A mixture of diester 2c (0.9 g,
4 mmol), hydrazine hydrate (3 ml), and 2-propanol (5 ml) was boiled for 30 min. After cooling, the solid was
filtered off, washed with methanol, and with ether. Product 4a (0.8 g) was obtained.
3-Carbazoyl-5-ethoxycarbonyl-6-methylpyridin-2(1H)-one (4b) was obtained analogously to
pyridone 4a from diester 2b.
5-(1-Benzyliminoethyl)-3-methoxycarbonyl-6-methylpyridin-2(1H)-one (5a). A mixture of pyridone
2d (0.21 g, 1 mmol) and benzylamine (0.11 g, 1 mmol) was stirred vigorously at room temperature and
maintained at the same temperature for 1 day. Absolute ether was then added, the precipitate was filtered off, and
washed with absolute ether. Azomethine 5a (0.26 g) was obtained as the hydrate.
5-(1-Benzyliminoethyl)-3-ethoxycarbonyl-6-methylpyridin-2(1H)-one (5b) was obtained analogously
to azomethine 5a from pyridone 2a, as the hydrate.
3-Benzylcarbamoyl-5-(1-benzyliminoethyl)-6-methylpyridin-2(1H)-one (6). A mixture of ester 2d
(0.63 g, 3 mmol) and benzylamine (1.0 g, 9 mmol) was maintained at 160°C for 20 min. The liquid reaction
mixture was evaporated in vacuum, ether was added to it, the solid was filtered off, and boiled in acetone for
5-10 min. After cooling, the solid was filtered off, washed with acetone, and product 6 (0.72 g) was obtained.
5-Acetyl-3-carbazoyl-6-methylpyridin-2(1H)-one (7). A mixture of pyridone 2d (0.21 g, 1 mmol) and
hydrazine hydrate (0.05 g, 1 mmol) in 2-propanol (0.85 ml) was boiled for 1 h. After cooling, the solid was
filtered off, washed with methanol, and with ether, and boiled for 5-10 min in acetone. The solid was then
filtered off, washed with acetone, with ether, and hydrazide 7 (0.18 g) was obtained. The same hydrazide 7 was
obtained analogously from pyridone 2e.
3-Carbazoyl-5-(1-hydrazonoethyl)-6-methylpyridin-2(1H)-one (8). A mixture of pyridone 2d (0.21 g,
1 mmol), hydrazine hydrate (1 ml, 17 mmol), and 2-propanol (1.5 ml) was boiled for 1 h, cooled, the slightly
yellowish solid was separated, and was thoroughly washed with absolute methanol, then with absolute ether.
Compound 8 (0.19 g) was obtained.
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1161