Condensation products of 1-aryl-3-ethoxycarbonyl-2-methyl-1,4,5,6- tetrahydro-4(1H)pyridones with hydrazine, phenylhydrazine, and hydroxylamine

Article abstract of DOI:10.1023/B:COHC.0000040773.29086.36

We have studied condensation of 1-(4-bromophenyl- and 2,5-dimethylphenyl)- 3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridones with hydrazine, phenylhydrazine, and hydroxylamine, as a result of which we obtained nucleophilic substitution and intra

Full text of DOI:10.1023/B:COHC.0000040773.29086.36

Chemistry of Heterocyclic Compounds, Vol. 40, No. 6, 2004
CONDENSATION PRODUCTS OF 1-ARYL-
3-ETHOXYCARBONYL-2-METHYL-
1,4,5,6-TETRAHYDRO-4(1H)PYRIDONES
WITH HYDRAZINE, PHENYLHYDRAZINE,
AND HYDROXYLAMINE
R. Vaickelioniene1, V. Mickevicius1, and G. Mikulskiene2
We have studied condensation of 1-(4-bromophenyl- and 2,5-dimethylphenyl)-3-ethoxycarbonyl-2-
methyl-1,4,5,6-tetrahydro-4(1H)pyridones with hydrazine, phenylhydrazine, and hydroxylamine, as a
result of which we obtained nucleophilic substitution and intramolecular cyclization products:
5-(4-bromophenyl- and 2,5-dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazole[4,3-c]pyridin-3-
ones, 5-(4-bromophenyl- and 2,5-dimethylphenyl)-4-methyl-6,7-dihydroisoxazole[4,3-c]pyridin-3(5H)-
ones. We used computer modeling of the molecules of the studied compounds to obtain additional
information on the structural features of the reaction products.
Keywords: 1-aryl-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridones, hydrazides of
pyridine-3-carboxylic acids, keto–enol tautomerism, condensation, exchange processes, 1H and
13C NMR spectroscopy, cyclization.
Pyridone derivatives include compounds known to have pharmaceutical [1, 2] and agrochemical [1-3]
activity.
In this paper, we have studied the reactions of 1-aryl-3-ethoxycarbonyltetrahydro-2-methyl-4(1H)-
pyridones with some nucleophiles. When tetrahydropyridones 1a,b are refluxed with hydrazine hydrate in
methanol, the hydrazides of 1-(4-bromophenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic acid (2a)
and 1-(2,5-dimethylphenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic acid (2b) are formed, which
separate out from the reaction mixture even during the reaction.
According to the 1H NMR spectra, the enol form is observed not only in the synthesized hydrazides 2a,b
but also in their condensation products with aromatic aldehydes: 2-(4-methoxyphenyl)methylidene hydrazide of
(1-(4-bromophenyl)-4-hydroxy-2-methyl-1,6-dihydro-3-pyridinecarboxylic acid (3a), 2-(3,4-dimethoxyphenyl)-
methylidene hydrazide of 1-(4-bromophenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic acid (4a),
2-(4-dimethylaminophenyl)methylidene
hydrazide
of
1-(2,5-dimethylphenyl)-4-hydroxy-2-methyl-1,6-
dihydropyridine-3-carboxylic acid (5b), apparently due to the strong intramolecular hydrogen bond between the
oxygen atom of the 4-OH group of the heterocycle and the hydrazine moiety. When compound 1a is heated with
phenylhydrazine in methanol, the carbonyl group in the 4 position of the heterocycle undergoes nucleophilic
__________________________________________________________________________________________
1
Kaunas University of Technology, Kaunas 50299, Lithuania; e-mail: Vytautas.Mickevicius@ktu.lt.
2 Institute of Biochemistry, Vilnius LT-08622, Lithuania; e-mail: gemam@bchi.lt. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 895-904, June, 2004. Original article submitted July 1, 2003;
revision submitted March 15, 2004.
0009-3122/04/4006-0767©2004 Plenum Publishing Corporation
767

attack first of all. In fact, in the 1H NMR spectrum of compound 8a, we observe signals from the ester group OEt
as a quartet at 4.24 ppm and a triplet at 1.28 ppm, and new signals also appear from the monosubstituted phenyl.
The reaction of 1-(4-bromophenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)pyridone (1a) with
hydrazine hydrate or phenylhydrazine in glacial acetic acid at the boiling point of the mixture leads to formation
of condensed bicyclic compounds: 5-(4-bromophenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazolo-[4,3-c]pyridin-
3-one (6a) and 5-(4-bromophenyl)-4-methyl-2-phenyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]-pyridin-3-one (7a).
By the same method, from compound 1b we also obtained 5-(2,5-dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro-
3H-pyrazolo[4,3-c]pyridin-3-one (6b). Upon condensation of tetrahydropyridones 1a,b with hydroxylamine
hydrochloride in a boiling mixture of 2-propanol and pyridine, the corresponding 5-aryl-4-methyl-6,7-
dihydroisoxazolo[4,3-c]pyridin-3(5H)-ones 9a,b are formed.
O
Me
O
N
NH2OH
R
N
Me
N
CO2Et
O
9a,b
R
N2H4
O
NH2
1a,b
Me
N
H
+
N2H4, H
4
5
R
N
H
OH
PhNHNH2
PhNHNH2, H+
2a,b
+
O
Me
N
Me
CO2Et
N
R1
N
+
H
ArCHO
N
N
R
R
N
N
H
Ph
8a
6a,b, 7a
O
Me
N
N
H
Ar
R
OH
3a, 4a, 5b
а R = 4-BrC6H4; b R = 2,5-Me2С6Н3; 3а Ar = 4-MeOC6H4; 4a Ar = 3,4-(MeO)2C6H3;
5b Ar = 4-Me2NC6H4; 6а,b R1 = H; 7а R1 = Ph
1
13
The structures of the synthesized compounds were confirmed by H and C NMR spectroscopy, with
assignment of the signals based on the general substituent additivity rules [4]. The appearance of new
characteristic signals in the NMR spectra of compounds 6a,b, 7a, 9b confirms the formation of new cyclic
structures. The NMR spectra of the compounds 2a,b, 3a, 4a, and 5b proved to be unexpectedly complex: the
1H NMR spectra were complicated by the presence of a large number of signals and some broadening of those
13
signals; the C NMR spectra were complicated by the absence of the required number of signals. Apparently
768

TABLE 1. 1H NMR Spectra (DMSO-d6) for Compounds 2-9
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
2a
2b
2.34 (3H, br. s, 2-CH3); 2.82 (2H, m*, CH2CO); 3.25 (2H, m*, CH2N);
5.30 (2H, br. s, NH2); 5.87 (1H, br. s*, CH=); 6.53 (2H, d, J = 8.9, H-2', H-6' arom.);
7.19 (2H, d, J = 8.9, H-3', H-5' arom.); 10.84 (1H, br. s, NH)
2.0 (3H, s, 2'-CH3); 2.20 (3H, s, 5'-CH3); 2.36 (3H, br. s, 2-CH3); 2.91 (2H, m*, CH2CO);
3.32 (2H, m*, CH2N); 4.76 (1H, br. s*, СH=); 5.33 (2H, br. s, NH2);
6.32 (1H, d, J = 7.4, H-3' arom.); 6.37 (1H, s, H-6' arom.);
6.82 (1H, d, J = 7.4, H-4' arom.); 10.87 (1H, br. s, NH)
3a
4a
5b
6а
2.62 (3H, br. s, 2-CH3); 2.92 (2H, m*, CH2CO); 3.33 (2H, m*, CH2N);
3.82 (3H, s, OCH3); 5.90 (1H, br. s*, CH=); 6.56 (2H, d, J = 8.8, H-2', H-6' arom.);
7.02 (2H, d, J = 8.8, H-2'', H-6'' arom.); 7.19 (2H, d, J = 8.8, H-3', H-5' arom.);
7.60 (2H, d, J = 8.8, 3''-, 5''-H); 8.39 (1H, s, CH=); 11.21 (1H, br. s, NH);
14.20 (1H, br. s, OH)
2.64 (3H, br. s, 2-CH3); 2.89 (2H, m*, CH2CO); 3.40 (2H, m*, CH2N);
3.82 (6H, s, OCH3); 5.89 (1H, br. s*, CH=); 6.56 (2H, d, J = 8.8, H-2', H-6' arom.);
7.05 (1H, d, J = 8.4, H-5'' arom.); 7.20 (2H, d, H-3', H-5' arom.);
7.35 (1H, d. d, H-6'' arom.); 7.41 (1H, s, H-2'' arom.); 8.38 (1H, s, CH=);
11.21, 12.20 (1H, br. s, NH); 14.20 (1H, br. s, OH)
2.01 (3H, s, 2'-CH3); 2.20 (3H, s, 5'-CH3); 2.65 (3H, br. s, 2-CH3); 2.96 (2H, m*, CH2CO);
3.00 (6H, s, N(CH3)2); 3.37 (2H, m*, СH2N); 4.80 (1H, m*, CH=); 6.32 (1H, d, J = 7.4,
H-3' arom.); 6.41 (1H, s, H-6' arom.); 6.76 (2H, d, J = 8.9, H-3'', H-5'' arom.);
6.84 (1H, d, J = 7.4, H-4' arom.); 7.63 (2H, d, J = 8.9, H-2'', H-6'' arom.);
8.28 (1H, s, СH=); 11.17, 12.01 (1H, br. s, NH); 14.03, 14.26 (1H, br. s, OH)
2.18 (3H, s, 2-CH3); 2.78 (2H, t, J = 6.7, CH2C=N); 3.90 (2H, t, J = 6.7, CH2N);
7.42 (2H, d, J = 8.6, H-2', H-6' arom.); 7.70 (2H, d, J = 8.6, H-3', H-5' arom.);
10.50 (1H, s, NH)
6b
2.06 (3H, s, 2'-CH3); 2.18 (3H, s, 5'-CH3); 2.30 (3H, s, 2-CH3); 2.81 (2H, m , CH2C=N);
3.78 (2H, m , CH2N); 7.10-7.32 (3H, m , H-3', H-4', H-6' arom.); 10.50 (1H, s, NH)
7а
2.36 (3H, s, 2-CH3); 2.99 (2H, t, J = 7.2, CH2C=N); 3.91 (2H, t, J = 7.2, CH2N);
7.08 (2H, d, J = 8.8, H-2', H-6' arom.); 7.12 (1H, t, J = 7.4, H-4" arom.);
7.38 (2H, t, J = 7.4, H-3'', H-5" arom.); 7.59 (2H, d, J = 8.8, H-3', H-5' arom.);
8.02 (2H, d, J = 7.4, H-2", H-6" arom.)
8а
9а
9b
1.28 (3H, t, CH2CH3); 1.76 (3H, s, 2-CH3); 2.93 (2H, t, CH2C=N); 3.93 (2H, t, CH2N);
4.24 (2H, q, CH2CH3); 6.60-8.20 (9H, m , H arom.); 8.86 (1H, s, NH)
2.15 (3Н, s, СН3); 2.94 (2H, t, CH2C=N); 3.98 (2H, t, CH2N);
7.43 and 7.74 (4Н, 2d, J = 8.8, H arom.)
2.18 (3H, s, 2'-CH3); 2.21 (3H, s, 5'-CH3); 2.37 (3H, s, 2-CH3);
3.83 (2H, t, J = 6.6, CH2C=N); 3.77-3.91 (2H, m , CH2N); 6.96 (1H, s, H-6' arom.);
7.15-7.27 (2H, m , H-3', H-4' arom.)
_______
* Signals for exchange multiplets of the keto–enol form.
1
keto–enol tautomerism is typical of compounds 2a,b, 3a, 4a, and 5b [5-8]. Detailed study of the H NMR
spectra of compounds 2a,b, 3a, 4a, and 5b showed that in solution the compounds exist simultaneously in both
the ketone and enol forms. The process of keto–enol tautomerism explains the broadening of the multiplets and
the intensity distribution among them. We know that depending on the proton exchange rate between the keto–
1
enol forms, in the H NMR spectra [4] we observe either individual multiplets or broadened exchange signals.
Computer modeling of the molecules, based on the concepts of molecular mechanics (MM2 method) and
semiempirical molecular orbital methods (MOPAC program), is quite useful in studying keto–enol forms [9]. By
minimization of the total energy of the model molecules, we established that the enol form is typically lower in
energy (2a enol form, -6.79 kcal/mol) than the keto form (-3.43 kcal/mol).
1
In the H NMR spectra of compounds 2a,b, 3a, 4a, and 5b, we observe individual multiplet signals for
the protons of the NCH2 moiety (~3.3 ppm) and the CH2CO moiety (~2.9 ppm) and broad singlets for the
CH=COH moiety (~5.9 ppm and 4.8 ppm). The integrated intensity of the multiplet signal from the protons of
769

TABLE 2. 13C NMR Spectra (DMSO-d6) for Compounds 6a, 6b, 71, 9b
R2 = Br, X = N, R, R1, R3 = H
6а
6b
R = H, X = N, R1, R3 = CH3
O
R1
CH3
R2 = Br, X = N, R1, R3 = H,
C
3' 2'
3
XR
2
2''
3''
1'
R2
N
N
1''
7а
4
4'
R =
4''
5
6
5'
6'
R3
X = O, R1, R3 = CH3
9b
Chemical chifts, δ, ppm
Carbon atoms
6а
6b
7а
9b
C(2)
C(3)
160.92
100.40
144.82
23.30
161.37
99.45
163.89
102.40
145.28
23.88
164.98
91.45
C(4)
144.83
23.35
156.30
22.38
C(5)
C(6)
52.96
52.02
53.38
51.87
C=O
2-CH3
C(1')
166.76
14.97
166.77
14.52
162.56
15.40
172.05
15.40
141.92
128.79
132.50
120.90
132.50
128.79
141.02
131.13
131.34
129.46
136.90
127.62
16.66
141.40
128.66
133.33
122.58
133.33
128.66
140.43
131.02
131.77
130.50
138.22
127.13
17.05
C(2')
C(3')
C(4')
C(5')
C(6')
2'-CH3
5'-CH3
C(1")
C(2")
C(3")
C(4")
20.32
20.81
139.17
118.89
127.95
123.93
the NCH2 group is equal to the sum of the intensities of the signals from the CH2CO and CH=COH moieties.
The multiplet from the NCH2 moiety is broadened and quartet-shaped, probably due to overlap of a doublet (for
the enol form) and a triplet (for the ketone form). The multiplet from the CH2CO moiety (the ketone form) is
broadened and triplet-shaped.
In the spectra of compounds 2a,b, 3a, 4a, and 5b, we observed significant broadening and a signal from
the protons of the 2-CH3 group, although this group is not involved in the direct process of keto–enol exchange.
Detailed study of the data obtained by computer modeling (Table 3) indicated the presence of charge transfer
(the appearance of a partial double bond N–C(2)) between the benzene ring and the heterocycle in the studied
structures. In this case, an extended double bond system is formed. Since the CH=CH group has a greater -I
effect [10] than the phenyl moiety, the shielding of the 2-CH3 group will change. A change in the electron
density in the heterocycle is also indicated by the appearance of conjugation between C(2)=C(3) and C(4)=C(5) upon
formation of the enol form, and also formation and breaking of the intramolecular hydrogen bond [4, 6, 11-13]
between the 4-OH and 3-C–C=O groups. The change in the electron density in the heterocycle affects the
chemical shift of the signals from the protons of the 2-CH3 group and thus is responsible for broadening of such
signals.
770

The presence of a NHN=CHAr moiety in compounds 3a, 4a, and 5b is why Z/E-isomerism is possible,
In the 1H NMR spectra of compounds 4a and 5b, there are rather intense signals from protons of the NH group at
11.21 ppm and 11.17 ppm respectively, and there are low-intensity broadened signals at 12.0 ppm. Based on
TABLE 3. Models of Synthesized Compounds (Total Energy Optimized to a
Global Minimum)
2а (keto form)
2а (enol form)
-6.79 kcal/mol
-3.43 kcal/mol
3а (E)
3а (Z)
-4.06 kcal/mol
-16.51 kcal/mol
4а (E)
4a (Z)
-5.75 kcal/mol
-16.41 kcal/mol
771

TABLE 3 (continued)
5b (E)
5b (Z)
-10.51 kcal/mol
-18.71 kcal/mol
6а
6b
15.40 kcal/mol
15.35 kcal/mol
7а
9b
18.62 kcal/mol
15.33 kcal/mol
8а (Z-isomer relative to the C(5) atom in the
8а (E-isomer relative to the C(5) atom in the
heterocycle)
heterocycle)
2.61 kcal/mol
1.53 kcal/mol
772

this, we can conclude that the studied compounds 4a and 5b exist predominantly in the form of Z-isomers, but
with a fairly small E-isomer impurity. We do not observe Z/E-isomerism for compound 3a. The computer
modeling data for 3a, 4a, and 5b showed that the existence of Z-isomers is most favorable, since their energy is
about 10 kcal/mol lower than the energy of the E-isomer.
According to computer modeling data, compound 8a more likely exists in the form of the Z-isomer
(relative to the C(5) atom of the heterocycle), having lower total energy than the corresponding E isomer. The
bulky substituent at the C(3) atom probably hinders formation of the E-isomer [13].
The signals for the carbon atoms in the 13C NMR spectra of compounds 6a,b, 7a, 9b were fully assigned.
13
In these compounds, exchange processes are stopped by formation of cyclic structures. In the C NMR spectra
of compounds 2a,b, 3a, 4a, 5b, due to a dynamic equilibrium between the interconverting keto–enol isomers,
formation of a system of double bonds between the benzene and heterocyclic moieties, and formation of
intramolecular hydrogen bonds, the shielding effect for the carbon atoms becomes somewhat indeterminate. So
some signals in the compounds with a change in electron density may not be detected by the instrument. The
problem of assigning the lines in the 13C NMR spectra of such compounds is complicated by the averaged nature
of the effect of the substituents due to the keto–enol forms of the compounds formed, and also the possibility of
recording individuals signals for atoms of the keto–enol forms.
EXPERIMENTAL
The 1H and 13C NMR spectra were obtained on a Varian Unity Inova (300 MHz) and a Bruker AC 250-P
(250 MHz), internal standard TMS. The IR spectra in KBr disks were recorded on a Perkin-Elmer Spectrum BX
FT-IR system. The course of the reactions and the purity of the compounds obtained were monitored by TLC on
Silufol UV-254 plates, visualization in UV light or iodine vapors.
Hydrazide of 1-(4-Bromophenyl)-4-hydroxy-2-methyl-1,6-dihydropyridine-3-carboxylic Acid (2a).
1-(4-Bromophenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6-tetrahydro-4(1H)-pyridone (1a) (0.5 g, 1.5 mmol) and
hydrazine hydrate (0.15 g, 3.0 mmol) in methanol (10 ml) were refluxed for 2 h. The reaction mixture was
cooled down, the precipitated crystals were filtered out and washed with methanol and then ether, and then dried.
Yield 0.38 g (78%); mp 200-202°C (dioxane). IR spectrum, ν, cm-1: 3383.83, 3317.19, 3148.66; 1640.36.
Found, %: C 48.29; H 4.22; N 12.87. C13H14BrN3O2. Calculated, %: C 48.17; H 4.35; N 12.96.
Hydrazide of 1-(2,5-Dimethylphenyl)-4-hydroxy-2-methyl-1,6-dihydro-3-pyridinecarboxylic Acid
(2b) was obtained as for compound 2a, from 1-(2,5-dimethylphenyl)-3-ethoxycarbonyl-2-methyl-1,4,5,6-
tetrahydro-4(1H)-pyridone (1b) (1.0 g, 3.5 mmol), hydrazine hydrate (0.4 g, 8.0 mmol) and methanol (10 ml).
Yield 0.75 g (78%); mp 195-196°C (dioxane). Found, %: C 65.76; H 6.82; N 15.18. C15H19N3O2. Calculated, %:
C 65.91; H 7.01; N 15.37.
2-(4-Methoxyphenyl)methylidene Hydrazide of 1-(4-Bromophenyl)-4-hydroxy-2-methyl-1,6-
dihydropyridine-3-carboxylic Acid (3a). A mixture of hydrazide 2a (0.33 g, 1.0 mmol) and
4-methoxybenzaldehyde (0.27 g, 2.0 mmol) in 2-propanol (10 ml) was boiled for 2 h and cooled down; the
precipitate was filtered out and washed with propanol and then ether, and then dried. Yield 0.37 g (84%);
mp 219-221°C (2-propanol). IR spectrum, ν, cm-1: 3320.48, 3148.92; 1632.12, 1605.66. Found, %: C 57.17;
H 4.47; N 9.58. C21H20BrN3O3. Calculated, %: C 57.02; H 4.56; N 9.50.
2-(3,4-Dimethoxyphenyl)methylidene Hydrazide of 1-(4-Bromophenyl)-4-hydroxy-2-methyl-1,6-
dihydropyridine-3-carboxylic Acid (4a) was obtained as for methylidene hydrazide 3a from hydrazide 2a
(0.33 g, 1.0 mmol), 3,4-dimethoxybenzaldehyde (0.25 g, 1.5 mmol) in 2-propanol (10 ml). Yield 0.40 g (85%);
mp 217-219°C (2-propanol). Found, %: C 55.49; H 4.40; N 9.18. C22H22BrN3O4. Calculated, %: C 55.94;
H 4.69; N 8.90.
773

2-[4-(N,N-Dimethylamino)phenyl]methylidene Hydrazide of 1-(2,5-Dimethylphenyl)-4-hydroxy-2-
methyl-1,6-dihydropyridine-3-carboxylic Acid (5b) was obtained similarly, from hydrazide 2b (0.5 g,
1.8 mmol), 4-dimethylaminobenzaldehyde (0.3 g, 1.8 mmol) in 2-propanol (10 ml). Yield 0.34 g (47%);
mp 245-246°C (2-propanol). Found, %: C 71.44; H 6.75; N 13.98. C24H28N4O2. Calculated, %: C 71.26; H 6.98;
N 13.85.
5-(4-Bromophenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridin-3-one
(6a).
A.
Compound 1a (0.5 g, 1.5 mmol), hydrazine hydrate (0.15 g, 3.0 mmol), and glacial acetic acid (5 ml) were
refluxed for 3 h. The mixture was diluted with water (15 ml) and cooled down; the precipitated crystals of
compound 6a were filtered out and washed with water and then ethanol, and then dried. Yield 0.38 g (82%);
mp 277-278.5°C (dioxane). IR spectrum, ν, cm-1: 3258.10, 3142.43; 1644.53. Found, %: C 51.16; H 4.07;
N 13.65. C13H12BrN3O. Calculated, %: C 51.00; H 3.95; N 13.73.
B. Obtained by boiling hydrazide 2a (0.49 g, 1.5 mmol) and glacial acetic acid (5 ml) for 1.5 h. Isolated
as in method A. Yield 0.39 g (85%).
5-(2,5-Dimethylphenyl)-4-methyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridin-3-one (6b). A.
Synthesized and isolated as for pyrazolepyridinone 6a, from tetrahydropyridone 1b (1.0 g, 3.5 mmol), hydrazine
hydrate (0.3 g, 6.0 mmol), and glacial acetic acid (5 ml). Yield 0.62 g (70%); mp 300-301°C (dioxane).
Found, %: C 70.72; H 6.52; N 16.67. C15H17N3O. Calculated, %: C 70.56; H 6.71; N 16.46.
B. Obtained by boiling hydrazide 2b (0.5 g, 1.8 mmol) and glacial acetic acid (5 ml) for 1.5 h. Isolated
as in method A. Yield 0.65 g (73%).
5-(4-Bromophenyl)-4-methyl-2-phenyl-2,5,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridin-3-one (7a). A.
A mixture of compound 1a (0.5 g, 1.5 mmol), phenylhydrazine (0.32 g, 3.0 mmol) and glacial acetic acid (5 ml)
was boiled for 3 h. The reaction mixture was diluted with water (15 ml) and cooled down; the precipitated
crystals were filtered out and washed with methanol and then ether, and then dried. Yield 0.40 g (75%); mp 262-
263.5°C (dioxane). IR spectrum, ν, cm-1: 1649.42; 1592.23; 1571.49; 1498.90; 1482.46; 1330.71. Found, %: C
59.83; H 4.12; N 10.87. C19H16BrN3O. Calculated, %: C 59.70; H 4.22; N 10.99.
B. Compound 7a was obtained by boiling hydrazone 8a (0.43 g, 1.0 mmol) in glacial acetic acid (9 ml).
Isolated as in method A. Yield 0.42 g (80%).
Ethyl Ester of 1-(4-Bromophenyl)-2-methyl-4-(2-phenylhydrazono)-1,4,5,6-tetrahydropyridine-3-
carboxylic Acid (8a). A mixture of compound 1a (0.5 g, 1.5 mmol), phenylhydrazine (0.32 g, 3.0 mmol) in
methanol (10 ml) was boiled for 2 h. The reaction mixture was cooled down; the precipitated crystals were
filtered out and washed with methanol and then ether, and then dried. Yield 0.47 g (73%); mp 267-268.5°C
(2-propanol). IR spectra, ν, cm-1: 3275.83; 1649.96; 1591.96; 1571.21; 1482.75; 1330.82. Found, %: C 58.70;
H 5.26; N 9.97. C21H22BrN3O2. Calculated, %: C 58.89; H 5.18; N 9.81.
5-(4-Bromophenyl)-4-methyl-6,7-dihydroisoxazolo[4,3-c]pyridin-3(5H)-one (9a). A mixture of
tetrahydropyridone 1a (0.5 g, 1.5 mmol), hydroxylamine hydrochloride (0.16 g, 2.25 mmol), 2-propanol (5 ml),
and pyridine (1 ml) was boiled for 2 h and then diluted with water (10 ml). The precipitate was filtered out and
washed with propanol and then ether, and then dried. Yield 0.36 g (78%); mp 262-264°C (2-propanol).
IR spectrum, ν, cm-1: 3419.26, 3363.66, 3044.95, 2980.17, 1720.85, 1601.97. Found, %: C 50.98; H 3.52;
N 9.20. C13H11BrN2O2. Calculated, %: C 50.84; H 3.61; N 9.12.
5-(2,5-Dimethylphenyl)-4-methyl-6,7-dihydroisoxazolo[4,3-c]pyridin-3-(5H)-one (9b) was obtained
from pyridone 1b (0.43 g, 1.5 mmol), hydroxylamine hydrochloride (0.16 g, 2.25 mmol), 2-propanol (5 ml), and
pyridine (1 ml) by the method for synthesis and isolation of compound 7a. Yield 0.31 g (81%); mp 228-229°C
(2-propanol). Found, %: C 70.41; H 6.11; N 11.09. C15H16N2O2. Calculated, %: C 70.29; H 6.29; N 10.93.
774

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