Synthesis and hydrazinolysis of β-(1,3,4-oxadiazol-2-yl)pyridines

Article abstract of DOI:10.1007/s10593-011-0702-7

Cyclization of the hydrazide of 5-ethoxycarbonyl-2,6-dimethylpyridine-3- carboxylic acid by acylation with aromatic or aliphatic acid chlorides with subsequent boiling in POCl₃ or heating in orthoformic acid gave the corresponding ethyl 2,6-dimethyl-5-(5-R-1,3,4-oxadiazol-2-yl)pyridine-3- carboxylate. The cyclization of the reaction products with hydrazine hydrate has been studied. Cyclization of the dihydrazide of 2,6-dimethyl-3,5- pyridinedicarboxylic acid under analogous conditions gave only 3,5-bis-(5-R-1,3,4-oxadiazol-2-yl)-2,6-dimethylpyridines, containing R = 2-FC₆H₄, H.

Full text of DOI:10.1007/s10593-011-0702-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, March, 2011 (Russian Original Vol. 46, No. 12, December, 2010)
SYNTHESIS AND HYDRAZINOLYSIS
OF β-(1,3,4-OXADIAZOL-2-YL)PYRIDINES
O. U. Nesterova1*, A. S. Pugachova1, M. V. Voevudsky2,
O. V. Krischik2, and V. I. Musatov3
Cyclization of the hydrazide of 5-ethoxycarbonyl-2,6-dimethylpyridine-3-carboxylic acid by acylation
with aromatic or aliphatic acid chlorides with subsequent boiling in POCl3 or heating in orthoformic acid
gave the corresponding ethyl 2,6-dimethyl-5-(5-R-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate. The
cyclization of the reaction products with hydrazine hydrate has been studied. Cyclization of the
dihydrazide of 2,6-dimethyl-3,5-pyridinedicarboxylic acid under analogous conditions gave only 3,5-bis-
(5-R-1,3,4-oxadiazol-2-yl)-2,6-dimethylpyridines, containing R = 2-FC6H4, H.
Keywords: hydrazide, hydrazine, nicotinic acid, 1,3,4-oxadiazole, aromatic acid chlorides.
Derivatives of 1,3,4-oxadiazoles have found use as antimicrobial [1, 2], antifungal [3, 4], antibacterial [5],
and sedative preparations [6]. Preparation of 1,3,4-oxadiazoles containing pyridine units is coupled with a number of
difficulties, linked with their chemical instability and the complexity of isolating them from the reaction media [7].
Previously [8] we studied the reactivity of hydrazides of 3,5-pyridinedicarboxylic acid 1, 2 in acylation
reaction with aromatic acids chlorides which proceeded with formation of the hydrochlorides of the corresponding
mono- and bis-1,2-diacylhydrazine-2,6-dimethylpyridines 3, 4b-d, g, isolated in the form of the bases.
With the objective of preparing the (1,3,4-oxadiazol-2-yl)pyridines 5 and 6 we have investigated the
reaction of the heterocycles 3 and 4 with various dehydrating agents (phosphorus oxychloride, thionyl chloride,
oleum, and polyphosphoric acid). The most effective cyclizing agent is phosphorus oxychloride. The use of conc.
H2SO4 or oleum was ineffective since the reaction did not occur at low temperatures and strong resinification was
observed on heating the reaction mixture. Analogous results were obtained when polyphosphoric acid or thionyl
chloride were used.
Attempts to obtain the (1,3,4-oxadiazol-2-yl)pyridines 5b-d,g,i by heating the 1,2-diacylhydrazines 3b-d, g,i
in POCl3 proceeded in low yield, since, because of the poor solubility of the bases, prolonged heating was
required which lead to resinification.
_______
* To whom correspondence should be addressed, e-mail: kafedra_vms@mail.ru, e-mail: anni83@bk.ru.
1O. Gonchar Dnepropetrovsk National University, Dnepropetrovsk 49010, Ukraine.
2Ukrainian State University of Chemical Engineering, Dnepropetrovsk 49005, Ukraine; e-mail:
voevudsky@ukr.net, e-mail: peterkp@mail.ru.
3Institute for Single Crystals, National Academy of Sciences of Ukraine, Kharkiv 61001, Ukraine; e-mail:
musatov@sc.kharkov.com.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1879-1888, December, 2010. Original
article submitted January 27, 2010.
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0009-3122/11/4612-1520©2011 Springer Science+Business Media, Inc.

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The use in this reaction of 1,2-diacylhydrazine hydrochlorides 3b-d,g,i increased their solubility and
allowed the formation of the corresponding (1,3,4-oxadiazol-2-yl)pyridines in yields of 20-35%. As it was turned
out, the simplest and most effective method of cyclization is to carry out the whole process in one pot, beginning
with the acylation of hydrazides 1 with an acids chlorides followed by removal of the solvent in vacuum followed
by brief heating of the 1,2-diacylhydrazine 3b-i hydrochlorides obtained without isolation in phosphorus
oxychloride. In this way we succeeded in increasing the yields of compounds 5b-i (Table 1) to 60-88% and also
decreising the reaction time considerably. However with hydrazide 2 only with the use 2-fluorobenzoyl chloride
were we able to isolate the corresponding 3,5-bis(1,3,4-oxadiazol-2-yl)pyridine 6c in satisfactory yield.
Cyclization of the bis-1,2-diacylhydrazines 4b,d-g,i formed in situ did not occur because of the low solubility of
these salts, prolonged heating in POCl3 gave rise to resinification of the reaction masses.
Neutralization of the reaction mixture with sodium hydrogen carbonate in the process of isolation of the
compounds 5b-i was not acceptable in the case of (5-methyl-1,3,4-oxadiazol-2-yl)pyridine 5h which hydrolyzed
to the starting monohydrazide 1 under these conditions. Therefore for this compound neutralization was carried
out at 5-7°C with 10% ammonia solution.
TABLE 1. Physicochemical Characteristics of Compounds 5a-i, 6a,c,h, 7a-f,i
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
N
C12H13N3O3
C22H25N3O3
C18H16FN3O3
C19H19N3O4
C19H19N3O3
C18H16ClN3O3
C18H16N4O5
C13H15N3O3
C18H17N3O
58.13
58.29
69.32
69.64
60.31
60.43
64.47
64.58
67.73
67.64
60.32
60.43
57.74
58.70
59.85
59.77
65.72
66.87
54.28
54.32
61.11
61.92
56.83
57.53
51.42
51.50
65.56
65.74
55.93
55.90
60.28
60.17
5.22
5.30
6.71
6.64
4.62
4.51
5.34
5.42
5.52
5.68
4.56
4.51
4.11
4.35
5.81
5.74
5.08
5.26
3.40
3.73
3.63
3.69
4.83
4.80
4.68
4.75
6.42
6.34
4.12
4.10
5.22
5.05
17.08
16.99
11.23
11.07
11.79
11.74
11.69
11.89
12.38
12.45
11.57
11.74
14.57
15.22
15.57
16.09
12.78
13.00
28.61
28.79
17.36
17.20
25.55
25.83
29.75
30.03
19.08
19.16
20.34
20.37
20.47
20.64
94-95
88
68
77
64
72
78
25
58
60
90
45
67
98
88
93
96
93
92
89
5a
5b
5c
5d
5e
5f
148-149
116-117
133-135
153-155
108-109
168-170
96-97
5g
5h
5i
137-138
168-169
165-166
169-171
228-230
210-212
255-257
242-243
304-306
246-247
250-251
C11H9N5O2
6a
6c
6h
7a
7b
7c
7d
7e
7f
C21H15F2N5O2
C13H13N5O2
C10H11N5O2
C20H23N5O2
C16H14FN5O2
C17H17N5O3
C17H17N5O2
C16H14ClN5O2
C16H15N5O2
63.24
63.15
55.78
55.90
62.09
62.13
5.36
5.30
4.18
4.10
4.92
4.89
21.59
21.66
20.45
20.37
20.45
20.64
7i
1522

Use of acetic anhydride as the acylating agent for the dihydrazide 2 with subsequent short heating in
phosphorus oxychloride without isolation of the product of acylation led to the formation of the corresponding
bis(5-methyl-1,3,4-oxadiazol-2-yl)pyridine 6h with a yield of ~ 70%. This is apparently connected to the high
solubility of the acylation product in POCl3 and to the electron-donating character of the alkyl radical.
It has been shown [9] in a study of the mechanism of the heterocyclization 1,2-diacylhydrazines that a
necessary condition for the formation 1,3,4-oxadiazoles is the presence of different nucleophilicity of the carbonyl
oxygen atoms in the 1,2-diacylhydrazine unit. The salt form of the pyridine ring in the 1,2-diacylhydrazines
hydrohlorides 3, 4 evidently leads to decreased basicity of the oxygen of the β-carbonyl unit, so that cyclization is
facilitated by an electron donor substituent in the acyl component. If the acyl group has electron acceptor properties,
the basicity of both oxygen atoms of the carbonyl group is reduced which retards the protonation step and further
cyclization. Hence heterocyclization of the hydrochloride of ethyl 5-[(4-nitrobenzoyl)hydrazinocarbonyl]-
3-carboxylate (3g) occurs with low yield (~25%), and attempts to use trifluoroacetic anhydride, analogously to acetic
anhydride, in the synthesis of the corresponding bis(1,3,4-oxadiaxol-2-yl)pyridine 6 was unsuccessful.
It is known [10] that 2,5-unsubsituted 1,3,4-oxadiazoles can be obtained from hydrazides of carboxylic
acids by heating in an excess of ethyl orthoformate. Carrying out this reaction with mono- and dihydrazides of
pyridine 1 and 2 in a 20-fold excess of ethyl orthoformate showed that the expected mono- and bis-1,3,4-
oxadiazoles 5a and 6a were formed in high yields (78-85%).
Hydrazinolysis of the obtained 1,3,4-oxadiazoles 5a-i occurs both at the ester group and in the
recyclization of the 1,3,4-oxadiazole ring into the 1,2,4-triazole ring. This, in the first place, is concerned with
monosubstituted 1,3,4-oxadiazoles which are also easily hydrolyzed [10], whereas recyclization of 2,5-diaryl-
substituted 1,3,4-oxadiazoles was not successful [11, 12]. We have shown that hydrazinolysis with opening of the
1,3,4-oxadiazole ring occurs on boiling (5-methyl-1,3,4-oxadiazol-2-yl)pyridine 5h in an alcohol solution of
excess hydrazine hydrate to give the dihydrazide 2. On heating compounds 5a-f,i for a short time in ethanolic
solutions of 85% hydrazine hydrate, the hydrazides 7a-f,i are formed in high yields, prolonged heating of which
in alcoholic (ethanol, 2-propanol, butanol) and aqueous solution of hydrazine hydrate did not lead to products of
ring-opening or recyclization of the 1,3,4-oxadiazole ring, which is probably connected with their w solubility in
the reaction mixture.
TABLE 2. IR Spectra of Compounds 5a-i and 7a-f,i
Com-
pound
, cm–1
3140, 3000, 2935, 1720, 1590, 1560, 1535, 1450, 1320, 1280, 1100, 1090
5a
5b
3080, 2980, 2890, 1720, 1620, 1550, 1505, 1460, 1420, 1380, 1290, 1250, 1240, 1210,
160, 1110
3000, 2945, 1740, 1610, 1550, 1505, 1480, 1450, 1405, 1380, 1290, 1240, 1175, 1110
3000, 2960, 1740, 1610, 1550, 1485, 1440, 1300, 1290, 1240, 1190, 1100
5c
5d
5e
2990, 2940, 2870, 1735, 1620, 1595, 1570, 1510, 1465, 1380, 1290, 1270, 1240, 1225,
1195, 1180, 1110
3000, 2950, 1740, 1610, 1555, 1465, 1405, 1380, 1295, 1275, 1240, 1170, 1110
3000, 2950, 1735, 1610, 1553, 1475, 1380, 1295, 1275, 1240, 1175, 1110
3000, 2960, 1730, 1610, 1540, 1495, 1460, 1375, 1290, 1240, 1190, 1100
2990, 1740, 1610, 1572, 1510, 1465, 1380, 1290, 1270, 1245, 1190, 1110
3320, 3250, 3030, 2870, 1670, 1595, 1450, 1385, 1315, 1195, 1150, 1070
3310, 3190, 2980, 2890, 1650, 1550, 1510, 1460, 1380, 1330, 1280, 1260, 1120, 1 090
3290, 3180, 3080, 1650, 1550, 1500, 1480, 1330, 1375, 1275, 1240, 1180, 1170, 1 120
3310, 3220, 3100, 3000, 1640, 1620, 1550, 1510, 1470, 1330, 1290, 1270, 1180
5f
5g
5h
5i
7a
7b
7c
7d
7e
3285, 3180, 3075, 3010, 2940, 2870, 1645, 1560, 1510, 1465, 1370, 1335, 1275, 1250,
1225, 1190, 1175, 1115
3285, 3180, 1650, 1615, 1560, 1485, 1465, 1440, 1330, 1295, 1270, 1250, 1170, 1 110
3288, 3170, 1640, 1625, 1567, 1485, 1465, 1440, 1330, 1295, 1270, 1250, 1170, 1110
7f
7i
1523

1524

In the IR spectra of the synthesized (1,3,4-oxadiazol-2-yl)pyridines 5b-i (Table 2) there are intense
valence bands of the C=N bond in the 1610-1620 cm-1 range, which corresponds to previous date [4]. The
stretching bands of the ester groups (Table 2) undergo a high frequency shift in comparison with the starting
diacylhydrazines (from the 1710-1720 range for compounds 3c,d,g,i [8] to the range 1735-1740 cm-1 for the
corresponding oxadiazoles 5c,d,g,i), which may indicate the greater electron acceptor influence of the 1,3,4-
oxadiazole unit. The excluded compounds 3b and 5b contain the 4-tert-butylphenyl substituent.
In the IR spectra of the hydrazinolysis products 7a-f,i the NH-NH2 fragment appeared as two bands of
different intensity in the region of 3320-3100 cm-1, which is in agreement with data from [13] and indicates the
stretching vibrations of the unit as a whole. The intense "amide I" band, connected with νC=O of the hydrazide
group, appears in the 1640-1650 cm-1 region. The presence of an unsaturated oxadiazole unit in the structure of
compound 7a led to a high frequency shift of these bands to 1670 cm-1 (Table 2).
The highest information content on the electronic influence of the substituent on the pyridine ring can be
1
obtained, in our view, from analysis of the signal of the gamma-proton of the pyridine ring in the H NMR
spectra. Comparative analysis of the 1H NMR spectra shows that in going from the 1,2-diacylhydrazines 3b-d,g,i
[8] to the corresponding (1,3,4-oxadiazol-2-yl)pyridines 5b-d,g,i (Table 3) the signal of the pyridine proton
underwent a weak field shift from 7.9-8.2 to 8.7-8.8 ppm, while the introduction of a second oxadiazole ring in
the case of compound 6c, which contains a 2-fluorophenyl substituent, led to an additional shift of ~0.2 ppm to
weak field. As a result of a comparative analysis of the spectra of (1,3,4-oxadiazol-2-yl)pyridines 5a-i with the
spectra of the products of their hydrazinolysis 7a-f,i a shift of the signal of the gamma-proton by 0.3-1.1 ppm to
strong field was observed, which is explained by the electron donor characteristic of the hydrazine unit in
comparison with the ester group. The maximum shifts of the gamma-proton were observed in the cases of the
(1,3,4-oxadiazol-2-yl)pyridines 5a and 7a which contain 1,3,4-oxadiazole units unsubstituted at position 5.
Thus, hydrazinolysis of the ester groups in compounds 5a-i appears to be preferable if there is no
substituent or an aroyl unit at position 5 of the 1,3,4-oxadiazole ring is present, whereas the presence of a methyl
group leads to opening of the 1,3,4-ozadiazole ring and transhydrazinolysis occurs.
EXPERIMENTAL
1
IR spectra of KBr tablets were recorded on a Specord IR-75 instrument, H NMR spectra were recorded
with a Varian 300VXR (300 MHz) with TMS as internal standard. Monitoring of the course of reactions and of
purity of substances was carried out by TLC on Silufol UV-254 plates with a benzene–ethyl acetate–methanol,
10:7:1 solvent system and development with iodine vapor. Acetonitrile was purified and dried by boiling over
P2O5 with subsequent distillation from potash.
Ethyl 2,6-Dimethyl-5-(5-R-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylates 5b-i and 2,6-Dimethyl-
3,5-bis[5-(2-fluorophenyl)1,3,4oxadiazol-2-yl]pyridine (6c) (General Method). To a solution of the
corresponding hydrazide 1 or 2 (1 mmol) in dry acetonitrile (25 ml) was added acid chloride (1 mmol for each
hydrazide group) and the mixture was boiled for 1 h. After removing of the solvent in vacuum, the residue was
dissolved with heating in freshly distilled POCl3 (30 ml) until a clear solution was obtained. The phosphorus
oxychloride was removed in vacuum, and the solid or resinous residue was dissolved in the minimal amount of
methanol and neutralized with cooling with ice with saturated sodium hydrogen carbonate to a pH of 8-9. The
precipitate was filtered off, washed several times with water, and recrystallized from 2-propanol or octane.
Ethyl 2,6-Dimethyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinate (5h) was separated by mixing the oily
residue, after removing the POCl3, with ground ice and neutralized with 10% ammonia solution to a mildly basic
reaction. The reaction product was extracted with chloroform, the chloroform solution was dried over MgSO4.
After removal of the solvent the residue was crystallized from octane.
1525

2,6-Dimethyl-3,5-bis(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (6h). Acetic anhydride (0.2 g, 2 mmol)
was added to a solution of dihydrazide 2 (0.22 g, 1 mmol) in dry acetonitrile (10 ml) and boiled for 1 h. The
solvent was evaporated in vacuum, POCl3 (15 ml) was added to the residue and boiled for 30 min. The
phosphorus oxychloride was evaporated in vacuum, the resinous residue was dissolved in the minimum amount of
ethanol and the resulting solution was poured into a saturated aqueous solution of NaHCO3. The precipitate was
recrystallized from a mixture of ethanol and water.
Ethyl 2,6-Dimethyl-5-(1,3,4-oxadizol-2-yl)pyridine-3-carboxylate (5a). A solution of hydrazide 1
(1.00 g, 4 mmol) in ethyl orthoformate (10 ml) was boiled for 18 h, cooled in an ice bath, the colorless crystals
were filtered off and recrystallized from a minimum amount of ethanol.
2,6-Dimethyl-3,5-bis(1,3,4-oxadiazol-2-yl)pyridine (6a). A solution of dihydrazide 2 (1.00 g, 5 mmol)
in ethyl orthoformate (15 ml) was boiled for 24 h, cooled and kept in a refrigerator for 1-2 days, the colorless
crystalline precipitate was filtered off and recrystallized from ethanol.
2,6-Dimethyl-5-(5R-1,3,4-oxadiazol-2-yl)pyridine-3-carboxyhydrazides 7a-f,i (General Method).
85% hydrazine hydrate (10 ml) was added to a solution of the corresponding 5-(5-R-1,3,4-oxadiazol-2-yl)-
pyridine 5a-f,i (1 mmol) in the minimum amount of ethanol. The solution was boiled for 2-3 h. At the end of the
reaction (monitored by TLC) the hot reaction mixture was filtered and cooled. The pyridine-3-carboxyhydrazides
7a-f, i were recrystallized from DMF.
REFERENCES
1.
M. B. Talawr, S. R. Dejai, Y. S. Sommanavar, and S. C. Marihal, Indian J. Heterocycl. Chem., 5, 215
(1996).
2.
3.
4.
5.
6.
7.
8.
V. R. Shah, M. Vadodaria, and A. R. Parikh, Indian J. Chem., 36, 101 (1997).
B. S. Holla, K. N. Poojary, B. Kalluraya, and P. V. Gowda, Indian J. Heterocycl. Chem., 5, 273 (1996).
B. N. Goswami, J. C. S. Kataky, J. N. Baruah, and S. C. Nath, J. Heterocycl. Chem., 21, 205 (1984).
S. S. Shafi and T. R. Radhakrishnan, Indian J. Heterocycl. Chem., 5, 133 (1995).
F. A. Omar, N. M. Mahfouz, and M. A. Rahman, Eur. J. Med. Chem., 31, 819 (1996).
A. P. Grekov, Organic Chemistry of Hydrazines [in Russian], Kiev (1966).
O. U. Nesterova, M. V. Voevudskii, A. V. Samukha, R. V. Zubatyuk, and O. V. Shishkin, Khim.
Geterotsikl. Soedin., 1834 (2005). [Chem. Heterocycl. Comp., 41, 1511 (2005)].
O. P. Shvaika, Doklad. Akad. Nauk Ukr. SSR, 3, 1028 (1968).
9.
10.
11.
12.
13.
A. P. Grekov, O. P. Shvaika, and L. M. Erypova, Zh. Obshch. Khim., 29, 2027 (1959).
O. P. Shvaika and V. I. Fomenko, Doklad. Akad. Nauk, 200, 134 (1971).
O. P. Shvaika and V. N. Artemov, Usp. Khim., 41, 1789 (1972).
E. V. Titov, A. P. Grekov, V. I. Pybachenko, and V. V. Shevchenko, Teor. Eksp. Khim., 4, 742 (1968).
1526