Synthesis of substituted 1,3,4-oxadiazole derivatives

Article abstract of DOI:10.1007/s10593-009-0252-4

Monosubstituted oxadiazoles were synthesized by the reaction of hydrazides with triethyl orthoformate. Their reactions with benzoyl chloride gave benzoylcarbohydrazides, which under the action of thionyl chloride were cyclized to the respective 2,5-disubs

Full text of DOI:10.1007/s10593-009-0252-4

Chemistry of Heterocyclic Compounds, Vol. 45, No. 2, 2009
SYNTHESIS OF SUBSTITUTED
1,3,4-OXADIAZOLE DERIVATIVES
V. Mickevičius1*, R. Vaickelionienė1, B. Sapijanskaitė1
Monosubstituted oxadiazoles were synthesized by the reaction of hydrazides with triethyl orthoformate.
Their reactions with benzoyl chloride gave benzoylcarbohydrazides, which under the action of thionyl
chloride were cyclized to the respective 2,5-disubstituted oxadiazoles. 1-Aryl-4-(5-thioxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)-pyrrolidin-2-ones were synthesized from acid hydrazides using carbon disulfide
under basic conditions.
Keywords: acid hydrazides, benzoyl chloride, 2-pyrrolidinone, substituted oxadiazoles, thionyl
chloride, 5-thioxo-1,3,4-oxadiazoles.
1,3,4-Oxadiazoles are important for both chemical and biological purposes. A number of these
compounds have demonstrated antibacterial [1], antimicrobial [2], herbicidal [3], and anti-inflammatory [4−6]
activities.
The present work aims to investigate the synthesis of substituted 1,3,4-oxadiazoles from 1-aryl-
5-oxopyrrolidine-3-carbohydrazides and to establish the structure of the products by chemical and spectral
methods.
Monosubstituted derivatives of oxadiazole can be obtained directly from acid hydrazides and
triethoxymethane. 1,3,4-Oxadiazoles 3 were synthesized by refluxing hydrazides 1a,b in an excess of triethyl
orthoformate (Scheme). The target compounds crystallized from the reaction mixture after cooling. In their
1H NMR spectra the signals characteristic for the NHNH2 fragment of the initial hydrazines are absent, while the
proton signal of the CH=N fragment in the oxadiazole moiety is observed in lower field (9.23 ppm).
2,5-Disubstituted oxadiazoles 5 were obtained when the respective benzoyl hydrazydes were dehydrated with
thionyl chloride. The products were separated from the reaction mixture by column chromatography.
Acyl derivatives of the respective hydrazides 4 were synthesized by stirring acid hydrazides 1a,c−e with
benzoyl chloride in pyridine. Hydrazinocarbonyl compounds undergo reaction with carbon disulfide in the
presence of potassium hydroxide quite easily. 1-Aryl-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-
2-ones 6c−e were synthesized from acid hydrazides 1c−e according to the method described in the literature [7].
1
In their H NMR spectra, besides the characteristic proton signals of aromatic and pyrrolidinone ring moieties,
singlets of the NH group proton at 14.52, 14.52, and 14.49, are observed.
_______
* To whom correspondence should be addressed, e-mail: Vytautas.Mickevicius@ktu.lt.
1 Kaunas University of Technology, Kaunas LT-50254, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 269-272, February, 2009. Original
article submitted April 7, 2008.
0009-3122/09/4502-0215©2009 Springer Science+Business Media, Inc.
215

O
N
O
N
O
H
H
R
R
N
N
Me
N
O
N
H
O
O
2a, b
4a-e
CH(OEt)3
PhCOCl
R
O
N
SOCl2,
∆
∆
H
O
N
N
O
NH2
R
O
1a–e
O
R
N
O
N
N
KOH, CS2
O
N
N
5a, c–e
3a, b
S
O
N
N
R
NH
6c–e
a R = Ph; b R = 4-MeOC6H4; c R = 4-EtOC6H4; d R = 4-PhOC6H4; e R = 4-ClC6H4
EXPERIMENTAL
1
13
The H and C NMR spectra were obtained on a Varian Unity Inova spectrometer (300 and 75 MHz
respectively) in DMSO-d6 with TMS as internal standart. The IR spectra were recorded on a Perkin-Elmer
Spectrum Bx FT IR instrument in tablets with potassium bromide. The mass spectra were determined on a
Waters ZQ 2000 spectrometer with electrospray ionization (ESI, 20 V). Silica gel plates Alugram Sil G/UV-254
were used for monitoring the reaction and the purity of the products. Elemental analysis was carried out on the
C,H,N Analyzer CE 440, and the melting point was determined on the auto probe analyzer APA 1.
1-Aryl-4-(1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 3a,b (General Method). A mixture of the respective
hydrazide 1a,b (10 mmol) and triethyl orthoformate (13.3 ml, 80 mmol) was heated under reflux for 8 h and
cooled. The crystals that separated after the mixture was cooled were filtered off, washed with ether, and dried.
4-(1,3,4-Oxadiazol-2-yl)-1-phenylpyrrolidin-2-one (3a). Yield 89%; mp 135-136°C (2-propanol). IR
spectrum, ν, cm–1: 1693 (C=O). 1H NMR spectrum, δ, ppm: 2.9-3.2 (2H, m, H-3); 4.0-4.2 (2H, m, H-5); 4.2-4.3
13
(1H, m, H-4); 7.1–7.7 (5H, m, ArH); 9.23 (1H, s, CH). C NMR spectrum, δ, ppm: 27.29 (C-4); 35.62 (C-3);
50.25 (C-5); 119.29, 123.95, 128.36, 138.57 (C arom); 154.56 (C-4'); 166.09 (C-1'); 170.78 (C=O). Mass
spectrum, m/z (I, %): 230 [M+H]+ (100). Found, %: C 62.52; H 4.79; N 18.40. C12H11N3O2. Calculated, %:
C 62.87; H 4.84; N 18.33.
1-(4-Methoxyphenyl)-4-(1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (3b). Yield 82%; mp 133-134°C
1
(2-propanol). IR spectrum, ν, cm–1: 1694 (C=O). H NMR spectrum, δ, ppm (J, Hz): 2.8-3.1 (2H, m, H-3); 3.74
(3H, s, OCH3); 4.0-4.2 (2H, m, H-5); 4.2–4.3 (1H, m, H-4); 6.9–7.6 (4H, 2d, J = 9, ArH); 9.23 (1H, s, CH).
13C NMR spectrum, δ, ppm: 27.58 (C-4); 35.67 (C-3); 50.87 (C-5); 55.15 (CH3); 113.78, 121.48, 131.98,
155.987 (C arom); 154.82 (C-4′); 166.42 (C-1'); 170.54 (C=O). Mass spectrum, m/z (I, %): 260 [M+H]+ (100).
Found, %: C 60.16; H 5.01; N 16.30. C13H13N3O3. Calculated, %: C 60.23; H 5.05; N 16.21.
216

N'-Benzoyl-5-oxo-1-phenylpyrrolidine-3-carbohydrazides 4a−e (General Method). A solution of the
respective hydrazide 1a−e (10 mmol) in 10 ml of pyridine was stirred and over 10 min benzoyl chloride
(1.74 ml, 15 mmol) was added dropwise. A mixture was additionally stirred for 6 h and then diluted with 40 ml
of ~5% hydrochloric acid. The formed solid was filtered off, washed with water, and dried.
N'-Benzoyl-5-oxo-1-phenylpyrrolidine-3-carbohydrazide (4a). Yield 74%; mp 213-214°C (ethanol).
1
IR spectrum, ν, cm–1: 3196, 3030 (NH); 1677, 1594, 1577 (C=O). H NMR spectrum, δ, ppm: 2.6-2.9 (2H, m,
H-3); 3.6-3.8 (2H, m, H-5); 3.9–4.3 (1H, m, H-4); 7.2-8.1 (10H, m, ArH); 10.19 (1H, s, NH); 10.41 (1H, s, NH).
Mass spectrum, m/z (I, %): 324 [M+H]+ (100). Found, %: C 66.94; H 5.15; N 13.11. C18H17N3O3. Calculated, %:
C 66.86; H 5.30; N 13.00.
N'-Benzoyl-1-(4-methoxyphenyl)-5-oxopyrrolidine-3-carbohydrazide (4b). Yield 73%; mp
1
203-204°C (ethanol). IR spectrum, ν, cm–1: 3198, 3049 (NH); 1668, 1595, 1577 (C=O). H NMR spectrum, δ,
ppm: 2.6-2.9 (2H, m, H-3); 3.73 (3H, s, OCH3); 3.8-4.2 (3H, m, H-4, 5); 6.9-7.9 (9H, m, ArH); 10.21 (1H, s,
NH); 10.46 (1H, s, NH). Mass spectrum, m/z (I, %): 354 [M+H]+ (100). Found, %: C 64.51; H 5.38; N 11.95.
C19H19N3O4. Calculated, %: C 64.58; H 5.42; N 11.89.
N'-Benzoyl-1-(4-ethoxyphenyl)-5-oxopyrrolidine-3-carbohydrazide (4c). Yield 74%; mp 204-205°C
1
(ethanol). H NMR spectrum, δ, ppm (J, Hz): 1.31 (3H, t, J = 7.3, CH3); 2.6-2.9 (2H, m, H-3); 3.3-3.5 (2H, m,
H-5); 3.8-4.1 (3H, m, H-4, OCH2); 6.9–7.9 (9H, m, ArH); 10.21 (1H, s, NH); 10.45 (1H, s, NH). Mass spectrum,
m/z (I, %): 368 [M+H]+ (100). Found, %: C 65.50; H 5.48; N 11.37. C20H21N3O4. Calculated, %: C 5.38; H 5.76;
N 11.44.
N'-Benzoyl-5-oxo-1-(4-phenoxyphenyl)pyrrolidine-3-carbohydrazide (4d). Yield 81%; mp 194-195°C
(dioxane). 1H NMR spectrum, δ, ppm: 2.6-2.9 (2H, m, H-3); 3.3–3.6 (2H, m, H-5); 3.9-4.3 (1H, m, H-4); 6.7-8.0 (9H,
m, ArH); 10.22 (1H, s, NH); 10.45 (1H, s, NH). 13C NMR spectrum, δ, ppm: 33.86 (C-4); 35.45 (C-3); 50.67 (C-5);
118.08, 119.18, 121.22, 123.18, 127.39, 128.47, 129.99, 131.89, 132.23, 134.89, 152.51, 157.03 (C arom); 165.53
(NH−CO−CH); 171.60 (CH−CO−NH); 172.01 (C=O). Mass spectrum, m/z (I, %): 416 [M+H]+ (100). Found, %:
C 69.01; H 5.49; N 10.13. C24H21N3O4. Calculated, %: C 69.39; H 5.10; N 10.11.
N'-Benzoyl-1-(4-chlorophenyl)-5-oxopyrrolidine-3-carbohydrazide (4e). Yield 84%; mp 226-227°C
1
(dioxane). IR spectrum, ν, cm–1: 3302, 3208 (NH); 1678, 1654, 1648 (C=O). H NMR spectrum, δ, ppm: 2.6-2.9
(2H, m, H-3); 3.3-3.6 (2H, m, H-5); 3.9-4.3 (1H, m, H-4); 7.3-8.0 (9H, m, ArH); 10.18 (1H, s, NH); 10.41 (1H,
s, NH). Found, %: C 60.13; H 4.83; N 11.80. C18H16ClN3O3. Calculated, %: C 60.43; H 4.51; N 11.74.
1-Aryl-4-(5-aryl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 5a,c-e (General Method). A mixture of the
respective acylhydrazide 4a−c,e (0.01 mol) and chloroform (10 ml) was stirred and thionyl chloride (0.72 ml,
10 mmol) was added dropwise. The mixture was heated under reflux for 20 h, and the obtained transparent liquid
distilled in vacuo. The product formed after the vacuum distillation was purified by the method of column
chromatography.
1-Phenyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (5a). Yield 29%; mp 127–128°C; Rf 0.36
1
(acetone−hexane, 1:2). IR spectrum, ν, cm–1: 1697 (C=O). H NMR spectrum, δ, ppm: 2.8–3.1 (2H, m, H-3);
4.1–4.3 (3H, m, H-5, 4); 7.1–8.2 (10H, m, ArH). Mass spectrum, m/z (I, %): 306 [M+H]+ (100). Found, %:
C 70.41; H 4.71; N 13.83. C18H15N3O2. Calculated, %: C 70.81; H 4.95; N 13.76.
1-(4-Ethoxyphenyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (5c). Yield 27%; mp 126-127°C;
Rf 0.28 (acetone−hexane, 1:2). IR spectrum, ν, cm–1: 1697 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.33 (3H,
t, J = 7.3, CH3); 2.9-3.1 (2H, m, H-3); 3.98 and 4.10 (2H, q, J =7.3, OCH2); 4.2-4.6 (3H, m, H-5, 4); 6.9-8.1
(9H, m, ArH). Mass spectrum, m/z (I, %): 350 [M+H]+ (100). Found, %: C 68.90; H 5.27; N 11.87. C20H19N3O3.
Calculated, %: C 68.75; H 5.48; N 12.03.
1-(4-Phenoxyphenyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (5d). Yield 35%; mp
1
137-138°C; Rf 0.30 (acetone−hexane, 1:2). IR spectrum, ν, cm–1: 1691 (C=O). H NMR spectrum, δ, ppm:
2.9-3.1 (2H, m, CO−CH2); 4.1-4.3 (2H, m, NCH2); 6.9-7.7 (14H, m, ArH). Mass spectrum, m/z (I, %): 398
[M+H]+ (100). Found, %: C 72.44; H 4.89; N 10.48. C24H19N3O3. Calculated, %: C 72.53; H 4.82; N 10.57.
217

1-(4-Chlorophenyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (5e). Yield 33%; mp 163-164°C;
Rf 0. 30 (acetone−hexane, 1:2). 1H NMR spectrum, δ, ppm: 2.8-3.2 (2H, m, H-3); 4.2-4.7 (3H, m, H-5, 4); 6.8-
8.0 (9H, m, ArH). Mass spectrum, m/z (I, %): 340 [M+H]+ (100), 342 [M+2+H]+ (30). Found, %: C 63.51; H 4. 35;
N 12.42. C18H14ClN3O2. Calculated, %: C 63.63; H 4.15; N 12.37.
1-Aryl-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 6c-e (General Method). A
mixture of the respective hydrazide 1c-e (10 mmol), potassium hydroxide (0.56 g, 10 mmol), and carbon
disulfide (1.52 g, 20 mmol) was heated for 48 h in 2-propanol (40 ml), cooled, and acidified with glacial acetic
acid. The formed residue was filtered off, washed with water, and dried.
1-(4-Ethoxyphenyl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (6c). Yield 62%;
mp 176–177°C (2-propanol). 1H NMR spectrum, δ, ppm (J, Hz): 1.33 (3H, t, J =7.2, CH3); 2.8-3.0 (2H, m, H-3);
3.9-4.1 (5H, m, H-5, H-4, OCH2CH3); 6.95 and 7.52 (4H, 2d, J = 8.1, ArH,); 14.49 (1H, s, NH). Mass spectrum,
m/z (I, %): 306 [M+H]+ (100). Found, %: C 55.37; H 5.20; N 13.79. C14H15N3O3S. Calculated, %: C 55.07;
H 4.95; N 13.76.
1-(4-Phenoxyphenyl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (6d). Yield 78%;
mp 211-212°C (2-propanol). IR spectrum, ν, cm–1: 1666 (C=O), 693 (C=S). 1H NMR spectrum, δ, ppm: 2.9-3.1
(2H, m, H-3); 3.8-4.2 (3H, m, H-5, 4); 7.0-7.8 (9H, m, ArH); 14.52 (1H, s, NH). Mass spectrum, m/z (I, %): 354
[M+H]+ (100). Found, %: C 61.10; H 4.43; N 12.00. C18H15N3O3S. Calculated, %: C 61.18; H 4.28; N 11.89.
1-(4-Chlorophenyl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (6e). Yield 77%;
mp 222-223°C (2-propanol). 1H NMR spectrum, δ, ppm (J, Hz): 2.9-3.1 (2H, m, H-3); 4.0-4.4 (3H, m, H-5, 4);
7.46 and 7.71 (4H, 2d, J = 6.9, ArH); 14.52 (1H, s, NH). Mass spectrum, m/z (I, %): 296 [M+H]+ (100), 296
(M+2+H)+ (30). Found, %: C 48.32; H 3.13; N 14.36. C12H10ClN3O2S. Calculated, %: C 48.74; H 3.41; N 14.21.
REFERENCES
1.
2.
3.
4.
5.
6.
H. K. Misra, Arch. Pharm., 316, 487 (2006).
P. Mishra, H. Rajak, and A. Mehta, J. Gen. Appl., Microbiol., 51, 133 (2005).
T. W. Newton, US Pat. 5591695 (1997). http://www.patentstorm.us/patents/5591695-claqims.html
M. Amir and S. Kumar, Acta Pharm., 57, 31 (2007).
P. V. Frank, K. S. Girish, and B. Kalluraya, J. Chem. Sci. 119, 41 (2007).
M. D. Mullican, M. W. Wilson, D. T. Connor, C. R. Kostlan, D. J. Schrier, and R. D. Duer, J. Med.
Chem., 36, 1090 (1993).
7.
D. A. Charistos, G. V. Vagenas, L. C. Tzavellas, C. A. Tsoleridis, and N. A. Rodios, J. Heterocycl.
Chem., 31, 1593 (1994).
218