A facile route to the synthesis of 1,3,4-oxadiazoline derivatives

Article abstract of DOI:10.3184/174751914X14057771815483

N-Acyl araldehyde hydrazones when treated with Ac₂O/pyridine were acetylated and cyclised to 5-substituted 2-aryl-3-acetyl-1,3,4- oxadiazolines in good yield.

Full text of DOI:10.3184/174751914X14057771815483

496 RESEARCH PAPER
VOL. 38 AUGUST, 496–497
JOURNAL OF CHEMICAL RESEARCH 2014
A facile route to the synthesis of 1,3,4-oxadiazoline derivatives
Alireza Hassanabadia* and Rahele Zhianib
aDepartment of Chemistry, College of Sciences, Zahedan Branch, Islamic Azad University, PO Box 98135-978, Zahedan, Iran
bDepartment of Chemistry, College of Sciences, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
N-Acyl araldehyde hydrazones when treated with Ac2O/pyridine were acetylated and cyclised to 5-substituted 2-aryl-3-acetyl-
1,3,4-oxadiazolines in good yield.
Keywords: N‑acyl araldehyde hydrazones, acetic anhydride/pyridine, acetylation/cyclisation, 2‑aryl‑3‑acetyl‑1,3,4‑oxadiazolines
The synthesis of 1,3,4‑oxadiazoline derivatives is a well‑
known reaction and, although there is a lot of information
on this topic, in recent years, the number of publications has
increased due to the great potential of these heterocyclic
compounds as chemotherapeutic agents.1,2 Nonetheless, some
aspects of heterocyclisation reaction are not so well known.
Sahu et al. 2 used a procedure first described by Martins Alho
et al.3 in which they synthesised a series of functionalised
1,3,4‑oxadiazoline derivatives from carbohydrate‑derived
benzoylhydrazones using acetic anhydride in the presence of
pyridine. In this study, we have also used the procedure of
Martins Alho and co‑workers3 to synthesise another class of
functionalised 1,3,4‑oxadiazoline derivatives starting from
N‑acyl araldehyde hydrazones.
The present procedure carries the advantage that, not only
is the reaction performed under neutral conditions, but also
the starting materials and reagents can be mixed without any
activation or modification.
Experimental
All melting points are uncorrected. NMR spectra were obtained on a
Bruker DRX‑500 Avance spectrometer (1H NMR at 500 Hz, 13C NMR
at 125.8 Hz) in CDCl3 using TMS as internal standard. Chemical
shifts (δ) are given in ppm. Elemental analyses were performed using
a Heraeus CHN‑O‑Rapid analyser. Mass spectra were recorded on a
Finnigan‑MAT 8430 mass spectrometer operating at an ionisation
potential of 70 eV. IR spectra were recorded on a Shimadzu IR‑470
spectrometer. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further
purification. Compounds 1a–f were prepared as previously described
in the literature.4
Results and discussion
The N‑acyl araldehyde hydrazones
1 were synthesised
using a literature method.4 Compounds 1a and 1e are known
compounds,4 but 1b–d,f are novel and were characterised
by their spectra and elemental analysis. Reaction at reflux
between N‑Acyl araldehyde hydrazones 1a–f and acetic
anhydride 2 in solvent pyridine led to 5‑substituted 2‑aryl‑3‑
acetyl‑1,3,4‑oxadiazoline derivatives 3a–f (Scheme 1) in good
yields (Table 1).
Table 1 Acetylation/cyclisation of N-Acyl araldehyde hydrazones 1 to
5-substituted 2-aryl-3-acetyl-1,3,4-oxadiazolines 3 with acetic anhydride
2 and pyridine at reflux (Scheme 1)
Entry
1
Product
AR
C6H5
R
Yield/%a
3a
Me
89
Compounds 3a–f were characterised by their IR, 1H and 13
C
2
3
3b
3c
C6H5
C6H5
90
87
N
NMR, and MS spectra and their elemental analyses.
1
The H NMR spectrum of 3a was simple and exhibited
two sharp singlets, for the protons of the two methyl groups
at δ 2.01, 2.27 ppm and another for the methine proton at δ
6.12 ppm. The aromatic protons appeared as multiplets at δ
7.23–8.13 ppm. The 13C NMR spectrum of 3a showed nine
distinct resonances in agreement with the proposed structure.
The IR spectrum showed an absorption bond at 1668 cm–1 for
the carbonyl group. The mass spectrum of 3a displayed the
molecular ion peak at m/z=204. The mechanism of the reaction
is probably similar to that published by Martins Alho et al.3,5
In summary, N‑acyl araldehyde hydrazones when treated with
Ac2O/pyridine were acetylated and cyclised to 5‑substituted
2‑aryl‑3‑acetyl‑1,3,4‑oxadiazolines in good yield.
O
4
3d
3e
3f
C6H5
93
94
92
5
4-ClC6H4
4-ClC6H4
Me
6
aIsolated yield.
O
H
CH3
O
O
R
N
N
N
N
N
+
O
O
H3C
CH3
Reflux, 5 h
Ar
R
Ar
O
3
2
1
Scheme 1
* Correspondent. E‑mail: ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2014 497
Isonicotinic acid benzylidenehydrazide (1b): White powder, yield
80%; m.p. 145–147 °C (EtOH); IR (KBr) (νmax, cm–1): 1678 (C=O); 1H
NMR: δ 6.73 (1H, broad s, NH), 7.23–8.67 (9H, m, aromatic), 8.24
(1H, s, N=CH) ppm; 13C NMR: δ 121.9, 127.1, 128.7, 129.4, 133.3, 141.5
and 151.5 (aromatic), 157.5 (C=N), 168.1 (C=O) ppm; MS (m/z,%): 225
(M+, 4). Anal calcd for C13H11N3O: C, 69.32; H, 4.92; N, 18.65; found:
C, 67.52; H, 4.85; N, 18.74%.
157.3 (C=N), 167.5 (C=O) ppm; MS (m/z,%): 267 (M+, 7). Anal calcd
for C15H13N3O2: C, 67.41; H, 4.90; N, 15.72; found: C, 67.55; H, 5.02; N,
15.63%.
1-(5-Furan-2-yl-2-phenyl-[1,3,4]oxadiazol-3-yl)ethanone (3c):
White powder, yield 87%; m.p. 124–126 °C (EtOH);, IR (KBr) (νmax
,
cm–1): 1671 (C=O); H NMR: δ 2.26 (3H, s, NCOCH3), 6.19 (1H, s,
CH), 6.52 (1H, m, CH furan), 7.40 (1H, s, CH furan), 7.63 (1H, d,
3JHH =2 Hz, CH furan), 7.23–8.07 (5H, m, aromatic) ppm; 13C NMR: δ
21.4 (CH3), 90.6 (CH), 111.7, 120.6, 143.5 and 145.6 (4C Furan), 126.9,
128.8, 129.1, 132.9, (aromatic), 157.5 (C=N), 167.7 (C=O) ppm; MS
(m/z,%): 256 (M+, 3). Anal calcd for C14H12N2O3: C, 65.62; H, 4.72; N,
10.93; found: C, 65.78; H, 4.90; N, 10.85%.
1
Furan-2-carboxylic acid benzylidenehydrazide (1c): White powder,
yield 77%; m.p. 112–114 °C (EtOH);, IR (KBr) (νmax, cm–1): 1672
1
(C=O); H NMR: δ 6.47 (1H, m, CH furan), 6.61 (1H, broad s, NH),
3
7.45 (1H, s, CH furan), 7.60 (1H, d, JHH =2 Hz, CH furan), 7.23–8.17
(5H, m, aromatic), 8.34 (1H, s, N=CH) ppm; 13C NMR: δ 111.5, 120.5,
143.7 and 145.5 (4C Furan), 126.7, 128.6, 129.2, 132.8, (aromatic), 157.7
(C=N), 167.5 (C=O) ppm; MS (m/z,%): 214 (M+, 7). Anal calcd for
C12H10N2O2: C, 67.28; H, 4.71; N, 13.08; found: C, 67.40; H, 4.65; N,
13.22%.
1-(2,5-Diphenyl-[1,3,4]oxadiazol-3-yl)ethanone (3d): White powder,
yield 93%; m.p. 111–113 °C (EtOH); IR (KBr) (νmax, cm–1): 1667
(C=O); 1H NMR: δ 2.14 (3H, s, NCOCH3), 6.10 (1H, s, CH), 7.23–8.16
(10H, m, aromatic) ppm; 13C NMR: δ 21.2 (CH3), 90.2 (CH), 126.7,
127.00, 128.7, 128.8, 129.1, 129.1, 132.4 and 132.5 (aromatic), 157.2
(C=N), 167.4 (C=O) ppm; MS (m/z,%): 266 (M+, 5). Anal calcd for
C16H14N2O2: C, 72.17; H, 5.30; N, 10.52; found: C, 72.30; H, 5.41; N,
10.60%.
Benzoic acid benzylidenehydrazide (1d): White powder, yield 82%;
m.p. 125–127 °C (EtOH); IR (KBr) (νmax, cm–1): 1667 (C=O); 1H NMR:
δ 6.55 (1H, broad s, NH), 7.27–8.27 (10H, m, aromatic), 8.30 (1H, s,
N=CH) ppm; 13C NMR: δ 126.6, 127.1, 128.6, 128.9, 129.1, 129.2, 132.4
and 132.6 (aromatic), 157.3 (C=N), 167.5 (C=O) ppm; MS (m/z,%): 225
(M+, 3). Anal calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49; found:
C, 75.15; H, 5.50; N, 12.35%.
Benzoic acid (4-chlorobenzylidene)hydrazide (1f): White powder,
yield 85%; m.p. 103–107 °C (EtOH); IR (KBr) (νmax, cm–1): 1672
(C=O); 1H NMR: δ 6.48 (1H, broad s, NH), 7.23–8.22 (5H, m,
aromatic), 7.40 (2H, d, 3JHH =7 Hz, aromatic), 7.75 (2H, d, 3JHH =7 Hz,
aromatic), 8.41 (1H, s, N=CH) ppm; 13C NMR: δ 126.8, 128.7, 128.6,
129.0, 129.3, 132.5, 133.1 and 135.7 (aromatic), 156.5 (C=N), 167.5
(C=O) ppm; MS (m/z,%): 258 (M+, 5). Anal calcd for C14H11ClN2O: C,
65.00; H, 4.29; N, 10.83; found: C, 65.13; H, 4.20; N, 10.90%.
1-[2-(4-Chlorophenyl)-5-methyl-[1,3,4]oxadiazol-3-yl]ethanone
(3e): White powder, yield 94%; m.p. 148–150 °C (EtOH); IR (KBr)
1
(νmax, cm–1): 1675 (C=O); H NMR: δ 2.04 (3H, s, CH3), 2.28 (3H, s,
3
NCOCH3), 6.15 (1H, s, CH), 7.36 (2H, d, JHH =7 Hz, aromatic), 7.65
(2H, d, 3JHH =7 Hz, aromatic) ppm; 13C NMR: δ 11.1 (CH3), 21.4 (CH3),
90.3 (CH), 128.8, 129.1, 133.1 and 135.8 (aromatic), 156.8 (C=N), 167.6
(C=O) ppm; MS (m/z,%): 238 (M+, 6). Anal calcd for C11H11ClN2O2: C,
55.36; H, 4.65; N, 11.74; found: C, 55.28; H, 4.50; N, 11.87%.
1-[2-(4-Chlorophenyl)-5-phenyl-[1,3,4]oxadiazol-3-yl]ethanone
(3f): White powder, yield 92%; m.p. 120–122 °C (EtOH); IR (KBr)
1
(νmax, cm–1): 1670 (C=O); H NMR: δ 2.10 (3H, s, NCOCH3), 6.11
3
(1H, s, CH), 7.23–8.12 (5H, m, aromatic), 7.34 (2H, d, JHH =7 Hz,
General procedure:
3
aromatic), 7.68 (2H, d, JHH =7 Hz, aromatic) ppm; 13C NMR: δ 21.2
Compound 1 (1 mmol) was dissolved in a mixture of pyridine
(2.5 mL) and acetic anhydride (2.5 mL), refluxed for 5 h, and then
left to reach room temperature. Once cold, some ethanol was added
and evaporation at reduced pressure gave a glassy residue which was
subjected to silica gel column chromatography using hexane/ethyl
acetate as the eluent. The product was recrystallised from EtOH.
1-(5-Methyl-2-phenyl-[1,3,4]oxadiazol-3-yl)ethanone (3a): White
powder, yield 89%; m.p. 154–156 °C (EtOH); IR (νmax, cm–1): 1668
(CH3), 90.3 (CH), 126.7, 128.7, 128.8, 129.1, 129.2, 132.4, 133.1 and
135.8 (aromatic), 156.7 (C=N), 167.6 (C=O) ppm; MS (m/z,%): 300 (M+,
7). Anal calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31; found: C,
63.72; H, 4.52; N, 9.20%.
Received 30 May 2014 ; accepted 10 July 2014
Paper 1402698 doi : 10.3184/174751914X14057771815483
Published online : 12 August 3014
1
(C=O); H NMR: δ 2.01 (3H, s, CH3), 2.27 (3H, s, NCOCH3), 6.12
(1H, s, CH), 7.23–8.13 (5H, m, aromatic) ppm; 13C NMR: δ 11.1 (CH3),
21.2 (CH3), 90.3 (CH), 126.7, 128.8, 129.1 and 132.5 (aromatic), 156.7
(C=N), 167.4 (C=O) ppm; MS (m/z,%): 204 (M+, 5). Anal calcd for
C11H12N2O2: C, 64.69; H, 5.92; N, 13.72; found: C, 64.50; H, 5.83; N,
13.60%.
References
1
2
S. Rollas and S. Karakus, Marmara Pharm. J., 2012, 16, 120.
V.K.R. Sahu, A.K. Singh and D. Yadav, Int. J. Chem. Tech. Res., 2011, 3,
1362.
1-(2-Phenyl-5-pyridin-4-yl-[1,3,4]oxadiazol-3-yl)ethanone (3b):
3
4
M.A. Martins Alho, R. Baggio and N.B. D’Accorso, Arkivoc, 2013, iii, 129.
J.R. Dimmock, S.C. Vashishtha and J.P. Stables, Eur. J. Med. Chem., 2000,
35, 241.
White powder, yield 90%), m.p. 132–135 °C (EtOH); IR (KBr) (νmax
,
1
cm–1): 1666 (C=O); H NMR: δ 2.20 (3H, s, NCOCH3), 6.17 (1H, s,
CH), 7.28–8.58 (9H, m, aromatic) ppm; 13C NMR: δ 21.3 (CH3), 90.4
(CH), 122.3, 127.1, 128.8, 129.2, 133.1, 141.7 and 151.6 (aromatic),
5
D. Han, X.‑B. Meng, L.‑N. Wang, H. Liu, Y. Yao, Z. Wang, Z.‑J. Yang,
Z.‑M. Liu and Z.‑J. Li, Tetrahedron-Asymmetr., 2009, 20, 399.