Utilization of 2-benzo[b]furan carboxylic acid hydrazide in the synthesis of 1,3,4-oxadiazole derivatives

Article abstract of DOI:10.1002/jhet.142

(Chemical Equation Presented) In this study, the synthesis of series of 2-benzo[b]furan-substituted 1,3,4-oxadiazole derivatives using readily available 2-benzo[b]furan carboxylic acid hydrazide as starting material has been investigated.

Full text of DOI:10.1002/jhet.142

July 2009
Utilization of 2-Benzo[b]furan Carboxylic Acid Hydrazide in the
Synthesis of 1,3,4-Oxadiazole Derivatives
737
Yu-Xia Da, Zhi Yang, Zheng-Jun Quan, Zhang Zhang, and Xi-Cun Wang*
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, Gansu, People’s Republic of China
*E-mail: wangxicun@nwnu.edu.cn
Received February 28, 2009
DOI 10.1002/jhet.142
Published online 14 July 2009 in Wiley InterScience (www.interscience.wiley.com).
In this study, the synthesis of series of 2-benzo[b]furan-substituted 1,3,4-oxadiazole derivatives using
readily available 2-benzo[b]furan carboxylic acid hydrazide as starting material has been investigated.
J. Heterocyclic Chem., 46, 737 (2009).
INTRODUCTION
2-Substituted benzo[b]furans [14,15] are widely dis-
tributed in nature and have a range of biological activ-
ities [16], for example, as insulin-sensitivity enhancers
[17], inhibitors of tubulin polymerase [18], antagonists
of the A1 adenosine receptor [19], inhibitors of testos-
terone 5R-reductase [20], and inhibitors of 5-lipoxygen-
ase [21]. Recently, of particular interest is BPAP, which
enhances impulse propagation mediated by the release
of catecholamines and serotonin in the brain and so may
slow progression of Parkinson’s and Alzheimer’s disease
[22].
1,3,4-Oxadiazoles are five-membered aromatic hetero-
cycles with great utility in synthetic, medicinal, and ma-
terial chemistry [1–4]. The widespread use of 1,3,4-oxa-
diazoles as a scaffold in medicinal chemistry establishes
this moiety as an important bioactive class of hetero-
cycles. These molecules are also utilized as pharmaco-
phores because of their favorable metabolic profile and
ability to engage in hydrogen bonding. In particular,
marketed antihypertensive agents, such as tiodazosin [5]
and nesapidil [6], and antibiotics, such as furamizole
[7], contain the oxadiazole nucleus. They are also useful
as HIV integrase inhibitors and angiogenesis inhibitors
[7,8]. 2,5-Disubstituted 1,3,4-oxadiazoles have also
attracted significant interest because of their applications
in organic light-emitting diodes, photoluminescence,
polymers, and material science [9,10].
In previous reports, we demonstrated the use of 2-
benzo[b]furan carboxylic acid and 2-benzo[b]furan car-
boxylic acid hydrazide as versatile building blocks for
the synthesis of functionalized heterocycles [23]. We
now report the investigations on the use of 2-benzo[b]-
furan carboxylic acid hydrazide (1) for the synthesis of
2,5-disubstituted 1,3,4-oxadiazole derivatives 4a–f, 5a–f,
10a–f, and 13a–f (Schemes 1).
Several methods have been reported in the literature
for the synthesis of 1,3,4-oxadiazoles. Most of these
protocols are multistep in nature and generally involve
the cyclization of diacylhydrazides or acylthiosemicarba-
zides and the oxidation of acylhydrozones [11] with a
variety of reagents such as thionyl chloride, phosphorus
oxychloride, or sulfuric acid, usually under harsh reac-
tion conditions. Recently, a few efficient examples have
been reported for the synthesis of 1,3,4-oxadiazoles by
treatment of readily available carboxylic acids with acid
hydrazides under acid conditions [12]. 1,3,4-Oxadiazoles
by condensation of acid hydrazide and triethyl orthoal-
kanates under microwave irradiations have also been
reported. This green protocol was catalyzed efficiently
by solid-supported Nafion_NR50 [13].
RESULTS AND DISCUSSION
Scheme 1 outlines the synthetic sequences used in our
laboratories for the preparation of the key intermediate
1 and its derivatives 1,3,4-oxadiazoles 4, 5, 10, and 13.
Synthesis of 2-aryl-5-(2-benzo[b]furan)-1,3,4-oxa-
diazoles 4a–f and 2-aryloxymethyl-5-(2-benzo[b]-
furan)-1,3,4-oxadiazoles 5a–f. Treatment of 2-benzo-
furoyl hydrazine (1) with 1 equiv of substituted benzoic
acids (2a–f) in the presence of POCl3 under reflux for
6 h produced 2,5-diaryl-substituted 1,3,4-oxadiazoles
(4a–f) in high yields. However, the reaction of compound
C
V
2009 HeteroCorporation

738
Y.-X. Da, Z. Yang, Z.-J. Quan, Z. Zhang, and X.-C. Wang
Vol 46
Scheme 1
1 with aryloxyacetic acids (3a–f) need catalytic amounts
of pyridine in reflux POCl3 and longer time (8 h) to give
the corresponding 1,3,4-oxadiazoles (5a–f) in higher
yields (method A) (entries 7–12, Table 1).
the presence of POCl3 under reflux for 8 h gave com-
pound 7 in 89% yield. Treatment of 7 with 1.1 equiv of
substituted phenylamines (9a–f) gave 2-arylamine-
methyl-5-(2-benzo[b]furan)-1,3,4-oxadiazoles
(10a–f)
Synthesis of 2-chloromethyl-5-(2-benzo[b]furan)-
1,3,4-oxadiazole (7) and its utilization for the synthe-
sis of 2-aryloxymethyl-5-(2-benzo[b]furan)-1,3,4-oxa-
diazoles (5a–f) and 2-arylaminomethyl-5-(2-benzo
[b]furan)-1,3,4-oxadiazoles (10a–f). The reaction of
acylhydrazine (1) with 2-chloroacetic acid in xylene in
(entries 13–18, Table 1), which cannot be synthesized
by cyclization reaction of corresponding acids and
acylhydrazines, and the reaction gave high yields. In
examining the reactivity of 2-chloromethyl-5-(2-ben-
zo[b]furan)-1,3,4-oxadiazole (7), the reaction of 7 with
aryl-substituted phenols (8) was carried out in the
Table 1
Physical and analytical data of compounds.a
Yieldb
(%)
Molecular
formula
Entry
Compd.
Aryl
Analysis (%) calcd./found
H
C
N
1
2
3
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
10a
10b
10c
10d
10e
10f
13a
13b
13c
13d
13e
13f
C6H5
4-CH3OC6H4
2-ClC6H4
81
75
81
73
C16H10N2O2
C17H12N2O3
C16H9ClN2O2
C16H9ClN2O2
C16H9N3O4
73.27/73.05
69.86/69.64
64.77/64.49
64.77/64.95
62.54/62.40
62.54/62.74
69.86/69.98
62.49/62.31
70.58/70.80
70.58/70.35
67.17/67.07
60.54/60.68
70.09/70.28
70.81/71.01
67.28/67.42
62.68/62.56
60.71/60.48
60.71/60.98
70.58/70.76
67.85/68.02
63.44/63.62
63.44/63.19
61.54/61.73
61.54/61.32
3.84/3.92
4.14/4.10
3.06/3.18
3.06/3.13
2.95/3.05
2.95/2.86
4.14/4.20
3.39/3.48
4.61/4.53
4.61/4.69
4.45/4.38
3.29/3.35
4.50/4.41
4.95/4.90
4.71/4.67
3.71/3.78
3.60/3.72
3.60/3.72
4.61/4.55
4.79/4.70
3.85/3.92
3.85/3.91
3.73/3.90
3.73/3.81
10.68/10.51
9.58/9.45
9.44/9.38
4
4-ClC6H4
9.44/9.25
5
6
2-NO2C6H4
4-NO2C6H4
C6H5OCH2
4-ClC6H4OCH2
2-CH3C6H4OCH2
4-CH3C6H4OCH2
4-CH3OC6H4OCH2
2-NO2C6H4OCH2
C6H5
83
78
13.68/13.56
13.68/13.49
9.58/9.68
8.57/8.68
9.15/9.04
C16H9N3O4
7
8
65(88)
68(93)
72(96)
60(77)
63(88)
60(83)
78
C17H12N2O3
C17H11ClN2O3
C18H14N2O3
C18H14N2O3
C18H14N2O4
C17H11N3O5
C18H16N3O2
C18H15N3O2
C18H15N3O3
C17H12ClN3O2
C17H12N4O4
C17H12N4O4
C18H14N2O3
C19H16N2O4
C18H13ClN2O3
C18H13ClN2O3
C18H13N3O5
C18H13N3O5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
9.15/9.26
8.58/8.69
12.46/12.39
14.42/14.55
13.76/14.68
13.08/13.17
12.90/11.78
16.66/16.84
16.66/16.84
9.15/9.06
8.33/8.42
8.22/8.08
8.22/8.31
11.96/12.08
11.96/11.77
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
2-NO2C6H4
4-NO2C6H4
C6H5
4-CH3OC6H4
2-ClC6H4
4-ClC6H4
86
80
75
76
81
70(78)
72(80)
60(67)
62(75)
65(78)
65(79)
3-NO2C6H4
4-NO2C6H4
The values in parenthesis indicate the yields of method B for compounds 5 and 13.
a Isolated yield.
b Yields of method A for compounds 5 and 13.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Utilization of 2-Benzo[b]furan Carboxylic Acid Hydrazide in the Synthesis
of 1,3,4-Oxadiazole Derivatives
739
9H, Ar-H), 3.80 (s, 3H, OCH3); 13C NMR (75 Hz, CDCl3): d
¼ 164.5, 161.2, 159.2, 144.5, 130.0, 128.2, 127.6, 126.9,
124.9, 124.2, 123.0, 116.3, 112.6, 110.7, 57.9.
presence of NaOH powder under reflux ethanol condi-
tion. Compounds 5a–f could also be obtained in good
yields (method B) (entries 7–12, Table 1).
4c: m.p. 126–128ꢀC; IR (KBr): 1640, 1577, 1511, 1202,
One-pot synthesis of 3-acetyl-2-aryl-5-(2-benzo[b]-
furan)-1,3,4-oxadiazolines (13a–f). First, the synthesis
of 1,3,4-oxadiazoles 13a–f were investigated through a
two-step pathway. Treatment of 1 with aromatic alde-
hydes (11a–f) in the presence of catalytic amounts of
Ac2O under refluxing ethanol for 6 h gave 2-benzo[b]-
furoyl hydrazones 12a–f, which upon treatment in
refluxing Ac2O afforded 1,3,4-oxadiazolines 13a–f in
moderate total yields (entries 19–24, Table 1).
1056 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.15–7.81 (m,
9H, Ar-H); 13C NMR (75 Hz, CDCl3): d ¼ 164.7, 158.6,
156.4, 144.3, 139.8, 132.8, 129.5, 128.2, 127.7, 127.4, 124.9,
124.2, 122.9, 122.2, 116.7, 110.1.
4d: m.p. 177–179ꢀC; IR (KBr): 1638, 1582, 1505, 1209,
1052 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.00–7.84 (m,
9H, Ar-H); 13C NMR (75 Hz, CDCl3): d ¼ 164.5, 158.3,
156.4, 144.4, 136.8, 130.3, 127.6, 127.2, 124.5, 124.3, 122.3,
120.4, 116.4, 110.2.
4e: m.p. 140–142ꢀC; IR (KBr): 1640, 1577, 1511, 1202,
1056 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.16–8.14 (m,
The ability of Ac2O to promote both steps led us to
investigate the one-pot synthesis of oxadiazolines 13a–f
starting from the same substrates. When acylhydrazine
(1) and aromatic aldehydes (11a–f) were stirred in Ac2O
under reflux, the corresponding oxadiazolines 13a–f
were obtained in good yields after 2 h (entries 19–24,
Table 1). It could be seen from Table 1 that the one-pot
method was a more efficient way than the two-step pro-
cedures for the preparation of compounds 13a–f.
In conclusion, the synthesis of series of 2-benzo[b]-
furan-substituted 1,3,4-oxadiazole derivatives using
readily available 2-benzo[b]furan carboxylic acid hydra-
zide as starting material has been investigated. These
processes are highly efficient with good yields and use
cheap and easily available aldehydes and acids.
9H, Ar-H); 13C NMR (75 Hz, CDCl3): d ¼ 164.8, 160.5,
158.6, 155.3, 147.3, 140.2, 130.8, 129.7, 128.4, 127.4, 124.6,
124.0, 122.8, 122.5, 116.9, 110.4.
4f: Yield 78%, m.p. 257–259ꢀC; IR (KBr): 1638, 1582,
1505, 1209, 1052 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼
7.16–8.46 (m, 9H, Ar-H); 13C NMR (75 Hz, CDCl3): d ¼
164.7, 158.8, 155.3, 147.5, 136.2, 135.2, 131.8, 129.3, 128.6,
124.9, 124.3, 122.3, 116.6, 110.6.
General procedure for the synthesis of 2-aryl-5-(2-ben-
zo[b]furan)-1,3,4-oxadiazoles (5a–f).
Method A. The mixture of 2-benzo[b]furan carboxylic acid
hydrazide (1) (1 mmol), substituted aryloxyacetic acids (3a–f)
(1 mmol), pyridine (0.1 mL), and POCl3 (5 mL) were stirred
under reflux condition for 8 h. The excess of POCl3 was
evaporated under reduced pressure. The residue was poured
into ice water (50 mL). Then the precipitate was filtered and
washed with aqueous solution of NaOH (1%) and subsequently
with water. The solid was recrystallized from EtOH to give
the products 2-aryloxymethyl-5-(2-benzo[b]furan)-1,3,4-oxadia-
zoles (5a–f).
EXPERIMENTAL
All reagents were obtained commercially and used without
further purification. Melting points were determined on an XT-
4 electrothermal micromelting point apparatus and uncorrected.
IR spectra were recorded using KBr pellets on Nicolet AVA-
TAR 36 FTIR spectrophotometer. For compounds 4a–f and
5a–f, NMR spectra were recorded on an Avanci-D2X-200
instrument using CDCl3 as solvent and TMS as internal stand-
ard. For compounds 7, 10a–f, and 13a–f, NMR spectra were
recorded at 400 (1H) and 100 (13C) MHz, respectively, on a
Varian Mercury plus-400 instrument using CDCl3 as solvent
and TMS as internal standard.
Method B. The mixture of 2-chloromethyl-5-(2-benzo[b]-
furan)-1,3,4-oxadiazole (7) (1 mmol), substituted phenols (8)
(1.1 mmol), and NaOH (1.1 mmol) in 10 mL ethanol were
stirred at 80ꢀC for 12 h. The mixture was poured into ice
water (50 mL). Then the precipitate was filtered and washed
with water (3 ꢂ 10 mL). The solid was recrystallized from
EtOH to give the product 2-aryloxymethyl-5-(2-benzo[b]-
furan)-1,3,4-oxadiazoles (5a–f).
5a: m.p. 184–186ꢀC, IR (KBr): 1640, 1577, 1511, 1202,
1056 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.01–7.76 (m,
10H, Ar-H), 5.37 (s, 2H, CH2); 13C NMR (75 Hz, CDCl3): d
¼ 164.4, 161.2, 158.3, 157.8, 154.6, 129.8, 128.0, 127.7,
124.3, 122.8, 120.3, 114.0, 112.3, 110.5, 72.6.
General procedure for the synthesis of 2-aryl-5-(2-ben-
zo[b]furan)-1,3,4-oxadiazoles (4a–f). The mixture of 2-ben-
zo[b]furan carboxylic acid hydrazide (1) (1 mmol), substituted
benzoic acids (2a–f) (1 mmol), and POCl3 (5 mL) was stirred
under reflux condition for 6 h. The excess of POCl3 was evapo-
rated under reduced pressure. The residue was poured into ice
water (50 mL). Then the precipitate was filtered and washed
with aqueous solution of NaOH (1%) and subsequently with
water. The solid was recrystallized from EtOH to give the
products 2-aryl-5-(2-benzo[b]furan)-1,3,4-oxadiazoles (4a–f).
4a: m.p. 170–172ꢀC; IR (KBr): 1633, 1579, 1506, 1210, 1058
cmꢁ1; 1H NMR (200 Hz, CDCl3): d ¼ 7.00–8.14 (m, 10H, Ar-H);
13C NMR (75 Hz, CDCl3): d ¼ 164.5, 159.8, 158.4, 144.1, 129.8,
128.1, 127.7, 127.1, 124.8, 124.6, 122.9, 121.2, 116.9, 110.4.
4b: m.p. 153–155ꢀC; IR (KBr): 1639, 1580, 1501, 1209,
5b: m.p. 130–132ꢀC, IR (KBr): 1638, 1580, 1489, 1214,
1048 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.10–7.91 (m,
9H, Ar-H), 5.37 (s, 2H, CH2); 13C NMR (75 Hz, CDCl3): d ¼
164.6, 161.3, 158.3, 156.6, 154.8, 131.4, 130.9, 127.5, 126.5,
124.8, 123.2, 122.5, 114.1, 112.6, 110.3, 72.6.
5c: m.p. 187–189ꢀC; IR (KBr): 1651, 1564, 1512, 1214,
1056 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 6.88–7.92 (m,
9H, Ar-H), 5.37 (s, 2H, CH2), 2.36 (s, 3H, CH3); 13C NMR
(75 Hz, CDCl3): d ¼ 164.3, 161.5, 158.6, 156.3, 154.1, 131.3,
131.4, 130.1, 127.7, 124.7, 124.8, 123.0, 122.1, 121.7, 112.6,
110.2, 72.9, 22.1.
5d: m.p. 137–139ꢀC; IR (KBr): 1650, 1569, 1520, 1214,
1
1052 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.00–8.14 (m,
1059 cmꢁ1; H NMR (200 Hz, CDCl3): d ¼ 6.94–7.92 (m, 9H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Y.-X. Da, Z. Yang, Z.-J. Quan, Z. Zhang, and X.-C. Wang
Vol 46
Ar-H), 5.36 (s, 2H, CH2), 2.35 (s, 3H, CH3); 13C NMR (75 Hz,
CDCl3): d ¼ 164.8, 160.4, 158.9, 156.9, 157.4, 131.1, 130.8,
128.1, 127.5, 124.0, 122.3, 120.8, 111.9, 110.3, 72.5, 22.2.
5e: m.p. 141–142ꢀC; IR (KBr) 1639, 1567, 1501, 1208,
10d: m.p. 169–171ꢀC; IR (KBr): 3352, 1511, 1640, 1170,
1
1089 cmꢁ1; H NMR (400 Hz, CDCl3): d ¼ 7.69 (d, 1H, J ¼
8.0 Hz, Ar-H), 7.65 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.62–7.52 (m,
2H, Ar-H), 7.50–7.34 (m, 1H, Ar-H), 7.32–7.14 (m, 2H, Ar-
H), 6.73–6.66 (m, 2H, Ar-H), 4.68 (s, 2H, CH2), 4.33 (s, 1H,
NH); 13C NMR (100 Hz, CDCl3): d ¼ 164.1, 158.5, 155.7,
144.8, 140.2, 129.3, 127.3, 127.1, 124.1, 123.9, 122.4, 114.4,
112.1, 110.5, 39.2.
1052 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 6.84–7.73 (m,
9H, Ar-H), 5.37 (s, 2H, CH2), 3.77 (s, 3H, CH3O); 13C NMR
(75 Hz, CDCl3): 161.9, 160.3, 157.8, 156.9, 155.0, 154.0,
130.7, 128.8, 127.1, 126.0, 118.5, 115.7, 112.2, 111.2, 58.9,
56.1.
10e: m.p. 200–202ꢀC; IR (KBr): 3347, 1569, 1650, 1206,
1196 cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 8.24–7.75 (m,
5f: m.p. 192–194ꢀC; IR (KBr): 1652, 1580, 1508, 1206,
1056 cmꢁ1
;
1H NMR (200 Hz, CDCl3): d ¼ 7.02–8.21 (m,
2H, Ar-H), 7.68 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.67 (d, 1H, J ¼
8.0 Hz, Ar-H), 7.63–7.52 (m, 2H, Ar-H), 7.51–7.35 (m, 1H,
Ar-H), 7.20–6.98 (m, 2H, Ar-H), 4.68 (s, 2H, CH2), 4.43 (s,
1H, NH); 13C NMR (100 Hz, CDCl3): d ¼ 163.4, 158.1,
154.9, 141.1, 138.4, 134.8, 132.9, 128.0, 123.8, 123.0, 122.6,
121.0, 117.6, 113.9, 111.7, 111.1, 39.8.
9H, Ar-H), 5.37 (s, 2H,CH2); 13C NMR (75 Hz, CDCl3): d ¼
164.9, 160.9, 158.8, 156.0, 155.8, 145.8, 132.3, 130.2, 127.3,
124.2, 124.0, 122.8, 121.1, 114.4, 112.2, 110.5, 70.7.
Synthesis of 2-chloromethyl-5-(2-benzo[b]furan)-1,3,4-
oxadiazole (7). The mixture of 2-benzo[b]furan carboxylic acid
hydrazide (1) (10 mmol), 2-chloroacetic acid (6) (11 mmol), xy-
lene (10 mL), and POCl3 (5 mL) were stirred under reflux for 8
h. The excess of POCl3 and solvent were evaporated under
reduced pressure. The residue was poured into ice water (50
mL). Then the precipitate was filtered and washed with aqueous
solution of NaOH (1%) and subsequently with water. The solid
was recrystallized from EtOH to give the product 2-chloro-
methyl-5-(2-benzo[b]furan)-1,3,4-oxadiazole (7).
10f: m.p. 142–144ꢀC; IR (KBr): 3351, 1571, 1652, 1210,
1200 cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 8.27–8.05 (m,
2H, Ar-H), 7.68 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.67 (d, 1H, J ¼
8.0 Hz, Ar-H), 7.63–7.52 (m, 2H, Ar-H), 7.51–7.35 (m, 1H,
Ar-H), 7.05–6.95 (m, 2H, Ar-H), 4.67 (s, 2H, CH2), 4.43 (s,
1H, NH); 13C NMR (100 Hz, CDCl3): d ¼ 165.0, 158.8,
156.2, 154.6, 142.1, 137.5, 128.0, 124.5, 124.4, 123.0, 122.2,
114.8, 112.9, 111.1, 44.8.
Yield 89%, m.p. 149–151ꢀC; IR (KBr): 3024, 1638, 1574
General procedure for one-pot synthesis of 3-acetyl-2-
aryl-5-(2-benzo[b]furan)-1,3,4-oxadiazolines
1
cmꢁ1; H NMR (400 MHz, CDCl3): d ¼ 7.71 (d ,1H, J ¼ 8.0
(13a–f). The
Hz, Ar-H), 7.63 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.58 (s, 1H, Ar-
H),7.47 (t, J ¼ 8.0 Hz, Ar-H), 7.34 (t, J ¼ 8.0 Hz, Ar-H),
4.82 (s, 2H, CH2).
mixture of 2-benzo[b]furan carboxylic acid hydrazide (1) (1
mmol), aromatic aldehydes (11a–f) (1 mmol), and Ac2O (5
mL) were stirred under reflux condition for 2 h. The excess of
Ac2O was evaporated under reduced pressure. The residue was
recrystallized from benzene to give the product 2-aryl-5-(2-
benzo[b]furan)-3-acetyl-1,3,4-oxadiazoline (13a–f).
General procedure for the synthesis of 2-arylamine-
methyl-5-(2-benzo[b]furan)-1,3,4-oxadiazoles
(10a–f). The
mixture of 2-chloromethyl-5-(2-benzo[b]furan)-1,3,4-oxadia-
zole (7) (1 mmol), arylamines (9) (1.1 mmol), and NaOH (1.1
mmol) in 10 mL ethanol were stirred at 80ꢀC for 12 h. The
mixture was poured into ice water (50 mL). Then the precipi-
tate was filtered and washed with water (3 ꢂ 10 mL). The
solid was recrystallized from EtOH to give the product 2-ary-
loxymethyl-5-(2-benzo[b]furan)-1,3,4-oxadiazoles (10a–f).
10a: m.p. 204–205ꢀC; IR (KBr): 3334, 1579, 1642, 1203,
13a: m.p. 150–151ꢀC; IR (KBr): 1671, 1588, 1260, 1073
cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 7.66 (d, 1H, J ¼ 8.0
Hz, Ar-H), 7.59 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.52 (s, 1H, Ar-
H), 7.49 (t, 1H, 8.0 Hz, Ar-H), 7.45 (t, 1H, J ¼ 8.0 Hz, Ar-H),
7.29–7.43 (m, 5H, Ar-H), 7.13 (s, 1H, oxadiazoline-H), 2.42
(s, 3H, COCH3); 13C NMR (100 Hz, CDCl3): d ¼ 167.9,
155.8, 149.1, 141.1, 135.8, 130.1, 128.8, 127.1, 127.0, 126.6,
123.9, 122.2, 111.9, 111.2, 92.7, 21.6.
1
1060 cmꢁ1; H NMR (400 Hz, CDCl3): d ¼ 7.63 (d, 1H, J ¼
13b: m.p. 153–155ꢀC; IR (KBr): 1693, 1636, 1277, 1083
8.0 Hz, Ar-H), 7.57 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.74–7.40 (m,
2H, Ar-H), 7.34–7.23 (m, 1H, Ar-H), 7.21–6.85 (m, 5H, Ar-
H), 4.30 (s, 1H, NH); 13C NMR (100 Hz, CDCl3): d ¼ 163.9,
158.0, 154.9, 146.5, 140.8, 128.7, 128.2, 126.8, 126.9, 124.5,
123.0, 115.2, 111.8, 109.5, 38.8.
cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 7.66 (d, 1H, J ¼ 8.0
Hz, Ar-H), 7.57 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.51 (s, 1H, Ar-
H), 7.47 (t, 1H, J ¼ 8.8 Hz, Ar-H), 7.44 (t, 1H, J ¼ 8.8 Hz,
Ar-H), 6.80 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.34 (d, 2H, J ¼ 8.0
Hz, Ar-H), 7.10 (s, 1H, oxadiazoline-H), 2.40 (s, 3H, COCH3),
3.73 (s, 3H, OCH3); 13C NMR (100 Hz, CDCl3): d ¼ 167.8,
155.7, 148.7, 140.8, 135.8, 131.0, 128.4, 127.0, 126.7, 126.4,
123.7, 122.1, 111.7, 111.0, 92.3, 21.3.
10b: m.p. 150–151ꢀC; IR (KBr): 3384, 1558, 1644, 1206,
1
1171 cmꢁ1; H NMR (400 Hz, CDCl3): d ¼ 7.65 (d, 1H, J ¼
8.0 Hz, Ar-H), 7.58 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.46–7.40 (m,
2H, Ar-H), 7.33–7.25 (m, 1H, Ar-H), 7.01 (d, 2H, J ¼ 8.0 Hz,
Ar-H), 6.68 (d, 2H, J ¼ 8.0 Hz, Ar-H), 4.35 (s, 2H, NH); 4.31
(s, 1H, NH), 2.23 (s, 3H, CH3); 13C NMR (100 Hz, CDCl3): d
¼ 164.6, 158.3, 155.6, 143.9, 140.3, 129.9, 128.3, 127.1,
127.1, 124.0, 122.3, 113.4, 110.3, 39.4, 20.3.
13c: m.p. 192–194ꢀC; IR (KBr): 1681, 1623, 1280, 1063
cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 7.65 (d, 1H, J ¼ 8.0
Hz, Ar-H), 7.60 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.50 (s, 1H, Ar-
H), 7.48 (t, 1H, J ¼ 8.8 Hz, Ar-H), 7.48 (t, 1H, J ¼ 8.8 Hz,
Ar-H), 7.17–7.40 (m, 5H, Ar-H), 7.16 (s, 1H, oxadiazoline-H),
2.45 (s, 3H, COCH3); 13C NMR (100 Hz, CDCl3): d ¼ 167.9,
155.8, 149.3, 141.3, 136.3, 130.2, 128.4, 128.0, 126.9, 126.5,
123.6, 122.5, 111.6, 111.4, 92.9, 21.8.
10c: m.p. 128–130ꢀC; IR (KBr): 3304, 1557, 1641, 1241,
1
1173 cmꢁ1; H NMR (400 Hz, CDCl3): d ¼ 7.64 (d, 1H, J ¼
8.0 Hz, Ar-H), 7.54 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.45–7.39 (m,
2H, Ar-H), 7.31–7.28 (m, 1H, Ar-H), 6.72 (d, 2H, J ¼ 8.0 Hz,
Ar-H), 6.69 (d, 2H, J ¼ 8.0 Hz, Ar-H), 4.32 (s, 1H, NH), 3.77
(s, 3H, CH3O); 13C NMR (100 Hz, CDCl3): d ¼ 164.9, 159.3,
155.8, 154.8, 140.9, 136.7, 128.5, 127.9, 124.8, 123.0, 116.0,
113.9, 113.0, 110.8, 40.4, 23.6.
13d: m.p. 118–120ꢀC; IR (KBr): 1688, 1612, 1272, 1075
cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 7.69 (d, 1H, J ¼ 8.0
Hz, Ar-H), 7.59 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.54 (s, 1H, Ar-
H), 7.49 (t, 1H, J ¼ 8.0 Hz, Ar-H), 7.47 (t, 1H, J ¼ 8.8 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Utilization of 2-Benzo[b]furan Carboxylic Acid Hydrazide in the Synthesis
of 1,3,4-Oxadiazole Derivatives
741
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Ar-H), 7.23 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.47 (d, 2H, J ¼ 8.0
Hz, Ar-H), 7.15 (s, 1H, oxadiazoline-H), 2.43 (s, 3H, COCH3);
13C NMR (100 Hz, CDCl3): d ¼ 167.9, 155.9, 149.0, 141.1,
136.2, 130.4, 129.1, 127.9, 126.8, 126.1, 123.9, 122.2, 111.7,
111.1, 92.7, 21.6.
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13e: m.p. 158–160ꢀC; IR (KBr): 1719, 1635, 1280, 1088
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;
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8.34–7.75 (m, 3H, Ar-H), 7.69 (d, 1H, J ¼ 8.0 Hz, Ar-H),
7.59 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.56 (s, 1H, Ar-H), 7.51 (t,
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(S, 1H, oxadiazoline-H), 2.43 (S, 3H, COCH3); 13C NMR (100
Hz, CDCl3): d ¼ 167.9, 155.8, 149.2, 141.0, 136.0, 130.0,
129.1, 127.1, 127.0, 126.8, 124.2, 122.0, 111.8, 111.1, 92.5,
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13f: m.p. 144–146ꢀC; IR (KBr): 1721, 1630, 1287, 1093
cmꢁ1
;
1H NMR (400 Hz, CDCl3): d ¼ 8.28 (d, 2H, J ¼ 8.0
Hz, Ar-H), 7.68 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.60 (d, 1H, J ¼
8.0 Hz, Ar-H), 7.55 (s, 1H, Ar-H), 7.50 (t, 1H, J ¼ 8.8 Hz,
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13C NMR (100 Hz, CDCl3): d ¼ 167.9, 155.8, 149.2, 140.8,
136.2, 132.1, 128.8, 127.3, 126.5, 126.9, 123.9, 122.1, 111.6,
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Acknowledgments. The authors are thankful for the financial
support from the Natural Science Foundation of Gansu Province
(3ZS061-A25-019) and the Scientific Research Fund of Gansu
Provincial Education Department (0601-25).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet