Iron(III) Chloride/l-Proline as an Efficient Catalyst for the Synthesis of 3-Substituted 1,2,4-Oxadiazoles from Amidoximes and Triethyl Orthoformate

Article abstract of DOI:10.1055/s-0035-1562431

A general, facile, and efficient method is presented for the synthesis of 3-substituted 1,2,4-oxadiazoles from amidoximes and triethyl orthoformate. The procedure employs an iron(III) chloride/l-proline catalytic system and the 3-substituted 1,2,4-oxadiaz

Full text of DOI:10.1055/s-0035-1562431

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
B. Kaboudin et al.
Paper
Synthesis
Iron(III) Chloride/L-Proline as an Efficient Catalyst for the Synthesis
of 3-Substituted 1,2,4-Oxadiazoles from Amidoximes and Triethyl
Orthoformate
Babak Kaboudin*a
Foad Kazemia
Maryam Pirouza
Aysan Baharian Khoshkhooa
Jun-ya Katob
FeCl3 (10 mol%)
O
N
N
OH
N
L-proline (10 mol%)
H
R
+
H
C(OEt)3
80 °C, 12 h
NH2
R
excess
12 examples
up to 88% yield
Tsutomu Yokomatsub
a Department of Chemistry, Institute for Advanced Studies in
Basic Sciences (IASBS), Zanjan 45137-66731, Iran
kaboudin@iasbs.ac.ir
b School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received: 10.03.2016
Accepted after revision: 28.04.2016
Published online: 15.06.2016
O
N
O
N
O
O
N
N
N
N
N
N
DOI: 10.1055/s-0035-1562431; Art ID: ss-2016-z0172-op
1,2,4-
1,3,4-
1,2,5-
1,2,3-
Abstract A general, facile, and efficient method is presented for the
synthesis of 3-substituted 1,2,4-oxadiazoles from amidoximes and tri-
ethyl orthoformate. The procedure employs an iron(III) chloride/L-pro-
line catalytic system and the 3-substituted 1,2,4-oxadiazole products
are obtained in moderate to good yields.
Figure 1 Structures of oxadiazoles
O
N
O
N
N
O
N
Key words 1,2,4-oxadiazoles, iron(III) chloride, L-proline, amidoximes,
triethyl orthoformate
S
C
N
O
C
N
N
N
F
HO
1
2
3
The chemistry of heterocyclic compounds is an import-
ant research area in organic chemistry due to their use in
pharmaceuticals and their presence in natural products as
well as new materials. Oxadiazoles are five-membered het-
erocyclic compounds that occupy a special place due to the
growing importance of these heterocycles for the design of
biologically active compounds and for materials construc-
tion.1 Among oxadiazoles, 1,2,4-oxadiazoles are particularly
important (Figure 1).2,3 They function as hydrolytically sta-
ble bioisosteres for esters or amides showing biological
properties as antidiabetic,4 anti-inflammatory,5 antimicro-
bial,6 antitumor,7 anticonvulsant,8 and neuroprotective9
agents. 1,2,4-Oxadiazoles are also found in several drugs in-
cluding muscarinic receptor agonists for the treatment of
Alzheimer’s disease,10 Duchenne muscular dystrophy and
potentially other genetic disorders,11 and helminthiasis12
(Figure 2).
Figure 2 Examples of drugs containing a 1,2,4-oxadiazole ring: musca-
rinic receptor for the treatment of Alzheimer’s (1), Duchenne muscular
dystrophy and potentially other genetic disorders (2) (Ataluren), and
helminthiasis (3)
oximes (Scheme 1).16 Heterocyclization can be effected by
treating an O-acylamidoxime with bases such as NaH or
NaOEt at room temperature, or pyridine with heating.17
1,2,4-Oxadiazoles are also prepared by [3+2]-cycloaddition
of nitrile oxides with nitriles.18 In contrast to the widely
studied 3,5-disubstituted 1,2,4-oxadiazoles, relatively few
papers have been reported on the synthesis of 3-monosub-
stituted 1,2,4-oxadiazoles.
3-Monosubstituted 1,2,4-oxadiazoles are prepared by
the reaction of amidoximes with ethyl orthoformate at high
temperature.19 Recently, Makhova et al. reported scandium
triflate as an efficient catalyst for the synthesis of 3-methyl-
4-(1,2,4-oxadiazol-3-yl)furoxan via tandem reaction of fur-
oxanylamidoxime with a trialkyl orthoformate at ambient
temperature.20 However, to the best our knowledge, there is
The most common routes for the synthesis of 1,2,4-oxa-
diazoles are shown in Scheme 1.13–15 In general, 1,2,4-oxa-
diazoles are prepared by heterocyclization of O-acylated
amidoximes derived from an active acyl chloride and amid-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
B. Kaboudin et al.
Paper
Synthesis
catalytic preparation of oxadiazoles. Further, the effect of
the amount of FeCl3/L-proline and the reaction temperature
was investigated (Table 1, entries 16–19). The results indi-
cated that decreasing the amount of catalyst (0.1 equiv of
each) did not lead to a significant decrease in the yield of 2a
(Table 1, entry 16). Similarly, decreasing the reaction time
from 24 to 12 hours resulted in only a slight decrease in the
yield of the oxadiazole. Decreasing the reaction tempera-
ture (from 80 °C to 50 °C) or the amount of catalyst (0.05
equiv of each) resulted in lower yields of 2a (Table 1, entries
18 and 19). Thus, the optimum reaction conditions for the
synthesis of oxadiazole 2a involved the use of 0.1 equiv of
FeCl3/L-proline at 80 °C for 12 hours.
OH
O
R2
N
N
NH2OH
R2COX
R1
C N
O
EtOH, reflux
R1
NH2
R1
NH2
heat
or catalyst
catalyst
– NH3
R1
N
R2
C N
R1
C
N
O
N
R2
O
Scheme 1 Different methods for the synthesis of 1,2,4-oxadiazoles
no report of a general method for the synthesis of 3-mono-
substituted 1,2,4-oxadiazoles via the reaction of amidox-
imes with triethyl orthoformate.
Therefore, it is highly desirable to develop novel, simple
and mild methods for the synthesis of 3-monosubstituted
1,2,4-oxadiazoles. In this study, we report an efficient
FeCl3/L-proline catalyzed condensation and cyclization of
amidoximes with triethyl orthoformate for the synthesis of
3-monosubstituted 1,2,4-oxadiazoles.
Initially, the one-pot reaction of 4-chlorobenzamid-
oxime (1a) (1 equiv) with triethyl orthoformate (1 equiv)
was chosen as a model reaction to be studied under various
reaction conditions, and the results are summarized in Ta-
ble 1. Treatment of 1a with triethyl orthoformate (1 equiv)
in DMF at 80 °C in the absence of any catalyst gave the cor-
responding oxadiazole 2a in 12% yield after 24 hours (Table
1, entry 1). In toluene and DMSO (Table 1, entries 2 and 3),
the reaction failed to give the corresponding adduct 2a after
24 hours at 80 °C, while the yield increased to only 18% at
reflux temperature in ethanol (Table 1, entry 4).
Treatment of 1a with triethyl orthoformate (excess) un-
der solvent-free conditions at 80 °C for 24 hours gave 2a in
only 21% yield (Table 1, entry 5), and the same reaction pro-
ceeded only marginally better under solvent-free condi-
tions at reflux temperature for 24 hours to give 2a in 27%
yield (Table 1, entry 6). While treatment of 1a with triethyl
orthoformate (excess) for 24 hours gave 2a in only 35% yield
in the presence of triethylamine as a basic catalyst (Table 1,
entry 7), further experiments on the same reaction in the
presence of different bases (Table 1, entries 8–10) revealed
that the reaction did not give satisfactory results. After
screening several bases, the effects of various Lewis acid
catalysts on oxadiazole formation were also investigated
(Table 1, entries 11–17). There was no reaction when ZnCl2
was used as the catalyst, while employing HgCl2 or FeCl3 re-
sulted in yields of 2a of only 35% and 51%, respectively (Ta-
ble 1, entries 11–13). Interestingly, when the reaction was
conducted with FeCl3/phenanthroline (0.2 equiv of each) or
FeCl3/L-proline, the oxadiazole 2a was obtained in 90% yield
(Table 1, entries 14 and 15). Compared to phenanthroline, L-
proline is much cheaper, non-toxic and is more readily
available, and it was therefore selected as the ligand for the
Table 1 Reaction of 4-Chlorobenzamidoxime (1a) with Triethyl Ortho-
formatea
O
N
OH
N
OEt
OEt
N
+
H
OEt
NH2
Cl
Cl
2a
1a
Entry Catalyst
Solvent
Temp (°C) Time (h) Yield (%)b
1
2
–
DMF
80
24
24
24
24
24
48
24
24
24
24
24
24
24
24
24
24
12
12
12
12
–
–
toluene
DMSO
EtOH
80
3
–
80
–
4
–
reflux
80
18
21
27
35
20
21
30
–
c
5
–
–
c
6
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
reflux
80
c,d
c,d
c,d
c,d
c,e
c,e
c,e
c,e
c,e
c,f
7
Et3N
K2CO3
KF
8
80
9
80
10
11
12
13
14
15
16
17
18
19
(NH4)2CO3
ZnCl2
80
80
HgCl2
80
35
51
90
90
89
87
68
73
FeCl3
80
FeCl3/phenanthroline
FeCl3/L-proline
FeCl3/L-proline
FeCl3/L-proline
FeCl3/L-proline
FeCl3/L-proline
80
80
80
c,f
80
c,f
50
c,g
80
a Amidoxime (1 equiv) and triethyl orthoformate (1 equiv) were used unless
otherwise noted.
b Yield of isolated product.
c Excess triethyl orthoformate was used.
d In the presence of a base (1 equiv).
e In the presence of a Lewis acid (0.2 equiv).
f In the presence of FeCl3/L-proline (0.1 equiv of each).
g In the presence of FeCl3/L-proline (0.05 equiv of each).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
B. Kaboudin et al.
Paper
Synthesis
Table 2 (continued)
Entry Amidoxime
To explore the scope of the synthesis of 3-monosubsti-
tuted 1,2,4-oxadiazoles, we applied this protocol to a range
of amidoximes. The methodology proved suitable for the
synthesis of 3-monosubstituted 1,2,4-oxadiazoles in mod-
erate to good yields as shown in Table 2.
Oxadiazole
Yield
(%)b
OH
O
N
N
10
2j
20
45
Ph
Ph
Ph
Ph
N
NH2
Table 2 Reactions of Amidoximes 1 with Triethyl Orthoformate in the
Ph
Presence of FeCl3/L-Prolinea
OH
O
N
N
11
12
2k
FeCl3 (10 mol%)
N
O
N
N
OH
NH2
OH
Ph
N
L-proline (10 mol%)
80 °C, 12 h
H
R
+
H
C(OEt)3
NH2
R
excess
N
c
–
–
–
NH2
Entry Amidoxime
Oxadiazole
Yield
(%)b
a Amidoxime (1 equiv), triethyl orthoformate (excess) and FeCl3/L-proline
(10 mol%) were used.
OH
O
b Yield of isolated product after column chromatography.
c No reaction.
N
N
N
1
2a
87
NH2
Cl
Cl
Substituted benzamidoximes reacted with triethyl or-
thoformate in the presence of 10 mol% of FeCl3/L-proline to
afford the desired products 2b–g in moderate to good yields
(Table 2, entries 2–7). Benzylamidoximes 1h–j also reacted
with triethyl orthoformate to give the corresponding oxadi-
azoles 2h–j (Table 2, entries 8–10). The process was also
successfully applied to unsaturated amidoxime 1k and the
desired product 2k was obtained in 45% isolated yield (Ta-
ble 2, entry 11). However, treatment of cyclohexylamid-
oxime 1l with triethyl orthoformate under the same condi-
tions failed to give the expected 1,2,4-oxadiazole (Table 2,
entry 12).
Next, we used trimethyl orthoformate for the synthesis
of oxadiazoles from amidoximes in the presence of FeCl3/
L-proline (10 mol%). Similar treatment of 1a with trimethyl
orthoformate (excess) at 80 °C gave the corresponding oxa-
diazole 2a in 86% yield after 12 hours (Scheme 2).
OH
O
N
N
2
2b
2c
83
73
N
NH2
OH
O
N
N
Cl
Cl
3
N
NH2
OH
O
N
N
4
2d
2e
2f
51
88
72
N
NH2
O2N
O2N
OH
O
N
N
N
N
5
N
NH2
Br
Br
OMe
OH
O
Cl
Cl
O
OMe
N
OH
N
OMe
OMe
OMe
H
6
N
NH2
NH2
+
H
NH2
Cl
Cl
Cl
Cl
1a
3a
OH
O
N
N
N
7
2g
47
NH2
O
O
O
N
N
OMe
O
N
N
H
H
H
N
H
N
OH
O
N
N
Cl
Cl
8
2h
2i
45
32
N
2a
4a
NH2
MeO
MeO
MeO
Scheme 2 Proposed mechanism for the synthesis of oxadiazoles
OH
O
N
N
MeO
9
N
NH2
When the reaction carried out for six hours, intermedi-
ate 3a was separated from the reaction mixture and charac-
terized by NMR spectroscopy. A proposed mechanism is
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
B. Kaboudin et al.
Paper
Synthesis
outlined in Scheme 2 for the synthesis of oxadiazoles 2. The
present process is thought to proceed via the reaction of
amidoxime 1a with trimethyl orthoformate to give inter-
mediate 3a, followed by internal cyclization to give the oxa-
diazole 2a.
We found that it was also possible to carry out this reac-
tion with trimethyl orthoacetate to give the corresponding
oxadiazole 5 in 87% isolated yield (Scheme 3).
solvent under reduced pressure gave pure products in 20–88% isolat-
ed yields. All products gave satisfactory spectral data in accordance
with the assigned structures.
3-(4-Chlorophenyl)-1,2,4-oxadiazole (2a)
Yield: 155 mg (87%); mp 97–98 °C (Lit.19 100–103 °C); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.0 Hz, 2 H), 8.08 (d, J = 8.0
Hz, 2 H), 8.78 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 124.8, 128.9, 129.3, 137.6, 164.9,
O
N
167.0.
OH
FeCl3 (10 mol%)
N
OMe
OMe
OMe
L-proline (10 mol%)
N
3-Phenyl-1,2,4-oxadiazole (2b)19
Me
+
NH2
100 °C, 24 h
Cl
Yield: 120 mg (83%); yellow oil.
Cl
1a
5
1H NMR (400 MHz, CDCl3): δ = 7.44–7.59 (m, 3 H), 8.12–8.19 (m, 2 H),
8.71 (s, 1 H).
Scheme 3 Reaction of 4-chlorobenzamidoxime 1a (1 equiv) with
13C NMR (100 MHz, CDCl3): δ = 126.3, 127.6, 128.9, 130.4, 164.8,
trimethyl orthoacetate (excess) in the presence of FeCl3/L-proline
167.8.
In conclusion, we have reported a simple and conve-
nient method for the synthesis of 3-monosubstituted 1,2,4-
oxadiazoles via the reaction of amidoximes with triethyl or-
thoformate in the presence of 10 mol% of FeCl3/L-proline.
The simple work-up, mild reaction conditions, moderate to
good yields, and clean reactions should make this method
an attractive and useful contribution to present methodolo-
gies.
3-(3-Chlorophenyl)-1,2,4-oxadiazole (2c)
Yield: 130 mg (73%); mp 43–45 °C (Lit.19 42 °C); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.55 (m, 2 H), 8.04 (dd, J1 = 7.6,
J2 = 1.2 Hz, 1 H), 8.14–8.16 (m, 1 H), 8.81 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 125.6, 127.7, 127.9, 130.3, 131.5,
135.0, 165.0, 166.8.
3-(4-Nitrophenyl)-1,2,4-oxadiazole (2d)
Yield: 97 mg (51%); mp 148–151 °C (Lit.21 162–164 °C); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.8 Hz, 2 H), 8.39 (d, J = 8.0
Hz, 2 H), 8.88 (s, 1H).
13C NMR (100 MHz, CDCl3): δ = 124.2, 128.6, 132.1, 149.6, 165.4,
166.3.
All chemicals were commercial products and were distilled or recrys-
tallized before use. Silica gel column chromatography was carried out
with silica gel 100 (Merck No. 10184). Merck silica gel 60 F254 plates
(No. 5744) were used for preparative TLC. Melting points are uncor-
rected. NMR spectra were recorded with a 400 MHz Bruker Avance
instrument with the chemical shifts (δ) being reported in ppm and
coupling constants expressed in Hz. Elemental analysis was per-
formed using an Elementar Vario EL III analyzer.
3-(4-Bromophenyl)-1,2,4-oxadiazole (2e)
Yield: 196 mg (88%); mp 107–110 °C (Lit.19 110 °C); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz, 2 H), 8.03 (d, J = 8.4
Hz, 2 H), 8.79 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 125.2, 126.9, 129.0, 132.3, 164.9,
167.1.
Amidoximes 1; General Procedure
The amidoximes were prepared according to our previous report.16h
To a solution of the appropriate nitrile (0.01 mol) in EtOH (200 mL)
was added a solution of hydroxylamine hydrochloride (0.695 g, 0.01
mol) in H2O (10 mL), followed by the addition of Na2CO3 (0.420 g,
0.005 mol) in H2O (10 mL). The reaction was stirred overnight at r.t.
and then concentrated to a small volume under vacuum, diluted with
cold H2O, and placed in a refrigerator overnight. The precipitate that
formed was recovered and recrystallized from EtOH. All the prepared
amidoximes are known and were characterized by comparison of
their physical data with those prepared in accordance with literature
procedures.
3-(2,4-Dichlorophenyl)-1,2,4-oxadiazole (2f)
Yield: 154 mg (72%); mp 79–81 °C; white solid.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 8.4 Hz, 1 H), 7.62 (s, 1 H),
7.96 (d, J = 8.4 Hz, 1 H), 8.86 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 124.1, 127.7, 131.5, 132.6, 134.4,
137.6, 164.3, 165.9.
Anal. Calcd for C8H4N2Cl2O: C, 44.86; H, 1.88; N, 13.09. Found: C,
45.12; H, 2.15; N, 13.05.
3-Monosubstituted 1,2,4-Oxadiazoles 2; General Procedure
N-[4-(1,2,4-Oxadiazol-3-yl)phenyl]acetamide (2g)
Yield: 95 mg (47%); mp 99–101 °C (Lit.22 142–143 °C); white solid.
1H NMR (400 MHz, CDCl3): δ = 2.15 (s, 3 H), 7.43 (d, J = 6.8 Hz, 2 H),
8.05 (d, J = 6.8 Hz, 2 H), 9.33 (s, 1 H), 9.47 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 23.5, 119.1, 128.1, 142.4, 159.1, 166.2,
Triethyl orthoformate (4 mL) was added to a mixture of FeCl3 (9–10
mg, 0.05 mmol), L-proline (5–6 mg, 0.05 mmol) and Et3N (0.014 mL,
0.1 mmol), and the resulting solution was stirred for 1 h at ambient
temperature. The amidoxime 1 (1 mmol) was added and the mixture
was stirred at 80 °C for 12 h. After cooling, the reaction mixture was
washed with Et2O (3 × 10 mL). The organic layer was dried over
MgSO4 and evaporated. The residue was subjected to column chroma-
tography on silica gel (EtOAc–n-hexane, 5:95) and evaporation of the
168.6, 205.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

E
B. Kaboudin et al.
Paper
Synthesis
3-(3-Methoxybenzyl)-1,2,4-oxadiazole (2h)
(2) Bora, R. O.; Dar, B.; Pradhan, V.; Farooqui, M. Mini Rev. Med.
Chem. 2014, 14, 355.
Yield: 86 mg (45%); yellow oil.
(3) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337.
(4) Xu, J.; Wei, L.; Mathvink, R.; He, J.; Park, Y.-J.; He, H.; Leiting, B.;
Lyons, K. A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Thornberry, N. A.;
Weber, A. E. Bioorg. Med. Chem. Lett. 2005, 15, 2533.
(5) Weidner-Wells, M. A.; Henninger, T. C.; Fraga-Spano, S. A.;
Boggs, C. M.; Matheis, M.; Ritchie, D. M.; Argentieri, D. C.;
Wachter, M. P.; Hlasta, D. J. Bioorg. Med. Chem. Lett. 2004, 14,
4307.
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 4.13 (s, 2 H), 6.83 (dd, J1 =
2.0, J2 = 8.0 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H),
7.27 (t, J = 8.0 Hz, 1 H), 8.65 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 32.1, 55.2, 112.8, 114.8, 121.3, 129.8,
136.6, 159.9, 164.9, 168.7.
Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.27; N, 14.65. Found: C,
63.10; H, 5.15; N, 14.38.
(6) Tyrkov, A. G.; Sukhenko, L. T. Pharm. Chem. J. 2004, 38, 376.
(7) Zhang, H.-Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.; Ollis-
Mason, K.; Qiu, L.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S.
X. J. Med. Chem. 2005, 48, 5215.
(8) Lankau, H. J.; Unverferth, K.; Grunwald, C.; Hartenhauer, H.;
Heinecke, K.; Bemoster, K.; Dost, R.; Egerland, U.; Rundfeldt, C.
Eur. J. Med. Chem. 2007, 42, 873.
3-(4-Methoxybenzyl)-1,2,4-oxadiazole (2i)23
Yield: 60 mg (32%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 4.11 (s, 2 H), 6.89 (d, J =
8.8 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 2 H), 8.64 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 31.3, 55.3, 114.2, 127.2, 130.1, 158.8,
(9) Huhtiniemi, T.; Suuronen, T.; Rinne, V. M.; Wittekindt, C.;
Lahtela-Kakkonen, M.; Jarho, E.; Wallen, E. A. A.; Salminen, A.;
Poso, A.; Leppanen, J. J. Med. Chem. 2008, 51, 4377.
(10) Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.; MacLeod, A. M.;
Merchant, K. J.; Showell, G. A.; Saunders, J.; Herbert, R. H.;
Freedman, S. B.; Harley, E. A. J. Med. Chem. 1990, 33, 2690.
(11) Wilschanski, M. Discovery Med. 2013, 15, 127.
(12) (a) Li, Z.; Chen, W.; Hale, J. J.; Lynch, C. L.; Mills, S. G.; Hajdu, R.;
Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.;
Cherbert, G.; Parent, S. A.; Bergstrom, J.; Card, D.; Forrest, M.;
Quackenbush, E. J.; Wickham, L. A.; Vargas, H.; Evans, R. M.;
Rosen, H.; Mandala, S. J. Med. Chem. 2005, 48, 6169.
(b) Haugwitz, R. D.; Martinez, A. J.; Venslavsky, J.; Angel, R. G.;
Maurer, B. V.; Jacobs, G. A.; Narayanan, V. L.; Cruthers, L. R.;
Szanto, J. J. Med. Chem. 1985, 28, 1234.
164.8, 169.1.
3-Benzhydryl-1,2,4-oxadiazole (2j)
Yield: 47 mg (20%); mp 93–94 °C; white solid.
1H NMR (400 MHz, CDCl3): δ = 5.75 (s, 1 H), 7.29–7.38 (m, 10 H), 8.72
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 48.4, 127.4, 128.7, 128.8, 139.4, 164.9,
171.0.
Anal. Calcd for C15H12N2O: C, 76.24; H, 5.12; N, 11.86. Found: C, 76.50;
H, 5.18; N, 11.58.
3-Styryl-1,2,4-oxadiazole (2k)
Yield: 77 mg (45%); mp 80–82 °C (Lit.24 82 °C); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 16.0 Hz, 1 H), 7.35–7.50 (m,
3 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 16.0 Hz, 1 H), 8.70 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 112.0, 127.5, 128.9, 129.6, 135.1,
(13) (a) LaMattina, J. L.; Mularski, C. J. J. Org. Chem. 1984, 49, 4800.
(b) Liang, G. B.; Qian, X. Bioorg. Med. Chem. Lett. 1999, 9, 2101.
(c) Liang, G. B.; Feng, D. D. Tetrahedron Lett. 1996, 37, 6627.
(d) Young, J. R.; DeVita, R. J. Tetrahedron Lett. 1998, 39, 3931.
(14) (a) Neidlein, R.; Sheng, L. Synth. Commun. 1995, 25, 2379.
(b) Neidlein, R.; Sheng, L. J. Heterocycl. Chem. 1996, 33, 1943.
(15) (a) Clapp, L. B. Adv. Heterocycl. Chem. 1976, 20, 65. (b) Ryu, H. C.;
Hong, Y. T.; Kang, S. K. Heterocycles 2001, 54, 985. (c) Bell, C. L.;
Nambury, C. N. V.; Bauer, L. J. Org. Chem. 1964, 29, 2873.
(d) Eloy, F.; Lenaers, R. Chem. Rev. 1962, 62, 155.
139.7, 164.0, 167.1.
3-(4-Chlorophenyl)-5-methyl-1,2,4-oxadiazole (5)
Yield: 170 mg (87%); mp 93–94 °C (Lit.25 92–95 °C); white solid.
1H NMR (400 MHz, CDCl3): δ = 2.69 (s, 3 H), 7.50 (d, J = 8.0 Hz, 2 H),
8.05 (d, J = 8.0 Hz, 2 H).
(16) (a) Korbonits, D.; Horvath, K. Heterocycles 1994, 37, 2051.
(b) Chiou, S.; Shine, H. J. J. Heterocycl. Chem. 1989, 26, 125.
(c) Kayukova, L. A.; Praliev, K. D.; Zhumadildaeva, I. S.;
Klepikova, S. G. Chem. Heterocycl. Compd. 1999, 35, 630. (d) Ooi,
N. S.; Wilson, D. A. J. Chem. Soc., Perkin Trans. 2 1980, 1792.
(e) Andersen, K. E.; Lundt, B. F.; Jørgensen, A. S.; Braestrup, C.
Eur. J. Med. Chem. 1996, 31, 417. (f) Kaboudin, B.; Saadati, F. Tet-
rahedron Lett. 2007, 48, 2829. (g) Kaboudin, B.; Saadati, F. J. Het-
erocycl. Chem. 2005, 42, 699. (h) Kaboudin, B.; Malekzadeh, L.
Tetrahedron Lett. 2011, 52, 6424. (i) Kaboudin, B.; Navaee, K.
Heterocycles 2001, 55, 1443.
(17) (a) Gangloff, A. R.; Litvak, J.; Shelton, J. E. J.; Sperandio, D.; Wang,
V. R.; Rice, K. D. Tetrahedron Lett. 2001, 42, 1441. (b) Hebert, N.;
Hannah, A. L.; Sutton, S. C. Tetrahedron Lett. 1999, 40, 8547.
(18) Augustine, J. K.; Akabote, V.; Hegde, S. G.; Alagarsamy, P. J. Org.
Chem. 2009, 74, 5640.
13C NMR (100 MHz, CDCl3): δ = 12.4, 125.3, 128.7, 129.2, 137.3, 167.6,
176.8.
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562431.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(19) Buting, W. E.; Cameron, A. US Patent 33566984 (A), 1967.
(20) Fershtat, L. L.; Ananyev, I. V.; Makhova, N. N. RSC Adv. 2015, 5,
47248.
References
(1) (a) Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.; Plowright, A.
T. J. Med. Chem. 2012, 55, 1817. (b) Saha, R.; Tanwar, O.; Marella,
A.; Alam, M. M.; Akhtar, M. Mini Rev. Med. Chem. 2013, 13, 1027.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
B. Kaboudin et al.
Paper
Synthesis
(21) Hemming, K. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations: Five-Membered Hetarenes with
Three or More Heteroatoms; Vol. 13; Storr, R. C.; Gilchrist, T. L.,
Eds.; Georg Thieme: Stuttgart, 2004, 127–184.
(23) Steglich, W.; Van Ree, T. Synth. Commun. 1982, 12, 457.
(24) Claisse, J. A.; Foxton, M. W.; Gregory, G. I.; Sheppard, A. H.; Tiley,
E. P.; Warburton, W. K.; Wilson, M. J. J. Chem. Soc., Perkin. Trans.
1 1973, 2241.
(22) Suresh Dhanusu, S.; Kuppusamy, K.; Kasi, P. Tetrahedron Lett.
2014, 55, 3678.
(25) Movassagh, B.; Talebsereshki, F. Synth. Commun. 2014, 44, 188.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F