Regioselective synthesis of 2-amino-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives via reagent-based cyclization of thiosemicarbazide intermediate

Article abstract of DOI:10.1021/jo302324r

A regioselective, reagent-based method for the cyclization reaction of 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole core skeletons is described. The thiosemicarbazide intermediate 3 was reacted with EDC·HCl in DMSO or p-TsCl, triethylamine in N-

Full text of DOI:10.1021/jo302324r

Article
pubs.acs.org/joc
Regioselective Synthesis of 2‑Amino-Substituted 1,3,4-Oxadiazole
and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of
Thiosemicarbazide Intermediate
Seung-Ju Yang, Seok-Hyeong Lee, Hyun-Jung Kwak, and Young-Dae Gong*
Center for Innovative Drug Library Research, Department of Chemistry, College of Science, Dongguk University, 26, 3-ga, Pil-dong
Jung-gu, Seoul 100-715, Korea
S
* Supporting Information
ABSTRACT: A regioselective, reagent-based method for the cyclization reaction of 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-
thiadiazole core skeletons is described. The thiosemicarbazide intermediate 3 was reacted with EDC·HCl in DMSO or p-TsCl,
triethylamine in N-methyl-2-pyrrolidone to give the corresponding 2-amino-1,3,4-oxadiazoles 4 and 2-amino-1,3,4-thiadiazoles 5
through regioselcective cyclization processes. The regioselectivity was affected by both R1 and R2 in p-TsCl mediated cyclization.
It is shown in select sets of thiosemicarbazide 3 with R1(benzyl) and R2(phenyl). 2-Amino-1,3,4-oxadiazole 4 was also shown in
the reaction of p-TsCl mediated cyclization. The resulting 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole core skeleton
are functionalized with various electrophiles such as alkyl halide, acid halides, and sulfornyl chloride in high yields.
preparation of 2-aminosulfonamide-1,3,4-oxadiazole and 2-
aminosulfonamide-1,3,4-thiadiazole was reported by Ley.10b
In this literature, only a sulfonamide group can be introduced
on the 2-position of 1,3,4-oxadiazole and 1,3,4-thiadiazole and
thus did not correspond our purpose that various substituent
are introduced to the 2-position of 1,3,4-oxadiazole and 1,3,4-
thiadiazole. Several methods have been tried to develop an
efficient synthesis of 1,3,4-oxadiazole and 1,3,4-thiadiazole
derivatives using the same key intermediate. Zoumpoulakis
reported the synthetic method of 2-amino-1,3,4-oxadiazole and
2-amino-1,3,4-thiadiazole by using the I2/NaOH in ethanol and
INTRODUCTION
■
Heterocyclic compounds are commonly used scaffolds on
which pharmacophores are arranged to provide potent and
selective drugs.1 This is especially true for five-membered ring
heterocyclic compounds, which serve as the core components
of many substances that possess a wide range of interesting
biological activities. In this family, 1,3,4-oxadiazoles and 1,3,4-
thiadiazoles have been used as “privileged” scaffolds to produce
substances of interest in numerous therapeutic areas, such as
anti-inflammatory,2 antimicrobial,3 anticonvulsant,4 and anti-
hypertensive.5 As a result of these applications, 1,3,4-oxadiazole
and 1,3,4-thiadiazole derivatives have been targets of a number
of solution- and solid-phase synthesis studies. 1,3,4-Oxadiazole
was synthesized with a Burgess reagent,6a KMnO4,6b and
thiosemicarbazide was used to prepare 2-amino-1,3,4-oxadia-
zole as a starting material with several desulfurating agent such
as p-TsCl,7a EDC·HCl,7b methyl iodide,7c ethyl bromoace-
tate,7d and mercury oxide.7e Acidic reagents were generally used
to prepare 2-amino-1,3,4-thiadiazole such as POCl3,8a H3PO4,8b
and methanesulfonic acid.8c Recently, Saidi reported synthetic
method of 2-amino-1,3,4-thiadiazole with triethylamine in
water.9 Lau also reported synthetic method to produce both
2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole.10a
However, the methods developed thus far lack diversity since
they employ different intermediates for the syntheses of the
oxygen- and sulfur-containing heterocyclic compounds. The
11
H2SO4. However, protic solvents such as ethanol and water
are not suitable for the traditional polystyrene resin in the solid-
phase synthesis, and H2SO4 cannot be used with some acid
sensitive functional group such as N-Boc, tetrahydropyranyl,
and tert-butyldimethylsilyl ether. As a part of our drug discovery
program, we developed a facile and a regioselective synthesis of
druglike 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives
generated by cyclodehydration or cyclodesulfurization reactions
via reagent-based cyclization of acyldithiocarbazate intermedi-
ate in the previous study.12 However, the developed method
suffered a limitation in which some amine substituents could be
introduced since the sulfone leaving group was unaffected by
Received: October 18, 2012
Published: December 7, 2012
© 2012 American Chemical Society
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Article
substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries in a
high throughput manner (Scheme 1).
Scheme 1. Construction of 2-Amino-Substituted 1,3,4-
Oxadiazole and 1,3,4-Thiadiazole
a
RESULTS AND DISCUSSION
■
The sequence used to prepare the thiosemicarbazide useful
intermediate 3 uses the isothiocyanate 1 as the starting material.
Treatment of 1 with various acylhydrazides 2 in the presence of
triethylamine at room temperature leads to the production of
the corresponding thiosemicarbazide intermediate 3. To
investigate suitable methods for reagent-based skeletal diver-
sity-oriented synthesis of 2-amino-substituted 1,3,4-oxadiazoles
4 or 1,3,4-thiadiazoles 5, cyclization reactions of thiosemicarba-
zide 3 were investigated by using various reagents, including 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC·HCl), p-
TsCl, TMSCl, and diphenylchlorophosphate in various
conditions. The results of the cyclization reactions of 3a are
summarized in Table 1. Reactions of the thiosemicarbazide
intermediate with p-TsCl/triethylamine in 1,2-dichloroethane
(DCE), which is the desulfurative cyclization condition used in
our previous study,12 gave 2-amino-1,3,4-oxadiazole 4a and 2-
amino-1,3,4-thiadiazole 5a in low regioselectivity (entry 8 of
Table 1). Otherwise, the use of EDC·HCl, which was well-
known as a desulfurizing agent,7b leads to 2-amino-1,3,4-
oxadiazole 4a as a major product with regioselectivity (100:0)
and a high yield (entry 1 of Table 1). The liquid
chromatography mass spectrometry (LC/MS) spectrum of
the crude product mixture containing the 2-amino-1,3,4-
oxadiazole 4a formed in the EDC·HCl-initiated process is
shown as Figure 1a in the Supporting Information. Next, we
tried to make 2-amino-1,3,4-thiadiazole 5a in various
conditions. According to our previous study,12 we used
TMSCl and (PhO)2P(O)Cl (entries 2 and 3 of Table 1).
However, in this condition, thiosemicarbazide 3a was not
a
Reaction conditions: (a) triethylamine, THF, rt, 16 h. (b) EDC·HCl,
DMSO, 60 °C, 2 h. (c) p-TsCl, TEA, NMP, rt, 2 h. (d) Electrophiles,
NaH, NMP, rt, 8 h. (e) Electrophiles, NaH, THF, rt, 1 h.
the various nucleophiles, such as alcohol, thiol, and carboxylic
acid groups. Therefore, we undertook an investigation aimed at
developing efficient and synthetic methods to produce various
2-amino-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole
derivatives, which can be used to introduce various electrophile
substituents on the 2-position of 1,3,4-oxadiazole and 1,3,4-
thiadiazole rings. Herein we report our recent progress on this
project, which includes the first regioselective synthesis
protocol for 2-amino-substituted 1,3,4-oxadiazole and 1,3,4-
thiadiazole derivatives 6 and 7 by cyclodesulfurization or
cyclodehydration reactions via reagent-based cyclization of
thiosemicarbazide intermediate 3. We believe our efficient
approach is suitable for the construction of druglike 2-amino-
a
Table 1. Results of the Cyclization of the Thiosemicarbazide Intermediate 3a
b
c
ratio
yield (%)
entry
reagent
solvent
temp (°C)
time (h)
4a
5a
4a
5a
1
EDC·HCl
TMSCl
DMSO
DCE
DCE
THF
THF
THF
THF
DCE
ACN
HMPA
DMF
NMP
60
60
60
60
rt
2
12
12
16
2
100
0
99
d
2
NR
d
3
(PhO)2P(O)Cl
p-TsCl/Pyridine
p-TsCl/t-BuOk
p-TsCl/NaOH
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
NR
4
100
85
85
55
40
15
9
0
15
15
45
60
85
91
94
96
87
71
75
50
38
14
8
5
11
14
41
56
81
71
74
92
6
rt
2
7
60
rt
2
8
2
9
rt
2
10
11
12
rt
2
rt
2
6
3
rt
2
4
3
a
Reaction conditions: Thiosemicarbazide was treated with 1.2 equiv of EDC·HCl in DMSO at 60 °C for 2 h. Thiosemicarbazide was treated with 1.2
b
c
d
equiv of p-TsCl and 2.2 equiv of TEA in NMP at room temperature for 2 h. Calculated by using LC/MS. Yield is obtained yield. NR = no
reaction.
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transformed to 2-amino-1,3,4-thiadiazole 5a. Dolman reported
a synthesis method for 2-amino-1,3,4-oxadiazole.7a In this
method, p-TsCl was used as a desulfurizing agent (entry 4 of
Table 1), and we also knew that p-TsCl can be used as a
dehydrating agent (entry 8 of Table 1). So we investigated
using p-TsCl as a dehydrating agent in various conditions. First,
we used various bases in tetrahydrofuran (THF) (entries 5−7
of Table 1). Among these bases, t-BuOK and NaOH showed
regioselectivity for 2-amino-1,3,4-oxadiazole 4a. Therefore, we
used triethylamine (TEA) to synthesize 2-amino-1,3,4-
thiadiazole 5a. Second, we used p-TsCl and TEA in various
solvents. In nonpolar solvent, it showed low regioselectivity
(entries 7 and 8 of Table 1). Otherwise, in the polar solvent, it
showed regioselectivity for 2-amino-1,3,4-thiadiazole 5a (en-
tries 9−12 of Table 1). Among these polar solvents, N-methyl-
2-pyrrolidone (NMP) showed high regioselectivity (96:4) and
high yield. Therefore, we used p-TsCl/TEA/NMP for the
synthesis of 2-amino-1,3,4-thiadiazole 5a. The LC/MS
spectrum of the crude product mixture containing the 2-
amino-1,3,4-thiadiazole formed 5a in the p-TsCl/TEA/NMP
initiated process is shown as Figure 1b in the Supporting
Information.
Table 3. Result of the Thiosemicarbazide 3 via p-TsCl/TEA-
Based Cyclization
a
b
ratio
c
entry
R1
R2
4
5
no. (% yield )
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Ph
4
96
92
99
99
96
95
97
99
47
62
51
3
5a (92)
5b (81)
5c (87)
5d (63)
5e (73)
5f (67)
5g (94)
5h (87)
5i (40)
5j (53)
5k (44)
4l (87)
5m (84)
4-methoxy-Ph
8
1
4-F-Ph
4-NO2-Ph
Ph
1
4-methoxy-Bn
4-CF3-Bn
ethyl
4
Ph
5
Ph
3
2,4-dimethoxy-Bn
Ph
4-NO2-Ph
Ph
1
d
9
53
38
49
97
5
d
10
4-methoxy-Ph
4-F-Ph
Ph
d
11
Ph
d
12
4-NO2-Ph
4-methoxy-Ph
Ph
d
13
4-NO2-Ph
95
To explore the various substrates, we used various acyl-
hydrazides and isothiocyanates. The results of the cyclization
reactions of thiosemicarbazide 3 are summarized in Tables 2
and 3.
a
Thiosemicarbazide was treated with 1.2 equiv of p-TsCl and 2.2 equiv
b
of TEA in NMP at room temperature for 2 h. Calculated by using
c
d
LC/MS. Yield is obtained yield after column chromatography. Ratio
and yield were determined by NMR integration of mixture of 2-amino-
1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole.
Table 2. Result of Thiosemicarbazide 3 via EDC·HCl-Based
a
Cyclization
and 4 of Table 3) showed increasing regioselectivity for 2-
amino-1,3,4-thiadiazole 5. Second, we used benzoylhydrazide
and various benzyl and aliphatic isothiocyanates (entries 5−7 of
Table 3). Isothiocyanate with an electron-donating group
(entries 5 and 7 of Table 3) showed high regioselectivity and
good yields. Otherwise, benzylisothiocyanate with an elctron-
withdrawing group (entry 6 of Table 3) showed slightly
decreasing regioselectivity for 2-amino-1,3,4-thiadiazole 5. To
optimize the regioselectivity for 2-amino-1,3,4-thiadiazole 5, we
used 2,4-dimethoxy-benzylisothiocyanate and 4-nitro-benzoyl-
hydrazide (entry 8 of Table 1). Third, we used benzoylhy-
drazide and phenyl isothiocyanate (entries 9−12 of Table 3). In
the case of phenylisothiocyanate, the regioselectivity for 2-
amino-1,3,4-thiadiazole 5 was decreased. Moreover, phenyl-
isothiocyanate with an electron-withdrawing group (entry 12 of
b
ratio
c
entry
R1
R2
4
5
no. (% yield )
1
Bn
Bn
Bn
Bn
Ph
100
100
100
100
100
100
100
100
100
100
100
100
100
0
0
0
0
0
0
0
0
0
0
0
0
0
4a (99)
4b (82)
4c (91)
4d (78)
4e (69)
4f (51)
4g (99)
4h (80)
4i (94)
4j (72)
4k (96)
4l (87)
4m (74)
2
4-methoxy-Ph
3
4-F-Ph
4-NO2-Ph
Ph
4
5
4-methoxy-Bn
4-CF3-Bn
ethyl
6
Ph
7
Ph
8
2,4-dimethoxy-Bn
Ph
4-NO2-Ph
Ph
Scheme 2. Proposed Mechanism of Cyclization 3 Promoted
by p-TsCl/TEA in NMP
9
10
11
12
13
4-methoxy-Ph
4-F-Ph
Ph
Ph
4-NO2-Ph
4-methoxy-Ph
Ph
4-NO2-Ph
a
Reaction condition: Thiosemicarbazide was treated with 1.2 equiv of
b
EDC·HCl in DMSO at 60 °C for 2 h. Calculated by using LC/MS.
c
Yield is obtained yield after column chromatography.
In the case of EDC·HCl-based cyclization, various thiosemi-
carbazides 3 showed regioselectivity and high yields. Otherwise,
in the case of p-TsCl-based cyclization, various thiosemicarba-
zides 3 showed different regioselectivity depending on the
substituent. First, we used benzylisothiocyanate and various
acylhydrazides (entries 1−4 of Table 3). Acylhydrazide with an
electron-donating group (entry 2 of Table 3) showed
decreasing regioselectivity for 2-amino-1,3,4-thiadiazole 5.
Acylhydrazide with an electron-withdrawing group (entries 3
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a
Table 4. N-Substitution of 1,3,4-Oxadiazole 4h and 1,3,4-Thiadiazole 5h
b
b
no.
R3
time (h)
yield (%)
no.
R3
time (h)
yield (%)
c
c
6a
benzyl
benzoyl
p-tosyl
8
1
1
87
41
60
7a
benzyl
benzoyl
p-tosyl
8
1
1
80
82
97
d
d
6b
7b
d
d
6c
7c
a
Reaction condition: 2-amino-1,3,4-oxadiazole 4h was treated with 1.2 equiv of electrophiles and 1.2 equiv of NaH (60% dispersion in mineral oil) in
b
c
d
solvent. Yield is obtained yield after column chromatography. Reaction was mediated in NMP. Reaction was mediated in THF.
Table 3) showed high regioselectivity for 2-amino-1,3,4-
oxadiazole 4l. To increase the regioselectivity for 2-amino-
1,3,4-thiadiazole 5 with phenylisothiocyanate, we introduced an
electron-withdrawing group to acylhydrazide and an electron-
donating group to phenylisothiocyanate (entry 13 of Table 3).
In this case, we generated 2-amino-1,3,4-thiadiazole 5m in high
regioselectivity and high yields. The proposed mechanism is
shown in Scheme 2. According to our study, the regioselectivity
depends on the pKa of amine which can be affected by R1 and
R2. At entry 9 in Table 3, the phenyl group on the R1 position
acted as an electron-withdrawing group and decreased the pKa
of proton A as you can see in Scheme 2. It caused increasing of
regioselectivity for 2-amino-1,3,4-oxadiazole 4 (entries 9−12 of
Table 3).
Next, to explore the diversity of this methodology, various
electrophiles were used to generate 2-amino-substituted 1,3,4-
oxadiazole and 1,3,4-thiadiazole derivatives from 2-amino-1,3,4-
oxadiazole 4h and 2-amino-1,3,4-thiadiazole 5h core skeletons
(Table 4). Alkylation reactions with benzylchloride gave high
yields (Table 4, nos. 6a and 7a). We then introduced various
electrophiles to the 2-amino-1,3,4-oxadiazole 4h and 2-amino-
1,3,4-thiadiazole 5h with acid chlorides and sulfonyl chlorides.
Generally, N-acylation and sulfonylation reaction can occur
with simple organic bases such as TEA and pyridine. However,
in the case of our experiment, it was not going well because of
its low nucleophilicity. So we used NaH, which is a strong
inorganic base, and then we obtained the desired substituted
products 6b, 6c, 7b, and 7c, respectively, in good yields, as
shown in Table 4.
EXPERIMENTAL SECTION
■
General Procedure for Synthesis. All chemicals were reagent
grade and used as purchased. Reactions were monitored by thin-layer
chromatography (TLC). Flash column chromatography was carried
1
out on silica gel (230−400 mesh). H NMR and 13C NMR spectra
were recorded in δ units relative to deuterated solvent as an internal
reference using a 400-MHz NMR instrument. LC/MS analysis was
performed on an electrospray ionization (ESI) mass spectrometer with
photodiode-array detector (PDA) detection. High-resolution MS
spectra were obtained using a time-of-flight LC/MS system.
Representative Procedure for the Preparation of Thiosemi-
carbazide (3a−3h). Benzyl-isothiocyanate 1a (358 mg, 2.40 mmol)
was added to a stirred solution of benzoylhydrazide 2a (272 mg, 2.00
mmol) and triethylamine (202 mg, 2.00 mmol) in 10 mL of THF. The
reaction mixture was stirred at room temperature for 16 h, and then
the solvents were removed via a rotary evaporator. The residue was
triturated with diethyl ether/ethyl acetate (95:5) to afford 543 mg
(95% yield, white solid) of the desired thiosemicarbazide 3a. 1H NMR
(400 MHz, DMSO) δ 10.64−10.29 (s, 1H), 9.62−9.22 (s, 1H), 8.86−
8.45 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.63−7.54 (m, 1H), 7.50 (d, J =
7.7 Hz, 2H), 7.36−7.27 (m, 4H), 7.26−7.14 (m, 1H), 4.75 (d, J = 5.9
Hz, 2H). Mp 193−195 °C. LC/MS (ESI): m/z = 284.0 [M−1]−.
Representative Procedure for the Preparation of Thiosemi-
carbazide (3i−3m). Phenyl-isothiocyanate 1i (324 mg, 2.40 mmol)
was added to a stirred solution of benzoylhydrazide 2i (272 mg, 2.00
mmol) in 1 mL of DMSO. The reaction mixture was stirred at room
temperature for 4 h. Distilled water (2 mL) was added to a reaction
mixture at 0 °C and then filtered to afford a white solid. The solid was
triturated with diethyl ether/ethyl acetate (95:5) to afford 504 mg
(93% yield, white solid) of the desired thiosemicarbazide 3i. 1H NMR
(400 MHz, DMSO) δ 10.55 (s, 1H), 9.83 (s, 1 H), 9.74 (s, 1 H),
7.97−7.94 (d, J = 6 Hz, 2 H), 7.59−7.11 (m, 8 H). Mp 166−168 °C.
LC/MS (ESI): m/z = 270.0 [M−1]−.
Representative Procedure for the Preparation of 2-Amino-
1,3,4-oxadiazole (4a−4m). EDC·HCl (115 mg, 0.6 mmol) was
added to a stirred solution of thiosemicarbazide 3a (143 mg, 0.50
mmol) in 1 mL of DMSO. The reaction mixture was stirred at 60 °C
for 2 h and extracted with dichloromethane (DCM, 15 mL) and
distilled water (10 mL), after which the aqueous layer was removed.
The aqueous layer was back-extracted with DCM (3 × 10 mL). The
combined organic layers were dried over MgSO4 and evaporated to
afford the crude product, which was purified by column chromatog-
raphy on silica gel (hexane/THF) to afford 124 mg (99% yield, white
solid) of the desired 2-amino-1,3,4-oxadiazole 4a. 1H NMR (400
MHz, CDCl3) δ 7.94−7.86 (m, 2H), 7.51−7.28 (m, 8H), 5.05 (s, 1H),
4.62 (d, J = 5.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 163.3, 159.3,
137.4, 130.6, 128.9, 128.9, 128.1, 127.8, 125.9, 124.5, 47.8. Mp 177−
179 °C. LC/MS (ESI): m/z = 250.0 [M−1]−.
In summary, an efficient regioselective synthesis method has
been developed for the synthesis of 2-amino-substituted 1,3,4-
oxadiazole and 1,3,4-thiadiazole derivatives. The thiosemicarba-
zides 3, which serve as useful intermediates in this process, are
generated by reaction of the isothiocyanate starting material
with acylhydrazides. Regioselective cyclization reactions of the
resulting intermediate successfully give the 2-amino-1,3,4-
oxadiazole and 1,3,4-thiadiazole core skeletons as the key
step, culminating in reagent-based, skeletal diversity-oriented
synthesis. The resulting 2-amino-1,3,4-oxadiazole and 1,3,4-
thiadiazole core skeletons are subjected to various substitution
reactions with alkyl halides, acid chlorides, and sulfonyl
chlorides to afford various druglike 2-amino-substituted 1,3,4-
oxadiazole and 1,3,4-thiadiazole derivatives. In further work, we
will carry out this methodology on the solid-phase with a
backbone amide linker (BAL) to construct a 1,3,4-oxadiazole
and 1,3,4-thiadiazole library.
N-Benzyl-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine
(4b). Yield, 82% (115 mg, white solid). 1H NMR (400 MHz, DMSO)
δ 8.23 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.44−7.23 (m, 5H), 7.08 (d, J
= 8.9 Hz, 2H), 4.44 (d, J = 6.2 Hz, 2H), 3.82 (s, 3H). 13C NMR (101
MHz, DMSO) δ 163.8, 161.4, 158.2, 139.3, 128.9, 127.9, 127.6, 127.4,
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117.2, 115.2, 55.9, 46.6. Mp 166−167 °C. LC/MS (ESI): m/z = 280.0
[M−1]−. HRMS (ESI): m/z [M+1]+ calcd for C16H15N3O2, 282.1243;
found, 282.1245.
N-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazol-2-amine (4l).
Yield, 87% (123 mg, white solid). H NMR (400 MHz, DMSO) δ
1
11.54 (s, 1H), 8.30 (d, J = 9.2 Hz, 2H), 7.98−7.90 (m, 2H), 7.83 (d, J
= 9.2 Hz, 2H), 7.64−7.55 (m, 3H). 13C NMR (101 MHz, DMSO) δ
159.7, 159.1, 145.3, 141.7, 131.8, 129.9, 126.3, 126.0, 124.0, 117.4. Mp
263−266 °C. LC/MS (ESI): m/z = 281.0 [M−1]−.
N-(4-Methoxyphenyl)-5-(4-nitrophenyl)-1,3,4-oxadiazol-2-
amine (4m). Yield, 74% (116 mg, orange solid). 1H NMR (400 MHz,
DMSO) δ 10.63 (s, 1H), 8.40 (d, J = 8.9 Hz, 2H), 8.11 (d, J = 8.9 Hz,
2H), 7.54 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 3.75 (s, 3H).
13C NMR (101 MHz, DMSO) δ 161.4, 156.8, 155.2, 148.8, 132.0,
N-Benzyl-5-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (4c).
1
Yield, 91% (122 mg, white solid). H NMR (400 MHz, DMSO) δ
8.34 (t, J = 6.1 Hz, 1H), 7.91−7.81 (m, 2H), 7.47−7.21 (m, 7H), 4.46
(d, J = 6.1 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 169.0, 163.2 (d,
3
1JCF = 248.5 Hz), 155.6, 139.0, 129.0 (d, JCF = 9.1 Hz), 128.9, 128.0,
4
2
127.9 (d, JCF = 3.0 Hz), 127.6, 116.7 (d, JCF = 22.2 Hz), 48.52. Mp
170−173 °C. LC/MS (ESI): m/z = 268.0 [M−1]−.
N-Benzyl-5-(4-nitrophenyl)-1,3,4-oxadiazol-2-amine (4d).
Yield, 78% (115 mg, yellow solid). H NMR (400 MHz, DMSO) δ
1
123.0, 127.0, 125.1, 119.4, 114.9, 55.7. Mp 270−272 °C. LC/MS
(ESI): m/z = 311.0 [M−1]−.
8.62 (t, J = 6.2 Hz, 1H), 8.37 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 9.0 Hz,
2H), 7.43−7.25 (m, 5H), 4.50 (d, J = 6.2 Hz, 2H). 13C NMR (101
MHz, DMSO) δ 164.8, 157.0, 148.5, 139.0, 130.1, 128.9, 127.9, 127.7,
126.6, 125.1, 46.6. Mp 190−193 °C. LC/MS (ESI): m/z = 295.0 [M−
1]−.
N-(4-Methoxybenzyl)-5-phenyl-1,3,4-oxadiazol-2-amine
(4e). Yield, 69% (97 mg, white solid). 1H NMR (400 MHz, DMSO) δ
8.25 (t, J = 6.1 Hz, 1H), 7.86−7.77 (m, 2H), 7.57−7.49 (m, 3H), 7.32
(d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.38 (d, J = 6.1 Hz, 2H),
3.74 (s, 3H). 13C NMR (101 MHz, DMSO) δ 164.1, 159.0, 158.1,
131.2, 130.9, 129.7, 129.3, 125.6, 124.7, 114.2, 55.6, 46.1. Mp 182−185
°C. LC/MS (ESI): m/z = 280.0 [M−1]−. HRMS (ESI): m/z [M+1]+
calcd for C16H15N3O2, 282.1243; found, 282.1252.
Representative Procedure for the Preparation of 2-Amino-
1,3,4-thiadiazole (5a−5h). p-TsCl (114 mg, 0.60 mmol) was added
to a stirred solution of thiosemicarbazide 3a (143 mg, 0.50 mmol) and
triethylamine (111 mg, 1.10 mmol) in 4 mL of NMP. The reaction
mixture was stirred at room temperature for 2 h. The reaction mixture
was extracted with DCM (15 mL) and distilled water (10 mL), and
then the aqueous layer was removed. The aqueous layer was back-
extracted with DCM (3 × 10 mL). The combined organic layers were
dried over MgSO4 and evaporated to afford the crude product, which
was purified by column chromatography on silica gel (hexane/ethyl
acetate) to afford 123 mg (92% yield, white solid) of the desired 2-
amino-1,3,4-thiadiazole 5a. 1H NMR (400 MHz, CDCl3) δ 7.82−7.76
(m, 2H), 7.43−7.31 (m, 8H), 5.72 (s, 1H), 4.60 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 169.5, 158.4, 137.0, 131.0, 123.0, 128.9, 128.9,
128.1, 127.8, 126.9, 50.8. Mp 179−181 °C. LC/MS (ESI): m/z =
266.0 [M−1]−.
5-Phenyl-N-(4-(trifluoromethyl)benzyl)-1,3,4-oxadiazol-2-
1
amine (4f). Yield, 51% (81 mg, white solid). H NMR (400 MHz,
CDCl3) δ 7.92−7.85 (m, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.0
Hz, 2H), 7.48−7.40 (m, 3H), 5.31 (s, 1H), 4.69 (d, J = 2.9 Hz, 2H).
13C NMR (101 MHz, DMSO) δ 164.0, 158.4, 144.1, 131.0, 129.7,
N-Benzyl-5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
(5b). Yield, 81% (120 mg, white solid). 1H NMR (400 MHz, DMSO)
δ 8.34 (t, J = 5.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.45−7.22 (m,
5H), 7.02 (d, J = 8.9 Hz, 2H), 4.53 (d, J = 5.8 Hz, 2H), 3.81 (s, 3H).
13C NMR (101 MHz, DMSO) δ 168.3, 160.9, 156.6, 139.1, 128.9,
128.5, 128.3 (q, 2JCF = 31.3 Hz), 125.7 (q, 3JCF = 3.0 Hz), 125.7, 124.7
(q, 1JCF = 273.1 Hz) 124.7, 46.1. Mp 192−195 °C. LC/MS (ESI): m/z
= 318.0 [M−1]−. HRMS (ESI): m/z [M+1]+ calcd for C16H12F3N3O,
320.1011; found, 320.1012.
128.3, 128.0, 127.6, 123.9, 115.0, 55.8, 48.5. Mp 165−167 °C. LC/MS
N-Ethyl-5-phenyl-1,3,4-oxadiazol-2-amine (4g). Yield, 99%
(94 mg, white solid). 1H NMR (400 MHz, CDCl3) δ 7.97−7.83
(m, 2H), 7.52−7.39 (m, 3H), 5.20 (s, 1H), 3.57−3.42 (m, 2H), 1.33
(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.5, 159.0,
130.4, 128.8, 125.8, 124.6, 38.6, 15.1. Mp 122−126 °C. LC/MS (ESI):
m/z = 187.9 [M−1]−.
N-(2,4-Dimethoxybenzyl)-5-(4-nitrophenyl)-1,3,4-oxadiazol-
2-amine (4h). Yield, 80% (143 mg, white solid). 1H NMR (400 MHz,
DMSO) δ 8.41−8.29 (m, 3H), 8.04 (d, J = 9.0 Hz, 2H), 7.24 (d, J =
8.3 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H),
4.38 (d, J = 5.9 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H). 13C NMR (101
MHz, DMSO) δ 164.8, 160.6, 158.4, 156.8, 148.5, 130.2, 129.9, 126.5,
125.1, 118.5, 104.8, 98.8, 56.0, 55.7, 41.5. Mp 182−184 °C. LC/MS
(ESI): m/z = 355.0 [M−1]−. HRMS (ESI), m/z [M+1]+ calcd for
C17H16N4O5, 357.1199; found, 357.1200.
N,5-Diphenyl-1,3,4-oxadiazol-2-amine (4i). Yield, 94% (112
mg, white solid). 1H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 8.01−
7.86 (m, 2H), 7.72−7.51 (m, 5H), 7.38 (t, J = 7.9 Hz, 2H), 7.02 (t, J =
7.3 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 160.4, 158.2, 139.1,
131.4, 129.8, 129.6, 126.0, 124.4, 122.4, 117.6. Mp 213−216 °C. LC/
MS (ESI): m/z = 236.0 [M−1]−.
(ESI): m/z = 295.9 [M−1]−.
N-Benzyl-5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (5c).
1
Yield, 87% (124 mg, white solid). H NMR (400 MHz, DMSO) δ
8.45 (t, J = 5.8 Hz, 1H), 7.87−7.75 (m, 2H), 7.45−7.24 (m, 7H), 4.55
(d, J = 5.7 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 169.0, 163.2
(1JCF = 248.5 Hz), 155.6, 139.0, 119.9 (3JCF = 9.1 Hz), 128.9, 128.0,
127.9 (4JCF = 3.0 Hz), 127.6, 116.7 (2JCF = 22.2 Hz); 48.5. Mp 172−
174 °C. LC/MS (ESI): m/z = 284.0 [M−1]−. HRMS (ESI): m/z [M
+1]+ calcd for C15H12FN3S, 286.0814; found, 286.0824.
N-Benzyl-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (5d).
1
Yield, 63% (98 mg, yellow solid). H NMR (400 MHz, DMSO) δ
8.74 (t, J = 5.7 Hz, 1H), 8.30 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz,
2H), 7.46−7.24 (m, 5H), 4.59 (d, J = 5.8 Hz, 2H). 13C NMR (101
MHz, DMSO) δ 170.2, 154.5, 148.0, 138.7, 137.1, 128.9, 128.1, 127.8,
127.6, 124.9, 48.6. Mp 198−200 °C. LC/MS (ESI): m/z = 310.9 [M−
1]−.
N-(4-Methoxybenzyl)-5-phenyl-1,3,4-thiadiazol-2-amine
(5e). Yield, 73% (109 mg, white solid). 1H NMR (400 MHz, DMSO)
δ 8.39 (t, J = 5.6 Hz, 1H), 7.80−7.70 (m, 2H), 7.51−7.39 (m, 3H),
7.33 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 4.47 (d, J = 5.6 Hz,
2H), 3.74 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.6, 163.8,
161.3, 136.1, 135.6, 134.9, 134.4, 134.2, 131.5, 119.0, 60.3, 52.9. Mp
128−130 °C. LC/MS (ESI): m/z = 295.9 [M−1]−.
N-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazol-2-amine
(4j). Yield, 72% (96 mg, white solid). 1H NMR (400 MHz, DMSO) δ
10.45 (s, 1H), 7.96−7.83 (m, 2H), 7.65−7.49 (m, 5H), 6.96 (d, J = 9.0
Hz, 2H), 3.74 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.7, 158.0,
155.0, 132.4, 131.3, 129.8, 125.9, 124.5, 119.1, 114.8, 55.7. Mp 211−
215 °C. LC/MS (ESI): m/z = 266.0 [M−1]−.
5-Phenyl-N-(4-(trifluoromethyl)benzyl)-1,3,4-thiadiazol-2-
1
amine (5f). Yield, 67% (112 mg, white solid). H NMR (400 MHz,
DMSO) δ 8.57 (t, J = 5.9 Hz, 1H), 7.81−7.70 (m, 4H), 7.61 (d, J = 8.1
Hz, 2H), 7.51−7.41 (m, 3H), 4.66 (d, J = 5.6 Hz, 2H). 13C NMR (101
MHz, DMSO) δ 168.7, 157.1, 144.1, 131.2, 130.2, 129.6, 128.6, 126.9,
128.2 (2JCF = 31.3 Hz), 125.7 (3JCF = 3.8 Hz),124.8 (1JCF = 273.7 Hz),
47.9. Mp 153−155 °C. LC/MS (ESI): m/z = 333.9 [M−1]−. HRMS
(ESI): m/z [M+1]+ calcd for C16H12F3N3S, 336.0782; found,
336.0782.
N-Ethyl-5-phenyl-1,3,4-thiadiazol-2-amine (5g). Yield, 94%
(96 mg, white solid). 1H NMR (400 MHz, CDCl3) δ 7.89−7.76
(m, 2H), 7.49−7.37 (m, 3H), 5.78 (s, 1H), 3.46 (q, J = 7.2 Hz, 2H),
N-(4-Fluorophenyl)-5-phenyl-1,3,4-oxadiazol-2-amine (4k).
1
Yield, 96% (123 mg, white solid). H NMR (400 MHz, DMSO) δ
10.70 (s, 1H), 7.98−7.84 (m, 2H), 7.70−7.53 (m, 5H), 7.30−7.11 (m,
2H). 13C NMR (101 MHz, DMSO) δ 160.4, 158.2, 157.8 (1JCF
=
238.4 Hz), 135.5 (4JCF = 2.0 Hz), 131.4, 129.8, 126.0, 124.3, 119.1
(3JCF = 8.1 Hz), 116.1 (2JCF = 23.2 Hz). Mp 244−247 °C. LC/MS
(ESI): m/z = 254.0 [M−1]−. HRMS (ESI): m/z [M+1]+ calcd for
C14H10FN3O, 256.0886; found, 256.0897.
442
dx.doi.org/10.1021/jo302324r | J. Org. Chem. 2013, 78, 438−444

The Journal of Organic Chemistry
Article
1.38 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.0, 157.7,
131.1, 129.8, 128.9, 126.8, 42.1, 14.7; mp 175 - 178 °C. LC/MS (ESI):
m/z = 204.1 [M−1]−.
N-(2,4-Dimethoxybenzyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-
2-amine (5h). Yield, 87% (162 mg, white solid. 1H NMR (400 MHz,
DMSO) δ 8.46 (s, 1H), 8.30 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz,
2H), 7.24 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.51 (dd, J =
8.3, 2.4 Hz, 1H), 4.45 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H).
13C NMR (101 MHz, DMSO) δ 170.1, 160.7, 158.6, 154.1, 147.9,
J = 8.3 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 6.50 (dd, J = 8.3, 2.1 Hz,
1H), 4.65 (s, 2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H). 13C NMR
(101 MHz, DMSO) δ 165.3, 161.0, 158.9, 157.2, 148.5, 137.2, 131.0,
130.1, 129.0, 128.0, 127.9, 126.6, 125.0, 116.3, 105.1, 98.2, 55.9, 55.7,
51.8, 47.2. LC/MS (ESI): m/z = 447.0 [M+1]+. HRMS (ESI): m/z
[M+1]+ calcd for C24H22N4O5, 447.1668; found, 447.1667.
Representative Procedure for the Preparation of N-Benzyl-
N-(2,4-dimethoxybenzyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-
amine (7a). Benzyl chloride (46 mg, 0.36 mmol) was added to a
stirred solution of 2-amino-1,3,4-thiadiazole 5h (112 mg, 0.3 mmol)
and NaH (14.4 mg, 0.36 mmol, 60% dispersion in mineral oil) in 1 mL
of NMP. The reaction mixture was stirred at room temperature for 8
h. The reaction mixture was extracted with ethyl acetate (10 mL) and
distilled water (5 mL), and then the aqueous layer was removed. The
aqueous layer was back-extracted with ethyl acetate (3 × 5 mL). The
combined organic layers were washed with brine (5 mL) and then
dried over MgSO4. The organic layers were evaporated to afford the
crude yellow solid. The crude yellow solid was triturated with diethyl
ether/ethyl acetate (95:5) to afford 111 mg (80% yield, yellow solid)
of desired N-benzyl-N-(2,4-dimethoxybenzyl)-5-(4-nitrophenyl)-1,3,4-
thiadiazol-2-amine 7a. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 8.8
Hz, 4H), 8.00 (d, J = 8.8 Hz, 4H), 7.37−7.25 (m, 11H), 7.16 (d, J =
8.3 Hz, 2H), 6.59 (d, J = 2.2 Hz, 2H), 6.50 (dd, J = 8.3, 2.3 Hz, 2H),
4.80 (s, 4H), 4.65 (s, 4H), 3.77 (s, 6H), 3.75 (s, 6H). 13C NMR (101
MHz, DMSO) δ 192.3, 172.3, 161.0, 158.9, 154.8, 147.9, 136.9, 130.5,
129.0, 127.9, 127.8, 127.5, 124.9, 115.6, 105.0, 99.0, 55.9, 55.7, 55.2,
52.1. Mp 176−178 °C. LC/MS (ESI): m/z = 463.0 [M + 1]+. HRMS
(ESI): m/z [M+1]+ calcd for C24H22N4O4S, 463.1440; found,
463.1441.
137.2, 130.2, 127.6, 124.9, 118.2, 104.9, 98.9, 56.0, 55.7, 43.8. Mp
213−217 °C. LC/MS (ESI): m/z = 371.0 [M−1]−. HRMS (ESI): m/z
[M+1]+ calcd for C17H16N4O4S, 373.0971; found, 373.0959.
Representative Procedure for the Preparation of 2-amino-
1,3,4-thiadiazole (5i−5m). p-TsCl (114 mg, 0.60 mmol) was added
to a stirred solution of thiosemicarbazide 3i (136 mg, 0.50 mmol) and
triethylamine (111 mg, 1.10 mmol) in 4 mL of NMP. The reaction
mixture was stirred at room temperature for 2 h and extracted with
DCM (15 mL) and distilled water (10 mL), after which the aqueous
layer was removed. The aqueous layer was back-extracted with DCM
(3 × 10 mL). The combined organic layers were dried over MgSO4
and evaporated to afford the crude product, which was purified by
column chromatography on silica gel (hexane/ethyl acetate) to afford
107 mg of a mixture of 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-
thiadiazole. The mixture was separated by preparative TLC to confirm
the authenticity of the desired 2-amino-1,3,4-thiadiazole 5i. Yield, 40%
1
(yield is determined by NMR integration of mixture, white solid). H
NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 7.96−7.82 (m, 2H), 7.51−
7.37 (m, 7H), 7.18−7.09 (m, 1H). 13C NMR (101 MHz, DMSO) δ
169.1, 151.0, 135.0, 130.8, 129.8, 129.8, 129.2, 129.0, 128.7, 126.3. Mp
279−283 °C. LC/MS (ESI): m/z = 252.0 [M−1]−.
Representative Procedure for the Preparation of N-(2,4-
Dimethoxybenzyl)-N-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-
benzamide (6b). Benzoyl chloride (51 mg, 0.36 mmol) was added to
a stirred solution of 2-amino-1,3,4-oxadiazole 4h (107 mg, 0.3 mmol)
and NaH (14.4 mg, 0.36 mmol, 60% dispersion in mineral oil) in 6 mL
of THF. The reaction mixture was stirred at room temperature for 1 h
and extracted with ethyl acetate (10 mL) and distilled water (5 mL),
after which the aqueous layer was removed. The aqueous layer was
back-extracted with ethyl acetate (3 × 5 mL). The combined organic
layers were washed with brine (5 mL) and then dried MgSO4. The
organic layers were evaporated to afford the crude pale yellow solid.
The crude pale yellow solid was triturated with diethyl ether/ethyl
acetate (95:5) to afford 57 mg (41% yield, pale yellow solid) of desired
N-(2,4-dimethoxybenzyl)-N-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-
N-(4-Methoxyphenyl)-5-phenyl-1,3,4-thiadiazol-2-amine
(5j). Yield, 53% (yield is determined by NMR integration of mixture,
white solid). 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 6.9, 1.9 Hz,
2H), 7.47−7.40 (m, 3H), 7.39−7.32 (m, 2H), 6.95 (d, J = 8.7 Hz,
2H), 3.83 (t, J = 2.1 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 169.3,
159.9, 151.1, 130.7, 130.3, 129.0, 128.6, 127.6, 126.4, 114.9, 55.8. Mp
227−229 °C. LC/MS (ESI): m/z = 282.0 [M−1]−.
N-(4-Fluorophenyl)-5-phenyl-1,3,4-thiadiazol-2-amine (5k).
Yield, 44% (yield is determined by NMR integration of mixture,
1
white solid). H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 7.88−7.82
(m, 2H), 7.48−7.41 (m, 5H), 7.15−7.08 (m, 2H). 13C NMR (101
1
MHz, DMSO) δ 169.1, 162.5 (d, JCF = 248.0 Hz), 151.1, 131.6 (d,
4
3JCF = 9.4 Hz), 131.3 (d, JCF = 3.1 Hz), 130.8, 129.0, 128.8, 126.2,
1
2
benzamide 6b. H NMR (400 MHz, DMSO) δ 8.39 (d, J = 8.9 Hz,
116.7 (d, JCF = 22.6 Hz). Mp 247−250 °C. LC/MS (ESI): m/z =
269.9 [M−1]−.
2H), 8.00 (d, J = 8.8 Hz, 2H), 7.55−7.47 (m, 3H), 7.45−7.33 (m,
3H), 6.58−6.50 (m, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 3.58 (s, 3H). 13C
NMR (101 MHz, DMSO) δ 169.2, 161.8, 161.3, 161.0, 158.7, 149.7,
134.6, 132.1, 131.4, 129.1, 128.8, 128.1, 127.8, 125.2, 116.0, 105.2,
98.7, 55.9, 55.7, 47.5. Mp 166 −168 °C. LC/MS (ESI): m/z = 461.0
[M+1]+. HRMS (ESI): m/z [M+1]+ calcd for C24H21N4O6, 461.1461;
found, 461.1477.
N-(2,4-Dimethoxybenzyl)-N-(5-(4-nitrophenyl)-1,3,4-thiadia-
zol-2-yl)benzamide (7b). Yield, 82% (117 mg, pale yellow solid). 1H
NMR (400 MHz, DMSO) δ 8.36 (d, J = 8.6 Hz, 2H), 8.24 (d, J = 8.8
Hz, 2H), 7.67−7.49 (m, 5H), 7.07 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 2.2
Hz, 1H), 6.43 (dd, J = 8.4, 2.2 Hz, 1H), 5.30 (s, 2H), 3.70 (s, 3H),
3.65 (s, 3H). 13C NMR (101 MHz, DMSO) δ 171.1, 161.8, 161.0,
160.5, 158.1, 148.8, 136.3, 133.8, 131.8, 129.7, 129.0, 128.6, 127.9,
125.0, 116.0, 104.9, 98.8, 55.7, 55.6, 49.8. Mp 178−180 °C. LC/MS
(ESI): m/z = 477.0 [M+1]+. HRMS (ESI): m/z [M+1]+ calcd for
C24H21N4O5S, 477.1233; found, 477.1240.
Representative Procedure for the Preparation of N-(2,4-
Dimethoxybenzyl)-4-methyl-N-(5-(4-nitrophenyl)-1,3,4-oxa-
diazol-2-yl)benzenesulfonamide (6c). p-TsCl (69 mg, 0.36 mmol)
was added to a stirred solution of 2-amino-1,3,4-oxadiazole 4h (107
mg, 0.3 mmol) and NaH (14.4 mg, 0.36 mmol, 60% dispersion in
mineral oil) in 6 mL of THF. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was extracted with ethyl
acetate (10 mL) and distilled water (5 mL), and then the aqueous
layer was removed. The aqueous layer was back-extracted with ethyl
N-(4-Methoxyphenyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-
amine (5m). Yield, 84% (yield is determined by NMR integration of
1
mixture, white solid). H NMR (400 MHz, DMSO) δ 10.59 (s, 1H),
8.31 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 9.0 Hz,
2H), 6.97 (d, J = 9.0 Hz, 2H), 3.75 (s, J = 4.0 Hz, 3H). 13C NMR (101
MHz, DMSO) δ 166.6, 155.5, 155.0, 148.1, 136.7, 1334.1, 127.9,
124.9, 120.2, 114.8, 55.7. Mp 238−242 °C. LC/MS (ESI): m/z =
326.9 [M−1]−. HRMS (ESI): m/z [M+1]+ calcd for C15H12N4O3S,
329.0708; found, 329.0710.
Representative Procedure for the Preparation of N-Benzyl-
N-(2,4-dimethoxybenzyl)-5-(4-nitrophenyl)-1,3,4-oxadiazol-2-
amine (6a). Benzyl chloride (46 mg, 0.36 mmol) was added to a
stirred solution of 2-amino-1,3,4-oxadiazole 4h (107 mg, 0.3 mmol)
and NaH (14.4 mg, 0.36 mmol, 60% dispersion in mineral oil) in 1 mL
of NMP. The reaction mixture was stirred at room temperature for 8
h. The reaction mixture was extracted with ethyl acetate (10 mL) and
distilled water (5 mL), and then the aqueous layer was removed. The
aqueous layer was back-extracted with ethyl acetate (3 × 5 mL). The
combined organic layers were washed with brine (5 mL) and then
dried over MgSO4. The organic layers were evaporated to afford the
crude product, which was purified by column chromatography on silica
gel (hexane/ethyl acetate) to afford 116 mg (87% yield, yellow oil) of
the desired N-benzyl-N-(2,4-dimethoxybenzyl)-5-(4-nitrophenyl)-
1
1,3,4-oxadiazol-2-amine 6a. H NMR (400 MHz, DMSO) δ 8.35 (d,
J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.38−7.26 (m, 5H), 7.22 (d,
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dx.doi.org/10.1021/jo302324r | J. Org. Chem. 2013, 78, 438−444

The Journal of Organic Chemistry
Article
acetate (3 × 5 mL). The combined organic layers were washed with
brine (5 mL) and then dried over MgSO4. The organic layers were
evaporated to afford the crude product, which was purified by column
chromatography on silica gel (hexane/ethyl acetate) to afford 92 mg
(60% yield, pale yellow solid) of the desired N-(2,4-dimethoxybenzyl)-
4-methyl-N-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)benzenesulfon-
Rollas, S.; Sener, G.; Uysal, M. K.; Gulen, D. Bioorg. Med. Chem. 2002,
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(4) (a) Chapleo, C. B.; Myers, M.; Myers, P. L.; Saville, J. F.; Smith,
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1
amide 6c. H NMR (400 MHz, DMSO) δ 8.43 (d, J = 8.8 Hz, 2H),
8.17 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz,
2H), 7.18 (d, J = 8.8 Hz, 1H), 6.47 (dd, J = 8.0, 2.4 Hz, 1H), 6.43 (d, J
= 2.4 Hz, 1H), 4.97 (s, 2H), 3.73 (s, 3H), 3.48 (s, 3H), 2.42 (s, 3H).
13C NMR (101 MHz, DMSO) δ 161.4, 159.7, 158.7, 149.7, 145.6,
135.0, 131.4, 130.3, 128.8, 128.4, 127.9, 125.3, 125.2, 114.8, 105.0,
98.7, 55.8, 55.7, 50.0, 21.5. Mp 108−112 °C. LC/MS (ESI): m/z =
511.0 [M+1]+. HRMS (ESI): m/z [M+1]+ calcd for C24H23N4O7S,
511.1287; found, 511.1294.
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N-(2,4-Dimethoxybenzyl)-4-methyl-N-(5-(4-nitrophenyl)-
1,3,4-thiadiazol-2-yl)benzenesulfonamide (7c). Yield, 97% (153
mg, pale yellow solid). 1H NMR (400 MHz, DMSO) δ 8.35 (d, J = 8.8
Hz, 2H), 8.19 (d, J = 9.2 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.46 (d, J
= 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.46
(dd, J = 12.0, 2.4 Hz, 1H), 5.10 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H),
2.51 (s, 3H). 13C NMR (101 MHz, DMSO) δ 163.5, 163.0, 161.0,
158.4, 149.1, 146.1, 135.5, 134.2, 130.8, 129.3, 128.8, 127.7, 124.9,
115.4, 105.1, 98.8, 55.9, 55.6, 48.8, 21.5. Mp 143−146 °C. LC/MS
(ESI): m/z = 526.9 [M+1]+. HRMS (ESI): m/z [M+1]+ calcd for
C24H23N4O6S2, 527.1059; found, 527.1061.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Full analytical data of compounds, along with copies of H
NMR, 13C NMR, LC/MS, and HRMS spectra of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ydgong@dongguk.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by grants from the National
Research Foundation of Korea (2010-0004128) funded by the
Ministry of Education, Science and Technology, and (2010) by
the Ministry of Knowledge Economy, Korea.
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