A Highly Efficient Diversification of 2-Amino/Amido-1,3,4-oxadiazole and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of Thiosemicarbazide Intermediate on Solid-Phase

Article abstract of DOI:10.1021/acscombsci.5b00140

A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library has been constructed on solid-phase organic synthesis. The key step on this solid-phase synthesis involves the preparation of polymer-bound 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core

Full text of DOI:10.1021/acscombsci.5b00140

Research Article
pubs.acs.org/acscombsci
A Highly Efficient Diversification of 2‑Amino/Amido-1,3,4-oxadiazole
and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of
Thiosemicarbazide Intermediate on Solid-Phase
Seung-Ju Yang, Ji-Hye Choe, Aizhan Abdildinova, and Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science, Dongguk University, 26, 3-ga, Pil-dong
Jung-gu, Seoul 100-715, Korea
S
* Supporting Information
ABSTRACT: A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-
thiadiazole library has been constructed on solid-phase organic
synthesis. The key step on this solid-phase synthesis involves
the preparation of polymer-bound 2-amino-1,3,4-oxadiazole
and 1,3,4-thiadiazole core skeleton resin by cyclization of
thiosemicarbazide with EDC·HCl and p-TsCl, respectively.
The resulting core skeleton undergoes functionalization reaction with various electrophiles such as alkyl halides, and acid
chlorides to generate N-alkylamino and N-acylamino-1,3,4-oxadiazole, and 1,3,4-thiadiazole resin, respectively. Finally, the 2-
amino and 2-amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library was then generated in good yields and high purities by cleavage
of the respective resin under trifluoroacetic acid(TFA) in dichloromethane(DCM). The constructed library shows reasonable,
oral bioavailability drug properties as determine by using the Lipinski’s Rule and similar parameters.
KEYWORDS: solid-phase, BOMBA, thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole
thiadiazole analogues on the solid-phase synthesis from
different kinds of intermediates.17 In the literature, a reliable
and efficient synthetic method for both 1,3,4-oxadiazole and
1,3,4-thiadiazole from one key intermediate on the solid-phase
synthesis has not been reported, excepted by our previous
methodology.18 In our previous methodology, we used an
acyldithiocarbazate intermediate for both 1,3,4-oxadiazole and
1,3,4-thiadiazole synthesis on the solid-phase. However, our
method was limited as we could not efficiently introduce
various substituents at the 2-position of 1,3,4-oxadiazole and
1,3,4-thadiazole (Scheme 1a).
Accordingly, we had an interest in developing a useful
synthetic method for both 1,3,4-oxadiazoles and 1,3,4-
thiadiazoles with a various substituents at the 2-position.
Along these lines, in our own research, we developed a
synthetic method to afford 1,3,4-oxadiazole and 1,3,4-
thiadiazole analogues which were functionalized on the 2-
position of 1,3,4-oxadiazole and 1,3,4-thiadiazole with amines,
amides, and sulfone amides in the solution-phase organic
synthesis19 and now our interest focuses on the construction of
a 1,3,4-oxadiazole and 1,3,4-thadiazole library on the solid-
phase organic synthesis. To achieve this, we introduced a
thiosemicarbazide intermediate as a key intermediate for 1,3,4-
oxadiazole and 1,3,4-thiadiazole on the back bond amide linker
(BAL) (Scheme 1b). As can be seen in Scheme 1, our previous
methodology used resin as a electrophile and only amine
INTRODUCTION
■
Solid-phase organic synthesis (SPOS) is routinely used to
prepare drug-like, small organic molecules in medicinal
chemistry programs. This procedure enables the generation
of massive numbers of hit and lead compounds as part of high-
throughput screening techniques.1 Heterocyclic skeletons serve
as ideal scaffolds on which pharmacophores can be appended to
yield potent and selective drugs.2 This is especially true for five-
member-ring heterocycles, which are core components of a
large number of 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,3 antimicrobial,4 anticonvul-
sant,5 anticancer,6 and antihypertensive.7 Especially, according
to our previous research, 1,3,4-oxadiazole analogues show
potent biological activity in the canonical Wnt signaling
pathway,8 which has been considered as a key pathway that
regulates adipogenesis,9 osteoporosis,10 and stem cell differ-
entiation.11 For this reason, we became interested in the
synthesis of 1,3,4-oxadiazole and 1,3,4-thiadiazole analogues.
The synthesis of 1,3,4-oxadiazole with polymer-bound α-
selenopropionic acid was reported by Huang.12 Brill13 reported
1,3,4-oxadiazole synthesis as a traceless release on the solid
support and Lee14 reported synthesis of 2-amido-1,3,4-
oxadiazole derivatives on solid-phase synthesis. Clemens used
diisopropylcarbodiimide to afford 1,3,4-oxadiazole from semi-
carbazide intermediate on solid-phase synthesis.15 Synthesis of
1,3,4-thiadiazoles on solid-phase was reported by Liu.16 Kilburn
and Lau reported useful synthesis of 1,3,4-oxadiazole and 1,3,4-
Received: September 3, 2015
Revised: October 30, 2015
© XXXX American Chemical Society
A
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Scheme 1. Strategy Used to Generate Various 2-Amino/Amido-1,3,4-oxadiazoles and 1,3,4-Thiadiazoles
a
Scheme 2
a
Reaction condition: (a) CS2, p-TsCl, TEA, THF, room temperature, 18 h; (b) benzhydrazide, TEA, THF, room temperature, 16 h; (c) EDC·HCl,
DMSO, 60 °C, 16 h; (d) p-TsCl, TEA, rt, 12 h; (e) alkyl halide, t-BuOK, DMF, 60 °C, 16 h; (f) acid chloride, pyridine, 60 °C, 12 h; (g) TFA/DCM
(1:4, v/v), 40 °C, 8 h; (h) TFA/DCM (1:4, v/v), room temperature, 6 h.
nucleophiles could be introduced at the 2-position of both
1,3,4-oxadiazole and 1,3,4-thiadiazole. On the other hand, in
our present methodology, resin was used as a nucleophile and
various electrophiles such as alkyl halides and acid chlorides
were introduced at the 2-position of both 1,3,4-oxadiazole and
1,3,4-thiadiazole. Herein, we report our recent efforts on this
project, which includes the regioselective synthetic protocol for
2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole deriva-
tives with a thiosemicarbazide intermediate on the solid-phase
synthesis.
RESULTS AND DISCUSSION
■
The sequence used to prepare the thiosemicarbazide
intermediate resin uses the 4-benzyloxy-2-
3
methoxybenzylamine(BOMBA) resin 1 as the starting material.
Treatment of resin 1 with CS2, p-TsCl, and triethylamine
(Et3N) in tetrahydrofuran (THF) generated the desired
isothiocyanate terminated resin 2.20 The formation of resin 2
was confirmed by inspection of its attenuated total reflection
(ATR) single bead Fourier transform infrared (FTIR)
spectrum, which showed the presence of a typical isothiocya-
B
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Figure 1. Biologically active compounds containing 1,3,4-oxadiazole, and 1,3,4-thiadiazole core skeleton.
Table 1. Results of Cyclization Condition of Thiosemicarbazide Resin 3
d
ratio
entry
R1
cyclization
solvent
DMSO
14
15
1
H
EDC·HCl
EDC·HCl
EDC·HCl
EDC·HCl
100
100
100
100
100
41
0
0
2
p-methoxy
p-nitro
p-fluoro
m-nitro
H
DMSO
DMSO
DMSO
DMSO
NMP
3
0
4
0
5
EDC·HCl
0
6
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
p-TsCl/TEA
59
29
88
34
62
55
88
7
p-methoxy
p-nitro
p-fluoro
m-nitro
p-H
NMP
71
8
NMP
12
9
NMP
66
10
11
12
NMP
38
NMP/THF
NMP/THF
45
p-nitro
12
a
Thiosemicarbazide resin 3 was treated with 3.0 equiv of EDC·HCl in DMSO at 60 °C for 16 h. Thiosemicarbazide resin 3 was treated with 3.0
b
c
d
e
equiv p-TsCl and 3.0 equiv TEA in NMP. NMP/THF(v/v = 1:1). At room temperature for 12 h. Ratio was checked by LC/MS. The mixture of
cyclized resin and cleavage cocktail (TFA/DCM = 1:4, v/v) was shaken at 40 °C for 6 h.
nate band at 2070 cm−1 (Figure 1b in the Supporting
Information). The isothiocyanate terminated resin 2 reacted
with substituted benzhydrazide in the presence of Et3N and
THF to obtain thiosemicarbazide intermediate resin 3, signaled
by the absence of the isothiocyanate band at 2070 cm−1 and by
the appearance of the broad amine peak at 3312 cm−1 and
amide peak at 1670 cm−1 (Figure 1c in the Supporting
Information).
From the thiosemicarbazide resin 3, we tried to synthesize
both 1,3,4-oxadiazole resin 4 and 1,3,4-thiadiazole resin 9 via
EDC·HCl or p-TsCl mediated cyclization. The use of EDC·
HCl led to 1,3,4-oxadiazole resin 4 with various substituents at
the R1 position via desulfurative cyclization. (Table 1, entries
1−5) The formation of resin 4 was confirmed by the absence of
3312 and 1670 cm−1 of resin 3 and by the appearance of an
imine peak at 1604 cm−1 (Figure 1d in the Supporting
Information (SI)). To determine the exact ratio of
regioselectivity, we cleaved the resin after cyclization and
confirmed only the 1,3,4-oxadiazole 14 in the LC/MS (SI
Figure 2a, 2c, 2e, 2g, and 2i). On the other hand, in the case of
p-TsCl mediated cyclization, the regioselectivity depended on
the substituent at the R1 position. First, a phenyl
thiosemicarbazide showed low regioselectivity (Table 1, entry
6; SI Figure 2b) and thiosemicarbazides substituted with p-
methoxy or p-fluoro which could donate electron pairs showed
slight regioselectivity for 1,3,4-oxadiazole (Table 1, entries 7
and 9; SI Figure 2d and 2h). To increase regioselectivity for
1,3,4-thiadiazole, we introduced a nitro group as a strong
electron withdrawing group at the para and meta positions of
thiosemicarbazide 3. The m-nitro substituted thiosemicarbazide
showed slightly increased regioselectivity for 1,3,4-thiadiazole
(Table 1, entry 10; SI Figure 2j) and p-nitro substituted
thiosemicarbazide showed good regioselectivity for 1,3,4-
thiadiazole (Table 1, entry 8; SI Figure 2f). The formation of
resin 9 was confirmed by the absence of 3291 cm−1 (br) and
1683 cm−1 (amide) peaks of resin 3 (SI Figure 1g). To know
C
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Scheme 3. Proposed Mechanism of Cyclization of Thiosemicarbazide Resin 3 Promoted by p-TsCl/Et3N in NMP
Table 2. Yields and Purities of the 2-Amino-1,3,4-oxadiazole Derivatives 7
a
b
Five-step overall obtained yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of purified products were checked by LC/MS.
the exact ratio of regioselectivity, we cleaved the resin after
cyclization and then confirmed 1,3,4-thiadiazole 15 as a major
product in LC/MS (SI Figure 2f). According to our solution-
phase study.19 the regioselectivity was affected by both
electronic and solvent effects in the p-TsCl mediated
cyclization. Generally, NMP as a solvent and the p-nitro
group on the R1 position show good regioselectivity for the
1,3,4-thiadiazole. However, on the solid-phase synthesis, the
regioselectivity was not affected by solvent effect, while the
electronic effect showed similar regioselectivity with solution-
phase synthesis because the resin 3 had not sufficiently swollen
in NMP (Table 1, entries 6 and 8). Thus, to increase
regioselectivity for the 1,3,4-thiadiazole, we used THF as a
cosolvent to enhance the solvent effect which easily swells in
D
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Table 3. Yields and Purities of the 2-Amido-1,3,4-oxadiazole Derivatives 8
a
b
Five-step overall obtained yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of purified products were checked by LC/MS.
the polystyrene resin (Table 1, entry 11 and 12). However, it
did not show an increase of regioselectivity for the 1,3,4-
thiadiazole (SI Figure 2k and 2l).
1249 cm−1 (SI Figure 1e) and cleavage from resin 5 by
treatment of TFA/DCM (1:4, v/v) at 40 °C for 8 h. To purify
the crude product mixture of 7, we used a short plug of silica
with hexane/tetrahydrofuran and then triturated this by using
the diethyl ether/hexane. Finally, we could obtain various 2-
amino-1,3,4-oxadiazole derivatives 7 in good yields and high
purities as shown in Table 2. We then used various acid
chlorides with NaH in THF to make a N-acylamino-1,3,4-
oxadiazole resin 6. However, the solid-phase synthesis was also
not successful. We therefore used neat pyridine. In this
condition, the acylation reaction proceeded smoothly to give
the desired N-acylamino-1,3,4-oxadiazole resin 6. The reaction
was monitored by ATR-FTIR spectroscopy, which revealed the
growth of the band intensity of the amide bond at 1685 cm−1
(SI Figure 1f). This N-acylamino-1,3,4-oxadiazole resin 6 could
be easily cleaved in TFA/DCM (5:95, v/v) at room
temperature for 6 h to afford the corresponding 2-amido-
1,3,4-oxadiazole 8. To purify the crude product mixture 8, we
triturated it with ethyl acetate/diethyl ether to obtain 2-amido-
1,3,4-oxadiazole 8 (The LC/MS result of the crude product
mixture 8a is shown in Figure 3 in the Supporting
Information). Finally, we obtained 2-amido-1,3,4-oxadiazole
derivatives 8 in high yields and purities as shown in Table 3.
Next, to generate 1,3,4-thiadiazole analogues, we used p-nitro
substituted thiosemicarbazide 3, which shows regioselectivity
for 1,3,4-thiadiazole (Table 1, entry 8). After cyclization of
thiosemicarbazide 3 with p-TsCl/Et3N in NMP, we used
various alkyl halides in the presence of t-BuOK in DMF. The
reaction was monitored by ATR-FTIR spectroscopy, which
revealed the growth of the bond intensity of C−N bond at
The proposed mechanism is described in Scheme 3.
According to our experimental results (Table 1, entries 6−
10), the regioselectivity in p-TsCl mediated cyclization seems
to be affected by the pKa of both proton A and proton B. When
we introduced p-nitro or m-nitro groups at the R1 position, it
caused a decrease of the pKa of proton B so proton B could be
easily deprotonated by Et3N leading to regioselectivity of the
1,3,4-thiadiazole resin 9 (Table 1, entries 6, 8, and 10). On the
other hand, p-methoxy and p-fluoro groups which could donate
an electron pair, caused an increase of the pKa of proton B that
led to regioselectivity of the 1,3,4-oxadiazole resin 4 (Table 1,
entries 6, 7, and 9). Next, in other to explore the diversity of
our experiment, we tried to synthesize 1,3,4-oxadiazole and
1,3,4-thiadiazole analogues. With the available resin 4, we
focused on the various alkyl and acyl substitution at the 2-N
position on 2-amino-1,3,4-oxadiazole core skeleton resin 4.
First, to make N-alkylamino-1,3,4-oxadiazole resin 5, we used
various alkyl halides in the presence of NaH in NMP at 60 °C
for 16 h. In the case of our solution phase synthesis, alkylation
was successful in this condition.19 However, on the solid phase
synthesis, it was unsuccessful because of the low solubility of
NaH in the organic solvent. We therefore used various bases
and solvents such as K2CO3, CsCO3, and t-BuOK in THF,
ACN, and DMF. Among these combinations, t-BuOK in DMF
showed good reactivity for the alkylation. The progress of this
reaction was monitored by ATR-FTIR spectroscopy, which
revealed the growth of the band intensity of the C−N bond at
E
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Table 4. Yields and Purities of the 2-Amino-1,3,4-thiadiazole Derivatives 12
a
b
Five-step overall obtained yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of purified products were checked by LC/MS.
Table 5. Yields and Purities of the 2-Amido-1,3,4-thiadiazole Derivatives 13
a
b
Five-step overall obtained yields from BAL resin 1 (loading capacity of resin 1 is 1.16 mmol/g). All of purified products were checked by LC/MS.
1260 cm−1 (SI Figure 1h) and cleavage from resin 10 by
treatment of TFA: DCM (1:4, v/v) at 40 °C for 8 h. To purify
the crude product mixture of 2-amino-1,3,4-thiadiazole 12, we
used a short plug of silica with hexane/ethyl acetate and then
triturated it by using diethyl ether/hexane. As a result, we
obtained the desired 2-amino-1,3,4-thiadiazole derivatives in
moderate yields and high purities as shown in Table 4.
Next, we tried to synthesize 2-amido-1,3,4-thiadiazole
analogues 13. Various acid chlorides were introduced on the
1,3,4-thiadiazole resin 9 in a neat pyridine condition to afford 2-
amido-1,3,4-thiadiazole resin 11, signaled by the amide peak at
1657 cm−1. (SI Figure 1i) and then cleaved from resin 11 in a
TFA/DCM (95:5, v/v) at room temperature for 4 h. To purify
crude product mixture 13, we triturated it with ethyl acetate/
ethanol (The LC/MS result of the crude product mixture 13a
is shown in Figure 4 in the Supporting Information). As a
result, we obtained the desired 2-amido-1,3,4-thiadiazole 13 in
a high yields and purities as shown in Table 5.
Finally, we had an interest to the evaluation of the potential
drug properties of the 2-amino/amido-1,3,4-oxadiazole and
1,3,4-thiadiazole library. In the drug development process, it is
important to develop orally available drug; Lipinski’s Rule21 and
similar parameters could be used as guidelines to an estimation
of physicochemical property. The key bioavailability parame-
ters, such as molecular weight, lipophilicity, number of
hydrogen bonding donors and acceptors, number of rotatable
bond, and polar surface area are displayed in the Figure 2. As
can be seen in this data, most of the key parameters of
constructed 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadia-
zole library fall within the range of those predicted for
reasonable oral bioavailable drugs.
In conclusion, we established a solid-phase synthetic method
to construct a 2-amino/amido-1,3,4-oxadiazole and 1,3,4-
thiadiazole library. The isothiocyanate terminated resin 2 was
prepared from BOMBA resin 1 by using the CS2, p-TsCl, and
Et3N in THF and was then reacted with various benzhydrazides
to give the thiosemicarbazide resin 3. Cyclization of resin 3 was
promoted by EDC·HCl in DMSO and p-TsCl/Et3N in NMP
to generate 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core
skeleton resin 4 and 9 respectively. In the case of p-TsCl
mediated cyclization, the regioselectivity for 1,3,4-thiadiazole
was shown with p-nitro substituted thiosemicarbazide while the
cyclization mediated in EDC·HCl showed regioselectivity for
1,3,4-oxadiazole with various substituent such as p-methoxy, p-
nitro, m-nitro, and p-F. To functionalize both 2-amino-1,3,4-
oxadiazole resin 4 and 1,3,4-thiadiazole resin 9, various alkyl
halides and acid chlorides were used to generate corresponding
2-amino/amido-1,3,4-oxadiazole resin 5 and 7 as well as 2-
amino/amido-1,3,4-thiadiazole resin 10 and 11. Finally, we
obtained the desired 2-amino/amido-1,3,4-oxadiazole and
1,3,4-thiadiazole analogues 7, 8, 12, and 13 after cleavage
with TFA/DCM in high yields and purities. The yields of 2-
amino/amido-1,3,4-oxadiazole analogues 7 and 8 are slightly
higher than the yields of 2-amino/amido-1,3,4-thiadiazole
analogues 12 and 13 because EDC·HCl mediated cyclization
for 1,3,4-oxadiazole resin 4 is a regiospecific reaction while p-
TsCl mediated cyclization for 1,3,4-thiadiazole resin 9 is a
regioselective reaction. To know the potential of bioavailable
drug properties of our constructed library, we used Lipinski’s
F
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Figure 2. Calculated physicochemical properties of constructed 1,3,4-oxadiazole and 1,3,4-thiadiazole library.
Representative Procedure for the Preparation of Isothiocyanate-
Terminated Resin 2. Et3N (5.87 g, 58.0 mmol) and CS2 (2.65 g, 34.8
mmol) was added to a mixture of BOMBA resin 1 (5 g, 5.8 mmol) in
THF (30 mL) at 0 °C. The mixture was stirred at room temperature
for 3 h. p-TsCl (5.52 g, 29.0 mmol) was added at 0 °C and the mixture
was stirred at room temperature for 15 h. The precipitate obtained by
filteration of the mixture was washed with THF, H2O, MeOH, and
CH2Cl2 and dried in a vacuum oven. This process made resin 2 a
Rule and similar parameters. As a result, we know that the
constructed library has the potential to be used as an orally
bioavailable drug. We envision that these libraries will be used
in the drug discovery process as well as for the exploration of
biological areas.
EXPERIMENTAL PROCEDURES
■
brown solid. Single-Bead ATR-FTIR: 3026, 2920, 2070 (NCS),
General Procedure for Synthesis. All chemicals were reagent
grade and used as purchased. Reactions were monitored by ATR-
FTIR. Flash column chromatography was carried out on silica gel
(230−400 mesh). 1H NMR and 13C NMR spectra were recorded in δ
units relative to deuterated solvent as an internal reference using a 500
MHz NMR instrument. Liquid chromatography tandem mass
spectrometry analysis was performed on an electro spray ionization
(ESI) mass spectrometer with photodiode-array detector (PDA)
detection. High-resolution mass spectrometry spectra were obtained
using TOF LC/MS system.
−1
1607, 1587, 1504, 1449, 1284, 1194, 1157, 1028, and 816 cm
.
Representative Procedure for the Preparation of Thiosemicarba-
zide Resin 3a. A mixture of isothiocyanate resin 2 (5.23 g. 5.8 mmol),
benzhydrazide (2.37 g, 17.4 mmol), and Et3N (2.43 g, 17.4 mmol) in
THF (30 mL) was stirred at room temperature for 16 h. The resin was
filtered and washed several times with MeOH and CH2Cl2 and then
dried in a vacuum oven. Resin 3a was obtained as a brown solid.
Single-Bead ATR-FTIR: 3312(br), 2923, 1670(CO), 1606, 1504,
−1
1449, 1280, 1193, 1156, 1016, and 818 cm
.
G
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Representative Procedure for the Preparation of 2-Amino-1,3,4-
oxadiazole Resin 4a. A mixture of thiosemicarbazide resin 3a (6.00 g,
5.8 mmol) and EDC·HCl (3.34 g, 17.4 mmol) in DMSO (30 mL) was
stirred at 60 °C for 16 h. The resin was filtered and washed several
times with MeOH, H2O, and CH2Cl2 and then dried in a vacuum
oven. Resin 4a was obtained as a brown solid. Single-Bead ATR-FTIR:
Representative Procedure for the Preparation of N-Benzylamino-
1,3,4-thiadiazole Resin 10a. A 2-amino-1,3,4-thiadiazole resin 9 (213
mg, 0.2 mmol) in DMF (3 mL) was added t-BuOK (112 mg, 1.0
mmol) at room temperature. The resulting mixture was stirred at
room temperature for 15 min. Benzyl chloride(127 mg, 1.0 mmol) was
added to a mixture and then stirred at 60 °C for 16 h. The resin was
filtered and washed several times with MeOH, H2O, and CH2Cl2 and
then dried in a vacuum oven. Resin 10a was obtained as a brown solid.
3023, 2922, 1604(CN), 1503, 1448, 1418, 1269, 1194, 1157, 1015,
−1
and 818 cm
.
Single-bead ATR-FTIR: 3023, 2915, 2852, 1597, 1520(NO2), 1505,
Representative Procedure for the Preparation of N-Benzylamino-
1,3,4-oxadiazole Resin 5a. A 2-amino-1,3,4-oxadiazole resin 4a (200
mg, 0.2 mmol) in DMF (3 mL) was added t-BuOK (112 mg, 1.0
mmol) at room temperature. The resulting mixture was stirred at
room temperature for 15 min. Benzyl chloride(127 mg, 1.0 mmol) was
added to a mixture and then stirred at 60 °C for 16 h. The resin was
filtered and washed several times with MeOH, H2O, and CH2Cl2 and
then dried in a vacuum oven. Resin 5a was obtained as a brown solid.
−1
1489, 1447, 1339(NO2) 1260(C−N), 1193, 1160, and 846 cm
.
Representative Procedure for the Preparation of N-Benzyl-5-
phenyl-1,3,4-thiadiazol-2-amine 12a. A resin 10a (213 mg, 0.2
mmol) was treated with a mixture of TFA/CH2Cl2 (1:4, v/v) at 40 °C
for 8 h. The resin was filtered and then washed several times with
CH2Cl2 and MeOH. The organic filtrate was evaporated and then
extracted with ethyl acetate and H2O followed by neutralized to pH 7
by using saturated NaHCO3 aqueous solution. The aqueous layer was
back-extracted with ethyl acetate. The combined organic layers were
dried over MgSO4 and evaporated to obtain the crude product, which
was purified by column chromatography on silica gel (hexane/ethyl
acetate) and triturated with diethyl ether/hexane(1:1) to obtain 6.6
mg (11%, 5 steps overall yield) of desired N-benzyl-5-phenyl-1,3,4-
Single-bead ATR-FTIR: 3023, 2019, 1606, 1491, 1448, 1285,
−1
1249(C−N), 1196, 1160, 1025, and 902 cm
.
Representative Procedure for the Preparation of N-Benzyl-5-
phenyl-1,3,4-oxadiazol-2-amine 7a. A resin 5a (200 mg, 0.2 mmol)
was treated with a mixture of TFA/CH2Cl2 (1:4, v/v) at 40 °C for 8 h.
The resin was filtered and then washed several times with CH2Cl2 and
MeOH. The organic filtrate was evaporated and then extracted with
CH2Cl2 and H2O followed by neutralized to pH 7 by using saturated
NaHCO3 aqueous solution. The aqueous layer was back-extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and
evaporated to obtain the crude product, which was purified by column
chromatography on silica gel (hexane/THF) and triturated with
diethyl ether/hexane(1:1) to obtain 11.9 mg (23.3%, 5 steps overall
yield) of desired N-benzyl-5-phenyl-1,3,4-oxadiazol-2-amine 7a. 1H
NMR (500 MHz, DMSO): δ 8.38 (s, 1H), 7.87−7.77 (m, 2H), 7.53
(d, J = 1.8 Hz, 3H), 7.38 (d, J = 17.5 Hz, 4H), 7.28 (s, 1H), 4.46 (d, J
= 2.1 Hz, 2H). 13C NMR (126 MHz, DMSO): δ 164.1, 158.2, 139.2,
131.0, 129.7, 128.9, 127.9, 127.6, 125.6, 124.7, 46.5. LC-MS (ESI): m/
z = 250.2 [M − H]−. HRMS (ESI) calcd for C14H10FN3O [M + H]+:
252.1131, found: 252.1137.
1
thiadiazol-2-amine 12a. H NMR (500 MHz, DMSO) δ 8.77 (t, J =
5.6 Hz, 1H), 8.30 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.43−
7.35 (m, J = 15.1, 7.5 Hz, 4H), 7.30 (t, J = 6.9 Hz, 1H), 4.59 (d, J = 5.6
Hz, 2H). 13C NMR (126 MHz, DMSO) δ 169.7, 154.0, 147.5, 138.2,
136.6, 128.5, 127.6, 127.3, 127.2, 124.5, 48.1. LC-MS (ESI): m/z =
313.2 [M + H]+. HRMS (ESI) calcd for C15H13N4O2S [M + H]+:
313.0754; found 313.0755.
Representative Procedure for the Preparation of N-Benzoylami-
no-1,3,4-thiadiazole Resin 11a. A 2-amino-1,3,4-oxadiazole resin 9a
(213 mg, 0.2 mmol) in pyridine (3 mL) was added benzoyl chloride
(140 mg, 1.0 mmol) at room temperature. The resulting mixture was
stirred at 60 °C for 12 h. The resin was filtered and washed several
times with MeOH, H2O, and CH2Cl2 and then dried in vacuum oven.
Resin 11a was obtained as a brown solid. Single-bead ATR-FTIR:
3023, 2921, 2852, 1657(amide), 1600, 1581, 1521(NO2), 1503, 1489,
−1
Representative Procedure for the Preparation of N-Benzoylami-
no-1,3,4-oxadiazole Resin 6a. A 2-amino-1,3,4-oxadiazole resin 4a
(200 mg, 0.2 mmol) in pyridine (3 mL) was added benzoyl chloride
(140 mg, 1.0 mmol) at room temperature. The resulting mixture was
stirred at 60 °C for 12 h. The resin was filtered and washed several
times with MeOH, H2O, and CH2Cl2 and then dried in vacuum oven.
Resin 6a was obtained as a brown solid. Single-bead ATR-FTIR: 3023,
2923, 1685(amide), 1607, 1576, 1504, 1448, 1265, 1195, 1025, 820 cm
1449, 1343(NO2), 1193, 1156, 1017, and 851 cm
.
Representative Procedure for the Preparation of N-(5-Phenyl-
1,3,4-oxadiazol-2-yl)benzamide 13a. A resin 11a (213 mg, 0.2
mmol) was treated with a mixture of TFA/CH2Cl2 (5:95, v/v) at
room temperature for 4 h. The resin was filtered and then washed with
several times CH2Cl2, and MeOH. The organic filtrate was evaporated
and then extracted with ethyl acetate and H2O. The aqueous layer was
back-extracted with ethyl acetate. The combined organic layers were
dried over MgSO4 and evaporated to afford the crude product, which
was triturated by ethyl acetate/ethanol to afford 31.5 mg (48%, 5 steps
overall yield) of desired N-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide
−1
.
Representative Procedure for the Preparation of N-(5-Phenyl-
1,3,4-oxadiazol-2-yl)benzamide 8a. A resin 6a (200 mg, 0.2 mmol)
was treated with a mixture of TFA/CH2Cl2 (5:95, v/v) at room
temperature for 6 h. The resin was filtered and then washed with
several times CH2Cl2, and MeOH. The organic filtrate was evaporated
and then extracted with ethyl acetate and H2O followed by neutralized
to pH 4 by saturated NaHCO3 aqueous solution. The aqueous layer
was back-extracted with ethyl acetate. The combined organic layers
were dried over MgSO4 and evaporated to afford the crude product,
which was triturated by ethyl acetate/diethyl ether to afford 33.4 mg
(63%, 5 steps overall yield) of desired N-(5-phenyl-1,3,4-oxadiazol-2-
1
13a. H NMR (500 MHz, DMSO): δ 13.31 (s, 1H), 8.37 (d, J = 8.4
Hz, 2H), 8.28 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 8.0 Hz, 2H), 7.69 (t, J =
7.1 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H). 13C NMR (126 MHz, DMSO):
δ 165.3, 160.6, 160.0, 148.2, 135.9, 133.1, 131.2, 128.6, 128.4, 128.0,
124.5. LC-MS (ESI): m/z = 327.1 [M + H]+. HRMS (ESI) calcd for
C15H11N4O3S [M + H]+: 327.0546; found 327.0539.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
yl)benzamide 8a. H NMR (500 MHz, DMSO): δ 12.19 (s, 1H),
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.5b00140.
8.16−7.89 (m, 4H), 7.75−7.44 (m, 6H). 13C NMR (126 MHz,
DMSO): δ 165.5, 161.7, 158.4, 133.4, 132.7, 132.3, 123.0, 129.2, 128.8,
126.6, 123.8. LC-MS (ESI): m/z = 263.9 [M − H]−. HRMS (ESI)
calcd for NaC15H12N3O2 [M + Na]+: 288.0743, found 288.0750.
Representative Procedure for the Preparation of 2-Amino-1,3,4-
thiadiazole Resin 9. A mixture of p-nitro-substituted thiosemicarba-
zide resin 3 (6.00 g, 5.8 mmol) and p-TsCl (3.32 g, 17.4 mmol) in
NMP (30 mL) was stirred at room temperature for 12 h. The resin
was filtered and washed several times with MeOH, H2O, and CH2Cl2
and then dried in a vacuum oven. Resin 9 was obtained as a brown
Full analytical data of compounds, along with copies of
1H NMR, 13C NMR, LC/MS, and HRMS spectra of all
synthesized compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
solid. Single-bead ATR-FTIR: 3026, 2924, 2850, 1600, 1521(NO2),
−1
1505, 1489, 1341(NO2), 1190, 1156, and 853 cm
.
*E-mail: ydgong@dongguk.edu.
H
DOI: 10.1021/acscombsci.5b00140
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
(4) (a) El-Emam, A. A.; Al-Deeb, O. A.; Al-Omar, M.; Lehmann, J.
Synthesis, antimicrobial, and anti-HIV-1 activity of certain 5-(1-
adamantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-adamantyl)-
3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones. Bioorg. Med.
Chem. 2004, 12, 5107−5113. (b) Dogan, H. N.; Duran, A.; Rollas, S.;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Sener, G.; Uysal, M. K.; Gulen, D. Synthesis of new 2,5-Disubstituted-
This research was supported by the Bio & Medical Technology
Development Program of the National Research Foundation
(NRF) funded by the Ministry of Science, ICT & Future
Planning (No. 2014M3A9A9073847). And this research was
also financially supported by the Ministry of Trade, Industry &
Energy (MOTIE), and the Korea Institute for Advancement of
Technology (KIAT) through the industrial infrastructure
program for fundamental technologies (Grant Number
M0000338).
̈
1,3,4-thiadiazoles and preliminary evaluation of anticonvulsant and
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DOI: 10.1021/acscombsci.5b00140
ACS Comb. Sci. XXXX, XXX, XXX−XXX