Solid-Phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin

Article abstract of DOI:10.1021/acscombsci.6b00071

A 1,3,4-thiadiazole library was constructed by solid-phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using

Full text of DOI:10.1021/acscombsci.6b00071

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Article
Solid-phase Synthesis of 1,3,4-Thiadiazole Derivatives via
Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin
Seung-Ju Yang, Ji-Hye Choe, and Young-Dae Gong
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00071 • Publication Date (Web): 30 Jun 2016
Downloaded from http://pubs.acs.org on July 5, 2016
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Solid-phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative
Cyclization of Thiosemicarbazide Intermediate Resin
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SeungꢀJu Yang,† JiꢀHye Choe,† YoungꢀDae Gong*
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Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong Jung-gu, Seoul 100-715, Korea
†These authors contributed equally to this work.
Abstract A 1,3,4ꢀthiadiazole library was constructed by solidꢀphase organic synthesis. The key step
of this solidꢀphase synthesis involves the preparation of polymerꢀbound 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀ
thiadiazole resin by the cyclization of thiosemicarbazide resin using pꢀTsCl as the desulfurative
agent, followed by the functionalization of the resin by alkylation, acylation, alkylation/acylation,
and Suzuki coupling reactions. Both the alkylation and acylation reactions chemoselectively
occurred at the 2ꢀamide position of 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazole resin and the 5ꢀamine
position of 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazole resin, respectively. Finally, these functionalized 1,3,4ꢀ
thiadiazole resins were treated with trifluoroacetic acid in dichloromethane, affording diverse 1,3,4ꢀ
thiadiazole analogs in high yields and purities. The 1,3,4ꢀthiadiazole analogs show a different
distribution of physicochemical and biological properties compared to our previously constructed
1,3,4ꢀoxadiazole and 1,3,4ꢀthiadiazole libraries in a range of orally available drug properties.
KEYWORDS: Solidꢀphase, BOMBA, Thiosemicarbazide, 1,3,4ꢀthiadiazole
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Introduction
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Solidꢀphase synthesis has emerged as a powerful tool in medicinal chemistry owing to its capability
to rapidly generate a massive number of small organic molecules.1 Among these small molecules,
heterocyclic compounds are now used to yield potent and selective drugs having unique
pharmacophores.2 Especially, fiveꢀmembered ring heterocycles have showed wide range of
intriguing biological activities. In this family, 1,3,4ꢀthiadiazole and 1,3,4ꢀoxadiazole derivatives have
shown potent biological activity such as antiꢀinflammatory,3 antimicrobial,4 anticonvulsant,5
anticancer,6 and antihypertensive7 in medicinal chemistry areas. The term bioisostere has been used
in medicinal chemistry area, because it frequently exhibits enhanced biological activity or
physicochemical property without significant changes in the chemical structure.8 Along these lines,
1,3,4ꢀthiadiazole and 1,3,4ꢀoxadiazole have been considered as a bioisostere for each other in drug
design. Lee et al. compared the binding affinity of compounds containing 1,3,4ꢀoxadiazole or 1,3,4ꢀ
thaidiazole in the same chemical structure toward CB1 receptor in the process of developing an
obesity drug.9 Both 1,3,4ꢀoxadiazoles and 1,3,4ꢀthiadiazoles were also used for the development
potent antibacterial agents by Kumar et al.10 Asai et al. reported a dramatic difference in the binding
affinity between identically substituted 1,3,4ꢀoxadiazoles and 1,3,4ꢀthiadiazoles toward signal
transducers and activators of transcription.11 Because of these biologically interesting properties of
1,3,4ꢀthiadiazoles and 1,3,4ꢀoxadiazoles, these core skeletons have been targeted for synthesis by
organic and medicinal chemists, and as a result, many synthetic methodologies have been reported in
the literature.12 Among these synthetic methodologies, solidꢀphase synthesis effectively facilitates
the rapid generation of various 1,3,4ꢀthiadiazoles and 1,3,4ꢀoxadiazoles.13 In our previous research,
we have also developed solidꢀphase synthetic methodologies to produce 1,3,4ꢀoxadiazoles and 1,3,4ꢀ
thiadiazoles.14 Unfortunately our methodology was limited to the synthesis of pꢀnitro substituted
1,3,4ꢀthiadiazole derivatives (Scheme 1a). To improve over methodology, we attempted to develop a
new intermediate to afford various 1,3,4ꢀthiadiazoles. As shown in Scheme 1b, we designed a new
thiosemicarbazide key intermediate, and herein, we report our research progress in this area,
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including a desulfurative cyclization process to generate various 1,3,4ꢀthiadiazole derivatives with a
high level of diversity via solidꢀphase synthesis.
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Scheme 1 Strategy used to generate various 1,3,4ꢀthiadiazole analogs
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Results and Discussion
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Scheme 2. Synthesis of 1,3,4ꢀthiadiazole analog by solidꢀphase synthesis
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aReaction conditions: (a) CS2, pꢀTsCl, TEA, Tetrahydrofuran, rt, 18 h (b) Hydrazine, DMSO, 50 °C, 4 h (c) Acyl
isothiocyanate, Tetrahydrofuran, rt, 3 h (d) pꢀTsCl, Pyridine, DCM, rt, 5 h (e) Alkyl halide, NaH, DMF, 60 °C, 16 h (f)
TFA : DCM (1:4, v/v), 40 °C, 4 h (g) Acid chloride, Pyridine, rt, 16 h (h) TFA : DCM (1:4, v/v), rt, 4 h (i) Boronic acid,
K3PO4, Pd(PPh3)4, 1,4ꢀDioxane : H2O (9:1), 80 °C, 20 h
Based on solidꢀphase parallel synthesis, the synthetic route used to prepare 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀ
thiadiazole and its derivatives 7, 9, 11, 13 and 15 is outlined in Scheme 2. To synthesize
thiosemicarbazide intermediate 4, 4ꢀbenzyloxyꢀ2ꢀmethoxybenzylamine (BOMBA) resin 1 was used
as the starting material. The reaction of resin 1 with CS2, pꢀTsCl, and triethylamine (TEA) in
tetrahydrofuran (THF) generated isothiocyanate terminated resin 2,15 and the formation of resin 2
was confirmed by its attenuated total reflection (ATR) single bead Fourier transform infrared (FTIR)
spectrum, showing the presence of a typical isothiocyanate peak at 2071 cmꢀ1 (Figure 3b in the
Supporting Information). After the treatment of resin 2 with hydrazine in dimethyl sulfoxide
(DMSO), the typical isothiocyanate peak at 2071 cmꢀ1 disappeared (Figure 3c in the Supporting
Information). The following reaction of hydrazinecarbothioamide resin 3 with several acyl
isothiocyanates in THF formed thiosemicarbazide resin 4 as the key intermediate, whose ATRꢀFTIR
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spectrum showed the amide peak at 1677 cmꢀ1 (Figure 3d in the Supporting Information). As a result,
various thiosemicarbazide resins 4 equipped with electron donating groups, electron withdrawing
groups, and aliphatic groups at the R1 position were obtained. Next, thiosemicarbazide resin 4 was
reacted with pꢀTsCl and pyridine in dichloromethane (DCM) to afford 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀ
thiadiazole resin 5 via desulfurative cyclization process, and its FTIR spectrum showed a shift of the
amide peak from 1677 cmꢀ1 to 1664 cmꢀ1 (Figure 3e in the Supporting Information). For effective
diversification, 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazole resin 5 was reacted with various alkyl halides in
the presence of sodium hydride (NaH) in N,Nꢀdimethyl formamide (DMF) at 60 °C for 16 h, and
various alkyl groups were chemoselectively introduced at the 2ꢀamide position instead of the 5ꢀ
amine position. The chemoselectivity of the alkylation reaction was investigated by HPLC and
COSY analysis (Pages 2–7, the Supporting information). Consequently, alkyl substituted 2ꢀamidoꢀ5ꢀ
aminoꢀ1,3,4ꢀthiadiazole resin 6 was successfully generated. To release our desired 2ꢀamidoꢀ5ꢀ
aminoꢀ1,3,4ꢀthiadiazole analog 7 from the solid support, the resin 6 was treated with TFA:DCM (1:4,
v/v) at 40 °C for 4 h (The LC/MS spectrum of the crude product mixture 7a is shown in Figure 1 of
the Supporting Information). As a result, 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazole analogs 7 were
obtained in good yields and high purities (Table 1).
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Table 1. Yields and purities of the 2ꢀN-alkylamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazole derivatives 7
Yield
per step
(%)a
Yield
per step
(%)a
Purity
(%)b
Purity
No
R1
R2
No
R1
R2
(%)b
Ph
Ph
Ph
Ph
81.4
82.3
74.4
78.3
100
100
96
Ph
Ph
Ph
Ph
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85.1
86.2
71.2
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7b
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Ph
Ph
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66.9
98
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71.2
78.8
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100
100
7f
7o
7p
Ph
74.4
100
78.3
89
7g
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Ph
Ph
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77.7
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aAverage yield per step calculated over six steps (loading capacity of resin 1 is 1.15 mmol/g). All the purified products
b
7
were checked by LC/MS.
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Next, we tried to synthesize 2ꢀamidoꢀ5ꢀamidoꢀ1,3,4ꢀthiadiazole resin 8. Various acid chlorides were
used to chemoselectively introduce diverse amide functionality at the amine position of resin 5 at 60
°C for 16 h in neat pyridine (Each 1H NMR spectrum of 2,5ꢀdiꢀamidoꢀ1,3,4ꢀthiadiazoles 9 confirmed
the chemoselective substitution at the amine position). To obtain 2,5ꢀdiamidoꢀ1,3,4ꢀthiadiazole
analogs 9, resin 8 was treated with TFA:DCM (1:4, v/v) at room temperature for 4 h. As a result,
2,5ꢀdiamidoꢀ1,3,4ꢀthiadiazole analogs 9 were obtained in good yields and high purities (Table 2).
Table 2. Yields and purities of the 2,5ꢀdiamidoꢀ1,3,4ꢀthiadiazole derivatives 9
Yield
per step
(%)a
Yield
per step
(%)a
Purity
(%)b
Purity
No
R1
R3
No
R1
R3
(%)b
Ph
Ph
Ph
Ph
Ph
75.8
75.1
77.1
74.4
79.9
91
85
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97
91
Ph
Ph
Ph
Ph
Ph
68.1
69.2
69.2
68.1
68.1
98
99
98
95
93
9a
9b
9c
9d
9e
9j
9k
9l
9m
9n
Ph
Ph
79.4
83.9
94
91
77.7
77.7
71.2
81
61
96
9f
9o
9p
9q
9g
Ph
Ph
69.2
74.4
92
96
9h
9i
b
aAverage yield per step calculated over six steps (loading capacity of resin 1 is 1.15 mmol/g). All the purified products
were checked by LC/MS.
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To maximize the structural diversity of 1,3,4ꢀthiadiazole core skeleton, alkyl and acyl groups were
introduced at the amide and amine positions, respectively. First, resin 5 was reacted with alkyl halide
in the presence of sodium hydride NaH in DMF at 60 °C for 16 h to afford resin 6, and subsequently
acyl groups were introduced at 60 °C for 16 h in neat pyridine. As a result, 2,5ꢀdiamidoꢀ1,3,4ꢀ
thiadiazole resin 10 functionalized at the amide and amine positions were obtained. To afford 2,5ꢀ
diamido 1,3,4ꢀthiadiazole analog 11, resin 10 was treated with TFA:DCM (1:4, v/v) at room
temperature for 4 h. The yields and purities are summarized in Table 3.
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Table 3. Yields and purities of the 2ꢀN-alkylamidoꢀ5ꢀamidoꢀ1,3,4ꢀthiadiazole derivatives 11
Yield
R3
Purity
R1
R2
per step
No
(%)b
(%)a
Ph
Ph
Ph
72
100
11a
11b
11c
80
98
99
66.9
Ph
Ph
Ph
79.5
73.9
68.4
98
99
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11e
11f
100
Ph
Ph
68.4
68.4
79.5
73.9
73
95
97
11g
11h
11i
100
99
11j
100
11k
aAverage yield per step calculated over seven steps (loading capacity of resin 1 is 1.15 mmol/g). bAll the
purified products were checked by LC/MS.
For further diversification of the 1,3,4ꢀthiadiazole core skeleton, the R1 position was functionalized
by Suzuki coupling reaction. Resins 6 and 8 equipped with aryl iodine at the R1 position were
reacted with various boronic acids in the presence of K3PO4 and Pd(PPh)3 in 1,4ꢀdioxane and water
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(9:1, v/v) to produce Suzukiꢀcoupled resins 12 and 14, respectively, followed by the cleavage
reaction in TFA:DCM (1:4, v/v) at 40 °C for 4 h or in TFA:DCM (1:4, v/v) at room temperature for
4 h. As a result, Suzukiꢀcoupled products 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazoles 13 and 2,5ꢀdiamidoꢀ
1,3,4ꢀthiadiazoles 15 were obtained. The yields and purities are listed in Table 4.
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Table 4. Yields and purities of the N-(5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)ꢀN-isopentylbiphenylꢀ3ꢀ
carboxamide 13 and N-(5ꢀ(3ꢀchlorobenzamido)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)biphenylꢀ3ꢀcarboxꢀ
amide 15
Yield
per step
(%)a
Yield
per step
(%)a
Purity
(%)b
Purity
(%)b
No
R2
R4
No
R3
R4
81.6
98
100
98
73
52
91
65
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13b
13c
15a
15b
15c
80
73.9
80
66.9
b
aAverage yield per step calculated over seven steps (loading capacity of resin 1 is 1.15 mmol/g). All the purified
products were checked by LC/MS.
In the drug discovery process, the development of orally available drug is very important, and
Lipinski’s Rule16 and biological parameters have been used as guidelines to determine orally
available drug property. In this respect, physicochemical and biological parameters such as
molecular weight, ALogP, number of rotatable bonds, polar surface area, and number of hydrogen
bond acceptors and donors are displayed and compared to those of our previously constructed 1,3,4ꢀ
oxadiazole and 1,3,4ꢀthiadiazole library14 in Figure 1. As shown in this data, in the case of molecular
weight, ALogP, and number of rotatable bonds, our present library (blue) showed a better
distribution in a range of those predicted for reasonable orally bioavailable drugs than the previous
library (red), whereas it showed a slightly narrower range of distribution in the polar surface area,
and both libraries showed a similar distribution in the number of hydrogen bonding acceptors and
donors.
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Figure 1. Calculation and comparison of physicochemical and biological properties for our present
and previous libraries
In conclusion, we established a solidꢀphase synthetic method to construct a 1,3,4ꢀthiadiazole library.
This method involves a desulfurative cyclization process of thiosemicarbazide resin 4 to afford
1,3,4ꢀthiadiazole core skeleton resin 5 and various functionalization reactions to maximize the
structural diversity by reactions such as alkylation, acylation, alkylation/acylation, and Suzukiꢀ
coupling reactions. In the functionalization reactions, various alkyl groups were chemoselectively
introduced at the 2ꢀamide position of 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀthiadiazole resin 5, and various acyl
groups were chemoselectively introduced at the 5ꢀamine position of 2ꢀamidoꢀ5ꢀaminoꢀ1,3,4ꢀ
thiadiazole resin 5. Furthermore, physicochemical and biological properties of 1,3,4ꢀthiadiazole
library were calculated and compared to those of our previous library. As a result, our present library
showed a different distribution of physicochemical and biological properties compared to that of our
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previous library in a range of bioavailable drug property by Lipinski’s Rule and parameters.
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Experimental
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General procedure for synthesis All the chemicals were reagent grade and used as purchased.
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Reactions were monitored by ATRꢀFTIR. Flash column chromatography was carried out on silica gel
1
(230–400 mesh). H NMR and 13C NMR spectra were recorded in
δ units relative to deuterated
solvent as the internal reference using a 500 MHz NMR instrument. Liquid chromatography tandem
mass spectrometry analysis was performed using an electrospray ionization (ESI) mass spectrometer
with photodiodeꢀarray detector (PDA) detection. Highꢀresolution mass spectrometry spectra were
obtained using a TOF LC/MS system.
Representative procedure for the preparation of isothiocyanateterminated resin 2
A mixture of BOMBA resin 1 (5.00 g, 5.80 mmol) and Et3N (5.86 g, 58.0 mmol) in THF (30.0mL)
was added to CS2 (2.65 g, 34.8 mmol) at 0
°C, and then the reaction mixture was stirred at room
temperature for 3 h. The mixture was cooled down to 0
°C, followed by adding pꢀTsCl (5.53 g, 29.0
mmol). The reaction mixture was stirred at room temperature for 15 h. The precipitate obtained by
the filtration of the mixture was stirred at room temperature, washed with THF, H2O, MeOH, and
CH2Cl2, and dried in a vacuum oven, affording resin 2 as a brown solid. SingleꢀBead ATRꢀFTIR:
3022, 2920, 2072 (N=C=S), 1604, 1505, 1450, 1266, 1195, 1159, 1122, 1033, 818, 734, and 697 cmꢀ
1
.
Representative procedure for the preparation of hydrazinecarbothioamide resin 3
A mixture of isothiocyanate resin 2 (5.28 g, 5.80 mmol) and hydrazine (1.86 g, 58.0 mmol) in
DMSO (20.0 mL) was stirred at 50 °C for 4 h. The resin was filtered and washed several times with
DMSO, THF, H2O, MeOH, and CH2Cl2 and then dried in a vacuum oven. Resin 3 was obtained as a
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yellow brown solid. SingleꢀBead ATRꢀFTIR: 3025, 2917, 1606, 1503, 1491, 1450, 1419, 1282, 1265,
1194, 1158, 1125, 1028, 818, 733, and 697cmꢀ1.
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2
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4
5
6
7
8
Representative procedure for the preparation of thiosemicarbazide resins 4a
9
A mixture of hydrazinecarbothioamide resin 3 (5.47 g, 5.80 mmol) and benzoyl isothiocynate (3.79 g,
23.2 mmol) in THF (20 mL) was stirred at room temperature for 3 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. SingleꢀBead ATRꢀFTIR: 3025, 2920, 1684 (C=O), 1600, 1506, 1449,
1419, 1254, 1194, 1159, 1124, 1028, 733, and 697 cmꢀ1.
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Representative procedure for the preparation of 2-N-alkylamido-5-amino-1,3,4-thiadiazole
resin 5a
A mixture of thiosemicarbazide resin 4a (6.42 g, 5.80 mmol), pꢀTsCl (3.32 g, 17.4 mmol) and
pyridine (1.38 g, 17.4 mmol) in CH2Cl2 (30.0 mL) was stirred at room temperature for 5 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. SingleꢀBead ATRꢀFTIR: 3022, 2925, 1663 (C=O),
1577, 1505, 1450, 1264, 1195, 1160, 1123, 1028, 823, 733, and 697 cmꢀ1.
Representative procedure for the preparation of 2-N-alkylamido-5-amino-1,3,4-thiadiazole
resin 6a
A mixture of 2,5ꢀaminoꢀ1,3,4ꢀthiadiazole resin 5a (214 mg, 0.2 mmol) in DMF (2.00 mL) was added
sodium hydride (32.0 mg, 0.8 mmol) at room temperature. The resulting mixture was stirred at room
temperature for 1 h. Benzyl chloride (127 mg, 1.00 mmol) was added to the reaction mixture and
stirred at 60 °C for 12 h. The resin was filtered and washed several times with MeOH, H2O, and
CH2Cl2 and then dried in a vacuum oven. Resin 6a was obtained as a brown solid. SingleꢀBead ATRꢀ
FTIR: 3025, 2923, 1673 (C=O), 1601, 1492, 1450, 1381, 1286, 1264, 1196, 1159, 1114, 1020, 818,
733, and 697 cmꢀ1.
Representative procedure for the preparation of
N-(5-amino-1,3,4-thiadiazol-2-yl)-N-
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benzylbenzamide 7a
Resin 6a (232 mg, 0.2 mmol) was treated with a mixture of TFA/CH2Cl2 (1:4, v/v) at 40
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4
°C for 4 h.
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6
7
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The resin was filtered and then washed several times with CH2Cl2 and MeOH. The organic filtrate
was neutralized to pH 6–7 with a saturated aqueous NaHCO3 solution and then extracted with
CH2Cl2 and H2O. The aqueous layer was backꢀextracted with CH2Cl2. The combined organic layers
were dried over anhydrous MgSO4 and evaporated to obtain the crude product, which was purified
diethyl ether/hexane (1:1) to obtain 18.0 mg (81.4%, average yield per step calculated over six steps)
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of the desired Nꢀ(5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)ꢀNꢀbenzylbenzamide 7a. H NMR (500 MHz,
DMSO) δ 8.21 (d, J = 7.1 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.39–7.33 (m,
4H), 7.33–7.29 (m, 1H), 7.14 (s, 2H), 5.44 (s, 2H). 13C NMR (126 MHz, DMSO) δ 172.4, 161.8,
159.1, 136.8, 136.7, 132.1, 129.3, 129.1, 128.7, 128.6, 128.3, 53.2, LCꢀMS (ESI): m/z = 309.1 [Mꢀ
H]ꢀ. HRMS (ESI) calcd for C16H14N4OS [M + H]+: 311.0961, found: 311.0961.
Representative procedure for the preparation of 2,5-diamido-1,3,4-thiadiazole resin 8a
A mixture of 2,5ꢀaminoꢀ1,3,4ꢀthiadiazole resin 5a (214 mg, 0.2 mmol) in Pyridine (2.00 mL) was
added Benzoyl chloride(140 mg, 1.0 mmol) The resulting mixture was stirred at 60 oC for 12 h. The
resin was filtered and washed several times with MeOH, H2O, and CH2Cl2 and then dried in a
vacuum oven. Resin 8a was obtained as a brown solid. SingleꢀBead ATRꢀFTIR : 3023, 2919, 1671,
1600, 1506, 1449, 1373, 1262, 1195, 1158, 1114, 1024, 817, 749 and 696cm ꢀ1.
Representative procedure for the preparation of
9a
N,N'-(1,3,4- thiadiazole-2,5-diyl)dibenzamide
A resin 8a (235 mg, 0.2 mmol) was treated with a mixture of TFA/CH2Cl2 (1:4, v/v) at rt for 4 h. The
resin was filtered and then washed several times with CH2Cl2 and MeOH. The organic filtrate was
neutralized to pH 6ꢀ7 with a saturated NaHCO3 aqueous solution and then extracted with CH2Cl2
and H2O. The aqueous layer was backꢀextracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and evaporated to obtain the crude product, which was purified by column
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chromatography on silica gel (hexane/THF) to afford 12.0 mg (75.8%, average yield per step
1
2
3
1
calculated over six step) of desired N,N'ꢀ (1,3,4ꢀthiadiazoleꢀ2,5ꢀdiyl)dibenzamide 9a. H NMR (500
4
5
6
7
8
MHz, DMSO) δ 12.75 (s, 2H), 8.12 (d, J = 7.4 Hz, 4H), 7.67 (t, J = 7.4 Hz, 2H), 7.57 (t, J = 7.6 Hz,
13
4H). C NMR (126 MHz, DMSO) δ 165.5, 156.4, 133.3, 132.2, 129.1, 128.8. LCꢀMS (ESI): m/z =
9
323.1 [MꢀH] ꢀ . HRMS (ESI) calcd for C16H12N4O2S [M + Na]+ : 347.0573, found :347.0574.
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Representative procedure for the preparation of 2-N-alkylamido-5-amido-1,3,4-thiadiazole
resin 10a A mixture of 2ꢀNꢀalkylamidoꢀ5ꢀlaminoꢀ1,3,4ꢀthiadiazole resin 6a (232 mg, 0.2 mmol) in
Pyridine (2.00 mL) was added Benzoyl chloride (140 mg, 1.0 mmol) The resulting mixture was
o
stirred at 60 C for 12 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. SingleꢀBead
ATRꢀFTIR : 3021, 2924, 1664(C=O), 1600, 1493, 1449, 1371, 1269, 1194, 1159, 1110, 1026, 823,
761 and 696 cm ꢀ1 .
Representative procedure for the preparation of
N-(5-benzamido-1,3,4-thiadiazol-2-yl)-N-
benzylbenzamide 11a A resin 10a (253 mg, 0.2 mmol) was treated with a mixture of TFA/CH2Cl2
(1:4, v/v) at rt for 4 h. The resin was filtered and then washed several times with CH2Cl2 and MeOH.
The organic filtrate was neutralized to pH 6ꢀ7 with a saturated NaHCO3 aqueous solution and then
extracted with CH2Cl2 and H2O. The aqueous layer was backꢀextracted 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) to afford 8.28 mg (72%, average
yield per step calculated over seven steps) of desired Nꢀ(5ꢀbenzamidoꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)ꢀNꢀ
1
benzylbenzamide 11a. H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.28 (d, J = 7.2 Hz, 2H), 8.08
(d, J = 7.5 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.61 – 7.54 (m, 3H), 7.53 (d, J = 4.9 Hz, 1H), 7.51 (d, J
= 7.3 Hz, 1H), 7.42 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.1 Hz, 1H), 5.66 (s,
2H). 13C NMR (126 MHz, DMSO) δ 173.3, 166.4, 163.7, 152.3, 136.5, 136.4, 133.6, 132.5, 131.8,
129.5, 129.2, 129.1, 128.9, 128.8, 128.5, 128.5, 53.5. LCꢀMS (ESI): m/z = 413.2 [MꢀH]ꢀ. HRMS
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(ESI) calcd for C23H18N4O2S [M + Na]+ : 437.1043, found :437.1044.
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Representative procedure for the preparation of
isopentylbiphenyl-3-carboxamide resin 12a
N-(5-(ethylamino)-1,3,4-thiadiazol-2-yl)-N-
9
A resin 6r (127 mg, 0.1 mmol) was added successively K3PO4 (106.14 mg, 0.5 mmol),
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Phenylboronic acid (60.9 mg, 0.5 mmol) in 1,4ꢀDioxane : H2O(9:1), and Pd(PPh3)4 (23.1 mg, 0.02
o
mmol) was added under nitrogen atmosphere. The mixture was shaken for 20 h at 80 C. Nꢀ(5ꢀ
aminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)ꢀNꢀisopentylbiphenylꢀ3ꢀcarboxamide resin 12a was filtered and washed
with H2O, MeOH, and CH2Cl2 and dried in a vacuum oven. This process made resin 12a as a dark
brown solid. SingleꢀBead ATRFTIR :3023, 2926, 2864, 1669(C=O), 1588, 1491, 1449, 1419, 1387,
1313, 1258, 1193, 1157, 1115, 1026, 818, 744 and 695cm ꢀ1 .
Representative procedure for the preparation of
N-(5-amino-1,3,4-thiadiazol-2-yl)-N-
isopentylbiphenyl-3-carboxamide 13a A resin 12a (122 mg, 0.1 mmol) was treated with a mixture
of TFA/CH2Cl2 (1:4, v/v) at 40 oC for 4 h. The resin was filtered and then washed several times with
CH2Cl2 and MeOH. The organic filtrate was neutralized to pH 6ꢀ7 with a saturated NaHCO3 aqueous
solution and then extracted with CH2Cl2 and H2O. The aqueous layer was backꢀextracted 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) to afford 8.8
mg (81.6%, average yield per step calculated over seven steps) of desired Nꢀ(5ꢀ aminoꢀ1,3,4ꢀ
1
thiadiazolꢀ2ꢀyl)ꢀNꢀisopentylbiphenylꢀ3ꢀ carboxamide 13a. H NMR (500 MHz, DMSO) δ 8.46 (s,
1H), 8.16 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.7 Hz,
1H), 7.50 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.14 (s, 2H), 4.29 (t, J = 7.0 Hz, 2H), 1.71 (dd,
J = 13.9, 6.9 Hz, 2H), 1.57 (dt, J = 13.1, 6.5 Hz, 1H), 0.97 (d, J = 6.6 Hz, 6H). 13C NMR (126 MHz,
DMSO) δ 171.9, 161.2, 159.2, 140.6, 140.3, 137.7, 130.3, 129.5, 129.4, 129.1, 128.2, 127.3, 127.2,
48.3, 37.0, 25.4, 22.7. MS (ESI): m/z = 365.2 [MꢀH]ꢀ. HRMS (ESI) calcd for C20H22N4OS [M + H]+ :
367.1587, found :367.1587.
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Representative procedure for the preparation of
thiadiazol-2-yl)biphenyl-3- carboxamide resin 14a
N-(5-(3-chloroN-ethylbenzamido)-1,3,4-
6
7
8
A resin 8r (267.3 mg, 0.2 mmol) was added successively K3PO4 (212.3 mg, 1.0 mmol),
9
Phenylboronic acid (121.9 mg, 1.0 mmol) in 1,4ꢀDioxane : H2O (9:1), and Pd(PPh3)4 (46.2 mg, 0.04
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o
mmol) was added under nitrogen atmosphere. The mixture was shaken for 20 h at 80 C. Nꢀ(5ꢀ(3ꢀ
chloroꢀNꢀethylbenzamido)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)biphenylꢀ3ꢀcarboxamide resin 14a was filtered and
washed with H2O, MeOH, and CH2Cl2 and dried in a vacuum oven. This process made resin 14a as
a dark brown solid. SingleꢀBead ATRꢀFTIR :3026, 2924, 2852, 1664(C=O), 1600, 1506, 1449, 1419,
1364, 1285, 1260, 1194, 1157, 1115, 1024, 899, 816, 747 and 696 cmꢀ1.
Representative procedure for the preparation of
yl)biphenyl-3-carboxamide 15a
N-(5-(3- chlorobenzamido)-1,3,4-thiadiazol-2-
A resin 14a (257 mg, 0.2 mmol) was treated with a mixture of TFA/CH2Cl2 (1:4, v/v) at rt for 4 h.
The resin was filtered and then washed several times with CH2Cl2 and MeOH. The organic filtrate
was neutralized to pH 6ꢀ7 with a saturated NaHCO3 aqueous solution and then extracted with
CH2Cl2 and H2O. The aqueous layer was backꢀextracted 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) to afford 9.6 mg (73%, average yield per step over
seven steps) of desired Nꢀ(5ꢀ(3ꢀ chlorobenzamido)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)biphenylꢀ3ꢀcarboxamide
15a. 1H NMR (500 MHz, DMSO) δ 12.89 (s, 2H), 8.48 (s, 1H), 8.19 (s, 1H), 8.09 (dd, J = 19.2, 7.7
Hz, 2H), 8.03 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.74 (d, J = 7.7
Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.1
Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H). 13C NMR (126 MHz, DMSO) δ 141.7, 140.9, 139.7, 137.1, 134.2,
133.9, 133.1, 131.2, 131.1, 129.9, 129.5, 129.1, 128.8, 128.6, 128.5, 128.2, 128.0, 127.6, 127.4,
126.8. MS (ESI): m/z = 433.2[MꢀH]ꢀ. HRMS (ESI) calcd for C23H17ClN4OS [M + H]+ : 435.0677,
found :435.0676.
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Acknowledgment This study was supported by the Bio & Medical Technology Development
Program of the National Research Foundation funded by the Ministry of Science, ICT & Future
Planning (No. 2014M3A9A9073847), the Ministry of Trade, Industry & Energy, and the Korean
Institute for Advancement of Technology through the industrial infrastructure program for
fundamental technologies (Grant Number M0000338).
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Supporting Information Available: Full analytical data of compounds, along with the copies of 1H
NMR, 13C NMR, LC/MS, and HRMS spectra of all the synthesized compounds; analytical data of
chemoselective alkylation reactions; the LC/MS spectra of the crude product mixture 7a and 9a. the
representative ATRꢀFTIR spectrum of the corresponding resins; this material is available free of
charge via the Internet at http://pubs.acs.org.
References
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and ꢀ1,2,4ꢀtriazoles as orally active, nonulcerogenic antiinflammatory agents. J. Med. Chem.
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and in Vivo Evaluations of Substituted Diꢀtertꢀbutylphenols as a Novel Class of Potent,
Selective, and Orally Active Cyclooxygenaseꢀ2 Inhibitors. 2. 1,3,4ꢀ and 1,2,4ꢀThiadiazole
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Chaturvedi, S. C. 2ꢀAminoꢀ5ꢀsulfanylꢀ1,3,4ꢀthiadiazoles: A new series of selective
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5ꢀ(1ꢀadamantyl)ꢀ3ꢀsubstituted aminomethylꢀ1,3,4ꢀoxadiazolineꢀ2ꢀthiones. Bioorg. Med.
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Solid-phase Synthesis of 1,3,4-Thiadiazole Derivatives via
Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin
Seung-Ju Yang,† Ji-Hye Choe,† 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
†These authors contributed equally to this work.
* Corresponding author. Tel. : +82-2-2260-3206, Fax : +82-2-2290-1349 ; e-mail: ydgong@dongguk.edu
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