Parallel synthesis of drug-like 5-amino-substituted 1,2,4-thiadiazole libraries using cyclization reactions of a carboxamidine dithiocarbamate linker

Article abstract of DOI:10.1055/s-0028-1087970

A general method has been developed for the solution-phase parallel synthesis of various drug-like 5-amino-substituted 1,2,4-thiadiazole derivatives, which employs initial cyclization reaction of carboxamidine dithiocarbamate 2 with p-toluenesulfonyl chlo

Full text of DOI:10.1055/s-0028-1087970

PAPER
913
Parallel Synthesis of Drug-like 5-Amino-Substituted 1,2,4-Thiadiazole
Libraries Using Cyclization Reactions of a Carboxamidine Dithiocarbamate
Linker
P
arallel Sy
o
nthesis of
D
o
rug-like 5-Amino-S
Y
ubstituted 1,2,4-T
e
hiadiazole
o
L
ibrarie
s
n Park,a,b In Ae Ryu,a,b Ji Hoon Park,a Duck Chan Ha,b Young-Dae Gong*a
a
Center for High Throughput Synthesis Platform Technology, Korea Research Institute of Chemical Technology,
P.O. Box 107, Yuseong, Daejon 305-600, Korea
Department of Chemistry, Korea University, Sungbuk-gu, Seoul 136-701, Korea
Fax +82(42)8607698; E-mail: ydgong@krict.re.kr
b
Received 14 October 2008; revised 19 November 2008
1,2,4-thiadiazole derivatives (Scheme 1). However, meth-
ods to readily introduce 5-amino substituents onto a pre-
existing 1,2,4-thiadiazole backbone have not been fully
explored. As a matter of fact, for this reason most of the
Abstract: A general method has been developed for the solution-
phase parallel synthesis of various drug-like 5-amino-substituted
1,2,4-thiadiazole derivatives, which employs initial cyclization re-
action of carboxamidine dithiocarbamate 2 with p-toluenesulfonyl
chloride. The carboxamidine dithiocarbamate 2 was produced by a known 5-amino-substituted 1,2,4-thiadiazole have been
prepared by reactions of phenyl thiocyanate.9 Unfortu-
three-component nucleophilic substitution reaction between carbon
disulfide, benzamidine 1, and benzyl chloride. The key intermediate
in this sequence, 5-(benzylsulfanyl)-3-phenyl-1,2,4-thiadiazole (3),
1,2,4-thiadiazoles can be prepared by using the phenyl
is then transformed to the desired 5-amino-substituted 3-phenyl-
nately, only a limited number of 5-amino-substituted
thiocyanate based strategy. Consequently, procedures to
1,2,4-thiadiazoles 6 in good yields and purities via oxidation of the
produce 5-hydroxy- or 5-sulfanyl-substituted 1,2,4-thia-
diazoles starting with carbon disulfide are rare.10 Thus, the
goal of the current study was to uncover simple and effi-
cient parallel synthetic methods to produce various 5-ami-
no-substituted 1,2,4-thiadiazole derivatives in order to
uncover novel hit compounds that would be active toward
multiple biological targets. Selection of the 5-amino-
1,2,4-thiadiazole targets was based on consideration of
the physicochemical properties that would lead to in-
creased biological activity.11
sulfide group to form the corresponding sulfone followed by substi-
tution reactions with various amines.
Key words: parallel synthesis, drug-like properties, 5-amino-1,2,4-
thiadiazole, dithiocarbamate linker
Heterocyclic skeletons serve as ideal scaffolds on which
pharmacophores can be appended to yield potent and se-
lective drugs.1 This is especially true for five-membered
heterocyclic compounds, which are core components of a
large number of substances that possess a wide range of
interesting biological activity. In this respect, the potential
of the thiadiazole scaffold to serve as a privileged struc-
ture for the generation of drug-like libraries in drug dis-
covery programs has been amply demonstrated.2 In this
heterocycle family, 1,2,4-thiadiazoles have been used as
the basic framework for substances of interest in numer-
ous therapeutic areas, for example, as anti-inflammatory,3
antimicrobial,4 anticonvulsant,5 and antihypertensive
agents.6 As a part of a research program aimed at drug dis-
covery and high throughput organic synthesis, we needed
to develop a facile and rapid parallel approach for the con-
struction of drug-like small heterocyclic molecules.7 Our
concern was focused specifically on modulators of G-pro-
tein coupled receptors (GPCR), which have been identi-
fied as allosteric modulators of a wide variety of untreated
GPCR, including the human m-, d-, and k- and b-adrener-
gic, muscarinic M1 and M2, and dopaminergic D1 and D2
receptors.8 Since these types of modulators possess 3-phe-
nyl and 5-amino functionality, our efforts concentrated on
the construction of GPCR focused, 5-amino-substituted
Herein, we describe the results of an investigation that led
to the development of an efficient procedure for the syn-
thesis of drug-like 5-amino-substituted 1,2,4-thiadiazoles
that relies on the cyclization of carboxamidine dithiocar-
Me
N
S
N
N
Me
N
S
N
N
SCH-202676
MW: 269.36, A⋅log P: 3.87
MSA: 253.88
LUF 5792
MW: 283.39, A⋅log P: 4.35
MSA: 273.30
R1
R2
N
S
N
O
N
OMe
N
novelty with good
physico-chemical properties
NH
N
S
LUF 5417
MW: 311.36, A⋅log P: 3.09
MSA: 293.09
SYNTHESIS 2009, No. 6, pp 0913–0920
Advanced online publication: 24.02.2009
x
x
.
x
x
.2
0
0
9
MSA = molecular surface area
DOI: 10.1055/s-0028-1087970; Art ID: F21508SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

914
J. Y. Park et al.
PAPER
NH2
S
N
S
NH•HCl•xH2O
i
ii
N
S
N
S
NH2
1
2
3
iii
R2
R3
NH
iv
5
N
S
N
S
R2
O
N
S
N
N
R1
O
6
4
Scheme 2 Reagents and conditions: (i) Cs2CO3, CS2, BnCl, TBAI (cat.), THF, r.t., 24 h, 74%; (ii) TsCl, Et3N, DCE, 60 °C, 24 h, 99%; (iii)
MCPBA, CH2Cl2, r.t., 2 h, 99%; (iv) Et3N, amine 5, MeCN, 80 °C, 20 h.
bamate 2 with p-toluenesulfonyl chloride. The sequence tenuated total reflection (ATR) FT-IR spectrum
used for this purpose is outlined in Scheme 2. Benzami- (Figure 1).
dine dithiocarbamate 2, the key intermediate in this route,
was selected since it serves as the precursor of 5-(benzyl-
sulfanyl)-1,2,4-thiadiazole 3, which is readily converted
into the target 5-amino-substituted 1,2,4-thiadiazoles 6 by
Various methods were explored to promote the cycliza-
tion reaction of benzamidine dithiocarbamate 2. The
methods focused on the incorporation of proper nitrogen
leaving groups by reaction with various reagents (e.g.,
oxidation and reaction with various amines 5.
EDC·HCl, DCC, TMSCl, TsCl, Ph3P, SOCl2, PCl5, or
In the first step in the synthetic sequence, benzamidine diphenyl chlorophosphate) based on our previous re-
dithiocarbamate 2 was prepared by reaction of benzyl search results.12 This effort showed that the best reaction
chloride with benzamidine hydrochloride hydrate (1) in conditions for transforming 2 to 5-(benzylsulfanyl)-3-
the presence of carbon disulfide and cesium carbonate in phenyl-1,2,4-thiadiazole (3) involve treatment with p-tol-
tetrahydrofuran. Formation of the benzamidine dithiocar- uenesulfonyl chloride in the presence of triethylamine in
bamate 2 in this process was confirmed by the appearance 1,2-dichloroethane at 60 °C.
of the typical dithiocarbamate band at 1436 cm–1 in the at-
Table 1 Yields and Purities of the Desired Products 6
Product
R1R2NH
Yielda (%) Purityb (%)
Product
R1R2NH
Yielda (%) Purityb (%)
HN
6a
86
72
99
97
6y
21
55
94
HN
N
NO2
HN
6b
6c
6z
>99
H2N
H2N
O
HN
HN
79
98
6aa
56
>99
6d
6e
6f
75
35
65
88
71
91
6ab
6ac
6ad
OMe
66
77
75
>99
94
H2N
H2N
N
Me
NMe2
H2N
HN
O
82
H2N
H2N
NMe2
OMe
HN
NEt2
NEt2
6g
6h
57
74
>99
71
6ae
6af
70
72
94
99
Me
N
HN
Me
HN
Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York

PAPER
Parallel Synthesis of Drug-like 5-Amino-Substituted 1,2,4-Thiadiazole Libraries
915
Table 1 Yields and Purities of the Desired Products 6 (continued)
Product
R1R2NH
Yielda (%) Purityb (%)
Product
R1R2NH
Yielda (%) Purityb (%)
6i
67
64
80
82
>99
97
6ag
27
61
69
91
99
95
NMe2
H2N
H2N
N
N
HN
6j
6ah
6ai
HN
O
H2N
OH
6k
HN
HN
N
OMe
OMe
HN
Me
6l
72
75
76
>99
96
6aj
6ak
6al
52
55
64
>99
>99
>99
HN
Me
6m
6n
HN
HN
N
N
F
>99
N
N
H2N
6o
6p
53
65
>99
97
6am
6an
90
67
90
98
HN
N
Me
N
N
N
H
OMe
F
HN
Me
N
N
OMe
6q
6r
66
86
>99
83
6ao
6ap
56
60
>99
91
HN
N
F
H2N
H2N
HN
HN
N
O
MeO
6s
81
>99
6aq
65
95
N
H2N
H2N
S
OMe
6t
79
68
54
>99
94
6ar
6as
6at
51
80
86
98
>99
98
N
N
HN
HN
N
N
Ph
6u
6v
H2N
OMe
Ph
Cl
HN
98
HN
N
NC
O
O
H2N
6w
6x
68
32
>99
>99
6au
57
94
N
HN
HN
O
N
a Isolated yield.
b All of the crude products were checked by LC–MS.
Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York

916
J. Y. Park et al.
PAPER
Figure 1 ATR-FTIR spectra of intermediates [1 (A), 2 (B), 3 (C), and 4 (D) and product 6a (E)] in the 5-amino-substituted 1,2,4-thiadiazole
preparative sequence
Reaction of the 5-(benzylsulfanyl)-1,2,4-thiadiazole 1,2,4-thiadiazole derivatives 6 can be efficiently synthe-
dithiocarbamate 3 with 3-chloroperoxybenzoic acid in sized by a concise sequence involving the carboxamidine
dichloromethane at room temperature for two hours gave dithiocarbamate intermediate 2. Cyclization of 2, promot-
the desired 5-(benzylsulfonyl)-substituted 3-phenyl- ed by reaction with p-toluenesulfonyl chloride, followed
1,2,4-thiadiazole 4, which showed the typical sulfonyl by oxidation and reactions with amines provides the de-
stretching bands at 1323 and 1149 cm–1 (Figure 1). The sired 5-amino-substituted 3-phenyl-1,2,4-thiadiazole de-
target 5-amino-substituted 3-phenyl-1,2,4-thiadiazoles 6 rivatives 6 in good yields and high purities. Finally, the
are then produced by efficient substitution reactions of 4 calculated physicochemical properties of the libraries
with various drug-like amines 5 (Table 1) in the presence generated in this manner fall within drug-like ranges.
of triethylamine (MeCN, 80 °C, 20 h). As the data given
in Table 1 show, by using this sequence, 5-amino-substi-
tuted 3-phenyl-1,2,4-thiadiazoles 6 are furnished in good
yields and high purities.
Having established a flexible method for parallel synthe-
sis of 5-amino-substituted 3-phenyl-1,2,4-thiadiazole an-
alogues, our attention next turned to the evaluation of the
potential drug properties of members of this family. In
general, the goal of drug discovery efforts is to synthesize
substances that are orally bioavailable (i.e., they possess
physiological properties that enable absorption into the
gastrointestinal system).13 Of particular interest are the
key bioavailability parameters, including molecular
weight, lipophilicity, number of hydrogen bond donors
and acceptors, number of rotatable bonds, and polar sur-
face area. The results of these calculations are displayed
in Figure 2. As can be seen by viewing the data, all of the
key parameters for members of the constructed library fall
in the range of those predicted to be reasonable drugs by
using the commonly known rules.14
In conclusion, the results of the investigation described
above demonstrate that 5-amino-substituted 3-phenyl-
Figure 2 Calculated physicochemical properties of the 5-amino-
substituted 3-phenyl-1,2,4-thiadiazole 6 library
Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York

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Parallel Synthesis of Drug-like 5-Amino-Substituted 1,2,4-Thiadiazole Libraries
917
All reagents were obtained from commercial suppliers and used
without further purification. Reactions, filtration, and washings
were carried out on a multi-reactor (Heidolph Synthesis 1). Crude
products were purified by parallel chromatography using a silica-
cartridge. All of the intermediates were monitored by ATR-FTIR
before checking NMR and LC–MS. The structures of the final prod-
ucts were confirmed by using 1H NMR and 13C NMR spectroscopy.
LC–MS data were recorded on a Waters ZQ electrospray mass
spectrometer (EI) equipped with PDA (200–600 nm) detection us-
ing FortisTM MS column (C18, 5 mm, 4.6 × 100 mm).
H2O. The organic layer was dried (MgSO4) and concentrated in
vacuo. The residue was subjected to flash column chromatography
(n-hexane–EtOAc, 20:1) to give 6a (31 mg, 86%).
FT-IR (ATR): 1569 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.22–8.19 (m, 2 H), 7.44–7.39 (m,
3 H), 3.52 (m, 4 H), 2.09–2.04 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 180.9, 170.3, 133.7, 129.6, 128.3,
128.0, 49.9, 25.7.
LC–MS (ESI): m/z = 232 [M + H]+.
N1-[(Benzylsulfanyl)thiocarbonyl]benzamidine (2)
5-(Morpholin-4-yl)-3-phenyl-1,2,4-thiadiazole (6b)
1H NMR (500 MHz, CDCl3): d = 8.20–8.17 (m, 2 H), 7.44–7.40 (m,
3 H), 3.83 (t, J = 5.0 Hz, 4 H), 3.59 (t, J = 4.9 Hz, 4 H).
LC–MS (ESI): m/z = 248 [M + H]+.
A mixture of benzamidine hydrochloride hydrate (1, 1.00 g, 6.39
mmol) and Cs2CO3 (6.26 g, 19.2 mmol) in anhyd THF (10 mL) was
stirred at r.t. for 15 min. To the mixture was added successively CS2
(1.46 g, 19.2 mmol), BnCl (890 mg, 7.03 mmol), and TBAI (236
mg, 0.639 mmol) at r.t. The mixture was stirred at r.t. for 24 h and
partitioned between EtOAc and H2O. The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was subjected to
flash column chromatography (n-hexane–EtOAc, 20:1) to give 2
(1.35 g, 74%) as a yellow solid.
3-Phenyl-5-(piperidin-1-yl)-1,2,4-thiadiazole (6c)
1H NMR (500 MHz, CDCl3): d = 8.19–8.16 (m, 2 H), 7.42–7.37 (m,
3 H), 3.54 (m, 4 H), 1.71–1.68 (m, 6 H).
LC–MS (ESI): m/z = 246 [M + H]+.
FT-IR (ATR): 3297, 1601, 1436 cm–1.
5-(4-Methylpiperazin-1-yl)-3-phenyl-1,2,4-thiadiazole (6d)
1H NMR (500 MHz, CDCl3): d = 8.22–8.20 (m, 2 H), 7.46–7.42 (m,
3 H), 3.66 (t, J = 4.7 Hz, 4 H), 2.58 (t, J = 5.1 Hz, 4 H), 2.39 (s, 3 H).
LC–MS (ESI): m/z = 261 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 7.93–7.91 (m, 2 H), 7.58 (t, J = 7.4
Hz, 1 H), 7.49 (t, J = 7.7 Hz, 2 H), 7.39 (d, J = 7.3 Hz, 2 H), 7.30 (t,
J = 7.4 Hz, 2 H), 7.24–7.22 (m, 1 H), 4.50 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 217.1, 161.9, 136.6, 134.4, 132.8,
129.1, 129.0, 128.5, 127.6, 127.2, 40.2.
N-Cyclopropyl-3-phenyl-1,2,4-thiadiazol-5-amime (6e)
1H NMR (500 MHz, CDCl3): d = 8.15–8.13 (m, 2 H), 7.44–7.41 (m,
3 H), 6.89 (s, 1 H), 2.70–2.67 (m, 1 H), 0.84–0.80 (m, 2 H), 0.74–
0.71 (m, 2 H).
LC–MS (ESI): m/z = 287 [M + H]+.
5-(Benzylsulfanyl)-3-phenyl-1,2,4-thiadiazole (3)
To a soln of 2 (500 mg, 1.75 mmol) in DCE (5 mL) at r.t. was added
Et3N (354 mg, 3.50 mmol) and TsCl (400 mg, 2.10 mmol). The
mixture was stirred at 60 °C for 24 h, cooled, and partitioned be-
tween CH2Cl2 and H2O. The organic layer was dried (MgSO4) and
concentrated in vacuo. The residue was subjected to flash column
chromatography (n-hexane–EtOAc, 50:1) to give 3 (493 mg, 99%)
as a white solid.
LC–MS (ESI): m/z = 218 [M + H]+.
Methyl 1-(3-Phenyl-1,2,4-thiadiazol-5-yl)piperidine-4-carboxy-
late (6f)
1H NMR (500 MHz, CDCl3): d = 8.22–8.20 (m, 2 H), 7.46–7.42 (m,
3 H), 4.00 (d, J = 12.5 Hz, 2 H), 3.75 (s, 3 H), 3.34–3.28 (m, 2 H),
2.66–2.60 (m, 1 H), 2.11–2.06 (m, 2 H), 1.94–1.89 (m, 2 H).
1H NMR (500 MHz, CDCl3): d = 8.28–8.25 (m, 2 H), 7.46–7.41 (m,
5 H), 7.33–7.30 (m, 2 H), 7.28–7.26 (m, 1 H), 4.51 (s, 2 H).
LC–MS (ESI): m/z = 304 [M + H]+.
13C NMR (125 MHz, CDCl3): d = 186.6, 172.1, 135.4, 132.4, 130.3,
5-(Azepan-1-yl)-3-phenyl-1,2,4-thiadiazole (6g)
1H NMR (500 MHz, CDCl3): d = 8.21 (dd, J = 1.8, 7.8 Hz, 2 H),
7.42–7.40 (m, 3 H), 3.75–3.53 (m, 4 H), 1.86 (m, 4 H), 1.64–1.61
(m, 4 H).
129.0, 128.8, 128.6, 128.2, 128.0, 38.4.
LC–MS (ESI): m/z = 285 [M + H]+.
LC–MS (ESI): m/z = 260 [M + H]+.
5-(Benzylsulfonyl)-3-phenyl-1,2,4-thiadiazole (4)
To a soln of 3 (500 mg, 1.76 mmol) in CH2Cl2 (5 mL) at r.t. was
added MCPBA (986 mg, 4.40 mmol). The mixture was stirred at r.t.
for 2 h, washed with sat. aq NaHCO3 soln and brine, dried (MgSO4),
and concentrated in vacuo. The residue was subjected to flash col-
umn chromatography (n-hexane–EtOAc, 30:1) to give 4 (548 mg,
99%) as a white solid.
5-(4-Methyl-1,4-diazepan-1-yl)-3-phenyl-1,2,4-thiadiazole (6h)
1H NMR (500 MHz, CDCl3): d = 8.17–8.15 (m, 2 H), 7.42–7.37 (m,
3 H), 3.87–3.59 (m, 4 H), 2.80 (t, J = 4.8 Hz, 2 H), 2.68 (t, J = 5.3
Hz, 2 H), 2.41 (s, 3 H), 2.10–2.07 (m, 2 H).
LC–MS (ESI): m/z = 275 [M + H]+.
FT-IR (ATR): 1323, 1149 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.35–8.32 (m, 2 H), 7.56–7.51 (m,
3-Phenyl-5-[4-(pyrrolidin-1-yl)piperidin-1-yl]-1,2,4-thiadi-
azole (6i)
3 H), 7.37–7.29 (m, 3 H), 7.28–7.25 (m, 2 H), 4.76 (s, 2 H).
1H NMR (500 MHz, CDCl3): d = 8.20–8.17 (m, 2 H), 7.44–7.38 (m,
3 H), 3.98 (m, 2 H), 3.28–3.22 (m, 2 H), 2.68 (m, 4 H), 2.42–2.37
(m, 1 H), 2.03 (dd, J = 2.3, 12.8 Hz, 2 H), 1.86–1.83 (m, 4 H), 1.78–
1.69 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 185.4, 174.4, 131.5, 131.4, 131.1,
129.6, 129.1, 129.0, 128.6, 125.8, 61.3.
LC–MS (ESI): m/z = 317 [M + H]+.
LC–MS (ESI): m/z = 315 [M + H]+.
3-Phenyl-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole (6a); Typical
Procedure
To a soln of 4 (50.0 mg, 0.158 mmol) in MeCN (2 mL) at r.t. was
added Et3N (31.9 mg, 0.316 mmol) and pyrrolidine (16.9 mg, 0.237
mmol). The mixture was stirred at 80 °C for 20 h and concentrated
in vacuo, giving a residue that was partitioned between CH2Cl2 and
5-[4-(Morpholin-4-yl)piperidin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6j)
1H NMR (500 MHz, CDCl3): d = 8.19–8.16 (m, 2 H), 7.44–7.39 (m,
3 H), 4.02 (m, 2 H), 3.72 (t, J = 4.6 Hz, 4 H), 3.21 (dt, J = 2.6, 12.4
Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York

918
J. Y. Park et al.
PAPER
Hz, 2 H), 2.56 (t, J = 4.6 Hz, 4 H), 2.48 (tt, J = 3.4, 10.9 Hz, 1 H),
1.97–1.93 (m, 2 H), 1.66 (ddd, J = 4.2, 12.0, 23.8 Hz, 2 H).
LC–MS (ESI): m/z = 353 [M + H]+.
5-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6t)
LC–MS (ESI): m/z = 331 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.22–8.20 (m, 2 H), 7.46–7.40 (m,
3 H), 7.22 (t, J = 8.1 Hz, 1 H), 6.60–6.57 (m, 1 H), 6.52–6.48 (m, 2
H), 3.81 (s, 3 H), 3.75 (t, J = 5.1 Hz, 4 H), 3.33 (t, J = 5.2 Hz, 4 H).
5-[4-(2-Hydroxyethyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6k)
1H NMR (500 MHz, CDCl3): d = 8.20–8.17 (m, 2 H), 7.44–7.40 (m,
3 H), 3.67 (t, J = 5.3 Hz, 2 H), 3.63 (t, J = 4.9 Hz, 4 H), 2.66 (t,
J = 5.2 Hz, 4 H), 2.62 (t, J = 5.3 Hz, 2 H).
LC–MS (ESI): m/z = 353 [M + H]+.
5-[4-(4-Methoxyphenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6u)
LC–MS (ESI): m/z = 291 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.21–8.19 (m, 2 H), 7.46–7.40 (m,
3 H), 6.95 (d, J = 9.1 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2 H), 3.79 (s, 3
H), 3.77 (t, J = 5.0 Hz, 4 H), 3.21 (t, J = 5.2 Hz, 4 H).
5-[3,4-Dihydroisoquinolin-2(1H)-yl]-3-phenyl-1,2,4-thiadi-
azole (6l)
1H NMR (500 MHz, CDCl3): d = 8.23 (dd, J = 1.8, 7.8 Hz, 2 H),
7.46–7.41 (m, 3 H), 7.26–7.23 (m, 2 H), 7.22–7.20 (m, 2 H), 4.75
(s, 2 H), 3.86 (m, 2 H), 3.04 (t, J = 5.9 Hz, 2 H).
LC–MS (ESI): m/z = 353 [M + H]+.
5-[4-(3-Chlorophenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6v)
LC–MS (ESI): m/z = 294 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.22–8.20 (m, 2 H), 7.45–7.40 (m,
4 H), 7.27–7.24 (m, 1 H), 7.07–7.02 (m, 2 H), 3.80 (t, J = 4.6 Hz, 4
H), 3.20 (t, J = 5.1 Hz, 4 H).
3-Phenyl-5-(4-phenylpiperazin-1-yl)-1,2,4-thiadiazole (6m)
1H NMR (500 MHz, CDCl3): d = 8.24–8.21 (m, 2 H), 7.47–7.42 (m,
3 H), 7.34–7.30 (m, 2 H), 6.98 (d, J = 7.9 Hz, 2 H), 6.96 (t, J = 7.9
Hz, 1 H), 3.77 (t, J = 5.1 Hz, 4 H), 3.34 (t, J = 5.2 Hz, 4 H).
LC–MS (ESI): m/z = 357 [M + H]+.
LC–MS (ESI): m/z = 323 [M + H]+.
5-[4-(2-Cyanophenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6w)
3-Phenyl-5-[4-(pyridin-2-yl)piperazin-1-yl]-1,2,4-thiadiazole
(6n)
1H NMR (500 MHz, CDCl3): d = 8.23–8.18 (m, 2 H), 7.62 (dd,
J = 1.5, 7.7 Hz, 1 H), 7.55–7.51 (m, 1 H), 7.46–7.39 (m, 3 H), 7.12–
7.08 (m, 1 H), 7.04 (d, J = 8.3 Hz, 1 H), 3.84 (t, J = 4.9 Hz, 4 H),
3.34 (t, J = 5.1 Hz, 4 H).
1H NMR (500 MHz, CDCl3): d = 8.21–8.17 (m, 3 H), 7.53–7.49 (m,
1 H), 7.44–7.39 (m, 3 H), 6.69–6.67 (m, 2 H), 3.74–3.69 (m, 8 H).
LC–MS (ESI): m/z = 324 [M + H]+.
LC–MS (ESI): m/z = 348 [M + H]+.
3-Phenyl-5-[4-(pyrimidin-2-yl)piperazin-1-yl]-1,2,4-thiadi-
azole (6o)
5-[4-(4-Acetylphenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6x)
1H NMR (500 MHz, CDCl3): d = 8.38 (d, J = 4.8 Hz, 2 H), 8.26–
8.21 (m, 2 H), 7.48–7.42 (m, 3 H), 6.60 (t, J = 4.7 Hz, 1 H), 4.06 (t,
J = 5.3 Hz, 4 H), 3.71 (t, J = 5.2 Hz, 4 H).
1H NMR (500 MHz, CDCl3): d = 8.21–8.19 (m, 2 H), 7.91 (d,
J = 9.0 Hz, 2 H), 7.45–7.42 (m, 3 H), 6.92 (d, J = 9.0 Hz, 2 H), 3.78
(t, J = 5.2 Hz, 4 H), 3.53 (t, J = 5.3 Hz, 4 H), 2.54 (s, 3 H).
LC–MS (ESI): m/z = 325 [M + H]+.
LC–MS (ESI): m/z = 365 [M + H]+.
5-[4-(2-Fluorophenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6p)
5-[4-(4-Nitrophenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadiazole
(6y)
1H NMR (500 MHz, CDCl3): d = 8.22–8.20 (m, 2 H), 7.46–7.41 (m,
3 H), 7.12–7.05 (m, 2 H), 7.03–6.98 (m, 2 H), 3.79 (t, J = 4.9 Hz, 4
H), 3.23 (t, J = 5.1 Hz, 4 H).
1H NMR (500 MHz, CDCl3): d = 8.22–8.18 (m, 2 H), 8.17 (d,
J = 9.3 Hz, 2 H), 7.45–7.42 (m, 3 H), 6.88 (d, J = 9.4 Hz, 2 H), 3.80
(t, J = 5.3 Hz, 4 H), 3.62 (t, J = 5.3 Hz, 4 H).
LC–MS (ESI): m/z = 341 [M + H]+.
LC–MS (ESI): m/z = 368 [M + H]+.
5-[4-(4-Fluorophenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6q)
3-Phenyl-N-propyl-1,2,4-thiadiazol-5-amine (6z)
1H NMR (500 MHz, CDCl3): d = 8.16–8.14 (m, 2 H), 7.45–7.40 (m,
3 H), 6.35 (s, 1 H), 3.23 (q, J = 6.7 Hz, 2 H), 1.72–1.65 (m, 2 H),
0.98 (t, J = 7.4 Hz, 3 H).
1H NMR (500 MHz, CDCl3): d = 8.24–8.20 (m, 2 H), 7.46–7.40 (m,
3 H), 7.03–6.99 (m, 2 H), 6.95–6.92 (m, 2 H), 3.76 (t, J = 5.1 Hz, 4
H), 3.24 (t, J = 5.2 Hz, 4 H).
LC–MS (ESI): m/z = 220 [M + H]+.
LC–MS (ESI): m/z = 341 [M + H]+.
N-Butyl-3-phenyl-1,2,4-thiadiazol-5-amine (6aa)
3-Phenyl-5-[4-(2-tolyl)piperazin-1-yl]-1,2,4-thiadiazole (6r)
1H NMR (500 MHz, CDCl3): d = 8.22–8.20 (m, 2 H), 7.44–7.40 (m,
3 H), 7.23–7.16 (m, 2 H), 7.05–7.00 (m, 2 H), 3.73 (m, 4 H), 3.03
(t, J = 4.9 Hz, 4 H), 2.34 (s, 3 H).
1H NMR (500 MHz, CDCl3): d = 8.15–8.13 (m, 2 H), 7.45–7.41 (m,
3 H), 6.42 (s, 1 H), 3.25 (q, J = 6.9 Hz, 2 H), 1.65–1.59 (m, 2 H),
1.42–1.34 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H).
LC–MS (ESI): m/z = 234 [M + H]+.
LC–MS (ESI): m/z = 337 [M + H]+.
N-(2-Methoxyethyl)-3-phenyl-1,2,4-thiadiazol-5-amine (6ab)
1H NMR (500 MHz, CDCl3): d = 8.18–8.15 (m, 2 H), 7.44–7.40 (m,
3 H), 6.32 (s, 1 H), 3.62 (t, J = 5.1 Hz, 2 H), 3.53 (q, J = 5.3 Hz, 2
H), 3.39 (s, 3 H).
5-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-phenyl-1,2,4-thiadi-
azole (6s)
1H NMR (500 MHz, CDCl3): d = 8.23–8.20 (m, 2 H), 7.46–7.40 (m,
3 H), 7.08–7.04 (m, 1 H), 6.95 (d, J = 4.1 Hz, 2 H), 6.91 (d, J = 8.0
Hz, 1 H), 3.90 (s, 3 H), 3.80–3.78 (m, 4 H), 3.21 (t, J = 5.1 Hz, 4 H).
LC–MS (ESI): m/z = 236 [M + H]+.
Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York

PAPER
Parallel Synthesis of Drug-like 5-Amino-Substituted 1,2,4-Thiadiazole Libraries
919
N-[2-(Dimethylamino)ethyl]-3-phenyl-1,2,4-thiadiazol-5-amine
(6ac)
N-[2-(4-Fluorophenyl)ethyl]-3-phenyl-1,2,4-thiadiazol-5-amine
(6al)
1H NMR (500 MHz, CDCl3): d = 8.15 (dd, J = 1.8, 5.2 Hz, 2 H),
7.43–7.39 (m, 3 H), 6.88 (s, 1 H), 3.43–3.41 (m, 2 H), 2.65 (t,
J = 5.8 Hz, 2 H), 2.31 (s, 6 H).
1H NMR (500 MHz, CDCl3): d = 8.15–8.13 (m, 2 H), 7.45–7.42 (m,
3 H), 7.09–7.06 (m, 2 H), 6.98–6.94 (m, 2 H), 6.68 (s, 1 H), 3.50 (q,
J = 6.9 Hz, 2 H), 2.89 (t, J = 7.0 Hz, 2 H).
LC–MS (ESI): m/z = 249 [M + H]+.
LC–MS (ESI): m/z = 300 [M + H]+.
N-[3-(Dimethylamino)propyl]-3-phenyl-1,2,4-thiadiazol-5-
amine (6ad)
N-Methyl-3-phenyl-N-[2-(pyridin-2-yl)ethyl]-1,2,4-thiadiazol-
5-amine (6am)
1H NMR (500 MHz, CDCl3): d = 8.16–8.14 (m, 2 H), 7.65 (s, 1 H),
7.44–7.39 (m, 3 H), 3.40 (t, J = 6.0 Hz, 2 H), 2.52 (t, J = 6.2 Hz, 2
H), 2.29 (s, 6 H), 1.87–1.82 (m, 2 H).
1H NMR (500 MHz, CDCl3): d = 8.56–8.55 (m, 1 H), 8.21–8.18 (m,
2 H), 7.58 (dt, J = 1.8, 7.7 Hz, 1 H), 7.44–7.36 (m, 3 H), 7.18 (d,
J = 7.8 Hz, 1 H), 7.15–7.11 (m, 1 H), 3.95 (m, 2 H), 3.19 (t, J = 7.2
Hz, 2 H), 3.07 (s, 3 H).
LC–MS (ESI): m/z = 263 [M + H]+.
LC–MS (ESI): m/z = 297 [M + H]+.
N-[2-(Diethylamino)ethyl]-3-phenyl-1,2,4-thiadiazol-5-amine
(6ae)
N-(2,4-Dimethoxybenzyl)-N-methyl-3-phenyl-1,2,4-thiadiazol-
5-amine (6an)
1H NMR (500 MHz, CDCl3): d = 8.17–8.14 (m, 2 H), 7.44–7.39 (m,
3 H), 6.97 (s, 1 H), 3.43–3.42 (m, 2 H), 2.84 (t, J = 5.8 Hz, 2 H),
2.67 (q, J = 7.2 Hz, 4 H), 1.08 (t, J = 7.2 Hz, 6 H).
1H NMR (500 MHz, CDCl3): d = 8.24–8.21 (m, 2 H), 7.45–7.39 (m,
3 H), 6.88–6.81 (m, 3 H), 4.70 (s, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H),
3.08 (s, 3 H).
LC–MS (ESI): m/z = 277 [M + H]+.
LC–MS (ESI): m/z = 342 [M + H]+.
N-[2-(Diethylamino)ethyl]-N-methyl-3-phenyl-1,2,4-thiadiazol-
5-amine (6af)
N-Phenethyl-3-phenyl-1,2,4-thiadiazol-5-amine (6ao)
1H NMR (500 MHz, CDCl3): d = 8.21–8.18 (m, 2 H), 7.43–7.37 (m,
3 H), 3.61 (m, 2 H), 3.19 (s, 3 H), 2.73 (t, J = 7.0 Hz, 2 H), 2.58 (q,
J = 7.1 Hz, 4 H), 1.04 (t, J = 7.1 Hz, 6 H).
1H NMR (500 MHz, CDCl3): d = 8.15–8.13 (m, 2 H), 7.43–7.42 (m,
3 H), 7.31–7.28 (m, 2 H), 7.25–7.22 (m, 1 H), 7.15 (d, J = 7.2 Hz, 2
H), 6.43 (s, 1 H), 3.53 (q, J = 6.6 Hz, 2 H), 2.93 (t, J = 6.9 Hz, 2 H).
LC–MS (ESI): m/z = 291 [M + H]+.
LC–MS (ESI): m/z = 282 [M + H]+.
N-[2,2-Dimethyl-3-(dimethylamino)propyl]-3-phenyl-1,2,4-thi-
adiazol-5-amine (6ag)
N-(Furan-2-ylmethyl)-3-phenyl-1,2,4-thiadiazol-5-amine (6ap)
1H NMR (500 MHz, CDCl3): d = 8.17–8.13 (m, 2 H), 7.41–7.39 (m,
3 H), 7.36 (d, J = 0.9 Hz, 1 H), 7.11 (s, 1 H), 6.32–6.30 (m, 2 H),
4.45 (d, J = 4.5 Hz, 2 H).
1H NMR (500 MHz, CDCl3): d = 8.32 (s, 1 H), 8.19–8.14 (m, 2 H),
7.44–7.39 (m, 3 H), 3.16 (s, 2 H), 2.35 (s, 2 H), 2.34 (s, 6 H), 1.02
(s, 6 H).
LC–MS (ESI): m/z = 258 [M + H]+.
LC–MS (ESI): m/z = 291 [M + H]+.
3-Phenyl-N-[2-(thiophen-2-yl)ethyl]-1,2,4-thiadiazol-5-
amine(6aq)
N-Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine (6ah)
1H NMR (500 MHz, CDCl3): d = 8.14–8.11 (m, 2 H), 7.39–7.34 (m,
3 H), 7.33–7.29 (m, 4 H), 7.22 (s, 1 H), 4.44 (d, J = 5.2 Hz, 2 H).
1H NMR (500 MHz, CDCl3): d = 8.15–8.14 (m, 2 H), 7.44–7.41 (m,
3 H), 7.17 (dd, J = 1.1, 5.2 Hz, 1 H), 6.94 (dd, J = 3.4, 5.2 Hz, 1 H),
6.83–6.82 (m, 1 H), 6.38 (s, 1 H), 3.59 (q, J = 6.5 Hz, 2 H), 3.17 (t,
J = 6.6 Hz, 2 H).
LC–MS (ESI): m/z = 268 [M + H]+.
N-(4-Methoxybenzyl)-3-phenyl-1,2,4-thiadiazol-5-amine (6ai)
1H NMR (500 MHz, CDCl3): d = 8.14–8.11 (m, 2 H), 7.39–7.35 (m,
3 H), 7.22–7.19 (m, 3 H), 6.84 (dd, J = 2.7, 11.3 Hz, 2 H), 4.36 (d,
J = 5.2 Hz, 2 H), 3.78 (s, 3 H).
LC–MS (ESI): m/z = 288 [M + H]+.
N-[3-(1H-Imidazol-1-yl)propyl]-3-phenyl-1,2,4-thiadiazol-5-
amine (6ar)
1H NMR (500 MHz, CDCl3): d = 8.15–8.13 (m, 2 H), 7.58 (s, 1 H),
7.46 (s, 1 H), 7.42–7.40 (m, 3 H), 7.09 (s, 1 H), 6.93 (s, 1 H), 4.07
(t, J = 6.2 Hz, 2 H), 3.36–3.35 (m, 2 H), 2.19–2.14 (m, 2 H).
LC–MS (ESI): m/z = 298 [M + H]+.
N-(3-Methoxybenzyl)-N-methyl-3-phenyl-1,2,4-thiadiazol-5-
amine (6aj)
LC–MS (ESI): m/z = 286 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.24–8.21 (m, 2 H), 7.44–7.39 (m,
3 H), 7.29–7.25 (m, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 6.87–6.83 (m, 2
H), 4.75 (s, 2 H), 3.78 (s, 3 H), 3.11 (s, 3 H).
N-(2,2-Diphenylethyl)-3-phenyl-1,2,4-thiadiazol-5-amine (6as)
1H NMR (500 MHz, CDCl3): d = 8.13 (dd, J = 2.1, 5.4 Hz, 2 H),
7.43–7.40 (m, 3 H), 7.31–7.28 (m, 4 H), 7.24–7.22 (m, 2 H), 7.19–
7.17 (m, 4 H), 6.28 (s, 1 H), 4.28 (t, J = 7.9 Hz, 1 H), 3.88 (dd,
J = 5.9, 7.8 Hz, 2 H).
LC–MS (ESI): m/z = 312 [M + H]+.
N-Methyl-N-(3-methylbenzyl)-3-phenyl-1,2,4-thiadiazol-5-
amine (6ak)
LC–MS (ESI): m/z = 358 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.24–8.22 (m, 2 H), 7.45–7.40 (m,
3 H), 7.26–7.22 (m, 1 H), 7.13–7.10 (m, 3 H), 4.73 (s, 2 H), 3.10 (s,
3 H), 2.34 (s, 3 H).
5-(1,3-Dihydro-2H-isoindolin-2-yl)-3-phenyl-1,2,4-thiadiazole
(6at)
1H NMR (500 MHz, CDCl3): d = 8.24–8.21 (m, 2 H), 7.44–7.37 (m,
3 H), 7.31 (m, 4 H), 4.83–4.81 (m, 4 H).
LC–MS (ESI): m/z = 296 [M + H]+.
LC–MS (ESI): m/z = 280 [M + H]+.
Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York

920
J. Y. Park et al.
PAPER
N-(1,3-Benzodioxol-5-ylmethyl)-3-phenyl-1,2,4-thiadiazol-5-
amine (6au)
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Zarrindast, M. R.; Shafiee, A. Pharm. Pharmacol. Commun.
2000, 6, 1.
1H NMR (500 MHz, CDCl3): d = 8.14–8.11 (m, 2 H), 7.41–7.39 (m,
3 H), 6.97 (s, 1 H), 6.80–6.74 (m, 3 H), 5.96 (s, 2 H), 4.36 (d, J = 5.5
Hz, 2 H).
LC–MS (ESI): m/z = 312 [M + H]+.
Acknowledgment
This research was supported by a grant (CBM32-B1000-01-00-00)
from the Center for Biological Modulators of the 21st Century
Frontier R&D Program, the Ministry of Education Science and
Technology, Korea, and Korea Research Institute of Chemical
Technology.
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Synthesis 2009, No. 6, 913–920 © Thieme Stuttgart · New York