Electrochemical Oxidative Intramolecular N-S Bond Formation: Synthesis of 3-Substituted 5-Amino-1,2,4-Thiadiazoles

Article abstract of DOI:10.1021/acs.joc.9b03155

A facile and efficient protocol for the synthesis of 3-substituted 5-amino-1,2,4-thiadiazoles has been developed through the electro-oxidative intramolecular dehydrogenative N-S bond formation of imidoyl thioureas. Various 1,2,4-thiadiazole derivatives we

Full text of DOI:10.1021/acs.joc.9b03155

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Article
Electrochemical Oxidative Intramolecular N-S Bond Formation:
Synthesis of 3-Substituted 5-Amino-1,2,4-thiadiazoles
Zan Yang, Jiaqi Zhang, Liping Hu, Lijun Li, Kun Liu, Tao Yang, and Congshan Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03155 • Publication Date (Web): 23 Jan 2020
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Electrochemical Oxidative Intramolecular N-S Bond Formation:
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Synthesis of 3-Substituted 5-Amino-1,2,4-thiadiazoles
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Zan Yang, Jiaqi Zhang, Liping Hu, Lijun Li, Kun Liu*, Tao Yang*, Congshan Zhou*
College of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang
414006, China
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liukun328@126.com, yangtaozcs@126.com and zhoucongsh@126.com
N
NH
S
S
undivided cell
R1
R
R
R1
N
N
N
N
(+)C/(-)Pt, I = 10 mA
n-Bu4NBF4, MeCN, rt
H
H
H
catalyst and oxidant free
up to 92% yield
ABSTRACT
A facile and efficient protocol for the construction of 3-substituted 5-amino-1,2,4-thiadiazoles has been
developed through the electro-oxidative intramolecular dehydrogenative N-S bond formation of imidoyl
thioureas. Various 1,2,4-thiadiazole derivatives were synthesized in good to excellent yields with broad
substrate scope and excellent functional group tolerance under catalyst- and oxidant-free electrolytic
conditions at room temperature.
hypervalent iodine(III)-mediated intramolecular oxidative
INTRODUCTION
N-S bond formation of imidoyl thiourea for the synthesis
Sulfur-containing compounds are ubiquitous structural
motifs in natural products, biologically active compounds,
materials and synthetic intermediates.1 Among them, the
1,2,4-thiadiazole derivatives, which have a wide of
biological and pharmaceutical properties.2 Therefore, the
synthesis of 1,2,4-thiadiazole derivatives have received
considerable attention. Traditionally, 1,2,4-thiadiazole
derivatives can be achieved by the oxidative cyclization of
thioamides and thiourea with various metal-catalysts and
oxidants.3 Gong developed an N-S bond formation
reaction for the synthesis of 5-amino-1,2,4-thiadiazoles via
copper-catalyzed intramolecular dehydrogenative of
of 5-amino-1,2,4-thiadiazoles.5 Later, I2-mediated
intramolecular oxidative cyclization for the synthesis of 5-
amino-1,2,4-thiadiazoles has also been achieved by
Chang.6 However, most of these methods require
stoichiometric oxidants, bases and transition-metal
catalysts (scheme 1). In this context, the development of
environmentally friendly, atom economy and effective
methods without metal catalyst or external oxidant for the
synthesis of 5-amino-1,2,4-thiadiazoles are highly
desirable.
Electrochemical
anodic
oxidation,
which
is
environmentally friendly, atom-economical and emerging
powerful synthetic methodology7 has attracted much
imidoyl thiourea.4 Muthusubramanian reported
a
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attention in the construction of carbon-carbon8 or carbon-
was observed (table 1, entry 6). Next, the effect of the
heteroatom9 or heteroatom-heteroatom10 bonds for the
synthesis of various functional molecules. However, the
electrochemical oxidative N-S bond formation is still rare.
Yuan reported an electrochemical oxidation of S-H/N-H
cross-coupling reaction to produce sulfonamides.11 More
recently, an environmentally method for the synthesis of
sulfonamides from amines and thiols was developed via
microflow electrochemical oxidative N-S bond
formation.12 Encouraged by previous studies on N-S bond
formation reaction13a-c and our interest in the
electrochemical13d, herein, we disclose an electrochemical
oxidative intramolecular N-S bond formation for the
construction of 3-substituted 5-amino-1,2,4-thiadiazoles
under catalyst, metal and oxidant-free conditions.
solvents was screened, aqueous MeCN was unsuitable for
the electrooxidized N-S bond formation reaction (table 1,
entry 7). Using EtOH and DMSO as solvents isolated the
corresponding product 2a in 28% and 47% yields,
respectively (table 1, entries 8-9). This result demonstrated
that MeCN was the best solvent for this transformation.
Graphite and platinum electrode were tested, no
improvement yield of 2a can be achieved (table 1, entries
10-11). Using graphite as the anode and nickel foam as the
cathode, the yield of desired product 2a decreased from 85%
to 75% (table 1, entry 12). Additionally, no product was
obtained in the absence of current after the reaction (table
1, entry 13).
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Table 1. Optimization of reaction conditionsa
Previous works
N
NH
S
S
chemical oxidant
R1
R
NH
S
R
R1
N
N
N
undivided cell
N
S
N
H
H
H
N
N
N
(+)C/(-)Pt, I = 10 mA
n-Bu4NBF4, MeCN, rt
H
H
N
H
Gong et al: Cu(OTf)2, Cs2CO3
Muthusubramanian et al: PIFA
Chang et al: I2, K2CO3
1a
2a
Variation from the standard
Yield
[%]
85
This work
Entry
conditions
none
N
NH
S
S
undivided cell
1
2
3
R1
R
R
R1
N
N
N
N
anodic oxidant
LiClO4 instead of n-BuNBF4
n-Bu4NPF6 instead of n-
Bu4NBF4
42
H
H
H
catalyst and oxidant free
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Scheme 1. Synthesis of 5-amino-1,2,4-thiadiazoles
4
5b
KI instead of n-Bu4NBF4
I = 5 mA instead of I = 10 mA
(3.7 F/mol)
51
53
RESULTS AND DISCUSSION
In the initial experiment, imidoyl thiourea 1a was selected
as model substrate to investigate the optimization of the
reaction conditions. As shown in table 1, in an undivided
cell (a two-necked round-bottomed flask) with a carbon
rod anode and Pt plate cathode, when 10 mA constant
current and 0.03 M n-Bu4NBF4 electrolyte was used in 10
mL MeCN at room temperature, the desired 5-amino-
1,2,4-thiadiazole 2a was isolated in 85% yield (table 1,
entry 1). Encouraged by this result, various electrolytes
were also tested such as LiClO4, n-Bu4NPF6 and KI, no
further improved the yield of 2a was observed (table 1,
entries 2-4). Further, the product yield of 2a was dropped
to 53% when 5 mA constant current was used (table 1,
entry 5). And, when the constant current was increased
from 10 mA to 15 mA, no significant effect of the yield
6b
7
I = 15 mA instead of I = 10 mA
(2.8 F/mol)
82
MeCN/H2O (4:1) instead of
MeCN
Trace
8
9
EtOH instead of MeCN
DMSO instead of MeCN
(+)C/(−)C instead of (+)C/(−)Pt
(+)Pt/(−)Pt instead of
(+)C/(−)Pt
28
47
66
72
10
11
12
13
(+)C/(−)Ni instead of
(+)C/(−)Pt
75
no electric current, 24 h
N. R.
aReaction conditions: carbon rod anode, Pt plate
cathode (1cm×1cm), undivided cell, I = 10 mA (Janode
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= 10 mA/cm2), 1a (0.3 mmol), n-Bu4NBF4 (0.3 mmol),
aReaction conditions: carbon rod anode, Pt plate
MeCN (10 mL), under air atmosphere at room
temperature for 2.5 h, 3.1 F/mol. bUntil complete
consumption of 1a.
cathode (1cm×1cm), undivided cell, I = 10 mA (Janode
= 10 mA/cm2), 1 (0.3 mmol), n-Bu4NBF4 (0.3 mmol),
MeCN (10 mL), under air atmosphere at room
temperature for 2.5 h, 3.1 F/mol.
With the optimized protocol in hand, we explored the
scope of the electrochemical N-S bond formation reaction
with various imidoyl thioureas 1 synthesized from
different amidines with 4-methylphenyl isothiocyanate. As
shown in table 2, a variety of imidoyl thioureas 1 with
electron-donating groups, electron-withdrawing groups
and halogens on the aryamidines side were investigated
which were converted to the desired products 2a-2f in
good yields. In addition, 4-pyridine (1g), 3-pyridine (1h)
and pyrazole (1i) of imidoyl thioureas, were also
compatible and produced the desired products 2g, 2h and
2i in 80-86% yield. Importantly, alkyl of imidoyl thioureas
were tolerated in this transformation, and the
corresponding products 2j and 2k were generated in 89%
and 88% yield, respectively.
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Furthermore, the imidoyl thioureas 3 from
isothiocyanates with benzamidine were investigated the
compatibility of the electrochemical dehydrogenative N-S
bond formation protocol in table 3. The imidoyl thioureas
3 from aryl isothiocyanates with various functional
groups such as, Me, i-Pr, t-Bu, OMe, OEt, F and Cl were
tolerated and afford the 1,2,4-thiadiazoles 4a-4k in good
yields. Generally, the imidoyl thioureas 3 with electron-
donating groups (Me, OMe, OEt) shown higher reactivity
than electron-withdrawing groups (F, Cl). Additionally,
imidoyl thioureas 3l and 3m from naphthyl and benzyl
isothiocyanate underwent the reaction smoothly and
produce the 4l and 4m in 85% and 78% yield,
respectively. Moreover, 2-alkyl substituted desired
products 4n and 4o have been synthesized under the
electrochemical conditions in good yields. However, a
complex mixture of 4p was obtained, when imidoyl
thiourea with alkenyl group was tested.
Table 2. Substrate Scope of 5-Amino-1,2,4-thiadiazole
Synthesisa
Table 3. Substrate Scope of 5-Amino-1,2,4-thiadiazole
Synthesisa
N
NH
S
S
undivided cell
R1
N
R1
N
N
N
(+)C/(-)Pt, I = 10 mA
H
H
H
n-Bu4NBF4, MeCN, rt
1
2
NH
S
N
S
undivided cell
R
R
N
N
N
N
H
S
S
N
N
H
H
S
N
(+)C/(-)Pt, I = 10 mA
N
N
N
N
H
N
N
H
H
3
4
n-Bu4NBF4, MeCN, rt
MeO
2a, 85%
2b, 87%
2c, 83%
S
S
N
S
N
N
N
N
N
H
N
H
N
N
H
S
S
S
N
N
N
N
N
N
N
H
N
N
H
H
Cl
4a, 86%
4b, 84%
4c, 83%
Br
F
2d, 82%
2e, 78%
2f, 75%
S
N
S
S
N
N
S
S
N
N
S
N
N
N
N
N
H
N
N
N
H
N
H
N
N
N
N
H
H
N
N
H
N
N
2g, 86%
2h, 82%
2i, 80%
4d, 89%
4e, 92%
4f, 87%
OMe
OEt
F
S
S
S
N
N
N
S
N
S
N
N
N
N
N
N
H
N
H
N
N
H
N
H
N
H
2j, 89%
2k, 88%
4g, 84%
4h, 87%
4i, 86%
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Cl
Cl
S
S
N
N
S
N
e-
N
N
N
e-
N
N
H
H
N
H
6
NH
S
NH SH
7
8
9
H2
N
N
4j, 83%
4k, 74%
4l, 85%
N
N
H
H
H
A
3a
S
N
S
S
N
N
NH
NH
2 H+
N
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N
H+
HN
N
S
N
H
- e-
S
S
NH
NH
NH
HN
N
N
- H+
N
N
4m, 78%
4n, 84%
4o, 80%
B
C
4a
S
N
NH
N
Scheme 3. Proposed Reaction Mechanism
4p, complex
mixture
aReaction conditions: carbon rod anode, Pt plate
cathode (1cm×1cm), undivided cell, I = 10 mA (Janode
= 10 mA/cm2), 3 (0.3 mmol), n-Bu4NBF4 (0.3 mmol),
MeCN (10 mL), under air atmosphere at room
temperature for 2.5 h, 3.1 F/mol.
Subsequently, to further illustrate the scalability of this
dehydrogenative N-S bond formation protocol, a gram-
scale reaction was evaluated in scheme 2. To our delight,
5 mmol of 1a was treated under the electrochemical
conditions in 100 mL MeCN, and the desired product 2a
was isolated in 74% yield.
Scheme 4. Cyclic voltammograms, scan rate: 25 mV/s.
A) 1a (0.3 mmol) + n-Bu4NBF4 (0.3 mmol) in MeCN (10
mL); B) n-Bu4NBF4 (0.3 mmol) in MeCN (10 mL)
In summary, we have demonstrated an efficient and
atom-economic protocol for the construction of 3-
substituted 5-amino-1,2,4-thiadiazoles via
NH
S
undivided cell
S
N
N
N
N
(+)C/(-)Pt, I = 10 mA
n-Bu4NBF4, MeCN, rt
H
H
N
H
1a
2a,
74%, 0.988 g
electrochemical oxidative dehydrogenative of N-S bond
formation. This electrochemical strategy provides a
simple and efficient method for the synthesis of 1,2,4-
thiadiazole derivatives in good to excellent yields with
broad substrate scope under mild conditions, which
avoids use of metal catalysts and stoichiometric oxidants.
Scheme 2. Gram-scale experiments
According to the previous work14 and experimental
results15, a plausible mechanism for this dehydrogenative
N-S bond formation is proposed in scheme 3. The imidoyl
thiourea 3a could isomerize to the thioiminol A which was
then oxidized at the anode to formed the radical
intermediate B via single electron transfer (SET) process.
The radical intermediate B afford in an anodic was
supported by the CV experiments (scheme 4). Then, the
radical cation B underwent radical cyclization to produce
the intermediate C. Finally, the desired product 4a was
obtained by oxidative rearomatization of the intermediate
C.
EXPERIMENTAL SECTION
General methods: H (400 MHz), 13C{1H} (101 MHz)
1
spectra were recorded on a Bruker 400MHz spectrometer
in CDCl3 or DMSO-d6 using TMS as internal standard.
HRMS was recorded on a Bruker micrOTOF-Q II. Melting
points are uncorrected. The Pt plate electrode
(1cm×1cm×0.15cm),
Ni
plate
electrode
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(1cm×1.5cm×0.15cm) and carbon rod electrode
298.1009, found 298.1003.
(0.4cm×6cm) were obtained from Shanghai yueci
Electronic Technology Co., Ltd, China.
3-(4-fluorophenyl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2d). White solid, mp 198-200 oC, yield: 82% (70 mg). 1H
NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.38 – 8.13 (m,
2H), 7.54 (d, J = 8.5 Hz, 2H), 7.42 – 7.34 (m, 2H), 7.26 (d, J
= 8.2 Hz, 2H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 180.0, 168.1, 162.6, 138.1, 132.8, 130.5, 130.4,
130.1, 118.5, 116.4 (d, J = 22.0 Hz), 21.1.19F NMR (376 MHz,
DMSO-d6) δ -110.56. HRMS (ESI-TOF) m/z calcd for
C15H13FN3S [M+H]+ 286.0809, found 286.0813.
General procedure for synthesis of imidoyl thioureas 1
or 3:4, 5 Amidine (0.3 mmol), isothiocyanate (0.33 mmol),
and K2CO3 (0.45 mmol, 62 mg) in 2 mL dichloromethane,
and stirred for 20 h at room temperature. Upon completion
of the reaction, the mixture was washed with water, and
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extracted with ethyl acetate (3×20 mL ). The combined
organic layers were dried over anhydrous Na2SO4,
concentrated, and afford the target products without further
purification.
3-(4-chlorophenyl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2e).6 White solid, mp 220-222 oC, yield: 78% (70 mg). 1H
NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.32 – 8.13 (m,
2H), 7.67 – 7.58 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.26 (d, J
= 8.2 Hz, 2H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 180.2, 168.3, 138.2, 135.7, 133.0, 132.4, 130.7,
130.1, 129.8, 118.8, 21.3.
General procedure for synthesis of 2 or 4: In 25 mL two-
necked round bottom flask, with carbon rod anode, Pt plate
cathode (1cm×1cm), 0.3 mmol imidoyl thiourea 1 or 3, n-
Bu4NBF4 (0.3 mmol, 99 mg) and MeCN (10 mL). The
mixture was magnetic stirred with constant current 10 mA
at room temperature for 1-2 hour. Upon completion of the
reaction, the mixture was concentrated in vacuo and the
residue was purified by column chromatography
(EtOAc/n-Hexane=1:10) to afford the desired products 2
or 4.
3-(4-bromophenyl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2f).6 White solid, mp 240-242 oC, yield: 75% (78 mg). 1H
NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.19 – 8.09 (m,
2H), 7.79 – 7.74 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.27 (d, J
= 8.3 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 180.0, 168.0, 137.9, 132.7, 132.4, 132.3, 130.3,
130.0, 124.2, 118.5, 21.0.
3-phenyl-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2a).6
White solid, mp 154-156 oC, yield: 85% (68 mg). 1H NMR
(400 MHz, CDCl3) δ 8.77 (s, 1H), 8.24 – 8.14 (m, 2H), 7.48
– 7.39 (m, 3H), 7.16 (d, J = 8.1 Hz, 2H), 7.11 – 7.03 (m, 2H),
2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 181.6,
169.5, 136.8, 134.6, 133.0, 130.4, 130.2, 128.7, 128.1, 119.1,
21.0.
3-(pyridin-4-yl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2g).3 White solid, mp 240-242 oC, yield: 86% (69 mg).
1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.72 (d, J =
6.0 Hz, 2H), 8.02 (d, J = 6.2 Hz, 2H), 7.52 (d, J = 8.5 Hz,
2H), 7.24 (d, J = 7.4 Hz, 2H), 2.28 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ 181.2, 167.7, 151.2, 140.0, 138.2,
133.1, 130.3, 122.2, 118.7, 21.1.
N,3-di-p-tolyl-1,2,4-thiadiazol-5-amine (2b).6 White solid,
o
1
mp 180-183 C, yield: 87% (73 mg). H NMR (400 MHz,
CDCl3) δ 8.35 (d, J = 19.8 Hz, 1H), 8.18 – 8.01 (m, 2H), 7.25
– 7.15 (m, 4H), 7.13 – 7.08 (m, 2H), 2.39 (s, 3H), 2.35 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 181.2, 169.5, 140.3,
136.7, 134.4, 130.4, 130.3, 129.3, 127.9, 118.9, 21.5, 20.9.
3-(4-methoxyphenyl)-N-(p-tolyl)-1,2,4-thiadiazol-5-
3-(pyridin-3-yl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2h).3 78% White solid, mp 238-240 C, yield: 82% (66
mg). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.27 – 7.11
(m, 8H), 2.35 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
181.4, 180.4, 137.3, 136.0, 134.5, 130.2, 130.0, 129.5, 126.5,
125.6, 125.6.
o
o
amine (2c). White solid, mp 145-147 C, yield: 83% (74
3-(1H-pyrazol-1-yl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2i).5 White solid, mp 200-202 oC, yield: 80% (62 mg). 1H
NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.30 (d, J = 5.6 Hz,
1H), 7.53 (s, 1H), 7.28 – 7.12 (m, 4H), 6.46 – 6.35 (m, 1H),
2.36 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 183.3,
158.5, 142.9, 136.3, 135.6, 130.4, 128.9, 121.0, 108.0, 21.1.
mg). 1H NMR (400 MHz, CDCl3) δ 8.97 (2brs, 1H), 8.12 (d,
J = 8.9 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.3 Hz,
2H), 6.91 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.32 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 181.5, 169.2, 161.2,
136.9, 134.4, 130.4, 129.7, 125.9, 119.1, 114.0, 55.5, 21.0.
HRMS (ESI-TOF) m/z calcd for C16H16N3OS [M+H]+
3-methyl-N-(p-tolyl)-1,2,4-thiadiazol-5-amine
(2j).6
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White solid, mp 144-147 oC, yield: 89% (55 mg). 1H NMR
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 181.5, 169.4, 147.7,
(400 MHz, CDCl3) δ 9.66 (s, 1H), 7.22 (d, J = 8.2 Hz, 2H),
7.19 – 7.11 (m, 2H), 2.43 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 182.3, 169.5, 137.0, 134.9, 130.4, 119.8,
20.9, 19.1.
3-cyclopropyl-N-(p-tolyl)-1,2,4-thiadiazol-5-amine (2k).6
White solid, mp 135-137 oC, yield: 88% (61 mg). 1H NMR
(400 MHz, CDCl3) δ 8.64 (s, 1H), 7.12 (d, J = 8.2 Hz, 2H),
7.07 – 7.01 (m, 2H), 2.27 (s, 3H), 2.03 (ddd, J = 13.2, 8.3, 4.9
Hz, 1H), 0.99 (dt, J = 6.2, 3.1 Hz, 2H), 0.89 (dt, J = 8.3, 3.2
Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 181.3, 174.9,
137.0, 134.5, 130.4, 119.2, 21.0, 13.7, 9.0.
136.7, 132.9, 130.2, 128.6, 128.1, 126.7, 118.7, 34.5, 31.4.
HRMS (ESI-TOF) m/z calcd for C18H20N3S [M+H]+
310.1372, found 310.1368
N-(2,4-dimethylphenyl)-3-phenyl-1,2,4-thiadiazol-5-
o
amine (4f). White solid, mp 132-135 C, yield: 87% (73
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19
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60
mg). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.07 (d, J =
6.8 Hz, 2H), 7.40 – 7.28 (m, 4H), 7.13 – 7.06 (m, 2H), 2.34
(s, 3H), 2.24 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
184.1, 169.8, 136.8, 135.4, 133.0, 132.3, 131.8, 130.0, 128.5,
128.2, 127.9, 122.6, 21.1, 17.7. HRMS (ESI-TOF) m/z calcd
for C16H16N3S [M+H]+ 282.1059, found 282.1054.
N-(4-methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4g).5 White solid, mp 117-120 oC, yield: 84% (71 mg). 1H
NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.20 – 8.12 (m, 2H),
7.41 (dd, J = 5.2, 2.0 Hz, 3H), 7.22 – 7.18 (m, 2H), 6.95 –
6.89 (m, 2H), 3.82 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 182.9, 169.7, 157.3, 133.1, 132.5, 130.2, 128.7, 128.1, 122.2,
115.2, 55.7.
N,3-diphenyl-1,2,4-thiadiazol-5-amine (4a).5 White solid,
o
1
mp 174-175 C, yield: 86% (65 mg). H NMR (400 MHz,
CDCl3) δ 8.28 (s, 1H), 8.15 – 8.12 (m, 2H), 7.39 – 7.32 (m,
5H), 7.20 – 7.16 (m, 2H), 7.13 – 7.07 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 180.8, 169.5, 139.2, 133.0, 130.3, 130.0,
128.7, 128.1, 124.5, 118.5.
3-phenyl-N-(m-tolyl)-1,2,4-thiadiazol-5-amine (4b).5
White solid, mp 108-110 oC, yield: 84% (67 mg). 1H
NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.27 – 8.13 (m,
2H), 7.42 (dd, J = 5.1, 1.8 Hz, 3H), 7.26 – 7.20 (m, 1H),
7.00 (dd, J = 8.0, 2.3 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.87
(s, 1H), 2.24 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
181.3, 169.3, 140.0, 139.2, 132.9, 130.3, 129.7, 128.7,
128.2, 125.3, 119.6, 115.3, 21.5.
N-(4-ethoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4h). White solid, mp 135-137 oC, yield: 87% (78 mg). 1H
NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.15 – 7.98 (m, 2H),
7.38 – 7.27 (m, 3H), 7.13 – 7.03 (m, 2H), 6.85 – 6.74 (m, 2H),
3.94 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 183.1, 169.7, 156.7,
133.0, 132.4, 130.2, 128.6, 128.0, 122.2, 115.6, 63.9, 14.9.
HRMS (ESI-TOF) m/z calcd for C16H16N3OS [M+H]+
298.1009, found 298.1003.
3-phenyl-N-(o-tolyl)-1,2,4-thiadiazol-5-amine
(4c).5
White solid, mp 167-170 oC, yield: 83% (66 mg). 1H NMR
(400 MHz, CDCl3) δ 8.55 (s, 1H), 8.15 – 8.06 (m, 2H), 7.46
(d, J = 7.9 Hz, 1H), 7.42 – 7.23 (m, 4H), 7.18 (td, J = 7.4, 1.2
Hz, 1H), 2.29 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
183.2, 169.7, 137.9, 133.0, 131.6, 130.9, 130.1, 128.6, 127.9,
127.7, 126.4, 121.3, 17.8.
N-(4-fluorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4i).5 White solid, mp 170-172 oC, yield: 86% (70 mg). 1H
NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.30 – 8.17 (m,
2H), 7.79 – 7.70 (m, 2H), 7.60 – 7.52 (m, 3H), 7.36 – 7.28 (m,
2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 180.1, 169.5,
158.8 (d, J = 240.4 Hz), 137.3 (d, J = 3.0 Hz), 133.7, 131.2,
129.7, 128.5, 120.5 (d, J = 8.1 Hz), 117.0 (d, J = 23.2 Hz). 19F
NMR (376 MHz, DMSO-d6) δ -119.75.
N-(4-isopropylphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4d).5 White solid, mp 130-132 oC, yield: 89% (79 mg). 1H
NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.17 – 8.07 (m, 2H),
7.39 – 7.31 (m, 3H), 7.18 – 7.12 (m, 2H), 7.10 – 7.03 (m, 2H),
2.83 (hept, J = 6.9 Hz, 1H), 1.18 (s, 3H), 1.16 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 181.4, 169.5, 145.5, 137.0, 133.0,
130.2, 128.7, 128.1, 127.9, 119.0, 33.7, 24.1.
N-(4-chlorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4j).5 White solid, mp 194-196 oC, yield: 83% (71 mg).
1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.20 –
8.18 (m, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.53 – 7.48 (m,
5H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 179.6,
169.1, 139.5, 133.2, 130.7, 129.7, 129.2, 128.3, 126.9,
119.7.
N-(4-(tert-butyl)phenyl)-3-phenyl-1,2,4-thiadiazol-5-
o
amine (4e). White solid, mp 145-147 C, yield: 92% (85
mg). 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.23 – 8.15
(m, 2H), 7.42 – 7.31 (m, 5H), 7.13 – 7.07 (m, 2H), 1.30 (s,
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N-(3-chlorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
This work was supported by Natural Science Foundation
(4k).5 White solid, mp 156-158 oC, yield: 74% (64 mg).
1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.21 – 8.18
(m, 2H), 7.46 – 7.43 (m, 3H), 7.31 – 7.26 (m, 2H), 7.15 –
7.09 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.6,
140.3, 135.6, 132.8, 130.9, 130.5, 130.4, 128.8, 128.1,
124.3, 118.6, 116.2.
of China (No. 51974122), National Natural Science
Foundation of Hunan Province (No. 2019JJ50214).
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N-(naphthalen-1-yl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4l).5 White solid, mp 150-152 oC, yield: 85% (77 mg).
1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.04 – 7.89 (m,
3H), 7.85 – 7.78 (m, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.58 (dd,
J = 7.4, 0.9 Hz, 1H), 7.48 – 7.36 (m, 3H), 7.23 – 7.15 (m,
1H), 7.10 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 184.4, 169.9, 135.5, 134.7, 132.9, 130.0, 128.8,
128.4, 127.9, 127.9, 127.3, 127.1, 127.0, 125.87, 121.4,
119.7.
N-benzyl-3-phenyl-1,2,4-thiadiazol-5-amine (4m).3 White
o
1
solid, mp 100-103 C, yield: 78% (62 mg). H NMR (400
MHz, CDCl3) δ 8.10 – 8.03 (m, 2H), 7.35 – 7.23 (m, 8H), 6.85
(s, 1H), 4.40 (d, J = 5.5 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 184.7, 169.9, 136.2, 133.3, 130.1, 129.0, 128.6,
128.3, 128.0, 127.7, 50.6.
N-(tert-butyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4n).
1
Yellow liquid, yield: 84% (59 mg). H NMR (400 MHz,
CDCl3) δ 9.13 (s, 1H), 8.12 – 8.02 (m, 2H), 7.32 – 7.23 (m,
5H), 7.04 – 7.00 (m, 2H), 1.22 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 181.6, 169.3, 133.3, 129.9, 128.6, 128.0, 53.2,
28.6. HRMS (ESI-TOF) m/z calcd for C12H16N3S [M+H]+
234.1059, found 234.1063.
Mediated
C-S/C-N
Bond
Formation:
One-Pot
Regioselective
Synthesis
of 5H-Thiazolo[3,2-
a]pyrimidines. ChemistrySelect 2019, 4, 6583.
N-(sec-butyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(4o).
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Yellow liquid, yield: 80% (56 mg). H NMR (400 MHz,
CDCl3) δ 8.16 – 8.03 (m, 2H), 7.35 (dd, J = 5.2, 2.0 Hz, 3H),
5.98 (d, J = 8.5 Hz, 1H), 3.25 (dh, J = 8.3, 6.4 Hz, 1H), 1.52
(qd, J = 7.4, 6.3 Hz, 2H), 1.20 (d, J = 6.5 Hz, 3H), 0.89 (t, J
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HRMS (ESI-TOF) m/z calcd for C12H16N3S [M+H]+
234.1059, found 234.1056.
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Supporting Information Available: The copies of 1H and
13C{1H} NMR spectra (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
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TEMPO was added to the electrochemical reaction.
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