One-pot synthesis of 3,5-disubstituted 1,2,4-thiadiazoles from nitriles and thioamides: Via I2-mediated oxidative formation of an N-S bond

Article abstract of DOI:10.1039/c7ob01887h

A simple and practical method for I₂-mediated one-pot synthesis of 3-alkyl-5-aryl-1,2,4-thiadiazoles has been developed; the one-pot reaction includes sequential intermolecular addition of thioamides to nitriles, and intramolecular oxidative coupling of N-H and S-H bonds mediated by molecular iodine. Meanwhile the protocol uses readily available nitriles and thioamides as the starting materials, molecular iodine as the oxidant, and generates various 1,2,4-thiadiazoles in moderate to good yields with a wide array of functional groups. This method is an efficient approach for the synthesis of unsymmetrically disubstituted 1,2,4-thiadiazoles.

Full text of DOI:10.1039/c7ob01887h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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One-pot Synthesis of 3,5-Disubstituted 1,2,4-Thiadiazoles from
Nitriles and Thioamides via I2-Mediated Oxidative Formation of N-
S Bond
Received 00th January 20xx,
Accepted 00th January 20xx
Ling Chai,a,‡ Yuanqing Xu,a,‡ Tao Ding,a,‡ Xiaomin Fang,a Wenkai Zhang,a Yanpeng Wang,a Minghua
Lu,a Hao Xu,*,a Xiaobo Yang*,b
DOI: 10.1039/x0xx00000x
www.rsc.org/obc
A simple and practical method for I2-mediated one-pot synthesis of 3-alkyl-5-aryl-1,2,4-thiadiazoles has been developed;
the one-pot reaction includes sequential intermolecular addition of thioamides to nitriles, and intramolecular oxidative
coupling of N-H and S-H bonds mediated by molecular iodine. Meanwhile the protocol uses readily available nitriles and
thioamides as the starting materials, molecular iodine as the oxidant, and generates various 1,2,4-thiadiazoles in moderate
to good yields with a wide array of functional groups. This method is an efficient approach for the synthesis of
unsymmetrically disubstituted 1,2,4-thiadiazoles.
Introduction
1,2,4-Thiadiazoles, an important class of five-membered
heterocycles, are the focus of numerous biological studies
because of their wide applications as pharmacophores in
medicinal chemistry.1 The general methods for the synthesis of
3,5-disubstituted 1,2,4-thiadiazoles from readily available
substrates mainly relied on oxidative dimerization of
thioamides, and various oxidants were employed for this
procedure.2 Alternatively, these compounds could also be
synthesized from other substrates such as aryl nitriles3 and
3,5-dichloro-1,2,4-thiadiazole.4 However, the methods above
were restricted to synthesis of 1,2,4-thiadiazoles with identical
substituents at 3- and 5-positions. Recently, a novel method
for the synthesis of 3,5-diaryl-1,2,4-thiadiazoles from amidines,
elemental sulfur, and 2-methylquinolines or aldehydes has
been developed (Scheme 1A,1B),5 and the 1,2,4-thiadiazoles
with different aryl-substituents at 3- and 5- positions could be
synthesized efficiently. But there remain some limitations in
this method such as high reaction temperature, extra
elemental sulfur and relatively low yield of many products.
Scheme 1 Easy synthesis of unsymmetrically 3,5-disubstituted 1,2,4-Thiadiazoles
from readily available substrates.
Therefore,
a simple and practical approach to 1,2,4-
step-economy. Such a transformation was usually performed
through copper-catalyzed aerobic oxidation6 or using
hypervalent iodine as oxidants.7 As a readily available and eco-
friendly oxidant, molecular iodine (I2) has been applied in the
transformation recently. In 2017, Nakka’s group developed a
simple synthesis of 3,4-disubstituted 5-imino-1,2,4-
thiadiazoles from N-arylbenzamidines and isothiocyanate via
I2-catalyzed (50 mol%) oxidative coupling of N-H and S-H bonds
(Scheme 1C);8 Very recently, Yu’s group developed a method
thiadiazoles with different substituents at 3- and 5- positions
from readily available substrates is still highly desirable.
N-S bond formation via oxidative coupling of N-H and S-H
bonds has engrossed significant attention for its atom- and
a.College of Chemistry and Chemical Engineering, Henan University, Kaifeng
475004, P. R. China.
b.College of Chemistry & Chemical Engineering, Shenyang Normal University,
Shenyang, Liaoning, 110034, P. R. China.
* Email: xuhao@henu.edu.cn; bxy1223@gmail.com.
‡ These authors contributed equally to this work.
† Electronic Supplementary Informaꢀon (ESI) available: NMR spectra for all target
compounds.. See DOI: 10.1039/x0xx00000x
for I2-mediated synthesis of
amino-substituted 1,2,4-
thiadiazoles from substituted N-carbamothioylamidines or N-
carbamothioylguanidines (Scheme 1D).9 Although the amino or
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imino-substituted 1,2,4-thiadiazoles could be synthesized by
the methods above, the substrates were hard to be prepared
or toxic (such as isothiocyanate). In continuation of our Table 1. (contd.)
Entry
Lewis acid
--
Solvent
Yield (%)b
Trace
83
endeavors to develop simple methods for the synthesis of N-
heterocycles from readily available substrates,10 we herein
13
n-BuAc
n-BuAc
n-BuAc
n-BuAc
n-BuAc
n-BuAc
n-BuAc
14d
15e
16f
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
report a one-pot chemoselective synthesis of 3,5-disubstituted
1,2,4-thiadiazoles from nitriles and thioamides via I2-mediated
oxidative formation of N-S bond (Scheme 1E).
92
70
17g,e
18h,e
19i
68
44
Results and discussion
Trace
At first, benzonitrile (1g) and benzothioamide (2a) were
a Reaction condition: (1) 1g (0.8 mmol), 2a [0.4 mmol, added (4×0.1 mmol per 5
chosen as model substrates to optimize the conditions
including solvents, Lewis acid additives and the amount of min)], lewis acid (0.8 mmol), solvent (1 mL), reaction time (5 h) at 70 oC in air; (2)
b
then H2O (0.3 mL), I2 (0.8 mmol), reaction time (24 h) at room temperature.
molecular iodine. As shown in Table 1, n-butyl acetate (n-BuAc)
c
d
e
Isolated yield. 35 oC for the first step. under nitrogen atmosphere (1 atm).
was the best choice of solvent (entries 1-6). Among the
different Lewis acids tested (2 equiv., relative to 2a), AlCl3
showed the best activity (compare entries 3, 7-12). No product
f
g
under oxygen atmosphere (1 atm). I2 (0.4 mmol) for the second step. I2 (0.2
mmol). h I2 (0.08 mmol). i without addition of water in the second step.
(
3g) was observed in the absence of Lewis acid for the first
Under the optimized conditions, various aliphatic nitriles
and aromatic thioamides were used to investigate the
step (entry 13); this result proved that the addition of Lewis
acid was necessary for the coupling of benzonitrile (1g) with
benzothioamide (2a), because of the weak nucleophilicity of
thioamides. It was noticed that a high yield could also be
obtained under nitrogen atmosphere (entry 14), so molecular
iodine (I2) should be the main oxidant in the following
oxidative formation of N-S bond. Decrease of the amount of I2
would lead to a declined yield (entries 16). We also attempted
to perform the transformation under I2-catalyzed oxidative
conditions, but the yield was lower than before (entries 17-18);
these results also proved the role of I2 as oxidant for this
transformation. Additionally, no product 3g could be obtained
without addition of water (entry 19); so water was needed to
substrate scope, and
a
series of 3-alkyl-5-aryl-1,2,4-
thiadiazoles were synthesized in moderate to good yields
(Table 2). Diverse electron-withdrawing (Cl, Br, NO2, CF3;
entries 21-26) and electron-donating substituents (Me; entries
17-20) on the aryl group of aromatic thioamides were well
tolerated; the aromatic thioamides with strongly electron-
withdrawing substituents gave relatively lower yields, perhaps
because of its relatively weaker nucleophilicity (entries 21,26).
Furthermore, the position of the substituents on the aryl group
also affected the yield of
3, with the para-substituted
substrates giving relatively higher yields (compare entries 8,9;
entries 18,20; entries 22,24). Delightfully, heterocyclic
thioamides worked well too in this reaction (entries 27-28).
The one-pot synthesis of 1,2,4-thiadiazoles above could
tolerate various functional groups including alkene (entry 5),
ether (entries 12-13), carbon-halogen bond (entries 6, 11, 22-
25), cyclopentyl (entry 4), phenolic hydroxyl (entry 14), nitro
(entry 15), trifluoromethyl (entry 21) and heteroaryl groups
(27-28). But there were still some limitations in this method,
the substrates with keto-carbonyl or amino groups could not
be transformed into the corresponding products (Scheme S1A-
B). Meanwhile, tertiary nitrile (t-BuCN) failed to generate the
intended product due to steric hindrance (Scheme S1C).
Moreover, aliphatic thioamides and aromatic nitriles were also
used to perform this transformation. However when aliphatic
thioamides were employed as the substrates (such as
thioacetamide and thiopropanamide), no target compound
could be obtained (Scheme S1D); but if aromatic nitriles were
employed as substrates to react with aromatic thioamides, the
unsymmetrically and symmetrically 3,5-disubstituted 1,2,4-
thiadiazoles are always generated simultaneously (Scheme S1E;
Figure S1,S2 in the ESI), and they are difficult to separate due
to their very close value of Rf.
generate 3g
.
Table 1. Optimization of conditions on I2-mediated one-pot synthesis of 3-benzyl-5-
phenyl-1,2,4-thiadiazole (3g) from phenylacetonitrile (1g) and benzothioamide (2a)a
Entry
1
Lewis acid
AlCl3
Solvent
DMSO
Yield (%)b
Trace
75
2
AlCl3
Toluene
n-BuAc
Ethyl acetate
THF
3
AlCl3
AlCl3
91
4
68
5
AlCl3
21
6c
AlCl3
CH2Cl2
65
7
AlBr3
MgCl2
ZnCl2
CaCl2
TiCl4
n-BuAc
n-BuAc
n-BuAc
n-BuAc
n-BuAc
n-BuAc
71
8
Trace
Trace
Trace
Trace
Trace
9
10
11
12
BF3
2 | J. Name., 2012, 00, 1-3
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Table 2. I2-mediated one-pot synthesis of 3-alkyl-5-aryl-1,2,4-thiadiazoles (3) from
nitriles (1) and thioamides (2)a
Table 2. (contd.)
Yield
(%)b
Entry
1
2
3
14
2a
73
15
16
2a
2a
81
77
17
1c
2b
72
Yield
18
19
20
1g
1o
1g
2b
2b
2c
84
73
94
Entry
1
1
2
3
(%)b
2a
52
2
3
2a
2a
68
60
N
n-Bu
Ph
N
S
CF3
N
Bn
3c
21
22
23
24
25
1g
1g
1b
1g
1g
2d
2e
2f
78
N
S
3u
4
2a
62
56
65
94
89
5
6
7
2a
2a
2a
37
59
91
2f
2g
8
2a
79
9
2a
2a
2a
84
77
88
26
27
1g
1g
1g
2h
2i
77
76
64
10
11
28
2j
12
13
2a
2a
80
60
a
Reaction condition: (1) 1 (0.8 mmol), 2 [0.4 mmol, added (4×0.1 mmol per 5
min)], AlCl3 (0.8 mmol),
H2O (0.3 mL), I2 (0.8 mmol), reaction time (24 h) at room temperature. b Isolated
(1 mL), reaction time (5 h) at 70 oC in air; (2) then
yield.
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In order to explore the mechanism, some control mainly to remove the relevant Al salts coordinating with
experiments were performed. Expected intermediate III-1 intermediate III-1, and the molecular iodine acted as an
could be prepared successfully from 1o and 2a in the presence excellent oxidant in our method. During the preparation of 3g
,
of AlCl3 (Scheme 2A); meanwhile if without addition of water, a small amount of 4a could be monitored and separated; and
only 6% yield of III-1 could be isolated by column when the substrate 2a was added at one time, more 4a would
chromatography; so the addition of H2O was necessary for be generated though the 3g was still the main product
removing the Al salts coordinating with III-1. Then the III-1 (Scheme 2C). Furthermore, 4a could be generated easily from
could be transformed into the product 3o smoothly under I2- benzothioamide 2a without addition of nitriles (such as 3o
)
mediated conditions at room temperature (Scheme 2B). The under standard conditions (Scheme 2D), so our method
effect of solvents on the reaction was also studied, and the showed rational chemoselectivity for the formation of product
addition of water didn’t affect the reaction yield significantly.
Given the experiments above (Scheme 2A-B and entry 19 in
Table 1), it could be confirmed that the role of water was
3.
Scheme 2. (A) Synthesis of III-1 from 1o and 2a in the presence of AlCl3; (B) I2-mediated synthsis of 3o from III-1; (C) I2-mediated one-pot synthesis of 3g from 1g and 2a; (D)
Oxidative dimerization of 2a without addition of nitriles under standard conditions
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S
aryl-1,2,4-thiadiazoles were inaccessible to be prepared
directly from readily available substrates in the previous
methods. Molecular iodine (I2), as a readily available and eco-
friendly oxidant, has been rarely used in the oxidative coupling
of N-H and S-H bonds because of its low oxidation power. In
view of the potential of the products and the easy availability
of the starting materials, this approach will have a promising
application in the synthesis of 1,2,4-thiadizole derivatives.
Al(III)
H2N
Ar2
N
C
Alk1
S
Al(III)
2
Alk1 CN
Alk1 CN Al(III)
H2N
Ar2
1
I
2
I
Al(III)
N
NH
C
S
S
H2O
I2
C
N
H
II
Alk1
N
Ar2
Alk1
Ar2
H+
HI
Al(III)
H
III
Experimental Section
I
I2
N
Alk1
Ar2
NH
C
S
General experimental procedures: All reactions were carried
out under air. Proton and carbon magnetic resonance spectra
(1H NMR and 13C NMR) were recorded using tetramethylsilane
(TMS) in the solvent of CDCl3 as the internal standard (1H NMR:
TMS at 0.00 ppm,CHCl3 at 7.26 ppm; 13C NMR: CDCl3 at 77.16
ppm) or were recorded using tetramethylsilane (TMS) in the
solvent of d6-DMSO as the internal standard (1H NMR: TMS at
0.00 ppm, DMSO at 2.50 ppm; 13C NMR: DMSO at 39.51 ppm).
General procedure for synthesis of compounds (3a-w):
Aliphatic nitrile (0.8 mmol), AlCl3 (0.8 mmol, 107 mg) and n-
butyl acetate (1 mL) were added into a 10 mL reaction tube
Alk1
HI +
N
Ar2
N S
3
HI+I2
IV
1/2 O2
partial reaction
HI
I2 + H2O
Scheme 3. Possible mechanism for the synthesis of products 3
On the basis of the above control experiments and previous
reports,8,9 a plausible reaction mechanism is proposed in
Scheme 3. Firstly, intermolecular necleophilic addition of
o
charged with a magnetic stirrer; then it was heated to 70 C,
amino group of thioamide
2 to the cyano group of nitrile 1 in
and the aromatic thioamide (4×0.1 mmol per 5 min) was
portionwise added into the tube; the tube was sealed and
the presence of AlCl3 affords aluminum complex II. Then
addition of H2O releases the intermediate III from aluminum
complex II. Subsequently, oxidative iodination of III leads to a
possible iodide IV. Finally, the S-I bond of IV cleaves in the
presence of molecular iodine, and then intramolecular
neclophilic attack of the imino group in iodide IV forms the
o
stirred for 5 h under 70 C in the first step. After cooled down
to the room temperature, 0.3 mL water and iodine (0.8 mmol,
203 mg) was added into the tube; the mixture was stirred for
24 h at room temperature for the second step. The resulting
solution was quenched with saturated aqueous solution of
Na2S2O3. The organic and aqueous layers were separated, and
the aqueous layer was extracted with EtOAc (3×10 mL). The
combined organic layers were dried over anhydrous Na2SO4,
concentrated and purified by column chromatography on silica
gel employing petroleum ether/ EtOAc as eluent to afford
target product (3a-3b’).
target compound 3. It was noticed that a moderate yield could
also be obtained under I2-catalyzed oxidative conditions (entry
15 in Table 1, 50 mol% of I2 under oxygen atmosphere). So the
generated HI could be partially transformed into molecular
iodine (I2) under air or oxygen atmosphere.
3-Methyl-5-phenyl-1,2,4-thiadiazole (3a):11 Eluent: petroleum
ether/ethyl acetate (60:1). Yield 37 mg (52%). White solid, mp
Conclusions
In summary, we have developed a simple and practical 57-58 oC ( lit.11 m.p. 54-56 oC). 1H NMR (300 MHz, CDCl3, 25 oC)
method for I2-mediated one-pot synthesis of 3-alkyl-5-aryl- δ 7.93 (d, J = 7.5 Hz, 2H), 7.60-7.41 (m, 3H), 2.72 (s, 3H). 13C
1,2,4-thiadiazoles from nitriles and thioamides. The one-pot NMR (75 MHz, CDCl3, 25 oC) δ 188.1, 174.1, 131.9, 130.5,
reaction includes sequential intermolecular addition of 129.30, 127.4, 19.1. ESI-MS [M+H]+ m/z 177.2.
thioamides to nitriles in the presence of AlCl3, and 5-Phenyl-3-propyl-1,2,4-thiadiazole (3b): Eluent: petroleum
intramolecular oxidative coupling of N-H and S-H bonds ether/ethyl acetate (200:1). Yield 55mg (68%). Colorless oil. 1H
o
mediated by molecular iodine; and the corresponding 1,2,4- NMR (300 MHz, CDCl3, 25 C) δ 7.95 (d, J = 6.6 Hz, 2H), 7.56-
thiadiazoles derivatives could be obtained in moderate to good 7.42 (m, 3H), 3.02 (t, J = 7.5 Hz, 2H), 2.01-1.83 (m, 3H), 1.03 (t,
yields. Furthermore, the method for the synthesis of 1,2,4- J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3, 25 oC) δ 187.9, 179.0,
thiadiazoles with different substituents at 3- and 5-positions 131.9, 130.7, 129.3, 127.5, 35.2, 21.7, 14.0. ESI-HRMS [M+H]+
from readily available substrates is very rare; and the 3-alkyl-5- m/z calcd for C11H13N2S 205.0794, found 205.0799.
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3-Butyl-5-phenyl-1,2,4-thiadiazole (3c): Eluent: petroleum 8.00 (d, J = 6.8 Hz, 2H), 7.66-7.52 (m, 2H), 7.44-7.31 (m, 1H),
ether/ethyl acetate (200:1). Yield 52 mg (60%). Colorless oil. 1H 7.27-7.16 (m, 2H), 7.13-7.05 (m, 1H), 4.40 (s, 2H). 13C NMR
NMR (400 MHz, d6-DMSO, 25 oC) δ 8.04-7.98 (m, 2H), 7.66- (100 MHz, d6-DMSO, 25 oC) δ 187.9, 175.2, 163.3, 160.9, 140.0
7.54 (m, 3H), 3.04-2.91 (m, 2H), 1.87-1.71 (m, 2H), 1.46 -1.29 (d, J = 7.8 Hz), 132.4, 130.4 (d, J = 8.5 Hz), 129.6 (d, J = 6.1 Hz),
(m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, d6-DMSO, 127.3, 125.2 (d, J = 2.8 Hz), 115.8 (d, J = 21.4 Hz), 113.5 (d, J =
25 oC) δ 187.26, 177.56, 132.22, 129.86, 129.56, 127.25, 32.08, 20.8 Hz), 38.0 (d, J = 1.8 Hz). ESI-HRMS [M+H]+ m/z calcd for
29.71, 21.77, 13.69. ESI-HRMS [M+H]+ m/z calcd for C12H15N2S C15H12FN2S 271.0700, found 207.0701.
219.0950, found 219.0961.
3-(4-Chlorobenzyl)-5-phenyl-1,2,4-thiadiazole (3k): Eluent:
3-Cyclopentyl-5-phenyl-1,2,4-thiadiazole(3d):
Eluent: petroleum ether/ethyl acetate (150:1). Yield 101 mg (88%).
petroleum ether/ethyl acetate (200:1). Yield 57 mg (62%). White solid, mp 83-84oC. 1H NMR (300 MHz, CDCl3, 25 oC) δ
1
Colorless oil. H NMR (400 MHz, d6-DMSO, 25 C) δ 8.07-7.95 7.86 (d, J = 6.7 Hz, 2H), 7.49-7.34 (m, 3H), 7.31-7.16 (m, 4H),
(m, 2H), 7.66-7.54 (m, 3H), 3.52-3.42 (m, 1H), 2.16-2.02 (m, 4.27 (s, 2H). 13C NMR (75 MHz, CDCl3, 25 C) δ 188.7, 175.7,
o
o
2H), 1.99-1.87 (m, 2H), 1.83-1.60 (m, 4H). 13C NMR (100 MHz, 135.7, 132.8, 132.1, 130.6, 130.5, 129.4, 128.8, 127.5, 38.8.
d6-DMSO, 25 oC) δ 187.3, 181.1, 132.2, 129.9, 129.6, 127.3, ESI-HRMS [M+H]+ m/z calcd for C15H12ClN2S 287.0404, found
42.7, 32.0, 25.2. ESI-HRMS [M+H]+ m/z calcd for C13H15N2S 287.0405.
231.0950, found 231.0961.
3-(4-Methoxybenzyl)-5-phenyl-1,2,4-thiadiazole (3l): Eluent:
3-Allyl-5-phenyl-1,2,4-thiadiazole (3e): Eluent: petroleum petroleum ether/ethyl acetate (150:1). Yield 90 mg (80%).
o
o
ether/ethyl acetate (200:1). Yield 30 mg (37%). Colorless oil.
White solid, mp 64-68 C. 1H NMR (400 MHz, d6-DMSO, 25 C)
1H NMR (400 MHz, d6-DMSO, 25 C) δ 8.07-7.94 (m, 2H), 7.73- δ 7.99 (d, J = 7.9 Hz, 2H), 7.66-7.49 (m, 3H), 7.27 (d, J = 8.5 Hz,
7.51 (m, 3H), 6.24-6.05 (m, 1H), 5.30-5.08 (m, 2H), 3.79 (d, J = 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.27 (s, 2H), 3.72 (s, 3H). 13C NMR
6.7 Hz, 2H). 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 187.6, 175.2, (100 MHz, d6-DMSO, 25 oC) δ 187.7, 176.2, 158.0, 132.3, 129.9,
133.7, 132.3, 129.7, 129.5, 127.2, 117.4, 36.8. ESI-HRMS 129.7, 129.5, 129.1, 127.2, 113.9, 55.0, 37.6.ESI-HRMS [M+H]+
o
[M+H]+ m/z calcd for C11H11N2S 203.0637, found 203.0638.
m/z calcd for C16H5N2OS 283.0900, found 283.0899.
3-(3-Chloropropyl)-5-phenyl-1,2,4-thiadiazole (3f): Eluent: 3-[4-(Trifluoromethoxy)benzyl]-5-phenyl-1,2,4-thiadiazole
petroleum ether/ethyl acetate (100:1). Yield 56 mg (59%). (3m): Eluent: petroleum ether/ethyl acetate (150:1). Yield 81
1
o
Colorless oil. H NMR (400 MHz, d6-DMSO, 25 C) δ 8.09-7.90 mg (60%). White solid, mp 63-64 oC. 1H NMR (400 MHz, d6-
(m, 2H), 7.69-7.43 (m, 3H), 3.76 (t, J = 6.5 Hz, 2H), 3.11 (t, J = DMSO, 25 oC) δ 8.00 (d, J = 6.8 Hz, 2H), 7.65-7.54 (m, 3H), 7.50
7.4 Hz, 2H), 2.35-2.14 (m, 2H). 13C NMR (100 MHz, d6-DMSO, (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.41 (s, 2H). 13C NMR
25 oC) δ 187.5, 176.2, 132.2, 129.7, 129.5, 127.2, 44.6, 30.3, (100 MHz, d6-DMSO, 25 oC) δ 187.9, 175.3, 147.1 (q, J = 1.6 Hz),
29.6. ESI-HRMS [M+H]+ m/z calcd for C11H12ClN2S 239.0404, 136.7, 132.3, 130.8, 129.6, 127.2, 121.0, 120.0 (q, J = 256.0 Hz),
found 239.0407.
37.6. ESI-HRMS [M+H]+ m/z calcd for C16H12F3N2OS 337.0617,
3-Benzyl-5-phenyl-1,2,4-thiadiazole (3g):12 Eluent: petroleum found 337.0612.
ether/ethyl acetate (150:1). Yield 92mg (91%). White solid, mp 3-(4-Hydroxybenzyl)-5-phenyl-1,2,4-thiadiazole (3n): Eluent:
o
o
1
o
83-84 C ( lit.12 m.p. 77 C). H NMR (300 MHz, CDCl3, 25 C) δ petroleum ether/ethyl acetate (10:1). Yield 78 mg (73%).
o
7.86 (d, J = 6.6 Hz, 2H), 7.48-7.36 (m, 3H), 7.36-7.30 (m, 2H), White solid, mp 131-136 C. H NMR (400 MHz, d6-DMSO, 25
1
7.30-7.21 (m, 2H), 7.21-7.12 (m, 1H), 4.31 (s, 2H). 13C NMR (75 oC) δ 9.26 (s, 1H), 8.06-7.92 (m, 2H), 7.68-7.50 (m, 2H), 7.14 (d,
MHz, CDCl3, 25 C) δ 188.4, 176.2, 137.3, 132.0, 130.6, 129.3, J = 8.4 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 4.22 (s, 2H). 13C NMR
o
129.2, 128.7, 127.5, 126.9, 39.4. ESI-MS [M+H]+ m/z 253.2.
(100 MHz, d6-DMSO, 25 oC) δ 187.6, 176.5, 156.0, 132.3, 129.8,
3-(2-Methylbenzyl)-5-phenyl-1,2,4-thiadiazole (3h): Eluent: 129.7, 129.5, 127.3, 127.2, 115.2, 37.7. ESI-HRMS [M+H]+ m/z
petroleum ether/ethyl acetate (150:1). Yield 84 mg (79%). calcd for C15H13N2OS 269.0743, found 269.0740.
1
White solid, mp 36-38oC. H NMR (300 MHz, CDCl3, 25 oC) δ 3-(4-Nitrobenzyl)-5-phenyl-1,2,4-thiadiazole (3o): Eluent:
7.85 (d, J = 6.4 Hz, 2H), 7.50-7.31 (m, 3H), 7.28-7.19 (m, 1H), petroleum ether/ethyl acetate (50:1). Yield 96 mg (81%). Pale
7.15-7.02 (m, 3H), 4.30 (s, 2H), 2.33 (s, 3H). 13C NMR (75 MHz, yellow solid, mp 147-148 oC. 1H NMR (300 MHz, CDCl3, 25 oC) δ
CDCl3, 25 oC) δ 188.3, 176.2, 136.9, 135.9, 132.0, 130.7, 130.5, 8.13 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 7.4 Hz, 2H), 7.60-7.32 (m,
130.1, 129.4, 127.6, 127.2, 126.3, 37.3, 20.0. ESI-HRMS [M+H]+ 5H), 4.41 (s, 2H). 13C NMR (75 MHz, CDCl3, 25 oC) δ 189.1,
m/z calcd for C16H15N2S 267.0950, found 267.0962.
174.4, 147.1, 144.7, 132.3, 130.4, 130.2, 129.5, 127.6, 123.9,
3-(4-Methylbenzyl)-5-phenyl-1,2,4-thiadiazole (3i): Eluent: 39.2. ESI-HRMS [M+H]+ m/z calcd for C15H12N3O2S 298.0645,
petroleum ether/ethyl acetate (150:1). Yield 89 mg (84%). found 298.0644.
1
o
White solid, mp 62-64 oC. H NMR (300 MHz, CDCl3, 25 C) δ 3-(Naphthalen-2-ylmethyl)-5-phenyl-1,2,4-thiadiazole (3p):
7.86 (d, J = 6.5 Hz, 2H), 7.47-7.34 (m, 3H), 7.23 (d, J = 7.5 Hz, Eluent: petroleum ether/ethyl acetate (50:1). Yield 93 mg
1
2H), 7.07 (d, J = 7.6 Hz, 2H), 4.27 (s, 2H), 2.25 (s, 3H). 13C NMR (77%). Pale yellow solid, mp 85-87 oC. H NMR (400 MHz, d6-
(75 MHz, CDCl3, 25 oC) δ 187.8, 176.1, 135.6, 134.2, 132.4, DMSO, 25 oC) δ 8.19 (d, J = 7.6 Hz, 1H), 7.98-7.78 (m, 4H), 7.62-
129.7, 129.6, 129.1, 128.9, 127.3, 38.1, 20.7. ESI-HRMS [M+H]+ 7.38 (m, 7H), 4.81 (s, 2H). 13C NMR (100 MHz, d6-DMSO, 25 oC)
m/z calcd for C16H15N2S 267.0950, found 267.0950.
δ 187.7, 175.9, 133.6, 133.5, 132.4, 131.6, 129.7, 129.6, 128.5,
3-(3-Fluorobenzyl)-5-phenyl-1,2,4-thiadiazole (3j): Eluent: 127.6, 127.5, 127.3, 126.2, 125.8, 125.7, 124.2, 36.3. ESI-HRMS
petroleum ether/ethyl acetate (80:1). Yield 63 mg (77%). [M+H]+ m/z calcd for C19H15N2S 303.0950, found 303.0957.
White solid, mp 66-67oC. 1H NMR (400 MHz, d6-DMSO, 25 oC) δ
6 | J. Name., 2012, 00, 1-3
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3-Butyl-5-(m-tolyl)-1,2,4-thiadiazole (3q): Eluent: petroleum 3-Benzyl-5-(4-chlorophenyl)-1,2,4-thiadiazole (3x): Eluent:
ether/ethyl acetate (200:1). Yield 67 mg (72%). Colorless oil. 1H petroleum ether/ethyl acetate (150:1). Yield 108 mg (94%).
1
o
NMR (400 MHz, d6-DMSO, 25 oC) δ 7.89-7.73 (m, 2H), 7.53- White solid, mp 56-57 oC. H NMR (400 MHz, CDCl3, 25 C) δ
7.37 (m, 2H), 3.03-2.91 (m, 2H), 2.41 (s, 3H), 1.84-1.73 (m, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.42-7.37 (m,
1.43-1.31 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, 2H), 7.36-7.30 (m, 2H), 7.28-7.22 (m, 1H), 4.37 (s, 2H). 13C NMR
d6-DMSO, 25 oC) δ 187.4, 177.5, 139.1, 132.9, 129.8, 127.5, (100 MHz, CDCl3, 25 oC) δ 187.1, 176.4, 138.1, 137.1, 129.6,
124.4, 32.1, 29.7, 21.8, 20.8, 13.7. ESI-HRMS [M+H]+ m/z calcd 129.3, 129.1, 128.8, 128.7, 126.9, 39.4. ESI-HRMS [M+H]+ m/z
for C13H17N2S 233.1107, found 233.1108.
calcd for C15H12ClN2S 287.0404, found 287.0416.
3-Benzyl-5-(m-tolyl)-1,2,4-thiadiazole (3r): Eluent: petroleum 3-Benzyl-5-(4-bromophenyl)-1,2,4-thiadiazole (3y): Eluent:
ether/ethyl acetate (150:1). Yield 89 mg (84%). White solid, mp petroleum ether/ethyl acetate (150:1). Yield 118 mg (89%).
1
o
1
o
33-34 oC. H NMR (400 MHz, d6-DMSO, 25 C) δ 7.84-7.74 (m, White solid, mp 75-76 oC. H NMR (400 MHz, d6-DMSO, 25 C)
2H), 7.48-7.39 (m, 2H), 7.39-7.30 (m, 4H), 7.27-7.21 (m, 1H), δ 7.98-7.85 (m, 2H), 7.80-7.71 (m, 2H), 7.38-7.28 (m, 4H), 7.26-
4.35 (s, 2H), 2.39 (s, 3H). 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 7.20 (m, 1H), 4.34 (s, 2H). 13C NMR (100 MHz, d6-DMSO, 25 oC)
188.0, 175.8, 139.1, 137.3, 133.0, 129.7, 129.5, 128.9, 128.5, δ 186.6, 175.9, 137.2, 132.6, 129.2, 129.0, 128.8, 128.5, 126.6,
127.6, 126.6, 124.5, 38.5, 20.8. ESI-HRMS [M+H]+ m/z calcd for 125.8, 38.4. ESI-HRMS [M+H]+ m/z calcd for C15H12BrN2S
C16H15N2S 267.0950, found 267.0961.
330.9899, found 330.9901.
3-(4-Nitrobenzyl)-5-(m-tolyl)-1,2,4-thiadiazole (3s): Eluent: 3-Benzyl-5-(4-nitrophenyl)-1,2,4-thiadiazole (3z): Eluent:
petroleum ether/ethyl acetate (50:1). Yield 91 mg (73%). petroleum ether/ethyl acetate (60:1). Yield 91 mg (77%).
1
o
o
White solid, mp 92-93 oC. H NMR (400 MHz, d6-DMSO, 25 C) Yellow solid, mp 95-96 oC. 1H NMR (400 MHz, d6-DMSO, 25 C)
δ 8.21 (d, J = 8.8 Hz, 2H), 7.84-7.76 (m, 2H), 7.65 (d, J = 8.8 Hz, δ 8.35 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 8.7 Hz, 1H), 7.40-7.28 (m,
2H), 7.49-7.41 (m, 2H), 4.54 (s, 2H), 2.40 (s, 3H). 13C NMR (100 4H), 7.28-7.17 (m, 1H), 4.38 (s, 2H). 13C NMR (100 MHz, d6-
MHz, d6-DMSO, 25 oC) δ 188.3, 174.5, 146.4, 145.2, 139.2, DMSO, 25 oC) δ 185.5, 176.3, 149.2, 137.0, 134.9, 129.0, 128.7,
133.1, 130.4, 129.5, 127.6, 124.5, 123.6, 38.1, 20.7. ESI-HRMS 128.5, 126.7, 124.7, 38.4. ESI-HRMS [M+H]+ m/z calcd for
[M+H]+ m/z calcd for C16H14N3O2S 312.0801, found 312.0812.
C15H12N3O2S 298.0645, found 298.0644.
3-Benzyl-5-(p-tolyl)-1,2,4-thiadiazole (3t): Eluent: petroleum 3-Benzyl-5-(thiophen-2-yl)-1,2,4-thiadiazole (3a’): Eluent:
ether/ethyl acetate (150:1). Yield 100 mg (94%). White solid, petroleum ether/ethyl acetate (200:1). Yield 78 mg (76%).
o
1
mp 50-53 oC. 1H NMR (300 MHz, CDCl3, 25 oC) δ 7.74 (d, J = 7.8 White solid, mp 43-46 oC. H NMR (400 MHz, d6-DMSO, 25 C)
Hz, 2H), 7.39-7.29 (m, 2H), 7.29-7.12 (m, 5H), 4.29 (s, 2H), 2.33 δ 7.98-7.91 (m, 2H), 7.37-7.30 (m, 4H), 7.28-7.21 (m, 2H), 4.31
o
(s, 3H). 13C NMR (75 MHz, CDCl3, 25 C) δ 188.5, 176.1, 142.6, (s, 2H). 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 180.5, 175.1,
137.3, 130.0, 129.3, 128.7, 128.0, 127.5, 126.8, 39.5, 21.8. ESI- 137.2, 132.1, 132.0, 131.5, 129.2, 128.9, 128.5, 126.6, 38.2.
HRMS [M+H]+ m/z calcd for C16H15N2S 267.0950, found ESI-HRMS [M+H]+ m/z calcd for C13H11N3S2 259.0358, found
267.0962.
259.0370.
3-Benzyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (3u): 3-Benzyl-5-(thiophen-3-yl)-1,2,4-thiadiazole (3b’): Eluent:
Eluent: petroleum ether/ethyl acetate (150:1). Yield 100 mg petroleum ether/ethyl acetate (200:1). Yield 66 mg (64%).
1
1
o
(78%). White solid, mp 60-61 oC. H NMR (400 MHz, d6-DMSO) White solid, mp 32-34 oC. H NMR (400 MHz, d6-DMSO, 25 C)
δ 8.22 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.42-7.30 (m, δ 8.47-8.41 (m, 1H), 7.81-7.75 (m, 1H), 7.66-7.61 (m, 1H), 7.37-
1H), 7.29-7.20 (m, 1H), 4.39 (s, 2H). 13C NMR (100 MHz, d6- 7.28 (m, 4H), 7.27-7.20 (m, 1H), 4.33 (s, 2H). 13C NMR (100
DMSO, 25 C) δ 186.2, 176.1, 137.1, 133.2, 131.7 (q, J = 32.2 MHz, d6-DMSO, 25 oC) δ 182.0, 175.5, 137.3, 131.5, 128.9,
Hz), 129.0, 128.5, 128.2, 126.7, 126.5 (q, J = 3.8 Hz), 38.4. ESI- 128.5, 126.6, 126.3, 38.4. ESI-HRMS [M+H]+ m/z calcd for
HRMS [M+H]+ m/z calcd for C16H12F3N2S 321.0668, found C13H11N3S2 259.0358, found 259.0362.
o
321.0678.
Synthesis of N-[1-imino-2-(4-nitrophenyl)ethyl]benzothio
3-Benzyl-5-(2-chlorophenyl)-1,2,4-thiadiazole (3v): Eluent: amide (III-1): 1o (4 mmol, 648 mg), AlCl3 (4 mmol, 533 mg) and
petroleum ether/ethyl acetate (100:1). Yield 64 mg (56%). n-butyl acetate (5 mL) were added into a 25 mL reaction tube
o
1
o
o
White solid, mp 87-88 C. H NMR (400 MHz, d6-DMSO, 25 C) charged with a magnetic stirrer, then it was heated to 70 C,
δ 8.41 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66-7.54 (m, and thiobenzamide (4×0.5 mmol per 5 min) was portionwise
2H), 7.34 (m, 4H), 7.25 (t, J = 7.3 Hz, 1H), 4.39 (s, 2H). 13C NMR added into the tube. The tube was sealed and stirred for 5 h
o
(100 MHz, d6-DMSO, 25 oC) δ 183.3, 174.3, 137.7, 133.5, 133.1, under 70 C. After cooled down to the room temperature, 5
131.1, 130.5, 129.4, 128.9, 128.6, 127.1, 38.7. ESI-HRMS mL water was added into the tube with stirring and cooling.
[M+H]+ m/z calcd for C15H12ClN2S 287.0404, found 287.0409.
The organic and aqueous layers were separated, and the
5-(4-Chlorophenyl)-3-propyl-1,2,4-thiadiazole (3w): Eluent: aqueous layer was extracted with EtOAc (3×20 mL). The
petroleum ether/ethyl acetate (200:1). Yield 62 mg (65%). combined organic layers were dried over anhydrous Na2SO4,
1
o
White solid, mp 42-43 oC. H NMR (400 MHz, d6-DMSO, 25 C) concentrated and purified by column chromatography on silica
δ 8.08-7.96 (m, 2H), 7.70-7.57 (m, 2H), 2.95 (t, J = 7.4 Hz, 2H), gel, employing petroleum ether/dichloromethane (1:1) as
1.92-1.74 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, eluent to afford red solid the desired compound (III-1). Yield
d6-DMSO, 25 oC) δ 185.9, 177.5, 136.8, 129.6, 129.0, 128.6, 311 mg (52%). Orange solid, mp 127-130 oC. 1H NMR (400 MHz,
34.2, 20.9, 13.6. ESI-HRMS [M+H]+ m/z calcd for C11H12ClN2S d6-DMSO, 25 oC) δ 10.24 (s, 1H), 9.53 (s, 1H), 8.21 (d, J = 8.8 Hz,
239.0404, found 239.0407.
2H), 8.08-8.03 (m, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.50-7.40 (m,
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1H), 7.38-7.29 (m, 2H), 4.11 (s, 2H). 13C NMR (100 MHz, d6-
DMSO, 25 oC) δ 208.0, 168.5, 146.5, 144.1, 143.4, 131.2, 130.5,
128.0, 127.6, 123.5, 40.4. ESI-HRMS [M-H]- m/z calcd for
C15H12N3O2S 298.0656, found 298.0652.
3
4
5
6
J. Noei and A. -R. Khosropour, Tetrahedron Lett., 2013, 54
9.
D. -W. Boykin and A. -A. Farahat, Heterocycles, 2012, 85
2437.
H. Xie, J. -H. Cai, Z. -L. Wang, H. -W. Huang and G. -J. Deng,
Org. Lett., 2016, 18, 2196.
(a) Z. Wang, Y. Kuninobu and M. Kanai, J. Org. Chem., 2013,
78, 7337; (b) C. Lee, X. Wang and H. -Y. Jang, Org. Lett.,
2015, 17, 1130.
(a) A. Correa, I. Tellitu, E. Domínguez and R. SanMartin, Org.
Lett., 2006, 8, 4811; (b) A. Mariappan, K. Rajaguru, N.
Merukan Chola, S. Muthusubramanian and N. Bhuvanesh, J.
Org. Chem., 2016, 81, 6573; (c) E. Rattanangkool, W. Krailat,
T. Vilaivan, P. Phuwapraisirisan, M. Sukwattanasinitt and S.
Wacharasindhu, Eur. J. Org. Chem., 2014, 2014, 4795.
N. Tumula, N. Jatangi, R. K. Palakodety, S. Balasubramanian
and M. Nakka, J. Org. Chem, 2017, 82, 5310.
,
,
Synthesis of 3o from III-1: III-1 (0.4 mmol, 120 mg), iodine (0.8
mmol, 203 mg) and solvent [n-BuAc (1 mL) or n-BuAc/H2O
(1/0.3 mL)] were added into a 10 mL reaction tube charged
with a magnetic stirrer. The mixture was stirred for 24 h at
room tempereture. The resulting solution was quenched with
saturated aqueous solution of Na2S2O3. The organic and
aqueous layers were separated, and the aqueous layer was
extracted with EtOAc (3×10 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated and purified
by column chromatography on silica gel employing petroleum
ether/ EtOAc as eluent to afford target product 3o (90 mg,
76%, n-BuAc as solvent; 97 mg, 82%, n-BuAc/H2O as solvent).
Synthesis of 3,5-diphenyl-1,2,4-thiadiazole (4a): AlCl3 (0.8
mmol, 107 mg) and n-butyl acetate (1 mL) were added into a
10 mL reaction tube charged with a magnetic stirrer; then it
was heated to 70 oC, and thiobenzamide (0.4 mmol, 55 mg)
was added into the tube; the tube was sealed and stirred for 5
7
8
9
B. -N. Wang, Y. -G. Meng, Y. -M. Zhou, L. -N. Ren, J. Wu, W. -
Q. Yu and J. -B. Chang, J. Org. Chem., 2017, 82, 5898.
10 (a) H. Xu, S. -F. Li, H. -X. Liu, H. Fu and Y. -Y. Jiang, Chem.
Commun., 2010, 46, 7617; (b) H. Xu and H. Fu, Chem. Eur. J.
2012, 18, 1180; (c) H. Xu, S. Ma, Y. -Q. Xu, L. -X. Bian, Ding,T.
X. -X. Fang, W. -K. Zhang and Y. -R. Ren, J. Org. Chem., 2015,
80, 1789; (d) H. -Y. Li, J. -Y. Jie, S. -X. Wu, X. -B. Yang and H.
Xu, Org. Chem. Front., 2017, 4, 250; (e) H. -M. Su, L. -Y.
o
Wang, H. -H. Rao and H. Xu, Org. Lett., 2017, 19, 2226.
11 J. Goerdeler and H. Porrmann, Chem. Ber., 1962, 95, 627.
12 Y. -I. Lin, S. A. Lang and S. R. Petty, J. Org. Chem., 1980, 45
3750.
h under 70 C in the first step. After cooled down to the room
temperature, 0.3 mL water and iodine (0.8 mmol, 203 mg) was
added into the tube; the mixture was stirred for 24 h at room
temperature for the second step. The resulting solution was
quenched with saturated aqueous solution of Na2S2O3. The
organic and aqueous layers were separated, and the aqueous
layer was extracted with EtOAc (3×10 mL). The combined
organic layers were dried over anhydrous Na2SO4,
concentrated and purified by column chromatography on silica
gel employing petroleum ether/ EtOAc (100:1) as eluent to
afford target product (4a). Yield 34 mg (72%). White solid, mp
,
o
o
95-96 C. 1H NMR (300 MHz, d6-DMSO, 25 C) δ 8.44-8.25 (m,
2H), 8.22-8.04 (m, 2H), 7.74-7.50 (m, 6H). 13C NMR (75 MHz,
d6-DMSO, 25 oC) δ 188.0, 172.8, 132.5, 132.1, 130.7 , 129.7,
129.6, 129.0, 127.9, 127.4. ESI-MS [M+H]+ m/z 239.1.
Acknowledgements
This work was supported by National Natural Science
Foundation of China (Grant No. 21502042, 21402126,
51403051, 21477033), Scientific Research Key Project Fund of
Henan Provincial Education Department (Grant No.
15A150041, 16A150003).
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,
8 | J. Name., 2012, 00, 1-3
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