Synthesis of 5-Amino and 3,5-Diamino Substituted 1,2,4-Thiadiazoles by I2-Mediated Oxidative N-S Bond Formation

Article abstract of DOI:10.1021/acs.joc.7b00814

An oxidative N-S bond formation reaction has been established for 1,2,4-thiadiazole synthesis employing molecular iodine as the sole oxidant. The features of the present reaction include no use of transition metals, mild reaction conditions, simple operat

Full text of DOI:10.1021/acs.joc.7b00814

Subscriber access provided by Eastern Michigan University | Bruce T. Halle Library
Article
Synthesis of 5-Amino and 3,5-Diamino Substituted 1,2,4-
Thiadiazoles by I2-Mediated Oxidative N-S Bond Formation
Bingnan Wang, Yinggao Meng, Yiming Zhou, Linning Ren, Jie Wu, Wenquan Yu, and Junbiao Chang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 May 2017
Downloaded from http://pubs.acs.org on May 12, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Synthesis of 5ꢀAmino and 3,5ꢀDiamino Substituted 1,2,4ꢀThiadiazoles
by I2ꢀMediated Oxidative N−S Bond Formation
7
8
9
Bingnan Wang, Yinggao Meng, Yiming Zhou, Linning Ren, Jie Wu, Wenquan Yu,*
and Junbiao Chang*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan
Province 450001, P. R. China
Abstract: An oxidative N–S bond formation reaction has been established for
1,2,4ꢀthiadiazole synthesis employing molecular iodine as the sole oxidant. The
features of the present reaction include no use of transition metals, mild reaction
conditions, simple operation, and short reaction time. This versatile synthetic
approach is broadly applicable to a variety of imidoyl and guanyl thiourea substrates
to produce 5ꢀamino and 3,5ꢀdiamino substituted 1,2,4ꢀthiadiazole derivatives,
respectively, in an efficient and scalable fashion.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
ꢀ Introduction
5
6
7
8
Oxidative N−S bond formation is a useful synthetic approach for the construction of
nitrogenꢀ and sulfurꢀcontaining frameworks. In recent years, such transformations
were accomplished via copperꢀcatalyzed aerobic oxidation1 and hypervalent
iodine(III)ꢀmediated oxidative cyclization.2 As an inexpensive and lowꢀtoxic reagent,
molecular iodine has been successfully employed to construct C−C and C−X (X = N,
O, or S) bonds via direct C−H functionalization.3 However, applications of iodine in
heteroatomꢀheteroatom bond formation reactions remain relatively undeveloped. In
2016, Jiang and Li4 disclosed an intermolecular [3 + 2] heterocyclization for
1,2,3ꢀthiadiazole synthesis by using the combination of I2 and O2 as oxidantion
sources. Previously, we also described an I2/KIꢀenabled oxidative cyclization of
Nꢀaryl amidines to synthesize 1,5ꢀfused 1,2,4ꢀtriazoles via N−N bond formation5
(Scheme 1).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Proposed Route to Access 1,2,4ꢀThiadiazoles via I2ꢀMediated
Oxidative N‒S Bond Formation Based on the Previous Work
N
N
S
N
H
N
R1
R1
R2
previous work:
X
N
H
R2
N–N bond formation
N
X
X = N or CH
iodine
N
H
S
N
this work:
N–S bond formation
R1
R1
N
H
N
H
R2
N
R2
N
H
1,2,4ꢀThiadiazole is an important sulfurꢀcontaining heterocylclic moiety occurring
frequently in many compounds with diverse biological and pharmaceutical
properties,6 such as enzyme inhibitory,7 receptor modulation,8 antiinflammatory9
antibiotic,10 fungicidal,11 antiulcerative,12 and antidiabetic activities.13 Among the
various synthetic methods reported for 1,2,4ꢀthiadiazole preparation,6,14 several
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
approaches provide access to the 5ꢀamino substituted derivatives through oxidative
cyclization using oxidants2a,15,16 (e.g. PIFA, Br2, and H2O2), Cu(II)ꢀcatalyzed
dehydrogenative coupling,17 thermolysis of N3ꢀthiocarbamoylamidrazone ylides,18
or KF/Al2O3ꢀmediated cyclocondensation of amidoximes with thioureas.19 However,
synthetic pathways towards 3,5ꢀdiaminoꢀ1,2,4ꢀthiadiazoles are rarely reported in the
literature.20 The existing methods only allow for the synthesis of N3,N5ꢀsymmetrically
substituted derivatives through oxidative annulations of two molecules of the same
thiourea precursors. Thus, more general and practical synthetic methods for the
preparation of amino substituted 1,2,4ꢀthiadiazoles are still in high demand and would
be of great importance to medicinal chemistry research. Encouraged by our previous
work5 on I2ꢀmediated heteroatomꢀheteroatom bond construction, herein we developed
a versatile and efficient N−S bond formation reaction to access both 5ꢀamino and
3,5ꢀdiamino substituted 1,2,4ꢀthiadiazole derivatives from readily available precursors
(Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ Results and Discussion
The required substrates 3 were readily prepared via the addition reaction of amidines
to corresponding isothiocyanates (see Experimental Section). Initially, we took
imidoyl thiourea 3b as the model substrate with which to investigate the I2ꢀmediated
oxidative cyclization for 5ꢀaminoꢀ1,2,4ꢀthiadiazole synthesis. The expected product
1b was formed in absence of base in CH2Cl2 at room temperature; however, the
conversion was still incomplete after 32 h, giving product 1b in 89% yield (entry 1,
Table 1). Addition of inorganic bases could accelerate the reaction (entries 2−3), with
K2CO3 resulting in a better yield. Further solvent screening (entries 4−8) suggested
that MeCN is the most effective media for this transformation. Nevertheless, both the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
conversion rate and the yield of the product were affected in MeCN without base
(entry 9).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the Reaction Conditions for the Synthesis of
5ꢀAminoꢀ1,2,4ꢀthiadiazole 1ba
entry
base
solvent
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
DCE
time
32 h
6 h
yieldb
89%
90%
99%
90%
82%
82%
97%
99%
87%
c
1
2
3
4
5
6
7
8
9
−
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
−
5 h
6 h
17 h
7 h
1,4ꢀdioxane
toluene
MeCN
MeCN
21 h
15 min
5 h
aReaction conditions unless specified otherwise: 3b (0.5 mmol), iodine (0.6 mmol), base (0.75 mmol),
solvent (5 mL), rt. bIsolated yields are given. cIn the absence of base.
Having established the optimal reaction conditions (entry 8 in Table 1), we sought
to examine the substrate scope and the generality of this methodology for thiadiazole
synthesis. A range of imidoyl thioureas 3 were subjected to the above oxidative
cyclization conditions, and all were smoothly and efficiently converted into the
desired 5ꢀaminoꢀ1,2,4ꢀthiadiazoles 1 (Scheme 2). Taking the synthesis of 1a as an
example, the reaction was successfully conducted on the gram scale. It is compatible
with both electronꢀdonating groups (EDGs) and electronꢀwithdrawing groups (EWGs)
on the N5ꢀphenyl ring (R1) (1a−j). The good functional group tolerance allows for the
presence of a carboxylic ester moiety in the substrate, as in 1i. The
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N5ꢀcyclohexylaminoꢀ1,2,4ꢀthiadiazole (1k) was also prepared from the corresponding
precursor in an excellent yield. Moreover, both 2ꢀaryl and 2ꢀalkyl substituted
5ꢀaminoꢀ1,2,4ꢀthiadiazoles (1l−u) were synthesized under these mild reaction
conditions in high yields. Among them, the 3ꢀ(2,6ꢀdichlorophenyl)ꢀ5ꢀ(4ꢀchloroanilino)
analogue (1u) has previously been demonstrated with potent fungicidal and squalene
epoxidase inhibitory activity.11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Substrate Scope for 5ꢀAminoꢀ1,2,4ꢀthiadiazole Synthesisa
S
NH
R2
S N
R1
R1
I2, K2CO3
MeCN, rt
N
N
N
R2
N
H
H
H
3
1
S N
N
1a, 99% (96%b)
R'
1b
(R' = 4-Me), 99%
Ph
S
N
1c (R' = 3-Me), 99%
1d (R' = 2-Me), 99%
N
Ph
H
N
Ph
N
H
R'
MeO
NC
S
N
S
N
S N
N
Ph
N
N
Ph
N
Ph
H
N
N
H
H
1f (R' = Cl), 98%
1g (R' = I), 98%
1e, 99%
1h, 96%
Me
MeO2C
Me
S
N
S N
S
N
N
Ph
N
N
N
Ph
N
H
Ph
H
N
H
Me
1i, 98%
1j, 98%
1k, 99%
S
N
S
N
S
N
Arc
N
Ar
Ar
N
N
N
N
N
H
H
H
N
R''
CF3
1l (R'' = Me), 99%
1m (R'' = Br), 99%
1n
, 99%
1o
, 99%
S N
S
N
S N
Ar
Ar
Ar
N
N
N
N
Me
N
N
N
N
H
H
H
1p, 99%
1q, 98%
1r, 99%
Cl
Cl
S
N
S N
N
S
N
Ar
Ar
N
N
H
N
N
N
H
H
Cl
1s
, 94%
1t
, 98%
1u
, 93%
aReaction conditions: 3 (0.5 mmol), iodine (0.6 mmol), K2CO3 (0.75 mmol), MeCN, rt, 15 min
(isolated yields are given). bThe yield of gramꢀscale synthesis (5 mmol). cAr = 4ꢀmethylphenyl.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
5
6
7
8
9
Furthermore, this synthetic protocol can be extended to the preparation of
3,5ꢀdiamino substituted 1,2,4ꢀthiadiazole derivatives. The required guanyl thiourea
substrates 4 were obtained through the addition of guanidines to isothiocyanates (see
Experimental Section). Then, I2ꢀmediated oxidative cyclization of these substrates
afforded a series of N3,N5ꢀsymmetrically and N3,N5ꢀasymmetrically substituted
3,5ꢀdiaminoꢀ1,2,4ꢀthiadiazoles (2a−j) in good yields (Scheme 3). The structure of
N5ꢀmesityl analogue 2e was further confirmed by Xꢀray crystallography (see
Supporting Information). The present reaction works well with both Nꢀaryl and
Nꢀalkyl (R1, R3 and R4) substituted guanyl thioureas. It is worth to mention that the
substrate bearing no substituents at R3 or R4 position was also successfully cyclized
into the expected product (2h). In addition, the synthesis of 2h in CH2Cl2 gave
slightly better than the one in MeCN did, but the former required much longer
reaction time.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Substrate Scope for 3,5ꢀDiaminoꢀ1,2,4ꢀthiadiazole Synthesisa
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
aReaction conditions: 4 (0.5 mmol), iodine (0.6 mmol), K2CO3 (0.75 mmol), MeCN, rt, 15 min
(isolated yields are given). bThe yield of the reaction preformed in CH2Cl2 for 16 h.
5
6
7
8
9
Based on these experimental results along with our previous work of I2ꢀmediated
oxidative N–N bond formation,5 a tentative reaction mechanism for this
intramolecular N–S formation reaction is proposed (Scheme 4). Taking the formation
of thiadiazole 1a as an example, the baseꢀpromoted oxidative iodination of substrate
3a generates a plausible iodo species A. Then the S−I bond in iodide A cleaves, and
consequently an ammonium ion B is formed via a SN2'ꢀtype cyclization of A with a
new N−S bond formed. Finally, the subsequent deprotonation by base affords the
5ꢀaminoꢀ1,2,4ꢀthiadiazole framework 1a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Proposed Mechanism for the Formation of 1,2,4ꢀThiadiazole 1a
ꢀ Conclusion
In summary, we have established an I2ꢀmediated oxidative N−S bond formation
reaction for 1,2,4ꢀthiadiazole synthesis. This practical and transitionꢀmetalꢀfree
synthetic approach works well with a wide range of imidoyl and guanyl thiourea
substrates and can be safely conducted on the gram scale. The features such as high
efficiency, mild reaction conditions, simple operation, and short reaction time make it
an attractive alternative for the preparation of 5ꢀaminoꢀ1,2,4ꢀthiadiazoles. Moreover,
for the first time, this synthetic method provides a direct access to both
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
N3,N5ꢀsymmetrically and N3,N5ꢀasymmetrically substituted 3,5ꢀdiaminoꢀ1,2,4ꢀ
5
6
thiadiazole derivatives.
7
8
9
ꢀ Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Information. 1H and 13C NMR spectra were recorded on a 400 MHz (100
MHz for 13C NMR) spectrometer. Chemical shift values are given in parts per million
(ppm) with tetramethylsilane (TMS) as an internal standard. The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; hept, heptet; m, multiplet. The
coupling constants (J) are reported in hertz (Hz). Melting points were determined on a
micromelting point apparatus without corrections. Infrared (IR) spectra were obtained
on an FTꢀIR spectrometer. Highꢀresolution mass spectra (HRMSꢀESI) were obtained
on a QꢀTOF mass spectrometer. Flash column chromatography was performed over
silica gel 200−300 mesh, and the eluent was a mixture of EtOAc and petroleum ether
(PE). CH2Cl2 and EtOH was analytical reagent grade and used without any
pretreatment.
General Procedure A for the Preparation of Substrates 3. A mixture of an
amidine salt (2.0 mmol), the corresponding isothiocyanate (2.2 mmol), and K2CO3
(414 mg, 3.0 mmol) in CH2Cl2 (10 mL) (for 3n and 3s, EtOH was used) was stirred at
room temperature for 12 h, then quenched with H2O (10 mL), and extracted with
CH2Cl2 (15 mL × 3). The combined organic layer was dried over anhydrous Na2SO4,
concentrated, and purified through silica gel column chromatography to afford the
substrate 3.
General Procedure B for the Preparation of Substrates 4. A mixture of an
guanidine salt (2.4 mmol), the corresponding isothiocyanate (2.0 mmol), and K2CO3
(553 mg, 4.0 mmol) in EtOH (10 mL) was stirred at room temperature for 12 h (for
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4f−i, it was performed at 70 °C for 3 h), and then concentrated under reduced pressure.
The resulting residue was treated with H2O (15 mL) and extracted with EtOAc (15
mL × 3). The combined organic layer was dried over anhydrous Na2SO4, concentrated,
and purified through silica gel column chromatography to give the substrate 4.
General Procedure C for the Synthesis of Products 1 and 2. A stirred solution of
the substrates 3 or 4 (0.5 mmol) in MeCN (5 mL) was treated with iodine (153 mg,
0.6 mmol) and K2CO3 (104 mg, 0.75 mmol) in sequence, and then stirred at room
temperature for 15 min. The reaction was quenched with 5% Na2S2O3 (5 mL), diluted
with H2O (10 mL), and extracted with EtOAc (15 mL × 3). The combined organic
layer was dried over anhydrous Na2SO4, concentrated, and then purified through silica
gel column chromatography to afford the product 1 or 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N,3ꢀDiphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1a). Eluent: EtOAc/PE 10:90; yield: 126
1
mg, 99%; white solid, mp 174−176 °C (lit2a 170−173 °C); H NMR (400 MHz,
CDCl3) δ 8.36 (s, 1H), 8.22−8.20 (m, 2H), 7.45−7.39 (m, 5H), 7.24 (d, J = 7.6 Hz,
2H), 7.17 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 180.6, 169.2, 139.1,
132.8, 130.2, 129.9, 128.6, 128.0, 124.4, 118.4; HRMS (m/z) [M + H]+ calcd for
C14H12N3S 254.0746, found 254.0746.
3ꢀPhenylꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1b). Eluent: EtOAc/PE 17:83; yield:
1
132 mg, 99%; white solid, mp 153−155 °C (lit21 156−157 °C) H NMR (400 MHz,
CDCl3) δ 8.37 (s, 1H), 8.20−8.18 (m, 2H), 7.44−7.43 (m, 3H), 7.20 (d, J = 8.4 Hz,
2H), 7.12 (d, J = 8.4 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 181.3,
169.2, 136.6, 134.6, 132.8, 130.4, 130.2, 128.6, 128.0, 119.0, 20.9; HRMS (m/z) [M +
H]+ calcd for C15H14N3S 268.0903, found 268.0899.
3ꢀPhenylꢀNꢀ(mꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1c). Eluent: EtOAc/PE 17:83; yield:
1
132 mg, 99%; offꢀwhite solid, mp 113−114 °C (lit2a 110−113 °C); H NMR (400
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
9
MHz, CDCl3) δ 8.74 (s, 1H), 8.21−8.19 (m, 2H), 7.44−7.42 (m, 3H), 7.28−7.25 (m,
1H), 7.03−7.01 (m, 1H), 6.96−6.94 (m, 2H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 181.1, 169.3, 140.0, 139.1, 132.9, 130.2, 129.6, 128.6, 128.1, 125.2, 119.5,
115.3, 21.4; HRMS (m/z) [M + H]+ calcd for C15H14N3S 268.0903, found 268.0906.
3ꢀPhenylꢀNꢀ(oꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1d). Eluent: EtOAc/PE 17:83; yield:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
132 mg, 99%; white solid, mp 173−175 °C (lit2a 168−171 °C); H NMR (400 MHz,
CDCl3) δ 8.28 (s, 1H), 8.13−8.11 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.41−7.25 (m,
5H), 7.18 (t, J = 7.2 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.9,
169.7, 137.8, 132.9, 131.5, 130.5, 130.0, 128.5, 127.9, 127.6, 126.2, 121.0, 17.7;
HRMS (m/z) [M + H]+ calcd for C15H14N3S 268.0903, found 268.0897.
Nꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1e).2a Eluent: EtOAc/PE
1
17:83; yield: 140 mg, 99%; white solid, mp 144−145 °C; H NMR (400 MHz,
DMSOꢀd6) δ 10.84 (s, 1H), 8.17−8.15 (m, 2H), 7.56−7.50 (m, 5H), 7.02−7.00 (m, 2H),
3.76 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 180.1, 169.0, 155.8, 133.8, 133.3,
130.6, 129.2, 128.0, 120.2, 115.1, 55.8; HRMS (m/z) [M + H]+ calcd for C15H14N3OS
284.0852, found 284.0856.
Nꢀ(4ꢀChlorophenyl)ꢀ3ꢀphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1f). Eluent: EtOAc/PE
1
25:75; yield: 141 mg, 98%; white solid, mp 197−199 °C (lit2a 194−196 °C); H NMR
(400 MHz, DMSOꢀd6) δ 11.14 (s, 1H), 8.20−8.18 (m, 2H), 7.72 (d, J = 8.8 Hz, 2H),
7.53−7.47 (m, 5H); 13C NMR (100 MHz, DMSOꢀd6) δ 179.3, 169.0, 139.2, 133.1,
130.7, 129.7, 129.2, 128.1, 126.8, 119.7; HRMS (m/z) [M + H]+ calcd for
C14H11ClN3S 288.0357, found 288.0357.
Nꢀ(4ꢀIodophenyl)ꢀ3ꢀphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1g).2a Eluent: EtOAc/PE
1
17:83; yield: 186 mg, 98%; white solid, mp 210−212 °C; H NMR (400 MHz,
DMSOꢀd6) δ 11.12 (s, 1H), 8.20−8.18 (m, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.54−7.52 (m,
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
5H); 13C NMR (100 MHz, DMSOꢀd6) δ 179.2, 169.0, 140.1, 138.4, 133.1, 130.7,
129.2, 128.1, 120.4, 86.4; HRMS (m/z) [M + H]+ calcd for C14H11IN3S 379.9713,
found 379.9693.
9
4ꢀ((3ꢀPhenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀyl)amino)benzonitrile (1h).2a Eluent: EtOAc/PE
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
25:75; yield: 134 mg, 96%; white solid, mp 194ꢀ196 °C; H NMR (400 MHz,
13
DMSOꢀd6) δ 11.48 (s, 1H), 8.23−8.21 (m, 2H), 7.89 (s, 4H), 7.56−7.53 (m, 3H); C
NMR (100 MHz, DMSOꢀd6) δ 179.0, 169.1, 143.9, 134.3, 133.0, 130.8, 129.3, 128.1,
119.6, 118.2, 104.6; HRMS (m/z) [M + H]+ calcd for C15H11N4S 279.0699, found
279.0697.
Methyl 4ꢀ((3ꢀphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀyl)amino)benzoate (1i).2a Eluent: EtOAc/PE
1
33:67; yield: 153 mg, 98%; offꢀwhite solid, mp 213−215 °C; H NMR (400 MHz,
DMSOꢀd6) δ 11.41 (s, 1H), 8.24−8.21 (m, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.82 (d, J =
8.8 Hz, 2H), 7.56−7.53 (m, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ
179.1, 169.1, 166.2, 144.2, 133.0, 131.4, 130.8, 129.3, 128.1, 123.7, 117.5, 52.4;
HRMS (m/z) [M + H]+ calcd for C16H14N3O2S 312.0801, found 312.0804.
NꢀMesitylꢀ3ꢀphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1j). Eluent: EtOAc/PE17:83; yield:
1
145 mg, 98%; offꢀwhite solid, mp 199−200 °C; H NMR (400 MHz, CDCl3) δ 8.38
(br, s, 1H), 8.05−8.03 (m, 2H), 7.38−7.28 (m, 3H), 6.98 (s, 2H), 2.33 (s, 3H), 2.29 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 186.2, 169.9, 138.8, 136.3, 133.9, 133.0, 129.9,
128.3, 127.7, 21.1, 17.9; IR (film) 2916(w), 1568(m), 1470(m), 1427(m), 1340(m),
1118(m), 703(s), 688(s); HRMS (m/z) [M + H]+ calcd for C17H18N3S 296.1216, found
296.1217.
NꢀCyclohexylꢀ3ꢀphenylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1k). Eluent: EtOAc/PE 17:83;
yield: 128 mg, 99%; white solid, mp 126−127 °C (lit18 120−122 °C); H NMR (400
1
MHz, CDCl3) δ 8.17−8.14 (m, 2H), 7.44−7.41 (m, 3H), 6.10 (br, s, 1H), 3.25−3.18 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
6
7
8
9
1H), 2.10−2.07 (m, 2H), 1.77−1.74 (m, 2H), 1.65−1.62 (m, 1H), 1.43−1.19 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 183.3, 169.8, 133.2, 129.9, 128.5, 127.9, 56.2, 32.6,
25.3, 24.6; HRMS (m/z) [M + H]+ calcd for C14H18N3S 260.1216, found 260.1216.
N,3ꢀDiꢀpꢀtolylꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1l). Eluent: EtOAc/PE 20:80; yield: 138
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mg, 98%; white solid, mp 180−182 °C (lit19 180−182 °C); H NMR (400 MHz,
CDCl3) δ 8.12 (br, s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.20 (d, J
= 8.0 Hz, 2H), 7.14−7.11 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 181.1, 169.5, 140.2, 136.7, 134.4, 130.4, 130.3, 129.3, 127.9, 118.9, 21.5,
20.9; HRMS (m/z) [M + H]+ calcd for C16H16N3S 282.1059, found 282.1065.
3ꢀ(4ꢀBromophenyl)ꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1m). Eluent: EtOAc/PE
17:83; yield: 171 mg, 99%; white solid, mp 238−239 °C (lit2a 241−243 °C); H NMR
1
(400 MHz, DMSOꢀd6) δ 10.97 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz,
2H), 7.50 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H); 13C NMR (100
MHz, DMSOꢀd6) δ 179.9, 168.0, 137.9, 132.7, 132.4, 132.3, 130.3, 130.0, 124.1,
118.4, 20.9; HRMS (m/z) [M + H]+ calcd for C15H13BrN3S 346.0008, found 346.0018.
Nꢀ(pꢀtolyl)ꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1n). Eluent:
1
EtOAc/PE 17:83; yield: 161 mg, 96%; offꢀwhite solid, mp 234−236 °C; H NMR
(400 MHz, DMSOꢀd6) δ 11.03 (s, 1H), 8.36 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.0 Hz,
2H), 7.52 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H); 13C NMR (100
MHz, DMSOꢀd6) δ 180.1, 167.5, 137.8, 136.7, 132.8, 130.5 (q, JCꢀF = 32.0 Hz), 130.3,
128.7, 126.3, (q, JCꢀF = 3.8 Hz), 124.6 (q, JCꢀF = 270.6 Hz), 118.5, 20.9; IR (film)
3238(w), 1561(m), 1444(m), 1314(m), 1129(vs), 1103(m), 709(s), 658(s); HRMS
(m/z) [M + H]+ calcd for C16H13F3 N3S 336.0777, found 336.0795.
3ꢀ(Pyridinꢀ4ꢀyl)ꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1o). Eluent: EtOAc/PE 25:75;
yield: 132 mg, 99%; offꢀwhite solid, mp 241−243 °C; 1H NMR (400 MHz, DMSOꢀd6)
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
δ 11.06 (s, 1H), 8.76−8.75 (m, 2H), 8.05−8.04 (m, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.25
(d, J = 8.0 Hz, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 180.3, 167.0,
151.0, 139.7, 137.7, 132.9, 130.3, 121.9, 118.5, 20.9; IR (film) 2854(w), 1640(m),
1445(s), 1359(s), 806(m), 698(vs); HRMS (m/z) [M + H]+ calcd for C14H13N4S
269.0855, found 269.0855.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀ(1Hꢀpyrazolꢀ1ꢀyl)ꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1p).2a Eluent: EtOAc/PE
1
50:50; yield: 127 mg, 99%; light yellow solid, mp 200−203 °C; H NMR (400 MHz,
CDCl3) δ 9.02 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.52 (s, 1H), 7.24−7.16 (m, 4H), 6.39
(t, J = 2.4Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.0, 158.4, 142.5,
136.4, 135.7, 130.4, 129.1, 121.0, 108.0, 21.0; HRMS (m/z) [M + H]+ calcd for
C12H12N5S 258.0808, found 258.0811.
3ꢀMethylꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1q).16 Eluent: EtOAc/PE 17:83;
1
yield: 103 mg, 98%; offꢀwhite solid, mp 144−146 °C; H NMR (400 MHz, CDCl3) δ
9.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 2.43 (s, 3H), 2.36 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 182.3, 169.5, 137.0, 134.9, 130.4, 119.7, 20.9,
19.1; HRMS (m/z) [M + H]+ calcd for C10H12N3S 206.0746, found 206.0741.
3ꢀCyclopropylꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1r). Eluent: EtOAc/PE 17:83;
1
yield: 115 mg, 99%; offꢀwhite solid, mp 135−136 °C; H NMR (400 MHz, CDCl3) δ
8.54 (s, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 2.34 (s, 3H),
2.14−2.07 (m, 1H), 1.09−1.05 (m, 2H), 0.99−0.94 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 181.1, 174.5, 136.8, 134.5, 130.3, 119.1, 20.9, 13.6, 8.9; IR (film) 2918(w),
1556(m), 1440(m), 1359(s), 814(m); HRMS (m/z) [M + H]+ calcd for C12H14N3S
232.0903, found 232.0901.
3ꢀIsopropylꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1s).22 Eluent: EtOAc/PE 17:83;
1
yield: 110 mg, 94%; offꢀwhite solid, mp 114−115 °C; H NMR (400 MHz, CDCl3) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
5
6
7
8
9
8.80 (br, s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 3.06 (hept, J = 7.2
Hz, 1H), 2.35 (s, 3H), 1.31 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 181.9,
178.4, 137.0, 134.7, 130.4, 119.6, 32.7, 21.4, 20.9; HRMS (m/z) [M + H]+ calcd for
C12H16N3S 234.1059,found 234.1061.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3ꢀ(tertꢀButyl)ꢀNꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1t). Eluent: EtOAc/PE 17:83;
1
yield: 121 mg, 98%; offꢀwhite solid, mp 125−126 °C; H NMR (400 MHz, CDCl3) δ
7.75 (br, s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 2.34 (s, 3H), 1.39
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 181.0, 180.9, 136.9, 134.2, 130.3, 118.8, 36.9,
29.4, 20.8; IR (film) 2961(w), 1608(m), 1558(s), 1361(s), 816(m); HRMS (m/z) [M +
H]+ calcd for C13H18N3S 248.1216, found 248.1217.
Nꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(2,6ꢀdichlorophenyl)ꢀ1,2,4ꢀthiadiazolꢀ5ꢀamine (1u).11 Eluent:
1
EtOAc/PE 20:80; yield: 154 mg, 93%; light yellow solid, mp 216−217 °C; H NMR
(400 MHz, CDCl3) δ 10.22 (br, s, 1H), 7.33−7.29 (m, 3H), 7.20 (d, J = 8.8 Hz, 2H),
6.96 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 182.3, 164.8, 137.8, 135.2,
132.7, 130.9, 130.2, 129.7, 128.0, 120.9; HRMS (m/z) [M + H]+ calcd for
C14H9Cl3N3S 355.9577, found 355.9590 .
N3,N5ꢀDiphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2a).20b Eluent: EtOAc/PE 17:83;
1
yield: 131 mg, 98%; white solid, mp 203−205 °C (lit1 203−205 °C); H NMR (400
MHz, DMSOꢀd6) δ 10.73 (s, 1H), 9.74 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.62 (d, J =
8.0 Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H), 7.26 (t, J = 8.4 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H),
6.89 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ 176.8, 162.7, 141.5, 140.4,
129.7, 129.0, 123.2, 121.0, 118.2, 117.3; HRMS (m/z) [M + H]+ calcd for C14H13N4S
269.0855, found 269.0867.
N3ꢀPhenylꢀN5ꢀ(pꢀtolyl)ꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2b).23 Eluent: EtOAc/PE
17:83; yield: 123 mg, 87%; white solid, mp 172−173 °C; 1H NMR (400 MHz, CDCl3
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mixture of tautomers, *peaks of the minor one) δ 8.41* (br, s, 0.2H), 8.33 (s, 0.8H),
7.55 (d, J = 7.6 Hz, 1.6H), 7.43−7.39 (m, 0.8H), 7.33−7.29 (m, 2.4H), 7.21−7.19 (m,
2.2H), 7.16−7.14* (m, 0.2H), 7.11−7.08 (m, 2H), 6.99 (t, J = 7.6 Hz, 0.8H), 2.35 (s,
2.4H), 2.30* (s, 0.6H); 13C NMR (100 MHz, CDCl3 mixture of tautomers) major
isomer δ 179.5, 162.2, 140.0, 136.5, 134.6, 130.4, 129.1, 121.9, 119.1, 117.6, 20.9;
minor isomer δ 178.9, 161.9, 139.0, 137.5, 131.5, 129.9, 129.5, 124.5, 118.6, 117.9,
20.7; HRMS (m/z) [M + H]+ calcd for C15H15N4S 283.1012, found 283.1011.
N3ꢀPhenylꢀN5ꢀ(mꢀtolyl)ꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2c). Eluent: EtOAc/PE
17:83; yield: 130 mg, 92%; white solid, mp 161−162 °C; 1H NMR (400 MHz, CDCl3
mixture of tautomers, *peaks of the minor one) δ 8.48 (br, s, 1H), 7.55 (d, J = 7.6 Hz,
1.8H), 7.43−7.26 (m, 4.3H), 7.22−7.15* (m, 0.7H), 7.02−6.97 (m, 3.4H), 6.81* (d, J =
7.6 Hz, 0.1H), 2.36 (s, 2.6H), 2.33* (s, 0.4H); 13C NMR (100 MHz, CDCl3 mixture of
tautomers) major isomer δ 178.9, 161.6, 140.1, 139.9, 138.86, 129.7, 129.1, 125.4,
122.0, 119.4, 117.6, 115.6, 21.5; minor isomer δ 178.8, 161.7, 139.8, 138.92, 129.9,
128.9, 124.5, 123.0, 118.6, 118.3, 114.8, 21.6; IR (film) 3080(w), 2960(w), 1515(s),
1439(s), 1362(m), 727(m), 676(m); HRMS (m/z) [M + H]+ calcd for C15H15N4S
283.1012, found 283.1017.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N5ꢀ(4ꢀMethoxyphenyl)ꢀN3ꢀphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine
(2d).
Eluent:
1
EtOAc/PE 17:83; yield: 139 mg, 93%; offꢀwhite solid, mp 187−189 °C; H NMR
(400 MHz, DMSOꢀd6) δ 10.51 (s, 1H), 9.68 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.50 (d,
J = 8.8 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.88 (t, J = 7.6 Hz,
1H), 3.75 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 177.3, 162.7, 155.7, 141.6,
133.8, 129.0, 120.9, 120.4, 117.3, 114.9, 55.8; IR (film) 3080(w), 2961(w), 1536(s),
1440(s), 751(m), 695(m); HRMS (m/z) [M + H]+ calcd for C15H15N4OS 299.0961,
found 299.0974.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
5
6
7
8
9
N5ꢀMesitylꢀN3ꢀphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2e). Eluent: EtOAc/PE 17:83;
yield: 146 mg, 94%; offꢀwhite solid, mp 166−167 °C; 1H NMR (400 MHz, DMSOꢀd6)
δ 9.70 (br, s, 1H), 9.58 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 7.6 Hz, 2H), 6.96
(s, 2H), 6.84 (t, J = 7.6 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 183.6, 162.5, 140.1, 138.8, 136.3, 133.0, 129.8, 129.0, 121.8, 117.6, 21.1,
17.9; IR (film) 3264(w), 1517(s), 1445(m), 1335(m), 742(s), 689(m); HRMS (m/z) [M
+ H]+ calcd for C17H19N4S 311.1325, found 311.1334.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N5ꢀCyclohexylꢀN3ꢀphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2f). Eluent: EtOAc/PE
1
17:83; yield: 129 mg, 94%; white solid, mp 128−129 °C; H NMR (400 MHz,
DMSOꢀd6) δ 9.50 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H ), 7.70 (d, J = 8.0 Hz, 2H), 7.20 (t, J
= 8.0 Hz, 2H), 6.83 (t, J = 7.2 Hz, 1H), 3.47 (br, s, 1H), 1.99−1.95 (m, 2H), 1.74−1.71
(m, 2H), 1.59−1.56 (m, 1H), 1.32−1.17 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 181.2,
162.4, 140.2, 129.0, 121.6, 117.4, 55.7, 32.9, 25.3, 24.6; IR (film) 3267(w), 2927(w),
1520(vs), 1443(m), 1336(m), 748(s), 697(m); HRMS (m/z) [M + H]+ calcd for
C14H19N4S 275.1325, found 275.1312.
N3ꢀ(2ꢀMethylꢀ5ꢀnitrophenyl)ꢀN5ꢀphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2g). Eluent:
1
EtOAc/PE 25:75; yield: 141 mg, 86%; yellow solid, mp 235−237 °C; H NMR (400
MHz, DMSOꢀd6) δ 10.83 (s, 1H), 9.03 (br, s, 2H), 7.80−7.78 (m, 1H), 7.65 (d, J = 8.0
Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.08 (t, J = 7.6 Hz, 1H),
2.44 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 177.5, 162.6, 146.6, 140.3, 140.2,
136.2, 131.6, 129.7, 123.3, 118.3, 116.9, 114.2, 18.8; IR (film) 3268(w), 2929(w),
1521(vs), 1444(m), 1333(m), 750(m), 735(m); HRMS (m/z) [M + H]+ calcd for
C15H14N5O2S 328.0863, found 328.0862.
N5ꢀPhenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2h).21 Eluent: EtOAc/PE 33:67; yield: 78
mg, 81% (yield of the reaction in CH2Cl2 for 16 h: 88 mg, 92%); offꢀwhite solid, mp
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
1
210−212 °C (lit1 214−215 °C); H NMR (400 MHz, DMSOꢀd6) δ 10.55 (s, 1H),
7.53−7.51 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.26 (s, 2H); 13C
NMR (100 MHz, DMSOꢀd6) δ 177.7, 167.2, 140.6, 129.6, 122.7, 117.9; HRMS (m/z)
[M + H]+ calcd for C8H9N4S 193.0542, found 193.0545.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N3ꢀMethylꢀN5ꢀphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2i).24 Eluent: EtOAc/PE 25:75;
1
yield: 100 mg, 97%; offꢀwhite solid, mp 137ꢀ138 °C (lit1 137ꢀ138 °C); H NMR (400
MHz, CDCl3) δ 8.80 (br, s, 1H), 7.41−7.39 (m, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.13 (t,
J = 7.6 Hz, 1H),4.91 (br, s, 1H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.5,
166.9, 139.2, 129.8, 124.1, 118.4, 29.9; HRMS (m/z) [M + H]+ calcd for C9H11N4S
207.0699, found 207.0698.
N3,N3ꢀDimethylꢀN5ꢀphenylꢀ1,2,4ꢀthiadiazoleꢀ3,5ꢀdiamine (2j). Eluent: EtOAc/PE
1
25:75; yield: 107 mg, 97%; offꢀwhite solid, mp 176−177 °C; H NMR (400 MHz,
CDCl3) δ 8.18 (br, s, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.19−7.17 (m, 2H), 7.11 (t, J = 7.6
Hz, 1H), 3.13 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 179.1, 168.1, 139.3, 129.7,
123.8, 118.1, 38.8; IR (film) 2925(w), 1533(s), 1465(m), 1381(m), 1220(m), 755(m),
689(s); HRMS (m/z) [M + H]+ calcd for C10H13N4S 221.0855, found 221.0853.
ꢀ Associated Content
Supporting Information
1
Copies of H and 13C NMR spectra of products 1 and 2 (PDF), and Xꢀray structures
and data of compound 2e (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ Author Information
Corresponding Authors
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
*Eꢀmail: wenquan_yu@zzu.edu.cn
5
6
7
8
*Eꢀmail: changjunbiao@zzu.edu.cn
Notes
9
The authors declare no competing financial interest.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ Acknowledgements
We thank the Outstanding Young Talent Research Fund of Zhengzhou University (No.
1521316004) and the National Natural Science Foundation of China (Nos. 81330075
and 81302637) for financial support.
ꢀ References
(1) (a) Zhu, H.; Yu, J. T.; Cheng, J. Chem. Commun. 2016, 52, 11908. (b) Lee, C.;
Wang, X.; Jang, H. Y. Org. Lett. 2015, 17, 1130. (c) Chen, F. J.; Liao, G.; Li, X.;
Wu, J.; Shi, B. F. Org. Lett. 2014, 16, 5644. (d) Wang, Z.; Kuninobu, Y.; Kanai,
M. J. Org. Chem. 2013, 78, 7337.
(2) (a) Mariappan, A.; Rajaguru, K.; Merukan Chola, N.; Muthusubramanian, S.;
Bhuvanesh, N. J. Org. Chem. 2016, 81, 6573. (b) Anand, D.; Patel, O. P. S.;
Maurya, R. K.; Kant, R.; Yadav, P. P. J. Org. Chem. 2015, 80, 12410. (c)
Rattanangkool, E.; Krailat, W.; Vilaivan, T.; Phuwapraisirisan, P.;
Sukwattanasinitt, M.; Wacharasindhu, S. Eur. J. Org. Chem. 2014, 4795. (d) Ma,
W. B.; Li, S. N.; Zhou, Z. H.; Shen, H. S.; Li, X.; Sun, Q.; He, L.; Xue, Y. Eur. J.
Org. Chem. 2012, 1554.
(3) (a) Zi, W.; Zuo, Z.; Ma, D. Acc. Chem. Res. 2015, 48, 702. (b) Zhao, J.; Gao, W.;
Chang, H.; Li, X.; Liu, Q.; Wei, W. Chin. J. Org. Chem. 2014, 34, 1941. (c) Ren,
Y.ꢀM.; Cai, C.; Yang, R.ꢀC. RSC Adv. 2013, 3, 7182. (d) Parvatkar, P. T.;
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Parameswaran, P. S.; Tilve, S. G. Chem. Eur. J. 2012, 18, 5460. (e) Veisi, H.
Curr. Org. Chem. 2011, 15, 2438.
7
8
9
(4) Fan, W.; Li, Q.; Li, Y.; Sun, H.; Jiang, B.; Li, G. Org. Lett. 2016, 18, 1258.
(5) Song, L.; Tian, X.; Lv, Z.; Li, E.; Wu, J.; Liu, Y.; Yu, W.; Chang, J. J. Org.
Chem. 2015, 80, 7219.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) Castro, A.; Castaño, T.; Encinas, A.; Porcal, W.; Gil, C. Bioorg. Med. Chem.
2006, 14, 1644.
(7) (a) Dahlin, J. L.; Nissink, J. W.; Strasser, J. M.; Francis, S.; Higgins, L.; Zhou, H.;
Zhang, Z.; Walters, M. A. J. Med. Chem. 2015, 58, 2091. (b) Martinez, A.;
Alonso, M.; Castro, A.; Pérez, C.; Moreno, F. J. J. Med. Chem. 2002, 45, 1292.
(8) (a) Göblyös, A.; de Vries, H.; Brussee, J.; Ijzerman, A. P. J. Med. Chem. 2005, 48,
1145. (b) van den Nieuwendijk, A. M. C. H.; Pietra, D.; Heitman, L.; Göblyös, A.;
Ijzerman, A. P. J. Med. Chem. 2004, 47, 663. (c) Fawzi, A. B.; Macdonald, D.;
Benbow, L. L.; SmithꢀTorhan, A.; Zhang, H.; Weig, B. C.; Ho, G.; Tulshian, D.;
Linder, M. E.; Graziano, M. P. Mol. Pharmacol. 2001, 59, 30.
(9) Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.; Schrier, D. J. J. Med.
Chem. 1992, 35, 3691.
(10)Iizawa, Y.; Okonogi, K.; Hayashi, R.; Iwahi, T.; Yamazaki, T.; Imada, A.
Antimicrob. Agents Chemother. 1993, 37, 100.
(11)Kumita, I.; Niwa, A. J. Pestic. Sci. 2001, 26, 60.
(12)Kharimian, K.; Tam, T. F.; LeungꢀToung, R. C.; Li, W. PCT Int. Appl.
WO1999051584 A1, 1999.
(13)Johnstone, C.; Mckerrecher, D.; Pike, K. G.; Waring, M. J. PCT Int. Appl.
WO2005121110 A1, 2005.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
(14)Frija, L. M. T.; Pombeiro, A. J. L.; Kopylovich, M. N. Eur. J. Org. Chem., Early
View, DOI: 10.1002/ejoc.201601642.
7
8
9
(15)Zyabrev, V. S.; Rensky, M. A.; Rusanov, E. B.; Drach, B. S. Heteroatom Chem.
2003, 14, 474.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16)Kurzer, F.; Tertiuk, W. J. Chem. Soc. 1959, 2851.
(17)Kim, H.ꢀY.; Kwak, S. H.; Lee, G.ꢀH.; Gong, Y.ꢀD. Tetrahedron 2014, 70, 8737.
(18)Smith, R. F.; Feltz, T. P. J. Heterocycl. Chem. 1981, 18, 201.
(19)Dürüst, Y.; Yıldırım, M.; Aycan, A. J. Chem. Res. 2008, 235.
(20)(a) Castro, A.; Castaño, T.; Encinas, A.; Porcal, W.; Gil, C. Bioorg. Med. Chem.
2006, 14, 1644. (b) Castro, A.; Encinas, A.; Gil, C.; Bräse, S.; Porcal, W.; Pérez,
C.; Moreno, F. J.; Martínez, A. Bioorg. Med. Chem. 2008, 16, 495. (c) Mamaeva,
E. A.; Bakibaev, A. A. Tetrahedron 2003, 59, 7521.
(21)Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.; Yamasaki, T.; Furukawa, M.
Synthesis 1990, 11, 1020.
(22)Bracha, P.; Lovich, M. Israeli Patent, IL35743 A, 1974.
(23)Akiba, K.ꢀY.; Tsuchiya, T.; Ochiumi, M.; Inamoto, N. Tetrahedron Lett. 1975, 16,
455.
(24)Kurzer, F. J. Chem. Soc. 1956, 2345.
ACS Paragon Plus Environment