I2-Mediated Oxidative C-N and N-S Bond Formation in Water: A Metal-Free Synthesis of 4,5-Disubstituted/N-Fused 3-Amino-1,2,4-triazoles and 3-Substituted 5-Amino-1,2,4-thiadiazoles

Article abstract of DOI:10.1021/acs.joc.8b00753

An environmentally benign and convenient strategy for the synthesis of 4,5-disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4-thiadiazoles from isothiocyanates has been developed. This metal-free method involves I₂-me

Full text of DOI:10.1021/acs.joc.8b00753

Subscriber access provided by Kaohsiung Medical University
Article
I2-Mediated oxidative C-N and N-S bond formation in water:
A metal-free synthesis of 4,5-disubstituted/N-fused 3-
amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4-thiadiazoles
Nagesh Jatangi, Nagaraju Tumula, Radha Krishna Palakodety, and Mangarao Nakka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00753 • Publication Date (Web): 02 May 2018
Downloaded from http://pubs.acs.org on May 2, 2018
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 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 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.
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 31
The Journal of Organic Chemistry
1
2
3
4
I2-Mediated oxidative C-N and N-S bond formation in water: A metal-free synthesis of 4,5-
5
6
disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4-thiadiazoles
7
8
9
Nagesh Jatangi, Nagaraju Tumula, Radha Krishna Palakodety, Mangarao Nakka*
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
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad-500007, India.
An environmentally benign and convenient strategy for the synthesis of 4,5-disubstituted/N-
fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4-thiadiazoles from isothiocyanates
has been developed. This metal-free method involves I2-mediated oxidative C-N and N-S bond
formations in water. Furthermore, this facile protocol exhibited excellent substrate tolerance in
good to high yields and scalable fashion.
INTRODUCTION
N-Containing heterocyclic molecules constitute an important class of compounds in the
fields of material and pharmaceutical chemistry due to their many fold applications. Among
them, 1,2,4-triazoles and 1,2,4-thiadiazoles have emerged as an important structural motif
present in a large number of functionalized molecules with a broad range of biological activities,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 31
1
2
3
4
5
6
7
8
9
such as antibacterial,1 anti-inflammatory,2 antifungal3 and antiviral.4 Moreover, they are also
found in valuable pharmaceuticals, including sitagliptin,5 maraviroc,6 trizaolam,7 deferasirox8
and cefozopran.9 Owing to its broad spectrum of functions, the efficient methods for the
synthesis of 1,2,4-triazoles and 1,2,4-thiadiazoles has attracted much attention. The most
generally explored synthetic pathways for 1,2,4-triazoles involve cyclodehydration of N-
acylamidrazone obtained from hydrazines and carboxylic acid derivatives.10 Whereas, the simple
oxidative dimerization of thioamides using various oxidants is very common protocol for the
synthesis of 1,2,4-thiadiazoles.11 Apart from these, some other synthetic methods to access 1,2,4-
triazoles or 1,2,4-thiadiazoles were also disclosed.12 These protocols suffer from one or more
drawbacks, such as use of transition-metals, harsh reaction conditions with high temperatures or
strong acids, or use of organic solvent. Thus, more general and practical synthetic methods for
the preparation of 4,5-disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-
1,2,4-thiadiazoles are still in high demand.
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
On the other hand, molecular iodine has attracted considerable attention because of its
low toxicity, ready availability, inexpensive in contrast to transition-metal catalysts. As a potent
catalyst, iodine is widely used in various organic reactions.13 Recently, our group developed an
efficient and regiospecific protocol by using molecular iodine as a catalyst for the synthesis of N-
fused 1,2,4-thiadiazoles and 3,4-disubstituted 5-imino-1,2,4-thiadiazoles via N-S bond
formations.14a In addition, the development of reactions in the presence of water has become
highly advantageous to meet environmentally friendly processes in life sciences. Inspired by
these advances, in connection with previous work and continuation of our studies on the
construction of valuable synthetic methodologies for diverse biologically active heterocyclic
scaffolds14b-c herein, we report a novel and environmentally benign protocol for the formation of
ACS Paragon Plus Environment

Page 3 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
C-N and N-S bond using molecular iodine as an oxidant in water for the synthesis of 4,5-
disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4-thiadiazoles
(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
Scheme 1. Synthesis of 4,5-disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-
amino-1,2,4-thiadiazoles.
RESULTS AND DISCUSSION
We began our study by examining the reaction of phenyl isothiocyanate (1a), N-
phenylbenzamidrazone (2a) and iodine (0.5 equiv.) in DMSO at rt for 3 h, provided the desired
product 3a in 38% yield (Table 1, entry 1). To improve the reaction yield, we have screened
various solvents under the same conditions. Polar solvents such as DMF and MeOH provided
moderate yields (Table 1, entries 2 & 3). Moderate conversions were observed using MeCN and
DCM, whereas no reaction took place in EtOAc (Table 1, entries 4-6). The reaction efficiency
was observed in a protic solvent, considering the requirements of green chemistry, we attempted
the water as solvent. The reaction was significantly accelerated in water to give 3a in 52% yield
(Table 1, entry 7). Subsequently, other iodine containing catalysts were also studied, such as
TBAI, KI, NIS and PIDA showed a lower yield of 3a (Table 1, entries 8-11). Next, we studied
on the amount of iodine, raising the quantity of iodine from 0.5 equiv. to 1 equiv. provided the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 31
1
2
3
4
5
6
7
8
9
product 3a in 92% yield (Table 1, entry 12). However, further increase of iodine did not improve
the yield (Table 1, entry 13). Thus, the optimized reaction conditions are isothiocyanate (1.0
mmol), N-phenylbenzamidrazone (1.0 mmol) and iodine (1.0 equiv.) in water at room
temperature were chosen as the optimum reaction conditions for the synthesis of 4,5-
disubstituted 3-amino- 1,2,4-triazoles.
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.a
Entry
1
Oxidant (mol%)
I2 (50)
Solvent
DMSO
Yield (%)
38
2
I2 (50)
DMF
MeOH
MeCN
DCM
EtOAc
H2O
31
3
I2 (50)
43
4
I2 (50)
18
5
I2 (50)
22
6
I2 (50)
--
7
I2 (50)
52
8
TBAI (50)
KI (50)
H2O
30
9
H2O
26
10
11
12
NIS (50)
PIDA (50)
I2 (100)
H2O
35
H2O
trace
92
H2O
ACS Paragon Plus Environment

Page 5 of 31
The Journal of Organic Chemistry
1
2
3
4
13
I2 (150)
H2O
92
5
6
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol) and oxidant (x mol%) in
7
8
9
solvent (2 mL) at room temperature for 3 h.
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
With this promising result in hand, the scope and generality of the reaction was
investigated and the results are summarized in Scheme 2. The reaction is applicable to a wide
variety of isothiocyanates under the established reaction conditions, giving the corresponding
4,5-disubstituted 3-amino-1,2,4-triazoles in good to high yields. Simple phenyl isothiocyanate
(1a) with N-phenylbenzamidrazone (2a) gave the corresponding 3-amino-1,2,4-triazole (3a) in
92% yield (entry 3a). Electron- donating groups, such as o-methoxy, m-methoxy, p-methoxy, m-
methyl and p-methyl on the phenyl ring of isothiocyanates underwent the reaction efficiently in
excellent yields (entries 3b, 3c & 3g-3i). Meanwhile, the steric hindrance is not obvious for o-
methoxy group on the phenyl isothiocyanate in this protocol (entry 3i). On the other hand,
phenyl isothiocyanates with electron-deficient groups, like chloro, nitro and trifluoro methyl on
para position generated the corresponding 3-amino-substituted 1,2,4-triazoles in good yields
(entries 3d-3f & 3j). These results demonstrate that substitutent’s on phenyl isothiocyanates have
no bearing on the reaction yield. To our delight, alkyl isothiocyanates such as tert-butyl, butyl
and alicyclic isothiocyanate like cyclohexyl also reacted smoothly to afford the desired products
3l-3o in 73% to 76% yield. Furthermore, we investigated the scope of the method by varying the
N-phenylbenzamidrazones, which proceeded successfully to afford the corresponding 3-amino-
1,2,4-triazoles in good yields (entries 3j, 3k, 3m & 3o). After the successful study of substrate
scope, we have evaluated this green methodology towards gram scale level. Importantly, the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 31
1
2
3
4
methodology can be carried out in gram scale without any complications, and 3a was isolated in
5
6
89% yield, demonstrating the efficiency and practicality of this methodology.
7
8
9
Scheme 2. Synthesis of 4,5-disubstituted 3-amino-substituted 1,2,4-triazoles.a
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
3a, X = H, 92% (89%)b
3b, X = Me, 91%
3c, X = OMe, 95%
3d, X = Cl, 87%
3g, X = Me, 89%
3e, X = NO2, 82%
3h, X = OMe, 92%
3f, X = CF3, 82%
N
N
N
N
OMe
H
3i, 81%
3j, 90%
3k, 79%
3l, 76%
3m, 75%
3n, X = H, 76%
ACS Paragon Plus Environment

Page 7 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
3o, X = Cl, 73%
b
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol) and iodine (1.0 equiv.) in water at rt for 3 h. Gram scale
7
8
9
reaction.
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
Encouraged by these successful results, the utility of this iodine mediated protocol was
further investigated for the synthesis of N-fused-3-amino-substituted 1,2,4-triazoles. For this
purpose, amidrazone (2) was replaced with 2-hydrazinopyridine (4) under the established
optimized reaction conditions (Scheme 3). Gratifyingly, we were able to prepare the desired
product N-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5a) in 87% yield. Furthermore, the
substrate scope of phenyl isothiocyanate was examined, both electron-donating and electron-
withdrawing groups at different positions of the phenyl ring gave the desired products 5b-5i in
82% to 88% yields. On replacing the 2-hydrazinopyridine with 2-hydrazineylquinoline was also
compatible with the reaction conditions to deliver 5j in 79% yield. However, the alkyl
isothiocyanates didn’t provide the desired product under the optimal reaction conditions, only the
uncyclized products were observed (Scheme 3, 5k and 5l).
Schme 3. Synthesis of N-fused-3-amino-1,2,4-triazoles.a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 31
1
2
3
4
5
6
7
8
9
5a, X = H, 87% (83%)b
5b, X = Me, 87%
5c, X = OMe, 88%
5d, X = Cl, 85%
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
5g, X = Me, 87%
5e, X = F, 83%
5h, X = OMe, 88%
5f, X = CF3, 83%
5k, R = propyl, 0%
5l, R = butyl, 0%
5j, 79%
5i, 82%
aReaction conditions: 1 (1.0 mmol), 4 (1.0 mmol) and iodine (1.0 equiv) in water at rt for 3 h.
bGram scale reaction.
Table 2. Optimization of reaction conditions for the synthesis 3-substituted 5-amino-1,2,4-
thiadiazoles.a
Entry
1
Iodine (mol%)
I2 (50)
Base
---
temp
rt
Yield (%)
NR
ACS Paragon Plus Environment

Page 9 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
3
4
5
6
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (100)
K2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
rt
74
20
26
90
90
rt
rt
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
60
60
aReaction conditions: 1a (1.0 mmol), 6a (1.0 mmol), Base (1.0 mmol) and iodine (x mol%) in
water for 4-5 h.
In light of our above consecutive results, we attempted to synthesize 1,2,4-oxadiazoles
(7) by replacing amidrazones (2) with amidoximes (6). Surprisingly, we observed the unexpected
product 3-substituted 5-amino-1,2,4-thiadiazoles (8) in the presence of I2 (0.5 equiv.) and K2CO3
(1 equiv.) at room temperature within 5 h in 74% yield (Table 2, entry 2), while the other bases
Na2CO3 and Cs2CO3 gave the product in 20% and 26% yields respectively (Table 2, entries 3
and 4). However, the unexpected product yield could be improved to 90% by raising the
temperature to 60°C in 4 h (Table 2, entry 5). Raising the amount of iodine from 0.5 to 1.0 equiv,
the yield of 8a did not improve (Table 2, entry 6). With the results in hand, we proceeded to
investigate the substrate scope on the outcome of the reaction. It was observed that
benzamidoxime reacts with different isothiocyanites to furnish the respective products in good to
high yields. The phenyl isothiocyanates containing electron-donating groups like methyl and
methoxy at ortho, para and meta position provided of the corresponding products in 86% to 95%
yield (Scheme 4, entries 8b, 8c, 8f & 8g). Phenyl isothiocyanites with electron-withdrawing
groups on the para-positions like -F and -NO2 generated the corresponding products in 88% and
87% yields respectively (Scheme 4, entries 8d & 8e). Interestingly, the reaction also proceeded
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 31
1
2
3
4
5
6
7
8
9
with propyl and cyclohexyl isothiocyanates to afford the desired compounds 8h and 8i in good
yields. Furthermore, we investigated the scope of the method with various amidoximes, such as
p-methy and p-chloro benzamidoximes, which proceeded successfully to afford the
corresponding products in 91% and 89% yields respectively (Scheme 4, entries 8j & 8k).
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. Synthesis of 3-substituted 5-amino-1,2,4-thiadiazoles.a
8a, X = H, 90% (88%)b
8b, X = Me, 92%
8c, X = OMe, 95%
8f, 86%
8d, X = F, 88%
8e, X = NO2, 87%
8h, 84%
8g, 89%
8i, 81%
8j, 91%
8k, 89%
aReaction conditions: 1 (1.0 mmol), 6 (1.0 mmol), iodine (0.5 equiv.) and
K2CO3 (1.09 mmol) in water at 60°C for 4 h. bGram scale reaction.
ACS Paragon Plus Environment

Page 11 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In order to gain more insights into the mechanism of this I2-catalyzed reaction, a series of
control experiments were performed, as shown in Scheme 3. The radical inhibition studies under
the standard reaction conditions with TEMPO, benzoquinone and BHT gave the corresponding
compound 3a in 92%, 91% and 91% yields respectively (Scheme 5, eq 1). These results amply
proved a radical mechanism can be ruled out. Next, the reaction of 1a with (Z)-N-(4-
chlorophenyl)benzohydrazonamide (2k) was carried out in the absence of I2 in water for 1.5 h
gave the intermediate A, whose structure was assigned by 1H, 13C NMR and HRMS (Scheme 5,
eq 2). Furthermore, the intermediate A under the standard conditions produces 3k, indicating that
A might be intermediate for this transformation (Scheme 5, eq 3).
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 5. Control experiments.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 31
1
2
3
4
5
6
7
8
9
On the basis of these experimental results and previous reports,15 a plausible reaction
mechanism for the formation of 4,5-disubstituted 3-amino-1,2,4-triazoles and 3-substituted 5-
amino-1,2,4-thiadiazoles is proposed as shown in Scheme 6. Initially, 1a condensed with 2a in
water to afford intermediate A. Next an intramolecular attack on the carbon atom by the NH
group gave the intermediate B through the formation of S-I bond, which on cleavage of HI and S
gave the desired product 3a. Whereas 1a condensed with 6a to afford intermediate C the
intermediate C reacts with iodine under basic condition generates the plausible iodo species D.
Then the S-I bond cleaves in intermediate D gave the desired 8a with formation of a new N-S
bond.
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 6. Proposed reaction mechanism.
CONCLUSION
In conclusion, we have developed a metal-free and ecofriendly strategy for the oxidative
C-N and N-S bond formation for the synthesis of 4,5-disubstituted/N-fused 3-amino-1,2,4-
triazoles and 4,5-disubstituted 5-amino-1,2,4-thiadiazoles from isothiocyanates for the first time.
Furthermore, this efficient and operationally simple protocol features nontoxic and inexpensive
ACS Paragon Plus Environment

Page 13 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
molecular iodine as the catalyst and water as an environmentally friendly solvent. Moreover, the
wide variety of substrate tolerance in good to excellent yields and amenable to gram-scale
synthesis of our method allowed the construction of library of compounds.
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 and Reagents:
The glassware to be used in reactions was thoroughly washed and dried in an oven and the
experiments were carried out with required precautions. Chemicals and all solvents were
1
obtained from commercial suppliers and used without further purification. H-NMR was
13
measured on Bruker Avance-300, Varian Unity-400 MHz and Avance New-500 MHz and C-
NMR was measured with Varian Unity-400 MHz (100 MHz) and with Avance New-500 MHz
(125 MHz), as specified and referred as the internal standard to TMS (tetramethylsilane).
Chemical shifts (δ) are given in ppm and J values are given in Hz. High Resolution Mass Spectra
(HRMS) were performed on a high resolution magnetic sector mass spectrometer. TLC analysis
was performed on Merck silica gel 60 F254 plates. Column chromatography was performed on
silica gel (100-200 mesh) from Merck. Melting points were measured using melting point
apparatus and were uncorrected. Evaporation of solvents was performed at reduced pressure,
using a rotary vacuum evaporator.
The Scale-up Reaction:
The mixture of isothiocyanate (1a) (7.4 mmol), N-phenylbenzamidrazone (2a) (7.4 mmol)/2-
hydrazinopyridine (4a) (7.4 mmol) and I2 (100 mol%, 933 mg, 7.4 mmol) in water (15 mL) was
stirred magnetically at room temperature. After completion of the reaction as monitored by TLC,
the reaction mixture was quenched with a saturated aqueous solution of Na2S2O3. The organic
and aqueous layers were then separated and the aqueous layer was extracted with ethyl acetate
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 31
1
2
3
4
5
6
7
8
9
twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude. The crude was purified by silica gel column chromatography using
EtOAc : hexane as eluents to afford corresponding product 3a/5a.
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
Typical procedure for the synthesis of intermediate A:
The mixture of phenyl isothiocyanate (1a) (1.0 mmol, 135mg) and N-phenylbenzamidrazone
(2k) (1.0 mmol, 245mg) in water (2 mL) was stirred magnetically at room temperature. After
completion of the reaction as monitored by TLC, the reaction mixture was treated with NaHCO3
and extracted with EtOAc. The organic and aqueous layers were then separated and the aqueous
layer was extracted with ethyl acetate twice. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure to get crude. The crude was purified
by silica gel column chromatography using EtOAc : hexane as eluents to afford corresponding
product A.
(Z)-2-(((4-chlorophenyl)amino)(phenyl)methylene)-N-phenylhydrazinecarbothioamide (A):
White solid; Mp 165-167 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.91 (s, 1H), 9.12
(s, 1H), 7.62 (t, J = 8.5 Hz, 4H), 7.37 (dd, J = 14.9, 7.8 Hz, 5H), 7.19 (d, J = 8.4 Hz, 3H), 6.65
(d, J = 8.6 Hz, 2H);13C NMR (75 MHz, DMSO-d6) δ 175.4, 142.2, 140.1, 139.0, 132.9, 129.7,
128.8, 128.5, 128.2, 128.0, 125.1, 125.0, 120.9; HRMS (ESI) calcd for C20H17N4ClS [M+H]+:
381.0935; found: 381.0962.
Typical procedure for the synthesis of 4,5-disubstituted 3-amino-1,2,4-triazoles 3a-3o:
The mixture of isothiocyanate (1) (1.0 mmol), N-phenylbenzamidrazone (2) (1.0 mmol) and I2
(100 mol%, 126 mg, 1.0 mmol) in water (2 mL) was stirred magnetically at room temperature.
After completion of the reaction as monitored by TLC, the reaction mixture was quenched with a
saturated aqueous solution of Na2S2O3. The organic and aqueous layers were then separated and
ACS Paragon Plus Environment

Page 15 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude. The crude
was purified by silica gel column chromatography using EtOAc : hexane as eluents to afford
corresponding product 3a-3o.
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,4,5-Triphenyl-4H-1,2,4-triazol-3-amine (3a):16 White solid; Yield: 92% (287 mg); Mp 210-
211 °C; eluent: hexane/ethyl acetate 70:30; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.55-
7.50 (m, 5H), 7.43-7.40 (m, 2H), 7.35-7.31 (m, 5H), 7.23 (t, J = 7.9 Hz, 2H), 6.87 (t, J = 7.3 Hz,
13
1H); C{1H}NMR (75 MHz, DMSO-d6) δ 151.9, 150.0, 141.6, 133.3, 129.9, 129.6, 129.1,
128.5, 128.4, 128.3, 127.7, 127.4, 120.4, 117.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H17N4 313.1447; Found 313.1437.
4,5-Diphenyl-N-(p-tolyl)-4H-1,2,4-triazol-3-amine (3b): White solid; Yield: 91% (299 mg); Mp
1
198-200 °C; eluent: hexane/ethyl acetate 72:28; H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H),
7.54-7.53 (m, 3H), 7.42-7.40 (m, 4H), 7.34-7.30 (m, 5H), 7.04 (d, J = 8.3 Hz, 2H), 2.22 (s, 3H);
13C{1H}NMR (75 MHz, DMSO-d6) δ 152.2, 149.8, 138.9, 133.3, 129.9, 129.6, 129.2, 129.0,
128.9, 128.4, 128.3, 127.6, 127.4, 117.2, 20.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H19N4 327.1604; Found 327.1593.
N-(4-Methoxyphenyl)-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3c): White solid; Yield: 95% (324
mg); Mp 178-180 °C; eluent: hexane/ethyl acetate 68:32; 1H NMR (400 MHz, DMSO-d6) δ 7.93
(s, 1H), 7.55-7.53 (m, 3H), 7.49 (d, J = 9.0 Hz, 2H), 7.42 (dd, J = 6.4, 3.1 Hz, 2H), 7.35-7.29 (m,
13
5H), 6.84 (d, J = 9.0 Hz, 2H), 3.70 (s, 3H); C{1H}NMR (75 MHz, DMSO-d6) δ 153.6, 152.6,
149.5, 134.6, 133.3, 129.9, 129.6, 129.0, 128.4, 128.3, 127.6, 127.5, 119.0, 113.7, 55.1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H19N4O 343.1553; Found 343.1544.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 31
1
2
3
4
5
6
7
8
9
N-(4-Chlorophenyl)-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3d): White solid; Yield: 87% (301
mg); Mp 178-180 °C; eluent: hexane/ethyl acetate 74:26; 1H NMR (400 MHz, DMSO-d6) δ 8.38
(s, 1H), 7.59-7.54 (m, 5H), 7.44-7.41 (m, 2H), 7.38-7.27 (m, 7H); 13C{1H}NMR (75 MHz,
DMSO-d6) δ 151.7, 150.0, 140.5, 133.1, 129.9, 129.7, 129.2, 128.4, 128.3, 127.7, 127.3, 123.8,
118.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H16ClN4 347.1058; Found 347.1049.
N-(4-Nitrophenyl)-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3e): Yellow solid; Yield: 82% (292
mg); Mp 270-272 °C; eluent: hexane/ethyl acetate 67:33; 1H NMR (400 MHz, DMSO-d6) δ 9.24
(s, 1H), 8.15 (d, J = 9.3 Hz, 2H), 7.64 (d, J = 9.2 Hz, 2H), 7.55-7.54 (m, 3H), 7.45 (dd, J = 6.4,
3.1 Hz, 2H), 7.44-7.34 (m, 5H); 13C{1H}NMR (100 MHz, DMSO-d6) δ 151.5, 150.9, 148.9,
140.3, 133.4, 130.4, 129.9, 128.9, 128.8, 128.4, 127.5, 125.7, 116.4; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C20H16N5O2 358.1298; Found 358.1288.
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
4,5-Diphenyl-N-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-amine (3f): White solid; Yield:
82% (311 mg); Mp 230-232 °C; eluent: hexane/ethyl acetate 68:32; 1H NMR (500 MHz, DMSO-
d6) δ 8.75 (s, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.59-7.54 (m, 5H), 7.44 (dd, J = 6.7, 2.9 Hz, 2H),
7.39-7.31 (m, 5H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 151.1, 150.5, 145.3, 133.1, 129.9,
129.8, 129.3, 128.3, 127.8, 127.2, 125.9 (d, J= 3 Hz), 122.9, 120.4 (d, J= 32 Hz), 116.4; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H16F3N4 381.1321; Found 381.1314.
4,5-Diphenyl-N-(m-tolyl)-4H-1,2,4-triazol-3-amine (3g): White solid; Yield: 89% (290 mg); Mp
1
196-198 °C; eluent: hexane/ethyl acetate 73:27; H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H),
7.54 (s, 3H), 7.37 (d, J = 29.2 Hz, 9H), 7.10 (t, J = 7.7 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 2.24 (s,
3H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 151.9, 149.9, 141.5, 137.6, 133.3, 129.9, 129.6,
129.1, 128.4, 128.3, 127.7, 127.4, 121.16, 117.4, 114.1, 21.2; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C21H19N4 327.1604; Found 327.1594.
ACS Paragon Plus Environment

Page 17 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-(3-Methoxyphenyl)-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3h): White solid; Yield: 92% (314
mg); Mp 203-205 °C; eluent: hexane/ethyl acetate 68:32; 1H NMR (400 MHz, DMSO-d6) δ 8.16
(s, 1H), 7.55-7.54 (m, 3H), 7.42-7.40 (m, 2H), 7.32-7.31 (m, 5H), 7.18 (t, J = 2.1 Hz, 1H), 7.13-
7.10 (m, 2H), 6.47-6.44 (m, 1H), 3.71 (s, 3H); 13C{1H}NMR (100 MHz, DMSO-d6) δ 160.2,
152.3, 150.5, 143.2, 133.7, 130.4, 130.2, 129.8, 129.6, 128.9, 128.8, 128.2, 127.8, 110.0, 106.6,
103.2, 55.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H19N4O 343.1553; Found 343.1542.
N-(2-Methoxyphenyl)-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3i): White solid; Yield: 81% (277
mg); Mp 203-205 °C; eluent: hexane/ethyl acetate 69:31; 1H NMR (500 MHz, DMSO-d6) δ 8.07
(d, J = 8.0 Hz, 1H), 7.62-7.60 (m, 3H), 7.53-7.49 (m, 2H), 7.37-7.35 (m, 5H), 6.97-6.89 (m, 4H),
3.70 (s, 3H); 13C{1H}NMR (100 MHz, DMSO-d6) δ 151.7, 150.1, 147.2, 133.7, 130.9, 130.6,
130.0, 129.7, 129.0, 128.4, 128.0, 127.6, 121.5, 121.3, 116.5, 111.1, 56.4; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C21H19N4O 343.1553; Found 343.1541.
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-(4-Chlorophenyl)-4-phenyl-5-(p-tolyl)-4H-1,2,4-triazol-3-amine (3j): White solid; Yield: 90%
(324 mg); Mp 210-212 °C; eluent: hexane/ethyl acetate 75:25; 1H NMR (400 MHz, DMSO-d6) δ
8.35 (s, 1H), 7.58-7.53 (m, 5H), 7.40 (dd, J = 6.3, 2.7 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.19 (d,
13
J = 8.1 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.26 (s, 3H); C{1H}NMR (75 MHz, DMSO-d6) δ
151.5, 150.1, 140.6, 138.8, 133.2, 129.9, 129.7, 128.9, 128.4, 128.3, 127.6, 124.4, 123.8, 118.5,
20.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H18N4Cl 361.1214; Found 361.1206.
4-(4-Chlorophenyl)-N,5-diphenyl-4H-1,2,4-triazol-3-amine (3k): White solid; Yield: 79% (273
mg); Mp 259-260 °C; eluent: hexane/ethyl acetate 75:25; 1H NMR (300 MHz, DMSO-d6) δ 8.24
(s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.37-7.34 (m,
13
5H); 7.24 (t, J = 7.9 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H); C{1H}NMR (75 MHz, DMSO-d6) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 31
1
2
3
4
5
6
151.9, 149.7, 141.3, 134.3, 132.2, 130.4, 130.0, 129.2, 128.5, 128.4, 127.8, 127.2, 120.5, 117.1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H16N4Cl 347.1058; Found 347.1049.
7
8
9
N-(tert-Butyl)-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3l): White solid; Yield: 76% (221 mg);
Mp 198-200 °C; eluent: hexane/ethyl acetate 72:28; 1H NMR (400 MHz, DMSO-d6) δ 7.53-7.51
(m, 3H), 7.33-7.23 (m, 7H), 4.60 (s, 1H), 1.36 (s, 9H); 13C{1H}NMR (75 MHz, DMSO-d6) δ
154.0, 148.6, 133.78, 130.0, 129.3, 128.7, 128.2, 128.0, 127.6, 127.3, 51.5, 28.6; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C18H21N4 293.1760; Found 293.1749.
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-Butyl-4-(4-chlorophenyl)-5-phenyl-4H-1,2,4-triazol-3-amine (3m): White solid; Yield: 75%
(244 mg); Mp 162-164 °C; eluent: hexane/ethyl acetate 70:30; 1H NMR (300 MHz, DMSO-d6) δ
7.59 (d, J = 8.6 Hz, 2H), 7.39-7.25 (m, 7H), 5.89 (t, J = 5.6 Hz, 1H), 3.22 (dd, J = 13.1, 6.7 Hz,
2H), 1.53 (dd, J = 14.5, 7.5 Hz, 2H), 1.36-1.24 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C{1H}NMR
(75 MHz, DMSO-d6) δ 160.8, 153.9, 139.2, 137.7, 135.3, 134.1, 133.6, 132.6, 47.7, 36.1, 24.7,
19.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H20N4Cl 327.1371; Found 327.1363.
N-Cyclohexyl-4,5-diphenyl-4H-1,2,4-triazol-3-amine (3n): White solid; Yield: 76% (241 mg);
Mp 202-204 °C; eluent: hexane/ethyl acetate 71:29; 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.51
(m, 3H), 7.39-7.24 (m, 7H), 5.23 (d, J = 7.8 Hz, 1H), 3.39 (s, 1H), 1.95 (s, 2H), 1.67-1.56 (m,
3H), 1.17 (d, J = 49.1 Hz, 5H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 155.19, 148.87, 133.75,
130.00, 129.29, 128.62, 128.27, 128.04, 127.78, 127.26, 52.03, 32.34, 25.37, 24.93; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H23N4 319.1917; Found 319.1905.
4-(4-Chlorophenyl)-N-cyclohexyl-5-phenyl-4H-1,2,4-triazol-3-amine (3o): White solid; Yield:
73% (256 mg); Mp 203-204 °C; eluent: hexane/ethyl acetate 72:28; 1H NMR (400 MHz, DMSO-
d6) δ 7.57 (d, J = 8.2 Hz, 2H), 7.36-7.26 (m, 7H), 5.45 (d, J = 7.6 Hz, 1H), 3.50 (s, 1H), 1.93 (d,
J = 15.2 Hz, 2H), 1.68 (s, 2H), 1.58 (d, J = 12.5 Hz, 1H), 1.25 (dd, J = 19.5, 10.2 Hz, 4H), 1.07
ACS Paragon Plus Environment

Page 19 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(d, J = 10.7 Hz, 1H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 171.9, 155.1, 148.7, 133.8, 132.6,
130.0, 130.0, 128.7, 128.3, 127.6, 127.4, 52.0, 32.3, 25.4, 24.9, 21.0; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C20H22N4Cl 353.1527; Found 353.1518.
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
Typical procedure for the synthesis of N-fused-3-amino-1,2,4-triazoles 5a-5j:
The mixture of phenyl isothiocyanate (1) (1.0 mmol) and 2-hydrazinopyridine (4) (1.0 mmol)
and I2 (100 mol%, 126 mg, 1.0 mmol) in water (2 mL) was stirred magnetically at room
temperature. After completion of the reaction as monitored by TLC, the reaction mixture was
quenched with a saturated aqueous solution of Na2S2O3. The organic and aqueous layers were
then separated and the aqueous layer was extracted with ethyl acetate twice. The combined
organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to get
crude. The crude was purified by silica gel column chromatography using EtOAc : hexane as
eluents to afford corresponding product 5a-5j.
N-Phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5a):17 Pale yellow solid; Yield: 87% (182 mg);
1
Mp 229-230 °C; eluent: hexane/ethyl acetate 61:39; H NMR (400 MHz, DMSO-d6) δ 9.23 (s,
1H), 8.35 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 7.8
Hz, 2H), 7.26 (dd, J = 9.0, 6.7 Hz, 1H), 6.95-6.90 (m, 2H); 13C{1H}NMR (100 MHz, DMSO-d6)
δ 146.7, 144.7, 141.8, 129.4, 127.0, 123.1, 120.9, 116.6, 115.9, 112.8; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C12H11N4 211.0978; Found 211.0972.
N-(p-Tolyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5b):17 White solid; Yield: 87% (194 mg); Mp
1
265-267 °C; eluent: hexane/ethyl acetate 60:40; H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H),
8.32 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 9.3 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 8.6, 6.5
13
Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.88 (t, J = 6.6 Hz, 1H), 2.26 (s, 3H); C{1H}NMR (100
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 31
1
2
3
4
5
6
MHz, DMSO-d6) δ 146.6, 145.0, 139.3, 129.8, 129.6, 126.8, 123.0, 116.8, 116.0, 112.6, 20.7;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13N4 225.1134; Found 225.1129.
7
8
9
N-(4-Methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5c):18 White solid; Yield: 88% (211
mg); Mp 240 °C; eluent: hexane/ethyl acetate 58:42; 1H NMR (500 MHz, DMSO-d6) δ 9.04 (s,
1H), 8.31 (d, J = 7.0 Hz, 1H), 7.56 (dd, J = 19.6, 9.1 Hz, 3H), 7.21 (dd, J = 8.8, 6.4 Hz, 1H), 6.92
(d, J = 9.0 Hz, 2H), 6.87 (t, J = 6.5 Hz, 1H), 3.73 (s, 3H); 13C{1H}NMR (100 MHz, DMSO-d6) δ
154.0, 146.5, 145.4, 135.0, 126.8, 122.9, 118.4, 115.9, 114.7, 112.5, 55.7; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C13H13N4O 241.1083; Found 241.1077.
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-(4-Chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5d): White solid; Yield 85% (207
mg); Mp 220-221 °C; eluent: hexane/ethyl acetate 61:39; 1H NMR (500 MHz, DMSO-d6) δ 9.42
(s, 1H), 8.35 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 8.7 Hz, 3H), 7.36 (d, J = 8.8 Hz, 2H), 7.26 (dd, J =
8.9, 6.7 Hz, 1H), 6.92 (t, J = 6.6 Hz, 1H); 13C{1H}NMR (125 MHz, DMSO-d6) δ 146.7, 144.5,
140.7, 129.2, 127.1, 124.3, 123.0, 118.2, 115.9, 112.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C12H10N4Cl 245.0588; Found 245.0582.
N-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5e):17 White solid; Yield : 83% (189
mg); Mp 246-248 °C; eluent: hexane/ethyl acetate 62:38; 1H NMR (400 MHz, DMSO-d6) δ 9.28
(s, 1H), 8.34 (d, J = 7.1 Hz, 1H), 7.63-7.60 (m, 3H), 7.26-7.22 (m, 1H), 7.19-7.15 (m, 2H), 6.92-
13
6.89 (m, 1H); C{1H}NMR (100 MHz, DMSO-d6) δ 158.2, 155.8, 146.6, 144.9, 138.2, 127.0,
123.0, 118.2 (d, J=7 Hz), 116.0, 115.9 (d, J= 5 Hz), 112.7; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C12H10FN4 229.0884; Found 229.0877.
N-(4-(Trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5f):17 White solid; Yield:
83% (230 mg); Mp 240-241°C; eluent: hexane/ethyl acetate 60:40; 1H NMR (400 MHz, DMSO-
d6) δ 9.73 (s, 1H), 8.37 (d, J = 6.9 Hz, 1H), 7.73-7.66 (m, 5H), 7.32-7.30 (m, 1H), 6.95 (t, J = 6.6
ACS Paragon Plus Environment

Page 21 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
Hz, 1H); C{1H}NMR (75 MHz, DMSO-d6) δ 146.5, 144.9, 143.4, 126.8, 126.3 (d, J= 3 Hz),
122.7 (d, J= 32 Hz), 120.5, 120.1, 115.7 (d, J= 217 Hz), 115.5, 112.6; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C13H10F3N4 279.0852; Found 279.0842.
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-(m-Tolyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5g): White solid; Yield: 87% (194 mg); Mp
1
216-218 °C; eluent: hexane/ethyl acetate 62:38; H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H),
8.33 (d, J = 6.7 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.19-
7.17 (m, 2H), 6.90 (t, J = 6.4 Hz, 1H), 6.74 (d, J = 7.0 Hz, 1H), 2.30 (s, 3H); 13C{1H}NMR (75
MHz, DMSO-d6) δ 146.2, 144.2, 141.3, 138.1, 128.8, 126.4, 122.5, 121.2, 116.6, 115.4, 113.4,
112.2, 21.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13N4 225.1134; Found 225.1128.
N-(3-Methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5h): White solid; Yield: 88% (211
mg); Mp 205-207 °C; eluent: hexane/ethyl acetate 60:40; 1H NMR (400 MHz, DMSO-d6) δ 9.25
(s, 1H), 8.34 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H), 7.26-7.19 (m, 3H), 7.10 (d, J = 8.0 Hz,
1H), 6.91 (t, J = 6.6 Hz, 1H), 6.51 (dd, J = 8.0, 2.0 Hz, 1H), 3.75 (s, 3H); 13C{1H}NMR (75
MHz, DMSO-d6) δ 159.9, 146.1, 144.1, 142.5, 129.7, 126.6, 122.6, 115.4, 112.3, 108.7, 105.9,
102.1, 54.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13N4O 241.1083; Found 241.1078.
N-(2-Methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (5i): White solid; Yield: 82% (196
mg); Mp 106-108 °C; eluent: hexane/ethyl acetate 60:40; 1H NMR (400 MHz, DMSO-d6) δ 8.29
(s, 1H), 8.23 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 9.3 Hz, 1H), 7.44 (dd, J = 7.6, 1.8 Hz, 1H), 7.30-
7.26 (m, 1H), 7.05 (dd, J = 7.8, 1.5 Hz, 1H), 6.93-6.85 (m, 3H), 3.89 (s, 3H); 13C{1H}NMR (100
MHz, DMSO-d6) δ 148.3, 147.5, 144.7, 131.7, 127.3, 123.6, 121.4, 121.1, 116.4, 115.7, 112.6,
111.6, 56.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H13N4O 241.1083; Found 241.1077.
N-Phenyl-[1,2,4]triazolo[4,3-a]quinolin-1-amine (5j): White solid; Yield: 79% (205 mg); Mp
1
259-260 °C; eluent: hexane/ethyl acetate 64:36; H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 31
1
2
3
4
8.51 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.62 (t, J = 8.7 Hz,
5
6
13
2H), 7.54 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.7 Hz, 2H), 6.87 (d, J = 7.4 Hz, 3H); C{1H}NMR
7
8
9
(75 MHz, DMSO-d6) δ 147.8, 146.7, 143.9, 131.3, 129.3, 129.2, 128.9, 126.0, 124.0, 120.2,
116.2, 115.4, 114.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H13N4 261.1134; Found
261.11264.
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
Typical procedure for the synthesis of 3-substituted 5-amino-1,2,4-thiadiazoles 8a-8k:
The mixture of phenyl isothiocyanate (1) (1.0 mmol) and amidoximes (6) (1.0 mmol), I2 (50
mol%, 63 mg, 0.5 mmol) and K2CO3 (1.0 mmol) in water (2 mL) was stirred magnetically at
60°C. After completion of the reaction as monitored by TLC, The reaction mixture was cooled to
room temperature and then quenched with a saturated aqueous solution of Na2S2O3. The organic
and aqueous layers were then separated and the aqueous layer was extracted with ethyl acetate
twice. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude. The crude was purified by silica gel column chromatography using
EtOAc : hexane as eluents to afford corresponding product 8a-8k.
N,3-Diphenyl-1,2,4-thiadiazol-5-amine (8a):19 White solid; Yield: 90% (227 mg); Mp 174-176
1
°C; eluent: hexane/ethyl acetate 90:10; H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.20-
8.18 (m, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 6.4 Hz, 3H), 7.44 (t, J = 7.8 Hz, 2H), 7.11 (t,
J = 7.3 Hz, 1H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 179.1, 168.5, 139.8, 132.7, 130.1, 129.3,
128.7, 127.5, 122.9, 117.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H12N3S 254.0746;
Found 254.0740.
3-Phenyl-N-(p-tolyl)-1,2,4-thiadiazol-5-amine (8b):19 White solid; Yield: 92% (245 mg); Mp
1
153-155 °C; eluent: hexane/ethyl acetate 92:8; H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H),
13
8.19-8.17 (m, 2H), 7.55-7.48 (m, 5H), 7.24 (d, J = 8.3 Hz, 2H), 2.30 (s, 3H); C{1H}NMR (75
ACS Paragon Plus Environment

Page 23 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
MHz, DMSO-d6) δ 179.2, 168.5, 137.4, 132.7, 132.0, 130.0, 129.7, 128.7, 127.5, 117.8, 20.3;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H14N3S 268.0902; Found 268.0895.
7
8
9
N-(4-Methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (8c):20 White solid; Yield: 95% (268
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
mg); Mp 144-145 °C; eluent: hexane/ethyl acetate 90:10; H NMR (300 MHz, DMSO-d6) δ
10.85 (s, 1H), 8.19-8.16 (m, 2H), 7.58-7.50 (m, 5H), 7.02 (d, J = 9.0 Hz, 2H), 3.77 (s, 3H);
13C{1H}NMR (75 MHz, DMSO-d6) δ 179.6, 168.5, 155.3, 133.2, 132.8, 130.0, 128.6, 127.5,
119.7,114.5, 55.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H14N3OS 284.0852; Found
284.0844.
N-(4-Fluorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (8d):19 White solid; Yield: 88% (238
1
mg); Mp 170-173 °C; eluent: hexane/ethyl acetate 90:10; H NMR (500 MHz, DMSO-d6) δ
11.04 (s, 1H), 8.19 (d, J = 5.9 Hz, 2H), 7.71 (dd, J = 8.6, 4.6 Hz, 2H), 7.52 (d, J = 6.6 Hz, 3H),
7.28 (t, J = 8.7 Hz, 2H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 179.1, 168.5, 159.3, 156.2, 136.3,
132.7, 130.1, 128.7, 127.5, 119.5 (d, J= 7 Hz), 115.9 (d, J= 226 Hz); HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C14H11N3FS 272.0652; Found 272.0644.
N-(4-Nitrophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (8e):21 Yellow solid; Yield: 87% (259 mg);
Mp 216-218 °C; eluent: hexane/ethyl acetate 85:15; 1H NMR (500 MHz, DMSO-d6) δ 11.68 (s,
1H), 8.33 (d, J = 9.1 Hz, 2H), 8.25-8.24 (m, 2H), 7.95 (d, J = 9.1 Hz, 2H), 7.55 (d, J = 5.3 Hz,
3H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 178.4, 168.6, 145.2, 141.5, 132.4, 130.4, 128.8,
127.6, 125.6, 117.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H11N4O2S 299.0597; Found
299.0589.
N-(2-Methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (8f):21 White solid; Yield: 86% (243
1
mg); Mp 96-98 °C; eluent: hexane/ethyl acetate 88:12; H NMR (400 MHz, DMSO-d6) δ 10.44
(s, 1H), 8.49 (d, J = 6.9 Hz, 1H), 8.19-8.17 (m, 2H), 7.54-7.49 (m, 3H), 7.11-7.05 (m, 3H), 3.90
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 31
1
2
3
4
5
6
7
8
9
(s, 3H); 13C{1H}NMR (100 MHz, DMSO-d6) δ 179.97, 168.4, 148.9, 133.4, 130.4, 129.4, 129.2,
127.9, 124.0, 121.2, 119.4, 111.7, 56.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H14N3OS
284.0852; Found 284.0866
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-(3-Methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (8g): White solid; Yield: 89% (251
1
mg); Mp 123-125 °C; eluent: hexane/ethyl acetate 90:10; H NMR (400 MHz, DMSO-d6) δ
11.08 (s, 1H), 8.19 (d, J = 3.3 Hz, 2H), 7.52 (s, 3H), 7.37 (d, J = 14.1 Hz, 2H), 7.16 (s, 1H), 6.70
13
(d, J = 6.4 Hz, 1H), 3.82 (s, 3H); C{1H}NMR (100 MHz, DMSO-d6) δ 179.5, 168.9,160.5,
141.4, 133.2, 130.7, 130.6, 129.2, 127.9, 110.4, 108.7, 104.1, 55.5; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C15H14N2OS 284.0852; Found 284.0846.
3-Phenyl-N-propyl-1,2,4-thiadiazol-5-amine (8h): White solid; Yield: 84% (183 mg); Mp 82-84
1
°C; eluent: hexane/ethyl acetate 95:5; H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.11-8.07
(m, 2H), 7.50-7.43 (m, 3H), 3.30 (d, J = 5.9 Hz, 2H), 1.64 (dd, J = 14.3, 7.2 Hz, 2H), 0.95 (t, J =
7.4 Hz, 3H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 183.1, 168.5, 133.1, 129.7, 128.4, 127.4,
47.0, 21.8, 11.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H14N3S 220.0902; Found
220.0895.
N-Cyclohexyl-3-phenyl-1,2,4-thiadiazol-5-amine (8i):19 White powder; Yield: 81% (209 mg); mp
1
126-127 °C; eluent: hexane/ethyl acetate 94:6; H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H),
8.10 (s, 2H), 7.45 (s, 3H), 3.52 (s, 1H), 2.00 (s, 2H), 1.72 (s, 2H), 1.57 (s, 1H), 1.30 (t, J = 32.6
13
Hz, 5H); C{1H}NMR (75 MHz, DMSO-d6) δ 182.0, 168.4, 133.2, 129.6, 128.4, 127.4, 54.4,
31.9, 25.1, 24.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H18N3S 260.1215; Found
260.1210.
N-Phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5-amine (8j): White solid; Yield; 91% (242 mg); Mp 187-
188 °C; eluent: hexane/ethyl acetate 94:6; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.07
ACS Paragon Plus Environment

Page 25 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(d, J = 8.1 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H),
7.10 (t, J = 7.3 Hz, 1H), 2.38 (s, 3H); 13C{1H}NMR (100 MHz, DMSO-d6) δ 179.4, 169.0,
140.3, 140.3, 130.6, 129.9, 129.8, 128.0, 123.3, 118.1, 21.5; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H14N3S 268.0902; Found 268.0896.
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
3-(4-Chlorophenyl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine (8k): White solid; Yield: 89% (267
mg); Mp 220-222 °C; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, DMSO-d6) δ 10.97
(s, 1H), 8.18-8.15 (m, 2H), 7.59-7.57 (m, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H),
2.30 (s, 3H); 13C{1H}NMR (75 MHz, DMSO-d6) δ 179.4, 167.3, 137.3, 134.7, 132.2, 131.5,
129.7, 129.2, 128.8, 117.9, 20.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H13ClN3S
302.0513; Found 302.0505.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* E-mail: drmangarao@gmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge SERB, New Delhi, India for financial support in the form of NPDF
(PDF/2016/000177) in the form of NPDF. The authors J. N and T. N thank the UGC and CSIR,
New Delhi for financial support in the form of fellowships.
CSIR-IICT communication number: IICT/Pubs./2018/076.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 31
1
2
3
4
1H and 13C NMR copies of all products. (PDF)
5
6
7
8
9
REFERENCES
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) (a) Bhat, A. R.; Bhat, G. V.; Shenoy, G. G. Synthesis and In-Vitro Antimicrobial Activity of
New 1,2,4-Triazoles. J. Pharm. Pharmacol. 2001, 53, 267-272. (b) Katica, C. R.; Vesna,
D.; Vlado, K.; Dora, G. M.; Aleksandra, B. Synthesis, Antibacterial and Antifungal
Activity of 4-Substituted-5-aryl-1,2,4-triazoles. Molecules 2001, 6, 815-824. (c) Holla, B.
S.; Poorjary, K. N.; Rao, B. S.; Shivananda, M. K. New bis-Aminomercaptotriazoles and
bis-Triazolothiadiazoles as Possible Anticancer Agents. Eur. J. Med. Chem. 2002, 3, 511-
517. (d) Yamanaka, T.; Ohki, H.; Ohgaki, M.; Okuda, S.; Toda, A.; Kawabata, K.; Inoue, S.;
Misumi, K.; Itoh, K.; Satoh, K.; U. S. Patent US 2005004094 A1, 2005.
(2) (a) Bekircan, O.; Gumurkcuoglu, N. Synthesis of Some 3,5-Diphenyl-4H-1,2,4-triazole
Derivatives as Antitumor Agents. Indian J. Chem. 2005, 44B, 2107-2113. (b) Siddiqui, A.
A.; Arora, A.; Siddiqui, N.; Misra, A. Synthesis of Some 1,2,4-Triazoles as Potential
Antifungal Agents. Indian J. Chem. 2005, 44B, 838-841. (c) Boschelli, D. H.; Connor, D.
T.; U. S. Patent US 2005114958A, 2005.
(3) (a) Collin, X.; Sauleau, A.; Coulon, J. 1,2,4-Triazolo Mercapto and Aminonitriles as Potent
Antifungal Agents. Bioorg. Med. Chem. Lett. 2003, 13, 2601-2605. (b) Lamrence, E. K.; U.
S. Patent 4, 263, 312, 1981. (c) Rollas, S.; Kalyoncuoglu, N.; Sur-Altiner, D.; Yegenoglu,
Y. 5-(4-Aminophenyl)-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones: Synthesis
and Antibacterial and Antifungal Activities. Pharmazie 1993, 48, 308-309.
(4) (a) Clercq, E. De. Antiviral Drugs in Current Clinical Use. J. Clin. Virol. 2004, 30, 115-
133. (b) Kucukguzel, I.; Tatar, E.; Kucukguzel, S. G.; Rollas, S.; Clercq, E. De. Synthesis
ACS Paragon Plus Environment

Page 27 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
of Some Novel Thiourea Derivatives Obtained from 5-[(4-Aminophenoxy)methyl]-4-
alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and Evaluation as Antiviral/Anti-HIV
and Anti-Tuberculosis Agents. Eur. J. Med. Chem. 2008, 43, 381-392.
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
(5) Bo, Y.; Lin, C.; Ruiying, F.; Zhiping, G. Luteolytic Effects of DL111-IT in Pregnant Rats.
Eur. J. Pharmacol. 1999, 380, 145-152.
(6) Naveen, M.; Upendar Reddy, Ch.; Iqbal, J.; Pal, M. Synthesis of Dipeptidyl Peptidase-4
Inhibitors: A Brief Overview. Tetrahedron 2010, 66, 4919-4938.
(7) Li, C.-S.; An, C.-Y.; Li, X.-M.; Gao, S.-S.; Cui, C.-M.; Sun, H.-F.; Wang, B.-G. Triazole
and Dihydroimidazole Alkaloids from the Marine Sediment-Derived Fungus Penicillium
Paneum SD-44. J. Nat. Prod. 2011, 74, 1331-1334.
(8) Nisbet-Brown, E.; Olivieri, N. F.; Giardina, P. J.; Grady, R. W.; Neufeld, E. J.; Sechaud,
R.; Krebs-Brown, A. J.; Anderson, J. R.; Alberti, D.; Sizer, K. C.; Nathan, D. G.
Effectiveness and Safety of ICL670 in Iron-Loaded Patients with Thalassaemia: A
Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial. Lancet 2003, 361,
1597-1602.
(9) Iizawa, Y.; Okonogi, K.; Hayashi, R.; Iwahi, T.; Yamazaki, T.; Imada, A. Therapeutic
Effect of Cefozopran (SCE-2787), a New Parenteral Cephalosporin, Against Experimental
Infections in Mice. Antimicrob. Agents Chemother. 1993, 37, 100-105.
(10) (a) Larsen, S. D.; DiPaolo, B. A. Traceless Solid-Phase Synthesis of 1,2,4-Triazoles Using
a Novel Amine Resin. Org. Lett. 2001, 3, 3341-3344. (b) Stocks, M. J.; Cheshire, D. R.;
Reynolds, R. Efficient and Regiospecific One-Pot Synthesis of Substituted 1,2,4-Triazoles.
Org. Lett. 2004, 6, 2969-2971. (c) Balsells, J.; DiMichele, L.; Liu, J.; Kubryk, M.; Hansen,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 31
1
2
3
4
5
6
K.; Armstrong, J. D. Synthesis of [1,2,4]Triazolo[4,3-r]piperazines via Highly Reactive
Chloromethyloxadiazoles. Org. Lett. 2005, 7, 1039-1042.
7
8
9
(11) (a) Shah, A. A.; Khan, Z. A.; Choudhary, N.; Loholter, C.; Schafer, S.; Marie, G. P. L.;
Faroog, U.; Witulski, B.; Wirth, T. Iodoxolone-Based Hypervalent Iodine Reagents. Org.
Lett. 2009, 11, 3578-3581. (b) Cashman, J.-R.; Hanzlik, R.-P. Oxidation and Other
Reactions of Thiobenzamide Derivatives of Relevance to Their Hepatotoxicity. J. Org.
Chem. 1982, 47, 4645-4650. (c) Patil, P. C.; Bhalerao, D. S.; Dangate, P. S.; Akamanchi, K.
G. IBX/TEAB-Mediated Oxidative Dimerization of Thioamides: Synthesis of 3,5-
Disubstituted 1,2,4-Thiadiazoles. Tetrahedron Lett. 2009, 50, 5820-5822. (d) Khosropour,
A.-R.; Noei. A Convenient Strategy for the Synthesis of 3,5-Diaryl-1,2,4-thiadiazoles:
Oxidative Dimerization of Arylthioamides using CC-DMSO in PEG-400. Monatsh. Chem.
2010, 141, 649-651. (e) Xu, Y.; Chen, J.; Gao, W.; Jin, H.; Ding, J.; Wu, H. Solvent-Free
Synthesis of 3,5-Di(hetero)aryl-1,2,4-thiadiazoles by Grinding of Thioamides Under
Oxidative Conditions. J. Chem. Res. 2010, 34, 151-153. (f) Cheng, D.; Luo, R.; Zheng, W.;
Yan, J. Highly Efficient Oxidative Dimerization of Thioamides to 3,5-Disubstituted 1,2,4-
Thiadiazoles Mediated by DDQ. Synth. Commun. 2012, 42, 2007-2013.
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
(12) (a) Madhur, S.; Joshi, F.; Christopher, P. Construction of 1,2,4-Triazole Derivatives via
Cyclocondensation of Alkylidene Dihydropyridines and Aryldiazonium Salts. Org. Lett.
2016, 18, 5916-5919. (b) Murali Mohan, G.; Tharmalingam, P. Copper(II)-Catalyzed
Aerobic Oxidative Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles from
Bisarylhydrazones via C-H Functionalization/C-C/N-N/C-N Bonds Formation. J. Org.
Chem. 2012, 77, 5063-5073. (c) Zhengkai, C.; Hongli, L.; Weipeng, D.; Maozhong, M.;
Hongjun, R. I2-Catalyzed Oxidative Coupling Reactions of Hydrazones and Amines and
ACS Paragon Plus Environment

Page 29 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the Application in the Synthesis of 1,3,5-Trisubstituted 1,2,4-Triazoles. Org. Lett. 2016, 18,
1334-1337. (d) Bechara, W. S.; Khazhieva, I. S.; Elsa, R.; Charette, A. B. One-Pot
Synthesis of 3,4,5-Trisubstituted 1,2,4-Triazoles via the Addition of Hydrazides to
Activated Secondary Amides. Org. Lett. 2015, 17, 1184-1187. (e) Arumugam, M.;
Kandasamy, R.; Noufal, M. C.; Shanmugam, M.; Nattamai, B. Hypervalent Iodine(III)
Mediated Synthesis of 3-Substituted 5-Amino-1,2,4-thiadiazoles through Intramolecular
Oxidative S-N Bond Formation. J. Org. Chem. 2016, 81, 6573-6579.
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
(13) (a) Finkbeiner, P.; Nachtsheim, B. J. Iodine in Modern Oxidation Catalysis. Synthesis 2013,
45, 979-999. (b) Zhang, Z.-H; Liu, Q.-B. Organic Reaction Catalyzed by Molecular Iodine.
Prog. Chem. 2006, 18, 270-280. (c) Banerjee, A. K.; Vera, W.; Mora, H.; Laya, M. S.;
Bedoya, L.; Cabrera, E. V. Iodine in Organic Synthesis. J. Sci. Ind. Res. 2006, 65, 299-308.
(d) Wang, S.-Y. Molecular Iodine. Synlett 2004, 2642-2643. (e) Zhang, J.; Wu, X.; Gao, Q.;
Geng, X.; Zhao, P.; Wu, Y.-D.; Wu, A. Diamination/Oxidative Cross-
Coupling/Bicyclization of Anilines and Methyl Ketones: Direct I2‑Promoted Synthesis of
1,2-Fused Oxindoles. Org. Lett. 2017, 19, 408-411. (f) Naresh, G.; Kant, R.; Narender, T.
Molecular Iodine Promoted Divergent Synthesis of Benzimidazoles, Benzothiazoles, and
2‑Benzyl-3-phenyl-3,4-dihydro‑2H‑benzo[e][1,2,4]thiadiazines. J. Org. Chem. 2014, 79,
3821-3829. (g) Lv, Z.; Liu, J.; Wei, W.; Wu, J.; Yu, W.; Chang, J. Iodine-Mediated Aryl C-
H Amination for the Synthesis of Benzimidazoles and Pyrido[1,2-a]benzimidazoles. Adv.
Synth. Catal. 2016, 358, 2759-2766. (h) Cui, H.; Liu, X.; Wei, W.; Yang, D.; He, C.; Zhang,
T.; Wang, H. Molecular Iodine-Mediated Difunctionalization of Alkenes with Nitriles and
Thiols Leading to β‑Acetamido Sulfides. J. Org. Chem. 2016, 81, 2252-2260.
ACS Paragon Plus Environment