Synthesis of 1,2,4-Triazoles via Oxidative Heterocyclization: Selective C-N Bond over C-S Bond Formation

Article abstract of DOI:10.1021/acs.joc.5b00956

The higher propensity of C-N over C-S bond forming ability was demonstrated, through formal C-H functionalization during the construction of 4,5-disubstituted 1,2,4-triazole-3-thiones from arylidenearylthiosemicarbazides catalyzed by Cu(II). However, ster

Full text of DOI:10.1021/acs.joc.5b00956

Subscriber access provided by University of Sussex Library
Article
Synthesis of 1,2,4-Triazoles via Oxidative Heterocyclization:
Selective C-N Bond Over C-S Bond Formation
Anupal Gogoi, Srimanta Guin, Suresh Rajamanickam, Saroj Kumar Rout, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00956 • Publication Date (Web): 02 Sep 2015
Downloaded from http://pubs.acs.org on September 3, 2015
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 37
The Journal of Organic Chemistry
1
2
3
4
Synthesis of 1,2,4-Triazoles via Oxidative Heterocyclization: Selective
5
6
7
C−N Bond Over C−S Bond Formation
8
9
Anupal Gogoi, Srimanta Guin, Suresh Rajamanickam,
Saroj Kumar Rout, and Bhisma K. Patel*
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
Department of Chemistry
Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India
Fax: (+91)361ꢀ26909762.
Eꢀmail: patel@iitg.ernet.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted)
ABSTRACT: The higher propensity of C−N over C−S bond forming ability was demonstrated,
through formal C−H functionalization during the construction of 4,5ꢀdisubstituted 1,2,4ꢀtriazoleꢀ3ꢀ
thiones from arylidenearylthiosemicarbazides catalyzed by Cu(II). However, steric factor imparted
by the oꢀdisubstituted substrates tend to change the reaction path giving thiodiazole as the major or
an exclusive product. Upon prolonging the reaction time, the in situ generated thiones are
transformed to 4,5ꢀdisubstituted 1,2,4ꢀtriazoles via a desulfurization process. Two classes of
heterocycles viz. 4,5ꢀdisubstituted 1,2,4ꢀtriazoleꢀ3ꢀthiones and 4,5ꢀdisubstituted 1,2,4ꢀtriazoles can
be synthesized from arylidenearylthiosemicarbazides by simply adjusting the reaction time.
Desulfurization of 1,2,4ꢀtriazoleꢀ3ꢀthiones is assisted by thiophilic Cu to provide 1,2,4ꢀtriazoles
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 37
1
2
3
4
5
6
7
8
9
with concomitant formation of CuS and polynuclear sulphur anions as confirmed from scanning
electron microscope (SEM) and energyꢀdispersive Xꢀray spectroscopy (EDS) measurements. A
oneꢀpot synthesis of an antiꢀmicrobial compound has been successfully achieved following this
strategy.
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
INTRODUCTION
The nonꢀrequirement of substrate preꢀfunctionalization leads to step and atom economy in
transition metal catalyzed C−H bond functionalizations. Lately, the ubiquitous C−H bonds in
organic compounds can be foreseen as quiescent synthetic equivalent of several useful functional
groups. Because of the reduced number of steps in achieving the targeted synthesis these strategies
are of paramount importance.1 Of all C−H (sp, sp2 and sp3) bonds, the functionalizations of sp2
C−H bonds of aromatics and heteroꢀaromatics have been well scrutinized.2 However, analogous
manipulation of imine sp2 C−H bonds are relatively scarce. Some examples of late transition metal
catalyzed imine C−H bond functionalizations are: (i) addition of 2ꢀmethylazaꢀarenes to imine
catalyzed by Pd;3a (ii) benzonitrile addition to sulfenylamine catalyzed by Pd;3b,c (iii) oxidative
coupling of arylimines with alkynes3d and 2ꢀpyridyl3e using Rh and (iv) a Cuꢀcatalyzed arylation of
imine C−H bond in benzotriazepines.3f Besides, certain Cuꢀcatalyzed heterocyclization reactions
are known to proceed via oxidative C−O3g and/or C−N3h,i bond formations at imine C−H bonds.
Some of the imine bonds containing substrates are reported to undergo skeletal rearrangements in
the presence of transition metals.4
ACS Paragon Plus Environment

Page 3 of 37
The Journal of Organic Chemistry
1
2
3
4
Scheme 1. Imine C−H bond Functionalization Leading to Heterocycles
5
6
7
8
Previous report
N NH
N
N
Cu(OTf)2
Ph
Ph
Ph
Ph
Cs2CO3, DMF
H
O
O
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
Present work
N N
S
NH
N
H
C S bond
Ph
NH
Ph
Ph
Ph
N
H
Ph
(1c)
formation
S
CuBr2, DMSO
N NH
N
N
H
NH
C N bond
formation
S
Ph
S
HN
Ph
(1a)
Ph
(1)
N N
Desulfurization
H
Ph
N
Ph
(1b)
Recently we have achieved an elegant synthesis of 2,5ꢀsubstituted 1,3,4ꢀoxadiazole via C−H
bond activation (C−O bond formation) involving an amidic carbonyl and an imine C−H bond in Nꢀ
arylidenearoylhydrazide system.3g Herein, we wished to investigate if the imine C−H bond in
arylidenearylthiosemicarbazide (1) can similarly be functionalized. If the C−H functionalization
strategy works there exist two distinct possibilities viz. C−N bond or a C−S bond formation leading
to the formation of either a N,5ꢀdiphenylꢀ1,3,4ꢀthiadiazoleꢀ2ꢀamine (1c) or a 4,5ꢀdiphenylꢀ2,4ꢀ
dihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (1a) as shown in Scheme 1.
Figure 1. Some Biologically Active 1,2,4-Triazole-3-thiones
S
N NH
N
N
N
N
S
N
N
H3C
Cl
N
Br
Antibacterial (I)
Anti-microbial (II)
O
S
N
N
N
O
S
O
III
Antifungal (
)
H3C
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 37
1
2
3
4
5
6
7
8
9
Mercapto and thione derivatives of 1,2,4ꢀtriazoles are known to exhibit a variety of biological
activities such as antibacterial,7 antifungal,8 antitumor,9 antiꢀinflammatory,10 antiviral,11
antitubercular,12 anticonvulsant13 and antidepressant14 activities. Some of the biologically active
molecules bearing 1,2,4ꢀtriazoleꢀ3ꢀthiones (I−III) as the core unit are shown in Figure 1. A myriad
of applications of this scaffold has led to the development of various strategies for their synthesis.
The common routes to 1,2,4ꢀtriazoleꢀ3ꢀthiones include: (i) alkaline ring closure of
acylthiosemicarbazides,15 (ii) reaction of acid hydrazides with carbon disulfide and hydrazine
hydrate,16 (iii) cyclodehydration of Nꢀ(hydrazinecarbonothioyl)benzamides,17 and (iv) thionation
of 1,2,4ꢀtriazoleꢀ3ꢀones.18
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
Figure 2. Some Pharmaceuticals Possessing 1,2,4-Triazole Core
1,2,4ꢀTriazoles and their derivatives are important class of heterocycles because of their
prevalence in biologically active molecules including agrochemicals.19ꢀ22 Pharmacological
activities shown by derivatives of 1,2,4ꢀtriazoles include antiꢀinflammatory, CNS stimulants
sedatives, antianxiety, antimicrobial agents, diuretic activities and antimycotic activities. Further,
some of the drugs already available in market such as Triazolam (IV), Alprazolam (V) and
Etizolam (VI) have 1,2,4ꢀtriazole ring system (Figure 2). Triazolam is used for treating insomnia
under the brand name Halcion.23a Alprazolam (Xanax) is used to treat anxiety disorders, panic
disorders, and anxiety caused by depression23b and Etizolam (Etizola) is used as an anxiolytic
agent and hypnotic agent.23c
ACS Paragon Plus Environment

Page 5 of 37
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
With this objective and taking cues from our previous report3g arylidenearylthiosemicarbazide
(1) was treated with 10 mol % of Cu(OTf)2 in DMSO at 110 oC. The reaction after 2 h, provided a
product in 23% yield. The structure was revealed to be 4,5ꢀdiphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀ
triazoleꢀ3ꢀthione (1a) upon spectroscopic analysis. Thus, out of the two possibilities in Scheme 1,
selective formation of C−N bond involving the thioamidic NH and an imine C−H bond is taking
place. Similar oxidative C−N bond forming reactions have been reported recently both under
metal5 and metal free6 conditions. Under the aforesaid reaction conditions there was substantial
decomposition of starting material giving multitudes of unidentifiable side products; thus further
optimization was necessary.
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
In pursuit to achieve an improved yield of thione (1a) from (1) various other reaction
parameters such as catalyst quantity, salts of copper, solvents and reaction temperature were varied
and the results are summarized in Table 1. Increasing the Cu(OTf)2 loading to 20 mol % and 30
mol % resulted in an improved yield of the product (1a) (Table 1, entries 2ꢀ3). When the reaction
o
o
was carried out at 80 C instead of 110 C, no significant difference in yield was observed (Table
1, entry 4). Among all other Cu(II)ꢀsalts [Cu(ClO4)2.6H2O, CuBr2, CuSO4.5H2O, CuCl2,
Cu(OAc)2] and Cu(I) salts [CuCl and CuBr] tested, the use of CuBr2 provided the best yield of
(1a) (69%) in a shorter reaction time (Table 1, entries 5ꢀ11). Although catalysts Cu(ClO4)2.6H2O
and CuSO4.5H2O were equally effective in bringing about the transformation, but the time taken
for completion of the reactions were longer compared to the use of CuBr2. Except for DMSO, all
other polar solvents like DMF, DMA, acetonitrile and nonꢀpolar solvent like 1,4ꢀdioxane were
unsuitable for this reaction (Table 1, entries 12ꢀ15). Addition of base to the reaction was not
beneficial. When the reaction was carried out in the presence of a base Cs2CO3 (1 equiv) keeping
all other parameters constant it gave poor yield of the desired product along with several other side
o
products. No doubt at higher temperature (above 80 C), triazoleꢀthiones (Scheme 2) are formed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 37
1
2
3
4
rapidly but are also transform in situ to triazoles (Scheme 4). Thus higher temperature was not
5
6
suitable for the formation of triazoleꢀthiones (Scheme 2). Thus, the use of CuBr2 (30 mol %) in
7
8
o
DMSO solvent at 80 C was found to be optimal, and substrate scope study was achieved using
9
these conditions.
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. Screening of Reaction Conditions
Entry Catalyst (mol %)
Solvent
DMSO
DMSO
DMSO
DMSO
Temp(oC)
110
110
110
80
Time (h) Yielda (%)
1
Cu(OTf)2 (10)
Cu(OTf)2 (20)
Cu(OTf)2 (30)
Cu(OTf)2 (30)
2
23
37
64
61
67
69
68
59
62
60
56
0
2
2
3
2
4
2
5
Cu(ClO4)2.6H2O (30) DMSO
80
2
6
CuBr2 (30)
CuSO4.5H2O (30)
CuCl2 (30)
Cu(OAc)2 (30)
CuCl (30)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80
0.75
2
7
80
8
80
0.75
2
9
80
10
11
12
13
14
15
80
2
CuBr (30)
80
2
CuBr2 (30)
CuBr2 (30)
CuBr2 (30)
CuBr2 (30)
80
0.75
0.75
0.75
0.75
DMA
80
0
Dioxane
CH3CN
80
0
80
15
aIsolated yield
ACS Paragon Plus Environment

Page 7 of 37
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 2. Substrate Scope for the Synthesis of of 1,2,4-Triazole-3-thiones from
Arylidenearylthiosemicarbazidesa,b
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
aReaction conditions: Nꢀarylidenearylthiosemicarbazide (0.5 mmol), CuBr2 (0.15 mmol),
in DMSO (2 mL) at 80 oC. bIsolated yields of pure product.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 37
1
2
3
4
5
6
7
8
9
After figuring out the best optimum condition, we next explored the scope of various
substrates leading to the formation of thiones. First, Nꢀarylidenearylthiosemicarbazides derived
from various substituted arylaldehydes were subjected to the present reaction conditions to see the
effects of substitution. When the Ar1 ring is substituted with electronꢀdonating groups such as 4ꢀ
OCH3 (2), 4ꢀCH3 (3) or electronꢀwithdrawing groups such as 3ꢀBr (4), 4ꢀCl (5), all provided their
corresponding 1,2,4ꢀtriazoleꢀ3ꢀthiones (2a−5a) in yields ranging from 67ꢀ74%. No particular
correlation between the electronic nature of the substituents and the yields of products could be
ascertained; except slightly longer reaction times required for substrates (4) and (5) possessing
electronꢀwithdrawing groups (Scheme 2). When the aryl ring Ar2 bears an electronꢀdonating group
such as 4ꢀCH3 and Ar1 is unsubstituted as in (6), a moderate yield (67%) of the corresponding
1,2,4ꢀtriazoleꢀ3ꢀthione (6a) was obtained. Various possible permutations and combinations of
substituents in both the aryl (Ar1 and Ar2) rings of Nꢀarylidenearylthiosemicarbazides were next
investigated. Keeping the Ar2 (4ꢀCH3) part constant, when the substituents in the Ar1 ring were
varied with either electronꢀdonating [4ꢀCH3 (7) and 3,4ꢀdiꢀOCH3 (8)] or electronꢀwithdrawing [4ꢀ
Cl (9) and 4ꢀF (10)] groups all underwent effective cyclization via the formation of C−N bond.
With other combinations of electronꢀdonating substituents in the aryl rings [4ꢀCH3 and 2ꢀOCH3
(11), 4ꢀOBu and 4ꢀnBu (12), 3,4ꢀdiꢀOCH3 and 3,4ꢀdiꢀCH3 (13)], moderate to good yields of their
respective thiones (11a−13a) were obtained in shorter reaction times. An electronꢀwithdrawing
group (4ꢀBr) in Ar2 and an unsubstituted Ar1 ring as in (14), provided good yield (74%) of the
thione (14a). Keeping the substituent 4ꢀBr in ring Ar2 and varying the substituents in ring Ar1 viz.
4ꢀCH3 (15), 4ꢀOCH3 (16), 4ꢀCl (17) and 4ꢀBr (18), desired thiones (15a–18a) were obtained in the
range of 61ꢀ79% yields. Replacing 4ꢀBr with 4ꢀCl in the Ar2, and the Ar1 having 4ꢀCH3 (19) and 4ꢀ
Cl (20) substituents, a similar pattern in yields and reaction times were observed as with
aforementioned 4ꢀBr substituted (in Ar2 ring) substrates (15−18). The structure of thione (20a) has
been further confirmed by XRD analysis as shown in Figure S1 (see the Supporting Information).
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
ACS Paragon Plus Environment

Page 9 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The synthetic utility of this transformation has been demonstrated by the synthesis of an antiꢀ
microbial compound (21a)7e in 62% yield (Scheme 2) from its corresponding
arylidenearylthiosemicarbazide (21). The reaction was also successful with Nꢀ
arylidenethiosemicarbazide derived from a heterocyclic aldehyde, 2ꢀfuraldehyde (22), which gave
a moderate yield (64%) of the corresponding thione (22a). Judging from the yield patterns in all
the preceding set of substrates, it may be said that the electronic effects of substituents have no
significant role in controlling the product yields.
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. Change in the Reactivity of Sterically Hindered Substrates
A complete change in the reactivity pattern was observed when any one of the aryl rings
(derived from either aldehyde or thiosemicarbazide) in arylidenearylthiosemicarbazides is orthoꢀ
disubstituted. Arylidenearylthiosemicarbazides (23) derived from 2,6ꢀdichlorobenzaldehyde gave
exclusively 1,3,4ꢀthiadiazoleꢀ2ꢀamine (23c) and no traces of (23a) or (23b) (Scheme 3). Here,
probably due to the extreme steric reason imparted by both oꢀchloro groups (Scheme 3(i)) the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 37
1
2
3
4
5
6
7
8
9
thiourea moiety in (23) adopted a synꢀsyn conformation as oppose to synꢀanti conformation. This
brings the sulphur atom to the proximity of imine C−H for oxidative cyclization (C−S bond
formation) giving exclusively thiadiazole (23c). In yet another steric controlled reaction,
arylidenearylthiosemicarbazide (24) derived from 2,6ꢀdimethylthiosemicarbazide gave 1,3,4ꢀ
thiadiazoleꢀ2ꢀamine (24c) along with 1,2,4ꢀtriazole (24b) in the ratio of (3:2). Compound (24b)
must have originated from its corresponding thione (24a) which however could not be isolated.
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
It may be mentioned here that during the optimization process, when the reaction (Table 1,
entry 5) was prolonged, disappearance of the product (1a) and appearance of a new product having
lower Rf than (1a) was observed. This product upon isolation and usual characterization by
spectroscopic technique was found to be 1,2,4ꢀtriazole (1b) (Scheme 4) i.e. loss of a sulfur atom
from the parent molecule. It is likely that the product (1b) might have formed via the
desulfurization of (1a). To reconfirm the origin of the product (1b) when a preformed 4,5ꢀ
diphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (1a) was treated under the identical reaction
conditions; 1,2,4ꢀtriazole (1b) was formed exclusively after 1.5 h, confirming our assumption.
Thus, it was observed that by simply prolonging the reaction time, product (1b) was obtained
exclusively. With progress in time the percentage formation of (1a) and (1b) varies. Percentage of
(1a) and (1b) at different time (min) intervals are as follows: 30 min (55:00), 45 min (69:4), 60
min (58:15), 75 min (41:35), 90 min (20:57), 105 min (11:65) and 120 min (2:74).
ACS Paragon Plus Environment

Page 11 of 37
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 4. Substrate Scope for the Synthesis of 1,2,4-Triazoles from
Arylidenearylthiosemicarbazidesa,b
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
a Reaction conditions: Nꢀarylidenearylthiosemicarbazide (0.5 mmol) , CuBr2 (0.15 mmol), in DMSO (2 mL) at 80
oC. bIsolated yields of pure product.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 37
1
2
3
4
5
6
7
8
9
The same thiosemicarbazides (1−20) and (22) which were used for the synthesis of thiones
were now employed for the synthesis of a series of 4,5ꢀdiarylꢀ1,2,4ꢀtriazoles under the same
reaction conditions but just by prolonging the reaction times. All the thiosemicarbazides underwent
facile transformation to their respective triazoles (1b−20b) and (22b) via the loss of a sulphur atom
from their intermediate thiones (Scheme 4). Structure of the compound (7b) has been
unequivocally confirmed by Xꢀray crystallography as shown in Figure S2 (see the Supporting
Information).
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
Here again, no correlation between electronic effects of substituents and yields of products
were observed, but whatever little effect was seen it was similar to the one observed during the
formaton of their thiones. However, the time taken for the completion of reaction was shorter for
substrates possessing electronꢀdonating groups on either one or both the aryl rings than for
substrates bearing one or two electronꢀwithdrawing groups. This observation is consistent with the
formation of their intermediate thiones.
Scheme 5. Proposed Reaction Mechanism
H
Ar1
H
N
H
N
Ar1
Ar1
H+
CuIIBr2
N
S
N
S
N
S
HN
CuI
CuII
HN
Ar2
HN
Ar2
Air
HN
Ar2
(1)
(A)
(B)
H+
CuI
N N
N N
NH
N
H
Ar1
(1a)
Ar1
SH
N
SH
(C)
Ar1
S
.
N
N
Ar2
N
H
Ar2
Ar2
N
desulfurization
CuS and polynuclear
sulfur anions
Ar1
+
H
N
Ar2 (1b)
ACS Paragon Plus Environment

Page 13 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A plausible mechanism for the formation of thione (1a) is proposed (Scheme 5) which is in
accordance with the earlier reports on copper catalyzed oxidative heterocyclization.3h,24 Copper(II)
undergoes ligation with arylidenearylthiosemicarbazide (1) through its imine nitrogen and the soft
sulfur atom to give a 5ꢀmembered complex (A). The coꢀordinated Cu(II) is reduced to Cu(I) by a
single electron transfer from the imine nitrogen resulting in the formation of a nitrogen centered
radical cation (B). The Cu(I) generated in the medium is oxidized back to Cu(II) for the next
catalytic cycle by the atmospheric oxygen. This type of reduction and reoxidation has been
confirmed by EPR and UVꢀVis spectroscopic studies by others.24b The formation of a radical
cation (B) facilitates the nucleophilic attack onto its imine carbon by the terminal thioamidic
nitrogen resulting in a nitrogen centred radical (C). Loss of a hydrogen radical from (C) gives the
thione (1a). Similar cation radical and abstraction of H radical has been reported on analogous
system using Cu(II).25 It may be mentioned here that a FeCl3 mediated cyclization of
aldehydethiosemicarbazide (unsubstituted at N(2) nitrogen) gave 1,3,4ꢀthiadiazolic product
suggesting an intramolecular attack of S.24c However, for aldehydethiosemicarbazide substituted at
N(2) nitrogen depending on the nature of substituents (EWG or EDG) either S or N intramolecular
attack product is observed. For strongly electron withdrawing groups (ꢀNO2 and ꢀCF3) S attack
product predominates over N attack product. No variation in N versus S attack product was
observed for small change in the electronic effect. While a cupric perchlorate catalyzed cyclization
of N(2) substituted aldehydethiosemicarbazide gave intramolecular Nꢀattack product 1,2,4ꢀ
triazoleꢀ3ꢀthiones exclusively.24c This observation is consistent with our present cyclization
involving aldehydethiosemicarbazide (unsubstituted at N(2) nitrogen). The exact pathway leading
to the loss of sulphur to give 1,2,4ꢀtriazole (1b) is not clear at this moment. However, a similar
desulfurization of (1a) under an oxidative condition i.e. in the presence of AcOH / hydrogen
peroxide is reported.26 To find out the origin of Cꢀ5 hydrogen in (1b), the reaction of substrate (1)
was carried out in DMSOꢀd6 under otherwise identical conditions, no deuterium incorporated
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 37
1
2
3
4
5
6
7
8
9
product (dꢀ1b) was observed (Scheme 6 (i)). However, a deuterium incorporated product (dꢀ1b)
along with a non deuterated product (1b) (Scheme 6 (ii)) were obtained in the ratio of 4:1 when the
reaction was performed in the presence of DMSO : D2O (1:1, 1 mL). When the isolated product
(1b) was subjected to the present reaction condition, but in the presence of D2O, a deuterium
exchanged product (d-1b) at C5ꢀH was observed (Scheme 6, pathꢀa). Thus the Cꢀ5 hydrogen is not
originating from the solvent (DMSO) rather one of the proton (or deuterium, obtained by exchange
of NH with D2O) from nitrogen atom is transferred to Cꢀ5 position. Further the deuterated product
(d-1b) can be obtained from the non deuterated product (1b) in the presence of CuBr2 and D2O.
Scheme 6. Origin of C-5 Hydrogen
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
ACS Paragon Plus Environment

Page 15 of 37
The Journal of Organic Chemistry
1
2
3
4
Figure 3. SEM and EDS Analysis of the Isolated Cu Salt.
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
Formation of CuS in the reaction medium has been confirmed by solid state UV (see the
Supporting Information Figure S3).27 If sulphur extrusion is by the formation of CuS alone, than a
minimum of one equivalent of Cu salt is needed for the transformation of (1a) to (1b) (Scheme 5),
however, a complete transformation is taking place with just 30 mol % of the CuBr2. In addition to
the formation of CuS a range of polynuclear anions containing sulphur rings or chains are possible
and such has been observed by us earlier and also reported in literature.28 As can be seen from
SEM the flake like structures (Figure 3) resembles the formation of CuS/polysulfide which is also
evident from the elemental composition from EDS analysis.
In conclusion, we developed an efficient Cu(II) catalyzed strategy for the synthesis of two
important class of heterocycles viz. 4,5ꢀdisubstituted 1,2,4ꢀtriazoleꢀ3ꢀthiones and 4,5ꢀdisubstituted
1,2,4ꢀtriazoles from arylidenearylthiosemicarbazides by simple tuning the reaction time. Oxidative
C−N bond over C−S formations afforded 4,5ꢀdisubstituted 1,2,4ꢀtriazoleꢀ3ꢀthiones and their
desulfurization give 4,5ꢀdisubstituted 1,2,4ꢀtriazoles. However, steric factor imparted due to the
presence of oꢀdisubstituted substrates in any of the aryl rings of arylidenearylthiosemicarbazides,
the reactivity pattern changes giving thiodiazole as the major or an exclusive product. The
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 37
1
2
3
4
5
6
7
8
9
thiophilic Cu assist the desulfurization of thiones with concomitant formation of CuS or an array of
polynuclear sulfur anions which has been analyzed and confirmed by SEM and EDS analysis. The
synthetic utility of this strategy has been successfully applied for the synthesis of an antiꢀmicrobial
compound (21a).
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
EXPERIMENTAL SECTION
General information:
All the compounds were commercial grade and were used without further purification.
Organic extracts were dried over anhydrous sodium sulphate. Solvents were removed in a rotary
evaporator under reduced pressure. Silica gel (60−120 mesh size) was used for the column
chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25 mm). NMR
spectra were recorded in CDCl3 and DMSOꢀd6 with tetramethylsilane as the internal standard for
proton NMR (600 MHz) CDCl3 and DMSOꢀd6 solvent as internal standard for 13C NMR (150
MHz). HRMS spectra were recorded using ESI mode (QꢀTOF type Mass Analyzer). IR spectra
were recorded in KBr or neat.
Crystallographic Description:
Crystal data were collected ꢀ using graphite monochromated MoKα radiation (λ = 0.71073 Å) at
298 K. Cell parameters were retrieved using SMART31a software and refined with SAINT31a on all
observed reflections. Data reduction was performed with the SAINT software and corrected for
Lorentz and polarization effects. Absorption corrections were applied with the program
SADABS31b. The structure was solved by direct methods implemented in SHELXꢀ9731c program
and refined by fullꢀmatrix leastꢀsquares methods on F2. All nonꢀhydrogen atomic positions were
located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in
their geometrically generated positions. Colourless crystals were isolated in rectangular shape from
methanol at room temperature.
ACS Paragon Plus Environment

Page 17 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
General Procedure for the Synthesis of (E)ꢀ2ꢀBenzylideneꢀNꢀphenylhydrazinecarbothioamide (1):
This compound can be prepared following the procedure as reported.24cꢀd However, we
have adopted the following modified procedure.
9
To a solution of of Nꢀphenylhydrazinecarbothioamide (334.4 mg, 2 mmol) in EtOH (5 mL)
was added benzaldehyde (233.4, 2.2 mmol). The mixture was stirred under reflux for 1 h. The
reaction mixture was then cooled to room temperature and the precipitate solid so obtained was
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
filtered and washed with hexane (3
x
3
mL) to give (E)ꢀ2ꢀbenzylideneꢀNꢀ
phenylhydrazinecarbothioamide (1) (464.6 mg, 91%).
(E)ꢀ2ꢀ(4ꢀMethylbenzylidene)ꢀNꢀ(pꢀtolyl)hydrazinecarbothioamide (7). White solid; yield 498.8 mg,
o
88%; mp 194−196 C;1H NMR (600 MHz, CDCl3): δ 2.37 (s, 3H), 2.38 (s, 3H), 7.21 (t, J = 7.2
Hz, 4H), 7.49 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 9.12 (s, 1H), 10.57 (s,
1H); 13C NMR (150 MHz, CDCl3): δ 21.3, 21.7, 125.2, 127.6, 129.6, 129.8, 130.6, 135.4, 136.4,
141.3, 143.5, 176.1; IR (KBr): 3303, 3145, 2986, 1593, 1549, 1515, 1498, 1408, 1308, 1262, 1210,
1191, 1071, 814, 734 cmꢀ1.
(E)ꢀ2ꢀ(3,4ꢀDimethoxybenzylidene)ꢀNꢀ(pꢀtolyl)hydrazinecarbothioamide (8). White solid; yield
553.4 mg, 84%; mp 185−187 oC; 1H NMR (600 MHz, CDCl3): δ 2.37 (s, 3H), 3.92 (s, 3H), 3.93 (s,
3H), 6.88 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.21−7.23 (m, 3H), 7.48 (d, J = 8.4 Hz,
2H), 7.90 (s, 1H), 9.05 (s, 1H), 10.27 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 21.3, 56.2, 56.3,
108.8, 111.1, 122.6, 125.4, 126.2, 129.7, 135.5, 136.5, 143.6, 149.6, 151.7, 176.1; IR (KBr): 3330,
3144, 2987, 2959, 1601, 1545, 1509, 1463, 1421, 1265, 1236, 1207, 1196, 1137, 1018, 801, 732
cmꢀ1.
(E)ꢀ2ꢀ(4ꢀButoxybenzylidene)ꢀNꢀ(4ꢀbutylphenyl)hydrazinecarbothioamide (12). White solid; yield
690.3 mg, 90%; mp 148−150 oC; 1H NMR (600 MHz, CDCl3): δ 0.94 (t, J = 7.2 Hz, 3H), 0.99 (t,
J = 7.2 Hz, 3H), 1.38 (sextet, J = 7.8 Hz, 2H), 1.50 (sextet, J = 7.2 Hz, 2H), 1.62 (quintet, J = 7.8
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 37
1
2
3
4
5
6
7
8
9
Hz, 2H), 1.78 (quintet, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 3.99 (t, J = 6.6 Hz, 2H), 6.90 (d, J
= 9.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H) 7.59 (d, J = 9.0 Hz, 2H), 7.95 (s,
1H), 9.13 (s, 1H), 10.56 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 14.0, 14.1, 19.4, 22.5, 31.4, 33.7,
35.4, 68.0, 115.0, 124.9, 125.7, 128.9, 129.2, 135.6, 141.2, 143.4, 161.4, 175.6; IR (KBr): 3294,
3155, 2954, 2928, 1601, 1552, 1512, 1501, 1465, 1415, 1303, 1260, 1193, 1168, 1067, 1022, 971,
829 cmꢀ1.
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
(E)ꢀNꢀ(4ꢀBromophenyl)ꢀ2ꢀ(4ꢀmethylbenzylidene)hydrazinecarbothioamide (15). White solid; yield
585.3 mg, 86%; mp. 201−203 oC; 1H NMR (600 MHz, CDCl3): δ 2.39 (s, 3H), 7.22 (d, J = 7.2 Hz,
2H), 7.51(d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.2 Hz, 4H), 7.94 (s, 1H), 9.16 (s, 1H), 10.32 (s, 1H); 13C
NMR (150 MHz, CDCl3): δ 21.8, 119.5, 126.3, 127.7, 129.9, 130.3, 132.0, 137.1, 141.6, 144.0,
175.7; IR (KBr): 3315, 3145, 2989, 1604, 1586, 1547, 1502, 1400, 1329, 1262, 1199, 1067, 1009,
952, 931, 827, 810, 753 cmꢀ1.
1
(E)ꢀNꢀ(4ꢀBromophenyl)ꢀ2ꢀ(4ꢀmethoxybenzylidene)hydrazinecarbothioamide (16). White solid; H
NMR (600 MHz, CDCl3): δ 3.86 (s, 3H), 6.94 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.58
(d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.87 (s, 1H), 9.13 (s, 1H), 9.89 (s, 1H); 13C NMR
(150 MHz, CDCl3): δ 55.7, 114.7, 119.4, 125.6, 126.2, 129.4, 132.0, 137.2, 143.5, 162.1, 175.6; IR
(KBr): 3329, 3314, 3140, 2979, 1601, 1586, 1547, 1511, 1502, 1397, 1276, 1255, 1206, 1166,
1068, 1028, 1010, 826, 783 cmꢀ1.
General Procedure for the Synthesis of 4,5ꢀDiphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (1a).
To a solution of 1ꢀbenzylideneꢀ4ꢀphenylthiosemicarbazide (1) (127.67 mg, 0.5 mmol) in
DMSO (2 mL) was added CuBr2 (33.50 mg, 0.15 mmol) and the resultant solution was put into a
o
preheated oil bath (80 C) for 0.75 h. The reaction mixture was cooled to room temperature and
admixed with water (5 mL) and the product was extracted with ethyl acetate (2 x 20 mL). The
organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The
ACS Paragon Plus Environment

Page 19 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
crude product was purified over a column of silica gel and eluted with (8:2 hexane / ethyl acetate)
to give 4,5ꢀdiphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (1a) (87.40 mg, 69 % yield).
Deuterium Exchange Experiment.
9
2ꢀBenzylideneꢀNꢀphenylhydrazinecarbothioamide (1) (63.84 mg, 0.25 mmol) was taken in a 10
mL round bottom flask. To which was added DMSO (0.5 mL) and D2O (0.5 mL) and the mixture
was stirred at room temperature for 3 h. Then CuBr2 (16.75 mg, 0.075 mmol) was added to it and
the resultant reaction mixture was put into a preheated oil bath (80 oC) for 2 h. After completion of
the reaction it was admixed with water (5 mL) and the product was extracted with ethyl acetate (2
x 20 mL). The organic phase was dried over anhydrous sodium sulphate and concentrated in
vacuo. The crude product was purified over a column of silica gel and eluted with (8:2 hexane /
ethyl acetate) to give deuterated product (dꢀ1b) and nonꢀdeuterated product (1b). The ratio of
deuterated product (dꢀ1b) and nonꢀdeuterated product (1b) was determined by 1H NMR. The ratio
of (dꢀ1b) : (1b) was found to be 4:1 (See Supporting Information).
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
4,5ꢀDiphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (1a). White solid; yield 87 mg, 69%; mp
275−278 oC (Lit29a mp 291−292 oC, Yield 93%); 1H NMR (600 MHz, DMSOꢀd6):
6H), 7.40 (t, J = 7.8 Hz, 1H), 7.48−7.49 (m, 3H), 14.14 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ 7.30−7.36 (m,
δ
125.8, 128.2, 128.5, 128.7, 129.3, 129.4, 130.3, 134.5, 150.5, 168.6; IR (KBr): 3436, 3103, 2927,
2746, 1546, 1506, 1445, 1402, 1335, 1275, 1243, 1077, 969, 770, 701, 690, 609 cmꢀ1; HRMS
(ESI): calcd. for C14H12N3S+ [M + H+] 254.0746; found 254.0753.
5ꢀ(4ꢀMethoxyphenyl)ꢀ4ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (2a).29b White solid; yield
95 mg, 67%; mp 270−272 oC; 1H NMR (600 MHz, DMSOꢀd6):
2H), 7.22 (d, J = 9.0 Hz, 2H), 7.33−7.34 (m, 2H), 7.48ꢀ7.50 (m, 3H), 14.03 (s, 1H); 13C NMR (150
δ 3.72 (s, 3H), 6.88 (d, J = 8.4 Hz,
MHz, DMSOꢀd6):
δ 55.3, 114.0, 117.9, 128.7, 129.3, 129.4, 129.7, 134.7, 150.4, 160.6, 168.4; IR
(KBr): 3434, 3093, 2929, 1612, 1516, 1426, 1391, 1330, 1255, 1179, 1025, 968, 838, 752, 694,
594 cmꢀ1; HRMS (ESI): calcd. for C15H14N3OS+ [M + H+] 284.0852; found 284.0857.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 37
1
2
3
4
5
5ꢀ(4ꢀMethylphenyl)ꢀ4ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (3a).29c White solid; yield 95
o
mg, 71%; mp 261−263 C; 1H NMR (600 MHz, CDCl3):
δ 2.32 (s, 3H), 7.08 (d, J = 7.8 Hz, 2H),
6
7
8
9
7.19 (d, J = 8.4 Hz, 2H), 7.31–7.32 (m, 2H), 7.49–7.51 (m, 3H); 13C NMR (150 MHz, DMSOꢀd6):
20.8, 122.9, 128.1, 128.7, 129.1, 129.3, 129.4, 134.6, 140.2, 150.6, 168.5; IR (KBr): 3081, 3010,
δ
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
2921, 1514, 1497, 1420, 1329, 1278, 1240, 970, 822, 725, 696, 589 cmꢀ1; HRMS (ESI): calcd. for
C15H14N3S+ [M + H+] 268.0903; found 268.0915.
5ꢀ(3ꢀBromophenyl)ꢀ4ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (4a). Light yellow solid;
yield 123 mg, 74%; mp 223−225 oC; 1H NMR (600 MHz, DMSOꢀd6):
7.39 (m, 2H), 7.45 (s, 1H), 7.50–7.53 (m, 3H), 7.60–7.62 (m, 1H), 14.21 (s, 1H); 13C NMR (150
δ 7.28–7.31 (m, 2H), 7.37–
MHz, DMSOꢀd6):
δ 121.5, 127.2, 127.9, 128.7, 129.4, 129.5, 130.6, 130.8, 133.1, 134.3, 149.1,
168.7; IR (KBr): 3436, 3080, 2921, 1542, 1490, 1475, 1402, 1331, 1302, 1280, 1240, 975, 801,
715, 698, 618 cmꢀ1; HRMS (ESI): calcd. for C14H1179BrN3S+ [M + H+] 331.9852; found 331.9844.
5ꢀ(4ꢀChlorophenyl)ꢀ4ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (5a). White solid; yield 98
mg, 68%; mp 270−272 oC (Lit15l mp 271−272 oC, Yield 88%); 1H NMR (600 MHz, DMSOꢀd6):
δ
7.25 (d, J = 9.0 Hz, 2H), 7.28–7.30 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.46ꢀ7.48 (m, 3H), 14.12 (s,
1H); 13C NMR (150 MHz, DMSOꢀd6 + CDCl3):
δ
124.5, 128.5, 128.7, 129.4, 129.5, 129.8, 134.3,
135.5, 149.5, 168.8; IR (KBr): 3057, 2915, 1599, 1540, 1499, 1452, 1416, 1329, 1279, 1238, 1091,
1015, 970, 835, 744, 696 cmꢀ1; HRMS (ESI): calcd. for C14H1135ClN3S+ [M + H+] 288.0357; found
288.0353.
4ꢀ(4ꢀMethylphenyl)ꢀ5ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (6a).29a White solid; yield 90
o
mg, 67%; mp 219−221 C; 1H NMR (600 MHz, CDCl3):
δ 2.40 (s, 3H), 7.17 (d, J = 8.4 Hz, 2H),
7.27–7.28 (m, 4H), 7.32 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H); 13C NMR (150 MHz,
CDCl3): 21.6, 125.7, 128.1, 128.4, 128.8, 130.6, 130.8, 131.9, 140.2, 151.6, 169.6; IR (KBr):
δ
3109, 3033, 2933, 1548, 1516, 1500, 1482, 1445, 1398, 1333, 1276, 1239, 968, 819, 771, 696, 603
cmꢀ1; HRMS (ESI): calcd. for C15H14N3S+ [M + H+] 268.0903; found 268.0915.
ACS Paragon Plus Environment

Page 21 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
4,5ꢀBis(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (7a). White solid; yield 107 mg,
76%; mp 233−235 oC (Lit29d mp 220−222 oC, Yield 78%); 1H NMR (600 MHz, CDCl3):
δ 2.30 (s,
7
8
9
3H), 2.40 (s, 3H), 7.07 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.27
(d, J = 8.4 Hz, 2H), 12.27 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ
21.57, 21.59, 122.8, 128.2,
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
128.3, 129.6, 130.6, 132.1, 140.2, 141.2, 151.7, 169.6; IR (KBr): 3090, 2923, 1614, 1514, 1486,
1420, 1329, 1243, 1243, 1020, 969, 818, 717, 583 cmꢀ1; HRMS (ESI): calcd. for C16H16N3S+ [M +
H+] 282.1059; found 282.1055.
5ꢀ(3,4ꢀDimethoxyphenyl)ꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione
Brown solid; yield 118 mg, 72%; mp 215−217 oC; 1H NMR (600 MHz, DMSOꢀd6):
(8a).29e
δ
2.36 (s, 3H),
3.51 (s, 3H),3.72 (s, 3H), 6.82 (s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.90–6.92 (m, 1H), 7.21 (d, J = 7.8
Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 14.01 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ
20.7, 55.1,
55.5, 111.35, 111.41, 117.9, 121.1, 128.5, 129.8, 132.3, 139.0, 148.2, 150.3, 150.4, 168.6; IR
(KBr): 3273, 2929, 1608, 1515, 1477, 1464, 1397, 1335, 1286, 1257, 1234, 1137, 1018, 821, 769,
715, 583 cmꢀ1; HRMS (ESI): calcd. for C17H18N3O2S+ [M + H+] 328.1114; found 328.1107.
5ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (9a). White solid;
yield 110 mg, 73%; mp 223−226 oC; 1H NMR (600 MHz, DMSOꢀd6):
8.4 Hz, 2H), 7.27ꢀ7.31 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 14.12 (s, 1H); 13C NMR (150 MHz,
δ 2.33 (s, 3H), 7.21 (d, J =
DMSOꢀd6):
δ 20.7, 124.7, 128.3, 128.7, 129.8, 130.0, 131.7, 135.2, 139.0, 149.7, 168.8; IR (KBr):
3062, 3033, 2903, 1544, 1513, 1472, 1428, 1416, 1375, 1328, 1234, 1091, 1039, 1016, 832, 818,
745, 615 cmꢀ1; HRMS (ESI): calcd. for C15H1335ClN3S+ [M + H+] 302.0513; found 302.0516.
5ꢀ(4ꢀFluorophenyl)ꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (10a). White solid;
yield 110 mg, 77%; mp 222−224 oC; 1H NMR (600 MHz, CDCl3):
Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.33–7.35 (m, 2H); 13C NMR (150
δ 2.42 (s, 3H), 6.98 (t, J = 8.4
MHz, CDCl3):
δ 21.6, 116.1 (d, J = 21.9 Hz), 121.9, 128.1, 130.6 (d, J = 8.7 Hz), 130.7, 131.7,
140.4, 150.7, 164.0 (d, J = 251.3 Hz), 169.4; IR (KBr): 3075, 2923, 1609, 1510, 1422, 1391, 1329,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 37
1
2
3
4
5
1277, 1235, 1159, 971, 844, 816, 732, 718, 584 cmꢀ1; HRMS (ESI): calcd. for C15H13FN3S+ [M +
H+] 286.0809; found 286.0817.
6
7
8
4ꢀ(2ꢀMethoxyphenyl)ꢀ5ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (11a). White
9
o
1
solid; yield 104 mg, 70%; mp 256−259 C; H NMR (600 MHz, CDCl3):
δ 2.24 (s, 3H), 3.54 (s,
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
3H), 7.07 (t, J = 7.2 Hz, 1H), 7.11−7.13 (m, 3H), 7.18 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H),
7.46 (t, J = 7.8 Hz, 1H), 14.01 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ
20.8, 55.8, 112.9,
120.9, 123.1, 123.3, 127.2, 129.1, 130.4, 131.3, 140.2, 151.1, 154.5, 168.8; IR (KBr): 3436, 3082,
2924, 1603, 1509, 1464, 1430, 1326, 1259, 1183, 1118, 1022, 824, 757, 593 cmꢀ1; HRMS (ESI):
calcd. for C16H16N3OS+ [M + H+] 298.1009; found 298.1001.
4ꢀ(4ꢀButylphenyl)ꢀ5ꢀ(4ꢀbutoxyphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (12a). White solid;
yield 139 mg, 73%; mp 200−202 oC; 1H NMR (600 MHz, CDCl3):
δ 0.95 (t, J = 7.2 Hz, 6H), 1.38
(q, J = 7.8 Hz, 2H), 1.45 (q, J = 7.2 Hz, 2H), 1.64 (quintet, J = 7.8 Hz, 2H), 1.73 (quintet, J = 7.2
Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 3.92 (t, J = 6.6 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 7.20−7.24 (m,
4H), 7.29 (d, J = 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3):
δ 13.9, 14.1, 19.3, 22.5, 31.3, 33.3,
35.5, 67.9, 114.7, 117.7, 128.2, 129.8, 129.9, 132.2, 144.9, 151.5, 161.0, 168.9; IR (KBr): 3436,
3086, 2927, 2867, 1608, 1513, 1397, 1329, 1253, 1178, 1029, 968, 835, 738, 593 cmꢀ1; HRMS
(ESI): calcd. for C22H28N3OS+ [M + H+] 382.1948; found 382.1942.
5ꢀ(3,4ꢀDimethoxyphenyl)ꢀ4ꢀ(3,4ꢀdimethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione
(13a).
1
Light brown solid; yield 106 mg, 62%; H NMR (600 MHz, CDCl3):
δ 2.28 (s, 3H), 2.32 (s, 3H),
3.65 (s, 3H), 3.86 (s, 3H), 6.74 (d, J = 8.4 Hz, 1H), 6.90−6.92 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H),
7.10 (s, 1H), 7.27−7.28 (m, 1H); 13C NMR (150 MHz, CDCl3):
δ
19.8, 20.0, 55.8, 56.1, 111.0,
118.1, 121.5, 125.8, 129.2, 131.0, 132.5, 138.7, 138.9, 148.9, 150.9, 151.3, 169.3; IR (KBr): 3442,
3081, 2923, 1607, 1516, 1460, 1399, 1342, 1258, 1229, 1142, 1023, 863, 823, 768, 716, 596 cmꢀ1;
HRMS (ESI): calcd. for C18H20N3O2S+ [M + H+] 342.1271; found 342.1274.
ACS Paragon Plus Environment

Page 23 of 37
The Journal of Organic Chemistry
1
2
3
4
4ꢀ(4ꢀBromophenyl)ꢀ5ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (14a).29a White solid; yield
123 mg, 74%; mp 204−206 oC; 1H NMR (600 MHz, DMSOꢀd6):
7.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 14.17 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ 7.32–7.38 (m, 6H), 7.43 (t, J =
5
6
7
8
δ
122.6,
9
125.6, 128.4, 128.6, 130.4, 131.0, 132.3, 133.9, 150.4, 168.5; IR (KBr): 3078, 2925, 1616, 1547,
1491, 1396, 1329, 1278, 1235, 1021, 968, 825, 771, 695, 609 cmꢀ1; HRMS (ESI): calcd. for
C14H1179BrN3S+ [M + H+] 331.9852; found 331.9857.
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
4ꢀ(4ꢀBromophenyl)ꢀ5ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (15a). White solid;
o
1
yield 114 mg, 66%; mp 226−228 C; H NMR (600 MHz, DMSOꢀd6):
δ 2.26 (s, 3H), 7.16 ꢀ7.20
(m, 4H), 7.30 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 14.13 (s, 1H); 13C NMR (150 MHz,
DMSOꢀd6):
δ 21.0, 122.79, 122.84, 128.4, 129.4, 131.1, 132.5, 134.0, 140.6, 150.7, 168.5; IR
(KBr): 3060, 2919, 1546, 1513, 1492, 1418, 1393, 1330, 1281, 1238, 1070, 969, 821, 766, 716,
651, 588 cmꢀ1; HRMS (ESI): calcd. for C15H1379BrN3S+ [M + H+] 346.0008; found 346.0019.
4ꢀ(4ꢀBromophenyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (16a). White
o
1
solid; yield 143 mg, 79%; mp 233−235 C; H NMR (600 MHz, DMSOꢀd6):
δ 3.73 (s, 3H), 6.92
(d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 7.8 Hz, 2H),
14.10 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ
55.3, 114.1, 117.7, 122.6, 129.9, 131.0, 132.3,
134.0, 150.3, 160.7, 168.2; IR (KBr): 3434, 3074, 2924, 1609, 1508, 1395, 1328, 1256, 1178,
1073, 1022, 968, 833, 591 cmꢀ1; HRMS (ESI): calcd. for C15H1379BrN3OS+ [M + H+] 361.9957;
found 361.9962.
4ꢀ(4ꢀBromophenyl)ꢀ5ꢀ(4ꢀchlorophenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (17a). White solid;
o
1
yield 134 mg, 73%; mp 272−275 C (Lit29f Yield 82%); H NMR (600 MHz, DMSOꢀd6):
δ
7.32−7.36 (m, 4H), 7.47 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 14.22 (s, 1H); 13C NMR
(150 MHz, DMSOꢀd6):
δ 122.7, 124.5, 128.8, 130.2, 130.9, 132.4, 133.6, 135.3, 149.5, 168.5; IR
(KBr): 3436, 3062, 2920, 1604, 1489, 1425, 1369, 1324, 1255, 1091, 1011, 830, 731, 614, 550 cmꢀ
1; HRMS (ESI): calcd. for C14H1079Br35ClN3S+ [M + H+] 365.9462; found 365.9450.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 37
1
2
3
4
5
6
7
8
4,5ꢀBis(4ꢀbromophenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (18a). White solid; yield 125 mg,
61%; mp 266−269 oC; 1H NMR (600 MHz, DMSOꢀd6):
Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 14.21 (s, 1H); 13C NMR (150 MHz,
δ
7.26 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 8.4
9
DMSOꢀd6):
δ 122.7, 124.2, 124.9, 130.4, 130.9, 131.7, 132.4, 133.6, 149.6, 168.6; IR (KBr): 3437,
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
3061, 3024, 2922, 1597, 1543, 1492, 1413, 1328, 1232, 1069, 1024, 1010, 820, 735, 725, 613 cmꢀ
1; HRMS (ESI): calcd. for C14H1079Br2N3S+ [M + H+] 409.8957; found 409.8951.
4ꢀ(4ꢀChlorophenyl)ꢀ5ꢀ(4ꢀmethylphenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (19a). White solid;
o
o
1
yield 101 mg, 67%; mp 226−228 C (Lit29g mp 144−146 C, Yield 49%); H NMR (600 MHz,
CDCl3):
δ
2.34 (s, 3H), 7.12 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H),
13
7.46 (d, J = 8.4 Hz, 2H); C NMR (150 MHz, CDCl3):
δ 21.6, 122.4, 128.4, 129.7, 129.8, 130.2,
133.1, 136.1, 141.5, 151.5, 169.3; IR (KBr): 3440, 3084, 2923, 1513, 1497, 1384, 1330, 1094, 969,
821, 721, 590 cmꢀ1; HRMS (ESI): calcd. for C15H1335ClN3S+ [M + H+] 302.0513; found 302.0502.
4,5ꢀBis(4ꢀchlorophenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (20a). Light brown solid; yield
118 mg, 73%; mp 223−226 oC; 1H NMR (600 MHz, DMSOꢀd6):
7.43 (m, 4H), 7.54 (d, J = 8.4 Hz, 2H), 14.12 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ 7.29 (d, J = 8.4 Hz, 2H), 7.38ꢀ
δ
124.5,
128.8, 129.4, 130.2, 130.6, 133.2, 134.1, 135.3, 149.6, 168.8; IR (KBr): 3437, 3064, 2919, 1604,
1496, 1414, 1326, 1276, 1238, 1094, 968, 837, 744 cmꢀ1; HRMS (ESI): calcd. for C14H1035Cl2N3S+
[M + H+] 321.9967; found 321.9957. C14H9Cl2N3S, crystal dimensions 0.41 x 0.35 x 0.25mm, Mr
= 322.20, Monoclinic, space group P21/c, a =6.2831(3), b = 11.0852(6), c = 21.1130(11) Å, α = 90
o, β = 92.069(3) o, γ = 90 o, V = 1469.55(13) Å3, Z = 4, ρcalcd = 1.456 g/cm3, ꢁ = 0.575 mmꢀ1, F(000)
= 656.0, reflection collected / unique = 3689 / 2467, refinement method = fullꢀmatrix leastꢀsquares
on F2, final R indices [I > 2σ (I)]: R1 = 0.0567, wR2 = 0.1652, R indices (all data): R1 = 0.0880, wR2
= 0.1814, goodness of fit = 1.087. CCDCꢀ1055788 for 3,4ꢀBisꢀ(4ꢀchlorophenyl)ꢀ4Hꢀ1,2,4ꢀtriazole
(20a) contains the supplementary crystallographic data for this paper. These data can be obtained
ACS Paragon Plus Environment

Page 25 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
free
www.ccdc.cam.ac.uk/data_request/cif.
4ꢀ(4ꢀBromophenyl)ꢀ5ꢀ(3ꢀchlorophenyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (21a). White solid;
of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
9
o
o
1
yield 114 mg, 62%; mp 228−230 C (Lit7e mp 224−226 C, Yield 95%); H NMR (600 MHz,
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
DMSOꢀd6):
δ 7.23 (d, J = 7.8 Hz, 1H), 7.36–7.41 (m, 4H), 7.51 (d, J = 7.8 Hz, 1H), 7.72 (d, J =
8.4 Hz, 2H), 14.25 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ
122.8, 127.1, 127.6, 128.2, 130.4,
130.6, 130.9, 132.4, 133.2, 133.6, 149.2, 168.6; IR (KBr): 3443, 3060, 2920, 1541, 1491, 1435,
1329, 1281, 1237, 1069, 980, 825, 783, 713, 614 cmꢀ1; HRMS (ESI): calcd. for
C14H1079Br35ClN3S+ [M + H+] 365.9462; found 365.9471.
4ꢀ(4ꢀButylphenyl)ꢀ5ꢀ(furanꢀ2ꢀyl)ꢀ2,4ꢀdihydroꢀ3Hꢀ1,2,4ꢀtriazoleꢀ3ꢀthione (22a). Brown solid; yield
o
1
96 mg, 64%; mp 202ꢀ205 C; H NMR (600 MHz, CDCl3):
δ 0.97 (t, J = 7.2 Hz, 3H), 1.38−1.44
(m, 2H), 1.68 (quintet, J = 7.8 Hz, 2H), 2.72 (t, J = 7.8 Hz, 2H), 5.90−5.91 (m, 1H), 6.32−6.33 (m,
1H), 7.26−7.27 (m, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.47 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ
14.1, 22.6, 33.4, 35.6, 111.6, 113.1, 128.1, 130.0, 131.5, 140.2, 144.3, 144.9, 145.8, 169.0; IR
(KBr): 3437, 3084, 2925, 2863, 2774, 1621, 1523, 1452, 1325, 1280, 1247, 1024, 977, 839, 752,
624 cmꢀ1; HRMS (ESI): calcd. for C16H18N3OS+ [M + H+] 300.1165; found 300.1161.
3,4ꢀDiphenylꢀ4Hꢀ1,2,4ꢀtriazole (1b). White solid; yield 82 mg, 74%; mp 147−149 C (Lit30a mp
o
o
1
153−155 C, Yield 95%); H NMR (600 MHz, CDCl3):
δ 7.23−7.24 (m, 2H), 7.31 (t, J = 7.8 Hz,
2H), 7.37 (t, J = 7.2 Hz, 1H), 7.44−7.49 (m, 5H), 8.32 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ
125.8, 126.4, 128.6, 128.7, 129.5, 129.98, 130.04, 134.6, 144.9, 153.3; IR (KBr): 3111, 3053,
2921, 1721, 1598, 1555, 1507, 1468, 1389, 1214, 1072, 1017, 957, 770, 692, 568 cmꢀ1; HRMS
(ESI): calcd. for C14H12N3 [M + H+] 222.1026; found 222.1032.
+
3ꢀ(4ꢀMethoxyphenyl)ꢀ4ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazole (2b). White solid; yield 88 mg, 70%; mp
130−132 oC (Lit30b mp 141.5−142 oC, Yield 33%); 1H NMR (600 MHz, DMSOꢀd6):
δ 3.74 (s, 3H),
6.92 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.37−7.38 (m, 2H), 7.50−7.51 (m, 3H), 8.80 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 37
1
2
3
4
1H); 13C NMR (150 MHz, DMSOꢀd6):
δ 55.7, 114.5, 119.3, 126.6, 129.6, 130.2, 130.3, 135.2,
5
6
7
8
145.7, 152.6, 160.7; IR (KBr): 3115, 2927, 2850, 1613, 1502, 1469, 1379, 1254, 1209, 1174, 1024,
835, 769, 693, 563 cmꢀ1; HRMS (ESI): calcd. for C15H14N3O+ [M + H+] 252.1131; found
252.1135.
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
4ꢀPhenylꢀ3ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (3b). Light yellow solid; yield 86 mg, 73%; mp 163−165 oC
(Lit30b mp 165.5−166 oC, Yield 35%); 1H NMR (600 MHz, CDCl3):
Hz, 2H), 7.17−7.18 (m, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.40−7.42 (m, 3H), 8.24 (s, 1H).; 13C NMR
δ 2.27 (s, 3H), 7.05 (d, J = 7.8
(150 MHz, CDCl3): δ 21.4, 123.5, 125.8, 128.6, 129.3, 129.5, 130.0, 134.8, 140.1, 144.7, 153.3; IR
(KBr): 3108, 2924, 1596, 1502, 1474, 1452, 1383, 1202, 1183, 1087, 1011, 954, 822, 769, 729,
+
695, 664 cmꢀ1; HRMS (ESI): calcd. for C15H14N3 [M + H+] 236.1182; found 236.1195.
3ꢀ(3ꢀBromophenyl)ꢀ4ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazole (4b). Light brown solid; yield 107 mg, 71%; mp
150−152 oC; 1H NMR (600 MHz, CDCl3):
(d, J = 7.2 Hz, 1H), 7.49–7.54 (m, 4H), 7.70 (s, 1H), 8.34 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ 7.17 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 2H), 7.30
δ
122.8, 125.9, 127.1, 128.4, 129.9, 130.2, 130.3, 131.7, 133.1, 134.4, 145.1, 151.9; IR (KBr): 2923,
1636, 1597, 1502, 1445, 1379, 1202, 1071, 1018, 790, 767, 695, 683 cmꢀ1; HRMS (ESI): calcd. for
+
C14H1179BrN3 [M + H+] 300.0131; found 300.0139.
3ꢀ(4ꢀChlorophenyl)ꢀ4ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazole (5b). White solid; yield 84 mg, 66%; mp 165−168
oC (Lit30b mp 176−176.5 oC, Yield 34%); 1H NMR (600 MHz, CDCl3):
(d, J = 7.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.50–7.52 (m, 3H), 8.33 (s, 1H); 13C NMR (150
δ 7.24−7.26 (m, 2H), 7.30
MHz, CDCl3):
δ 125.0, 125.9, 129.1, 129.9, 130.0, 130.3, 134.6, 136.4, 145.1, 152.4; IR (KBr):
3106, 2923, 2853, 1595, 1569, 1502, 1467, 1453, 1406, 1380, 1205, 1094, 1083, 1016, 956, 831,
+
773, 740, 728, 696, 664 cmꢀ1; HRMS (ESI): calcd. for C14H1135ClN3 [M + H+] 256.0636; found
256.0631.
3ꢀPhenylꢀ4ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (6b). White solid; yield 81 mg, 69%; mp 144−147 oC (Lit30c
o
1
mp 151 C, Yield 57%); H NMR (600 MHz, CDCl3):
δ 2.38 (s, 3H), 7.07 (d, J = 7.8 Hz, 2H),
ACS Paragon Plus Environment

Page 27 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7.21 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.8 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 7.8 Hz, 2H),
8.25 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ 21.3, 125.7, 126.6, 128.67, 128.72, 130.0, 130.7,
7
8
132.2, 139.8, 145.0, 153.3; IR (KBr): 3109, 3063, 2921, 1515, 1495, 1467, 1442, 1390, 1284,
9
1198, 1073, 1016, 822, 775, 716, 696, 664 cmꢀ1; HRMS (ESI): calcd. for C15H14N3 [M + 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
236.1182; found 236.1175.
3,4ꢀDiꢀpꢀtolylꢀ4Hꢀ1,2,4ꢀtriazole (7b). White solid; yield 97 mg, 78%; mp 192−194 oC (Lit30d Yield
59%); 1H NMR (600 MHz, CDCl3):
Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 8.23 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ 2.30 (s, 3H), 2.39 (s, 3H),7.07–7.09 (m, 4H), 7.22 (d, J = 7.8
δ
21.1, 21.3, 123.6,
125.5, 128.4, 129.2, 130.4, 132.1, 139.6, 139.9, 144.8, 153.2; IR (KBr): 3116, 3033, 2920, 1612,
1517, 1474, 1385, 1206, 1037, 1008, 956, 731, 668 cmꢀ1; HRMS (ESI): calcd. for C16H16N3 [M +
+
H+] 250.1339; found 250.1335. C16H15N3, crystal dimensions 0.41 x 0.37 x 0.24 mm, Mr = 249.31,
o
Monoclinic, space group P21/c, a =5.9017(2), b = 14.1916(4), c = 16.0475(4) Å, α = 90 , β =
o
92.732(2) o, γ = 90 , V = 1342.52(7) Å3, Z = 4, ρcalcd = 1.234 g/cm3, ꢁ = 0.075 mmꢀ1, F(000) =
528.0, reflection collected / unique = 3295 / 2384, refinement method = fullꢀmatrix leastꢀsquares
on F2, final R indices [I > 2σ (I)]: R1 = 0.0454, wR2 = 0.1489, R indices (all data): R1 = 0.0653, wR2
= 0.1631, goodness of fit = 1.121. CCDCꢀ1054230 for 3,4ꢀDiꢀpꢀtolylꢀ4Hꢀ1,2,4ꢀtriazole (7b)
contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
3ꢀ(3,4ꢀDimethoxyphenyl)ꢀ4ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (8b). Light brown liquid; yield 106 mg,
72%; 1H NMR (600 MHz, CDCl3):
1H), 6.83 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 7.2 Hz, 3H), 7.22 (d, J = 7.8 Hz, 2H), 8.23 (s, 1H); 13C
δ
2.37 (s, 3H), 3.68 (s, 3H), 3.80 (s, 3H), 6.69 (d, J = 8.4 Hz,
NMR (150 MHz, CDCl3):
δ 21.3, 55.9, 56.0, 110.9, 111.7, 119.0, 121.5, 125.9, 130.6, 132.4,
139.8, 144.2, 148.9, 150.4, 153.6; IR (KBr): 3120, 2925, 1610, 1517, 1244, 1174, 1141, 1022, 871,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 37
1
2
3
4
5
820, 767, 733, 669, 550 cmꢀ1; HRMS (ESI): calcd. for C17H18N3O2 [M + H+] 296.1394; found
296.1390.
+
6
7
8
3ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (9b). Light brown solid; yield 100 mg, 74%; mp
9
163−166 oC (Lit30e mp 174−176 oC, Yield 40%); 1H NMR (600 MHz, CDCl3):
(d, J = 8.4 Hz, 2H), 7.25–7.28 (m, 4H), 7.39 (d, J = 7.2 Hz, 2H), 8.27 (s, 1H); 13C NMR (150
δ 2.41 (s, 3H), 7.08
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
MHz, CDCl3):
δ 21.3, 125.0, 125.6, 128.9, 129.8, 130.7, 131.8, 136.1, 140.0, 145.1, 152.3; IR
(KBr): 3108, 3035, 2920, 1602, 1569, 1516, 1463, 1407, 1384, 1318, 1207, 1095, 1015, 1008, 956,
+
859, 843, 817, 733, 669 cmꢀ1; HRMS (ESI): calcd. for C15H1335ClN3 [M + H+] 270.0793; found
270.0799.
3ꢀ(4ꢀFluorophenyl)ꢀ4ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (10b). White solid; yield 90 mg, 71%; mp
127−129 oC; 1H NMR (600 MHz, CDCl3):
δ
2.44 (s, 3H), 7.02 (t, J = 8.4 Hz, 2H),7.11 (d, J = 7.8
13
Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.46–7.48 (m, 2H), 8.32 (s, 1H); C NMR (150 MHz, CDCl3):
δ
21.3, 115.9 (d, J = 21.8 Hz), 122.8, 125.6, 130.7 (d, J = 6.5 Hz), 132.0, 140.0, 145.5, 153.3,
163.7 (d, J = 249.3 Hz); IR (KBr): 3108, 3059, 2923, 1605, 1518, 1469, 1386, 1319, 1226, 1209,
+
1182, 1086, 1010, 852, 814, 736, 670, 627 cmꢀ1; HRMS (ESI): calcd. for C15H13FN3 [M + H+]
254.1088; found 254.1085.
4ꢀ(2ꢀMethoxyphenyl)ꢀ3ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (11b). Light yellow solid; yield 96 mg, 72%;
o
1
mp 137−139 C; H NMR (600 MHz, CDCl3):
δ 2.26 (s, 3H), 3.59 (s, 3H), 6.94−6.98 (m, 2H).
7.03 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.38−7.41 (m, 1H),
8.17 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ
21.4, 55.7, 112.6, 121.1, 123.6, 124.2, 127.9, 128.1,
129.2, 131.2, 139.2, 145.2, 153.9, 154.1; IR (KBr): 3084, 3021, 2921, 1603, 1513, 1489, 1468,
1290, 1262, 1208, 1024, 822, 751, 739, 665, 529 cmꢀ1; HRMS (ESI): calcd. for C16H16N3O+ [M +
H+] 266.1288; found 266.1302.
3ꢀ(4ꢀButoxyphenyl)ꢀ4ꢀ(4ꢀbutylphenyl)ꢀ4Hꢀ1,2,4ꢀtriazole (12b). Light brown solid; yield 135 mg,
o
1
77%; mp 59−61 C; H NMR (600 MHz, CDCl3):
δ 0.85−0.91 (m, 6H), 1.30 (sextet, J = 7.8 Hz,
ACS Paragon Plus Environment

Page 29 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
2H), 1.40 (sextet, J = 7.2 Hz, 2H), 1.55 (quintet, J = 7.2 Hz, 2H), 1.66 (quintet, J = 7.8 Hz, 2H),
2.62 (t, J = 7.2 Hz, 2H), 3.94 (t, J = 6.6 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H),
7
8
7.28−7.32 (m, 4H), 8.74 (s, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ 13.6, 13.7, 18.7, 21.7, 30.7,
9
32.9, 34.3, 67.3, 114.4, 118.8, 125.9, 129.5, 129.8, 132.3, 143.6, 145.3, 152.1, 159.7; IR (KBr):
2957, 2929, 2871, 1613, 1515, 1466, 1385, 1288, 1251, 1177, 1026, 836, 737, 568 cmꢀ1; HRMS
(ESI): calcd. for C22H28N3O+ [M + H+] 350.2227; found 350.2239
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(3,4ꢀDimethoxyphenyl)ꢀ4ꢀ(3,4ꢀdimethylphenyl)ꢀ4Hꢀ1,2,4ꢀtriazole (13b). Light brown gummy;
yield 116 mg, 75%; 1H NMR (600 MHz, CDCl3):
δ 2.19 (s, 3H), 2.25 (s, 3H), 3.67 (s, 3H), 3.78 (s,
3H), 6.67 (d, J = 8.4 Hz, 1H), 6.81−6.83 (m, 1H), 6.89−6.90 (m, 1H), 6.97 (s, 1H), 7.12 (s, 1H),
7.15 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ
19.6, 19.8, 55.8, 55.9,
110.9, 111.6, 118.9, 121.4, 123.4, 126.8, 130.9, 132.5, 138.4, 138.7, 145.0, 148.8, 150.3, 153.1; IR
(KBr): 2928, 2848, 1609, 1498, 1259, 1141, 1023, 862, 819, 730, 659, 593 cmꢀ1; HRMS (ESI):
+
calcd. for C18H20N3O2 [M + H+] 310.1550; found 310.1542.
4ꢀ(4ꢀBromophenyl)ꢀ3ꢀphenylꢀ4Hꢀ1,2,4ꢀtriazole (14b). White solid; yield 111 mg, 74%; mp
o
o
1
219−222 C (Lit30c mp 214−216 C, Yield 60%); H NMR (600 MHz, CDCl3):
δ 7.08 (d, J = 8.4
Hz, 2H), 7.27–7.30 (m, 2H), 7.34–7.39 (m, 3H), 7.54ꢀ7.56 (m, 2H)
, 8.26 (s, 1H); 13C NMR (150 MHz, CDCl3):
δ 123.6, 126.1, 127.3, 128.8, 128.9, 130.3, 133.3,
133.7, 145.0, 153.7; IR (KBr): 3126, 3065, 3034, 1551, 1497, 1468, 1388, 1240, 1200, 1067, 1014,
+
838, 818, 707, 687, 662 cmꢀ1; HRMS (ESI): calcd. for C14H1179BrN3 [M + H+] 300.0131; found
300.0125.
4ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(pꢀtolyl)ꢀ4Hꢀ1,2,4ꢀtriazole (15b). White solid; yield 127 mg, 81%; mp
231−233 oC; 1H NMR (600 MHz, CDCl3):
Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 8.26 (s, 1H); 13C NMR (150 MHz,
δ 2.34 (s, 3H), 7.09 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 7.8
CDCl3):
δ
21.5, 119.4, 123.2, 123.5, 127.4, 128.7, 129.6, 133.3, 133.8, 140.5, 144.8, 153.4; IR
ACS Paragon Plus Environment