Iodine Catalyzed Oxidative Coupling of Diaminoazines and Amines for the Synthesis of 3,5-Disubstituted-1,2,4-Triazoles

Article abstract of DOI:10.1021/acs.joc.1c00704

A simple, convenient, transition metal-free one pot synthesis of 3,5-disubstituted-1,2,4-triazoles has been established. The innovation in this reaction is the use of easily available 1,1-diaminoazines as substrates. This method provides the products with wider substrate scope, at an expedited rate, and with relatively better yields in comparison to the reported methods. The reaction mechanism involves an initial intermolecular nucleophilic addition (facilitated by I2) followed by intramolecular nucleophilic cyclization.

Full text of DOI:10.1021/acs.joc.1c00704

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Article
Iodine Catalyzed Oxidative Coupling of Diaminoazines and Amines
for the Synthesis of 3,5-Disubstituted-1,2,4-Triazoles
Aabid A. Wani, Sumit S. Chourasiya, Deepika Kathuria, Subash C. Sahoo, Uwe Beifuss,
and Prasad V. Bharatam*
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ABSTRACT: A simple, convenient, transition metal-free one pot
synthesis of 3,5-disubstituted-1,2,4-triazoles has been established.
The innovation in this reaction is the use of easily available 1,1-
diaminoazines as substrates. This method provides the products with
wider substrate scope, at an expedited rate, and with relatively better
yields in comparison to the reported methods. The reaction
mechanism involves an initial intermolecular nucleophilic addition (facilitated by I2) followed by intramolecular nucleophilic
cyclization.
Scheme S1, SI). The most commonly studied pathways
involve cyclodehydration of N-acylamidrazone derivatives,
which can be obtained from several precursors, such as
amides, amidrazones, N-acetyl-N,N-dimethylhydrazonamides
and N-acylhydrazides.16r,s,u Boyle et al. in 1967 reported the
formation of 3,5-diphenyl-1,2,4-triazoles by the treatment of
benzaldehyde azine with potassium t-butoxide (1−2 mol) in
boiling toluene for 40 h.16b Scheiner and co-workers in 1970
reported the synthesis of 3,5-diphenyl-1,2,4-triazoles by
tetrazole photolysis. In this method, nitrogen is expelled
exclusively from positions 3 and 4 of the tetrazole ring
resulting in the formation of 1,2-dihydro-3,6-diphenyl-1,2,4,5-
tetrazine which subsequently produces 3,5-diphenyl-1,2,4-
triazole.16c Francis et al. in 1987 reported the condensation
of an acyl hydrazide and an amidine to afford an
acylamidrazone which upon the thermal cyclization gives
3,5-disubstituted-1,2,4-triazoles.16e Kelarev et al. in 1993
reported the reaction of indole substituted methyl acetimi-
dates with acid hydrazides giving N-acylamidrazones, which
upon heating, were converted to 3,5-disubstituted 1H-1,2,4-
triazoles.16f Rostamizadeh et al. in 2003 reported the synthesis
of 1,2,4-triazoles by three component condensation reaction
of acid hydrazide, S-methyl isothioamide hydroiodide, and
ammonium acetate on the surface of silica gel under
microwave irradiation.16i A one step base-catalyzed synthesis
of 3,5-disubstituted 1,2,4-triazoles by the condensation of a
nitrile and a hydrazide under microwave conditions (150 °C)
INTRODUCTION
■
Azines are 2,3-diaza-1,3-butadienes,1 which gained the
attention of organic as well as material chemists because of
their diverse structural,2 chemical,3 and biological properties.4
1,1-diaminoazines are a subclass of azines, which are proven to
have interesting structural properties5 and medicinal chemistry
applications.1a,5−7 The antihypertensive drug guanabenz is a
representative example containing 1,1-diaminoazine moie-
ty.5c,6 Recently, our group has explored the ring−chain
tautomerism8a and dimerization8b of 1,1-diaminoazines in the
synthesis of heterocyclic species. In this work, we report the
application of 1,1-diaminoazines in the generation of 3,5-
disubstituted-1,2,4-triazoles.
1,2,4-Triazoles are important structural moieties, which
attracted considerable attention of heterocyclic chemists
owing to their importance in the fields of medicine,9
pesticides, insecticides,10 material chemistry,11 as well as in
organocatalysis.12 1,2,4-Triazoles are useful as bioisosteres of
cis-amide bonds to mimic peptides and in drug design to
improve the pharmacological properties of the corresponding
lead molecules.13 Such heterocycles have been studied
extensively in metal-coordination chemistry also due to their
ability to form stable complexes.14 Among these, 3,5-
disubstituted-1,2,4-triazoles found many therapeutic applica-
tions. Topiroxostat is a well-known antigout drug that belongs
to this class of molecules.15a A few derivatives of 3,5-
disubstituted-1,2,4-triazoles (Figure 1) are known for their
neuroprotective, antimicrobial, antifertility, and antiviral
activities.15
Received: March 25, 2021
Published: May 18, 2021
Owing to their broad spectrum of functions, several
synthetic methods have been developed for the generation
of 3,5-disubstituted 1H-1,2,4-triazoles.16 Scheme 1A includes a
few representative metal-free methods for the synthesis of 3,5-
disubstituted-1,2,4-trizaoles (more examples are provided in
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© 2021 American Chemical Society
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Figure 1. Drugs/leads containing 3,5-disubstituted-1,2,4-triazole moiety.
was reported by Yeung et al. in 2005.16n Al-Masoudi et al. in
2007 reported the synthesis of 1,2,4-triazole C-nucleosides
RESULTS AND DISCUSSION
■
Reaction of 1a with 2a was chosen as a model reaction to start
this study. 1,1-Diaminobenzalazines (1a) could be synthesized
by the condensation of aromatic aldehydes and amino-
guanidine hydrochloride using water as solvent.5b Initially, a
trial reaction was performed (Table 1, Entry 1) in the
presence of 20 mol % I2 and 3 equiv TBHP in MeCN at 90
°C. Delightfully the desired product 3,5-diphenyl-4H-1,2,4-
triazole (3a) was formed with yield of 38%. The structure was
from hydrazonyl chlorides and nitriles.16o Szocs et al. in 2015
̈
reported the synthesis of 5-aryl-3-C-glycosyl- and unsym-
metrical 3,5-diaryl-1,2,4-triazoles from alkylidene-amidrazones
due to intramolecular cyclization.16aa Inturi and co-workers in
2016 reported I2 mediated one-pot synthesis of 1,2,4-triazoles
from amidines and imidates through sequential C−N and N−
N bond formation. This method was not suitable for the
synthesis of unsymmetrical triazoles as the mixture of
symmetrical and unsymmetrical products were obtained.16ab
This method can produce the symmetrical products in good
yields. Though this method involves the use of readily
available and inexpensive reagents, however, when tried for
the synthesis of unsymmetrical products, a mixture of
symmetrical and unsymmetrical products was obtained.
There are numerous available methods for the synthesis of
1,2,4-triazoles16 (Schemes 1A, S1), but most of the methods
require multistep synthetic procedures as well as the use of
nonreadily available starting materials. The metal-catalyzed
reactions (Scheme S1), although having wide applications,
suffer some specific limitations, especially in the pharmaceut-
ical industry, where removing traces of the metallic species
from the active pharmaceutical ingredient (API) turns out to
be a big challenge.17 There is a need for improved methods,
and this article reports an alternate transition metal-free
method which utilizes iodine catalysis18 (Scheme 1B) for the
generation of the title compounds. The noted advantages are
(i) mild reaction conditions (I2 catalysis and lower temper-
ature), (ii) low cost and easily available starting materials, and
(iii) shorter reaction time.
confirmed through spectrometric [NMR: H, 13C, and high
1
resolution mass spectrometry (HRMS): m/z 222.1050 (M +
H)+] data. The formation of triazole can be clearly seen by
1
analyzing H NMR spectra. The 1H NMR spectra showed the
appearance of a new peak at 14 ppm which is due to the ring
NH. The initial success prompted us to optimize the reaction
conditions. Hence, screening was carried out for solvents,
amounts of I2, TBHP, benzylamine and reaction temperature
(Table 1). Various solvents were evaluated, and DMF was
found to be the best solvent, providing the highest yield
(Table 1, Entry 4).
The finalized optimal conditions are 1.8 equiv of 2a, 20 mol
% of iodine, and 1.5 equiv of TBHP and 80 °C (Table 1,
Entry 21). With the optimal conditions in hand, the substrate
scope and limitations of the developed method were explored.
A variety of benzalazines and benzylamines containing both
electron donating and electron withdrawing groups were
screened, and the products were obtained with moderate to
good yields (Scheme 2). When nitro group is at meta position
(3j, 3ac, 3af) the products were obtained with higher yield in
comparison to 3a (may be due to −I effect). But when the
nitro group is present at the para position, no products were
obtained; this may be due to the −M effect of nitro group at
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Scheme 1. Metal-Free Methods for the Synthesis of 3,5-Disubstituted-1,2,4-Triazoles
the para position. Slightly higher yield was also noticed in 3ad
which carries a methoxy group at the para position (may be
due to +M effect). The very low yield of 3r may be attributed
to the +I effect from the alkyl group which decreases the
electrophilicity of C5 position in intermediate Int-2 (Scheme
3). The compounds containing heterocyclic substituents 3w,
3x could also be obtained using this method, however with
low yields.
Compound 3j was recrystallized from methanol using slow
evaporation method, and the single needle shaped yellow
crystals thus obtained were subjected to single crystal XRD
study, which supported the expectations (Figure 2). In the
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Table 1. Optimization of the Model Reaction
entry
iodine (mol %)
oxidant (equiv)
2a (equiv)
solvent
MeCN
DCE
Toluene
DMF
DMSO
MeCN
THF
t-BuOH
NMP
1,4-dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
time (h)
temp (°C)
yield (3a) (%)
1
2
3
4
5
6
7
8
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (10)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (30)
I2 (50)
TBHP (3.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (0.5)
TBHP (1.0)
TBHP (1.5)
TBHP (2.0)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.0
1.8
1.5
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
4
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
90
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
50
80
80
rt
38
21
37
60
26
54
traces
18
39
36
48
63
67
60
33
41
61
67
66
53
70
65
65
52
70
55
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
80
90
100
120
80
80
DMF
DMF
DMF
DMF
solid state, the 1-H tautomer was found to be present. This
tautomer is involved in intermolecular hydrogen bond
between the two monomeric units in the unit cell (Figure 2).
Further, intermolecular C−H···O interaction also stabilizes
the crystals. It can be attributed to the strong negative charge
on oxygen atom of the nitro group. The π-stacking due to
antiparallel arrangement of dimers stabilize the crystals (see
SI, Figure S2). Quantum chemical studies confirmed the
preference of this particular tautomeric state of the
moleculethe 1-H tautomer is more stable than the 4-H
tautomer by 4.83 kcal/mol according to B3LYP/6-31+G(d)
level of quantum chemical analysis. The NH···N hydrogen
bond and the CH···O(N) hydrogen bonds stabilize the dimer
by >10 kcal/mol.
Finally, a DFT (density functional theory) study was carried
out to explore the mechanism of formation of 3a (Scheme 3).
Molecular iodine being a Lewis acid forms a complex with 1a
initially to form 1a-I2; this process has been found to be
endergonic by 9.94 kcal/mol. The coordinated molecular
iodine activates the C4N bond (iminic center) by making
C4 center electron-deficient. The NBO (natural bond orbital)
charge analysis as well as the local electrophilicity values
indicated that the electrophilicity at C4 center is increased
significantly after coordination with iodine. Thus, though the
iodine coordination is an endergonic process, the change in
the electrostatic characteristics facilitates the progress of the
reaction. The next step involves the nucleophilic addition of
N5 group of benzylamine 2a at the iminic carbon C4 of 1a to
form the first C−N bond. This process leading to Int-1 is
exergonic by 2.11 kcal/mol, and involves an activation energy
of 34.73 kcal/mol (a transient intermediate was also noticed
along the reaction coordinate). Int-1 undergoes oxidation in
the presence of TBHP to form N5−C6 double bond which
gives rise to a 2,3,5-triaza-1,3,5-triene intermediate (Int-2), it
is an exergonic reaction (by 62.67 kcal/mol). The 3D
geometry of Int-2 suggests that the empty p-orbital of iminic
carbon C6 and the lone pair of N2 of guanidine unit face each
other and are ready to overlap with each other. Hence, the
second C−N bond formation takes place easily by cyclization
to form zwitterionic intermediate which undergoes proton
exchange to produce Int-3.
The potential energy diagram (Figure 3) depicts that (i) the
rate-determining step is the first C−N bond formation, (ii)
formation of Int-1 is not thermodynamically favorable
(endergonic by 7.83 kcal/mol); however, the following step
that is oxidation by TBHP is a highly favorable process (by
62.67 kcal/mol). Thus, the oxidation from Int-1 to Int-2 is
the driving force facilitating the formation of product. Int-2 to
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a
Scheme 2. Substrate Scope for the Synthesis of 3,5-Disubtituted-1,2,4-Triazoles Using Optimized Conditions
a
(#) 3r was the only isolable product with aliphatic amine where R is pentylamine. Several other aliphatic amines were tried using the developed
protocol; however, the products were only detectable but not isolable. The data for 3a, 3i, and 3r were compared with the literature,16y but the
solvents utilized for obtaining the data are different.
Int-3 conversion is marginally endergonic by 1.35 kcal/mol,
involving a reasonable activation energy (Ea = 15.70 kcal/
mol). Int-3 spontaneously releases formimidamide to yield the
final product 3a. The energy released during this aromatiza-
tion followed by tautomerism is 23.23 kcal/mol (Figure 3).
To further support the proposed mechanism, cross control
experiments were conducted. The oxidation of Int-1 to Int-2
mediated by TBHP20 (which releases ∼62 kcal/mol) must be
following a radical pathway. This was confirmed by carrying
out reaction using TEMPO (a radical scavenger) with the
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Scheme 3. Plausible Mechanism of Triazole Formation with
a
Energy Details
Figure 3. Potential energy surface (PES) diagram depicting the
energetic pathway for the formation of 3a.
side product, GC-MS analysis (see SI) has been carried out
which showed a mass peak at 44.13 (m/z) with 6.60 retention
time confirming the hypothesis [GC conditions: (1) 50 °C/
min, 2 min hold time; (2) 8 °C/min −280 °C/min, 5 min
hold time; (3) He flow rate 1 mL/min; (4) 1 μL split
injection, 50:50; (5) column: DB-5MS, 5% phenyl and 95%
polysiloxane; (6) Range 50−650 MS (m/z)]. To further
confirm the formation of formimidamide in the reaction
mixture, benzaldehyde (Scheme 5, R1) and acetophenone
(Scheme 5, R2) were separately added to the reaction
mixture. The formation of benzylideneformamide and
benzylideneacetamide, respectively, confirms the release of
side product in the title reaction.
a
Gibbs free energies (ΔG) and activation energies (Ea) are in kcal/
mol.
These control experiments demonstrated the catalytic role
of iodine,21 revealed that the co-oxidant TBHP is required for
the progress of the reaction and that the reaction follows a
radical pathway. Apart from playing the role as co-oxidant,
TBHP may also be playing a role in the regeneration of the
molecular iodine from HI22 (see SI), evidenced by changes in
color.
CONCLUSIONS
■
In conclusion, an efficient method for the generation of 3,5-
disubstituted-1,2,4-triazoles using diaminoazines and benzyl-
amines as substrates has been developed. This reaction
provides triazoles containing symmetrical as well as unsym-
metrical substituents under mild reaction conditions. The
mechanism of the reaction has been established with the help
of cross control experiments and by exploring each step using
quantum chemical methods. This method offers an efficient
(alternative) procedure for the generation of 3,5-disubstituted-
1,2,4-triazoles using low cost and easily available starting
materials.
Figure 2. ORTEP diagram of dimer of 3j showing intermolecular
NH···N and CH···O hydrogen bonding between two monomer units
(shown with red dotted lines). The ORTEP diagram of 3j with 50%
thermal probability ellipsoid plot is given as Figure S1. CCDC
(2003067).19
EXPERIMENTAL SECTION
■
optimized conditions, in which case, only trace amounts
(10%) of the product were noticed (Scheme 4).
Computational Methods. The quantum chemical calculations
were carried out using the Gaussian 09 suite of programs.23
Geometry optimization of compounds was performed by DFT
using B3LYP method.24 The basis set used was 6-31+G(d) for C, H,
N, O and LANL2DZ for I2. The frequency calculations were carried
out on all the structures to verify character of stationary points
(minima v/s saddle point). The NBO25 charges were estimated to
explore nucleophilicity and electrophilicity of the reacting centers.
To trace the intermediate, the aliquots of reaction mixtures
were collected at different time intervals of 5, 20, and 25 min
of onset of reaction and analyzed after 24 h. The
intermediates Int-1 and Int-2 could be traced in the mass
spectrum (LC-MS), though these species could not be
isolated. To establish the formation of formimidamide as
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Scheme 4. Determining the Nature of the Reaction Mechanism
Scheme 5. Chemical Evidence for the Formation of Formimidamide
Electrophilicity (ω) values have been estimated using density
functional methods.26
rotary evaporator to get crude 3a. The crude 3a was purified by
column chromatography using 30:70 EtOAC/Hexane as eluent to
get pure 3a with 72% yield (0.995 g).
Chemistry. The reagents and chemicals required for the study
were procured and all the reagents were used as such without further
purification unless otherwise mentioned. The progress of the reaction
was monitored by thin layer chromatography (TLC) performed on
silica gel aluminum plates and visualization was done by UV light. 1H
NMR and 13C NMR spectra were recorded at 400 and 100 MHz
3,5-Diphenyl-1H-1,2,4-triazole (3a).16y The title compound
was isolated by column chromatography (hexane−EtOAc 3:2), Yield:
70% (95.20 mg), white solid, mp 190−191 °C; 1H NMR (400 MHz,
CD3OD) δ 8.09 (s, 4 H), 7.54−7.52 (m, 6 H); 13C{1H} NMR (100
MHz, CD3OD) δ 159.3, 138.8, 130.1, 129.8, 127.5; IR (KBr,
cm−1)3435 (−N-H), 1657 (CN). HRMS (ESI) m/z [M + H]+
calcd for C14H12N3 222.1026, found 222.1050.
1
respectively, with TMS as an internal standard. The H NMR and
13C NMR spectra were recorded for MeOH-d6 and for a few
compounds DMSO-d6 at 2.50 and 39.51 ppm respectively. Chemical
shifts (δ) are reported in parts per million (ppm). Coupling
constants (J) were reported in hertz (Hz). The abbreviations used to
characterize the signals are as follows: s = singlet, m = multiplet, d =
doublet, br. s. = broad singlet, dd = doublet of doublet, t = triplet.
High resolution mass spectra were recorded using ESI-TOF method.
General Procedure for the Preparation of 3a. To the neat
and dried round-bottom flask with 25 mL capacity, azine 1a (100
mg, 0.61 mmol), benzylamine 2a (122 mg, 1.11 mmol) and
molecular iodine (31 mg, 20 mol %) were charged followed by
addition of 1 mL DMF. The reaction mass was stirred, and to the
reaction mass TBHP (84 mg, 0.93 mmol) was added. The reaction
mass was heated to 80 °C for 12 h using oil bath. The progress of the
reaction was monitored by TLC. After the completion of reaction,
the reaction mass was quenched with saturated aqueous solution of
sodium thiosulfate (5 mL). The reaction mass was extracted with
ethyl acetate/water (3 × 50 mL). The organic layers were combined
and subjected to drying by rotary evaporator to get crude 3a which
were purified by using column chromatography (hexane−EtOAc).
The product was obtained in 70% yield (95 mg). The representative
procedure was employed for the synthesis of 3b−3ag.
3-(3-Fluorophenyl)-5-phenyl-1H-1,2,4-triazole (3b). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 60% (79.20 mg), white solid, mp 196−197 °C; 1H NMR
(400 MHz, CD3OD) δ 8.29 (s, 1 H), 8.10−8.07 (m, 3 H), 7.65 (d, J
= 7.5 Hz, 1 H), 7.56−7.54 (m, 3 H), 7.45 (t, J = 7.9 Hz, 1 H);
1
13C{1H} NMR (100 MHz, CD3OD) δ 164.6 (d, JC−F = 234 Hz),
2
151.7, 148.1, 137.5, 133.0 (d, JC−F = 55 Hz), 129.8, 129.8, 127.6,
116.9, 116.7, 111.2; IR (KBr, cm−1) 3337(N−H), 1631(CN).
HRMS (ESI) m/z [M + H]+ calcd for C14H11FN3 240.0932, found
240.0951.
3-(2-Fluorophenyl)-5-phenyl-1H-1,2,4-triazole (3c). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 45% (59.71 mg), white solid, mp 186−188 °C; 1H NMR
(400 MHz, CD3OD) δ 8.04−7.96 (m, 3 H), 7.47−7.34 (m, 4 H),
7.29−7.18 (m, 2 H); 13C{1H} NMR (100 MHz, CD3OD) δ 159.9
1
(d, JC−F = 250 Hz), 151.6, 145.2, 133.7, 129.8, 129.5, 128.4, 126.2,
124.5, 116.0, 115.8; IR (KBr, cm−1) 3337 (N−H), 1640 (CN).
HRMS (ESI) m/z [M + H]+ calcd for C14H11FN3 240.0932, found
240.0950.
3-Phenyl-5-(p-tolyl)-1H-1,2,4-triazole (3d). The title com-
pound was isolated by column chromatography (hexane−EtOAc
3:1), Yield: 57% (76.10 mg), white solid, mp 244−246 °C; 1H NMR
(400 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.10 (d, J = 8.0 Hz, 2 H),
8.08 (d, J = 7.9 Hz, 2 H), 7.51 (bs, 3H), 7.35 (m, 2H), 7.33 (d, J =
7.5 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ
157.1, 141.9, 138.9, 131.3, 129.2, 128.1, 127.0, 126.9, 126.7, 126.1,
20.0.IR (KBr, cm−1) 3337 (N−H), 1631 (CN). HRMS (ESI) m/z
[M + H]+ calcd for C15H14N3 236.1183, found 236.1189.
3-(4-Chlorophenyl)-5-(p-tolyl)-1H-1,2,4-triazole (3e). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:1), Yield: 65% (89.20 mg), white solid, mp 292−294 °C;
1H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 8.5 Hz, 2 H), 7.94 (d, J
The Scale-up Reaction (3a). To the neat and dried round-
bottom flask with 25 mL capacity, azine 1a (1 g, 6.17 mmol),
benzylamine 2a (1.22 g, 11.11 mmol) and molecular iodine (0.310 g,
20 mol %) were charged followed by addition of 1 mL DMF. The
reaction mass was stirred and to the reaction mass TBHP (0.832 g,
9.25 mmol) was added. The reaction mass was heated to 80 °C for
12 h using oil bath. The progress of the reaction was monitored by
TLC. After the completion of reaction, the reaction mass was
quenched with saturated aqueous solution of sodium thiosulfate (20
mL). The reaction mass was extracted with EtOAc/water (3 × 50
mL). The organic layers were combined and subjected to drying by
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Article
= 8.0 Hz, 2 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H),
2.44 (s, 3 H); 13C{1H} NMR (100 MHz, CD3OD) δ 157.7, 133.0,
129.3, 128.7, 128.6, 128.3, 127.6, 127.2, 126.2, 20.02; IR (KBr, cm−1)
3361 (N−H),1628 (CN). HRMS (ESI) m/z [M + H]+ calcd for
C15H13ClN3 270.0793, found 270.0807.
3-(4-Chlorophenyl)-5-phenyl-1H-1,2,4-triazole (3f). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 72% (93.67 mg), white solid, mp 187−189 °C; 1H NMR
(400 MHz, CD3OD) δ 8.11 (t, J = 8.0 Hz, 4H), 7.61 (d, J = 8.0 Hz,
2 H), 7.5 (m, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 159.4,
138.6, 137.4, 132.9, 128.5, 128.3, 128.0, 127.2, 126.7, 126.1; IR (KBr,
cm−1) 3681 (N−H), 1633 (CN). HRMS (ESI) m/z [M + H]+
calcd for C14H11ClN3 256.0637, found 256.0652.
3:2), Yield: 61% (73.49 mg), white solid, m.p.177−178 °C; 1H NMR
(400 MHz, CD3OD) δ 8.49 (s, 1 H), 8.15−8.02 (m, 3 H), 7.85 (d, J
= 6.8 Hz, 1 H), 7.55 (d, J = 6.8 Hz, 3 H), 7.30 (t, J = 7.8 Hz, 1 H);
13C{1H} NMR (100 MHz, CD3OD) δ 160.8, 149.0, 143.0, 138.6,
138.4, 135.0, 130.3, 129.9, 128.6, 126.2, 125.3; IR (KBr, cm−1) 3290
(N−H),1640 (CN). HRMS (ESI) m/z [M + H]+ calcd for
C14H11IN3 347.9993, found 347.9997.
5-(3,5-Dimethoxyphenyl)-3-(p-tolyl)-1H-1,2,4-triazole (3n).
The title compound was isolated by column chromatography
(hexane−EtOAc 3:2), Yield: 50% (83.80 mg), white solid, mp
196−197 °C; 1H NMR (400 MHz, CD3OD) δ 7.95 (brs, 2 H)
7.36−7.28 (m, 4H), 6.61 (s, 1 H), 3.88 (s, 6 H), 2.43 (s, 3 H);
13C{1H} NMR (100 MHz, CD3OD) δ 161.3, 155.8, 143.0, 132.5,
5-Phenyl-3-(m-tolyl)-1H-1,2,4-triazole (3g). The title com-
pound was isolated by column chromatography (hexane−EtOAc
3:1), Yield: 60% (80.11 mg), white solid, mp 239−240 °C; 1H NMR
(400 MHz,CD3OD) δ 8.09 (dd, J = 1.5, 7.8 Hz, 2 H), 7.92 (s, 1 H),
7.87 (d, J = 7.8 Hz, 1 H), 7.56−7.49 (m, 3 H), 7.42 (t, J = 7.7 Hz, 1
H), 7.33 (d, J = 7.5 Hz, 1 H), 2.46 (s, 3 H); 13C{1H} NMR (100
MHz, CD3OD) δ 159.7, 142.7, 140.4, 140.0, 131.9, 131.1, 130.0,
129.9, 128.2, 127.6, 124.8, 21.5; IR (KBr, cm−1) 3356 (N−H), 1636
(CN). HRMS (ESI) m/z [M + H]+ calcd for C15H14N3 236.1183,
found 236.1189.
129.3, 128.7, 128.0, 126.9, 126.1, 104.0, 101.5, 54.5, 20.0; IR (KBr,
cm−1) 3390 (N−H), 1639 (CN). HRMS (ESI) m/z [M + H]+
calcd for C17H18N3O2 296.1394, found 296.1405.
5-(3-Bromophenyl)-3-(4-bromophenyl)-1H-1,2,4-triazole
(3o). The title compound was isolated by column chromatography
(hexane−EtOAc 3:2), Yield: 62% (97.50 mg), white solid, mp 292−
1
294 °C; H NMR (400 MHz, CD3OD) δ 8.28 (s, 1 H), 8.07 (d, J =
8.0 Hz, 1 H), 8.01 (d, J = 8.5 Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H),
7.66 (d, J = 7.8 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H); 13C{1H} NMR
(100 MHz, CD3OD) δ 158.0, 132.4, 131.8, 131.4, 131.2, 130.3,
130.2, 129.8, 129.0, 128.8, 127.8, 125.9, 124.7, 123.8, 122.4; IR (KBr,
cm−1) 3681 (N−H), 1657 (CN). HRMS (ESI) m/z [M + H]+
calcd for C14H10Br2N3 379.9216, found 379.9225.
3-Phenyl-5-(p-tolyl)-1H-1,2,4-triazole (3h). The title com-
pound was isolated by column chromatography (hexane−EtOAc
3:1), Yield: 55% (79.70 mg), white solid, mp 245−247 °C; 1H NMR
(400 MHz, CD3OD) δ 8.08 (d, J = 6.5 Hz, 2 H), 7.96 (d, J = 7.8 Hz,
2 H), 7.56−7.49 (m, 3 H), 7.36 (d, J = 7.8 Hz, 2 H), 2.44 (s, 3 H);
13C{1H} NMR (100 MHz, CD3OD) δ 159.4, 140.3, 137.5, 129.6,
129.2, 128.5, 126.1, 20.0; IR (KBr, cm−1) 3393 (N−H), 1637 (C
N). HRMS (ESI) m/z [M + H]+ calcd for C15H14N3 236.1183,
found 236.1189.
3-(4-Bromophenyl)-5-(4-(tert-butyl)phenyl)-1H-1,2,4-tria-
zole (3p). The title compound was isolated by column
chromatography (hexane−EtOAc 3:1), Yield: 56% (82.71), white
1
solid, mp 286−287 °C; H NMR (400 MHz, CD3OD) δ 8.03−7.98
(m, 4 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.61 (d, J = 8.0 Hz, 2 H), 1.39
(s, 9 H); 13C{1H} NMR (100 MHz, CD3OD) δ 153.5, 140.2, 138.7,
131.7, 131.6, 127.8, 126.0, 125.6, 123.4, 30.2, 29.3; IR (KBr, cm−1)
3412 (N−H), 1631 (CN). HRMS (ESI) m/z [M + H]+ calcd for
C18H19BrN3 356.0757, found 356.0755.
3,5-Di-p-tolyl-1H-1,2,4-triazole (3i).16y The title compound
was isolated by column chromatography (hexane−EtOAc 3:1), Yield:
55% (73.45 mg), white solid, mp 249−251 °C; 1H NMR (400 MHz,
CD3OD) δ 7.96 (d, J = 4 Hz, 4 H), 7.36 (d, J = 8.0 Hz, 4 H), 2.43
(s, 6 H); 13C{1H} NMR (100 MHz, CD3OD) δ 157.9, 129.6, 129.2,
127.1, 126.9, 20.0; IR (KBr, cm−1) 3457 (N−H), 1630 (CN).
HRMS (ESI) m/z [M + H]+ calcd for C16H16N3 250.1339, found
250.1367.
3-(4-Bromophenyl)-5-(p-tolyl)-4H-1,2,4-triazole (3q). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:1), Yield: 58% (72.96 mg), white solid, mp 262−263 °C;
1H NMR (400 MHz, CD3OD) δ 8.02 (d, J = 8.3 Hz, 2 H), 7.94 (d, J
= 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H),
2.44 (s, 3 H); 13C{1H} NMR (100 MHz, CD3OD) δ 157.6, 138.2,
137.3, 135.2, 133.4, 133.3, 131.6, 127.9, 126.2, 20.0; IR (KBr, cm−1)
3342 (N−H), 1620 (CN). HRMS (ESI) m/z [M + H]+ calcd for
C15H13BrN3 314.0288, found 314.0299.
3-(3-Nitrophenyl)-5-phenyl-1H-1,2,4-triazole (3j). The title
compound was isolated by column chromatography (hexane−EtOAc
1
3:2), Yield: 76% (97.66 mg), white solid, mp 250.0−252.0 °C; H
NMR (400 MHz, CD3OD) δ 8.98 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1
H), 8.35 (d, J = 8.0 Hz, 1 H), 8.10 (dd, J = 8.0 Hz, 2 H), 7.80 (t, J =
7.7 Hz, 1 H) 7.60−7.53 (m, 3 H); 13C{1H} NMR (100 MHz,
CD3OD) δ 159.2, 148.6, 131.7, 130.1, 129.8, 128.7, 128.1, 127.5,
126.2, 123.5, 120.6; IR (KBr, cm−1) 3411 (N−H), 1637(CN).
HRMS (ESI) m/z [M + H]+ calcd for C14H11N4O2 267.0877, found
267.0892.
3-(4-Bromophenyl)-5-butyl-1H-1,2,4-triazole (3r).16y The
title compound was isolated by column chromatography (hexane−
EtOAc 3:2), Yield: 10% (11.60 mg), white solid, mp 123−124 °C;
1H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 7.8 Hz, 2 H), 7.53 (d, J
= 7.3 Hz, 2 H), 2.73 (t, J = 6.9 Hz, 2 H), 1.67 (t, 2 H), 1.37−1.19
(m, 2 H), 0.88 (t, J = 7.0 Hz, 3 H); ESI-MS [M + H]+ m/z 188.1.
3-(Naphthalen-2-yl)-5-(phenyl)-1H-1,2,4-triazole (3s). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:2), Yield: 55% (70.30 mg), white solid, mp 223−224 °C;
1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1 H), 8.19 (d, J = 8.8 Hz, 1
H), 8.13 (d, J = 6.5 Hz, 2 H), 8.02 (d, J = 8.5 Hz, 2 H), 7.98−7.91
(m, 1 H), 7.62−7.51 (m, 5 H); 13C{1H} NMR (100 MHz, CD3OD)
δ 162.6, 134.1, 133.3, 129.8, 128.6, 128.4, 128.2, 127.5, 126.7, 126.4,
126.2, 125.8, 123.3; IR (KBr, cm−1) 3373 (N−H), 1637 (CN).
HRMS (ESI) m/z [M + H]+ calcd for C18H14N3 272.1183, found
272.1194.
3-(4-Fluorophenyl)-5-phenyl-1H-1,2,4-triazole (3k). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 51% (67.71 mg), white solid, mp 188−189 °C; 1H NMR
(400 MHz, CD3OD) δ 8.06−8.12 (m, 4H), 7.40−7.56 (m, 3H),
7.26−7.36 (m, 2H); 13C{1H} NMR (100 MHz, CD3OD) δ 164.9 (d,
1JC−F = 234 Hz), 159.0, 145.2, 131.2, 130.0,129.8, 129.7, 127.1,
2
126.1, 116.8 (d, JC−F = 22 Hz);IR (KBr, cm−1) 3436 (N−H), 1635
(CN). HRMS (ESI) m/z [M + H]+ calcd for C14H11FN3
240.0932, found 240.0950.
5-(4-(tert-Butyl)phenyl)-3-phenyl-1H-1,2,4-triazole (3l). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:1) Yield: 52% (88.90 mg), white solid, mp 234−236 °C;
1H NMR (400 MHz, CD3OD) δ 8.10 (d, J = 8.0 Hz, 2 H), 8.02 (d, J
= 8.0 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.55−7.50 (m, 3 H), 1.40
(s, 9 H); 13C{1H} NMR (100 MHz, CD3OD) δ 153.3, 129.6, 128.5,
128.1, 126.9, 126.2, 126.0, 125.5, 125.0, 30.3, 30.2; IR (KBr, cm−1)
3436 (N−H), 1642 (CN). HRMS (ESI) m/z [M + H]+ calcd for
C18H20N3 278.1652, found 278.1664.
5-(3,5-Dimethoxyphenyl)-3-phenyl-1H-1,2,4-triazole (3t).
The title compound was isolated by column chromatography
(hexane−EtOAc 3:2), Yield: 45% (78.05 mg), white solid, mp
1
175−177 °C; H NMR (400 MHz, CD3OD) δ 8.15−8.01 (m, 2H),
7.61−7.45 (m, 4 H), 7.28 (br. s., 2 H), 6.62 (br. s., 1 H), 3.89 (s, 6
H); 13C{1H} NMR (100 MHz, CD3OD) δ 161.4, 147.8, 146.5,
138.2, 137.4,129.6, 128.5, 128.2, 126.9, 126.2, 104.0, 54.6; IR (KBr,
cm−1) 3452 (N−H), 1602 (CN). HRMS (ESI) m/z [M + H]+
calcd for C16H16N3O2 282.1238, found 282.1248.
3-(3-Iodophenyl)-5-phenyl-1H-1,2,4-triazole (3m). The title
compound was isolated by column chromatography (hexane−EtOAc
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Article
5-(3,5-Difluorophenyl)-3-(naphthalen-2-yl)-1H-1,2,4-tria-
zole (3u). The title compound was isolated by column
chromatography (hexane−EtOAc 3:2), Yield: 62% (89.78 mg),
(KBr, cm−1) 3245 (N−H), 1606 (CN). HRMS (ESI) m/z [M +
H]+ calcd for C15H14N3O 252.1137, found 252.1148.
3-Phenyl-5-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole
(3ab). The title compound was isolated by column chromatography
(hexane−EtOAc 3:2), Yield: 52% (76.71 mg), white solid, mp 185−
1
white solid, mp 215−216 °C; H NMR (400 MHz, CD3OD) δ 8.58
(s, 1 H), 8.14 (dd, J = 1.8, 8.5 Hz, 1 H), 8.06−7.99 (m, 2 H), 7.95
(dd, J = 3.3, 6.0 Hz, 1 H), 7.74 (dd, J = 2.3, 8.5 Hz, 2 H), 7.62−7.56
(m, 2 H), 7.08 (tt, J = 2.3, 9.0 Hz, 1 H); 13C{1H} NMR (100 MHz,
1
186 °C; H NMR (400 MHz, CD3OD) δ 8.44 (s, 1 H), 8.39 (d, J =
8.0 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 2 H), 7.89−7.64 (m, 2 H), 7.55−
7.48 (m, 3 H); 13C{1H} NMR (100 MHz, CD3OD) δ 167.8 (d,
1
1
CD3OD) δ 163.5 (d, JC−F = 258 Hz), 163.3 (d, JC−F = 233 Hz),
2
1JC−F = 263 Hz), 131.0 (d, JC−F = 71 Hz), 130.0, 129.5, 129.4,
134.2, 133.2, 128.5, 128.2, 127.5, 127.0, 126.6, 126.0, 123.1, 109.1,
3
3
109.0, 108.8 (d, JC−F = 12 Hz), 104.1, 103.8; IR (KBr, cm−1)
128.7, 128.2, 126.9, 126.2, 125.7, 122.7(d, JC−F = 12 Hz), 122.7; IR
(KBr, cm−1) 3356 (N−H), 1658 (CN). HRMS (ESI) m/z [M +
3461(N−H), 1636 (CN). HRMS (ESI) m/z [M + H]+ calcd for
H]+ calcd for C15H11F3N3 290.0900, found 290.0916.
C18H12F2N3 308.0994, found 308.1000.
5-(3,5-Dimethoxyphenyl)-3-(3-nitrophenyl)-1H-1,2,4-tria-
zole (3ac). The title compound was isolated by column
chromatography (hexane−EtOAc 3:2), Yield: 77% (121.25 mg),
5-(3,5-Difluorophenyl)-3-phenyl-1H-1,2,4-triazole (3v). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:2), Yield: 74% (117.39 mg), white solid, mp 193−194 °C;
1H NMR (400 MHz, CD3OD) δ 8.11−8.00 (m, 2 H), 7.72 (d, J =
5.5 Hz, 2 H), 7.55 (br. s., 3 H), 7.13−7.00 (m, 1 H); 13C{1H} NMR
1
white solid, mp 193−195 °C; H NMR (400 MHz, CD3OD) δ 8.93
(s, 1 H), 8.49 (d, J = 8.0 Hz, 1 H), 8.32 (d, J = 8.0 Hz, 1 H), 7.77 (t,
J = 7.75, 1H), 7.23 (s, 2 H), 6.62 (s, 1 H), 3.88 (s, 6 H); 13C{1H}
NMR (100 MHz, CD3OD) δ 161.4, 160.6, 148.6, 146.9, 138.6,
131.7, 129.8, 123.5, 120.6, 118.0, 104.0, 109.0, 102.2, 54.6; IR (KBr,
cm−): 3316 (N−H),1615 (CN). HRMS (ESI) m/z [M + H]+
calcd for C16H15N4O4 327.1088, found 327.1094.
1
1
(100 MHz, CD3OD) δ 163.4(d, JC−F = 258 Hz), 163.3(d, JC−F
=
247 Hz), 155.5, 140.1, 137.9, 130.1, 128.7, 126.2, 109.0, 108.8 (d,
3JC−F = 12 Hz), 104.0; IR (KBr, cm−1) 3318 (N−H),1631 (CN).
HRMS (ESI) m/z [M + H]+ calcd for C14H10F2N3 258.0838, found
258.0841.
5-(4-Methoxyphenyl)-3-phenyl-1H-1,2,4-triazole (3ad). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:2), Yield: 73% (112.36 mg), white solid, mp 188−190 °C;
1H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 4.0 Hz, 2 H), 8.01 (d, J
= 4 Hz, 2 H), 7.51 (br. s., 3 H), 7.09 (br. s., 2 H), 3.88 (s, 3 H);
13C{1H} NMR (100 MHz, CD3OD) δ 161.3, 158.7, 148.6, 136.7,
2-(5-(4-(tert-Butyl)phenyl)-1H-1,2,4-triazol-3-yl)quinoline
(3w). The title compound was isolated by column chromatography
(hexane−EtOAc 3:2), Yield: 46% (70.83 mg), white solid, mp 230−
1
232 °C; H NMR (400 MHz, CD3OD) δ 8.50 (d, J = 8.0 Hz, 1 H),
8.35 (d, J = 8.0 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 8.09 (d, J = 8.0
Hz, 2 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.86 (t, J = 7.8 Hz 1 H), 7.60 (t,
J = 7.6 Hz, 1 H), 7.62−7.60 (m, 2 H), 1.4 (s, 9 H); 13C{1H} NMR
(100 MHz, CD3OD) δ 165.0, 161.1, 155.7, 147.7, 136.4, 138.0,
136.5, 130.8, 129.3, 129.2, 128.6, 127.7, 126.1, 119.8, 35.0, 31.5; IR
(KBr, cm−1) 3448 (N−H), 1637 (CN). HRMS (ESI) m/z [M +
H]+ calcd for C21H21N4 329.1761, found 329.1774.
2-(5-(p-Tolyl)-1H-1,2,4-triazol-3-yl)quinoline (3x). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 32% (42.96 mg), white solid, mp 240−241 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.49 (d, J = 8.0 Hz, 1 H), 8.35 (d, J = 8 Hz,
1 H), 8.22 (d, J = 8 Hz, 1 H), 8.05−7.99 (m, 3 H), 7.83 (d, J = 4 Hz
1 H), 7.6 (t, J = 7.66 Hz 1 H), 7.38 (d, 2 H), 2.45 (s, 3 H); 13C{1H}
NMR (100 MHz, CD3OD) δ 160.3, 159.1, 147.7, 142.5, 139.5,
138.1, 130.9, 129.9, 129.4, 128.6, 128.4, 127.8, 126.4, 119.8, 21.4; IR
(KBr, cm−1) 3317 (N−H), 1681 (CN). HRMS (ESI) m/z [M +
H]+ calcd for C18H15N4 287.1292, found 287.1299.
129.5, 128.5, 127.7, 126.1, 113.9, 54.4; IR (KBr, cm−1) 3351(N−H),
1615 (CN). HRMS (ESI) m/z [M + H]+ calcd for C15H14N3O
252.1132, found 252.1146.
3-(4-Bromophenyl)-5-(3,5-dimethoxyphenyl)-1H-1,2,4-tria-
zole (3ae). The title compound was isolated by column
chromatography (hexane−EtOAc 3:2), Yield: 58% (86.63 mg),
1
white solid, mp 180−181 °C; H NMR (400 MHz, CD3OD) δ 7.79
(d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8 Hz, 2 H), 6.53 (br. s., 2 H), 6.40
(t, J = 6.4 Hz, 1 H), 3.77 (s, 6 H); 13C{1H} NMR (100 MHz,
CD3OD) δ 161.4, 158.4, 140.3, 138.8, 131.6, 129.7, 127.8, 123.5,
113.6, 104.0, 102.0, 54.0. IR (KBr, cm−1) 3337 (N−H), 1640 (C
N). HRMS (ESI) m/z [M + H]+ calcd for C16H15BrN3O2 360.0343,
found 360.0347.
3-(3-Nitrophenyl)-5-(p-tolyl)-1H-1,2,4-triazole (3af). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 65% (87.91 mg), white solid, mp 252−253 °C; 1H NMR
(400 MHz, CD3OD) δ 8.98 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.35
(d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 7.78 Hz,
1 H), 7.41 (d, J = 8.0 Hz, 2 H), 2.45 (s, 3 H); 13C{1H} NMR (100
MHz, CD3OD) δ 165.3, 161.0, 148.7, 142.0, 140.7, 131.7, 129.8,
129.4, 126.1, 123.5, 120.7, 19.9; IR (KBr, cm−1) 3329 (N−H), 1610
(CN). HRMS (ESI) m/z [M + H]+ calcd for C15H13N4O2
281.1034, found 281.1040.
Methyl 4-(5-phenyl-1H-pyrrol-2-yl)benzoate (3ag). The title
compound was isolated by column chromatography (hexane−EtOAc
3:2), Yield: 42% (90.30 mg), white solid, mp 240−242 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.28 (d, J = 8 Hz, 2 H), 8.07(t, J = 8.06 Hz,
4 H), 7.52 (m, 3 H); 13C{1H} NMR (100 MHz, CD3OD) δ 166.39,
158.83, 144.83, 130.34, 129.72, 129.57, 129.07, 128.87, 127.48,
126.84, 52.66; IR (KBr, cm−1) 3350 (N−H), 1640 (CN), 1740
(CO). HRMS (ESI) m/z [M + H]+ calcd for C16H14N3O2
280.1081, found 280.1083.
3-([1,1′-Biphenyl]-4-yl)-5-phenyl-1H-1,2,4-triazole (3y). The
title compound was isolated by column chromatography (hexane−
1
EtOAc 3:2), Yield: 57% (71.12 mg), white solid, 222−223 °C; H
NMR (400 MHz, CD3OD) δ 8.16−8.09 (m, 4 H), 7.85−7.77 (m, 2
H), 7.76−7.67 (m, 2 H), 7.59−7.45 (m, 5 H), 7.41 (d, J = 8.0 Hz, 1
H); 13C{1H} NMR (100 MHz, CD3OD) δ 160.4, 142.6, 140.9,
135.2, 129.7, 128.6, 128.1, 127.5, 127.4, 127.0, 126.7, 126.6, 126.2;
IR (KBr, cm−1) 3435 (N−H), 1638 (CN). HRMS (ESI) m/z [M
+ H]+ calcd for C20H16N3 298.1339, found: 298.1339.
3-(5-Phenyl-1H-1,2,4-triazol-3-yl)benzonitrile (3z). The title
compound was isolated by column chromatography (hexane−EtOAc
1
3:2), Yield: 60% (78.93 mg), white solid, 202−203 °C; H NMR
(400 MHz, DMSO-d6) δ 8.45 (s, 1 H), 8.41 (d, J = 8.0 Hz, 1 H),
8.07 (d, J = 6.5 Hz, 2 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.70 (t, J = 7.8
Hz, 1 H), 7.55 (d, J = 5.3 Hz, 3 H); 13C{1H} NMR (100 MHz,
CD3OD) δ 158.4, 133.3, 130.8, 130.7, 130.5, 129.6, 129.5, 128.7,
127.8, 126.6, 118.8, 112.5; IR (KBr, cm−1) 3435 (N−H),1659 (C
N). HRMS (ESI) m/z [M + H]+ calcd for C15H11N4 247.0978,
found 247.0976.
ASSOCIATED CONTENT
■
sı
* Supporting Information
3-(2-Methoxyphenyl)-5-phenyl-1H-1,2,4-triazole (3aa). The
title compound was isolated by column chromatography (hexane−
EtOAc 3:2), Yield: 54% (70.58 mg), white solid, mp 183−184 °C;
1H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 8.0 Hz, 2 H), 7.54−
7.47 (m, 5 H), 7.26 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.15 Hz, 1 H),
3.95 (s, 3 H); 13C{1H} NMR (100 MHz, CD3OD) δ 157.1, 155.6,
131.6, 130.6, 129.3, 128.9, 128.2, 126.9, 126.1, 120.7, 111.1, 54.8; IR
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00704.
Scanned spectra (1H NMR, 13C NMR, and HRMS) for
all the new compounds, computational data, and
mechanistic studies (PDF)
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Coles, S. J.; Kostakis, G. E.; Lykakis, I. N. A Copper-Benzotriazole-
Based Coordination Polymer Catalyzes the Efficient One-Pot
Synthesis of (N′-Substituted)-hydrazo-4-aryl-1, 4-dihydropyridines
from Azines. Adv. Synth. Catal. 2017, 359, 138. (c) Herrmann, H.;
Accession Codes
CCDC 2003067 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Prasad V. Bharatam − Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and
Research (NIPER), S. A. S. Nagar, Punjab 160062, India;
orcid.org/0000-0002-7064-8561; Phone: +91-172-
2214682; Email: pvbharatam@niper.ac.in
Authors
Aabid A. Wani − Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and
Research (NIPER), S. A. S. Nagar, Punjab 160062, India
Sumit S. Chourasiya − Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and
Research (NIPER), S. A. S. Nagar, Punjab 160062, India
Deepika Kathuria − Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and
Research (NIPER), S. A. S. Nagar, Punjab 160062, India;
University Center for Research and Development,
Chandigarh University, Gharuan, Punjab 140413, India
Subash C. Sahoo − Department of Chemistry, Panjab
University, Chandigarh 160014, India; orcid.org/0000-
0003-2557-1937
́
́
́
́
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Falson, P.; Ferreira, M. J. U. Monoterpene indole alkaloid azine
derivatives as MDR reversal agents. Bioorg. Med. Chem. 2018, 26,
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Uwe Beifuss − Bioorganische Chemie, Institut fur Chemie,
̈
Universität Hohenheim, D-70599 Stuttgart, Germany;
orcid.org/0000-0001-7085-6574
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00704
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Authors thank DST-DAAD joint Indo-German project (No.
INT/FRG/DAAD/P-09/2017) for providing financial sup-
port.
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