A simple and facile synthesis of novel 1,2,3-triazole substituted pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.3964

A series of novel indole and pyrimidine scaffolds bearing 1,2,3-triazoles have been designed and synthesized using click chemistry reaction conditions. Target compounds 9a-j were synthesized in the multi-step process. In the first step 5-substituted-1-methyl-1H-indole-3-carbaldehyde 2a-b reacted with ethyl cyanoacetate 3 and guanidine hydrochloride 4 in presence of L-Proline in ethanol undergoes cyclisation to form 5a-b. Further, 5a-b condensed with various benzaldehydes to form Schiff's base 6a-f, which further proporgylated with propargyl bromide to form 7a-f. Finally, 7a-f was subjected to click-chemistry with various azides in the presence of CuSO₄.5H₂O + sodium ascorbate mixture in Dimethylformamide at room temperature to obtain 2 + 3 cycloaddition products 9a-j in high yield. All these synthetic methods are mostly green and inexpensive with excellent yields.

Full text of DOI:10.1002/jhet.3964

Received: 23 July 2019
DOI: 10.1002/jhet.3964
Revised: 23 November 2019
Accepted: 28 February 2020
A R T I C L E
A simple and facile synthesis of novel 1,2,3-triazole
substituted pyrimidine derivatives
Mahesh Goud Bakkolla
| Ashok Kumar Taduri | Rama Devi Bhoomireddy
Department of Chemistry, Jawaharlal
Nehru Technological University
Hyderabad, College of Engineering,
Hyderabad, Telangana, India
Abstract
A series of novel indole and pyrimidine scaffolds bearing 1,2,3-triazoles have
been designed and synthesized using click chemistry reaction conditions. Tar-
get compounds 9a-j were synthesized in the multi-step process. In the first step
5-substituted-1-methyl-1H-indole-3-carbaldehyde 2a-b reacted with ethyl
cyanoacetate 3 and guanidine hydrochloride 4 in presence of L-Proline in etha-
nol undergoes cyclisation to form 5a-b. Further, 5a-b condensed with various
benzaldehydes to form Schiff's base 6a-f, which further proporgylated with
propargyl bromide to form 7a-f. Finally, 7a-f was subjected to click-chemistry
with various azides in the presence of CuSO4.5H2O + sodium ascorbate mix-
ture in Dimethylformamide at room temperature to obtain 2 + 3 cycloaddition
products 9a-j in high yield. All these synthetic methods are mostly green and
inexpensive with excellent yields.
Correspondence
Mahesh Goud Bakkolla, Department of
Chemistry, Jawaharlal Nehru
Technological University Hyderabad,
College of Engineering, Hyderabad,
Telangana 500 085, India.
Email: mahesh.bakkolla@gmail.com
1 | INTRODUCTION
using a catalytic amount of copper salt have settled the
above issues to some extent and achieved regioselectivity
Click chemistry is a well-known synthetic methodology
that is beautifully represented among cycloaddition
reactions involving heteroatoms, such as hetero-Diels-
Alder[1,2] and, especially 1,3-dipolar cycloaddition reac-
tions.[3,4] These modular fusion reactions combine two
unsaturated reactants and provide fast access to an enor-
mous variety of interesting five- and six-membered het-
erocycles.[5] Among these powerful class of concerted
click reaction methods, Huisgen 1,3-dipolar Copper-
catalysed cycloaddition of azides and alkynes[6] for the
preparation of 1, 2, 3-triazoles regarded as the “cream of
the crop.” It fulfils all of the criteria of click chemistry
perfectly, no matter how subjective they may be, and is
therefore extremely reliable and easy to use. The major
advantages of this method are, it typically does not
require temperature elevation but can be performed over
a wide range of temperatures (0-160ꢀC), in a variety of
solvents (including water), and over a wide range of pH
values (5-12), proceeds as much as 107 times faster than
the uncatalyzed version, and easy purification
methods.[7–10] The recent advances in triazole synthesis
towards the 1,4-regioisomers of the triazole products.[11]
1,2,3-triazoles have an important role in medicinal
chemistry, organic chemistry, dyes and agrochemicals
due to their easy methods of syntheses by click chemis-
try.[12] For instance, some of the triazole compounds dis-
play a broad spectrum of pharmacological activities such
as the anti-fungal,[13] anti-HIV,[14] antibacterial,[15] anti-
inflammatory[16] and anti-tubercular properties.[17] The
pyrimidine skeleton is an important class of nitrogen-
containing heterocyclic compounds with a significant
pharmacological
efficiency including the anti-
bacterial,[18] anti-HIV,[19] anti-viral[20] and especially
anti-cancer properties.[21] On the other hand, when
1,2,3-triazoles and pyrimidines are linked by copper-
catalyzed click reactions at the specific ring positions of
bi- or tri-heterocyclic molecules, interesting physiological
proprieties are observed.
Kumbhare et al[22] have developed the synthesis and
anti-cancer evaluation of novel triazole-linked N-
(pyrimidin-2yl)benzo[d]thiazol-2-amine derivatives. Also,
C. Kurumurthy et al[23] have described the synthesis of
J Heterocyclic Chem. 2020;1–9.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

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BAKKOLLA ET AL.
novel triazole-functionalized pyrido[2, 3-d]pyrimidines as
the promising anti-cancer and anti-bacterial agents.
Therefore, the synthesis of 1,2,3-triazole linked to pyrimi-
dines has achieved an advantage in organic synthesis as
well as medicinal chemistry. Sharma et.al[24] proposed
that indole containing pyrimidines showing both antimi-
crobial and anticancer activities and Prasanna et.al[25]
mentioned the presence of indolyl pyrimidines balance
the dipole and hydrophobicity would lead to the increase
of biological activity. Haider and Sarwar[26] confirmed
that the presence of 1,2,3-triazole ring systems signifi-
cantly increases the biological activities because of the
high dipole moment of triazoles and also actively partici-
pates in hydrogen bonding as well as dipole-dipole inter-
actions helps them binding with the biological targets
and improve their solubility. Hence, we synthesized a
series of novel indole compounds bearing pyrimidine and
1,2,3-triazole hybrid scaffolds which always considered as
potent and biologically active compounds. It has been
observed from the above findings and literature survey,
there has not been much work reported towards the syn-
thesis of indole bearing pyrimidine and triazole moieties.
Here, we are focused on the synthesis of novel
1,2,3-triazole linked pyrimidine-indole derivatives.
Hence, in this study we synthesized a new class of
indole pyrimidine triazole hybrid scaffolds, that is,
2-([4-substituted benzylidene]amino)-4-([1-substituted-
1H-1,2,3-triazol-4-yl]methoxy)-6-(1-methyl-1H-indol-3-yl)
pyrimidine-5-carbonitriles 9a-j via the copper catalysed
click reaction.
All newly synthesized compounds were characterized
by IR, 1H-NMR, 13C-NMR and LC-MS spectroscopic
techniques.
2 | RESULTS AND DISCUSSION
Our initial study was carried out for the preparation of
2-([4-substituted benzylidene]amino)-4-([1-substituted-1H-
1,2,3-triazol-4-yl]methoxy)-6-(1-methyl-1H-indol-3-yl)
pyrimidine-5-carbonitrile derivatives 9a-j and explained in
Scheme 1. In this scheme primarily, 5-substituted indole-
3-carbaldehydes 1a-b reacted with alkylating agent
(dimethyl sulphate) in the presence of K2CO3 and a cata-
lytic amount of TBAB in acetonitrile to give N-methylated
indole-3-carbaldehydes 2a-b. In the second step, the mix-
ture of 2a-b, ethyl cyanoacetate 3, guanidine hydrochlo-
ride 4 and a catalytic amount of L-proline in ethanol were
refluxed on the water bath for 2 hours to give pyrimidine
derivatives 5a-b. Further, 5a-b condensed with
4-substituted benzaldehyde in ethanol under reflux condi-
tions to resulted schiff's base product 6a-f. Further, 6a-f
SCHEME 1 Synthesis of compounds 7a-f

BAKKOLLA ET AL.
3
undergo propargylation with propargyl bromide in the
presence of K2CO3 and TBAB in acetonitrile under stirring
condition at room temperature to get 7a-f products.
Finally, the compounds 7a treated with benzyl azide
8a in the presence of sodium ascorbate, a catalytic
amount of CuSO4.5H2O in DMF under stirring condition
at room temperature to yield (Z)-4-([1-benzyl-1H-1,-
2,3-triazol-4-yl]methoxy)-2-(benzylideneamino)-
6-(1-methyl-1H-indol-3-yl)pyrimidine-5-carbonitrile 9a.
To optimize the reaction conditions we have chosen
7a, benzyl azide 8a as an exemplar substrate and reaction
carried out using various catalysts in different solvent sys-
tems (Scheme 2). Initially, a set of reaction the reaction
mixture was stirred at room temperature in the presence
of CuSO4.5H2O and sodium ascorbate mixture in DMF.
In this case, the reaction was completed within 1 hour
with excellent yield (Table 1, entry-1). Furthermore, we
examined the same reaction in the presence of
CuSO4.5H2O + TMEDA mixture in DMF gave good
yields in 12 hours (Table 1, entry-2) and in the presence
of CuSO4.5H2O + L-proline the reaction completed in
more time with lower yields (Table 1, entry-3).
The catalytic activity of CuI was also examined on the
same reaction (Table 1, entry- 4-7). In this study we have
taken CuI alone (without Co-catalyst) in DMF at room
temperature (Table 1, entry-4) gave very low yields. Fur-
thermore, we used CuI with Co-catalyst like sodium
ascorbate (Table 1, entry-5), TMEDA (Table 1, entry-6)
and L-Proline (Table 1, entry-7). It is observed that the
reaction proceeded well in the presence of CuI and
sodium ascorbate mixture in DMF. Another set of the
reaction mixture was stir at room temperature within the
presence sodium ascorbate and CuSO4.5H2O in t-BtOH/
water (1:2; Table 1, entry-8), the reaction was accom-
plished in longer reaction time with good yield.
Finally, we examined the same reaction in different
solvent systems such as t-BtOH/water (2:1; Table 1,
entry-9), THF/Water (2:1; Table 1, entry-10), THF/water
(1:2; Table 1, entry-11). Among all these solvent systems,
DMF resulted in better yields in shorted time (1-2 hours)
rather than other solvents gave moderate yields in longer
time periods.
The effect of various amounts of the catalyst was also
tested on the exemplary reaction. It is confirmed 0.5 eq of
CuSO4.5H2O and 0.5 eq of sodium ascorbate (Table 2,
entry-5) is adequate to get good yields in a low reaction
time (1 hour). Excess amount of catalyst not showing any
effect on yields of the products and reaction time. Hence
it is confirmed that the reaction proceeds well when
CuSO4.5H2O (0.5 eq) and sodium ascorbate (0.5 eq) mix-
ture used in DMF (Table 1, entry-1 and Table 2, entry-5).
The structures of the products were confirmed on the
bases of their spectral data. For the product 9a, the mass
spectrometry showed its m/z = 525.14 (Q + 1); IR cm−1
(KBr): 2278 (CN), 1630 (C═N) 1165 (─O─); 1H-NMR
(400 MHz, DMSO-d6) δ 9.12 (s, 1H, N═CH), 8.40 (s, 1H,
Ar CH), 7.86-6.87 (m, 15H, ArH), 5.59 (s, 2H, CH2), 4.32
(s, 2H, CH2), 3.71 (s, 3H, CH3); 13C-NMR (100 MHz:
DMSO-d6): δ 174.22, 171.02, 168.21, 160.45, 142.36,
135.98, 135.82, 133.15, 131.31, 130.17, 129.32, 129.13,
127.45, 126.22, 125.17, 123.87, 123.18, 122.32, 121.34,
117.62, 87.60, 68.90, 48.60, 36.96. Using the above opti-
mum conditions the other derivatives 9b-j were synthe-
sized (Scheme 3) and these results were tabulated in
Table 3.
2.1 | Experimental section
All chemicals and reagents used in this work were pur-
chased from Sigma-Aldrich and were used as received
without further purification. Melting points were
recorded by using open capillary tubes and are
uncorrected. The progress of the reaction was monitored
by silica gel G-coated TLC plates under UV-light and
Iodine chamber. The IR spectra were recorded on
PerkinElmer 446 FT-IR spectrometer and are provided in
cm−1 (KBr). The 1H-NMR and 13C-NMR spectra were
recorded on a Bruker DRX-400 (400 MHz) respectively,
using TMS as internal standard in either CDCl3 or
DMSO-d6. For the 1H-NMR spectra, the signals were
recorded as singlet (s), doublet (d), triplet (t), quartet
(q) and multiplet (m). Mass spectra on an Agilent LC-MS
instrument giving only M+ values in Q + 1 mode.
SCHEME 2 Synthesis of
compound 9a

4
BAKKOLLA ET AL.
TABLE 1 Catalyst and solvent screening for the synthesis of 9a
S. no
Catalyst (eq)
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
CuI
Ligand (eq)
Na ascorbate
TMEDA
Solvent
Temp
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
R.T
Time (hour)
Yield (%)
1
DMF
1
5
92
80
20
25
85
80
20
75
90
65
70
2
DMF
3
L-proline
DMF
15
24
3
4
-
DMF
5
CuI
Na ascorbate
TMEDA
DMF
6
CuI
DMF
5
7
CuI
L-proline
DMF
15
8
8
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
Na ascorbate
Na ascorbate
Na ascorbate
Na ascorbate
t-BtOH/water(2:1)
t-BtOH/water(1:2)
THF/water (2:1)
THF/water (1:2)
9
5
10
11
20
18
Bold line signifies the best conditions for the synthesis of target molecules.
TABLE 2 Characterisation of catalyst and ligand in DMF for the preparation of 9a
S. no
Catalyst (eq)
0.10 eq
Na ascorbate (eq)
0.10 eq
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
Temp
R.T
Time(hour)
Yield (%)
1
2
3
4
5
6
2
2
76
80
85
88
92
92
0.20 eq
0.20 eq
R.T
0.30 eq
0.30 eq
R.T
12
1
0.40 eq
0.40 eq
R.T
0.5 eq
0.50 eq
R.T
R.T
1
0.60 eq
0.60 eq
1
Bold line signifies the best conditions for the synthesis of target molecules.
SCHEME 3 Synthesis of novel 9b-j derivatives

BAKKOLLA ET AL.
5
TABLE 3 synthesis of different derivatives 9a-j
S. no
Compound
Temp
Time (hour)
Yield (%)
1
R.T
1
92
2
R.T
1
90
3
R.T
1.5
90
4
R.T
1
92
5
R.T
1
90
(Continues)

6
BAKKOLLA ET AL.
TABLE 3 (Continued)
S. no
Compound
Temp
Time (hour)
Yield (%)
6
R.T
1
92
7
R.T
1
90
8
R.T
1.5
89
9
R.T
1
90
10
R.T
1
89
2.2 | General procedure for the
preparation of 2a-b
acetonitrile (20 mL) were taken in a round bottom flask
(50 mL). The reaction mixture was allowed to stir at
room temperature for 2 hours. The progress of the reac-
tion and purity of the compounds was checked by thin
layer chromatography (TLC). After completion of the
A mixture of 1a-b (1 mmol), dimethyl sulphate (1 mmol),
K2CO3 (3 mmol) and a catalytic amount of TBAB in

BAKKOLLA ET AL.
7
reaction, the reaction mixture was poured in to ice cold
water to obtain pure products 2a-b which do not need
any further purification.
DMF (20 mL) as a solvent were stirred at room tempera-
ture in a round bottom flask (50 mL). The reaction times
were varied according to the derivatives of 7a-f (men-
tioned in Table 3) and completion of the reactions were
monitored by TLC. After completion of the reaction, the
reaction mixtures were poured in ice cold water and neu-
tralized with acetic acid individually to obtain the cyclo-
addition products 9a-j in good yields.
2.3 | General procedure for the
preparation of 5a-b
A
mixture of 2a-b (1 mmol), ethyl cyanoacetate
(Z)-2-(benzylideneamino)-4-(1-methyl-1H-indol-
3-yl)-6-(prop-2-yn-1-yloxy) pyrimidine-5-carbonitrile
3 (1 mmol), guanidine hydrochloride 4 (2 mmol) and cat-
alytic amount of L-proline in ethanol (20 mL) were taken
in a round bottom flask (50 mL). The reaction mixture
was refluxed with stirring at 80ꢀC for 2 hours. The pro-
gress of the reaction was monitored by TLC. After com-
pletion of the reaction, the reaction mixture was cooled
to room temperature and poured into ice cold water to
get pure solid 5a-b.
1
7a: Yellow solid: yield 98%; M.P = 190-192ꢀC; H-NMR
(400 MHz, DMSO-d6) δ 9.25 (s, 1H, N═CH), 8.25 (s, 1H,
Indole-H), 7.92-7.41 (m, 9H, ArH), 3.93 (s, 2H, CH2), 3.40
(s, 3H, CH3, 2.50 (s, 1H, CH); 13C-NMR (100 MHz,
DMSO-d6): δ 174.10, 170.32, 167.03, 160.21, 138.21136.10,
132.55, 131.92, 129.96, 129.07, 128.12, 122.12, 121.86,
116.54, 115.38, 89.20, 72.98, 70.42, 49.26, 36.04; m/z:
392.12 (Q + 1).
(Z)-4-([1-benzyl-1H-1,2,3-triazol-4-yl]methoxy)-
2-(benzylideneamino)-6-(1-methyl-1H-indol-
3-yl)pyrimidine-5-carbonitrile 9a: Yellow solid: yield
92%; M.P = 220-222ꢀC; IR cm−1 (KBr):2278 (CN), 1630
(C═N), 1165 (─O─); 1H-NMR (400-MHz,DMSO-d6) δ
9.12 (s, 1H, N═CH), 8.40 (s,1H, ArCH), 7.86-6.87 (m,
15H, ArH), 5.59 (s, 2H, CH2), 4.32 (s, 2H, CH2), 3.71(s,
3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 174.22,
171.02, 168.21, 160.45, 142.36, 135.98, 135.82, 133.15,
131.31, 130.17, 129.32, 129.13, 127.45, 126.22, 125.17,
123.87, 123.18, 122.32, 121.34, 117.62, 87.60, 68.90, 48.60,
36.96; m/z:525.14 (Q + 1). Anal. Calcd for C31H24N8O
(524.16): C, 70.98; H, 4.61; N, 21.36; O, 3.05% Found: C,
70.90; H, 4.55; N, 21.39; O, 3.01%.
2.4 | General procedure for the
preparation of 6a-f
Compounds 5a-b (1 mmol) individually with various
benzaldehydes (1 mmol) were dissolved in ethanol
(20 mL) and added a catalytic amount of acetic acid in a
round bottom flask (50 mL). These reaction mixtures
were refluxed for 2 hours on a water bath. The progress
of the reactions was monitored by checking TLC. After
completion of the reaction the reaction mixture was
cooled to room temperature and poured into ice-cold
water to get pure products 6a-f.
(Z)-2-(benzylideneamino)-4-((1-[2-chlorobenzyl]-
1H-1,2,3-triazol-4-yl)methoxy)-6-(1-methyl-1H-indol-
3-yl)pyrimidine-5-carbonitrile 9b: Yellow solid: yield
90%; M.P = 232-233ꢀC; IR cm−1 (KBr): 2223 (CN), 1628
(C═N), 1164 (─O─); 1H NMR (400 MHz,DMSO-d6) δ
8.71 (s, 1H, N═CH), 8.36 (s, 1H, Ar CH), 7.89-6.84 (m,
14H, ArH), 5.56 (s, 2H, CH2), 4.36 (s, 2H, CH2), 3.73 (s,
3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 176.63,
173.20, 168.79, 160.11, 143.88, 139.58, 136.11, 133.08,
133.04, 131.81, 130.83, 130.70, 130.41, 130.07, 129.21,
129.06, 128.14, 125.12, 124.17, 123.92, 122.69, 116.27,
85.70, 51.04, 35.66, 33.04; m/z: 559.13 (Q + 1). Anal.
Calcd for C31H23ClN8O (558.17): C, 66.60; H, 4.15; N,
20.04; O, 2.86% Found: C, 66.57; H, 4.18; N,
20.12; O, 2.91%.
2.5 | General procedure for the
preparation of 7a-f
A mixture of 6a-f (1 mmol), propargyl bromide (1 mmol),
K2CO3 (3 mmol) and a catalytic amount of TBAB in ace-
tonitrile (20 mL) were taken in a round bottom flask
(50 mL). The reaction mixture was allowed to stir at
room temperature for 2 hours. The progress of the reac-
tion and purity of the compounds was checked by TLC.
After completion of the reaction, the reaction mixture
was poured in to ice cold water to obtain pure products
7a-f which do not need any further purification.
2.6 | General procedure for the
preparation of 9a-j
(Z)-4-([1H-1,2,3-triazol-4-yl]methoxy)-2-(benzylidene-
amino)-6-(1-methyl-1H-indol-3-yl)pyrimidine-
5-carbonitrile 9c: Yellow solid: yield 90%; M.
P = 210-213ꢀC; IR cm−1(KBr): 3240 (NH), 2235(CN),1642
A mixture of 7a-f (1 mmol) and 1 eq. of different azide
derivatives (1 mmol) individually in the presence of the
CuSO4.5H2O (10 mol%), sodium ascorbate (20 mol%) and
1
(C═N); H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H,
NH), 8.84 (s, 1H, N═CH), 8.14-7.30 (m, 10H, ArH), 4.12

8
BAKKOLLA ET AL.
(s, 2H, CH2), 3.71 (s, 3H, CH3); 13C-NMR (100 MHz,
DMSO-d6): δ 176.12, 173.32, 168.85, 167.63, 163.12,
160.87, 143.32, 137.96, 135.54, 134.63, 133.31, 132.87,
132.30, 129.75, 129.24, 129.07, 128.45, 128.42, 116.32,
93.60, 43.60, 37.96; m/z: 435.10 (Q + 1). Anal. Calcd for
C24H18N8O (434.16): C, 66.35; H, 4.18; N, 25.79; O, 3.68%
Found: C, 66.30; H, 4.54; N, 25.88; O, 3.76%.
(Z)-4-((1-[2-chlorobenzyl]-1H-1,2,3-triazol-4-yl)met-
hoxy)-2-([4-chlorobenzylidene]amino)-6-(1-methyl-
1H-indol-3-yl)pyrimidine-5-carbonitrile 9d: Yellow
solid: yield 92%, M.P = 206-208ꢀC; IR cm−1 (KBr): 2244
(CN), 1634 (C═N), 1184 (─O─); 1H-NMR (400 MHz,
DMSO-d6) δ 8.69 (s, 1H, N═CH), 8.12 (s, 1H, Ar CH),
7.90-7.12 (m, 13H, ArH), 5.60 (s, 2H, CH2), 4.23 (s, 2H,
CH2), 3.33 (s, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6):
δ 175.36, 171.60, 169.29, 161.22, 143.23, 139.42, 136.51,
133.23, 133.21, 131.11, 131.03, 130.90, 130.54, 130.07,
129.88, 129.62, 129.14, 128.12, 128.04, 124.22, 124.17,
123.92, 122.69, 116.27, 113.09, 89.60, 60.04, 40.06, 34.19;
m/z: 593.13 (Q + 1). Anal. Calcd for C21H22Cl2N8O
(592.18): C, 62.74; H, 3.74; N, 18.88; O, 2.70% Found: C,
62.68; H, 4.04; N, 18.78; O, 2.76%.
(Z)-4-((1-[2-chlorobenzyl]-1H-1,2,3-triazol-4-yl)met-
hoxy)-2-([4-methoxybenzylidene]amino)-6-(1-methyl-
1H-indol-3-yl)pyrimidine-5-carbonitrile9e: Yellow solid:
yield 90%; M.P = 224-226ꢀC; IR cm−1 (KBr): 2286 (CN),
1634 (C═N), 1203 (OCH3), 1176 (─O─); 1H-NMR
(400 MHz, DMSO-d6) δ 8.81 (s, 1H, N═CH), 7.89-7.13 (m,
14H, ArH), 5.43 (s, 2H, CH2), 4.19 (s, 2H, CH2), 3.71 (s,
3H, OCH3), 3.43 (s, 3H, CH3); 13C-NMR (100 MHz,
DMSO-d6): δ 174.16, 171.22, 169.19, 160.92, 143.15,
137.44, 136.51, 134.21, 133.21, 131.15, 131.13, 130.84,
130.64, 130.33, 129.80, 129.62, 129.61, 128.55, 128.04,
125.12, 123.17, 122.92, 121.59, 116.53, 112.29, 89.60,
60.04, 52.06, 41.06, 35.88; m/z: 589.12 (Q + 1). Anal.
Calcd for C32H25ClN8O2 (588.18): C, 65.25; H, 4.28; N,
19.02; O, 5.43% Found: C, 65.54; H, 4.28; N,
18.78; O, 5.47%.
(Z)-2-(benzylideneamino)-4-((1-[2-chlorobenzyl]-
1H-1,2,3-triazol-4-yl)methoxy)-6-(1-methyl-5-nitro-
1H-indol-3-yl)pyrimidine-5-carbonitrile 9 g: Yellow
solid: yield 90%; M.P = 228-230ꢀC; IR cm−1 (KBr): 2216
(CN), 1628 (C═N), 1528 (NO2), 1182(─O─); 1H NMR
(400 MHz, DMSO-d6) δ 8.80 (s, 1H, N═CH), 8.52-7.11 (m,
14H, ArH), 5.58 (s, 2H, CH2), 4.33 (s, 2H, CH2), 3.33 (s,
3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 175.75,
172.10, 167.70, 162.10, 147.10, 142.88, 142.69, 133.69,
133.63, 133.01, 130.78, 130.65, 130.04, 129.24, 128.11,
127.29, 127.01, 126.53, 125.79, 124.13, 120.73, 116.5,
114.13, 112.13, 110.11, 84.88, 49.10, 43.02, 36.10; m/z:
604.09 (Q + 1). Anal. Calcd for C31H22ClN9O3 (603.15): C,
61.64; H, 3.67; N, 20.87; O, 7.95% Found: C, 61.58; H,
3.68; N, 20.75; O, 7.66%.
(Z)-4-([1H-1,2,3-triazol-4-yl]methoxy)-2-(benzylidene-
amino)-6-(1-methyl-5-nitro-1H-indol-3-yl)pyrimidine-
5-carbonitrile 9 hours: Yellow solid, yield:89%, M.
P = 223-225ꢀC; IR cm−1(KBr): 3240 (N-H), 2215 (CN),
1642 (C═N), 1520 (NO2), 1176(─O─); 1H NMR δ
(400 MHz, DMSO-d6) 10.48 (s, 1H, NH), 8.92 (s, 1H,
N═CH), 8.48-7.13 (m, 10H, ArH), 4.57 (s, 2H, CH2), 3.48
(s, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 173.82,
170.62, 163.23, 161.12, 159.22, 146.03, 137.45, 135.54,
134.19, 132.91, 132.02, 129.24, 129.08, 128.62, 128.52,
123.09, 119.25, 116.54, 89.38, 53.90, 38.16; m/z: 480.11
(Q + 1). Anal. Calcd for C24H17N9O3 (479.15): C, 60.12; H,
3.57; N, 26.29; O, 10.01% Found: C, 60.08; H, 3.66; N,
25.95; O, 10.08%.
(Z)-4-((1-[2-chlorobenzyl]-1H-1,2,3-triazol-4-yl)
methoxy)-2-([4-chlorobenzylidene]amino)-6-(1-methyl-
5-nitro-1H-indol-3-yl)pyrimidine-5-carbonitrile 9i:
Yellow solid: yield 90%; M.P = 214-216ꢀC; IR cm−1 (KBr):
1
2200 (CN), 1642 (C═N), 1528 (NO2), 1176 (─O─); H-
NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H, N═CH), 8.33
(s, 1H, Ar CH), 7.79-7.10 (m,12H, ArH), 5.58 (s, 2H,
CH2), 4.30 (s, 2H, CH2), 3.39 (s, 3H, CH3); 13C-NMR
(100 MHz, DMSO-d6): δ 173.10, 167.70, 160.75, 157.10,
147.10, 145.79, 142.88, 142.57, 133.69, 133.63, 133.01,
130.78, 130.65, 130.04, 129.24, 128.11127.29, 127.04,
126.53, 125.79, 124.13, 120.73, 116.57, 114.13, 84.58,50.10,
43.02, 33.90; m/z: 638.10 (Q + 1). Anal. Calcd for
C31H21ClN9O3 (637.11): C, 58.32; H, 3.32; N, 19.74; O,
7.52% Found: C, 58.42; H, 3.36; N, 19.96; O, 7.48%.
(Z)-4-([1-benzyl-1H-1,2,3-triazol-4-yl]methoxy)-
2-(benzylideneamino)-6-(1-methyl-5-nitro-1H-indol-
3-yl)pyrimidine-5-carbonitrile 9f: Yellow solid: yield
92%; M.P = 231-232ꢀC; IR cm−1 (KBr): 2214 (CN), 1622
1
(C═N), 1560 (NO2), 1172 (─O─); H-NMR δ (400 MHz,
DMSO-d6) 9.02 (s, 1H, N═CH), 8.38 (s, 1H, ArCH),
8.20-7.12 (m, 13H, ArH), 5.18 (s, 2H, CH2), 4.45 (s, 2H,
CH2), 3.62 (s, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6):
δ 175.12, 172.22, 168.54, 161.95, 143.56, 136.98, 135.54,
133.29, 131.31, 131.07, 129.92, 129.83, 128.22, 127.52,
124.58, 123.37, 123.18, 121.32, 121.08, 116.92, 88.40,
66.98, 49.12, 37.74; m/z: 570.13 (Q + 1). Anal. Calcd for
C31H23N9O3 (569.19): C, 65.37; H, 4.07; N, 22.13; O,
8.43% Found: C, 65.38; H, 3.98; N, 22.16; O, 8.47%.
(Z)4-((1-[2-chlorobenzyl]-1H-1,2,3-triazol-4-yl)met-
hoxy)-2-([4-methoxybenzylidene]amino)6-(1-methyl-
5-nitro-1H-indol-3-yl) pyrimidine-5-carbonitrile 9j:
Yellow solid: yield 89%; M.P = 220-221ꢀC; IR cm−1 (KBr):
2286 (CN), 1634 (C═N), 1525 (NO2), 1196 (OCH3), 1185
1
(─O─); H NMR δ = (400 MHz, DMSO-d6) 9.22 (s, 1H,
N═CH), 8.36-6.90 (m, 13H, ArH), 5.59 (s, 2H, CH2),
4.33 (s, 2H, CH2), 3.88 (s, 3H, OCH3), 3.38 (s, 3H, CH3);

BAKKOLLA ET AL.
9
13C-NMR (100 MHz, DMSO-d6): δ 172.15, 169.12, 165.29,
160.94, 141.19, 137.58, 135.33, 133.28, 133.12, 131.28,
131.20, 130.84, 130.80, 129.94, 129.73, 129.61, 128.55,
127.74, 124.96, 123.34, 121.92, 121.79, 117.82, 88.60, 62.22,
53.38, 42.86, 34.38; m/z: 634.12 (Q + 1). Anal.Calcd for
C32H24ClN9O4 (633.16): C, 60.62; H, 3.82; N, 19.88; O,
10.09% Found: C, 60.84; H, 3.79; N, 19.86; O, 9.92%.
[9] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew Chem Int Ed Engl 2002, 41, 2596.
[10] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev,
L. Noodleman, K. B. Sharpless, V. V. Fokin, J Am Chem Soc
2005, 127, 210.
[11] C. W. Tornoe, C. Christensen, M. Meldal, J Org Chem 2002,
67, 3057.
[12] G. C. Tron, T. Pirali, R. A. Billington, P. L. Canonico,
G. Sorba, A. A. Genazzani, Med Res Rev 2008, 28, 278.
[13] N. G. Aher, V. S. Pore, N. N. Mishra, A. Kumar, P. K. Shukla,
A. Sharma, M. K. Bhat, Med Chem Lett 2009, 19, 759.
[14] M. Whiting, J. C. Tripp, Y. C. Lin, W. Lindstrom, A. J. Olson,
J. H. Elder, K. B. Sharpless, V. V. Fokin, J Med Chem 2006, 4, 7697.
[15] J. A. Demaray, J. E. Thuener, M. N. Dawson, S. J. Sucheck,
Bioorg Med Chem Lett 2008, 18, 4868.
[16] R. D. Simone, M. G. Chini, I. Bruno, R. Riccio, D. Mueller,
O. Werz, G. Bifulco, J Med Chem 2011, 54, 1565.
[17] S. R. Patpi, L. Pulipati, P. Yogeeswari, D. Sriram, N. Jain,
B. Sridhar, R. Murthy, D. T. Anjana, S. V. Kalivendi,
S. Kantevar, J Med Chem 2012, 55, 3911.
[18] M. S. S. Palanki, P. E. E. Erdman, L. M. Gayo-Fung, G. L. Shevlin,
R. W. Sullivan, M. E. Goldman, L. J. Ransone, B. L. Bennett,
A. M. Manning, M. J. Suto, J Med Chem 2000, 43(21), 3995.
[19] C. H. McGuigan, S. Blewett, A. Carangio, J. T. Erichsen,
G. Andrei, R. Snoeck, E. De Clercq, J Med Chem 2010, 43, 4993.
[20] H. Parveen, F. Hayat, A. Salahuddin, A. Azam, Eur J Med
Chem 2010, 45, 3497.
3 | CONCLUSION
In conclusion, we designed and synthesized novel hetero-
cyclic compounds 9a-j which contain indoles, pyrimi-
dines and triazole ring systems, highly effective for
biological activity due to the importance of the above
functional group scaffolds in drug discovery. Hence, syn-
thesis novel drug molecules such as indoles bearing
pyrimidines and triazole hybrid scaffolds always consid-
ered as potent biologically active compounds. In addition,
the synthetic procedure has many advantages like shorter
reaction times, higher yields, easy workup, purity of the
products with no by-products and inexpensive catalyst
and so on, make it a very practical protocol for the syn-
thesis of these important heterocycles.
[21] S. A. Rostom, H. Ashour, E. I. Abd, H. A. Razik, Arch Pharm
2009, 342, 299.
[22] R. M. Kumbhare, T. L. Dadmal, M. J. Ramaiah, K. S. Kishore,
S. P. Valli, S. K. Tiwari, K. Appalanaidu, Y. K. Rao, M. Pal
Bhadra, Bioorg Med Chem Lett 2015, 25, 654.
[23] C. Kurumurthy, P. Sambasiva Rao, B. Veera Swamy, G. Santhosh
Kumar, P. Shanthan Rao, B. Narsaiah, L. R. Velatooru,
R. Pamanji, J. Venkateswara Rao, Eur J Med Chem 2011, 46, 3462.
[24] S. K. Sharma, P. Kumar, B. S. Narasimhan, K. Ramasamy, V. Mani,
R. K. Mishra, A. B. A. Majeed, Eur J Med Chem 2012, 48, 16.
[25] A. D. Prasanna, J Comp Med 2014, 2014, 1. https://doi.org/10.
1155/2014/765457
ACKNOWLEDGMENTS
The authors are thankful to the authorities of Jawaharlal
Nehru Technological University, Hyderabad, for provid-
ing laboratory facilities.
ORCID
Mahesh Goud Bakkolla https://orcid.org/0000-0003-
2894-863X
REFERENCES
[26] S. Haider, A. M. Sarwar, Hamid. Inflamm Cell Signal 2019, 95, 1.
[1] L. F. Tietze, G. Kettschau, Curr Chem 1997, 189, 120.
[2] H. Waldmann, Synthesis 1994, 6, 535.
[3] R. Huisgen, 1,3-Dipolar Cycloaddition Chemistry, Wiley,
New York 1984, 1, 176.
[4] K. V. Gothelf, K. A. Jorgensen, Chem Rev 1998, 98, 863.
[5] W. Q. Fan; A. R. Katritzky. Comprehensive Heterocyclic Chem-
istry II, Pergamon, Oxford 1996, 4, 101.
SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of this article.
[6] R. Huisgen, G. Szeimies, L. Moebius, Chem Ber 1967, 100,
2494.
[7] V. D. Bock, H. Hiemstra, J. H. V. Maarseveen, Eur J Org Chem
2006, 1, 51.
[8] V. O. Rodionov, V. V. Fokin, M. G. Finn, Angew Chem Int Ed
Engl 2005, 44, 2210.
How to cite this article: Bakkolla MG,
Taduri AK, Bhoomireddy RD. A simple and facile
synthesis of novel 1,2,3-triazole substituted
pyrimidine derivatives. J Heterocyclic Chem. 2020;
1–9. https://doi.org/10.1002/jhet.3964