Facile, one-pot, four-component synthesis of a new series of imidazo[1,2-a]pyridines in presence of TPAB in EtOH under reflux conditions

Article abstract of DOI:10.1007/s11164-019-03797-1

Abstract: A convenient, regioselective, novel, and elegant one-pot, four-component reaction was designed for synthesis of a series of new of imidazo[1,2-a]pyridines using aryl glyoxal monohydrates, ethyl acetoacetate, hydrazine hydrate, and 2-aminopyridine in presence of tetrapropylammonium bromide under reflux in EtOH as solvent. The main advantages of this protocol include the availability and low cost of the starting materials, short reaction time, convenient operation, easy workup process, highly facile operation, nonhazardous byproducts, and high yield (82–94%). Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-019-03797-1

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03797-1
Facile, one‑pot, four‑component synthesis of a new series
of imidazo[1,2‑a]pyridines in presence of TPAB in EtOH
under refux conditions
Nasser Etivand1 · Jabbar Khalafy1 · Ahmad Poursattar Marjani1
Received: 31 January 2019 / Accepted: 2 March 2019
© Springer Nature B.V. 2019
Abstract
A convenient, regioselective, novel, and elegant one-pot, four-component reaction
was designed for synthesis of a series of new of imidazo[1,2-a]pyridines using aryl
glyoxal monohydrates, ethyl acetoacetate, hydrazine hydrate, and 2-aminopyridine
in presence of tetrapropylammonium bromide under refux in EtOH as solvent. The
main advantages of this protocol include the availability and low cost of the starting
materials, short reaction time, convenient operation, easy workup process, highly
facile operation, nonhazardous byproducts, and high yield (82–94%).
Graphical abstract
Keywords Imidazo[1,2–a]pyridines · 2-Aminopyridine · Aryl glyoxal
monohydrates · Ethyl acetoacetate · Hydrazine hydrate · One-pot four-component
reaction · TPAB
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-03797-1) contains supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0123456789)
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N. Etivand et al.
Introduction
One-pot, multicomponent reactions (MCRs) are efective, time-saving, and elaborate
processes in which three or more simple and readily available components are com-
bined together to form novel complex molecules containing features of each reagent.
Therefore, these reactions have been developed as powerful, highly efcient, and
useful tools for synthesis of fused heterocycle compounds in various branches of
organic and medicinal chemistry [1–5], due to their minimization of cost and waste.
Imidazo[1,2-a]pyridines are fused [5,6]-bicyclic heterocycles with one imi-
dazole moiety embedded with the pyridine ring, being an important class of
privileged bicyclic scafolds with widespread applications in pharmaceuticals, as
organic functional materials, and for their diverse biological activities [6].
The imidazo[1,2-a]pyridine moiety can be found in many pharmaceuticals,
natural products, bioactive compounds, biomolecules, and agrochemicals [7].
Imidazo[1,2-a]pyridines exhibit biological activities such as anticancer [8], anti-
bacterial [9], antifungal [10], antiviral [11], antiinfammatory [12], antimalarial
[13], antiparkinsonian [14], and antituberculosis efects [15]. In addition, a few
derivatives exhibit enzyme inhibition [16] and are used as drugs for Alzheimer’s
disease [17]. Compounds containing the imidazo[1,2-a]pyridine moiety are pre-
sent in many natural products and marketed drugs, such as alpidem (an anxiolytic
agent) [18], saripidem and necopidem (both anxiolytic agents) [19], zolpidem
(an hypnotic agent used in treatment of insomnia) [20], zolimidine (an antiulcer
drug) [21], miroprofen (an analgesic drug) [22], olprinone (a cardiotonic agent
for treatment of acute heart failure) [23], GSK812397 [with anti-human immu-
nodefciency virus (HIV) properties] [24], and minodronic acid (for treatment of
anxiety, heart failure, and osteoporosis) [25] (Fig. 1).
All these bioactivities make the imidazo[1,2-a]pyridine scafold remarkable
for chemists due to its excellent pharmaceutical and medicinal applications and
use in advanced organic chemistry.
Over recent years, several methods have been described for synthesis of fused
bicyclic imidazo[1,2-a]pyridines, as summarized in a review [26].
A popular approach involves condensation reaction of 2-aminopyridines with var-
ious precursors such as α-halocarbonyl compounds [27], one-pot reaction of 2-ami-
nopyridines, aldehydes, and nitroalkane [28], isonitrile [29], using copper cataly-
sis, one-pot multicomponent reaction of aryl glyoxals, 2-aminopyridine, and cyclic
1,3-dicarbonyls [30], oxidative coupling between substituted 2-aminopyridine and
propargylic alcohols [31], nitroolefns [32], α,β-unsaturated ketones [33], alkynes
[34], copper-catalyzed oxidative coupling trough C–H functionalization between
pyridine derivatives and N-(alkylidene)-4H-1,2,4-triazole-4-amines [35], etc.
Nevertheless, these strategies have drawbacks in terms of harsh reaction condi-
tions, use of excess amounts of expensive catalyst, complex workup procedures,
extended reaction time, extensive by-product formation, and low yield. Hence,
development of economic, practicable methods ofering operational simplicity
and high yield using basic chemicals as starting materials for multicomponent
synthesis of this series of compounds in a single step is still desired.
1 3

Facile, one-pot, four-component synthesis of a new series…
Fig. 1 Drugs possessing imidazo[1,2-a]pyridine unit
Tetrapropylammonium bromide (TPAB) was frst synthesized in 1990 [36]. This
quaternary ammonium salt is commonly used as a phase-transfer catalyst [37].
Recently, we used this compound as catalyst for synthesis of heterocycle scafolds
[38]. TPAB is a cheap, readily available, ecocompatible catalyst with noncorrosive
nature.
Results and discussion
In continuation of our work on aryl-glyoxal-based synthesis of heterocyclic com-
pounds using one-pot, multicomponent strategies [39–42], we report herein a
convenient one-pot, four-component process for synthesis of 2,3-disubstituted
imidazo[1,2-a]pyridine derivatives using aryl glyoxals, 2-aminopyridine, ethyl ace-
toacetate, and hydrazine hydrate in presence of TPAB in EtOH. This synthetic strat-
egy is promising for synthesis of novel alkaloid structures which may exhibit phar-
maceutical and biological activities (Scheme 1).
The aryl glyoxal monohydrates applied as starting material in this study were pre-
pared by oxidation of corresponding aryl methyl ketones with SeO2 in H2O:dioxane
under refux condition according to standard literature process [43].
We started our study on the synthesis of a new series of imidazo[1,2-a]pyridine
derivatives by investigating the model reaction of phenyl glyoxal monohydrate (1a),
2-aminopyridine (2), and 5-methyl-2,4-dihydro-3H-pyrazol-3-one (6) using various
solvents, catalysts, and temperatures to establish the optimum reaction conditions
(Table 1).
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N. Etivand et al.
Scheme 1 Synthesis of imidazo[1,2-a]pyridine derivatives 5a–l by one-pot, four-component reactions
To maintain green chemistry features, nonhazardous and safe solvents such as
water, ethanol, water:ethanol, and ethylene glycol were favored as solvents in all the
optimization tests. The one-pot reaction of the mixture of substrates in absence of
catalyst in various solvents did not aford the desired product 5a either at room tem-
perature or under stirring at refux even after 24 h (Table 1, entries 1–5).
Next, the same model reaction was tested in presence of a series of Brønsted
acids including p-toluene sulfonic acid (p-TSA), l-proline, l-alanine, AcOH, and
sulfamic acid in refuxing H2O or EtOH, forming the desired product in 17–35%
yield (Table 1, entries 6–11).
Common basic catalysts such as Et3N, K2CO3 and 1,4-diazabicyclo[2.2.2]octane
(DABCO) were also investigated but unfortunately did not lead to a noticeable
amount of product or increase in the yield (Table 1, entries 12–16).
When we shifted our attention to TPAB as a catalyst in water, water:acetone, or
water:ethanol under refux condition, the reaction proceeded well, and the desired
product was obtained within 3 h in 65–70% yield (Table 1, entries 17–19). Finally,
the optimized condition was obtained as TPAB (20 mol%) in ethanol as solvent
under stirring at refux within 3 h, which produced the desired product 5a in 87%
yield (Table 1, entry 20).
This method was successfully applied for synthesis of 3-methyl-4-(2-
phenylimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-5-ol (5a) using phenylglyoxal mono-
hydrate (1a), 2-aminopyridine (2), ethyl acetoacetate (3), and hydrazine hydrate
(4) (Table 2). The feasibility of this four-component strategy appears to rely on the
structure of 5-methyl-2,4-dihydro-3H-pyrazol-3-one (6) with the optimum reaction
conditions previously set up for the three-component synthesis.
As indicated in Table 2, the reaction in absence of catalyst in various solvents
under high-temperature condition failed to aford the product (Table 2, entries 1–3).
In presence of TPAB (15 mol%), the reaction gave the product in 60% yield in water
(Table 2, entry 4). Interestingly using the same amount of TPAB (15 mol%) in etha-
nol with stirring under refux for 3 h gave the desired four-component product in
91% yield (Table 2, entry 5). Elevation or reduction of the molar ratio of catalyst
1 3

Facile, one-pot, four-component synthesis of a new series…
Table 1 Optimization of model one-pot, three-component reaction
Entry
Catalyst
Solvent (v/v%)
T (°C)
Time (h)
Yield (%)a
b
1
2
3
4
5
6
7
8
–
–
–
–
H2O
H2O
EtOH
H2O:EtOH (1:1)
Ethylene glycol
H2O
H2O
H2O
H2O
H2O
EtOH
H2O
H2O
EtOH
EtOH
H2O
RT
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
3
–
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Trace
Trace
Trace
–
25
32
28
20
35
17
–
p-TSA
l-Proline
l-Alanine
AcOH
Sulfamic acid
p-TSA
Et3N
K2CO3
K2CO3
Et3N
DABCO
TPAB
TPAB
TPAB
TPAB
9
10
11
12
13
14
15
16
17
18
19
20
–
14
Trace
–
37
65
68
70
87
H2O
H2O:acetone (1:1)
H2O:EtOH (1:1)
EtOH
3
3
3
Reaction conditions: phenyl glyoxal monohydrate (1a, 1 mmol), 2-aminopyridine (2, 1 mmol), 5-methyl-
2,4-dihydro-3H-pyrazol-3-one (6, 1 mmol), and catalyst (20 mol%)
aIsolated yield
bReaction failed to occur
or changing the temperature to room temperature with duration of 3–10 h could not
improve the yield (Table 2, entries 6–9). The reusability of TPAB in synthesis of 5a
was also examined. For this purpose, the recovered catalyst was recycled up to four
times; the catalytic performance results are shown in Fig. 2.
Using the optimized condition, diferent aryl glyoxal derivatives 1a–l (mono-
hydrate form), 2-aminopyridine (2), ethyl acetoacetate (3), and hydrazine hydrate
(4) also aforded the desired products 5a–l in high yield. The results obtained with
1 3

N. Etivand et al.
Table 2 Optimization of model four-component reaction for synthesis of 5a
Entry
Catalyst (mol%)
Solvent (v/v%)
T (°C)
Time (h)
Yield (%)a
b
1
2
3
4
5
6
7
8
9
–
–
–
H2O
EtOH
H2O:EtOH (1:1)
H2O
EtOH
EtOH
EtOH
EtOH
100
80
24
24
24
3
3
5
5
5
10
–
–
–
Refux
Refux
Refux
Refux
Refux
Refux
RT
TPAB (15%)
TPAB (15%)
TPAB (20%)
TPAB (10%)
TPAB (5%)
TPAB (15%)
60
91c
88
84
73
62
EtOH
Reaction conditions: phenylglyoxal monohydrate (1a, 1 mmol), 2-aminopyridine (2, 1 mmol) ethyl ace-
toacetate (3, 1 mmol), and hydrazine hydrate (4, 1 mmol)
aIsolated yield
bReaction failed to occur
cThe bold type (entry 5) refers to the best reaction conditions
91
92
88
90
88
86
84
82
80
78
85
83
Run
1
2
3
4
Fig. 2 Reusability of TPAB in synthesis of imidazo[1,2-a]pyridine derivatives
1 3

Facile, one-pot, four-component synthesis of a new series…
Table 3 Synthesis of imidazo[1,2-a]pyridines 5a–l via one-pot, four-component reaction
Aryl glyoxal
Time
(h)
M.P.
(oC)
Yield
(%) b
Entry
Products
monohydrates
290
1
4
3
3
91
89
85
(Dec.)
294
2
3
(Dec.)
168-
169
168-
4
5
3
3
94
88
169
294
(Dec.)
266-
267
6
7
4
3
91
92
307
(Dec.)
300
8
9
3
3
6
90
86
82
(Dec.)
290
(Dec.)
300
10
11
(Dec.)
290
4
87
(Dec.)
324
12
6
84
(Dec.)
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N. Etivand et al.
Table 3 (continued)
Reaction conditions for synthesis of 5a–k: 1a–k (1 mmol), 2 (1 mmol), 3 (1 mmol), 4 (1 mmol); 5l: 1l
(1 mmol), 2 (2 mmol), 3 (2 mmol), 4 (2 mmol), and TPAB (20 mol%) in EtOH (5–10 mL) under refux
for 3–6 h
aIsolated yield
various aryl glyoxals, including the product, melting point (m.p.), and yield, are
summarized in Table 3.
The structure of all the imidazo[1,2-a]pyridine derivatives 5a–l was elucidated
using Fourier-transform infrared (FT-IR) spectroscopy, 1H and 13C nuclear magnetic
resonance (NMR) spectroscopy, and mass analysis. The FT-IR (KBr) spectra of 5a–l
showed absorption bonds due to vibrations of NH and OH group at 3433–3243 cm−1.
1
In the H NMR spectra, N–H and OH group of the products showed broad dou-
blets at δ=11.20–10.92 ppm, which disappeared on addition of D2O. The protons
of aromatic rings were located at around δ=8.22–6.73 ppm. The methyl hydrogens
of the pyrazole ring of the products appeared as a singlet at δ=1.83–1.58 ppm, and
in the 13C NMR spectra as a carbon signal located at around δ=11.7–10.2 ppm. In
the 13C NMR spectra of 5a–l, signals located at around δ=172.5–160.1 ppm and
δ=160.3–159.0 ppm were ascribed to C–OH and N–C=N group, respectively. The
signals located at around δ=148.9–90.7 ppm were assigned to other carbons of aro-
matic rings. The analytical and spectral data of the synthesized scafolds are all in
agreement with their proposed structure.
A reasonable reaction mechanism for the synthesis of imidazo[1,2-a]pyridine
derivatives 5a–l by a one-pot four-component strategy is depicted in Scheme 2. In
the frst step, 5-methyl-2,4-dihydro-3H-pyrazol-3-one (6) forms by condensation
of hydrazine hydrate (4) and ethyl acetoacetate (3), which would be stabilized by
keto–enol tautomerization. In the next step, intermediate 6 in enolate form reacts
with aryl glyoxal monohydrate 1a–l in presence of TPAB to form intermediate A.
TPAB plays an important role in the formation of intermediate A via Knoevenagel
condensation followed by loss of one molecule of water. Subsequently, 2-aminopyri-
dine (2) undergoes intermolecular condensation with the carbonyl group of interme-
diate A to form intermediate B, which then undergoes Baldwin 5-exo–trig cycliza-
tion [44] to give intermediate C. Finally, loss of a water molecule from intermediate
C gives the desired imidazo[1,2-a]pyridine derivative 5a–l in presence of TPAB, as
shown in Scheme 2.
Conclusions
We developed a simple and efcient protocol for regioselective synthesis of a series
of [5,6]-bicyclic fused imidazo[1,2-a]pyridines by one-pot, four-component reac-
tion between aryl glyoxal monohydrates, 2-aminopyridine, ethyl acetoacetate, and
hydrazine hydrate in EtOH under refux conditions, using TPAB as an inexpensive,
readily available, and ecocompatible catalyst, showing advantages in terms of reac-
tion time, easy workup, and facile operation. Considering the presence of pyrazole
1 3

Facile, one-pot, four-component synthesis of a new series…
Scheme 2 Mechanistic rationalization for synthesis of 3-methyl-4-(2-arylimidazo[1,2-a]pyridin-3-yl)-
1H-pyrazol-5-ol derivatives 5a–l
linked to the 3-position of the imidazo[1,2-a]pyridine moiety, it is expected that
these fused structures will show promising pharmaceutical activities. The use of an
inexpensive catalyst, metal-free conditions, short reaction time, high yield, and lack
of hazardous byproducts are the main advantages of this procedure.
1 3

N. Etivand et al.
Experimental
Materials and methods
The chemicals used in this work were obtained from Arcos and Merck companies
and used without purifcation. Melting points were measured on a Philip Harris
C4954718 apparatus and are uncorrected. Reaction progress was monitored by thin-
layer chromatography (TLC) on Merck silica plates. Infrared spectra were recorded
1
on a Thermo Nicolet Nexus 670 FT-IR instrument using KBr discs. H and 13C
NMR spectra were recorded on a Bruker Advance AQS 300 MHz spectrometer at
300 and 75.5 MHz, respectively. Chemical shifts were measured in dimethyl sul-
foxide (DMSO)-d6 as solvent relative to tetramethylsilane (TMS) as internal stand-
ard. Mass spectra and high-resolution mass spectra were recorded on a Kratos MS
25RF spectrometer; relative abundance of fragments is quoted in parentheses after
m/z values.
General procedure for synthesis of 3‑methyl‑4‑(2‑arylimidazo[1,2‑a]
pyridin‑3‑yl)‑1H‑pyrazol‑5‑ol derivatives (5a–k)
Hydrazine hydrate (4, 1 mmol) was added dropwise to a solution of ethyl acetoac-
etate (3, 1 mmol) in ethanol (5 mL). The reaction mixture was stirred at room tem-
perature and monitored by TLC (using chloroform:methanol 20:1 as eluent). After
reaction completion (5–10 min), white precipitate of 5-methyl-2,4-dihydro-3H-pyra-
zol-3-one (6) formed. To the reaction mixture, aryl glyoxal monohydrate 1a–k
(1 mmol), 2-aminopyridine (2, 1 mmol), and TPAB (15 mol%) were added, and
the mixture was refuxed for appropriate time as mentioned in Table 3. After reac-
tion completion as monitored by TLC (using chloroform:methanol 3:1 as eluent),
the reaction mixture was cooled to room temperature and the precipitate fltered,
washed with water, and cold ethanol to give the desired products 5a–k in high yield
(82–94%).
Synthesis of 4,4′‑(1,4‑phenylenebis(imidazo[1,2‑a]pyridine‑2,3‑diyl))
bis(3‑methyl‑1H‑pyrazol‑5‑ol) (5l)
Hydrazine hydrate (4, 2 mmol) was added dropwise to a solution of ethyl acetoac-
etate (3, 2 mmol) in ethanol (10 mL). The reaction mixture was stirred at room tem-
perature and monitored by TLC (using chloroform:methanol 20:1 as eluent). After
reaction completion (5–10 min), 5-methyl-2,4-dihydro-3H-pyrazol-3-one (6) formed
as white precipitate. To the reaction mixture, bis-phenylene glyoxal monohydrate
(1l, 1 mmol), 2-aminopyridine (2, 2 mmol), and TPAB (15 mol%) were added, and
the mixture was refuxed for 6 h. After reaction completion as monitored by TLC
(using chloroform:methanol 3:1 as eluent), the reaction mixture was cooled to room
temperature, and the orange precipitate fltered, washed with water, and cold ethanol
to give the desired product 5l in 84% yield.
1 3

Facile, one-pot, four-component synthesis of a new series…
Physical and spectral data for compounds 5a–l
3‑Methyl‑4‑(2‑phenylimidazo[1,2‑a]pyridin‑3‑yl)‑1H‑pyrazol‑5‑ol (5a)
White solid; yield 91% (264 mg); m.p. 290 °C (dec.). FT-IR (KBr) υ: 3243, 2976,
2923, 1633, 1606, 1571, 1505, 1440, 1337, 1283, 1236, 1149, 1106, 1031, 983, 738,
694 cm−1. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 11.78 (bs, 1H, OH, D2O exch.),
10.36 (bs, 1H, NH, D2O exch.), 7.85 (d, J=6.9 Hz, 1H, Ar), 7.78 (d, J=7.2 Hz, 2H,
Ar), 7.61 (d, J=9 Hz, 1H, Ar), 7.37–7.26 (m, 4H, Ar), 6.88 (t, J=6.9 Hz, 1H, Ar),
1.76 (s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ (ppm): 160.2, 160.1, 144.7,
142.3, 135.4, 132.0, 129.7, 128.6, 127.9, 126.7, 125.9, 124.3, 112.9, 91.3, 10.2.
LRMS (EI, 70 eV) m/z (%): 290 (M+, 100), 275 (5), 262 (13), 244 (5), 233 (29),
218 (19), 205 (22), 194 (6), 179 (3), 167 (2), 154 (4), 140 (2), 128 (8), 115 (5), 105
(7), 91 (3), 78 (36), 65 (4), 51 (3). HRMS (ESI): m/z (M)+ calcd. for C17H14N4O+:
290.1168; found: 290.1163.
4‑(2‑(4‑Methoxyphenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5b)
White solid; yield 89% (285 mg); m.p. 294 °C (dec.). FT-IR (KBr) υ: 3433, 3110,
3036, 3005, 2907, 2837, 2782, 2613, 1614, 1512, 1459, 1385, 1299, 1255, 1174,
1
1111, 1032, 973, 837, 788, 754 cm−1. H NMR (300 MHz, DMSO-d6) δ (ppm):
11.05 (bs, 2H, OH, NH, D2O exch.), 7.83 (d, J=6.6 Hz, 1H, Ar), 7.72 (d, J=6.9 Hz,
2H, Ar), 7.58 (d, J=8.7 Hz, 1H, Ar), 7.24 (t, J=6.9 Hz, 1H, Ar), 6.93–6.82 (m,
3H, Ar), 3.76 (s, 3H, OMe), 1.78 (s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ
(ppm): 160.2, 159.0, 144.7, 142.4, 140.3, 129.4, 127.9, 127.2, 125.8, 124.0, 114.7,
113.7, 111.9, 91.4, 56.2, 10.3. LRMS (EI, 70 eV) m/z (%): 320 (M+, 100), 305 (31),
290 (5), 277 (5), 262 (17), 248 (6), 234 (4), 219 (10), 205 (6), 192 (5), 181 (2), 170
(2), 153 (5), 142 (2), 131 (3), 115 (3), 103 (3), 91 (2), 78 (10), 65 (2), 51 (3). HRMS
+
(ESI): m/z (M)+ calcd. for C18H16N4O2 : 320.1273; found: 320.1275.
4‑(2‑(3‑Methoxyphenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5c)
White solid; yield 85% (272 mg); m.p. 168–169 °C. FT-IR (KBr) υ: 3407, 3206,
2943, 2840, 1606, 1503, 1459, 1435, 1390, 1343, 1288, 1246, 1219, 1042, 787,
1
754 cm−1. H NMR (300 MHz, DMSO-d6) δ (ppm): 11.00 (bs, 2H, OH, NH, D2O
exch.), 7.85 (d, J=6.3 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 1H, Ar), 7.36 (d, J=8.1 Hz,
2H, Ar), 7.30–7.22 (m, 2H, Ar), 6.90–6.82 (m, 2H, Ar), 3.72 (s, 3H, OMe), 1.79
(s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ (ppm): 160.2, 159.6, 144.6, 142.1,
140.4, 136.6, 130.8, 128.8, 126.3, 124.3, 123.8, 120.3, 118.4, 113.1, 111.2, 91.2,
55.9, 10.2. LRMS (EI, 70 eV) m/z (%): 320 (M+, 100), 305 (17), 290 (10), 275 (3),
263 (20), 247 (8), 231 (5), 219 (19), 205 (14), 192 (5), 159 (4), 145 (2), 127 (2), 109
+
(3), 98 (5), 78 (19), 67 (4), 57 (8). HRMS (ESI): m/z (M)+ calcd. for C18H16N4O2 :
320.1273; found: 320.1278.
1 3

N. Etivand et al.
4‑(2‑(3,4‑Dimethoxyphenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol
(5d)
White solid; yield 94% (329 mg); m.p. 168–169 °C; FT-IR (KBr) υ: 3367, 3097,
2995, 2940, 2836, 1589, 1523, 1464, 1434, 1392, 1257, 1237, 1178, 1142, 1024,
1
757 cm−1. H NMR (300 MHz, DMSO-d6) δ (ppm): 11.00 (bs, 2H, OH, NH, D2O
exch.), 7.84 (d, J=6.6 Hz, 1H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.45 (s, 1H, Ar),
7.32–7.23 (m, 2H, Ar), 6.93 (d, J=8.4 Hz, 1H, Ar), 6.86 (t, J=6.6 Hz, 1H, Ar), 3.75
(s, 3H, OMe), 3.68 (s, 3H, OMe), 1.70 (s, 3H, Me). 13C NMR (75.5 MHz, DMSO-
d6) δ (ppm): 172.5, 160.3, 148.9, 144.5, 142.4, 140.4, 128.0, 126.1, 124.0, 120.4,
118.5, 115.7, 113.4, 112.6, 112.0, 91.4, 56.6, 55.2, 10.2. LRMS (EI, 70 eV) m/z (%):
350 (M+, 44), 335 (8), 320 (100), 305 (23), 291 (6), 277 (10), 262 (31), 247 (8),
234 (7), 219 (19), 205 (17), 192 (7), 179 (3), 160 (3),145 (2), 130 (3), 115 (3), 105
+
(4), 93 (3), 78 (19), 67 (2), 57 (5). HRMS (ESI): m/z (M)+ calcd. for C19H18N4O3 :
350.1379; found: 350.1378.
3‑Methyl‑4‑(2‑(p‑tolyl)imidazo[1,2‑a]pyridin‑3‑yl)‑1H‑pyrazol‑5‑ol (5e)
White solid; yield 88% (268 mg); m.p. 294 °C (dec.). FT-IR (KBr) υ: 3405, 3182,
3133, 3028, 2923, 2862, 2738, 1609, 1520, 1476, 1443, 1419, 1387, 1332, 1237,
1100, 823, 747 cm−1. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.92 (bs, 2H, OH,
NH, D2O exch.), 7.82 (d, J=7.2 Hz, 1H, Ar), 7.66 (d, J=7.5 Hz, 2H, Ar), 7.58 (d,
J=9.6 Hz, 1H, Ar), 7.26 (t, J=7.5 Hz, 1H, Ar), 7.15 (d, J=7.8 Hz, 2H, Ar), 6.87
(t, J=6.6 Hz, 1H, Ar), 2.29 (s, 3H, Me), 1.58 (s, 3H, Me). 13C NMR (75.5 MHz,
DMSO-d6) δ (ppm): 160.2, 160.1, 144.7, 142.4, 140.2, 136.9, 132.5, 130.4, 128.6,
128.1, 126.1, 124.1, 112.5, 91.4, 22.4, 10.3. LRMS (EI, 70 eV) m/z (%): 304 (M+,
100), 289 (18), 273 (2), 261 (3), 247 (14), 232 (7), 219 (5), 205 (2), 195 (2), 183 (2),
169 (2),154 (2), 144 (4), 130 (3), 119 (5), 103 (2), 91 (5), 78 (14), 65 (2), 51 (3).
HRMS (ESI): m/z (M)+ calcd. for C18H16N4O+: 304.1324; found: 304.1319.
4‑(2‑(4‑Hydroxy‑3‑methoxyphenyl)imidazo[1,2‑a]
pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5f)
White solid; yield 91% (306 mg); m.p. 266–267 °C. FT-IR (KBr) υ: 3351, 3094,
3025, 2925, 2726, 2572, 1600, 1576, 1531, 1487, 1465, 1436, 1395, 1285, 1254,
1217, 1172, 1138, 1112, 1035, 819, 786, 754, 683, 640 cm−1. 1H NMR (300 MHz,
DMSO-d6) δ (ppm): 10.95 (bs, 2H, OH, NH, D2O exch.), 9.05 (s, 1H, OH, D2O
exch.), 7.81 (d, J=6.9 Hz, 1H, Ar), 7.57 (d, J=8.7 Hz, 1H, Ar), 7.42 (s, 1H, Ar),
7.26–7.17 (m, 2H, Ar), 6.85 (t, J=6.6 Hz, 1H, Ar), 6.73 (d, J=8.1 Hz, 1H, Ar),
3.70 (s, 3H, OMe), 1.80 (s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ (ppm):
160.6, 160.2, 147.8, 146.5, 144.5, 142.8, 140.4, 126.7, 123.8, 120.7, 118.8, 117.0,
115.8, 144.7, 111.6, 91.5, 56.7, 11.7. LRMS (EI, 70 eV) m/z (%): 336 (M+, 100),
320 (16), 306 (12), 293 (3), 277 (6), 264 (5), 247 (3), 235 (4), 221 (3), 207 (4), 193
(2), 181 (1), 168 (4),161 (2), 153 (1), 139 (1), 131 (1), 118 (1), 110 (1). HRMS
+
(ESI): m/z (M)+ calcd. for C18H16N4O3 : 336.1222; found: 336.1227.
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Facile, one-pot, four-component synthesis of a new series…
4‑(2‑(4‑Chlorophenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5g)
White solid; yield 92% (298 mg); m.p. 317 °C (dec.). FT-IR (KBr) υ: 3427, 3174,
3130, 3027, 2927, 2860, 2740, 1610, 1542, 1509, 1464, 1443, 1418, 1387, 1329,
1
1283, 1238, 1098, 974, 831, 743 cm−1. H NMR (300 MHz, DMSO-d6) δ (ppm):
11.10 (bs, 2H, OH, NH, D2O exch.), 7.85 (d, J=6.6 Hz, 1H, Ar), 7.79 (d, J=8.4 Hz,
2H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.41 (d, J=8.4 Hz, 2H, Ar), 7.29 (t, J=7.5 Hz,
1H, Ar), 6.89 (t, J=6.9 Hz, 1H, Ar), 1.80 (s, 3H, Me). 13C NMR (75.5 MHz,
DMSO-d6) δ (ppm): 160.1, 160.0, 144.9, 141.1, 140.3, 134.3, 132.3, 129.7, 127.5,
126.5, 124.6, 118.3, 113.2, 91.0, 10.6. LRMS (EI, 70 eV) m/z (%): 326 [(M+2)+,
45], 324 (M+, 100), 309 (18), 295 (3), 281 (3), 267 (14), 254 (4), 243 (2), 231 (9),
218 (3), 205 (5), 186 (1), 174 (1), 162 (3), 144 (2), 128 (2), 116 (1), 103 (2), 89 (1),
78 (10), 65 (1), 52 (1). HRMS (ESI): m/z (M)+ calcd. for C17H13ClN4O+: 324.0778;
found: 324.0783.
4‑(2‑(4‑Bromophenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5h)
White solid; yield 90% (331 mg); m.p. 300 °C (dec.). FT-IR (KBr) υ: 3430, 3178,
3130, 3028, 2926, 2858, 2738, 1610, 1505, 1540, 1465, 1441, 1418, 1385, 1327,
1
1238, 1100, 1077, 1007, 826, 744 cm−1. H NMR (300 MHz, DMSO-d6) δ (ppm):
11.00 (bs, 2H, OH, NH, D2O exch.), 7.85 (d, J=6.6 Hz, 1H, Ar), 7.72 (d, J=8.4 Hz,
2H, Ar), 7.62–7.53 (m, 1H, Ar), 7.28 (t, J=7.5 Hz, 2H, Ar), 6.89 (t, J=6.6 Hz,
1H, Ar), 1.80 (s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ (ppm): 160.5, 160.1,
144.6, 141.1, 134.6, 132.9, 130.7, 130.1, 127.8, 126.5, 124.5, 120.9, 113.3, 91.0,
11.5. LRMS (EI, 70 eV) m/z (%): 370 [(M+2)+, 100], 368 (M+, 90), 353 (16), 341
(1), 324 (9), 311 (10), 300 (2), 288 (2), 274 (9), 262 (12), 243 (3), 231 (17), 218 (5),
205 (8), 184 (2), 168 (1), 154 (1), 137 (7), 126 (1), 115 (1), 103 (2), 89 (1), 78 (17),
63 (1), 51 (2). HRMS (ESI): m/z (M)+ calcd. for C17H13BrN4O+: 368.0273; found:
368.0279.
4‑(2‑(4‑Fluorophenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5i)
White solid; yield 86% (265 mg); m.p. 290 °C (dec.). FT-IR (KBr) υ: 3174, 3127,
3029, 2927, 2862, 2745, 1608, 1519, 1477, 1420, 1388, 1331, 1298, 1233, 1155,
1099, 840, 803, 748 cm−1. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 11.02 (bs, 2H,
OH, NH, D2O exch.), 7.86–7.78 (m, 3H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.27 (t,
J=7.8 Hz, 1H, Ar), 7.19 (t, J=8.7 Hz, 2H, Ar), 6.88 (t, J=6.6 Hz, 1H, Ar), 1.78
(s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ (ppm): 163.5, 160.1, 144.8, 141.5,
140.3, 131.9, 130.1, 127.8, 126.3, 123.9, 116.7, 114.9, 112.7, 91.1, 10.3. LRMS (EI,
70 eV): m/z (%)=308 (M+, 100), 293 (14), 279 (3), 264 (2), 251 (17), 236 (8), 223
(11), 212 (2), 199 (1), 187 (1), 172 (3), 158 (2), 145 (4), 133 (2), 118 (1), 103 (1),
90 (1), 78 (17), 63 (2), 51 (4). HRMS (ESI): m/z (M)+ calcd. for C17H13FN4O+:
308.1073; found: 308.1075.
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N. Etivand et al.
3‑Methyl‑4‑(2‑(4‑nitrophenyl)imidazo[1,2‑a]pyridin‑3‑yl)‑1H‑pyrazol‑5‑ol (5j)
Yellow solid; yield 82% (275 mg); m.p. 300 °C (dec.). FT-IR (KBr) υ: 3418, 3110,
1
3028, 2888, 2783, 2614, 1602, 1513, 1453, 1346, 1280, 1108, 858, 753 cm−1. H
NMR (300 MHz, DMSO-d6) δ (ppm): 11.20 (bs, 2H, OH, NH, D2O exch.), 8.22 (d,
J=8.7 Hz, 2H, Ar), 8.03 (d, J=8.4 Hz, 2H, Ar), 7.90 (d, J=6.6 Hz, 1H, Ar), 7.65
(d, J=9 Hz, 1H, Ar), 7.34 (t, J=7.8 Hz, 1H, Ar), 6.94 (t, J=6.6 Hz, 1H, Ar), 1.83
(s, 3H, Me). 13C NMR (75.5 MHz, DMSO-d6) δ (ppm): 160.8, 160.0, 146.5, 145.1,
142.1, 139.9, 128.9, 128.6, 127.2, 126.7, 125.2, 123.3, 115.3, 90.7, 10.4. LRMS (EI,
70 eV) m/z (%): 335 (M+, 100), 324 (12), 314 (1), 304 (8), 288 (10), 274 (18), 262
(6), 244 (2), 231 (7), 218 (4), 205 (4), 192 (1), 177 (1), 168 (2), 150 (1), 140 (1), 123
(1), 113 (1), 103 (1) 92 (1), 78 (1), 67 (1), 56 (1). HRMS (ESI): m/z (M)+ calcd. for
+
C17H13N5O3 : 335.1018; found: 335.1015.
4‑(2‑([1,1′‑Biphenyl]‑4‑yl)imidazo[1,2‑a]pyridin‑3‑yl)‑3‑methyl‑1H‑pyrazol‑5‑ol (5k)
White solid; yield 87% (319 mg); m.p. 290 °C (dec.). FT-IR (KBr) υ: 3415, 3030,
2875, 2778, 2607, 1613, 1502, 1448, 1386, 1344, 1281, 1111, 847, 761, 740,
1
694 cm−1. H NMR (300 MHz, DMSO-d6) δ (ppm): 11.15 (bs, 2H, OH, NH, D2O
exch.), 7.90 (t, J=8.1 Hz, 3H, Ar), 7.68–7.58 (m, 5H, Ar), 7.45 (t, J=6.9 Hz, 2H,
Ar), 7.36–7.25 (m, 2H, Ar), 6.89 (t, J=6.9 Hz, 1H, Ar), 1.83 (s, 3H, Me). 13C NMR
(75.5 MHz, DMSO-d6) δ (ppm): 160.4, 160.2, 144.9, 141.9, 140.1, 139.1, 134.5,
130.5, 128.8, 128.6, 126.4, 124.3, 123.9, 118.2, 116.0, 113.1, 112.1, 91.3, 11.7.
LRMS (EI, 70 eV) m/z (%): 366 (M+, 100), 351 (15), 337 (2), 320 (8), 309 (14),
294 (7), 281 (8), 262 (5), 243 (3), 231 (10), 218 (4), 205 (7), 194 (2), 183 (4), 165
(2), 154 (3), 141 (1), 130 (3), 115 (1), 103 (1), 91 (1), 78 (15), 67 (1), 52 (1). HRMS
(ESI): m/z (M)+ calcd. for C23H18N4O+: 366.1481; found: 366.1489.
4,4′‑(1,4‑Phenylenebis(imidazo[1,2‑a]pyridine‑2,3‑diyl))
bis(3‑methyl‑1H‑pyrazol‑5‑ol) (5l)
Pale-yellow solid; yield 84% (422 mg); m.p. 324 °C (dec.). FT-IR (KBr) υ: 3388,
3215, 3043, 2926, 1609, 1508, 1439, 1388, 1343, 1239, 1104, 1046, 978, 843,
743 cm−1. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 11.01 (bs, 4H, 2×OH, 2×NH,
D2O exch.), 7.85 (d, J=6.6 Hz, 2H, Ar), 7.76 (s, 4H, Ar), 7.60 (d, J=8.7 Hz, 2H,
Ar), 7.28 (t, J=8.1 Hz, 2H, Ar), 6.89 (t, J=6.6 Hz, 2H, Ar), 1.79 (s, 6H, 2×Me).
13C NMR (75.5 MHz, DMSO-d6) δ (ppm): 160.3, 160.1, 144.7, 142.0, 140.4, 134.1,
128.0, 125.8, 123.9, 118.1, 115.9, 113.1, 91.3, 11.6. LRMS (EI, 70 eV) m/z (%):
502 (M+, 15), 369 (32), 354 (10), 313 (11), 299 (10), 285 (10), 260 (10), 236 (23),
222(10), 211 (11), 152 (11), 135 (10), 123 (13), 109 (19), 97 (37), 83 (52), 71
(53), 69 (58), 57 (86), 55 (67), 43 (100), 41 (57). HRMS (ESI): m/z (M)+ calcd. for
+
C28H22N8O2 : 502.1866; found: 502.1861.
Acknowledgements The authors gratefully acknowledge fnancial assistance from Urmia University.
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Facile, one-pot, four-component synthesis of a new series…
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Afliations
Nasser Etivand1 · Jabbar Khalafy1 · Ahmad Poursattar Marjani1
*
Jabbar Khalafy
jkhalaf@yahoo.com; j.khalaf@urmia.ac.ir
1
Department of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia 5756151818,
Iran
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