Solvent and catalyst-free synthesis of imidazo[1,2-a]pyridines by grindstone chemistry

Article abstract of DOI:10.1002/jhet.4164

The present work describes the solvent and catalyst-free synthesis of imidazo[1,2-a]pyridines in excellent to nearly quantitative yields from 2-aminopyridines and a wide variety of ω-bromomethylketones using a grindstone procedure at 25°C to 30°C for 3 to

Full text of DOI:10.1002/jhet.4164

Solvent and catalyst free synthesis of imidazo[1,2-a]pyridines by grindstone chemistry
Kumar Godugu and Chinna Gangi Reddy Nallagondu*
Department of Chemistry, Green and Sustainable Synthetic Organic Chemistry Laboratory, Yogi Vemana
University, Kadapa - 516 005, Andhra Pradesh, India.
Corresponding author: ncgreddy@yogivemanauniversity.ac.in
Abstract: The present work describes the solvent and catalyst free synthesis of imidazo[1,2-a]pyridines in
excellent to nearly quantitative yields from 2-aminopyridines and a wide variety of ω-bromomethylketones
using a grindstone procedure at 25-30 °C for 3-5 min. The absolute structure of the compound, 2-(3-
bromophenyl)-7-methylimidazo[1,2-a]pyridine is determined by X-ray crystallography. This green strategy
has several noteworthy advantages such as wide spread substrate scope, short reaction times, water work up
and the products do not require any chromatographic purification. Moreover, the method does not require
any specialized equipment and is highly economical, environmentally benign and easy to carry out in any
laboratory. Hence, the developed method meets the concept of “benign by design” and is greener
alternative to the reported procedures for the synthesis of imidazo[1,2-a]pyridines.
Keywords: 2-aminopyridines, ω-bromomethylketones, Imidazo[1,2-a]pyridines, Solvent and catalyst free,
Grindstone chemistry.
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Introduction
Imidazopyridines are considered as privileged nitrogen-fused heterocycles because of their
potential applications in biology [1]. Among various imidazopyridines, the imidazo[1,2-
a]pyridines have received substantial attention of the pharmaceutical industry owing to their
promising medicinal applications viz., anticancer, antiviral, antipyretic, analgesic, anti-
inflammatory, anticonvulsant, antifungal, anthelmintic, antibacterial, anti-protozonal, antiulcer,
antiepileptic, antiparasitic and antituberculosis properties [2–12]. These compounds also serve as
cyclin-dependent kinase (CDK) inhibitors [9], benzodiazepine receptor agonists, β-amyloid
formation inhibitor, calcium channel blockers [10], cardiotonic agent [7] and GABAA receptor
modulators [13-17]. More importantly, imidazo[1,2-a]pyridine nucleus is a key structural unit in
many commercially available pharmaceutical drugs including zolimidine (I) [18] zolpidem (II)
and alpidem (III) [19], GSK812397 (IV, optically active drug) [20], Rifaximin (V) [21],
olprinone (VI) [22], necopidem (VII) and saripidem (VIII) [23] (Figure 1). Besides, these
compounds are valuable building blocks in organometallic chemistry [24] and materials science
[25]. In view of their broad based utility, extensive research has been conducted and a huge
number of synthetic strategies have been reported for the synthesis of imidazo[1,2-a]pyridines
[26]. Among the developed synthetic routes, the reaction of 2-aminopyridines with α-
haloketones is the most common procedure for the synthesis of imidazo[1,2-a]pyridines in both
laboratory and industrial scale. This traditional synthesis has been conducted in the presence of
various catalysts such as neutral Al2O3, NaHCO3, K2CO3, NaI, TiCl4 etc., in organic solvents at
high temperature [27a-f,h-k] and polar organic solvents [27l]. Wu et al. developed a catalyst- and
solvent-free method for imidazo[1,2-a]pyridines under conventional stirring at 60°C for 5-130
min[27g]. Further, the same reaction has been examined under microwave irradiation [28]. For
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instance, water and isopropanol mediated catalyst-free microwave assisted synthesis at 75°C has
been developed by Rao [28a] et al.; Lin [28b] et al. reported the solvent and catalyst-free
synthetic route for imidazo[1,2-a]pyridines under microwave irradiation at 65°C.
Figure 1. Selected examples of Imidazo[1,2-a]pyridine-based drugs.
Despite these developments, there are still some drawbacks such as narrow substrate scope, use
of transition metal catalysts and toxic organic solvents, harsh reaction conditions, lengthy
reaction times, overheating of substrates, use of expensive techniques, tedious work up process
involving the use of large excess of organic solvents and the products require column
chromatographic purification. Therefore, the development of improved economic, green and
sustainable synthetic routes that can avoid or minimize the use of toxic solvents and catalysts for
the preparation of imidazo[1,2-a]pyridines is still highly desirable in pharmaceutical industries.
Based on the environmental concerns in pharmaceutical industry, grindstone chemistry (GSC)
recently has emerged as a promising green technique to perform solvent-free solid-state reactions
in various fields of chemistry [29-32] just by grinding solid reactants together with a mortar and
pestle. This technology meets the concept of “benign by design” because it does not need any
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specialized equipment and is therefore economical, ecological and simple to carry out in any
laboratory [33]. However, to date there are no reports on solvent and catalyst-free syntheses of
imidazo[1,2-a]pyridines at room temperature using grindstone chemistry.
Scheme 1. Methods for the synthesis of imidazo[1,2-a]pyridines
In continuation of our interest in the development of solvent-free solid-state reactions using grind
stone technology for the synthesis of pharmaceutically active compounds (PhACs)[34], we
demonstrated herein, a rapid, more efficient, green and sustainable synthetic route for the
synthesis of a series of imidazo[1,2-a]pyridines in nearly quantitative yields by simply grinding
of 2-aminopyridines and a wide variety of ω-bromomethylketones using mortar and pestle at 25-
30°C for 3-5 min under solvent and catalyst free conditions (Scheme 1C).
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Results and Discussion
Encouraged by the improvements in the development of green synthetic strategies for the
synthesis of clinically important imidazo[1,2-a]pyridines [28], we aimed to develop an easy, low
cost, highly efficient, scalable, clean and green procedure for the synthesis of imidazo[1,2-
a]pyridines (3). For this purpose, initially, we ground the model substrates, 2-aminopyridine (1a)
(5.0 mmol) and ω-bromoacetophenone (2a) (5.0 mmol) by adding two drops of water at 25-30
°C for 7 min and resulted in 80% yield of 2-phenyl imidazo[1,2-a]pyridine (3a) (entry 1, Table
1). Further, the same reaction was repeated by employing a variety of solvents (two drops) like
ethanol, isopropanol (IPA), poly (ethylene glycol) (PEG) and glycerol at 25-30 °C for 7-10 min.
This solvent-drop grinding (SDG) method revealed that the reaction proceeded smoothly and
afforded moderate to good yields of desired product, 3a that ranged from 60% to 85% (Table 1,
entries 2-5). To improve the yield of 3a, the same reactants, 1a and 2a were ground together
under solvent and catalyst free reaction conditions at 25-30°C. To our delight, the desired
product, 3a was obtained in nearly quantitative yield, 99% in a short reaction time (3 min) (Table
1, entry 6). Next, we examined the same reaction under ultrasound irradiation (USI) in different
solvents like water, ethanol, IPA, PEG and glycerol in the absence of catalyst at 55-60°C for 45-
60 min. From this study, it was noticed that the solvents, ethanol and IPA provided moderate
yields of 3a, 75% and 78%, respectively. The other solvents, water, PEG and glycerol resulted in
lower yields of product 3a (Table 1, entries 7-11) which may be due to the poor solubility of
reactants. From the above observations, it was concluded that the grinding of reactants under
solvent and catalyst free reaction conditions was superior when compared to both solvent-drop
grinding (SDG) method and ultrasound irradiation (USI) method in giving almost quantitative
yield of product 3a in a short period of time at 25-30°C (Table 1).
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Table 1. Optimization of the reaction conditions.a
Time Isolated
(min) yield
(%)e
Conditions
Entry
Solvent
Method
SDGb
1
2
Water (2 drops)
Ethanol (2 drops) SDGb
7
80
85
85
75
60
99
40
75
78
50
50
7
7
3
4
5
IPA (2 drops)
PEG (2 drops)
Glycerol (2 drops) SDGb
SDGb
SDGb
10
10
3
6
7
8
9
Solvent-free
Water (5mL)
Ethanol (5mL)
Isopropanol (5mL) USId
GSCc
USId
USId
45
30
30
60
60
10
11
PEG (5mL)
Glycerol (5mL)
USId
USId
Reactions conditions: 2-aminopyridine (1a) (5.0 mmol) and ω-bromoacetophenone (2a) (5.0
mmol), performed under specified conditions without any catalyst. [b] SDG: solvent-drop
grinding at 25-30°C. [c] GSC: grindstone chemistry at 25-30°C under solvent-free
conditions. [d] USI: ultrasound irradiation at 55-60°C in different solvents. [e] Isolated yields.
To study the efficiency and applicability of the above optimized procedure (Table 1, entry 6), the
scope of the reaction of diversely substituted ω-bromomethylketones (2) and 2-aminopyridines
(1) was investigated (Table 2). 2-Aminopyridine (1a) reacts with ω-bromoacetophenone (2a) to
give the corresponding 2-phenylimidazo[1,2-a]pyridine (3a) in 99% yield. ω-
bromoacetophenone bearing activating groups, 4-Me (2b), 4-OMe (2c) and 3-OMe (2d) at 4th/3rd
position of the aromatic ring showed excellent reactivity with the nucleophilic partner, 2-
aminopyridine (1a) to afford the 2-aryl imidazo[1,2-a]pyridines, 3b, 3c and 3d in nearly
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quantitative yields, 99%, 99% and 98%, respectively. 2-Aminopyridine (1a) reacted well with ω-
bromoacetophenone containing deactivating groups such as 4-Br (2e), 3-Br (2f), 4-Cl (2g), 3,4-
dichloro (2h) and 4-F (2i) at different positions of the aromatic ring to produce the desired
products, 3e-3i in excellent isolated yields that ranged from 95-99%. ω-bromoacetophenones 2i-
2l, bearing strongly deactivating groups, 4-CN(2j), 4-NO2 (2k), 3-NO2 (2l) at 4th/3rd position of
the aromatic ring underwent the reaction with 2-aminopyridine (1a) to obtain the products, 3j,
3k and 3l in excellent to almost quantitative yields, 99%, 99% and 97%, respectively.
Interestingly, the present procedure worked well for hindered ω-bromo-2-acetonaphthone (2m)
and ω-bromo-4-phenylacetophenone (2n) and heteroaromatic 3-(bromoacetyl)coumarin (2o)
producing the corresponding products 3m, 3n and 3o in excellent isolated yields. Similarly, ω-
bromoacetophenones with activating/deactivating groups, 2a-2l exhibited excellent reactivity
with 2-amino-4-methylpyridine (1b) to produce the desired products 3p-3aa in excellent to
nearly quantitative yields that ranged from 94-99%. The absolute structure of 3u was determined
by X-ray crystallography (Figure 2) and it is monoclinic with P21/c space group of one molecule
in the asymmetric unit (Z = 4). Further, it was also noticed that the sterically hindered ω-bromo-
2-acetonaphthone (2m) and ω-bromo-4-phenylacetophenone (2n) and heteroaromatic 3-
(bromoacetyl)coumarin (2o) were underwent the reaction with 2-amino-4-methylpyridine (1b)
and provided the corresponding products, 3ab-3ad in good isolated yields. From the above
study, it was concluded that the developed green strategy was successfully applied on
structurally diversified ω–bromomethylketones and 2-aminopyridines and found that all of the
substrates were well tolerated under the optimized reaction conditions.
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Figure 2. ORTEP diagram of compound 3u (50% probability).
Encouraged by the above results, the scalability of the process was then tested by the reaction
between 2-amino-4-methylpyridine (1b) and ω-bromo-3-bromoacetophenone (2f) in different
gram scale reactions, 5, 10, 15, 20 and 25 grams under the optimized procedure. The yields of
product 3u were obtained as 99%, 99%, 98%, 97% and 97% (Figure 3). It is worthy to state that
the solvent and catalyst free grindstone procedure is a promising greener alternative for the multi
gram-scale production of imidazo[1,2-a]pyridines (3).
Figure 3. Gram-scale synthesis of 3u.
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Table 2. Synthesis of a series of imidazo[1,2-a]pyridines (3) using grindstone chemistry.
Reaction conditions: 2-aminopyridines (1) (5.0 mmol) and ω-bromoacetophenone (2)
(5.0 mmol); All reactions performed under solvent and catalyst free conditions using
grindstone chemistry at 25-30°C.
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Conclusions
A facile, green and ecologically favourable grindstone procedure has been established for the
preparation of clinically imperative 2-substituted imidazo[1,2-a]pyridines from 2-aminopyridines
and a wide variety of ω-bromomethylketones under solvent and catalyst free conditions at 25-
30°C. Broad substrate scope, water work-up, no organic waste generation, excellent to nearly
quantitative yields in short reaction times; products free from chromatographic purification and
gram scale feasibility are the remarkable features of the present method. Furthermore, the
method does not need any specialized equipment and is easy to carry out in any laboratory.
Hence, the developed method meets the concept of “benign by design” and is greener alternative
to the reported procedures for the synthesis of imidazo[1,2-a]pyridines.
Experimental Section
General procedure for the synthesis of imidazo[1,2-a]pyridines (3):
A mixture of 2-aminopyridine (1) (5.0 mmol) and
ω-bromomethylketone (2) (5.0 mmol) was
gently ground in a mortar at 25-30°C. The reaction mixture was turned into a light yellow solid
mass within 3-5 min. After completion of the reaction as indicated by TLC, the reaction mixture
was washed with water twice (2 × 10 mL) and the obtained crude product (3) was purified by
recrystallization using aqueous ethanol. The spectroscopic (1H & 13C NMR, HRMS and LCMS)
and single crystal XRD data of the synthesized compounds are in accordance with their proposed
structures.
Procedure for gram-scale (25 g) synthesis of 2-(3-bromophenyl)-7-methylimidazo[1,2-
a]pyridine (3u):
A mixture of 2-amino-4-methylpyridine (1b) (0.09 mol) and ω-bromo-3-bromoacetophenone
(2f) (0.09 mol) was gently ground in a mortar at 25-30°C. The reaction mixture was turned into a
light yellow solid mass within 10-15 min. After completion of the reaction as indicated by TLC,
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the reaction mixture was washed with water twice (2 × 200 mL) and the obtained crude product
(3u) was purified by recrystallization using aqueous ethanol.
2-phenylimidazo [1,2-a]pyridine (3a):
Purified by recrystallization using aqueous ethanol; white solid; yield: 960 mg (99%); mp 131-
1
133°C. H NMR (500 MHz, CDCl3): 훿 8.06 (d, J =7.0 Hz, 1H, arom H), 7.93 (dd, J =8.5 Hz, J
=1.5 Hz, 2H, arom H), 7.81 (s, 1H, arom H), 7.60 (d, J =9.0 Hz, 1H, arom H), 7.41 (t, J =7.5 Hz,
2H, arom H), 7.30 (t, J =7.5 Hz, 1H, arom H), 7.15-7.11 (m, 1H, arom H), 6.73 (td, J =7.0 Hz, J
13
=1.0 Hz, 1H, arom H). C NMR (125 MHz, CDCl3): 145.91, 145.83, 133.89, 128.90, 128.15,
126.21, 125.77, 124.85, 117.68, 112.60, 108.30. HRMS (ESI): Anal. Calcd. For C13H11N2
[M+H]+ 195.0922; Found: 195.0882.
2-(p-tolyl)imidazo[1,2-a]pyridine (3b):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1030 mg (99%); mp 144-
1
146°C. H NMR (500 MHz, CDCl3): 훿 8.13 (d, J =6.5 Hz, 1H, arom H), 7.88 (s, 1H, arom H),
7.65 (d, J =9.0 Hz, 1H, arom H), 7.27 (d, J =8.5 Hz, 2H, arom H), 7.17 (t, J =8.0 Hz, 1H, arom
H), 6.79 (t, J =6.5 Hz, 1H, arom H), 2.41 (s, 3H, -CH3). HRMS (ESI): Anal. Calcd. For C14H13N2
[M+H]+ 209.1079; Found: 209.1124.
2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (3c):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1109 mg (99%); mp 132-
134°C. 1H NMR (500 MHz, CDCl3): 훿 8.05 (d, J =7.0 Hz, 1H, arom H), 7.85 (d, J =9.0 Hz, 2H,
arom H), 7.73 (s, 1H, arom H), 7.57 (d, J =9.5 Hz, 1H, arom H), 7.12-7.09 (m, 1H, arom H),
6.93 (d, J =9.0 Hz, 2H, arom H), 6.71 (td, J =7.0 Hz, J =1.0 Hz, 1H, arom H).
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13C NMR (125 MHz, CDCl3): 159.74, 145.73, 145.69, 127.45, 126.52, 125.67, 124.71, 117.34,
114.29, 112.45, 107.43, 55.47. HRMS (ESI): Anal. Calcd. For C14H13N2O [M+H]+ 225.1028;
Found :225.1029.
2-(4-bromophenyl)imidazo[1,2-a]pyridine (3e):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1351 mg (99%); mp 214-
216°C. 1H NMR (500 MHz, CDCl3 and d6-DMSO(few drops)): 훿 7.53 (s, 1H, arom H), 7.28 (dd,
J =7.5 Hz, J =2.5 Hz, 1H, arom H), 7.15 (dd, J =8.5 Hz, J =2.0 Hz, 2H, arom H), 6.91 (d, J =9.0
Hz, 1H, arom H), 6.86 (dd, J =8.0 Hz, J =1.5 Hz, 2H, arom H), 6.55-6.50 (m, 1H, arom H), 6.15-
6.13 (m, 1H, arom H). 13C NMR (125 MHz, CDCl3 and d6-DMSO (few drops)): 144.97, 143.57,
132.21, 131.26, 127.06, 125.58, 124.81, 121.19, 116.63, 112.26, 108.15. HRMS (ESI): Anal.
Calcd. For C13H10N2Br [M+H]+ 273.0027; Found : 273.0028, [M+H+2]+ 275.0009.
2-(3-bromophenyl)imidazo[1,2-a]pyridine (3f):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1310 mg (96%); mp 128-
1
130°C. H NMR (500 MHz, CDCl3): 훿 8.14 (s, 1H, arom H), 8.11 (d, J =6.5 Hz, 1H, arom H),
7.87 (d, J =7.5 Hz, 1H, arom H), 7.85 (s, 1H, arom H), 7.63 (d, J =9.0 Hz, 1H, arom H), 7.46 (d,
J =7.5 Hz, 1H, arom H), 7.30 (t, J =7.5 Hz, 1H, arom H), 7.19 (t, J =7.5 Hz, 1H, arom H), 6.80
(t, J =6.5 Hz, 1H, arom H). 13C NMR (125 MHz, CDCl3): 145.88, 144.40, 136.05, 130.99,
130.43, 129.15, 125.86, 125.22, 124.69, 123.13, 117.79, 112.88, 108.71. HRMS (ESI): Anal.
Calcd. For C13H10N2Br [M+H]+ 273.0022; Found : 273.0020, [M+H+2]+ 275.0007
2-(4-chlorophenyl)imidazo[1,2-a]pyridine (3g):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1134 mg (99%); mp 206-
208°C. 1H NMR (500 MHz, CDCl3): 훿 8.10 (dt, J = 7.0 Hz, J = 1.0 Hz, 1H, arom H), 7.87 (d, J =
8.5 Hz, 2H, arom H), 7.82 (s, 1H, arom H), 7.61 (dd, J = 9.0 Hz, J = 0.5 Hz, 1H, arom H), 7.38
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(d, J = 8.5 Hz, 2H, arom H), 7.18-7.15 (m, 1H, arom H), 6.77 (td, J = 7.0 Hz, J = 1.0 Hz, 1H,
arom H). HRMS (ESI): Anal. Calcd. For C13H10N2Cl [M+H]+ 229.0533; Found : 229.0583,
[M+H+2]+ 231.0554.
2-(4-fluorophenyl)imidazo[1,2-a]pyridine (3i):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1049 mg (99%); mp 114-
116°C. 1H NMR (500 MHz, CDCl3): 훿 8.05 (d, J =6.5 Hz, 1H, arom H), 7.88 (t, J =7.0 Hz, 2H,
arom H), 7.74 (s, 1H, arom H), 7.57 (d, J =9.0 Hz, 1H, arom H), 7.14-7.06 (m, 3H, arom H),
6.73 (t, J =6.5 Hz, 1H, arom H). 13C NMR (125 MHz, CDCl3): 162.87 (d, 1JC-F = 245.25 Hz, 1C),
4
3
145.85, 144.08, 130.17(d, JC-F =3.13 Hz, 1C), 127.86 (d, JC-F = 8.0 Hz, 2C), 125.75, 124.95,
2
117.63, 115.81(d, JC-F = 21.5 Hz, 2C), 112.65, 107.96, 21.57. HRMS (ESI): Anal. Calcd. For
C13H10FN2 [M+H]+ 213.0828; Found : 213.0873.
4-(imidazo[1,2-a]pyridin-2-yl)benzonitrile (3j):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1084 mg (99%); mp 208-
210°C. 1H NMR (500 MHz, CDCl3): 훿 8.08 (d, J =8.5 Hz, 1H, arom H), 7.99 (d, J =10.5 Hz, 2H,
arom H), 7.89 (s, 1H, arom H), 7.65 (d, J =10.5 Hz, 2H, arom H), 7.59 (d, J =11.5 Hz, 1H, arom
H), 7.18 (td, J =9.5 Hz, J =1.0 Hz, 1H, arom H), 6.78 (t, J =8.5 Hz, 1H, arom H). 13C NMR (125
MHz, CDCl3): 146.08, 143.77, 138.42, 132.69, 126.49, 125.97, 125.67, 119.21, 117.94, 113.20,
111.17, 109.70. HRMS (ESI): Anal. Calcd. For C14H10N3 [M+H]+ 220.0875; Found :220.0921.
2-(naphthalen-2-yl)imidazo[1,2-a]pyridine (3m):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1208 mg (99%); mp 82-
1
84°C. H NMR (500 MHz, CDCl3): 훿 8.49 (s, 1H, arom H), 8.04 (d, J =6.5 Hz, 1H, arom H),
7.96 (d, J =8.5 Hz, 1H, arom H), 7.90-7.80 (m, 4H, arom H), 7.63 (d, J =9.0 Hz, 1H, arom H),
7.48-7.42 (m, 2H, arom H), 7.13 (t, J =7.5 Hz, 1H, arom H), 6.71 (t, J =6.5 Hz, 1H, arom H).
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13C NMR (125 MHz, CDCl3): 145.96, 145.80, 133.89, 133.36, 131.19, 128.51, 128.47, 127.86,
126.45, 126.12, 125.79, 125.01, 124.89, 124.31, 117.62, 112.62, 108.76. HRMS (ESI): Anal.
Calcd. For C17H13N2 [M+H]+ 245.1079; Found : 245.1133.
3-(imidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one (3o):
Purified by recrystallization using aqueous ethanol; light yellow solid; yield: 1284 mg (98%); mp
256-258°C. 1H NMR (500 MHz, d6-DMSO): 훿 8.29 (s, 1H, arom H), 8.06 (s, 1H, arom H), 7.75
(d, J =6.5 Hz, 1H, arom H), 7.17 (d, J =8.0 Hz, 1H, arom H), 7.09 (d, J =9.0 Hz, 1H, arom H),
7.05 (t, J =8.0 Hz, 1H, arom H), 6.89 (t, J =8.5 Hz, 1H, arom H), 6.84 (t, J =7.5 Hz, 1H, arom
H), 6.75 (t, J =8.0 Hz, 1H, arom H), 6.34 (t, J =6.5 Hz, 1H, arom H). HRMS (ESI): Anal. Calcd.
For C16H11N2O2 [M+H]+ 263.0821; Found : 263.0880.
7-methyl-2-phenylimidazo[1,2-a]pyridine (3p):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1030 mg (99%); mp 162-
1
164°C. H NMR (500 MHz, CDCl3): 훿 7.92-7.89 (m, 3H, arom H), 7.71 (s, 1H, arom H), 7.39
(t, J =7.5 Hz, 2H, arom H), 7.34 (s, 1H, arom H), 7.28 (tt, J =7.5 Hz, J =1.0 Hz, 1H, arom H),
6.54 (dd, J =7.0 Hz, J =1.5 Hz, 1H, arom H), 2.35 (s, 3H, -CH3). 13C NMR (125 MHz, CDCl3):
146.30, 145.63, 135.75, 134.09, 128.83, 127.94, 126.11, 124.93, 116.01, 115.18, 107.69, 21.54.
HRMS (ESI): Anal. Calcd. For C14H13N2 [M+H]+ 209.1079; Found : 209.1073.
7-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3q):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1099 mg (99%); mp 166-
1
168°C. H NMR (500 MHz, d6-DMSO): 훿 8.36 (d, J =7.0 Hz, 1H, arom H), 8.22 (s, 1H, arom
H), 7.83 (d, J =8.0 Hz, 2H, arom H), 7.33 (s, 1H, arom H), 7.22 (d, J =7.5 Hz, 2H, arom H), 6.71
(dd, J =7.0 Hz, J =1.0 Hz, 1H, arom H), 2.33 (s, 3H, -CH3), 2.32 (s, 3H, -CH3). 13C NMR (125
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MHz, d6-DMSO): 145.12, 144.20, 136.74, 135.16, 131.28, 129.19, 125.92, 125.39, 114.76,
114.56, 107.96, 20.80, 20.78. LCMS (ESI): [M+H]+ 223.10
2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (3r):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1178 mg (99%); mp 159-
160°C. 1H NMR (500 MHz, CDCl3 and d6-DMSO (few drops)): 훿 8.10 (d, J =5.5 Hz, 1H, arom
H), 7.80 (s, 1H, arom H), 7.61 (brs, 2H, arom H), 7.32 (brs, 1H, arom H), 6.70 (brs, 2H, arom
H), 6.59 (brs, 1H, arom H), 3.59 (s, 3H, -OCH3), 2.20 (s, 3H, -CH3). 13C NMR (125 MHz, CDCl3
and d6-DMSO (few drops)): 159.97, 142.97, 140.63, 139.56, 127.29, 125.81, 122.41, 116.73,
114.09, 113.07, 107.32, 55.04, 21.19. LCMS (ESI): [M+H]+ 239.15
2-(4-bromophenyl)-7-methylimidazo[1,2-a]pyridine (3t):
Purified by recrystallization using aqueous ethanol; white solid, yield: 1406 mg (98%); mp 206-
1
208 °C. H NMR (500 MHz, CDCl3): 훿 7.91 (d, J =8.5 Hz, 1H, arom H), 7.75 (d, J =10.0 Hz,
2H, arom H), 7.69 (s, 1H, arom H), 7.49 (t, J =10.5 Hz, 2H, arom H), 7.32 (s, 1H, arom H), 6.56
13
(d, J =8.0 Hz, 1H, arom H), 2.35 (s, 3H, -CH3). C NMR (125 MHz, CDCl3): 146.36, 144.53,
136.10, 133.12, 131.93, 127.63, 124.96, 121.80, 116.04, 115.41, 107.82, 21.58. HRMS (ESI):
Anal. Calcd. For C14H12N2Br [M+H]+ 287.0184; Found : 287.0182, [M+H+2]+ 289.0162.
2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridine (3u):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1378 mg (96%); mp 152-
1
154 °C. H NMR (500 MHz, CDCl3): 훿 8.07 (s, 1H, arom H), 7.96 (d, J =8.5 Hz, 1H, arom H),
7.82 (d, J =9.5 Hz, 1H, arom H), 7.74 (s, 1H, arom H), 7.41 (d, J =10.0 Hz, 1H, arom H), 7.35 (s,
1H, arom H), 7.27 (d, J =10.0 Hz, 1H, arom H), 6.60 (dd, J =8.5 Hz, J =1.0 Hz, 1H, arom H),
2.38 (s, 3H, -CH3). LCMS (ESI): [M+H]+ 287.05
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2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine (3v):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1198 mg (99%); mp 238-
240 °C. 1H NMR (500 MHz, CDCl3): 훿 7.92 (d, J =7.0 Hz, 1H, arom H), 7.82 (d, J =8.5 Hz, 2H,
arom H), 7.69 (s, 1H, arom H), 7.34 (d, J =8.5 Hz, 2H, arom H), 7.33 (s, 1H, arom H), 6.57 (d, J
=6.0 Hz, 1H, arom H), 2.36 (s, 3H, -CH3). 13C NMR (125 MHz, CDCl3): 146.38, 144.59, 136.07,
133.65, 132.70, 129.01, 127.36, 124.97, 116.08, 115.40, 107.78, 21.57. HRMS (ESI): Anal.
Calcd. For C14H12N2Cl [M+H]+ 243.0684; Found: 243.0681, [M+H+2]+ 245.0660
2-(4-fluorophenyl)-7-methylimidazo[1,2-a]pyridine (3x):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1119 mg (99%); mp 118-
1
120 °C. H NMR (500 MHz, CDCl3): 훿 8.09 (d, J =8.5 Hz, 1H, arom H), 7.86 (s, 1H, arom H),
7.64-7.63 (m, 2H, arom H), 7.26 (s, 1H, arom H), 6.85-6.81 (m, 2H, arom H), 6.56 (d, J =7.5 Hz,
1H, arom H), 2.16 (s, 3H, -CH3). HRMS (ESI): Anal. Calcd. For C14H12FN2 [M+H]+ 227.0985;
Found : [M+H]+ 227.0989.
4-(7-methylimidazo[1,2-a]pyridin-2-yl)benzonitrile (3y):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1153 mg (99%); mp 201-
1
203°C. H NMR (500 MHz, d6-DMSO): 훿 8.46 (s, 1H, arom H), 8.41 (d, J =8.0 Hz, 1H, arom
H), 8.08 (d, J =9.5 Hz, 2H, arom H), 7.85 (d, J =9.5 Hz, 2H, arom H), 7.36 (s, 1H, arom H), 6.78
(d, J =8.0 Hz, 1H, arom H), 2.34 (s, 3H, -CH3). 13C NMR (125 MHz, d6-DMSO): 145.22,
141.62, 138.18, 136.76, 132.66, 126.39, 125.99, 119.01, 115.51, 114.78, 110.65, 109.68, 20.86.
LCMS (ESI): [M-H]+ 232.00
7-methyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine (3ab):
Purified by recrystallization using aqueous ethanol; white solid; yield: 1277 mg (99%); mp 188-
1
190 °C. H NMR (500 MHz, CDCl3): 훿 8.48 (s, 1H, arom H), 7.99 (d, J =7.0 Hz, 1H, arom H),
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7.96 (dd, J =8.5 Hz, J =1.5 Hz, 1H, arom H), 7.90 (d, J =8.0 Hz, 1H, arom H), 7.88-7.85 (m, 2H,
arom H), 7.81 (d, J =7.5 Hz, 1H, arom H), 7.48-7.42 (m, 2H, arom H), 7.40 (s, 1H, arom H),
6.60 (dd, J =7.0 Hz, J =1.0 Hz, 1H, arom H), 2.39 (s, 3H, -CH3). LCMS (ESI): [M+H]+ 259.10
3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one (3ad):
Purified by recrystallization using aqueous ethanol; light yellow solid; yield: 1339 mg (97%); mp
264-266 °C. 1H NMR (500 MHz, CDCl3): 훿 8.77 (s, 1H, arom H), 8.43 (s, 1H, arom H), 8.0 (d, J
=6.5 Hz, 1H, arom H), 7.62 (dd, J =7.5 Hz, J =1.0 Hz, 1H, arom H), 7.49 (td, J =7.5 Hz, J =2.0
Hz, 1H, arom H), 7.35-7.32 (m, 2H, arom H), 7.33 (s, 1H, arom H), 7.27 (td, J =7.5 Hz, J =1.0
Hz, 1H, arom H), 6.63 (dd, J =7.0 Hz, J =1.5 Hz, 1H, arom H), 2.38 (s, 3H, -CH3). LCMS (ESI):
[M+H]+ 276.95
Supporting Information
1
Supporting Information (SI) available: General information, Copies of H NMR, HRMS and
LCMS spectra of title compounds and crystallographic data of 3u (CCDC 1986012).
Acknowledgments
The authors gratefully acknowledge the financial support for this work from the
Department of Atomic Energy-Board of Research in Nuclear Sciences (Bhabha Atomic
Research Centre), Mumbai, Government of India through a major research project (No.
2011/37C/52/BRNS/2264) and Council of Scientific and Industrial Research (CSIR),
New Delhi, Government of India under a major research project (No. 01 (2391)/10/EMR-
II) Mr. G Kumar is thankful to Prof. Samar K. Das, School of Chemistry and University
Grants Commission Networking Resource Centre (UGC-NRC), School of Chemistry,
University of Hyderabad for providing infrastructural facilities.
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