Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04554-z
Survey reactivity of 2‑aminopyridine and Meldrum’s acid
in the presence of aryl glyoxals or aryl aldehydes; ethyl
2‑(3‑aryl imidazo[1,2‑a]pyridin‑2‑yl)acetates versus ethyl
3‑aryl‑3‑(pyridin‑2‑ylamino)propanoates
Sara Asadi1 · Maedeh Zebarjad1 · Hamidreza Masoudi1 · Hossein Mehrabi1
Received: 10 June 2021 / Accepted: 22 July 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
The aim of present investigation is survey reactivity of 2-aminopyridine and Meldrum’s acid in the presence of aryl glyoxals or aryl aldehydes. The ethyl 2-(3-aryl
imidazo[1,2-a]pyridin-2-yl)acetates were successfully synthesized by reaction
of 2-aminopyridine, Meldrum’s acid, and aryl glyoxals, while the ethyl 3-aryl-3(pyridin-2-ylamino)propanoates were synthesized in the presence of aryl aldehydes.
The reactions are performed in ethanol, catalyzed by acetic acid at reflux and microwave conditions.
Graphic abstract
Keywords 2-Aminopyridine · Meldrum’s acid · Aryl glyoxals. Aryl aldehydes.
Ethyl 2-(3-aryl imidazo[1,2-a]pyridin-2-yl)acetates. Ethyl 3-aryl-3-(pyridin-2ylamino)propanoates
* Hossein Mehrabi
mayu.yunokawa@jfcr.or.jp
Extended author information available on the last page of the article
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S. Asadi et al.
Fig. 1 Examples of biologically active compounds containing an imidazo-pyridine fused heterocycle
framework
Introduction
Significant importance of heterocyclic compounds containing nitrogen in the
pharmaceutical industry and biological properties has made them attractive targets of research for many years [1]. Among them, imidazo-pyridine derivatives
are of particular importance [2]. They have biological properties such as antiviral
[3], antiulcer [4], antibacterial [5, 6], antifungal [7], herbicidal [8], antipyretic
[9], immunosuppressive agents [10], H1-receptor antagonists [1], anti-inflammatory [11], potential antirhinoviral [12], GABAA receptor operator [13], long-acting local anesthetic [14], antiprotozoal [15], and as anthelmintic or bacteriostatic
agents [16]. Moreover, these compounds are versatile intermediates for synthetic
transformations and as fluorescent materials [17, 18]. Also, imidazo-pyridines
which are widely used in medicinal and agro-chemistry [19]. These compounds
are the core of many strategic and widely used drugs which have received excellent feedback in medical and chemical researches such as zolpidem A (used in the
treatment of insomnia) [20], alpidem B [21], zolimidine C (treatment of peptic
ulcer) [22], saripidem D (anxiolytic agent) [23], necopidem E [24], miroprofen F
[25], and minodronic acid G [26] (Fig. 1).
2-Aminopyridine, apart from being the central nucleus of imidazo-pyridine
compounds, it has applications in the formation of complexes by various metals.
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Survey reactivity of 2-aminopyridine and Meldrum’s acid in…
Cu(II) with n-butyl malonate ligand and protonated 2-aminopyridine [27], Cu(II)
and Mg(II) with diaqua-bis-malonate ligands bridges two protonated 2-aminopyridine [28–30], are part of these complexes.
Consequently, considering a wide range of applications imidazo-pyridine nuclei,
there are numerous reported synthesis of substituted imidazo[1,2-a]pyridines. These
include cycloaddition reaction of pyridine derivatives with α‑diazo oxime ethers [1],
coupling of 2-aminopyridine and aromatic terminal alkyne [3], and initial formation
of α-organosulfonyloxy ketones and their subsequent cyclocondensation by 2-aminopyridines [18]. Also, metallic and non-metallic catalysts the same as DABCO
[31], Fe(III) [32, 33], ­PdI2/KI [34], Rh(II) [35], Cu(II) [36], and Au [37, 38] have
been widely benefit to synthesis imidazo-pyridine scaffolds.
In recent years, the usage of microwave in organic synthesis has become very
prevalent. Microwave-assisted synthesis is a particularly appealing alternative to
synthesis under thermal conditions since they often proceed much faster and deliver
products with higher yields and higher purity. With conventional heating using an
external heat source such as an oil bath, the energy transfer to the sample is almost
slow and inefficient, conversely, microwave energy is transferred directly to the
reaction mixture through dielectric heating. The heating is mainly caused by dipolar polarization and ionic conduction [39]. In this regard, in the continuation of our
previous group works on the development of multicomponent reactions for the synthesis of imidazole derivatives [40, 41], we herein describe a facile and efficient
strategy for the synthesis of ethyl-2-(3-aryl imidazo[1,2-a]pyridin-2-yl)acetates and
ethyl 3-aryl-3-(pyridin-2-ylamino)propanoates via the three-component reaction of
2-aminopyridine and Meldrum’s acid in the presence of aryl glyoxals or aryl aldehydes in ethanol at reflux and microwave conditions.
Results and discussion
To find the optimized conditions, we studied the synthesis of ethyl 2-(3-(p-tolyl)
imidazo[1,2-a]pyridin-2-yl)acetate 4a via the three-component reaction of Meldrum’s acid 1 with 4-methylphenylglyoxal 2a and 2-aminopyridine 3 under a variety
of conditions (Table 1).
The optimization of the reaction conditions, including solvent, catalyst, and temperature was investigated. First, various solvents such as ­H2O, EtOH, ­H2O/ EtOH,
­CH3CN, THF, and toluene, were examined, and ethanol was proven to be the preeminent solvent for this reaction. Then, the reaction was carried out in the presence
of acetic acid as catalyst at room temperature in ethanol solvent (Table 1, entry 8).
Finally, we observed that the reaction temperature also have an important influence
on the reaction. So that the reaction was carried out at room temperature in 2 h,
the product was formed in 45% yield, but under reflux conditions in the same time,
the product was formed in 60% yield (Table 1, entries 8 and 11). It was found that
a longer time of the reaction in acetic acid at reflux conditions did not improve the
yield (Table 1, entry 12). A series of experiments revealed that the optimal results
were obtained when the reaction of Meldrum’s acid (1, 1.0 mmol) was conducted
with 4-methylphenylglyoxal (2a, 1.0 mmol), and 2-aminopyridine (3, 1.0 mmol)
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S. Asadi et al.
Table 1 Optimization of the reaction conditions in the synthesis of 4a
Entry
Solvent
Catalyst
Temp.a
Yield (%)b
1
EtOH
–
r.t
0
2
EtOH
–
Reflux
3
EtOH
–
Reflux c
15
4
THF
AcOH
r.t
0
5
Toluene
AcOH
r.t
0
6
H2O/EtOH(3:1)
AcOH
r.t
25
AcOH
r.t
35
45
7
CH3CN
15
8
EtOH
AcOH
r.t
9
H2O/EtOH(3:1)
AcOH
Reflux
42
AcOH
Reflux
46
10
11
12
CH3CN
EtOH
EtOH
AcOH
AcOH
Reflux
Refluxd
60
60
a
Reaction conditions: solvent was 5.0 mL ethanol, Meldrum’s acid (1, 1.0 mmol), 4-methylphenylglyoxal
(2a, 1.0 mmol), 2-amino pyridine (3, 1.0 mmol), AcOH (0.3 mmol), reaction time was 2 h
b
c
d
Isolated yields
Reaction time was 24 h
Reaction time was 24 h
in the presence of acetic acid (0.3 mmol) in ethanol reflux conditions. Under these
optimized conditions, the yield of 4a reached 60%.
Under the optimized reaction conditions, a series of ethyl 2-(3-arylimidazo[1,2a]pyridin-2-yl)acetate derivatives 4a–h were synthesized through Meldrum’s acid,
different aryl glyoxals, and 2-aminopyridine (Table 2). All the synthesized compounds were previously unknown to the best of our knowledge and were characterized by 1H and 13C NMR, IR, CHN analysis, and melting points. For instance, The
IR spectrum of ethyl 2-(3-(p-tolyl) imidazo[1,2-a]pyridin-2-yl)acetate 4a showed
absorption band at 1732 ­cm−1 for C = O group. The 1H NMR spectrum of compound 4a appears one triplet at δ = 1.17 ppm with coupling constant of 7.1 Hz for
the methyl group, and one singlet at δ = 2.32 ppm for the methyl group on the phenyl
ring. Also appears one quartet at δ = 4.11 ppm with coupling constant of 7.1 Hz, and
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Survey reactivity of 2-aminopyridine and Meldrum’s acid in…
Table 2 Synthesis of ethyl 2-(3-arylimidazo[1,2-a]pyridin-2-yl)acetates 4a–h and ethyl 3-aryl-3(pyridin-2-ylamino)propanoates 6a–f
Yield (%)a
Yield (%)b
4-Me
60
75
2
4-Cl
65
79
3
3-NO2
68
80
4
3,4-(OMe)2
62
75
5
4-NO2
67
89
Entry
R
1
Product
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S. Asadi et al.
Table 2 (continued)
Yield (%)a
Yield (%)b
H
60
70
7
4-Br
64
78
8
2-OMe
65
76
9
4-Me
58
65
10
3-Cl
67
80
Entry
R
6
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Product
Survey reactivity of 2-aminopyridine and Meldrum’s acid in…
Table 2 (continued)
Yield (%)a
Yield (%)b
4-Cl
62
73
12
4-OMe
59
72
13
3-Me
55
68
14
3-Br
65
78
Entry
R
11
Product
a
In thermal conditions (A): solvent was 5.0 mL, Meldrum’s acid (1, 1.0 mmol), aryl glyoxal (2a-h,
1.0 mmol) or aryl aldehyde (5a-f, 1.0 mmol), 2-amino pyridine (3, 1.0 mmol), AcOH (0.3 mmol), reaction time was 2 h
b
In microwave conditions (B): solvent was 5.0 mL, Meldrum’s acid (1, 1.0 mmol), aryl glyoxal (2a-h,
1.0 mmol) or aryl aldehyde (5a-f, 1.0 mmol), 2-amino pyridine (3, 1.0 mmol), AcOH (0.3 mmol), reaction time was 8 min
one singlet at δ = 4.21 ppm for methylene groups of the product. Aromatic protons
appear as two triplets at δ = 6.94 and 7.24 ppm with coupling constant of 6.7 and
6.3 Hz, respectively, and three doublets at δ = 7.27, 7.59 and 7.65 ppm with coupling
constant of 7.6, 9.0 and 8.1 Hz, respectively. The 13C NMR spectrum of compound
4a showed 16 distinct signals in agreement with the proposed structure. Spectral
information of other products is given in the experimental section.
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S. Asadi et al.
Then, for the reactivity of the compounds with a lower carbonyl group compared to the above reaction, the starting materials of Meldrum’s acid, aryl aldehydes instead of aryl glyoxals, and 2-aminopyridine were investigated. According
to this, a series of ethyl 3-aryl-3-(pyridin-2-ylamino)propanoate derivatives 6a–f
were also synthesized by the condensation of Meldrum’s acid (1, 1.0 mmol) with
aryl aldehydes (5, 1.0 mmol), and 2-aminopyridine (3, 1.0 mmol) in the presence
of acetic acid (0.3 mmol) in ethanol under reflux conditions (Table 2). The synthesized compounds were characterized by 1H and 13C NMR, IR, CHN analysis,
and melting points. For instance, the IR spectrum of ethyl 3-(pyridin-2-ylamino)3-(p-tolyl)propanoate 6a showed absorption band at 1734 ­cm−1 for C = O group.
The 1H NMR spectrum of compound 6a appears one triplet at δ = 0.72 ppm with
coupling constant of 7.1 Hz for the methyl group, and one singlet at δ = 1.86 ppm
for the methyl group on the phenyl ring. Also, one doublet of doublet appears at
δ = 2.33 ppm with geminal coupling constant 2j = 15.1 Hz and vicinal coupling
constant 3j = 6.3 Hz, and one doublet of doublet appears at δ = 2.49 ppm with
geminal coupling constant 2j = 15.1 Hz and vicinal coupling constant 3j = 7.7 Hz.
One quartet appears at δ = 3.61 ppm with coupling constant of 7.1 Hz for methylene group of the product. One multiplet was appeared at δ = 4.85 ppm for methine
group and one doublet at δ = 5.86 ppm with coupling constant of 8.1 Hz for NH
group. Aromatic protons appear as one doublet at δ = 5.98 ppm with coupling
constant of 8.4 Hz, one triplet at δ = 6.05 ppm with coupling constant of 4.9 Hz,
two doublets at δ = 6.66 and 7.55 ppm with coupling constant of 7.8 and 5.2 Hz,
respectively, and one multiplet at δ = 6.86–6.88 ppm for three aromatic hydrogens. The 13C NMR spectrum of compound 6a showed 15 distinct signals in
agreement with the proposed structure. Spectral information of other products is
given in the experimental section.
Also, same reactions were performed under microwave conditions. For example, the model reaction in EtOH at reflux conditions gave 4a in 60% yield after
2 h, whereas the microwave was rapid yielding 4a in 75% only within 8 min. As
shown in Table 2, the synthesis of ethyl 2-(3-arylimidazo[1,2-a]pyridin-2-yl)acetates 4a-h, and ethyl 3-aryl-3-(pyridin-2-ylamino)propanoates 6a-f via the reaction of Meldrum’s acid with aryl glyoxals or aryl aldehydes and 2-aminopyridine
were carried out in the presence of acetic acid within 8 min under microwave
conditions. It is apparent that microwave accelerates these transformations with
higher yields.
As given in Table 2, electronic effects and the nature of substituents on the aromatic ring in aryl glyoxals and aryl aldehydes did show effects in terms of yield
reaction. When aryl glyoxals and aryl aldehydes containing electron-withdrawing
groups (such as nitro or halides) were employed, a higher yield was achieved as a
consequence of effective.
The present study has made possible the synthesis of compounds 4 with inexpensive starting materials in green solvent. Also, these compounds were synthesized without the use of expensive or anti-environmental catalysts. Compared to
other synthesis methods, it is momentous use of conditions with the shortest possible time and good yields.
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Survey reactivity of 2-aminopyridine and Meldrum’s acid in…
Proposed mechanism
A proposed mechanism for the formation of ethyl 2-(3-aryl- imidazo[1,2-a]pyridin-2-yl)acetates 4a-h and ethyl 3-aryl-3-(pyridin-2-ylamino)propanoates 6a-f
is described in Scheme 1. The compounds 4a-h are prepared in five steps. In this
way, initially an intermediate A is prepared from the Knoevenagel condensation
between Meldrum’s acid 1 and aryl glyoxal 2. Subsequently, compound B is prepared through nucleophilic addition of 2-aminopyridine to the intermediate A. In
continuation, intermediate of C is obtained by intramolecular cyclization and elimination of one molecule acetone and carbon dioxide. Then, intermediate C undergoes
recyclization in ethanol medium to result in the formation of compound D. In the
last step, the compounds 4a-h are obtained by intramolecular nucleophilic addition
and removing one molecule of ­H2O, while the compounds 6a-f are prepared in four
steps. Firstly, intermediate E is formed through Knoevenagel condensation between
the Meldrum’s acid 1 and aryl aldehyde 5. Then, the formation of intermediate F
occurred via nucleophilic addition of 2-aminopyridine to the intermediate E. In
continuation, intermediate G is obtained by intramolecular cyclization and elimination of one molecule acetone and carbon dioxide. In the last step, intermediate G
afforded the products 6a-f through recyclization in ethanol medium.
Scheme 1 Proposed mechanism for the reactions
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S. Asadi et al.
By comparing the mechanism formation of products 4 and 6, where aryl glyoxal
is used, in the final stage by intramolecular nucleophilic addition to the carbonyl
group, compounds 2-(3-arylimidazo[1,2-a]pyridin-2-yl)acetate 4 are prepared.
While using aryl aldehyde instead of aryl glyoxal, the reaction stops during the formation of compounds ethyl 3-aryl-3-(pyridin-2-ylamino)propanoate 6.
Experimental section
General
All chemicals were purchased from Sigma-Aldrich and Merck with high-grade quality, and used without any purification. All products were obtained in the microwave
conditions with the microwave digestion device model; Ethos 1 from Millston company. All melting points were obtained by Barnstead Electro thermal 9200 apparatus
and are uncorrected. IR spectra were recorded on a Bruker FT-IR Equinax-55 spectrophotometer in KBr with absorption in ­cm−1. All the NMR spectra were recorded
on a Varian model UNITY Inova 500 MHz spectrometer (1H: 500, 13C: 125 MHz)
in DMSO and ­CDCl3 using TMS as an internal standard. Elemental analyses were
performed using a Carlo Erba EA 1108 instrument. All products were characterized
by their spectral and physical data.
General procedure for the synthesis of compounds 4a‑h and 6a‑f
A mixture of Meldrum’s acid (1, 1.0 mmol), aryl glyoxal (2, 1.0 mmol) or aryl
aldehyde (5, 1.0 mmol), and 2-aminopyridine (3, 1.0 mmol) was stirred in the presence of acetic acid (0.3 mmol) in ethanol (5.0 mL) under reflux conditions for 2 h.
After completion of the reaction, determined by TLC, the solvent was removed
under reduced pressure. The crude product was purified by plate chromatography
(20 × 20 cm) using n-hexane/EtOAc (1:2) as eluent to give the pure compounds 4a-h
(60–68%) and 6a-f (55–67%).
To improve the yield and time of the products, the above reactions were performed in the microwave conditions at 800 W in 150 °C for 8 min. After completion
of the reaction, determined by TLC, the solvent was removed under reduced pressure. The crude product was purified by plate chromatography (20 × 20 cm) using
n-hexane/EtOAc (1:2) as eluent to give the pure compounds 4a-h (70–89%) and 6a-f
(65–80%).
Physical and spectral data for compounds 4a‑h and 6a‑f
Ethyl 2‑(3‑(p‑tolyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4a)
Yellow solid; m.p. 121–123 °C. FT-IR (KBr) ʋ: 1732 ­cm−1. 1H NMR (500 MHz,
DMSO-d6) δ (ppm): 8.37 (s, 1H, Ar), 7.65 (d, J = 8.1 Hz, 2H, Ar), 7.59 (d, J = 9 Hz,
1H, Ar), 7.27 (d, J = 7.6 Hz, 2H, Ar), 7.24 (t, J = 6.3 Hz, 1H, Ar), 6.94 (t, J = 6.7 Hz,
1H, Ar), 4.21 (s, 2H, C
­ H2), 4.11 (q, J = 7.1 Hz, 2H, ­CH2), 2.32 (s, 3H, C
­ H3), 1.17
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Survey reactivity of 2-aminopyridine and Meldrum’s acid in…
(t, J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz, DMSO-d6) δ (ppm): 169.9, 144.4,
143.4, 137.3, 131.8, 129.6, 128.1, 125.2, 124.9, 117.0, 113.8, 111.7, 60.8, 30.2,
21.2, 14.4. Anal. Calcd for ­C18H18N2O2 (294.35): C, 73.45; H, 6.16; N, 9.52. Found:
C, 73.17; H, 6.12; N, 9.60%.
Ethyl 2‑(3‑(4‑chlorophenyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4b)
Yellow solid; m.p. 128–130 °C. FT-IR (KBr) ʋ: 1732 ­cm−1. 1H NMR (500 MHz,
DMSO-d6) δ (ppm): 8.03 (d, J = 6.9 Hz, 1H, Ar), 7.72 (d, J = 8.4 Hz, 2H, Ar), 7.54
(d, J = 7.9 Hz, 1H, Ar), 7.35 (d, J = 8.5 Hz, 2H, Ar), 7.12 (t, J = 9.1 Hz, 1H, Ar),
6.75 (t, J = 8.9 Hz, 1H, Ar), 4.13 (q, J = 7.1 Hz, 2H, ­CH2), 3.91 (s, 2H, ­CH2), 1.18
(t, J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz, DMSO-d6) δ (ppm):143.2, 133.7,
132.6, 129.6, 128.6, 124.5, 123.6, 117.3, 113.0, 112.3, 61.5, 30.6, 14.0. Anal. Calcd
for ­C17H15ClN2O2 (314.77): C, 64.87; H, 4.80; N, 8.90. Found: C, 65.11; H, 4.84; N,
8.84%.
Ethyl 2‑(3‑(3‑nitrophenyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4c)
Yellow solid; m.p. 131–133 °C. FT-IR (KBr) ʋ: 1729 ­cm−1. 1H NMR (500 MHz,
­CDCl3) δ (ppm): 8.45 (d, J = 6.9 Hz, 1H, Ar), 8.21 (d, J = 8.1 Hz, 1 Hz, Ar), 7.77
(t, J = 8 Hz, 1H, Ar), 7.65 (d, J = 9.0 Hz, 1H, Ar), 7.34 (t, J = 8.3 Hz, 1H, Ar), 7.01
(t, J = 6.9 Hz, 1H, Ar), 4.33 (s, 2H, C
­ H2), 4.14 (q, J = 7.0 Hz, 2H, ­CH2), 1.19 (t,
J = 7.1 Hz, 3H, ­CH3). 13 C NMR (125 MHz, ­CDCl3) δ (ppm): 169.6, 148.6, 144.7,
140.8, 136.3, 134.1, 130.7, 125.5, 122.4, 117.3, 115.4, 113.0, 61.5, 30.1, 14.4. Anal.
Calcd for ­C17H15N3O4 (325.32): C, 62.76; H, 4.65; N, 12.92. Found: C, 62.27; H,
4.59; N, 12.85%.
Ethyl 2‑(3‑(3,4‑dimethoxyphenyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4d)
Yellow solid; m.p. 132–134 °C. FT-IR (KBr) ʋ: 1730 ­cm−1. 1H NMR (500 MHz,
­CDCl3) δ (ppm): 7.77 (d, J = 8.4 Hz, 1H, Ar), 7.61 (s, 1H, Ar), 7.38 (t, J = 6.4 Hz,
1H, Ar), 6.90 (d, J = 8.4 Hz, 1H, Ar), 6.84 (d, J = 8.1 Hz, 1H, Ar), 6.61 (t, J = 4 Hz,
1H, Ar), 6.48 (d, J = 9.3 Hz, 1H, Ar), 3.96 (q, J = 5.1 Hz, 2H, ­CH2), 3.93 (s, 3H,
­OCH3), 3.87 (s, 2H, C
­ H2), 3.85 (s, 3H, O
­ CH3), 1.22 (t, J = 4.8 Hz, 3H, ­CH3). 13 C
NMR (125 MHz, ­CDCl3) δ (ppm): 172.1, 156.6, 149.1, 148.0, 147.7, 137.2, 122.9,
119.6, 116.8, 113.6, 111.2, 110.3, 109.5, 108.1, 60.8, 58.5, 55.9, 37.2, 14.0. Anal.
Calcd for C
­ 19H20N2O4 (340.38): C, 67.05; H, 5.92; N, 8.23. Found: C, 66.81; H,
5.90; N, 8.17%.
Ethyl 2‑(3‑(4‑nitrophenyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4e)
Yellow solid; m.p. 127–129 °C. FT-IR (KBr) ʋ: 1730 ­cm−1. 1H NMR (500 MHz,
­CDCl3) δ (ppm): 8.31 (d, J = 8.8 Hz, 2H, Ar), 8.17 (d, J = 6.9 Hz, 1H, Ar), 8.05 (d,
J = 8.7 Hz, 2H, Ar), 7.67 (d, J = 9.1 Hz, 1H, Ar), 7.28 (t, J = 7.9 Hz, 1H, Ar), 6.92
(t, J = 6.8 Hz, 1 H, Ar), 4.24 (q, J = 7.1 Hz, 2H, ­CH2), 4.05 (s, 2H, C
­ H2), 1.29 (t,
J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz, ­CDCl3) δ (ppm): 167.7, 147.3, 145.3,
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S. Asadi et al.
142.1, 141.6, 140.6, 129.0, 125.3, 123.8, 117.8, 114.4, 113.0, 61.9, 30.8, 14.1. Anal.
Calcd for C
­ 17H15N3O4 (325.32): C, 62.76; H, 4.65; N, 12.92. Found: C, 62.88; H,
4.68; N, 12.84%.
Ethyl 2‑(3‑phenylimidazo[1,2‑a]pyridin‑2‑yl)acetate (4f)
Yellow solid; m.p. 122–124 °C. FT-IR (KBr) ʋ: 1731 ­cm−1. 1H NMR (500 MHz,
DMSO-d6) δ (ppm): 8.13 (d, J = 6.8 Hz, 1H, Ar), 7.85 (d, J = 6.9 Hz, 2H, Ar), 7.67
(d, J = 9.0 Hz, 1H, Ar), 7.48 (t, J = 7.8 Hz, 2H, Ar), 7.38 (t, J = 7.5 Hz, 1H, Ar), 7.23
(t, J = 7.7 Hz, 1H, Ar), 6.86 (t, J = 6.7 Hz, 1H, Ar), 4.22 (q, J = 7.7 Hz, 2H, ­CH2),
4.05 (s, 2H, C
­ H2), 1.27 (t, J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz, DMSO-d6) δ
(ppm): 169.7, 156.6, 145.0, 132.1, 130.3, 129.5, 123.5, 120.9, 117.5, 116.3, 115.0,
112.0, 111.0, 61.1, 55.5, 30.7, 14.1. Anal. Calcd for C
­ 17H16N2O2 (280.33): C, 72.84;
H, 5.75; N, 9.99. Found: C, 72.63; H, 5.73; N, 9.90%.
Ethyl 2‑(3‑(4‑bromophenyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4 g)
Yellow solid; m.p. 137–139 °C. FT-IR (KBr) ʋ: 1721 ­cm−1. 1H NMR (500 MHz,
DMSO-d6) δ (ppm): 8.11 (d, J = 8.0 Hz, 1H, Ar), 7.72 (d, J = 8.5 Hz, 2H, Ar), 7.63
(d, J = 9.0 Hz, 1H, Ar), 7.58 (d, J = 8.4 Hz, 2H, Ar), 7.21 (t, J = 7.7 Hz, 1H, Ar),
6.85 (t, J = 8.0 Hz, 1H, Ar), 4.21 (q, J = 7.1 Hz, 2H, ­CH2), 3.98 (s, 2H, ­CH2), 1.25
(t, J = 7.0 Hz, 3H, ­CH3). 13C NMR (125 MHz, DMSO-d6) δ (ppm): 169.1, 145.0,
143.5, 133.1, 131.7, 130.0, 124.6, 123.7, 122.1, 117.6, 113.0, 114.4, 61.6, 30.8,
14.1. Anal. Calcd for ­C17H15BrN2O2 (359.22): C, 56.84; H, 4.21; N, 7.80. Found: C,
56.97; H, 4.22; N, 7.75%.
Ethyl 2‑(3‑(2‑methoxyphenyl)imidazo[1,2‑a]pyridin‑2‑yl)acetate (4 h)
Yellow solid; m.p. 126–128 °C. FT-IR (KBr) ʋ: 1734 ­cm−1. 1H NMR (500 MHz,
­CDCl3) δ (ppm): 8.01 (d, J = 6.8 Hz, 1H, Ar), 7.61–7.67 (m, 2H, Ar), 7.37 (t,
J = 7.7 Hz, 1H, Ar), 7.20 (d, J = 6.8 Hz, 1H, Ar), 7.07 (t, J = 7.6 Hz, 1H, Ar), 7.00
(d, J = 4.9 Hz, 1H, Ar), 6.83 (t, J = 6.3 Hz, 1H, Ar), 4.18 (q, J = 7.2 Hz, 2H, ­CH2),
3.88 (s, 2H, ­CH2), 3.76 (s, 3H, ­OCH3), 1.23 (t, J = 7.0 Hz, 3H, ­CH3). 13C NMR
(125 MHz, ­CDCl3) δ (ppm): 169.3, 144.9, 144.5, 134.1, 128.6, 128.5, 127.8, 124.3,
123.6, 117.6, 112.9, 112.3, 62.0, 30.8, 14.1. Anal. Calcd for ­C18H18N2O3 (310.35):
C, 69.66; H, 5.85; N, 9.03. Found: C, 69.84; H, 5.91; N, 8.94%.
Ethyl 3‑(pyridin‑2‑ylamino)‑3‑(p‑tolyl)propanoate (6a)
White solid; m.p. 121–123 °C. FT-IR (KBr) ʋ: 3252, 1734 ­
cm−1. 1H NMR
(500 MHz, DMSO-d6) δ (ppm): 7.55 (d, J = 5.2 Hz, 1H, Ar), 6.84–6.88 (m, 3H,
Ar), 6.66 (d, J = 7.8 Hz, 2H, Ar), 6.05 (t, J = 4.9 Hz, 1H, Ar), 5.98 (d, J = 8.4 Hz,
1H, Ar), 5.86 (d, J = 8.1 Hz, 1H, NH), 4.85 (m, 1H, CH), 3.61 (q, J = 7.1 Hz, 1H,
­CH2), 2.49 (dd, J = 15.1 Hz, J = 6.3 Hz, 1H, CHH), 2.33 (dd, J = 15.1 Hz, J = 7.7 Hz,
1H, CHH), 1.86 (s, 3H, ­CH3), 0.72 (t, J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz,
DMSO-d6) δ (ppm): 170.5, 157.6, 139.1, 136.7, 136.2, 128.7, 126.1, 112.3, 107.6,
13
Survey reactivity of 2-aminopyridine and Meldrum’s acid in…
59.9, 51.6, 41.8, 20.6, 13.7. Anal. Calcd for ­C17H20N2O2 (284.36): C, 71.81; H,
7.09; N, 9.85. Found: C, 71.64; H, 7.08; N, 9.77%.
Ethyl 3‑(3‑chlorophenyl)‑3‑(pyridin‑2‑ylamino)propanoate (6b)
White solid; m.p. 123–125 °C. FT-IR (KBr) ʋ: 3408, 1650 ­
cm−1. 1H NMR
(500 MHz, ­CDCl3) δ (ppm): 7.9 (d, J = 5.0 Hz, 1H, Ar), 7.44 (s, 1H, Ar), 7.32 (m,
3H, Ar), 7.23 (d, J = 7.8 Hz, 1H, Ar), 7.07 (d, J = 8.5 Hz, 1H, Ar), 6.49 (d, J = 8.4 Hz,
1H, NH), 6.46 (t, J = 5.1 Hz, 1H, Ar), 5.37 (m, 1H, CH), 3.99 (q, J = 7.1 Hz,
2H, ­CH2), 2.84 (dd, J = 15.2 Hz, J = 6.4 Hz, 1H, CHH), 2.74 (dd, J = 15.2 Hz,
J = 8.5 Hz, 1H, CHH), 1.06 (t, J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz, C
­ DCl3)
δ (ppm):170.6, 147.9, 137.1, 133.3, 130.5, 127.2, 126.8, 125.9, 118.8, 117.7, 112.7,
109.0, 60.3, 51.2, 41.9, 14.4. C
­ 16H17ClN2O2 (304.77): C, 63.06; H, 5.62; N, 9.19.
Found: C, 63.13; H, 5.70; N, 9.14%.
Ethyl 3‑(4‑chlorophenyl)‑3‑(pyridin‑2‑ylamino)propanoate (6c)
White solid; m.p. 130–132 °C. FT-IR (KBr) ʋ: 3258, 1732 ­
cm−1. 1H NMR
(500 MHz, DMSO-d6) δ (ppm): 7.76(d, J = 4.0 Hz, 1H, Ar), 7.06 (t, J = 6.9 Hz, 1H,
Ar), 7.02 9d, J = 8.0 Hz, 2H, Ar), 6.85 (d, J = 7.9 Hz, 2H, Ar), 6.25 (t, J = 6.3 Hz,
1H, Ar), 6.11 (d, J = 8.4 Hz, 1H, Ar), 5.49 (d, J = 7.6 Hz,1, NH), 4.98 (m, 1H, CH),
3.8 (q, J = 7.1 Hz, 2H, ­CH2), 2.67 (dd, J = 15.0 Hz, J = 6.1 Hz, 1H, CHH), 2.53
(dd, J = 15.0 Hz, J = 7.4 Hz, 1H, CHH), 0.91 (t, J = 7.1 Hz, 3H, ­CH3). 13C NMR
(125 MHz, DMSO-d6) δ (ppm): 170.6, 157.6, 147.6, 139.1, 136.7, 136.4, 128.9,
126.1, 112.5, 107.6, 60.0, 51.8, 41.8, 13.8. Anal. Calcd for C
­ 16H17ClN2O2 (304.77):
C, 63.06; H, 5.62; N, 9.19. Found: C, 62.89; H, 5.60; N, 9.15%.
Ethyl 3‑(4‑methoxyphenyl)‑3‑(pyridin‑2‑ylamino)propanoate (6d)
White solid; m.p. 120–122 °C. FT-IR (KBr) ʋ: 3428, 1651 ­
cm−1. 1H NMR
(500 MHz, DMSO-d6) δ (ppm): 7.92 (d, J = 4.7 Hz, 1H, Ar), 7.31 (m, 3H, Ar), 6.93
(d, J = 8.4 Hz, 1H, Ar), 6.84 (d, J = 8.5 Hz, 2H, Ar), 6.46 (d, J = 8.3 Hz, 1H, NH),
6.43 (t, J = 5.0 Hz, 1H, Ar), 5.33 (m, 1H, CH), 3.97 (q, J = 7.0 Hz, 2H, ­CH2), 3.69
(s, 3H, O
­ CH3), 2.86 (dd, J = 16.1 Hz, J = 8.2 Hz, 1H, CHH), 2.69 (dd, J = 16.1 Hz,
J = 6.7 Hz, 1H, CHH), 1.06 (t, J = 7.1 Hz, 3H, ­CH3). 13C NMR (125 MHz, DMSOd6) δ (ppm):169.9, 156.7, 156.0, 145.7, 136.1, 133.2, 126.3, 112.3, 111.2, 107.2,
59.0, 53.6, 49.5, 40.5, 12.3. Anal. Calcd for ­C17H20N2O3 (300.36): C, 67.98; H,
6.71; N, 9.33. Found: C, 68.12; H, 6.72; N, 9.29%.
Ethyl 3‑(pyridin‑2‑ylamino)‑3‑(m‑tolyl)propanoate (6e)
White solid; m.p. 122–124 °C. FT-IR (KBr) ʋ: 3407, 1620 ­
cm−1. 1H NMR
(500 MHz, ­CDCl3) δ (ppm): 8.06 (s, 1H, Ar), 7.35 (t, J = 7 Hz, 1H, Ar), 7.16–7.22
(m, 3H, Ar), 7.05 (d, J = 6.9 Hz, 1H, Ar), 6.55 (t, J = 6.1 Hz, 1H, Ar), 6.33 (d,
J = 8.4 Hz, 1H, Ar), 5.47 (s, 1H, NH), 5.17 (m, 1H, CH), 4.08 (q, J = 7.1 Hz, 2H,
­CH2), 2.89 (dd, J = 15.0 Hz, J = 7.5 Hz, 1H, CHH), 2.82 (dd, J = 15.0 Hz, J = 5.3 Hz,
13
S. Asadi et al.
1H, CHH), 2.32 (s, 3H, ­CH3), 1.16 (t, J = 7.15 Hz, 3H, ­CH3). 13 C NMR (125 MHz,
­CDCl3) δ (ppm): 169.9, 165.5, 162.1, 151.0, 146.9, 145.6, 138.3, 133.0, 129.6,
125.5, 121.5, 119.5, 57.6, 46.5, 29.6, 22.7, 17.5. Anal. Calcd for ­
C17H20N2O2
(284.36): C, 71.81; H, 7.09; N, 9.85. Found: C, 71.38; H, 7.02; N, 9.78%.
Ethyl 3‑(3‑bromophenyl)‑3‑(pyridin‑2‑ylamino)propanoate (6f)
White solid; m.p. 123–125 °C. FT-IR (KBr) ʋ: 3423, 1698 ­cm−1. 1H NMR (500 MHz,
DMSO-d6) δ (ppm): 7.91 (d, J = 7.0 Hz, 1H, Ar), 7.58 (s, 1H, Ar), 7.58 (m, 2H,
Ar), 7.24 (t, J = 6.9 Hz, 1H, Ar), 7.07 (d, J = 8.3 Hz, 1H, Ar), 6.49 (d, J = 8.4 Hz,
1H, NH), 6.46 (t, J = 6.1 Hz, 1H, Ar), 5.36 (m, 1H, CH), 3.99 (q, J = 7.1 Hz, 2H,
­CH2), 2.84 (dd, J = 15.2 Hz, J = 8.4 Hz, 1H, CHH), 2.73 (dd, J = 15.2 Hz, J = 6.4 Hz,
1H, CHH), 1.06 (t, J = 7.1 Hz, 3H, ­CH3). 13 C NMR (125 MHz, DMSO-d6) δ
(ppm):170.7, 163.0, 158.1, 157.7, 155.9, 130.9, 130.8, 129.7, 126.4, 112.7, 110.0,
108.9, 60.5, 51.1, 41.7, 14.4. Anal. Calcd for ­C16H17BrN2O2 (349.23): C, 55.03; H,
4.91; N, 8.02. Found: C, 55.27; H, 4.93; N, 7.92%.
Conclusions
In summary, we have described a convenient and efficient protocol for the synthesis
of ethyl 2-(3-arylimidazo[1,2-a]pyridin-2-yl)acetates and ethyl 3-aryl-3-(pyridin2-ylamino)propanoates via a three-component reaction of 2-aminopyridine and
Meldrum’s acid with aryl glyoxals or aryl aldehydes, respectively. By comparing
products from the starting materials, it is determined that the use of two different
carbonyl groups under the same reaction conditions has resulted in the formation of
two different product types. Moreover, the protocol has advantages in terms of high
yields, low cost of the starting materials, short reaction time, easy work-up, and mild
reaction conditions.
Acknowledgements We are thankful to the Office of Graduate Studies of Vali-e-Asr University of Rafsanjan for partial support of this work.
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Authors and Affiliations
Sara Asadi1 · Maedeh Zebarjad1 · Hamidreza Masoudi1 · Hossein Mehrabi1
1
Department of Chemistry, Vali-E-Asr University of Rafsanjan, 77176 Rafsanjan, Iran
13