Gluconic acid promoted cascade reactions of 2-phenylimidazo[1,2-a] pyridine-3-carbaldehyde with cyclohexane-1,3-dione to create novel fused bisheterocycles

Article abstract of DOI:10.1080/00397911.2019.1606920

Here in, we described the synthesis of novel bisheterocycles imidazopyridine bearing xanthenedione by reacting various substituted 2-phenylimidazo [1,2-a] pyridine-3-carbaldehyde with cyclohexane-1,3-dione in gluconic acid aqueous solution (GAAS) via a ta

Full text of DOI:10.1080/00397911.2019.1606920

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Gluconic acid promoted cascade reactions of 2-
phenylimidazo[1,2-a] pyridine-3-carbaldehyde
with cyclohexane-1,3-dione to create novel fused
bisheterocycles
Chetananda Patel, Ashima Thakur, Gavin Pereira & Abha Sharma
To cite this article: Chetananda Patel, Ashima Thakur, Gavin Pereira & Abha Sharma (2019):
Gluconic acid promoted cascade reactions of 2-phenylimidazo[1,2-a] pyridine-3-carbaldehyde with
cyclohexane-1,3-dione to create novel fused bisheterocycles, Synthetic Communications, DOI:
10.1080/00397911.2019.1606920
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SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2019.1606920
Gluconic acid promoted cascade reactions of
2
-phenylimidazo[1,2-a] pyridine-3-carbaldehyde with
cyclohexane-1,3-dione to create novel fused
bisheterocycles
Chetananda Patel, Ashima Thakur, Gavin Pereira, and Abha Sharma
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research,
Raebareli, India
ABSTRACT
ARTICLE HISTORY
Here in, we described the synthesis of novel bisheterocycles imidazo-
pyridine bearing xanthenedione by reacting various substituted
Received 14 March 2019
KEYWORDS
2
1
-phenylimidazo [1,2-a] pyridine-3-carbaldehyde with cyclohexane-
,3-dione in gluconic acid aqueous solution (GAAS) via a tandem
Bisheterocyclic; gluconic
acid; imidazopyridine;
reusable; xanthenedione
Knoevenagel followed by Michael, cyclization & tautomerization
sequence. The use of GAAS in organic synthesis offers significant
benefits like cost-effective, simple operation, reusable catalyst and
green method. The reaction completed in 2–12 h to afford white sta-
ble solid compounds with very good yield. The structures of the
1
13
compounds are confirmed by analyzing MS, IR, H NMR and
C
NMR spectra. Further, the structure of compound 3 h was confirmed
by XRD analysis.
GRAPHICAL ABSTRACT
Introduction
Nowadays, there is an increasing demand for the environmentally benevolent method-
ology for the preparation of organic compounds since the use of conventional organic
solvents pose a threat to the environment. In this direction, chemists are focused in
designing and implementing green chemistry methodology by exploiting reactions in
the natural based reagents and solvents that could improve the chemical process
CONTACT Abha Sharma
abha.sharma@niperraebareli.edu.in
Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research, Raebareli, India.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
C. PATEL ET AL.
including reuse of the materials and reduction of generation of the hazardous products.
One such natural based material is bio-based material which replaces the use of conven-
tional organic solvents. These are ethyl lactate, glycerol, 2-methyl-tetrahydrofuran,
d-valerolactone, gluconic acid, carbohydrates-based low melting mixture, deep eutectic
solvents, and ionic liquid have been reported as catalysts, eco-friendly, renewable, sus-
[
1–6]
tainable, and harmless material for the various types of organic transformation.
Interestingly, Gluconic acid aqueous solution (GAAS) has been projected as a green
environmentally friendly substance that can act as catalyst & solvent. It is present in a
natural product such as fruits, rice, dairy products, wine, meat, vinegar and honey and
possessing various advantageous qualities like nonvolatile, biodegradable, low-cost, and
recyclable. Several reports introduced GAAS as a promoting medium for many organic
[
7–10]
transformations.
Bisheterocycles have shown improved pharmacological and many other properties in
[
11]
[12]
[13]
different areas such as chelation ability,
antibacterial,
antifungal,
and antidia-
[
14]
betic activity.
due to their potential applications.
Bisheterocycles synthesis is gaining importance of synthetic community
[
12,15,16]
In this context, xanthenedione and imi-
dazo[1,2-a]pyridine scaffolds are important heterocycles that show many biological
activities. For example, xanthenedione exhibit several biological activities such as anti-
[
13]
[17]
[18,19]
[24]
[20]
[21]
[26]
microbial,
antihypertensive,
and acetylcholinesterase inhibition (AChE).
reported in luminescent sensor, laser technology, cosmetics, pigments, and in fluores-
anti-inflammatory,
anticancer,
antiviral,
antiplasmodial,
[
22]
[23]
[25]
phototoxicity,
antagonist,
leishmanicidal,
antioxidant,
[
27]
Besides these activities, its uses are also
[
28–30]
cent materials.
Xanthene nucleus is also found in the natural product like allan-
[
31–34]
xanthone C, oliganthins, funiculosone, and gaudichaudione.
Cyclohexanedione is
an important part present in various compounds and displaying different biological pro-
files. There are a variety of cyclohexanedione based derivatives reported for a various
[
35]
[36]
activity such as plant growth enhancers,
cidal activity
antimalarial,
HPPD inhibitors with herbi-
[
37–40]
[40]
, e.g. Cycloxydim, clethodim, and butroxydim.
1,3-cyclohexane-
dione is one of the reactants needed for the synthesis of xanthenedione moiety.
Additionally, imidazo[1,2-a]pyridine is the main class of fused heterocycles which
[
41]
represent the key core of various natural products and pharmaceuticals.
Imidazo[1,2-
a] pyridine derivatives exhibit various biological and pharmacological activities such as
anti-inflammatory, anticancer, antiviral, antiosteoporotic, antiparasitic, BACE-1 inhibi-
tors, acetylcholinesterase inhibitors, antihypertensive, antiviral, benzodiazepine and
[
42–45]
gamma-aminobutyric acid receptor agonists.
These types of molecules are also
Imidazopyridine based drugs such as
[
46]
used in psychiatry and autoimmune disorders.
zolpidem, alpidem, olprinone, zolimidine, necopidem, saripidem, GSK812397, and rifax-
[
47–50]
imin are used for the treatment of various types of disease.
Figure 1 represents
some medicinally important molecules of imidazopyridine and xanthenedione based
scaffold Based on such interest in heterocyclic chemistry, our research group is involved
in the development of new synthetic protocols for the creation of novel bioactive het-
[
35,36,51,52]
erocyclic molecules.
Therefore, we planned to synthesize bisheterocyclic imida-
zopyridine fused with xanthenedione moiety (Figure 1; synthetic target) in gluconic acid
aqueous solution (50 wt %, GAAS).

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SYNTHETIC COMMUNICATIONS
3
Figure 1. Biologically active imidazopyridine and xanthenedione based molecules.
Result and discussion
Synthesis of target molecule required a substituted 2-phenylimidazo[1,2-a]pyridine-3-
[
53]
carbaldehyde which was synthesized by the reported procedures in two steps.
Then
the reaction of various substituted 2-phenylimidazo [1,2-a]pyridine-3-carbaldehyde with
various 1,3-cyclohexandione was carried out to obtain novel fused synthetic target. In
order to find the optimized conditions, a model reaction was performed in different sol-
vents including GAAS at various temperatures for the synthesis of the target molecule
(3a) (Table 1). The reaction was monitored by TLC at various intervals of time for 12 h
at room temperature (rt). The reaction was monitored via TLC in 80% ethyl acetate:
hexane as the mobile phase and visualized under UV light at wavelength 254 nm. No
reaction was observed in the case of solvents and gluconic acid at room temperature
(
1
rt) (Table 1: Entries 1 to 7). After this, the reactions were performed at 60, 80, and
ꢀ
ꢀ
00 C in GAAS (Table 1: Entries 8–10). We observed trace product at 100 C on TLC.
ꢀ
Then, we tried a combination of GAAS and EtOH (1 ml each) at rt, 60, 80, and 100 C.
No product was obtained at room temperature (rt), followed by product formation
ꢀ
ꢀ
under 60, 80, and 100 C (Table 1: Entries 11 to 14). At 100 C, 34% yield was obtained
in 12 h (Table 1: Entry 14). After these encouraging results, further we increased the
amount of GAAS from 1 ml to 7 ml and fixed the 1 ml EtOH volume for each reaction.
The yield of the product was found to be increased with an increased amount of GAAS
up to 5 ml and became constant in 6 ml and 7 ml GAAS in 12 h (Table 1: Entries
15–20). We monitored the reaction at various time intervals in reaction conditions
(Table 1: Entry 18) and found that the reaction was completed in 2 h. TLC showed two
spots, one was between dimedone and 2-phenylimidazo [1,2-a]pyridine-3-carbaldehyde
and another spot was above the 2-phenylimidazo [1,2-a]pyridine-3-carbaldehyde. As
reactions proceeded the spot above the 2-phenylimidazo [1,2-a]pyridine-3-carbaldehyde
was disappeared with increase in intensity of spot between the 2-phenylimidazo [1,2-
a]pyridine-3-carbaldehyde and dimedone, Figure 2 of supporting information.
Therefore, the optimum reaction condition was 5 ml GAAS and 1 ml ethanol with 88%

4
C. PATEL ET AL.
a
Table 1. Optimization of reaction conditions .
o
b
Entry
Solvent
Quantity
Temperature ( C)
Time (h)
3a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
a
.
.
.
.
.
.
.
.
No solvent
Water
Ethanol
Methanol
PEG–400
Glycerol
GAAS
GAAS
GAAS
–
1 ml
1 ml
1 ml
1 ml
1 ml
1 ml
1 ml
rt
rt
rt
rt
rt
rt
rt
60
80
100
rt
60
80
100
100
100
100
100
100
100
100
100
100
100
100
100
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12/2
12
12
12
12
12
12
2
–
–
–
–
–
–
–
–
–
.
1 ml
1 ml
0.
1.
2.
3.
4.
5.
6.
7.
8.
9.
0.
1.
2.
3.
4.
5.
6.
GAAS
Trace
–
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ EtOH
GAAS þ Water
GAAS þ MeOH
GAAS þ PEG-400
GAAS þ Glycerol
1 ml each
1 ml each
1 ml each
1 ml each
2 ml þ 1
3 ml þ 1 ml
4 ml þ 1 ml
5 ml þ 1 ml
6 ml þ 1 ml
7 ml þ 1 ml
5 ml þ 1 ml
5 ml þ 1 ml
5 ml þ 1 ml
5 ml þ 1 ml
5 ml þ 1 ml
5 ml þ 1 ml
18
25
34
48
57
79
88/88
88
88
–
45
45
40
82
87
c
GAAS þ EtOH
d
GAAS þ EtOH
2
Reaction condition: 1a (1.0 mmol) and 2a (2.0 mmol).
b
Yield: Isolated yield after silica gel chromatography.
c
Recovered GAAS third run.
d
2
0 mmol scale.
yield in 2 hours. We checked the combination of GAAS with other solvents also. In all
the combinations and reaction conditions, a product was obtained in varying yield in
1
2 h (Table 1: Entries 21–24).
The optimum reaction condition was further investigated for the substrate scope and
the results obtained are summarized in Scheme 1. Various formylated imidazopyridines
bearing electron withdrawing and electron donating groups were reacted with substi-
tuted/unsubstituted cyclohexane-1,3-dione to afford the required products (Scheme 1).
The different functional groups bonded to imidazopyridines were stable in optimum
reaction condition.
The effect of reaction time on the yield of the product was determined by carrying
out a reaction at different intervals of time. The yield of the product was determined at
30, 60, 90, 120, 150, and 180 minutes. It was found that as time increased, the yield of
the desired product increased upto 120 minutes and further the yield didn’t increase at

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SYNTHETIC COMMUNICATIONS
5
Figure 2. ORTEP diagram of 3 h (CCDC 1584692).
1
50 and 180 minutes. Eventually, GAAS can be recovered by concentrating water layer
under reduced pressure using rotary evaporator. The recovered GAAS was further tested
for its catalytic potential for the same reactions. The yield obtained in the recovered
GAAS is given in Table 1. Furthermore, on scaling reactions upto 20 mmol, produced a
product in almost no significant difference in the yield, indicating an effective method-
ology for practical synthesis of target molecules.
The reaction mechanism of product formation as depicted in Scheme 2 involved two
name reactions knoevenagel condensation and Michael addition followed by cyclization
and tautomerization.
All novel compounds (3a–3m) are stable white solids with a 61–88% yield. The
photograph of compound 3 h is given in supporting information. Structures of com-
1
13
pounds were established by spectroscopic techniques (MS, IR, H NMR and C NMR
1
spectra). H-NMR spectrum of 3a compound showed characteristic peaks at 5.03 ppm
for CH proton as a singlet, 0.94–1.03 ppm for CH proton as a singlet and 2.22–2.04 for
3
1
3
CH proton as a multiplet. C-NMR spectrum showed characteristic peaks at 50.7 ppm
2
for xanthenedione carbon linked with imidazopyridine nucleus and 197.2 ppm for car-
ꢁ
1
bonyl carbon. Additionally, the characteristic IR peaks at 1658 and 1624 cm for C¼O
ꢁ
1
stretching for ketone functionality at the xanthenedione nucleus, 1192–1138 cm for
ꢁ
1
C–O stretching for ether at the pyran nucleus, 2952 and 2871 cm for C–H stretching
ꢁ1
of methyl substitutent at the xanthenedione nucleus and 1353 cm for C–N stretching
in the imidazopyridine nucleus were useful for predicting the synthesized compound 3a.
ꢀ
Melting point of the compound 3a was found to be in the range of 214–216 C.
Furthermore, 3 h compound was crystallized by using ethanol under slow evaporation
and characterized it by single crystal X-ray diffraction study. The data showed a triclinic
shape of the 3 h (Figure 2). The crystallography data (provided in the Supporting
Information) indicated that the crystallized compound is C H2 FN O . We observed
27
23
2 3
that the two 6-membered carbon rings in the xanthene-1,8(2H)-dione group fused to

6
C. PATEL ET AL.
Scheme 1. Synthesis of novel fused imidazopyridine bearing xanthenedione.
Scheme 2. Proposed reaction mechanism of imidazopyridine fused xanthenedione synthesis.

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SYNTHETIC COMMUNICATIONS
7
the central pyran group are puckered with slightly distorted envelope conformations
and the central pyran group is puckered in a slightly distorted boat conformation.
Conclusion
Synthesis of novel bisheterocyclic imidazopyridine bearing xanthenedione derivatives
using gluconic acid aqueous solution has been developed via domino reactions. The
reactions are completed within 2–12 h depending on the type of substitution. The proto-
col is green, easy to operate, cost-effective, and furnished product in very good yield.
The mechanism of reaction involves the knoevenagel condensation followed by Michael
addition along with cyclization and tautomerization steps.
General procedure for synthesis of 3a-3m (Scheme 1)
1,3-Cyclohexanedione/5,5-Dimethyl-1,3-cyclohexanedione (0.28 g, 2 mmol) was dissolved
in ethanol:GAAS (1 ml:5ml GAAS). Then, 2-Phenyl–imidazo [1,2-a] pyridine-3-carbal-
dehyde (0.22 g, 1 mmol) was added to the reaction mixture. The reaction mixture was
ꢀ
stirred at 100 C. After completion of the reaction (the progress of the reaction was
monitored by TLC using ethyl acetate:n-hexane as eluent), the reaction mixture was
cooled and then filtered. After filtration, the crude product was washed with hexane
and further purified by column chromatography wherever it was needed.
Spectroscopic data of 3a compound
3
,3,6,6-tetramethyl-9-(2-phenylimidazo[1,2-a]pyridine-3-yl)-3,4,5,6,7,9-hexahydro-1H-
xanthene-1,8 (2H)-dione
ꢀ
ꢁ1
White solid; Yield 90%; mp ¼ 214–216 C; FT-IR (cm ) 2952, 2871, 1658, 1624, 1353,
1
1
192, 1138, H-NMR (CDCl , 400 MHz): d ¼ 8.86 (d, J ¼ 6.8 Hz, 1 H, Ar), 7.56 (d,
3
J ¼ 8.8Hz, 1 H, Ar), 7.35 (s, 5H), 7.22 (t, J ¼ 7.2Hz, 1 H, Ar), 6.96 (t, J ¼ 6.8Hz, 1 H, Ar),
13
5
1
1
4
.03 (s, 1 H, CH), 2.22–2.04 (m, 8H), 1.03 (s, 6H), 0.94 (s,6H); C -NMR (CDCl ,
3
00 MHz): d ¼ 197.2, 162.5, 144.4, 144.0, 136.3, 129.5, 127.9, 127.6, 125.6, 124.6, 123.2,
þ
16.9, 113.4, 111.7, 50.7, 40.8, 31.9, 29.1, 27.9, 22.6; MS-ESI (M þ H) : 467.4 Found
þ
67.4. HRMS(m/z): Calcd for C H N O (M þ H) : 467.2356, found 467.2351
3
0
30 2 3
Acknowledgments
The authors are thankful to Dr. S. J. S. Flora, Director for his support in carrying out this
research work. The authors would like to acknowledge Department of Pharmaceuticals, Ministry
of Chemicals and Fertilizers, Govt. of India for financial support, SAIF, CSIR-CDRI, Lucknow
for the spectral analysis and Indian Institute of Technology, Kanpur for single crystal X-
ray analysis.
Supporting information
1
13
Full experimental detail, ESI-MS; HRMS, H and C NMR spectra of all compounds and XRD
data of 3 h can be found via the “Supplementary Content” section of this article’s webpage.

8
C. PATEL ET AL.
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