Catalyst-free UV365-assisted synthesis of pyran annulated heterocyclic scaffolds and evaluation of their antibacterial activities

Article abstract of DOI:10.1080/00397911.2020.1825741

A convenient and eco-friendly, one-pot synthetic protocol for pharmaceutically important pyran-based heterocyclic compounds is repeated herein. The reactions were carried out at room temperature in a water–ethanol solvent mixture under direct irradiation

Full text of DOI:10.1080/00397911.2020.1825741

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Catalyst-free UV365-assisted synthesis of pyran
annulated heterocyclic scaffolds and evaluation of
their antibacterial activities
Arup Dutta , Noimur Rahman , John Elisa Kumar , Jintu Rabha , Tridip
Phukan & Rishanlang Nongkhlaw
To cite this article: Arup Dutta , Noimur Rahman , John Elisa Kumar , Jintu Rabha , Tridip Phukan
& Rishanlang Nongkhlaw (2020): Catalyst-free UV365-assisted synthesis of pyran annulated
heterocyclic scaffolds and evaluation of their antibacterial activities, Synthetic Communications
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https://doi.org/10.1080/00397911.2020.1825741
Catalyst-free UV365-assisted synthesis of pyran annulated
heterocyclic scaffolds and evaluation of their
antibacterial activities
Arup Duttaa, Noimur Rahmana, John Elisa Kumarb, Jintu Rabhac, Tridip Phukanc,
and Rishanlang Nongkhlawa
b
aDepartment of Chemistry, North-Eastern Hill University, Shillong, Meghalaya, India; Photocatalysis Lab,
c
North-Eastern Hill University, Shillong, Meghalaya, India; Department of Botany, Gauhati University,
Guwahati, Assam, India
ABSTRACT
ARTICLE HISTORY
Received 18 July 2020
A
convenient and eco-friendly, one-pot synthetic protocol for
pharmaceutically important pyran-based heterocyclic compounds is
repeated herein. The reactions were carried out at room temperature
in a water–ethanol solvent mixture under direct irradiation of UV365
light source in the absence of photocatalyst. The merits of the pre-
sent protocol include mild and catalyst-free reactions, green proce-
dures, and high yields. The added advantage of this protocol is that
it can be applied for large-scale synthesis of various pyran-based het-
erocyclic compounds without employing any expensive catalyst.
Also, in vitro antibacterial screening of pyran derivative was investi-
gated against both Gram-positive Bacillus cereus (B. cereus) and
Gram-negative bacteria Escherichia coli (E. coli).
KEYWORDS
Antimicrobial activities;
catalyst-free; Knoevenagel
condensation; pyran-based
heterocycles; UV-365 photo-
irradiation
GRAPHICAL ABSTRACT
Introduction
Sustainable energy resources and environmental protection are the two most pressing
challenges in sustaining our mother earth.[1] The development of sustainable synthetic
protocols is one of the keys toward facing these challenges. It is the perfect aid for
CONTACT Rishanlang Nongkhlaw
rlnongkhlaw@gmail.com
Department of Chemistry, North-Eastern Hill
University, Shillong, Meghalaya, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
A. DUTTA ET AL.
eco-friendly synthesis of heterocyclic compounds as it activates organic molecules by
direct transfer of photons into the reaction substrates, thus facilitating smooth, chemical
transformations.[2] Photocatalytic degradation of natural dyes, industrial effluents, and
complex organic molecules using UV365 and UV254 has been reported by many research
groups.[3–10] UV365 lies in the region close to visible light in the electromagnetic spec-
trum, which is environmentally benign and does not pose any detrimental effects on
human health. As compared to other sources, UV365 is a more powerful catalytic substi-
tute because most of the organic compounds fail to absorb light in the visible region of
the electromagnetic spectrum.[11] Furthermore, when visible light is exploited, it
demands designing complicated strategies that should allow efficient energy transfer
from visible light to the concerned organic systems with or without the use of photo-
sensitizers/photocatalysts.[12,13] This reaction protocol is based on the photoredox acti-
vation phenomena, which involve energy transfer directly to the concerned organic
molecules through their photoexcited states.[14–18] However, these complex photocata-
lysts are expensive and, therefore, research on developing synthetic protocol using
photo-irradiation in the absence of photocatalyst becomes a topic of interest.
Photocatalysis is considered as one of the best possible means which can provide a
green and effective strategy for solving both environmental pollution problems and
alternative clean energy supply.[19,20] Some of the notable features of photocatalysis are
(i) eco-friendly, (ii) high efficiency, (iii) low cost, (iv) chemical inertness, (v) high redox
ability, etc. The use of UV365 under catalyst-free conditions in carrying out organic
transformations bridges the gap between high energy UV295 and photocatalyst depend-
ent visible light reactions.
Recently, our group utilized UV365 in the synthesis of pyrimido[4,5-b]quinoline-2,4-
diones in aqueous-glycerol medium.[21] Based on the prospect of carrying out organic
transformations using UV365 irradiation under catalyst-free condition, we envisioned
synthetic routes for various heterocyclic compounds containing pyran as the
core moiety.
Pyran-based heterocyclic compounds have received considerable attention due to the
wide spectrum of pharmacological activities such as antitumor agent,[22] cytotoxic
agent,[23,24] lactamase inhibitor,[25] anti-cancer,[26] etc. (Fig. 1). They are also found as
structural units of many natural products and photochromic materials.[27–29] Pyrazole is
another indispensable heterocyclic analog which plays a key role in the fields of
pharmaceutical and agrochemical industries.[30,31] Similarly, spirooxindoles are also cru-
cial structural moiety that are found in many synthetic derivatives with significant bio-
logical and pharmacological activities.[32] Literature survey reveals that significant efforts
have been made to synthesize polycyclic heterocycles by combining various structurally
diverse motifs.[33,34] Various protocols have been reported for the multicomponent syn-
thesis of these compounds using a variety of catalysts such as Et3N,[35] CeCl3ꢀ7H2O,[36]
NaF,[37] Cl3CCOOH,[38] pentafluoropropionic acid (PFPA),[39] (NH4)2HPO4,[40]
Na2SeO4,[41] SiO2@Pr@SO3H,[42] MMT-ZSA,[43] Bleaching earth clay[44] including nano
catalysts like Fe2O3@SiO2@VB1 NPs,[45] ZnS NPs,[46] PANI@Fe3O4@CNT,[47] etc.
Despite these advances, the aforesaid methods have limitations such as high energy con-
sumption, longer reaction time, low yields, use of toxic chemicals and tedious procedure
for catalyst preparation. Thus, the development of a convenient and practical method

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3
O
Cl
OH
HO
O
O
HO
H
HN
HO
NH2
HN
CN
O
L
a
NH
c
t
a
m
F3C
Cytotoxic agent24
O
a
s
e
i
n
NH2
h
i
b
i
t
o
r 25
O
H
O
O
H
N
O
O
Pyran
NH2
O
CN
A
n
t
i
-
c
O
2
a
2
n
O
O
c
e
t
r
n
a
e
g
O
g
a
r
e
2
N
n
6
t
o
m
u
t
i
t
n
A
HN
CN
NH2
Cytotoxic agent23
Figure 1. Some important medicinal agents with pyran based heterocycles.
Figure 2. Longitudinal section of multi-lamp photoreactor depicting the arrangement of 254 and
365 nm UV lamps (blue and red color represent either 254 or 365nm UV lamps; numbers 1–4 repre-
sent the position of sample tubes).
with high generality for the synthesis of these compounds remains challenging. Lately,
the application of photo-irradiation for different organic transformations have generated
a wide interest amongst the synthetic community due to the various advantages it offers
(Fig. 2).[48,49]

4
A. DUTTA ET AL.
Results and discussion
In continuation with our ongoing research on the application of UV365 in triggering
eco-friendly multicomponent reactions, we report herein a synthetic protocol toward
various pyran-based heterocyclic compounds by irradiating a mixture of C ꢁ H activated
cyclic ketones (pyrazolone/1,3-diketone), aromatic aldehydes/isatins and malononitrile
with ultraviolet light (i.e. UV365) in water–ethanol (1:1) medium. To optimize the reac-
tion conditions, a model reaction was chosen using benzaldehyde, malononitrile, and
dimedone to synthesize 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile 6a (Scheme 1). Initially, water was used as the medium, but it
gave a low yield of the product. To find out the best medium for the model reaction,
different media namely, glycerol, ethanol, glycerol–water have been employed, where it
was found that water–ethanol (1:1) combination exhibited good results (up to 97%
yield). The photocatalytic conversion required eight lamps of UV365 for this solvent sys-
tem (Table 1). The model reaction 6a was also carried out under different conditions
such as room temperature, reflux, and microwave heating (Table 1).
The one-pot multicomponent reaction of aryl aldehydes, 1,3-diketone and malononi-
trile often leads to the formation of undesired intermediates. To avoid the formation of
this intermediate, firstly, benzaldehyde/isatin and malononitrile were dispersed in the
water–ethanol medium under continuous photo-irradiation for 15 min followed by the
slow addition of pyrazolone/1,3-diketone and further irradiated for 30–45 minutes. In
order to avoid any residual starting components, the whole process was carried out
under continuous bubbling (air) conditions. The progress of the reaction was monitored
from the color change in the reaction and the appearance of the precipitate. The prod-
uct formed was separated from the reaction mixture by filtration and washed with
hot ethanol.
The model reaction for the synthesis of 6a was explored with all the possible lamp
combinations, and the solvent system was also varied in order to estimate the efficiency
of the synthetic protocol (Table 2). When the model reaction was studied in an aqueous
medium with 8 UV365 lamps, yield (69%) of the product was obtained. However, the
water-ethanol system provided yield (97%) of the product was obtained (Table 2, entry
10). It was also found that in the case of a water-mediated system, the optimum num-
ber of lamps was 12, thus, guiding us to use the water-ethanol system as the reac-
tion medium.
The multi-lamp photoreactor possesses 12 (twelve) UV365 lamps, and there can be a
possibility for several combinations for the lamps, i.e. 2, 4, 6, 8, and 12. The intensity of
each of the lamp combinations was also recorded, and the details are presented in
Table 2.
To explore the scope of the present synthetic approach, we investigated the reaction
of substituted aromatic aldehydes, malononitrile and pyrazolone/1,3-diketone under the
optimized conditions and obtained the desired products in good to excellent yields
(Table 3). A slight decrease in product yield was observed in benzaldehydes containing
electron-donating substituents compared to those with electron-withdrawing substitu-
ents. Aliphatic aldehydes did not produce appreciable yields and hence are not reported.
Also, isatin and substituted isatins were used in place of aromatic aldehydes, which also
gave excellent product yields (Table 3).

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5
(A)
(B)
Scheme 1. Synthesis of pyran based heterocyclic scaffolds.

6
A. DUTTA ET AL.
Table 1. Optimization for the synthesis of 6a.
Entry
Solvent
Condition
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Water
Glycerol
Water-Glycerol
Water-Glycerol
Water-Ethanol
Water-Ethanol
Ethanol
RT
RT
RT
10
10
10
2
2
5
5
1
1
1
0
0
0
Microwave
Microwave
Reflux
Reflux
Trace
45
40
57
69
41
92
62
97
Water
Glycerol
Ethanol
UV365 irradiation (8 lamps)
UV365 irradiation (8 lamps)
UV365 irradiation (8 lamps)
UV365 irradiation (8 lamps)
UV365 irradiation (8 lamps)
9
10
11
12
Water-Glycerol
Water-Ethanol
1
1
RT: room temperature.
aIsolated yield.
Table 2. Optimization of UV365 intensity by varying the number of lamps for the synthesis of 6a
under different solvents.
Intensity corresponding
Entry
Solvent
Number of UV365 lamps
to the lamps (lW cmꢁ2
)
Yielda (%)
1
2
3
4
5
6
7
8
9
Water
Water–ethanol
Water
Water–ethanol
Water
2
2
4
4
6
6
8
8
12
12
1260
1260
1803
1803
3840
3840
4590
4590
6940
6940
0
0
Trace
35
40
57
69
97
79
97
Water–ethanol
Water
Water–ethanol
Water
10
Water–ethanol
aIsolated yield of the product.
The proposed reaction mechanism for the synthesis of 6a is based on a free radical
pathway (Scheme 2). Initially, intermediate (A) was formed via tautomerization of
malononitrile upon irradiation with UV365. Intermediate (A) and benzaldehyde under-
went Knoevenagel condensation to give a cyanoolefin intermediate (B) with the elimin-
ation of water. Then, UV365 activated this intermediate (B) to form a free radical
intermediate (C), which then reacts with the activated 1,3-diketone radical (D) to give
the intermediate (E). Thereafter, intramolecular cyclization of (E) leads to the desired
product (6a).
Evaluation of antibacterial activities
Literature survey reveals that compounds encompassing a pyran moiety are known to
exhibit a wide spectrum of antimicrobial activities.[50,51] Some of the pyran
derivatives bearing 2-morpholinoquinoline nucleus[52] have been found to show
excellent antimicrobial activity against C. albicans, C. tetani and B. subtilis.
Dihydropyrano(c)chromene and pyrano[2,3-d]pyrimidine,[53] pyrano[2,3-c]pyrazoles,[54]
pyrano [4,3-b]pyrane,[55] 2-amino-4H-pyrans and 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-
chromenes,[56] 2-(indol-3-yl)-2-oxo spiro(indoline-3,4-pyran),[57] spiro [indole-

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7
Table 3. Synthesis of pyran based heterocyclic scaffolds under UV365 irradiation.
S. no.
1
Aldehyde/Isatin
C6H5CHO
Pyrazolone/1,3-dicarbonyl compound
3-Methyl-1H-pyrazol-5(4H)-one
Product
Time (min)
60
Yieldsa (%)
98
4a
2
3
4
4-Br C6H4CHO
4-Cl C6H4CHO
4-OH C6H4CHO
3-methyl-1H-pyrazol-5(4H)-one
3-METHYL-1H-pyrazol-5(4H)-one
3-Methyl-1H-pyrazol-5(4H)-one
45
45
60
93
94
92
4b
4b
4c
4c
4d
5
6
C6H5CHO
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
60
60
97
93
5a
4-OH C6H4CHO
5b
7
8
4-Cl C6H4CHO
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
45
45
93
97
5c
4-NO2ꢀC6H4CHO
5d
(continued)

8
A. DUTTA ET AL.
Table 3. Continued.
S. no.
9
Aldehyde/Isatin
4-OMe C6H4CHO
Pyrazolone/1,3-dicarbonyl compound
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
Product
Time (min)
60
Yieldsa (%)
96
5e
10
11
3-NO2 C6H4CHO
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
45
45
96
91
5f
5f
3-Cl C6H4CHO
5g
6a
12
13
14
C6H5CHO
Dimedone
Dimedone
Dimedone
60
45
60
97
92
95
4-Cl C6H4CHO
6b
6b
4-CH3 C6H4CHO
6c
6c
15
16
4-Br C6H4CHO
Dimedone
Dimedone
45
60
90
96
6d
6d
4-NO2 C6H4CHO
6e
6e
17
C6H5CHO
Cyclohexane-1,3-dione
60
95
7a
7a
(continued)

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9
Table 3. Continued.
S. no.
18
Aldehyde/Isatin
4-NO2 C6H4CHO
Pyrazolone/1,3-dicarbonyl compound
Cyclohexane-1,3-dione
Product
Time (min)
60
Yieldsa (%)
93
7b
7b
19
20
4-Br C6H4CHO
Cyclohexane-1,3-dione
45
60
89
98
7c
7c
C8H5NO2
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
8a
8a
21
22
5-NO2C8H4NO2
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one
3-Methyl-1H-pyrazol-5(4H)-one
60
45
94
93
8b
8b
5-ClC8H4NO2
8c
8c
aIsolated yield.
thiazolidine] spiro [indole-pyrans][51] derivatives have also been reported to show good
antibacterial activity against different microbial strains.
A series of pyran derivatives exhibited promising antibacterial activity as compared to
the standard toward Gram-positive bacterial strains.[56,58] Stimulated by the above
review, we also tried to explore the antimicrobial activity of the synthesized compounds.
The synthesized compounds were investigated for their antimicrobial activity, by the
agar cup diffusion method, against three bacterial pathogens, namely Bacillus cereus
Ehrenberg
&
Cohn (MTCC 736), Escherichia coli (MTCC 443) and
Klebsiellapneumoniae Friedlander (MTCC 3384).[59] The bacterial test isolates were
obtained from the Microbial Type Culture Collection (MTCC).
In vitro studies have demonstrated that some of the pyran derivatives exhibited anti-
bacterial activity against Gram-positive (B. cereus) and Gram-negative (E. coli) bacteria.
Among the tested derivatives, the best result was exhibited by 4c and 4d against B. cer-
eus with 12 mm zone of inhibition each which is comparable to the standard broad
spectrum polyketide antibiotic, tetracycline. The compound 5f showed a 6 mm zone of

10
A. DUTTA ET AL.
Scheme 2. Proposed mechanism for the UV365 mediated synthesis of 6a via a free radical pathway.
inhibition against B. cereus. 5b was the only compound which exhibited activity against
both B. cereus and E. coli and with 5 mm zone of inhibition in both cases. Growth
inhibition activity against K. pneumonia was not obtained for any of the tested com-
pounds. The summary of the antibacterial activity is presented in Table 4.
Morphological changes of the B. cereus at different concentration were analyzed by
SEM and are shown in Figure 3, indicated that bacterial cells from the control group
were intact, smooth, and uniform without noticeable damage (A & B). In contrast, B.
cereus cells treated with 3 mg/ml concentration of 4d and 5f compounds were observed
to be damaged, as evidenced by deep craters and burst cells (Figure 3C,D), including
debris of cells and dead cell (Fig. 3E,F). Furthermore, the number of burst cells
increased with increasing concentrations of the compounds.
Experimental
Chemicals and instrumentation
All the chemicals and solvents were purchased from Alfa Aesar (Ward Hill, MA), Sigma
Aldrich (St. Louis, MO), and Merck (Kenilworth, NJ) and were used without any fur-
ther purification. Melting points were recorded in open capillary tubes and are

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11
Table 4. Antimicrobial activity of synthesized compounds at 3 mg/ml by the agar cup diffu-
sion method.
Diameter of inhibition zone (mm)a
Compound
B. cereus (Gram-positive bacteria) (MTCC 736)
E. coli (Gram-negative bacteria) (MTCC 443)
4c
4d
5a
12 mm ( 0.094)
12 mm ( 0.094)
–
–
–
4 mm ( 0.094)
5b
5f
5 mm ( 0.081)
6 mm ( 0.141)
–
5 mm ( 0.081)
–
–
DMSO
Tetracycline
14 mm ( 0.094)
6 mm ( 0.141)
aValues are mean with standard deviation (in parenthesis)
"–" ¼ No activity has shown.
Figure 3. SEM images showing the effect of antibacterial activity of pyran derivatives against B. cer-
eus, (A) and (B) showed controlled condition; (C) and (D) showed deep craters and burst cells dam-
aged part, after treatment with the compound 4d and 5f; (E) and (F) showed debris of cells and cell
damaged part, after treatment with compound 4d and 5f, respectively.

12
A. DUTTA ET AL.
uncorrected. Infrared spectra were recorded in KBr pellets over the region
400–4000 cmꢁ1 on a Perkin Elmer Spectrum 400 FT-IR instrument (PerkinElmer,
Waltham, MA). Mass spectral data were obtained with a Waters ZQ-4000 (ESI) mass
1
spectrometer. H NMR and 13C NMR were recorded on a Bruker Avance II-400 spec-
trometer in DMSO-D6 solvent, and the chemical shifts are expressed in ppm units (d
scale). SEM images were carried out with a scanning electron microscope of JSM-6360
(JEOL, Tokyo, Japan) make. The UV365 light irradiation was conducted in a UV photo-
reactor fitted with twelve lamps (8 W each) of Herber Scientific (Riverside, CA) make;
model HML, Compact-LP-MP-812.
General procedure for preparation of pyran derivatives
In a 100 mL borosilicate tube, a mixture of aromatic aldehyde/isatin (5 mmol) and malo-
nonitrile (10 mmol) was mixed in 30 mL of water:ethanol (1:1) and irradiated under
eight lamps of UV365 light source for 15 min under continuous air-bubbling condition.
Then pyrazolone/1,3-cyclic diketone (5 mmol) was charged into the reaction mixture
and further irradiated for another 30–45 min under the same reaction condition. Upon
completion of the reaction (indicated by the appearance of thick precipitate), the prod-
uct was collected by simple filtration and washed with hot ethanol.
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile: 6a
White solid (yield: 97%), mp: 226–227 ꢂC [Lit.[35] 226–228 ꢂC]. IR (KBr): ꢀ 3396, 3323,
1
3211, 3029, 2961, 2202, 1681, 1601, 1248 cmꢁ1. H NMR (DMSO-d6, 400 MHz): d 7.28
(t, 2H, J ¼ 7.2 Hz), 7.19–7.12 (m, 3H), 7.02 (s, 2H), 4.15 (s, 1H), 2.56–2.46 (m, 2H), 2.25
(d, 1H, J ¼ 16 Hz), 2.09 (d, 1H, J ¼ 16 Hz), 1.03 (s, 3H), 0.94 (s, 3H) ppm; 13C NMR
(DMSO-d6, 100 MHz): d 195.7, 162.5, 158.5, 144.7, 128.3, 127.2, 126.6, 119.8, 112.7,
58.3, 50.0, 35.6, 31.8, 28.4, 26.8 ppm. Cal. ESI-MS: m/z 294, Found ESI-MS: m/z
295 [M þ 1]þ.
Conclusions
In summary, we have successfully developed an efficient and environmentally benign
UV365 light-induced synthesis of a variety of pyran-based heterocyclic scaffolds in water:
ethanol medium. This catalyst-free synthetic method offers a simple and sustainable
technique employing water–ethanol as a reaction medium. The noteworthy feature of
this protocol lies in its ease of operation under mild and simple reaction conditions.
This novel methodology meets all the requirements of green chemistry and opens up
doors for the synthesis of the wide number of heterocyclic scaffolds in the future. In
vitro studies of the prepared pyran derivatives showed antimicrobial activity. The obser-
vation can further be explored to examine biological activities in the near future.
Full experimental detail can be found via the “Supplementary Content” section of
this article.

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13
Acknowledgments
The authors would like to acknowledge Dr. M. K. Sahoo for allowing the use of the UV photo-
reactor. SAIF-NEHU, Department of Chemistry-NEHU, and CDRI Lucknow are highly acknowl-
edged for providing various analytical assistance. The support from Prof. Dhruva Kumar Jha
(Gauhati University) is gratefully acknowledged.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The authors would like to thank DST for financial support (sanctioned no.: EEQ/2016/000646).
DST-SERB.
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