Facile synthesis and docking studies of 7-hydroxyflavanone isoxazoles and acrylates as potential anti-microbial agents

Article abstract of DOI:10.1007/s00044-019-02476-5

The present study is aimed to synthesize the novel 7-hydroxyflavanone derived compounds and to assess their biological activity. Two series of compounds such as 2-phenyl-7-((3-phenylisoxazol-5-yl)methoxy)chroman-4-ones (6a–h) and 4-oxo-2-phenylchroman-7-yl acrylates (8a–k) were synthesized from 7-hydroxyflavanone. All the compounds were subjected to anti-microbial activity and molecular docking studies. The results showed that the compounds 6e, 6g–h, 8h–i and 8k were exhibited most potent anti-microbial activity when compared with the standard drugs. Further, the docking studies revealed that the compounds 6a and 8h have the highest binding affinity score of sterol 14-α demethylase and DNA gyrase B respectively. This is the first report assigning unique synthesis of 7-hydroxyflavanone derivatives and their anti-microbial activity proved with in silico studies. Furthermore, the present study is useful for constructive research to synthesize novel compounds along with their biological activity. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00044-019-02476-5

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02476-5
ORIGINAL RESEARCH
Facile synthesis and docking studies of 7-hydroxyflavanone
isoxazoles and acrylates as potential anti-microbial agents
P. Asha Bhanu1 B. China Raju Y. Jayavardhana Rao G. Narasimha B. Kesava Rao1
2 ●
3 ●
3 ●
●
Received: 22 August 2019 / Accepted: 8 November 2019
©
Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
The present study is aimed to synthesize the novel 7-hydroxyflavanone derived compounds and to assess their biological
activity. Two series of compounds such as 2-phenyl-7-((3-phenylisoxazol-5-yl)methoxy)chroman-4-ones (6a–h) and 4-oxo-
2
-phenylchroman-7-yl acrylates (8a–k) were synthesized from 7-hydroxyflavanone. All the compounds were subjected to
anti-microbial activity and molecular docking studies. The results showed that the compounds 6e, 6g–h, 8h–i and 8k were
exhibited most potent anti-microbial activity when compared with the standard drugs. Further, the docking studies revealed
that the compounds 6a and 8h have the highest binding affinity score of sterol 14-α demethylase and DNA gyrase B
respectively. This is the first report assigning unique synthesis of 7-hydroxyflavanone derivatives and their anti-microbial
activity proved with in silico studies. Furthermore, the present study is useful for constructive research to synthesize novel
compounds along with their biological activity.
Graphical Abstract
Series of 7-hydroxyflavanone based novel isoxazoles 6a–h and acrylates 8a–k were synthesized. Isoxazole compounds 6e,
6
g–h and acrylates 8h–i and 8k were identified as most potent anti-microbial agents.
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-019-02476-5) contains supplementary
material, which is available to authorized users.
2
3
*
B. Kesava Rao
krbhattiprolu@gmail.com
Department of Organic Synthesis & Process Chemistry, CSIR-
Indian Institute of Chemical Technology, Hyderbad, Telangana
5
00007, India
1
Department of Chemistry, University College of Sciences,
Acharya Nagarjuna University, Nagarjunanagar, Guntur Dt.,
Andhra Pradesh 522510, India
Department of Virology, Sri Venkateswara University,
Tirupathi, Andhra Pradesh 517502, India

Medicinal Chemistry Research
●
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●
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Keyword 7-Hydroxyflavanone Isoxazoles Acrylates Anti-microbial activity DNA gyrase
Introduction
hydroxyflavanone, there is an opportunity to prepare useful
heterocyclic compounds by chemical modification. The
present manuscript describes the preparation of 2-phenyl-7-
((3-phenylisoxazol-5-yl)methoxy)chroman-4-ones (6a–h) and
4-oxo-2-phenylchroman-7-yl cinnamates (8a–k) starting
from 7-hydroxyflavanone. The prepared compounds were
screened for their anti-microbial activity and explained the
structure activity relationships (SARs). Further, the com-
pounds were studied for their molecular modelling using
DNA gyrase B and sterol-14α-demethylase.
Flavanones (Harborne and Williams 1995) are important
natural products owing to their interesting pharmacological
properties such as antioxidant (Pietta 2000), anti-microbial
(
2
(
1
Wächter et al. 1999), anti-inflammatory (Njamen et al.
004, Domínguez-Villegas et al. 2013), antihypertensive
Oh et al. 2016, Chanet et al. 2012), antitumor (Bracke et al.
999) and antiviral (Paredes et al. 2003). The preparations
of flavanones have been achieved by synthetic approaches
or enzymatic modification of chalcones (Jurd 1962). 7-
Hydroxyflavanone is the major component isolated from
various plants and Syzygium samarangense is one of the
important medicinal plants to produce this compound in
major quantity. The literature reports have been dealt that 7-
hydroxyflavanone has been used for the preparation of few
heterocyclic compounds such as 4-triazolylflavans
Results and discussion
Chemistry
To achieve these objectives, the target compounds 2-phe-
nyl-7-((3-phenylisoxazol-5-yl)methoxy)chroman-4-ones
(6a–h) and 4-oxo-2-phenylchroman-7-yl acrylates (8a–k)
have been prepared starting from 7-hydroxyflavanone (5,
Schemes 1–3). Initially, we have prepared the oxime deri-
vatives (2a-h) by the condensation of benzaldehydes (1a–h)
with hydroxylamine hydrochloride in presence of sodium
bicarbonate in methanol at room temperature. The inter-
molecular cycloaddition reaction of 2a–h with propargyl
bromide (3) with N-chlorosuccinimide in the presence of
base (Liu et al. 2009) provided the compounds 5-(bromo-
methyl)-3-phenylisoxazoles (4a–h, Scheme 1).
(
Yahiaoui et al. 2004), tricyclic fused pyridines (Zheng
et al. 2016) and 4-imadazolylflavans (Pouget et al. 2002).
There is an opportunity to prepare novel heterocyclic
compounds by using this important natural compound.
Isoxazole (Pinho e Melo 2005) has two heteroatoms such
as oxygen and nitrogen at the adjacent position and C–C
and C–N double bonds are responsible for displaying the
biological properties (Zhu et al. 2018) which includes anti-
microbial (Kang et al. 2000), anticancer (Bargiotti et al.
2
012), antiviral (Lee and Kim 2002), anti-TB (Mao et al.
2
009) and anti-inflammatory (Pedada et al. 2016). Simi-
larly, cinnamates (α-β unsaturated esters) (Clifford 2000)
are natural products and important organic compounds
belongs to the family of phenyl propanoids. Ferulic acid,
Cumaric acid, Caffeic acid and Sinapic acid are natural
products and bioactive compounds, which are precursors of
the cinnamates. Further, cinnamates are important industrial
products used as graphics, lubricants and perfumes (Shu and
Hongjun 2012). Moreover, cinnamates have been explored
as potential anxiolytic compounds, which act as GABA
transaminase inhibitors (Awad et al. 2009). Several acryl
cinnamates have been used as intermediates for the synth-
esis of flavanones (Moghaddam and Abdi-Oskoui 1999),
chromones (Pinto et al. 1999), dihydrocoumarins (Aoki
et al. 2005), benzofuranones (Shankaran et al. 1985) and
pyrazoles (Li et al. 2005).
Thus obtained 5-(bromomethyl)-3-phenylisoxazole (4a)
was reacted with 7-hydroxyflavanone (5) in the presence of
potassium carbonate in acetonitrile at room temperature.
This provided the target compound 2-phenyl-7-((3-pheny-
lisoxazol-5-yl)methoxy)chroman-4-one (6a). The result has
encouraged us to prepare series of target compounds 6b–h,
which were prepared by the reaction of 5-(bromomethyl)-3-
phenylisoxazoles (4b–h) with 5 under our optimized con-
ditions (Scheme 2). The compounds 5-(bromomethyl)-3-
phenylisoxazoles 4a–c and 4h are known compounds and
compared with the literature data and unknown compounds
4d–g were well characterized by spectral data and incor-
porated in the supporting information. All the target com-
pounds 6a–h were unknown and well characterized by
spectral data.
As part of our ongoing research work on isolation of
natural products (Kesava et al. 1983, 1984, Rao et al.
Due to the medicinal importance of acrylates, the present
research work also has been designed to prepare 4-oxo-2-
phenylchroman-7-yl cinnamates (Scheme 3). Accordingly,
7-hydroxflavanone (5) was reacted with series of cinnamic
acids (7a–k) in the presence of DCC and DMAP at room
temperature. All these reactions were preceded smoothly
1
984, 1986, Hanumaiah et al. 1985), we have isolated 7-
hydroxyflavanone, Ellagic acid and Gallic acid as major
compounds from important medicinal plant Syzygium
samarangense. Owing to the importance of 7-

Medicinal Chemistry Research
Scheme 1 Preparation of 5-
(
bromomethyl)-3-
phenylisoxazoles (4a–h)
Scheme 2 Preparation of 2-
phenyl-7-((3-phenylisoxazol-5-
yl) methoxy) chroman-4-ones
(
6a–h)
Scheme 3 Preparation of 4-oxo-
-phenylchroman-7-yl acrylates
8a–k)
2
(
and provided the corresponding target acrylate compounds
8a–k). All these compounds are unknown and well char-
acterized by spectral data.
positive organisms i.e. Staphylococcus aureus, Bacillus
subtilis and 2 Gram negative organisms Escherichia coli,
Pseudomonas aeruginosa by using standard Agar well plate
method and the zone of inhibition (ZOI in millimetres)
values along with the standard drug Streptomycin are
shown in Table 1.
(
Biological evaluation
Thus prepared compounds 2-phenyl-7-((3-phenylisoxazol-
The in vitro results of isoxazoles revealed that the
compounds 6a, 6b–d and 6f shown moderate anti-
bacterial activity against representative bacterial strains.
The compound 6e exhibited equipotent activity against B
subtilis and E coli (ZOI 12.33 and 12.16) and most potent
activity against P aeruginosa (ZOI 16.82). The com-
pounds 6g–h exhibited equipotent activity against S
aureus, B subtilis and E coli (ZOI 6g 13.50, 12.80, 12.30;
6h 13.66, 12.83, 12.53, respectively) and most potent
against P aeruginosa (ZOI 6g 17.80; 6h 17.60,
5
-yl)methoxy)chroman-4-ones (6a–h) and 4-oxo-2-phenyl-
chroman-7-yl cinnamates (8a–k) were subjected to anti-
microbial activity. Further, the molecular modelling studies
were also performed.
Anti-bacterial activity
The target compounds 6a–h and 8a–k were evaluated for
their in vitro anti-bacterial activity against two Gram

Medicinal Chemistry Research
Table 1 Anti-bacterial activity
of compounds 6a–h and 8a–k
Compound
Zone of inhibition (in millimetres)
Gram positive bacteria
Gram negative bacteria
Staphylococcus aureus Bacillus subtilis Escherichia coli Pseudomonas aeruginosa
6
6
6
6
6
6
6
6
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
10.63 ± 0.24
10.05 ± 0.02
09.73 ± 0.20
11.33 ± 0.24
12.26 ± 0.20
11.73 ± 0.20
13.50 ± 0.24
13.66 ± 0.24
09.70 ± 0.25
11.20 ± 0.20
10.70 ± 0.30
10.53 ± 0.25
12.10 ± 0.20
11.86 ± 0.15
11.33 ± 0.30
12.26 ± 0.25
12.03 ± 0.35
11.86 ± 0.15
13.43 ± 0.40
10.46 ± 0.04
10.86 ± 0.12
11.30 ± 0.24
11.76 ± 0.20
12.33 ± 0.28
12.03 ± 0.33
12.80 ± 0.21
12.83 ± 0.28
10.26 ± 0.25
11.30 ± 0.30
11.20 ± 0.20
10.76 ± 0.25
12.26 ± 0.25
12.00 ± 0.20
11.86 ± 0.15
13.03 ± 0.15
12.73 ± 0.25
12.50 ± 0.26
13.23 ± 0.25
13.23 ± 0.25
10.63 ± 0.24
10.60 ± 0.12
11.06 ± 0.16
11.30 ± 0.24
12.16 ± 0.12
11.63 ± 0.28
12.30 ± 0.24
12.53 ± 0.20
09.73 ± 0.30
10.76 ± 0.25
10.56 ± 0.25
10.10 ± 0.36
11.26 ± 0.25
11.06 ± 0.20
11.00 ± 0.20
12.03 ± 0.25
11.86 ± 0.15
11.30 ± 0.30
12.26 ± 0.25
12.76 ± 0.25
09.55 ± 0.55
11.26 ± 0.20
11.43 ± 0.32
11.70 ± 0.32
16.82 ± 0.23
12.33 ± 0.28
17.80 ± 0.24
17.60 ± 0.32
10.26 ± 0.20
12.26 ± 0.25
12.03 ± 0.15
11.36 ± 0.40
13.76 ± 0.25
13.56 ± 0.20
13.20 ± 0.20
18.02 ± 0.02
17.26 ± 0.25
14.43 ± 0.40
18.56 ± 0.30
16.76 ± 0.25
g
h
a
b
c
d
e
f
g
h
i
j
k
Streptomycin 14.26 ± 0.25
respectively) in comparison with the standard drug
Streptomycin (ZOI 16.76).
The anti-bacterial activity of acrylate compounds 8a–k
and their ZOI values presented in Table 1. The compounds
Table 2 Anti-fungal activity of compounds 6a–h and 8a–k
Compound Zone of inhibition in millimetres
Aspergillus niger
Aspergillus fumigates
8
a–j were shown considerable anti-bacterial inhibitory
6
6
6
6
6
a
b
c
10.70 ± 0.20
11.46 ± 0.15
11.90 ± 0.20
12.30 ± 0.30
13.53 ± 0.25
12.80 ± 0.20
14.10 ± 0.20
14.26 ± 0.25
10.76 ± 0.25
11.76 ± 0.25
11.46 ± 0.15
11.06 ± 0.20
12.86 ± 0.15
12.50 ± 0.20
11.93 ± 0.40
13.76 ± 0.25
13.53 ± 0.25
13.26 ± 0.25
14.26 ± 0.25
14.53 ± 0.25
10.83 ± 0.15
11.06 ± 0.20
11.30 ± 0.30
11.13 ± 0.75
12.50 ± 0.20
12.16 ± 0.25
13.97 ± 0.06
14.05 ± 0.02
10.26 ± 0.25
10.26 ± 0.25
10.86 ± 0.15
10.56 ± 0.20
11.86 ± 0.15
11.53 ± 0.25
11.26 ± 0.25
14.26 ± 0.25
12.50 ± 0.20
12.20 ± 0.20
14.56 ± 0.30
13.7 ± 0.20
activity against tested strains. The compound 8k shows
moderate activity against S aureus, B subtilis and E coli
(
ZOI 13.43, 13.23 and 12.26, respectively) and shown
d
e
potent activity against B subtilis (ZOI 18.02). The com-
pounds 8h–i (ZOI 18.02, 17.26) and 8k (ZOI 18.56) show
potential anti-bacterial activity against P. aeruginosa when
compared with standard antibiotic (ZOI 16.76).
6f
6g
6
h
Anti-fungal activity
8a
8
b
The anti-fungal activity of compounds 6a–h and 8a–k were
studied with Agar well plate method using two repre-
sentative fungal species such as Aspergillus niger (ATCC
8c
8d
8
8
8
8
8
8
8
e
f
1
015) and Aspergillus fumigates (ATCC 1022) and
Cycloheximide was used as standard drug. The zones of
inhibition (ZOI in millimetres) values were showed in Table 2.
The compounds 6e shown moderate activity against Asper-
gillus niger (ZOI 13.53). The compounds 6g–h have shown
equipotent activity against tested strains (ZOI 6g 14.10, 13.97;
g
h
i
j
k
6h 14.26, 14.05, respectively) in comparison with standard
Cycloheximide
compound Cycloheximide (ZOI 14.53).

Medicinal Chemistry Research
Table 3 Binding affinity scores of 6a–h and 8a–k
Compound Binding affinity scores
The compounds 8h–j were showed moderate activity
against Aspergillus niger (ZOI 13.76, 13.53, 13.26). Inter-
estingly, compound 8h showed most potent activity against
Aspergillus fumigates (ZOI 14.26) and compounds 8k (ZOI
DNA gyrase B
PDB ID 6QTP)
Sterol 14-α demethylase
(PDB ID: 5TZ1)
(
1
4.26, 14.56) identified as most potent anti-fungal com-
6
6
6
a
b
c
−8.1
−8.6
−8.9
−7.8
−7.9
−7.4
−8.4
−8.3
−8.8
−8.5
−8.2
−8.1
−8.0
−8.2
−8.4
−9.2
−8.5
−8.4
−8.8
−12.2
−11.9
−11.3
−11.0
−10.7
−11.4
−10.4
−10.8
−10.6
−11.7
−10.8
−11.8
−11.4
−11.7
−10.9
−11.1
−11.1
−10.8
−10.8
pound against the tested strains when compared to standard
compound (ZOI 14.53, 13.70).
SAR studies
6d
6
e
From anti-bacterial and anti-fungal results, it was observed
that the compounds 6g, 6h, 8h, 8i and 8k showed the potent
activity. Compounds 6g and 6h that have an electron
donating methoxy groups on isoxazole ring showed the
good activity on all tested bacterial strains. Compounds 8d
and 8j having electron withdrawing fluoro and chloro
groups on acrylates showed the moderate anti-microbial
activity. Compounds 8h, 8i and 8k having electron with-
drawing bromo and nitro groups on acrylates showed the
potent activity. Due to strong electro negativity nature of
halogens (F and Cl) reduced the activity when compared
with bromo. The SAR results suggested that the electron
donating group on isoxazole and electron withdrawing
groups on acrylate enhances the anti-microbial activity.
6f
6g
6h
8a
8
8
8
8
8
8
8
8
8
8
b
c
d
e
f
g
h
i
j
k
Docking studies
Compounds 6a and 8h showed highest binding affinity
scores. This is first report on SAR studies with respect to
anti-microbial activity by isoxazoles and acrylates. The
present study dealt that the isoxazoles and acrylates are most
potent compounds and serve as model compounds for
design and development of pharmaceutical compounds.
Docking studies were performed to evaluate the binding
affinity of synthesized compounds 6a–h, 8a–k against tar-
get enzymes DNA gyrase B and sterol 14-α demethylase
and results were presented in Table 3. From the obtained
results, the compound 8h shown highest binding affinity
score (−9.2 K.cal/mol) against DNA gyrase B and com-
pound 6a shown the highest binding affinity score
(−12.2 K.cal/mol) against sterol 14-α demethylase (Table 3).
Materials and methods
The compound 8h shows two hydrogen interactions with
GLU609 and ASP610, while the compound 6a shows no
hydrogen bonding interactions. We assume that this com-
pound might be involved in the hydrophobic and other elec-
trostatic interactions. The interactions between the lead
molecule and target enzymes are represented in Fig. 1.
Chemistry
All the chemicals and reagents of analytical grade were
purchased from Aldrich (Sigma-Aldrich, USA), AVRA
Chemicals Pvt. Ltd (Hyderabad, India) and were used
without further purification. Reactions were monitored by
thin layer chromatography (TLC) on pre-coated silica gel
60 F254 (mesh); spots were visualized under UV light.
Column chromatography has been carried out by using
Merck silica gel (60–120 mesh). Melting points were
determined in open glass capillary tubes on
Mettler–Temp apparatus and are uncorrected. An IR
spectrum was recorded with a Thermo Nicolet Nexus
670 spectrometer. H NMR and C NMR spectra were
recorded on Bruker Avance 300, 400 and 500 MHz
spectrometers. Chemical shifts (δ) are quoted in parts per
million and are referenced to tetramethylsilane as internal
Conclusion
In conclusion, the synthetic method has been established for
the preparation of 2-phenyl-7-((3-phenylisoxazol-5-yl)
methoxy)chroman-4-ones (6a–h) and 4-oxo-2-phenylchro-
man-7-yl cinnamates (8a–k) starting from natural product 7-
hydroxyflavanone. All the titled compounds 6a–h and 8a–k
were screened for their anti-microbial activity. Compounds
a
1
13
6
e, 6g–h, 8h–i and 8k were identified most potent anti-
microbial activity when compared with the standard drugs.

Medicinal Chemistry Research
Fig. 1 3D Model interaction of
compounds 6a, 6g, 6h and 8k
standard. ESI-MS obtained on 7070H spectrometer
operating at 0 ev using a direct inlet system. HRMS were
carried out on Agilent 6510, Q-TOFLC/MS instrument
ESI-Technique.
organic layer was separated, and washed with 2.5% HCl
(15 ml) and followed by water (15 ml) and with brine
solution (15 ml). After the completion of the reaction
solvent was removed under reduced pressure and the
residue was purified by column chromatography using
silica gel (ethyl acetate/hexane 5:95) afforded 5-(bromo-
methyl)-3-phenylisoxazole 4a. The remaining oxime
compounds 2b–h were prepared from corresponding
benzaldehydes with hydroxylamine hydrochloride. Simi-
larly, the remaining isoxazole compounds 4b–h were
prepared from corresponding benzaldehyde oximes.
General procedure for the preparation of 5-
(bromomethyl)-3-phenylisoxazoles (4a–h)
NaHCO (5.6 mmol) was added portion wise at 0 °C to a
3
stirred solution of hydroxylamine hydrochloride
(
3.7 mmol) in water (7 ml) at room temperature and the
mixture was stirred for 30 min. The benzaldehyde (1a,
.1 mmol) has dissolved in methanol (5 ml) and added to
3
5-(bromomethyl)-3-p-tolylisoxazole (4b)
Pedada et al. (2016).
the above reaction mixture and stirring was continued for
an additional 6 h. Methanol was removed under reduced
pressure and the residue was extracted with diethyl ether.
The organic extract was washed with brine, dried over
Na SO and solvent has removed under reduced pressure
5-(bromomethyl)-3-(4-methoxyphenyl)isoxazole (4c)
Liu et al. (2009).
2
4
gave 2a as colourless solid in 85% yield. The crude oxime
was taken for further reaction without purification. N-
Chlorosuccinimide (1.3 mmol) and pyridine (2 drops)
were added to a stirred solution of oxime 2a (1.3 mmol) in
anhydrous CHCl3 (15 ml) at room temperature. The
reaction mixture was stirred for 1 h at 50–60 °C. The
Propargyl bromide (1.4 mmol) was added to the reaction
mixture and followed by triethylamine (1.95 mmol) in
5-(bromomethyl)-3-(2,3-dimethoxyphenyl)isoxazole (4d)
−1
Colourless solid; mp: 85–90 °C, Yield 52%, FT-IR νmax/cm :
3014, 1583, 1481, 1409, 1304, 1264, 1223, 1177, 1096,
1
1051, 1002, 935. H NMR (400 MHz, CDCl ): δ 7.54–7.39
3
(m, 1H, Ar-H), 7.22–7.10 (m, 1H, Ar-H), 7.02 (dd, J = 8.2,
1.4 Hz, 1H, Ar-H), 6.84 (s, 1H), 4.68–4.53 (m, 2H),
CHCl (5 ml) and the reaction mixture was stirred at room
3
+
temperature for 2 h and water was added (10 ml), the
3.92–3.80 (m, 6H). ESI-MS: m/z 298 [M+H] .

Medicinal Chemistry Research
5
-(bromomethyl)-3-(3,4-dimethoxyphenyl)isoxazole (4e)
Ar-H), 6.67 (s, 1H, Ar-H), 6.60 (d, J = 2.4 Hz, 1H, Ar-H),
.49 (dd, J = 13.3, 2.9 Hz, 1H), 5.24 (s, 2H), 3.06 (dd, J =
5
−1
13
Colourless solid; mp: 90–98 °C, Yield 68%, FT-IR νmax/cm :
16.9, 13.3 Hz, 1H), 2.86 (dd, J = 16.9, 2.9 Hz, 1H).
C
3
1
007, 2949, 2839, 1600, 1526, 1466, 1426, 1383, 1243,
NMR (126 MHz, CDCl ) δ 190.53, 167.30, 164.03, 163.86,
3
1
145, 1074, 1021, 930. H NMR (400 MHz, CDCl ): δ 7.38
163.43, 162.96, 162.62, 142.0, 138.61, 130.29, 129.13,
128.91, 128.59, 126.89, 126.22, 121.42, 115.74, 114.16,
110.42, 105.54, 102.06, 101.84, 80.12, 61.39, 44.32. ESI-
3
(
d, J = 2.0 Hz, 2H, Ar-H), 7.07–7.05 (m, 1H, Ar-H), 6.87
(
d, J = 8.3 Hz, 1H), 4.99 (dd, J = 6.3, 4.2 Hz, 2H), 3.92 (s,
+
+
+
6
H). ESI-MS: m/z 298 [M+H] .
MS: m/z 398 [M+H] , ESI-HRMS: m/z 398.1391 [M+H]
(
calcd for C H NO 398.1392).
25 19 4
5
-(bromomethyl)-3-(2,4-dimethoxyphenyl)isoxazole (4f)
2
-Phenyl-7-((3-(p-tolylisoxazol-5-yl) methoxy) chroman-4-
−1
Colourless solid; mp: 94–96 °C, Yield 72%, FT-IR νmax/cm :
one (6b)
2
945, 2837, 1580, 1479, 1407, 1304, 1263, 1228, 1174, 1094,
1
1049, 1001, 935. H NMR (400 MHz, CDCl ): δ 7.84 (dd,
Colourless solid, mp: 140–144 °C; Yield 62%, FT-IR νmax/
3
−
1
J = 8.5, 2.2 Hz, 1H, Ar-H), 6.82–6.76 (m, 1H, Ar-H),
cm : 2952, 2838, 1605, 1513, 1460, 1421, 1353, 1271,
1
6
.59–6.53 (m, 2H, Ar-H), 4.66–4.50 (m, 2H), 3.89–3.85 (m,
1215, 1159, 1030, 955. H NMR (500 MHz, CDCl ): δ 7.92
3
+
6H). ESI-MS: m/z 298 [M+H] .
(d, J = 8.8 Hz, 1H, Ar-H), 7.76–7.65 (m, 2H, Ar-H),
7
.54–7.41 (m, 5H, Ar-H), 7.41–7.37 (m, 1H, Ar-H), 7.27 (s,
1H, Ar-H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H, Ar-H), 6.64 (s,
H, Ar-H), 6.60 (d, J = 2.4 Hz, 1H, Ar-H), 5.49 (dd, J =
13.3, 2.9 Hz, 1H), 5.23 (s, 2H), 3.06 (dd, J = 16.9, 13.3 Hz,
5
-(bromomethyl)-3-(2,4,5-trimethoxyphenyl)isoxazole (4g)
1
Colourless solid; mp: 108–116 °C, Yield 78%, FT-IR νmax/
cm : 2945, 1672, 1611, 1525, 1470, 1363, 1280, 1220,
1
1
1
3
−
1
13
1H), 2.86 (dd, J = 16.9, 2.9 Hz, 1H), 2.40 (s, 3H).
C
1
035, 817. H NMR (400 MHz, CDCl ): δ 7.48 (d, J =
NMR (126 MHz, CDCl ): δ 190.53, 167.08, 164.06,
3
3
.7 Hz, 1H, Ar-H), 6.86 (s, 1H, Ar-H), 6.59 (d, J = 1.5 Hz,
H, Ar-H), 4.59 (d, J = 58.2 Hz, 2H), 3.95 (s, 3H), 3.90 (s,
163.84, 163.43, 162.95, 162.56, 140.47, 138.62, 129.70,
129.12, 128.90, 126.77, 126.21, 125.74, 115.71, 112.24,
+
H), 3.89 (s, 3H). ESI-MS: m/z 328 [M+H] .
110.43, 109.29, 102.29, 102.05, 101.77, 80.12, 61.40,
+
4
4.32, 21.48. ESI-MS: m/z 412 [M+H] , ESI-HRMS: m/z,
+
5
-(bromomethyl)-3-(3,4,5-trimethoxyphenyl)isoxazole (4h)
412.1552 [M+H] (calcd for C H NO 412.1548).
26 21 4
Suman et al. (2015).
7-((3-(4-methoxyphenyl) isoxazol-5-yl) methoxy)-2-
Phenylchroman-4-one (6c)
General procedure for the preparation of 2-phenyl-
7
-((3-phenylisoxazol-5-yl) methoxy) chroman-4-one
Colourless solid, mp: 123–126 °C; Yield 60%, FT-IR νmax/
−
1
(6a)
cm : 2947, 2837, 1581, 1480, 1407, 1304, 1264, 1227,
1
1
177, 1095, 1050, 1002, 934. H NMR (500 MHz, CDCl ):
3
7
-Hydroxyflavanone (5, 1 eq.) in acetonitrile was added to
δ 7.91 (d, J = 8.8 Hz, 1H, Ar-H), 7.81–7.70 (m, 2H, Ar-H),
7.50–7.36 (m, 5H, Ar-H), 7.02–6.93 (m, 2H, Ar-H), 6.71
(dd, J = 8.8, 2.4 Hz, 1H, Ar-H), 6.64–6.56 (m, 2H, Ar-H),
5.49 (dd, J = 13.3, 2.9 Hz, 1H), 5.22 (s, 2H), 3.85 (s, 3H),
3.06 (dd, J = 16.9, 13.3 Hz, 1H), 2.86 (dd, J = 16.9, 2.9 Hz,
the stirred solution of K CO (1.2 eq) and stirred for 30 min.
2
3
Then isoxazole (4a, 1.2 eq) in acetonitrile was added at
room temperature to the reaction mixture and stirring con-
tinued for 48 h. After completion of the reaction (TLC), the
reaction mixture was filtered through sintered funnel and the
solvent was removed under reduced pressure. The crude
product was purified by column chromatography using
silica gel (hexane/ethyl acetate 5%) afforded 6a.
1
3
1H). C NMR (126 MHz, CDCl ): δ 190.55, 166.99,
3
164.85, 164.07, 163.70, 163.43, 162.22, 161.20, 142.36,
138.60, 129.13, 128.90, 128.30, 126.20, 124.25, 121.07,
115.71, 114.40, 110.44, 102.04, 101.58, 80.13, 61.42,
+
5
5.40, 53.46, 44.33. ESI-MS: m/z 428 [M+H] , ESI-
+
2
-Phenyl-7-((3-phenylisoxazol-5-yl) methoxy) chroman-4-
HRMS: m/z 428.1484 [M+H] (calcd for C H NO
26 21 5
one (6a)
428.1497).
Colourless solid, mp: 132–136 °C; Yield 75%, FT-IR νmax/
cm : 3020, 2353, 1609, 1436, 1215, 1012, 922. H NMR
7-((3-(2,3-dimethoxyphenyl) isoxazol-5-yl) methoxy)-2-
Phenylchroman-4-one (6d)
−
1
1
(
500 MHz, CDCl ) δ 7.92 (d, J = 8.8 Hz, 1H, Ar-H),
3
7
7
.83–7.78 (m, 2H, Ar-H), 7.50–7.46 (m, 3H, Ar-H),
.46–7.36 (m, 5H, Ar-H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H,
Colourless solid; mp: 123–127 °C, Yield 57%, FT-IR νmax/
cm : 3014, 1583, 1481, 1409, 1304, 1264, 1223, 1177,
−
1

Medicinal Chemistry Research
1
1
096, 1051, 1002, 935. H NMR (400 MHz, CDCl ) δ 7.92
2-Phenyl-7-((3-(2,4,5-trimethoxyphenyl)isoxazol-5-yl)
3
(
d, J = 8.8 Hz, 1H, Ar-H), 7.47–7.42 (m, 5H, Ar-H), 7.40 (d,
methoxy) chroman-4-one (6g)
J = 3.0 Hz, 1H, Ar-H), 7.29 (dd, J = 8.3, 2.0 Hz, 1H, Ar-H),
6.92 (d, J = 8.4 Hz, 1H, Ar-H), 6.72 (dd, J = 8.8, 2.4 Hz,
1H, Ar-H), 6.63–6.60 (m, 2H, Ar-H), 5.49 (dd, J = 13.2,
2.9 Hz, 1H), 5.23 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.06
Colourless solid; mp: 132–140 °C, Yield 54%, FT-IR νmax/
−
1
cm : 2945, 1672, 1611, 1525, 1470, 1363, 1280, 1220,
1
1035. H NMR (400 MHz, CDCl ): δ 7.91 (d, J = 8.8 Hz,
3
(
dd, J = 16.9, 13.3 Hz, 1H), 2.86 (dd, J = 16.9, 3.0 Hz, 1H).
1H, Ar-H), 7.50–7.42 (m, 5H, Ar-H), 7.42–7.36 (m, 1H,
Ar-H), 6.91 (s, 1H, Ar-H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H,
Ar-H), 6.67–6.54 (m, 2H, Ar-H), 5.49 (dd, J = 13.2, 2.9 Hz,
1H), 5.22 (s, 2H), 3.90 (dd, J = 15.1, 10.8 Hz, 9H), 3.06
1
3
C NMR (101 MHz, CDCl ): δ 190.52, 167.09, 164.04,
3
1
1
1
5
4
63.43, 162.34, 152.80, 150.83, 149.39, 141.98, 138.59,
29.14, 128.90, 126.20, 121.28, 120.07, 115.74, 111.08,
10.43, 109.32, 102.04, 101.62, 99.59, 80.14, 61.43, 56.04,
(dd, J = 16.9, 13.3 Hz, 1H), 2.85 (dd, J = 16.9, 3.0 Hz, 1H).
+
13
6.0, 44.33. ESI-MS: m/z 458 [M+H] , ESI-HRMS: m/z
C NMR (101 MHz, CDCl ): δ 190.57, 165.81, 164.24,
3
+
58.1602 [M+H] (calcd for C H NO 458.1603).
163.42, 159.93, 152.28, 151.52, 143.45, 138.64, 135.29,
27
23
6
129.03, 128.89, 128.86, 128.42, 126.20, 115.61, 111.50,
7
-((3-(3, 4-dimethoxyphenyl) isoxazol-5-yl) methoxy)-2-
110.51, 108.76, 105.28, 102.06, 97.46, 80.10, 61.34, 56.49,
+
Phenylchroman-4-one (6e)
56.44, 56.10, 44.33. ESI-MS: m/z 488 [M+H] , ESI-
HRMS: m/z 488.1708 [M+H]+ (calcd for C H NO
2
8
25
7
Colourless solid; mp: 118–124 °C, Yield 58%, FT-IR νmax/
488.1709).
−
1
cm : 3007, 2949, 2839, 1600, 1526, 1466, 1426, 1383,
1
1
243, 1145, 1074, 1021, 930. H NMR (400 MHz, CDCl )
2-Phenyl-7-((3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)
methoxy) chroman-4-one (6h)
3
δ 7.92 (d, J = 8.8 Hz, 1H, Ar-H), 7.46 (dd, J = 16.4, 11.9,
5
8
.1 Hz, 5H, Ar-H), 7.41–7.33 (m, 1H, Ar-H), 7.29 (dd, J =
.3, 2.0 Hz, 2H, Ar-H), 6.93 (d, J = 8.4 Hz, 1H, Ar-H), 6.72
Colourless solid; mp: 117–120 °C, Yield 60%, FT-IR νmax/
−
1
(
dd, J = 8.8, 2.4 Hz, 1H, Ar-H), 6.66–6.53 (m, 1H, Ar-H),
.49 (dd, J = 13.2, 2.9 Hz, 1H), 5.23 (s, 2H), 3.94 (d, J =
cm : 2951, 1667, 1609, 1523, 1469, 1363, 1278, 1218,
1
5
8
1
1
1
1
8
1034. H NMR (400 MHz, CDCl ): δ 7.91 (d, J = 8.8 Hz,
3
.0 Hz, 6H), 3.06 (dd, J = 16.9, 13.3 Hz, 1H), 2.86 (dd, J =
1H, Ar-H), 7.46 (dtd, J = 7.4, 5.7, 1.9 Hz, 5H, Ar-H), 7.40
(dd, J = 5.0, 3.6 Hz, 1H, Ar-H), 6.91 (s, 1H, Ar-H), 6.72
(dd, J = 8.8, 2.4 Hz, 1H, Ar-H), 6.66–6.57 (m, 2H, Ar-H),
5.49 (dd, J = 13.2, 2.9 Hz, 1H), 5.22 (s, 2H), 3.90 (dd, J =
15.1, 10.8 Hz, 9H), 3.06 (dd, J = 16.9, 13.3 Hz, 1H), 2.85
6.9, 3.0 Hz, 1H). 13C NMR (101 MHz, CDCl ): δ 190.52,
3
67.10, 164.04, 163.42, 163.13, 162.34, 161.05, 150.83,
50.60, 149.39, 138.59, 129.13, 128.90, 126.20, 121.28,
20.07, 115.73, 111.09, 110.43, 109.32, 102.04, 101.63,
0.14, 61.42, 56.07, 56.0, 44.32. ESI-MS: m/z 458
1
3
(dd, J = 16.9, 3.0 Hz, 1H). C-NMR (101 MHz, CDCl ): δ
3
+
+
[
M+H] , ESI-HRMS: m/z 458.1604 [M+H] (calcd for
190.57, 165.81, 164.24, 163.42, 162.07, 159.93, 154.09,
C H NO 458.1603).
152.28, 151.52, 143.45, 138.64, 129.03, 128.89, 128.86,
2
7
23
6
126.20, 115.61, 111.50, 110.51, 108.76, 105.28, 102.06,
7
-((3-(2, 4-dimethoxyphenyl) isoxazol-5-yl) methoxy)-2-
97.46, 80.10, 61.34, 56.49, 56.44, 56.10, 44.33. ESI-MS:
+
+
Phenylchroman-4-one (6f)
m/z 488 [M+H] , ESI-HRMS: m/z 488.1710 [M+H]
calcd for C H NO 488.1709).
(
2
8
25
7
Colourless solid; mp: 119–126 °C, Yield 55%, FT-IR νmax/
−
1
cm : 2945, 2837, 1580, 1479, 1407, 1304, 1263, 1228,
General procedure for the preparation of 4-oxo-2-
phenylchroman-7-yl cinnamate (8a)
1
1
174, 1094, 1049, 1001, 935. H NMR (400 MHz, CDCl ):
3
δ 7.92 (d, J = 8.8 Hz, 1H, Ar-H), 7.52–7.42 (m, 5H, Ar-H),
7.40 (d, J = 6.9 Hz, 1H, Ar-H), 7.29 (dd, J = 8.3, 2.0 Hz,
1H, Ar-H), 6.92 (d, J = 8.4 Hz, 1H, Ar-H), 6.71 (dd, J =
8.8, 2.4 Hz, 1H, Ar-H), 6.67–6.54 (m, 2H, Ar-H), 5.49 (dd,
7-Hydroxyflavanone (5, 1eq) was added to the stirred
solution of cinnamic acid (7a, 1.2 eq.), N,N′-dicyclohex-
ylcarbodiimide (DCC, 1.2 eq), and 4-dimethylamin
opyridine (DMAP, 0.2 eq.) in dry dichloromethane at
room temperature and continued for 48 h. After comple-
tion of the reaction (TLC), water was added and extracted
with dichloromethane. The organic layer was washed with
brine solution and separate organic layer, dried over
Na SO and the solvent was removed under reduced
J = 13.2, 2.9 Hz, 1H), 5.22 (s, 2H), 3.94 (d, J = 8.0 Hz,
6
3
1
1
1
8
H), 3.06 (dd, J = 16.9, 13.3 Hz, 1H), 2.86 (dd, J = 16.9,
1
3
.0 Hz, 1H). C NMR (101 MHz, CDCl ) δ 190.52,
3
67.10, 164.77, 164.04, 163.42, 162.34, 160.83, 150.83,
49.39, 138.59, 129.13, 127.62, 126.20, 126.20, 125.69,
21.28, 120.07, 111.09, 110.42, 109.32, 102.04, 101.63,
2
4
+
0.13, 61.42, 56.07, 55.99, 44.32. ESI-MS: m/z 458 [M+H] ,
pressure and the residue was purified by column chro-
matography using silica gel (hexane/ethyl acetate 5%)
afforded to 8a.
+
ESI-HRMS: m/z 458.1603 [M+H] (calcd for C H NO
27
23
6
4
58.1603).

Medicinal Chemistry Research
4
-Oxo-2-phenylchroman-7-yl cinnamate (8a)
(E)-4-Oxo-2-phenylchroman-7-yl 3-(4-fluorophenyl) acrylate
8d)
(
Colourless solid; mp: 117–120 °C, Yield 63%; FT-IR νmax/
−
1
cm : 3026, 2930, 2859, 1735, 1695, 1645, 1614, 1529,
Colourless solid; mp: 132–138 °C, Yield 85%; FT-IR νmax/
1
−1
1
445, 1369, 1297, 1232, 1132, 1068, 989. H NMR
cm : 3054, 2932, 2859, 1734, 1692, 1607, 1512, 1443,
1
(
(
400 MHz, CDCl ): δ 7.99 (d, J = 8.6 Hz, 1H, Ar-H), 7.88
d, J = 16.0 Hz, 1H, Ar-H), 7.59 (dd, J = 6.5, 2.9 Hz, 2H,
1368, 1322, 1229, 1131, 1064, 989. H NMR (500 MHz,
3
CDCl ): δ 7.99 (d, J = 8.6 Hz, 1H, Ar-H), 7.84 (d, J =
3
Ar-H), 7.50–7.46 (m, 3H, Ar-H), 7.43 (dd, J = 4.7, 2.6 Hz,
16.0 Hz, 1H, Ar-H), 7.62–7.57 (m, 2H, Ar-H), 7.50–7.39 (m,
5H, Ar-H), 7.12 (t, J = 8.6 Hz, 2H, Ar-H), 6.96–6.86 (m, 2H,
Ar-H), 6.54 (d, J = 15.9 Hz, 1H), 5.53 (dd, J = 13.3, 2.8 Hz,
1H), 3.10 (dd, J = 16.9, 13.4 Hz, 1H), 2.91 (dd, J = 16.9,
5
1
1
H, Ar-H), 6.99–6.87 (m, 2H, Ar-H), 6.61 (d, J = 16.0 Hz,
H), 5.52 (dd, J = 13.3, 2.8 Hz, 1H), 3.09 (dd, J = 16.9,
3.3 Hz, 1H), 2.96–2.83 (m, 1H). 1 C NMR (101 MHz,
3
1
3
CDCl ): δ 190.91, 166.54, 166.05, 164.51, 162.53, 156.88,
2.9 Hz, 1H). C NMR (126 MHz, CDCl ): δ 190.91, 165.33,
3
3
1
1
1
54.08, 147.54, 143.35, 131.03, 130.06, 129.09, 128.91,
164.39, 162.52, 156.81, 154.04, 146.16, 142.06, 138.49,
130.45, 130.38, 128.91, 128.55, 126.18, 119.20, 118.83,
116.38, 116.21, 116.16, 115.98, 115.74, 111.20, 80.06, 44.46.
28.53, 128.46, 127.96, 126.19, 119.48, 118.81, 116.63,
+
15.78, 111.23, 80.04, 44.48. ESI-MS: m/z 371 [M+H] ,
+
+
ESI-HRMS: m/z 371.1258 [M+H] (calcd for C H O
ESI-MS: m/z 389 [M+H] , ESI-HRMS: m/z, 389.1182
2
4
18
4
+
3
71.1283).
E)-4-Oxo-2-phenylchroman-7-yl 3-p-tolylacrylate (8b)
Colourless solid; mp: 113–117 °C, Yield 60%; FT-IR νmax/
[M+H] (calcd for C H FO 389.1188).
2
4
17
4
(
(E)-4-Oxo-2-phenylchroman-7-yl 3-(4-chlorophenyl) acrylate
8e)
(
−
1
cm : 3023, 2927, 2859, 1731, 1692, 1611, 1515, 1442,
Colourless solid; mp: 116–125 °C; Yield 85%; FT-IR νmax/
1
−1
1
366, 1317, 1231, 1126, 1067, 989. H NMR (400 MHz,
cm : 3019, 2357, 2290, 2100, 1893, 1737, 1695, 1641,
CDCl ): δ 7.99 (d, J = 8.6 Hz, 1H, Ar-H), 7.85 (d, J =
1581, 1528, 1490, 1423, 1319, 1225, 1137, 1098, 1053,
3
1
1
6.0 Hz, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 7.48–7.36 (m, 6H,
985. H NMR (400 MHz, CDCl ): δ 7.99 (d, J = 8.6 Hz,
3
Ar-H), 7.23 (d, J = 8.0 Hz, 2H, Ar-H), 6.95–6.86 (m, 2H,
Ar-H), 6.56 (d, J = 16.0 Hz, 1H), 5.52 (dd, J = 13.3,
1H, Ar-H), 7.83 (d, J = 16.0 Hz, 1H, Ar-H), 7.55–7.51 (m,
4H, Ar-H), 7.50–7.46 (m, 5H, Ar-H), 6.97–6.83 (d, 2H, Ar-
H), 6.58 (d, J = 16.0 Hz, 1H), 5.53 (dd, J = 13.3, 2.9 Hz,
1H), 3.10 (dd, J = 16.9, 13.3 Hz, 1H), 2.91 (dd, J = 16.9,
2
.8 Hz, 1H), 3.09 (dd, J = 16.9, 13.3 Hz, 1H), 2.90 (dd, J =
13
1
6.9, 2.9 Hz, 1H), 2.40 (s, 3H). C NMR (101 MHz,
1
3
CDCl ): δ 190.92, 164.69, 162.53, 156.98, 154.19, 147.57,
2.9 Hz, 1H). C NMR (101 MHz, CDCl ): δ 190.90,
3
3
1
1
6
43.45, 141.61, 140.44, 138.55, 129.83, 128.90, 128.49,
166.20, 164.27, 162.52, 156.75, 153.98, 146.01, 138.47,
132.43, 129.59, 129.40, 129.21, 129.09, 128.91, 128.58,
126.18, 120.01, 118.86, 117.22, 115.71, 111.19, 80.07,
26.18, 118.76, 118.41, 115.82, 115.47, 111.23, 80.02,
+
8.18, 56.11, 49.91, 44.48, 21.60. ESI-MS: m/z 385 [M+H] ,
+
+
ESI-HRMS: m/z 385.1441 [M+H] (calcd for C H O
44.47, 31.02. ESI-MS: m/z 405 [M+H] , ESI-HRMS: m/z
2
5
20
4
+
3
85.1439).
E)-4-Oxo-2-phenylchroman-7-yl 3-m-tolylacrylate (8c)
Colourless solid; mp: 118–124 °C, Yield 76%; FT-IR νmax/
405.0895, [M+H] (calcd for C H ClO 405.0893).
2
4
17
4
(
(E)-4-Oxo-2-phenylchroman-7-yl 3-(3-chlorophenyl) acrylate
8f)
(
−
1
cm : 3025, 2927, 2855, 1734, 1694, 1615, 1442, 1370,
Colourless solid; mp: 129–132 °C; Yield 80%; FT-IR νmax/
1
−1
1
314, 1224, 1131, 1070, 991. H NMR (400 MHz, CDCl ):
cm : 3023, 2928, 1736, 1692, 1611, 1483, 1439, 1303,
3
1
δ 7.99 (d, J = 8.6 Hz, 1H, Ar-H), 7.86 (d, J = 16.0 Hz, 1H,
Ar-H), 7.45 (dd, J = 20.8, 8.9 Hz, 5H, Ar-H), 7.39 (d, J =
3
1229, 1134, 1068, 990. H NMR (400 MHz, CDCl ) δ 7.99
3
(d, J = 8.6 Hz, 1H, Ar-H), 7.81 (d, J = 16.0 Hz, 1H, Ar-H),
7.58 (d, J = 1.8 Hz, 1H, Ar-H), 7.54–7.43 (m, 5H, Ar-H),
7.42–7.33 (m, 3H, Ar-H), 7.00–6.78 (m, 2H, Ar-H), 6.61
(d, J = 16.0 Hz, 1H), 5.53 (dd, J = 13.3, 2.9 Hz, 1H), 3.10
(dd, J = 16.9, 13.3 Hz, 1H), 2.91 (dd, J = 16.9, 2.9 Hz, 1H).
.0 Hz, 2H, Ar-H), 7.31 (dd, J = 13.7, 5.5 Hz, 2H, Ar-H),
.99–6.84 (m, 2H, Ar-H), 6.60 (d, J = 16.0 Hz, 1H), 5.53
6
(
dd, J = 13.3, 2.8 Hz, 1H), 3.10 (dd, J = 16.9, 13.3 Hz, 1H),
13
2
.90 (dd, J = 16.9, 2.9 Hz, 1H), 2.40 (s, 3H). C NMR
1
3
(
101 MHz, CDCl ): δ 189.89, 163.53, 161.48, 155.87,
C NMR (101 MHz, CDCl ): δ 190.90, 164.10, 162.52,
3
3
1
1
1
46.70, 137.73, 137.47, 132.86, 130.83, 129.88, 128.05,
27.91, 127.85, 127.48, 125.13, 124.60, 117.74, 115.31,
14.75, 110.17, 78.99, 43.44, 29.96, 25.30, 20.31. ESI-MS:
156.69, 145.81, 141.67, 138.47, 135.74, 135.13, 130.85,
130.33, 128.92, 128.59, 128.13, 127.69, 126.60, 126.19,
120.92, 118.89, 118.15, 115.69, 111.18, 80.07, 44.47. ESI-
+
+
+
+
m/z 385 [M+H] , ESI-HRMS: m/z 385.1433, [M+H]
calcd for C H O 385.1439).
MS: m/z 405 [M+H] , ESI-HRMS: m/z 405.0889 [M+H]
(
(calcd for C H ClO 405.0893).
2
5
20
4
24 17
4

Medicinal Chemistry Research
+
(
(
E)-4-Oxo-2-phenylchroman-7-yl 3-(2-chlorophenyl) acrylate
8g)
MS: m/z 449 [M+H] , ESI-HRMS: m/z 451.0368,
+
[M+H] (calcd for C H BrO 449.0388).
2
4
17
4
Colourless solid; mp: 128–131 °C; Yield 84%; FT-IR νmax/
(E)-4-Oxo-2-phenylchroman-7-yl 3-(2-chloro-6-fluorophenyl)
acrylate (8j)
−
1
cm : 3023, 2930, 1735, 1691, 1611, 1440, 1368, 1316,
1
1
276, 1223, 1130, 1053. H NMR (500 MHz, CDCl ): δ
3
8
.30 (d, J = 16.0 Hz, 1H, Ar-H), 8.00 (d, J = 8.6 Hz, 1H,
Colourless solid; mp: 130–134 °C; Yield 60%; FT-IR νmax/
−
1
Ar-H), 7.70 (dd, J = 7.6, 1.8 Hz, 1H, Ar-H), 7.47 (ddd, J =
.0, 4.8, 3.8 Hz, 5H, Ar-H), 7.42–7.31 (m, 3H, Ar-H), 6.95
cm : 3021, 2935, 2859, 1738, 1693, 1609, 1527, 1447,
1
7
1368, 1311, 1220, 1135, 1065, 988. H NMR (500 MHz,
(
d, J = 2.1 Hz, 2H, Ar-H), 6.61 (d, J = 16.0 Hz, 1H), 5.53
CDCl ): δ 8.10 (d, J = 16.4 Hz, 1H, Ar-H), 8.00 (d, J =
3
(
2
dd, J = 13.3, 2.8 Hz, 1H), 3.10 (dd, J = 16.9, 13.3 Hz, 1H),
.91 (dd, J = 16.9, 2.9 Hz, 1H). C NMR (126 MHz,
8.6 Hz, 1H, Ar-H), 7.47 (dt, J = 8.7, 1.7 Hz, 5H, Ar-H),
7.10 (dd, J = 13.1, 5.2 Hz, 3H, Ar-H), 6.96 (d, J = 2.1 Hz,
1H, Ar-H), 6.92 (dd, J = 8.7, 2.1 Hz, 2H, Ar-H), 5.54 (dd, J =
13.3, 2.8 Hz, 1H), 3.10 (dd, J = 16.9, 13.3 Hz, 1H), 2.91
13
CDCl ): δ 190.90, 166.20, 164.27, 162.52, 156.75, 153.98,
3
1
1
1
46.01, 138.47, 132.43, 129.59, 129.40, 129.21, 129.09,
1
3
28.91, 128.58, 126.18, 120.01, 118.86, 117.22, 115.71,
(dd, J = 16.9, 2.9 Hz, 1H). C NMR (126 MHz, CDCl ): δ
3
+
11.19, 80.07, 56.06, 44.47. ESI-MS: m/z 405 [M+H] ,
190.90, 166.20, 164.27, 162.52, 156.75, 153.98, 146.01,
141.91, 138.47, 132.43, 129.59, 129.40, 129.21, 129.09,
+
ESI-HRMS: m/z 405.0892 [M+H] (calcd for C H ClO
24
17
4
4
05.0893).
128.91, 128.58, 126.18, 120.01, 118.86, 117.22, 115.71,
+
1
11.19, 80.07, 44.47. ESI-MS: m/z 423 [M+H] , ESI-
+
(
E)-4-Oxo-2-phenylchroman-7-yl 3-(4-bromophenyl)
HRMS: m/z 423.0798, [M+H] (calcd for: C H ClFO
24 16 4
acrylate (8h)
423.0799).
Colourless solid; mp:148–153 °C; Yield 71%; FT-IR νmax/
(E)-4-Oxo-2-phenylchroman-7-yl 3-(3-nitrophenyl) acrylate
(8k)
−
1
cm : 2931, 2858, 1734, 1696, 1645, 1614, 1529, 1489,
1
1
443, 1370, 1313, 1231, 1137, 1071. H NMR (500 MHz,
CDCl ) δ 7.99 (d, J = 8.6 Hz, 1H, Ar-H), 7.81 (d, J =
Colourless solid; mp: 146–150 °C; Yield 60%; FT-IR νmax/
3
−
1
1
6.0 Hz, 1H, Ar-H), 7.60–7.47 (m, 5H, Ar-H), 7.46–7.35
cm : 3078, 2930, 2858, 1735, 1687, 1609, 1533, 1445,
1
(
m, 4H, Ar-H), 6.96–6.84 (m, 2H, Ar-H), 6.60 (d, J =
1348, 1283, 1234, 1137, 1067, 992. H NMR (400 MHz,
1
1
6.0 Hz, 1H), 5.52 (dd, J = 13.2, 2.9 Hz, 1H), 3.10 (dd, J =
CDCl ): δ 8.46 (s, 1H, Ar-H), 8.29 (d, J = 8.1 Hz, 1H, Ar-
3
1
3
6.9, 13.3 Hz, 1H), 2.90 (dd, J = 16.9, 3.0 Hz, 1H).
C
H), 8.01 (d, J = 8.6 Hz, 1H, Ar-H), 7.92 (d, J = 15.8 Hz,
2H, Ar-H), 7.64 (t, J = 8.0 Hz, 2H, Ar-H), 7.46 (dd, J =
12.9, 6.2 Hz, 5H, Ar-H), 6.99–6.87 (m, 1H, Ar-H), 6.75 (d,
J = 16.0 Hz, 1H), 5.54 (dd, J = 13.3, 2.7 Hz, 1H), 3.11 (dd,
NMR (126 MHz, CDCl ): δ 190.90, 164.26, 162.52,
3
1
1
1
56.74, 146.09, 141.95, 138.47, 133.67, 132.85, 132.36,
32.17, 129.77, 129.29, 128.91, 128.58, 126.18, 125.41,
20.09, 118.87, 117.33, 115.70, 111.18, 80.07, 44.47. ESI-
1
3
J = 16.9, 13.3 Hz, 1H), 2.90 (d, J = 2.9 Hz, 1H). C NMR
+
+
MS: m/z 449 [M+H] , ESI-HRMS: m/z 451.0367 [M+H]
calcd for C H BrO 449.0388).
(101 MHz, CDCl ): δ 191.00, 163.73, 162.56, 156.53,
3
(
148.79, 144.49, 138.38, 135.64, 133.91, 130.20, 129.28,
2
4
17
4
128.93, 128.83, 128.68, 126.18, 125.18, 122.75, 119.90,
(
E)-4-Oxo-2-phenylchroman-7-yl 3-(3-bromophenyl)
118.99, 115.60, 110.87, 103.41, 80.12, 44.45. ESI-MS: m/z
416 [M+H] , ESI-HRMS: m/z 416.1139 [M+H] , (calcd
+
+
acrylate (8i)
for: C H NO 416.1133).
2
4
17
6
Colourless solid; mp:112–118 °C; Yield 76%; FT-IR νmax/
−
1
cm : 3024, 2920, 1736, 1691, 1611, 1574, 1475, 1439,
Biological activity
1
1
8
7
302, 1228, 1133, 1067, 990. H NMR (400 MHz, CDCl ) δ
3
.00 (d, J = 8.6 Hz, 1H, Ar-H), 7.86–7.71 (m, 2H, Ar-H),
.58–7.50 (m, 2H, Ar-H), 7.50–7.36 (m, 5H, Ar-H), 7.31 (t,
Chemicals and kits
J = 7.9 Hz, 1H, Ar-H), 7.00–6.80 (m, 2H, Ar-H), 6.61 (d,
J = 16.0 Hz, 1H), 5.53 (dd, J = 13.3, 2.9 Hz, 1H), 3.10 (dd,
J = 16.9, 13.3 Hz, 1H), 2.91 (dd, J = 16.9, 2.9 Hz, 1H).
Test microbial strains include Staphylococcus aureus
(ATCC 25923), Bacillus subtilis (ATCC 23857), Escher-
ichia coli (ATCC 25922), Pseudomonas aeruginosa
(ATCC 10145), Aspergillus niger (ATCC 1015) and
Aspergillus fumigates (ATCC 1022) were obtained Amer-
ican Type Culture Collection (ATCC, Manassas, USA).
Nutrient agar medium and Potato dextrose agar medium,
1
3
C-NMR (101 MHz, CDCl ) δ 191.63, 190.90, 176.04,
3
1
1
1
64.07, 162.52, 156.69, 147.19, 145.71, 138.47, 136.01,
33.76, 131.08, 130.58, 128.92, 128.60, 127.03, 126.19,
23.21, 118.89, 118.17, 115.69, 111.18, 80.07, 44.47. ESI-

Medicinal Chemistry Research
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
petridishes were purchased from Hi- media chemicals
(
Mumbai, India).
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