Synthesis, Characterization, and Evaluation of Antibacterial and Antioxidant Activities of Novel Benzoxazinones and Benzoxathiinones

Article abstract of DOI:10.1002/jhet.3523

In this work, the new benzoxazinones and benzoxathiinones were synthesized from reaction of alkyl X-phenylpropiolates and aminophenol (or 2-mercaptophenol) in the presence of triphenylphosphine. Their antibacterial activities were studied against Gram-pos

Full text of DOI:10.1002/jhet.3523

Month 2019
Synthesis, Characterization, and Evaluation of Antibacterial and
Antioxidant Activities of Novel Benzoxazinones and Benzoxathiinones
Hamid Reza Gholami,a Sakineh Asghari,a,b
and Mojtaba Mohsenib,c
*
aDepartment of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, 47416-95447, Iran
bNano and Biotechnology Research Group, University of Mazandaran, Babolsar, 47416-95447, Iran
cDepartment of Microbiology, Faculty of Science, University of Mazandaran, Babolsar, 47416-95447, Iran
*E-mail: s.asghari@umz.ac.ir
Received October 31, 2018
DOI 10.1002/jhet.3523
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
In this work, the new benzoxazinones and benzoxathiinones were synthesized from reaction of alkyl
X-phenylpropiolates and aminophenol (or 2-mercaptophenol) in the presence of triphenylphosphine. Their
antibacterial activities were studied against Gram-positive bacteria and Gram-negative bacteria using the disc
diffusion method. The obtained results showed that these compounds are more effective against Gram-
positive bacteria than against Gram-negative bacteria. Also, evaluation of antioxidant activity of the obtained
products showed that they have high to excellent antioxidant activity (79.2–93.6%).
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
desired heterocyclic compounds [21–23]. In this work,
2-aminophenol 1a or 2-mercaptophenol 1b were used as
a bifunctional ZH-acid in the reaction with alkyl
X-phenylpropiolates as Michael acceptors in the presence
of triphenylphosphine catalyst that lead to 3-aryl-2H-
benzo[b][1,4]oxazin-2-one (3) and (E)-3-arylbenzo[b]
[1,4]oxathiin-2(3H)-one (5), respectively (Scheme 1).
Oxazinones and oxathiinones constitute an important
class of heterocycles, which has attracted much synthetic
interest owing to their potential biological activities [1–4].
Benzenoid derivatives of oxazinones (benzoxazinones)
exhibit various pharmaceutical activities, such as
antitumor [5], antiviral [6,7], antithrombotic [8],
antimycobacterial [9], anti-inflammatory [10], antidiabetic,
and hypolipidemic [11] effects. Also, 4H-3,1-
benzoxathiin-4-ones A have been reported to have
insecticidal and fungicidal activities [12,13]. Considerable
attention has been focused on benzoxazinones since the
discovery of efavirenz B, which is a non-nucleoside
reverse transcriptase inhibitor and a selective anti-HIV
[14] drug. Also, compounds C and D are known as
antiviral [7] and anti-inflammatory agents [10],
respectively. Owing to the importance of these
compounds, the synthesis of novel oxazinones and
oxathiinones is an important subject to be investigated.
Among the new synthetic strategies, organocatalyzed
reactions induced by phosphines are a powerful approach
to produce oxygen, nitrogen, and sulfur heterocycles
[15–20]. In these reactions, the electron-deficient
acetylenic esters reacted with ZH-acids (Z = O, S, N, C)
in the presence of phosphine catalyst to afford the
RESULTS AND DISCUSSION
Initially, methyl and ethyl X-phenylpropiolates (2a–g)
were prepared via the Corey–Fuchs reaction as previously
reported [24]. Then, reaction of 2-aminophenol as an
OH-acid was carried out with ethyl phenylpropiolates
(2a) in the presence of triphenylphosphine that led to
3-benzyl-2H-1,4-benzoxazin-2-one (3a) (73%). When the
reaction was performed with electron-deficient alkyl
X-phenylpropiolates (X = 4-Cl, 2-Cl, and 4-CF3) 2b–g,
the reaction yields increased (86–92%), as shown in
Table 1 (entries 2–7). It could be due to more
electrophilicity of Cβ in electron-deficient alkyl
X-phenylpropiolates
(2b–g)
related
to
ethyl
phenylpropiolates (2a).
When the reaction was performed with 2-
mercaptophenol (1b) instead of 2-aminophenol, the
© 2019 Wiley Periodicals, Inc.

H. R. Gholami, S. Asghari, and M. Mohseni
Vol 000
Scheme 1. Reactions of 2-aminophenol 1a or 2-mercaptophenol 1b with alkyl X-phenylpropiolates in the presence of triphenylphosphine catalyst. [Color
figure can be viewed at wileyonlinelibrary.com]
strong absorption band at 1736 cmÀ1 for the carbonyl
Table 1
1
Synthesis of 3-aryl-2H-benzo[b][1,4]oxazin-2-one (3a–d)a.
group. The H NMR spectrum of 3b exhibited a singlet
at 4.18 ppm for the CH2 group. The aromatic protons
were displayed in the appropriate regions (7.28–
7.78 ppm). The 13C NMR spectrum of 3b showed 13
distinct resonances in agreement with the proposed
structure. The mass spectra of 3b displayed molecular ion
peaks at 273 (M+, 29) and 271 (M+, 87), due to the
existence of the isotopes of the chlorine atom, 35Cl and
37Cl, respectively.
Entry
Z
X
R
Product
Yield (%)b
1
2
3
4
5
6
7
NH2
NH2
NH2
NH2
NH2
NH2
NH2
H
Et
Me
Et
Me
Et
3a
3b
3b
3c
3c
3d
3d
73
88
91
89
92
86
90
4-Cl
4-Cl
2-Cl
2-Cl
4-CF3
4-CF3
Me
Et
The 1H NMR spectrum of 4a exhibited a triplet at
1.22 ppm for the methyl group, a quartet at 4.17 ppm for
the methylene group (OCH2), a singlet at 6.29 ppm for
the OH group, and a singlet at 8.02 ppm for the olefinic
proton (═CH). The 13C NMR spectrum of 4a showed 15
distinct resonances in agreement with the proposed
structure. The mass spectrum of 4a displayed a molecular
ion peak at 300 (M+, 93), which is in agreement with the
proposed structure.
aReaction conditions: triphenylphosphine (2 mmol) was added dropwise
to a stirred mixture of alkyl X-phenylpropiolate (2; R = Me, Et; X = 4-Cl,
2-Cl, 4-CF3) (2 mmol) and 2-aminophenol (2 mmol) at 0°C and then
stirred at room temperature for 24 h.
bIsolated product.
olefinic product 4 obtained at room temperature was
converted to (Z)-3-arylbenzo[b][1,4]oxathiin-2(3H)-one
(5) in toluene reflux (Table 2). The obtained results also
indicated that when alkyl X-phenylpropiolates containing
electron-deficient substituents (Cl and CF3) were used,
the reaction yields increased (Table 3, entries 2–7
compared with entry 1).
1
An investigation of H and 13C NMR spectra of 4d–e
showed that when 2-chloro-substituted phenylpropiolates
The structures of 3a–d and 4a–g were deduced by IR,
1H NMR, 13C NMR, and mass spectra as well as
elemental analyses. The IR spectrum of 3b displayed a
Table 3
Synthesis of alkyl (Z)-3-aryl-2-((2-hydroxyphenyl)thio)acrylates (4a–g)a.
Ratio of
Yield
(%)b
isomersc
Table 2
Entry
Z
X
R
Product
(Z : E)
Synthesis of (Z)-3-arylbenzo[b][1,4]oxathiin-2(3H)-one (5a–d)a.
1
2
3
4
5
6
7
SH
SH
SH
SH
SH
SH
SH
H
Et
Me
Et
Me
Et
4a
4b
4c
4d
4e
4f
78
91
93
91
89
92
94
>98:1
>98:1
>98:1
67:33
75:25
>98:1
>98:1
Yield (%)b
4-Cl
4-Cl
2-Cl
2-Cl
4-CF3
4-CF3
Entry
Z
X
R
Product
1
2
3
4
5
6
7
SH
SH
SH
SH
SH
SH
SH
H
Et
Me
Et
Me
Et
5a
5b
5b
5c
5c
5d
5d
52
55
59
61
65
58
63
4-Cl
4-Cl
2-Cl
2-Cl
4-CF3
4-CF3
Me
Et
4g
aReaction conditions: triarylphosphine (1) (2 mmol) was added dropwise
to a stirred mixture of alkyl X-phenylpropiolate (2; R = Me, Et; X = H, 4-
Cl, 2-Cl, 4-CF3) (2 mmol) and 2-mercaptophenol (2 mmol) at 0°C and
then stirred at room temperature for 12 h.
Me
Et
aReaction conditions: alkyl-3-aryl-2-((2-hydroxyphenyl)thio)acrylate
(4a–g) (1 mmol) was refluxed in toluene (10 mL) for 10 h.
bIsolated product.
bIsolated product.
cDetermined with 1H NMR.
Journal of Heterocyclic Chemistry
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Synthesis of Novel Benzoxazinones and Benzoxathiinones
(2d or 2e) were used in the reactions, two products formed
in that all our attempts for their isolation failed. It could be
due to the existence of two geometric isomers (Z- and E
isomers) as shown for 4d in Fig. 1. The 1H NMR
spectrum of the mixture of the two geometric isomers of
4d indicated two singlets at 8.16 and 6.91 ppm with a
ratio of 2 to 1, for their olefinic protons of their Z and E
isomers, respectively. The olefinic proton of Z isomer
appeared at higher frequency (8.16 ppm) that of the E
isomer (6.91 ppm) as reported previously [25,26]. It
could be due to the anisotropy effect of the carbonyl
group with the vicinal proton in Z-geometry. The 13C
NMR spectrum of 4d showed 32 distinct resonances in
agreement with the existence of the mixture of Z and E
Figure 1. Geometric isomers of 4d. [Color figure can be viewed at
wileyonlinelibrary.com]
Scheme 2. Proposed mechanism of formation of 3-aryl-2H-benzo[b][1,4]oxazin-2-one (3), alkyl (Z)-3-aryl-2-((2-hydroxyphenyl)thio)acrylate (4), and
(z)-3-arylbenzo[b][1,4]oxathiin-2(3H)-one (5). [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. R. Gholami, S. Asghari, and M. Mohseni
Vol 000
isomers for compound 4d. The other derivatives of
phenylpropiolates (X = 4-Cl and 4-CF3) only afford their
Z isomers in all cases.
Antioxidant activity. The in vitro antioxidant activity
for compounds 3a–d, 4a–g, and 5a–d was evaluated by
the DPPH radical scavenging according to Blois’s
method. Antioxidant compounds scavenge DPPH radicals
by the process of either hydrogen or electron donation;
and the purple color from the DPPH assay solution
becomes light yellow, which can be quantified by its
decrease of absorbance at wavelength 517 nm. As
illustrated in Fig. 2, all the synthesized compounds
exhibited high to excellent antioxidant activity (79.2–
93.6%). Among these compounds, 4e including hydroxy
group, chlorine, and sulfur atoms exhibited the highest
antioxidant activity (93.6%). It could be due to its
exchangeable proton (OH) or lone pair electrons (Cl and
S).
The 1H NMR spectrum of 5a exhibited a singlet at
8.01 ppm for the olefinic proton (═CH) and a doublet
and two multiplets for the aromatic protons at aromatic
range (7.08–7.63 ppm). The 13C NMR spectrum of 5a
showed 13 distinct resonances consist of the proposed
structure. The mass spectrum of 5a displayed a molecular
ion peak at 254 (M+, 100), which is in agreement with
the proposed structure. The 1H NMR and 13C NMR
spectra of 5b–d were similar to those of 5a except that
their substituents showed characteristic resonances in the
appropriate regions of the spectra.
A proposed mechanism for the formation of products 3,
4, and 5 is shown in Scheme 2. Initially, zwitterionic
intermediate 6 is formed from addition of Ph3P to alkyl
X-phenylpropiolate (2). Intermediate 6 can be protonated
by 2-aminophenol 1a and 2-mercaptophenol 1b to
produce vinylphosphonium cation 7 and the anionic
Antibacterial activity.
The synthesized compounds
were evaluated for their antibacterial activities against
two Gram-negative bacteria, Escherichia coli and
Pseudomonas aeruginosa, and two Gram-positive
bacteria, Staphylococcus aureus and Bacillus subtilis.
intermediates
intermediate
8
9
and 13, respectively. In path a,
is formed from the nucleophilic
Standard
antibacterial
drugs
gentamicin
and
chloramphenicol were also tested under similar
conditions against these organisms (Table 4). As shown in
Table 4, the synthesized compounds are effective against
both Gram-positive and Gram-negative bacteria.
Generally, these compounds exhibited more antibacterial
activities against Gram-positive related to Gram-negative
bacteria. Among compounds 3a–d, chlorinated
derivatives (3b and 3c) have more antibacterial activity
than has fluorine derivative 3d (entries 2 and 3 compared
with 4 in Table 4). The obtained results for 4a–g and 5a–
d revealed that antibacterial activity of compound 4 is
more than that of compound 5 (entries 5–11 compared
with entries 12–15 in Table 4). It seems that the existence
substitution reaction between 8 and 7. Compound 9 is
converted to compound 10 by intramolecular Michael
addition. Intermediate 10 leads to 12 by loss of proton
and subsequently 1,2-proton exchange. Compound 12 is
converted to 3 by elimination of PPh3 and then
tautomerization. In path b, intermediate 13 performs a
Michael addition to vinylphosphonium cation 7 to
generate phosphorus ylide 14. Intermediate 14 undergoes
1,2-proton exchange and then the loss of the
trihenylphosphine that leads to compound 4. It is
converted to (Z)-3-arylbenzo[b][1,4]oxathiin-2(3H)-one 5
by cyclization reaction and the loss of ROH.
Figure 2. Antioxidant activity of compounds 3a–d, 4a–g, and 5a–d (1.0 mg mLÀ1). Each value represents mean SD (n = 3). [Color figure can be
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Novel Benzoxazinones and Benzoxathiinones
Table 4
Antibacterial activity of the compounds using Kirby–Bauer technique (zone of growth inhibition, millimeter).
Microorganism
Gram positive
Gram negative
Pseudomonas aeruginosa
Entry
Compound
Staphylococcus aureus
Bacillus subtilis
Escherichia coli
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
10.0 1.4
12.0 1.4
12.0 1.4
NE
9.5 0.4
9.5 0.7
11.0 1.4
7.5 0.7
9.5 0.7
13.5 0.7
15.0 1.4
11.0 1.4
11.5 0.7
15.0 1.4
13.0 1.4
10.0 1.4
11.5 0.7
7.5 0.7
9.5 0.7
26.0 1.7
22.3 1.2
8.0 1.4
7.5 0.7
9.0 1.4
NE
7.5 0.7
7.5 0.7
8.5 0.7
NE
NE
NE
8.5 0.7
6.5 0.7
6.5 0.7
6.5 0.7
9.5 0.7
6.5 0.7
8.5 0.7
NE
9.5 0.7
10.5 0.7
12.5 0.7
10.5 0.7
11.0 1.4
13.0 1.4
12.5 0.7
7.5 0.7
8.5 0.7
NE
6.5 0.7
6.5 0.7
9.5 0.7
8.0 1.4
7.5 0.7
6.5 0.7
9.5 0.7
10.0 1.4
8.5 0.7
NE
9
10
11
12
13
14
15
16
6.5 0.7
20.3 1.5
21.7 0.6
7.5 0.7
19.6 1.1
20.7 1.5
6.5 0.7
15.6 0.5
NE
Gentamicin (10 μg per disc)
Chloramphenicol (30 μg per disc)
17
Concentration of compound: 20 mg mLÀ1. Mueller–Hinton agar plate.
NE, no effect.
of the OH group in compounds 4a–g plays an important
role in their antibacterial activities.
CHN–O rapid analyzer. NMR spectra were obtained on a
Bruker Vector 22 spectrometer (1H NMR at 400 MHz, 13
C
NMR at 100 MHz) in CDCl3 using tetramethylsilane as an
internal standard. Chemical shifts (δ) are given in ppm, and
coupling constants (J) are given in Hz. Melting points were
measured on an Electrothermal 9100 apparatus.
CONCLUSIONS
A convenient method for the preparation of new classes
of benzoxazinone and benzoxathiinone has been achieved
from the reactions of alkyl X-phenylpropiolates with 2-
aminophenol or 2-mercaptophenol in the presence of
triphenylphosphine. Our study showed that the
synthesized compounds have moderate to good
antibacterial activity against Gram-positive and Gram-
negative bacteria. Interestingly, these compounds
indicated high to excellent antioxidant activity. Therefore,
they can be further developed as effective antioxidant
agents.
General procedure for the synthesis of compounds 3 and
4.
To a stirred solution of the phenol derivative
(2 mmol) and the alkyl aryl propiolates (2 mmol) in
CH2Cl2 (10 mL) was added dropwise at 0°C for over
10 min Ph3P (2 mmol). The reaction mixture was then
allowed to warm to r.t. and stand for 12–24 h. The
solvent was removed under reduced pressure, and the
residue was purified by silica gel (Merck silica gel, 230–
400 mesh) column chromatography using n-hexane/ethyl
acetate (9:1) as eluent to give the product.
3-Benzyl-2H-benzo[b][1,4]oxazin-2-one (3a).
White
powder, 0.35 g (73%); m.p. 117–119°C; IR (KBr, cmÀ1):
1742 (C═O), 1610 and 1412 (C═C, arom), 1213 (Csp2
–
1
EXPERIMENTAL
O). H NMR (400.13 MHz, CDCl3): δH 4.23 (s, 2 H,
CH2), 7.27–7.29 (m, 2H, 2CHarom), 7.33–7.39 (m, 3H,
3CHarom), 7.45–7.51 (m, 3H, 3CHarom), 7.78 (dd,
Triphenylphosphine,
2-aminophenol,
and
2-
4
mercaptophenol were obtained from Fluka (Buchs,
Switzerland) and were used without further purification. Sol-
vents were dried before use. Alkyl aryl propiolates (3a–g)
were synthesized according to a reported method [24]. IR
spectra were recorded on an FTIR Bruker Vector 22 spec-
trometer. Mass spectra were recorded on a Finnigan-Mat
8430 mass spectrometer operating in electron impact mode.
Elemental analyses were performed using a Heraeus
3JHH = 8.0 Hz, JHH = 1.6 Hz, 1H, CHarom); 13C NMR
(100.6 MHz, CDCl3): δC 40.6 (CH2), 116.4 (CH), 125.4
(CH), 127.1 (CH), 128.6 (2CH), 129.1 (CH), 129.6
(2CH), 130.8 (CH), 131.3 (Cq), 135.5 (Cq), 146.6 (Cq),
152.8 (C═N), 156.3 (C═O). MS: m/z 237 (M+ ●, 100),
209 (100), 180 (29), 91 (70), 77 (8). Anal. Calcd for
C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C, 76.13;
H, 4.65; N, 5.92%.
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H. R. Gholami, S. Asghari, and M. Mohseni
Vol 000
3
3-(4-Chlorobenzyl)-2H-benzo[b][1,4]oxazin-2-one (3b).
Pale yellow powder, 0.49 g (91%); m.p. 127–129°C; IR
(KBr, cmÀ1): 3069 (Csp2–H), 1736 (C═O), 1612 and
1410 (C═C, arom), 1213 (Csp2–O); 1H NMR
(400.13 MHz, CDCl3): δH 4.18 (s, 2H, CH2), 7.28–7.32
(m, 3H, 3CHarom), 7.35–7.40 (m, 3H, 3CHarom), 7.50 (td,
CH3), 4.17 (q, 2H, JHH = 7.1 Hz, OCH2), 6.73 (td, 1H,
3JHH = 7.5 Hz, JHH = 1.0 Hz CHarom), 6.94 (dd, 1H,
4
3JHH = 8.1 Hz, JHH = 1.0 Hz CHarom), 7.18–7.25 (m,
4
2H, 2CHarom), 7.29 (s, 1H, OH), 7.41–7.49 (m, 3H,
3
4
3CHarom), 7.90 (dd, 2H, JHH = 7.2 Hz, JHH = 1.5 Hz
2CHarom), 8.02 (s, 1H, CHvinyl); 13C NMR (100.6 MHz,
CDCl3): δC 14.0 (CH3), 62.5 (OCH2), 116.1 (CH), 118.4
(Cq), 120.7 (CH), 127.0 (Cq), 128.5 (2CH), 130.2 (CH),
131.0 (2CH), 131.4 (CH), 134.1 (Cq), 135.8 (CH), 145.6
(CH), 157.4 (Cq), 166.5 (C═O); MS: m/z 300 (M+●, 95),
271 (4), 254 (67), 226 (100), 223 (66). Anal. Calcd. for
C17H16O3S: C, 67.98; H, 5.37. Found: C, 67.74; H, 5.35%.
3
4
1H, JHH = 8.2 Hz, JHH = 1.6 Hz, CHarom), 7.76 (dd,
3
4
1H, JHH = 7.8 Hz, JHH = 1.6 Hz, CHarom); 13C NMR
(100.6 MHz, CDCl3): δC 39.9 (CH2), 116.4 (CH), 125.5
(CH), 128.8 (2CH), 129.1 (CH), 130.9 (2CH), 131.0
(CH), 131.2 (Cq), 133.1 (Cq), 133.9 (Cq), 146.6 (Cq),
152.8 (C═N), 155.7 (C═O); MS: m/z 273 (M+●+2, 30),
271 (M+●, 90), 245 (33), 243 (100), 236 (2), 208 (69),
127 (28), 125 (84). Anal. Calcd. for C15H10ClNO2: C,
66.31; H, 3.71; N, 5.16. Found: C, 66.51; H, 3.72; N,
5.15%.
Methyl
(Z)-3-(4-chlorophenyl)-2-((2-hydroxyphenyl)thio)
acrylate (4b). Yellow powder, 0.58 g (91%); m.p. 94–
96°C; IR (KBr, cmÀ1): 3415 (O–H), 3068 (Csp2–H),
2942 and 2830 (Csp3–H), 1704 (C═O), 1589 and 1442
(C═C, arom), 1254 (Csp2–O), 1089 (Csp3–O); H NMR
(400.13 MHz, CDCl3): δH 3.74 (s, 3H, OCH3), 6.74 (t,
1
3-(2-Chlorobenzyl)-2H-benzo[b][1,4]oxazin-2-one (3c).
Pale yellow powder, 0.50 g (92%); m.p. 69–71°C; IR
(KBr, cmÀ1): 3070 (Csp2–H), 1749 (C═O), 1612 and
1440 (C═C, arom), 1210 (Csp2–O); 1H NMR
(400.13 MHz, CDCl3): δH 4.36 (s, 2H, CH2), 7.23–7.41
3
3
1H, JHH = 7.5 Hz, CHarom), 6.96 (d, 1H, JHH = 8.0 Hz,
CHarom), 7.20 (d, 1H, JHH = 7.4 Hz, CHarom), 7.20–7.23
3
(m, 1H, CHarom), 7.37 (s, 1H, OH), 7.44 (d, 2H,
3JHH = 8.4 Hz, 2CHarom), 7.88 (d, 2H, JHH = 8.4 Hz,
3
3
(m, 6H, 6CHarom), 7.47 (td, 1H, JHH = 7.5 Hz,
2CHarom), 7.95 (s, 1H, CHvinyl); 13C NMR (100.6 MHz,
CDCl3): δC 53.3 (OCH3), 116.4 (CH), 118.0 (Cq), 120.8
(CH), 127.4 (Cq), 128.8 (2CH), 131.0 (CH), 132.3
(2CH), 132.5 (Cq), 135.9 (CH), 136.3 (Cq), 144.4 (CH),
157.5 (Cq), 166.9 (C═O); MS: m/z 322 (M+●+2, 33), 320
(M+●, 100), 290 (15), 288 (45), 262 (20), 260 (60), 226
(37). Anal. Calcd. for C16H13ClO3S: C, 59.91; H, 4.08.
Found: C, 59.73; H, 4.09%.
3
4JHH = 1.4 Hz CHarom), 7.66 (dd, 1H, JHH = 7.9 Hz,
4JHH = 1.2 Hz, CHarom); 13C NMR (100.6 MHz, CDCl3):
δC 37.9 (CH2), 116.4 (CH), 125.4 (CH), 126.8 (CH),
128.5 (CH), 129.2 (CH), 129.6 (CH), 130.9 (CH), 131.2
(Cq), 131.7 (CH), 133.9 (Cq), 134.8 (Cq), 146.4 (Cq),
152.8 (C═N), 155.1 (C═O); MS: m/z 273 (M+●+2, 2),
271 (M+●, 6), 236 (83), 208 (100), 127 (5), 125 (15).
Anal. Calcd. for C15H10ClNO2: C, 66.31; H, 3.71; N,
5.16. Found: C, 66.47; H, 3.72; N, 5.17%.
Ethyl
(Z)-3-(4-chlorophenyl)-2-((2-hydroxyphenyl)thio)
acrylate (4c). Yellow powder, 0.62 g (93%); m.p. 73–
75°C; IR (KBr, cmÀ1): 3394 (O–H), 3068 (Csp2–H),
2990 and 2873 (Csp3–H), 1698 (C═O), 1590 and 1468
3-(4-(Trifluoromethyl)benzyl)-2H-benzo[b][1,4]oxazin-2-one
(3d). Pale yellow powder, 0.55 g (90%); m.p. 98–100°C;
IR (KBr, cmÀ1): 3063 (Csp2–H), 1739 (C═O), 1614 and
1465 (C═C, arom), 1214 (Csp2–O); 1H NMR
(400.1 MHz, CDCl3): δH 4.25 (s, 2H, CH2), 7.27 (d, 1H,
1
(C═C, arom), 1245 (Csp2–O), 1089 (Csp3–O); H NMR
3
(400.13 MHz, CDCl3): δH 1.22 (t, 3H, JHH = 7.1 Hz,
3
3JHH = 8.7 Hz, CHarom), 7.36 (t, 1H, JHH = 7.4 Hz,
3
CH3), 4.18 (q, 2H, JHH = 7.1 Hz, OCH2), 6.75 (td, 1H,
3
4
3JHH = 7.6 Hz, JHH = 1.1 Hz, CHarom), 6.96 (dd, 1H,
CHarom), 7.49 (t, 1H, JHH = 7.4 Hz, CHarom), 7.56 and
3
4
3JHH = 8.4 Hz, JHH = 1.1 Hz, CHarom), 7.20 (d, 1H,
7.58 (4H, ABq, JHH = 8.6 Hz, 4CHarom), 7.75 (d, 1H,
3JHH = 7.9 Hz, CHarom); 13C NMR (100.6 MHz, CDCl3):
δC 40.3 (CH2), 116.4 (CH), 124.2 (Cq, q,
3JHH = 7.7 Hz, CHarom), 7.23–7.30 (m, 1H, CHarom), 7.31
3
(s, 1H, OH), 7.44 (d, 2H, JHH = 8.4 Hz, 2CHarom), 7.87
3
1JCF = 271.9 Hz), 125.5 (2CH, q, JCF = 3.7 Hz), 125.6
3
(d, 2H, JHH = 8.4 Hz, 2CHarom), 7.94 (s, 1H, CHvinyl);
2
13C NMR (100.6 MHz, CDCl3): δC 14.0 (CH3), 62.6
(OCH2), 116.3 (CH), 118.1 (Cq), 120.8 (CH), 127.7 (Cq),
128.8 (2CH), 131.6 (CH), 132.2 (2CH), 132.5 (Cq),
135.7 (CH), 136.2 (Cq), 144.0 (CH), 157.4 (Cq), 166.3
(C═O); MS: m/z 336 (M+●+2, 33), 334 (M+●, 100), 290
(23), 288 (70), 262 (25), 260 (75), 226 (38). Anal. Calcd.
for C17H15ClO3S: C, 60.99; H, 4.52. Found: C, 60.81; H,
(CH), 129.2 (CH), 129.4 (Cq, q, JCF = 32.6 Hz), 130.0
(2CH), 131.2 (Cq), 131.2 (CH), 139.5 (Cq), 146.6 (Cq)
152.8 (C═N), 155.3 (C═O); MS: m/z 305 (M+●, 59), 286
(7), 277 (100), 248 (19), 159 (26). Anal. Calcd. for
C16H10F3NO2: C, 62.96; H, 3.30; N, 4.59. Found: C,
63.15; H, 3.29; N, 4.58%.
Ethyl
(Z)-2-((2-hydroxyphenyl)thio)-3-phenylacrylate
(4a). Yellow powder, 0.47 g (78%); m.p. 91–93°C; IR
(KBr, cmÀ1): 3380 (O–H), 3062 (Csp2–H), 2992 and
2928 (Csp3–H), 1685 (C═O), 1588 and 1445 (C═C,
arom), 1251 (Csp2–O), 1069 (Csp3–O); 1H NMR
4.51%.
Methyl (Z) and (E)-3-(2-chlorophenyl)-2-((2-hydroxyphenyl)
thio)acrylate (4d).
Yellow oil, 0.58 g (91%); IR (KBr,
cmÀ1): 3436 (O–H), 3066 (Csp2–H), 2952 and 2847
(Csp3–H), 1711 (C═O), 1581 and 1438 (C═C, arom),
3
(400.13 MHz, CDCl3): δH 1.22 (t, 3H, JHH = 7.1 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Novel Benzoxazinones and Benzoxathiinones
4
1248 (Csp2–O), 1047 (Csp3–O); MS: m/z 322 (M+●+2, 7),
320 (M+●, 21), 285 (100), 253 (96), 226 (20). Anal.
Calcd. for C16H13ClO3S: C, 59.91; H, 4.08. Found: C,
60.06; H, 4.07%.
3JHH = 7.8 Hz, JHH = 1.6 Hz, CHarom); 13C NMR
(100.6 MHz, CDCl3): δC 13.5 (CH3), 62.0 (OCH2),
115.2 (Cq), 116.1 (CH), 121.3 (CH), 126.3 (CH), 129.3
(CH), 129.6 (CH), 130.3 (CH), 131.3 (CH), 132.8 (Cq),
133.0 (CH), 133.2 (Cq), 134.2 (Cq), 136.8 (CH), 157.5
(Cq), 166.5 (C═O).
4d-Z isomer (major).
1H NMR (400.13 MHz, CDCl3):
3
δH 3.76 (s, 3H, OCH3), 6.72 (td, 1H, JHH = 8.4 Hz,
Methyl (Z)-2-((2-hydroxyphenyl)thio)-3-(4-(trifluoromethyl)
phenyl)acrylate (4f). Yellow powder, 0.65 g (92%); m.p.
4JHH = 1.2 Hz, CHarom), 6.93 (dd, 1H, JHH = 8.0 Hz,
3
4JHH = 0.8 Hz, CHarom), 7.10 (dd, 1H, JHH = 7.6 Hz,
3
70–72°C; IR (KBr, cmÀ1): 3431 (O–H), 3033 (Csp2–H),
2958 and 2845 (Csp3–H), 1712 (C═O), 1573 and 1470
4JHH = 1.2 Hz, CHarom), 7.16–7.22 (m, 2H, 2CHarom), 7.31
(s, 1H, OH), 7.34–7.43 (m, 2H, 2CHarom), 7.80–7.82 (m,
1H, CHarom), 8.16 (s, 1H, CHvinyl); 13C NMR
(100.6 MHz, CDCl3): δC 53.3 (OCH3), 116.2 (CH), 117.7
(Cq), 120.8 (CH), 126.5 (CH), 129.6 (CH), 130.1 (Cq),
130.8 (CH), 131.5 (CH), 131.6 (CH), 132.9 (Cq), 134.4
(Cq), 135.9 (CH), 142.9 (CH), 157.5 (Cq), 166.6 (C═O).
1
(C═C, arom), 1243 (Csp2–O), 1119 (Csp3–O); H NMR
(400.13 MHz, CDCl3): δH 3.77 (s, 3H, OCH3), 6.78 (td,
1H, JHH = 7.6 Hz, JHH = 1.2 Hz, CHarom), 6.99 (dd,
1H, JHH = 8.4 Hz, JHH = 1.2 Hz, CHarom), 7.20 (dd,
1H, JHH = 7.6 Hz, JHH = 1.6 Hz, CHarom), 7.23–7.28
(1H, OH), 7.26 (td, 1H, JHH = 7.6 Hz, JHH = 1.6 Hz,
3
4
3
4
3
4
3
4
3
CHarom), 7.75 (d, 2H, JHH = 8.4 Hz, 2CHarom), 7.97 (d,
4d-E isomer (minor).
δH 3.55 (s, 3H, OCH3), 6.81 (s, 1H, OH), 6.91 (s, 1H,
1H NMR (400.13 MHz, CDCl3):
2H, JHH = 8.4 Hz, 2CHarom), 8.00 (s, 1H, CHvinyl); 13C
3
NMR (100.6 MHz, CDCl3): δC 53.3 (OCH3), 116.4
3
4
CHvinyl), 7.04 (dd, 1H, JHH = 8.2 Hz, JHH = 0.8 Hz,
CHarom), 7.16–7.22 (m, 1H, CHarom), 7.34–7.38 (m, 2H,
2CHarom), 7.43–7.45 (m, 3H, CHarom), 7.53 (dd, 1H,
(CH), 117.5 (Cq), 120.9 (CH), 123.8 (Cq, q,
1JCF = 273.3 Hz), 125.4 (2CH, q, JCF = 3.8 Hz), 129.8
3
2
(Cq), 131.0 (2CH), 131.5 (Cq, q, JCF = 32.6 Hz), 131.8
4
3JHH = 7.8 Hz, JHH = 0.8 Hz, CHarom); 13C NMR
(CH), 135.9 (CH), 137.5 (Cq), 143.3 (CH), 157.4 (Cq),
166.5 (C═O); MS: m/z 354 (M+●, 90), 335 (7), 322 (82),
294 (100). Anal. Calcd. for C17H13F3O3S: C, 57.62; H,
3.70. Found: C, 57.80; H, 3.69%.
(100.6 MHz, CDCl3): δC 52.6 (OCH3), 115.1 (Cq), 116.1
(CH), 121.3 (CH), 126.4 (CH), 129.4 (CH), 129.5 (CH),
130.1 (CH), 130.5 (Cq), 132.7 (CH), 133.2 (Cq), 133.4
(CH), 134.0 (Cq), 136.8 (CH), 157.4 (Cq), 166.0 (C═O).
Ethyl (Z) and (E)-3-(2-chlorophenyl)-2-((2-hydroxyphenyl)
Ethyl (Z)-2-((2-hydroxyphenyl)thio)-3-(4-(trifluoromethyl)
phenyl)acrylate (4g). Yellow powder, 0.69 g (94%); m.p.
thio)acrylate (4e).
Yellow oil, 0.60 g (89%); IR (KBr,
61–63°C; IR (KBr, cmÀ1): 3456 (O–H), 3070 (Csp2–H),
2930 and 2854 (Csp3–H), 1717 (C═O), 1579 and 1471
cmÀ1): 3440 (O–H), 3066 (Csp2–H), 2983 and 2871
(Csp3–H), 1713 (C═O), 1578 and 1442 (C═C, arom),
1247 (Csp2–O), 1044 (Csp3–O); MS: m/z 336 (M+●+2,
10), 334 (M+●, 30), 299 (100), 271 (13), 253 (98), 226
(32). Anal. Calcd. for C17H15ClO3S: C, 60.99; H, 4.52.
Found: C, 61.13; H, 4.53%.
1
(C═C, arom), 1169 (Csp2–O), 1068 (Csp3–O); H NMR
(400.1 MHz, CDCl3): δH 1.24 (t, 3H, JHH = 7.2 Hz,
3
3
CH3), 4.21 (q, 2H, JHH = 7.2 Hz, OCH2), 6.78 (td, 1H,
3JHH = 7.6 Hz, JHH = 1.2 Hz, CHarom), 6.99 (dd, 1H,
4
3JHH = 8.2 Hz, JHH = 1.6 Hz, CHarom), 7.21 (dd, 1H,
4
3JHH = 7.6 Hz, JHH = 1.6 Hz, CHarom), 7.19–7.22 (1H,
4
4e-Z isomer (major).
1H NMR (400.13 MHz, CDCl3):
3
4
OH) 7.25 (td, 1H, JHH = 7.6 Hz, JHH = 1.6 Hz,
3
δH 1.16 (t, 3H, JHH = 7.2 Hz, CH3), 4.13 (q, 2H,
3
CHarom), 7.74 (d, 2H, JHH = 8.4 Hz, 2CHarom), 7.96 (d,
3JHH = 7.2 Hz, OCH2), 6.65 (td, 1H, JHH = 7.8 Hz,
3
2H, JHH = 8.4 Hz, 2CHarom), 7.99 (s, 1H, CHvinyl); 13C
3
4JHH = 1.2 Hz, CHarom), 6.86 (d, 1H, JHH = 8.4 Hz,
3
NMR (100.6 MHz, CDCl3): δC 13.9 (Me), 62.7 (OCH2),
3
4
CHarom), 7.03 (dd, 1H, JHH = 7.8 Hz, JHH = 1.6 Hz,
CHarom), 7.07–7.15 (m, 2H, 2CHarom), 7.18 (s, 1H, OH),
7.25–7.31 (m, 2H, 2CHarom), 7.72–7.74 (m, 1H, CHarom),
8.07 (s, 1H, CHvinyl); 13C NMR (100.6 MHz, CDCl3): δC
14.0 (CH3), 62.6 (OCH2), 116.2 (CH), 117.7 (Cq), 120.7
(CH), 126.5 (CH), 129.6 (CH), 130.7 (CH), 131.4 (CH),
131.5 (CH), 132.6 (Cq), 133.3 (Cq), 134.4 (Cq), 135.8
(CH), 142.5 (CH), 157.4 (Cq), 166.0 (C═O).
116.3 (CH), 117.7 (Cq), 120.9 (CH), 123.8 (Cq, q,
1JCF = 272.2 Hz), 125.4 (2CH, q, JCF = 3.8 Hz), 130.1
3
2
(Cq), 130.8 (2CH), 131.7 (Cq, q, JCF = 32.6 Hz) 131.7
(CH), 135.7 (CH), 137.6 (Cq), 142.8 (CH), 157.4 (Cq),
166.0 (C═O); MS: m/z 368 (M+●, 30), 349 (5), 323 (26),
294 (100). Anal. Calcd. for C18H15F3O3S: C, 58.69; H,
4.10. Found: C, C, 58.45; H, 4.11%.
General procedure for the synthesis of compound 5.
Alkyl-3-aryl-2-((2-hydroxyphenyl)thio)acrylate
4e-E isomer (minor).
1H NMR (400.13 MHz, CDCl3):
(4,
3
δH 0.90 (t, 3H, JHH = 7.2 Hz, CH3), 3.93 (q, 2H,
1 mmol) was refluxed in toluene (10 mL) for 10 h. After
the completion of the reaction (followed by thin-layer
chromatography), the solvent was removed under reduced
pressure and the residue was purified by silica gel (Merck
silica gel, 230–400 mesh) column chromatography using
3JHH = 7.2 Hz, OCH2), 6.74 (s, 1H, OH), 6.85 (s, 1H,
3
CHvinyl), 6.96 (d, 1H, JHH = 7.8 Hz, CHarom), 7.07–
7.14 (m, 2H, 2CHarom), 7.25–7.31 (m, 2H, 2CHarom),
7.36–7.39 (m, 2H, 2CHarom), 7.46 (dd, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. R. Gholami, S. Asghari, and M. Mohseni
Vol 000
n-hexane/ethyl acetate (9:1) as eluent. The solvent was
removed under reduced pressure, and the products 5a–d
were obtained as a white powder.
(M+●, 100), 294 (62), 265 (17), 253 (6), 233 (15). Anal.
Calcd. for C16H9F3O2S: C, 59.63; H, 2.81. Found: C,
59.86; H, 2.80%.
(Z)-3-Benzylidenebenzo[b][1,4]oxathiin-2(3H)-one (5a).
White powder, 0.13 g (52%); m.p. 57–59°C; IR (KBr,
cmÀ1): 3059 and 3018 (Csp2–H), 1728 (C═O), 1630 and
1439 (C═C, arom), 1229 (Csp2–O); 1H NMR
(400.13 MHz, CDCl3): δH 7.08–7.23 (m, 4H, 4CHarom),
General procedure for evaluation of antioxidant activity.
Radical-scavenging activities of the 3,4-dihydropyrimidin-
1(2H)-yl-1H-pyrrole 3a–d, 4a–g, and 5a–d were
determined
against
stable
DPPH
radical
spectrophotometrically
[27].
A
stock
solution
3
7.39–7.49 (m, 3H, 3CHarom), 7.63 (d, 2H, JHH = 7.5 Hz,
(1.0 mg mLÀ1) of compounds was prepared in methanol.
Then, 1.0 mL of each compound solution was added to
1.0 mL of a 0.004% methanol solution of the DPPH
radical and shaken vigorously. After 30 min of
incubation in the dark at room temperature, the
absorbance was observed against a blank at 517 nm. The
assay was carried out in triplicate, and the percentage of
inhibition was calculated using the following formula: %
inhibition = (AC À As)/AC × 100, where Ac is the
absorbance value of the control sample and As is the
absorbance value of the tested sample; and the results
were reported as mean SD after three repeats.
2CHarom), 8.01 (s, 1H, CHvinyl); 13C NMR (100.6 MHz,
CDCl3): δC 115.8 (Cq), 116.3 (Cq), 118.6 (CH), 125.3
(CH), 125.8 (CH), 127.7 (CH), 128.7 (2CH), 130.0 (CH),
130.7 (2CH), 133.9 (Cq), 138.9 (CH), 148.2 (Cq), 159.8
(C═O); MS: m/z 254 (M+●, 100), 226 (85), 210 (5), 197
(56), 165 (67). Anal. Calcd. for C15H10O2S: C, 70.85; H,
3.96. Found: C, 70.99; H, 3.95%.
(Z)-3-(4-Chlorobenzylidene)benzo[b][1,4]oxathiin-2(3H)-one
(5b). White powder, 0.17 g (59%); m.p. 118–120°C; IR
(KBr, cmÀ1): 3072 (Csp2–H), 1736 (C═O), 1584 and
1439 (C═C, arom), 1226 (Csp2–O); 1H NMR
(400.13 MHz, CDCl3): δH 7.03–7.16 (m, 4H, 4CHarom),
General procedure for evaluation of antibacterial
3
7.35 (d, 2H, JHH = 8.2 Hz, 2CHarom), 7.50 (d, 2H,
activity.
The in vitro biocidal screening antibacterial
3JHH = 8.2 Hz, 2CHarom), 7.86 (s, 1H, CHvinyl); 13C
NMR (100.6 MHz, CDCl3): δC 114.8 (Cq), 115.4 (Cq),
117.6 (CH), 124.3 (CH), 124.7 (CH), 126.8 (CH), 127.9
(2CH), 130.75 (2CH), 131.3 (Cq), 134.8 (Cq), 136.3
(CH), 147.1 (Cq), 158.4 (C═O); MS: m/z 290 (M+●+2,
33), 288 (M+●, 100), 262 (11), 260 (33), 225 (11), 209
(6), 197 (27). Anal. Calcd. for C15H9ClO2S: C, 62.40; H,
3.14. Found: C, 62.21; H, 3.15%.
activities of the synthesized compounds 3a–d, 4a–g, and
5a–d were assayed using Kirby–Bauer disc diffusion
method, where a filter disc was impregnated with
synthesized compounds and placed on the surface of
inoculated agar plates [28]. The synthesized compounds
were dissolved in DMSO to achieve 20 mg mLÀ1
solution and then filter sterilized using a 0.22-μm
Minisart (Sartorius, Goettingen, Germany). The antibacte-
rial activities of these compounds were investigated against
four bacterial species. Test organisms included E. coli
PTCC 1330, P. aeruginosa PTCC 1074, S. aureus ATCC
35923, and B. subtilis PTCC 1023. Late exponential
phase of the bacteria was prepared by inoculating 1%
(v/v) of the cultures into the fresh Mueller–Hinton broth
(Merck, Goettingen, Germany) and incubating on an or-
bital shaker at 37°C and 100 rpm overnight. Before the
cultures were used, they were standardized with a final
cell density of approximately 108 cfu\mL. Mueller–
Hinton agar (Merck) was prepared and inoculated from
the standardized cultures of test organisms and then
spread as uniformly as possible throughout the entire me-
dia. Sterile paper discs (6 mm in diameter; Padtan Teb,
Iran) were allowed to dry after being impregnated with
20 μL of the compound solution. The impregnated discs
were introduced on the upper layer of the seeded agar
plate and incubated at 37°C for 24 h. The antibacterial
activities of the synthesized compounds were compared
with those of known antibiotic gentamicin (10 μg per
disc) and chloramphenicol (30 μg per disc) as positive
control and DMSO (20 μL per disc) as negative control.
Antibacterial activity was evaluated by measuring the di-
ameter of inhibition zone (millimeter) on the surface of
(Z)-3-(2-Chlorobenzylidene)benzo[b][1,4]oxathiin-2(3H)-one
(5c). White powder, 0.19 g (65%); m.p. 129–131°C; IR
(KBr, cmÀ1): 3051 (Csp2–H), 1729 (C═O), 1591 and
1439 (C═C, arom), 1231 (Csp2–O); 1H NMR
(400.13 MHz, CDCl3): δH 7.10–7.59 (m, 8H, 8CHarom),
8.20 (s, 1H, CHvinyl); 13C NMR (100.6 MHz, CDCl3): δC
116.1 (Cq), 118.6 (CH), 118.8 (Cq), 125.3 (CH), 125.8
(CH), 126.6 (CH), 127.8 (CH), 130.0 (CH), 130.5 (CH),
130.9 (CH), 132.2 (Cq), 134.9 (Cq), 135.8 (CH), 148.2
(Cq), 159.2 (C═O); MS: m/z 290 (M+●+2, 15), 288 (M+●,
45), 253 (100), 224 (10), 208 (3), 197 (42), 165 (25).
Anal. Calcd. for C15H9ClO2S: C, 62.40; H, 3.14. Found:
C, 62.28; H, 3.15%.
(Z)-3-(4-(Trifluoromethyl)benzylidene)benzo[b][1,4]oxathiin-
2(3H)-one (5d). White powder, 0.20 g (63%); m.p. 71–
73°C; IR (KBr, cmÀ1): 3073 (Csp2–H), 1733 (C═O),
1
1586 and 1470 (C═C, arom), 1230 (Csp2–O); H NMR
(400.1 MHz, CDCl3): δH 7.15–7.30 (m, 4H, 4CHarom),
7.74–7.79 (m, 4H, 4CHarom), 8.05 (s, 1H, CHvinyl); 13C
NMR (100.6 MHz, CDCl3): δC 115.5 (Cq), 118.7 (CH),
1
123.2 (Cq, q, JCF = 274.7 Hz), 125.4 (CH), 125.6 (2CH,
3
q, JCF = 3.7 Hz), 125.8 (CH), 126.9 (Cq), 128.0 (CH),
2
129.8 (Cq), 130.6 (2CH), 131.2 (Cq, q, JCF = 32.7 Hz),
136.7 (CH), 148.1 (Cq), 159.0 (C═O); MS: m/z 322
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Novel Benzoxazinones and Benzoxathiinones
[12] Shimizu, M.; Yamanaka, M.; Shimada, S.; Ando, W.;
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1175.
the plates, and the results were reported as mean SD
after three repeats.
[14] Pierce, M. E.; Parsons, R. L.; Radesca, L. A.; Lo, Y. S.;
Silvermon, S.; Moore, J. R.; Islam, Q.; Chaodhury, A.; Fortunak, J. M.
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[15] Lu, X.; Zhang, C.; Xu, Z. Acc Chem Res 2001, 34, 535.
[16] Methot, J. L.; Roush, W. R. Adv Synth Catal 2004, 346,
1035.
Acknowledgment. We gratefully acknowledge the financial
support from the Research Council of University of Mazandaran.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet