Design, synthesis, and antitumor activity of novel paeonol derivatives containing the 1,4-benzoxazinone and 1,2,3-triazole moieties

Article abstract of DOI:10.1177/1747519819857479

A new series of paeonol derivatives containing the 1,4-benzoxazinone and 1,2,3-triazole moieties were synthesized and evaluated for their cytotoxicity in vitro against human non-small cell lung cancer NCI-H1299 cells and human cervical carcinoma HeLa cells. Among them, compared with that of paeonol, compounds 8-acetyl-4-{[(1-(5-chloro-2-nitrophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-methoxy-2H-1,4-benzoxazin-3(4H)-one, 8-acetyl-4-[(1-mesityl-1H-1,2,3-triazol-4-yl)methyl]-5-methoxy-2H-1,4-benzoxazin-3(4H)-one, and 8-acetyl-5-methoxy-4-{[(1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl]methyl}-2H-1,4-benzoxazin-3(4H)-one exhibited significant inhibitory activity toward the human non-small cell lung cancer NCI-H1299 cells (IC₅₀ = 13.36 ± 0.003, 19.75 ± 0.3, 15.79 ± 0.05 μg mL^?1). The last compound also exhibited significant inhibitory activity toward the human cervical carcinoma HeLa cells (IC₅₀ = 19.73 ± 1.0 μg mL^?1).

Full text of DOI:10.1177/1747519819857479

8
research-arti
5cle2019 7479CHL0010.1177/1747519819857479Journal of Chemical ResearchYang et al.
Research Paper
Journal of Chemical Research
–7
1
Design, synthesis, and antitumor activity
of novel paeonol derivatives containing the
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1,4-benzoxazinone and 1,2,3-triazole moieties
1
1
2
3
Tingting Yang , Xin Shi , Libing Guo , Shaohua Gu ,
1
1
1
1
Weiwei Zhang , Guiqing Xu , Wei Li and Yuqin Jiang
Abstract
A new series of paeonol derivatives containing the 1,4-benzoxazinone and 1,2,3-triazole moieties were synthesized and
evaluated for their cytotoxicity in vitro against human non-small cell lung cancer NCI-H1299 cells and human cervical
carcinoma HeLa cells. Among them, compared with that of paeonol, compounds 8-acetyl-4-{[(1-(5-chloro-2-nitrophenyl)-
1
H-1,2,3-triazol-4-yl]methyl}-5-methoxy-2H-1,4-benzoxazin-3(4H)-one, 8-acetyl-4-[(1-mesityl-1H-1,2,3-triazol-4-yl)
methyl]-5-methoxy-2H-1,4-benzoxazin-3(4H)-one, and 8-acetyl-5-methoxy-4-{[(1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-
yl]methyl}-2H-1,4-benzoxazin-3(4H)-one exhibited significant inhibitory activity toward the human non-small cell lung
−
1
cancer NCI-H1299 cells (IC =13.36±0.003, 19.75±0.3, 15.79±0.05 μgmL ). The last compound also exhibited
5
0
−1
significant inhibitory activity toward the human cervical carcinoma HeLa cells (IC =19.73±1.0 μgmL ).
5
0
Keywords
1
,2,3-triazole moieties, 1,4-benzoxazinone, HeLa cells, inhibitory activity, NCI-H1299 cells, paeonol derivatives
used in clinical treatment of inflammatory diseases, has
Introduction
1
–4
various bioactivities such as antineoplastic, antiinflam-
5
,6
7
8
Paeonol (1), the major phenolic component isolated from matory, antioxidant, and antithrombotic activities. More
Moutan Cortex and traditional Chinese medicine widely recent studies have shown that paeonol exhibits promising
1Henan Engineering Laboratory of Chemical Pharmaceuticals &
Biomedical Materials, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Key Laboratory
of Green Chemical Media and Reactions, Ministry of Education, School
Province for Green Manufacturing of Fine Chemicals, Key Laboratory
of Chemistry and Chemical Engineering, Henan Normal University,
of Green Chemical Media and Reactions, Ministry of Education, School
Xinxiang, P.R. China.
of Chemistry and Chemical Engineering, Henan Normal University,
Email: liweigq@163.com
Xinxiang, P.R. China
2
Yuqin Jiang, Henan Engineering Laboratory of Chemical Pharmaceuticals
& Biomedical Materials, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Key Laboratory
of Green Chemical Media and Reactions, Ministry of Education, School
of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang 453007, P.R. China.
Institute of Chemistry, Henan Academy of Sciences, Zhengzhou, P.R. China
Department of Obstetrics and Gynecology, Xinxiang Central Hospital,
3
4
53007 Xinxiang, P.R. China
Corresponding authors:
Wei Li, Henan Engineering Laboratory of Chemical Pharmaceuticals
&
Biomedical Materials, Collaborative Innovation Center of Henan
Email: jiangyuqin@htu.cn

2
Journal of Chemical Research 00(0)
Scheme 1. Synthesis of paeonol derivatives containing the 1,4-benzoxazinone and 1,2,3-triazole moieties.
bioactivities against tumor cells, which indicates that pae- In vitro anticancer activity
onol is a possible therapeutic measure in slowing down the
All the synthesized paeonol derivatives containing the
,4-benzoxazinone and 1,2,3-triazole moieties (6a–r) were
9
–12
pathogenic processes associated with cancer.
Efforts to
1
improve the pharmacological and biological activities of
paeonol has led to the development of its derivatives by
appropriate modification of paeonol as mentioned
evaluated for anticancer activity in in vitro mode using the
MTT method on the human non-small cell lung cancer
NCI-H1299 cells and the human cervical carcinoma HeLa
cells. Cells were obtained from the cell bank of typical cul-
ture preservation committee of Chinese Academy of
Sciences. Paeonol was used as a positive control (Table 1).
The results of cytotoxic activity in vitro were expressed as
1
3–15
elsewhere.
,4-Benzoxazinone derivatives have received much
attention in medicinal chemistry due to its numerous bio-
1
1
6–18
19,20
logical activities,
especially its anticancer activity.
2
1
22
Following Khan et al. and Nagavelli et al., we attempted
to enhance the anticancer activity of paeonol through intro-
ducing 1,4-benzoxazinone and 1,2,3-triazole moieties into
its structure.
−1
IC50 values (μgmL ; Table 1). The preliminary screening
results showed that most compounds exhibited moderate or
high activity against human non-small cell lung cancer
NCI-H1299 cells and the human cervical carcinoma HeLa
cells. Almost all the tested compounds showed inhibitory
activity against human non-small cell lung cancer NCI-
H1299 cells, while only five of them showed inhibitory
activity against the human cervical carcinoma HeLa cells.
Among the tested compounds, compounds 6k, 6l, and 6o
exhibited good inhibitory activity toward human non-small
cell lung cancer NCI-H1299 cells (IC =13.36±0.003,
Based on all the above considerations and as an exten-
sion of our research on the development of novel paeonol
derivatives, a new series of paeonol derivatives containing
the 1,4-benzoxazinone and 1,2,3-triazole moieties, which
could connect more pharmacophores for constructing bio-
2
3–28
active and functional molecules,
were synthesized and
exhibited preferable inhibitory activity toward human non-
small cell lung cancer NCI-H1299 cells and human cervical
carcinoma HeLa cells.
5
0
−1
1
9.75±0.3, 15.79±0.05 μgmL ; Table 1) compared with
that of paeonol (IC =122.5±0.03 μgmL ). And com-
−1
5
0
pound 6o exhibited good inhibitory activity toward the
human cervical carcinoma HeLa cells (IC =19.73±1.0
Results and discussion
5
0
−
1
μgmL ).
Chemistry
A new series of paeonol derivatives containing the 1,4-ben-
zoxazinone and 1,2,3-triazole moieties were synthesized in
Conclusion
five steps and the synthetic routine is shown in Scheme 1. In summary, a new series of paeonol derivatives containing
Paeonol (1) was first selectively introduced nitro group by the 1,4-benzoxazinone and 1,2,3-triazole moieties were syn-
reacting with HNO /H SO at the C-3 position to form thesized and their anticancer activities were evaluated. The
3
2
4
2
9
compound 2, which could be further converted to inter- anticancer activities were greatly enhanced by introducing
mediate 3 by reduction with zinc powder in acetic acid.
3
0
the 1,4-benzoxazinone and 1,2,3-triazole moieties into the
After successfully synthesizing compound 3 via amidation structure of paeonol. Three compounds exhibited good activ-
and cyclization reaction, intermediate 4 containing the ity against the human non-small cell lung cancer NCI-H1299
3
0
1
,4-benzoxazinone moiety was obtained. Then, com- cells and one compound showed good activity against the
pound 4 was used for the synthesis of compound 5 via human cervical carcinoma HeLa cells, for which the IC
50
3
1
−1
N-alkylation reaction. With compound 5 in hand, a series value was less than 20 μgmL . The research established
of paeonol derivatives linked with the 1,2,3-triazole moiety here will accelerate structure–activity relationship studies on
(
6a–r) were synthesized by reacting with organic azides via paeonol derivatives containing the 1,4-benzoxazinone and
3
2,33
1
,3-dipolar Huisgen cycloaddition reaction.
1,2,3-triazole scaffolds for potential use in bioassays in vitro.

Yang et al.
3
Table 1. Antitumor activity of compounds 6a–r against human non-small cell lung cancer NCI-H1299 cells and the human cervical
a
−1
carcinoma HeLa cells (IC μgmL ).
5
0
Compound
R=
C H
3-NO -C H
4-NO -C H
2-OH-C H
5-COCH -4-OH-2-OCH -C H
2-OH-4-OCH -C H
4-Br-C H
6 4
2-CH -5-NO -C H
2-F-C H
4-Cl-2-NO -C H
5-Cl-2-NO -C H
2,4,6-CH -C H
2-CH -C H
2,6-CH(CH ) -C H
Yield (%)b
NCI-H1299 (μgmL−1)
HeLa (μgmL−1)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
52
94
87
61
78
61
60
83
75
42
74
55
89
72
86
85
86
86
–
24.19±1.7
47.12±18.7
33.45±1.0
21.08±0.6
83.89±2.4
99.94±0.5
114.62±6.9
34.02±0.1
20.35±0.01
39.24±0.07
13.36±0.003
19.75±0.3
31.93±0.04
28.91±1.3
15.79±0.05
32.75±2.4
29.08±0.7
27.83±0.3
122.5±0.03
131.81±15.3
112.81±0.3
106.29±7.0
104.42±14.5
152.01±10.0
186.06±8.3
118.02±2.2
140.78±20.5
54.39±8.0
143.81±8.9
32.05±3.5
106.17±5.2
55.05±4.6
47.43±0.5
19.73±1.0
114.14±11.0
147.18±7.9
130.26±2.3
122.2±0.2
6
5
2
6
4
2
6
4
6
4
3
3
6
2
3
6
3
3
2
6
3
6
4
2
6
3
2 6
3
3
6
2
3
6
4
3
2
6
3
C H
1
0
7
CH -C H
5
2
6
4-F-C H
4-CH -C H
–
6
4
3
6
4
Paeonol
SEM: standard error of mean.
a
Values are expressed as mean±SEM.
b
Percentage yield.
Experimental
solution. After 30 min, the mixture was poured into ice
water (500 mL) with stirring and precipitated a large amount
of granular solids. The mixture was filtered and washed
with water until neutral. The resulting solid was purified by
silica gel column chromatography (petroleum/ethyl ace-
tate=4/3) to give compound 2 (5.91 g, 23%) as yellow gran-
All reagents were purchased from commercial sources and
used without further treatment unless otherwise indicated.
The unknown products were characterized using H nuclear
1
1
3
magnetic resonance (NMR), C NMR, melting points,
infrared (IR) spectra, and high-resolution mass spectrome-
try (HRMS). Melting points were determined on a YUHUA
X-3 melting point apparatus and were uncorrected. IR
spectra were recorded on a Bio-Rad FTS-40 spectrometer.
34
1
ular crystal. m.p. 211.0–212.0 °C; H NMR (400 MHz,
MSO-d ) δ 13.05 (s, 1H, OH), 8.17 (d, J=9.1 Hz, 1H,
ꢀ
6
ArH), 6.93 (d, J=9.1 Hz, 1H, ArH), 4.00 (s, 3H, CH ), 2.65
3
1
3
(
1
(
1
s, 3H, CH3); C NMR (100 MHz, ꢀMSO-d ) δ 204.7,
56.4, 154.4, 135.7, 130.4, 114.8, 104.25, 57.9, 27.2; IR
KBr) (vmax cm ): 3107, 2852, 1643, 1505, 1373, 1280,
090, 791, 607; HRMS: m/z calcd for C H NO (M+H)
6
1
13
H and C NMR spectra were determined on a Bruker
Avance (400 MHz) or Bruker Avance Ⅲ Hꢀ (600 MHz)
−
1
using CꢀCl or ꢀMSO-d as the solvent. ꢀata are repre-
3
6
+
9
9
5
sented as follows: chemical shift, integration, multiplicity
s=singlet, d=doublet, dd=double of doublets, t=triplet,
2
12.0559, found 212.0558.
(
q=quartet, m=multiplet, br=broad), and coupling con-
stants (J) in Hertz. HRMS was performed on a micrOTOF-
Q II mass spectrometer with an electrospray ionization
1
-(3-amino-2-hydroxy-4-methoxyphenyl)
ethanone (3)
(
ESI) source (Waters, Manchester, UK).
Compound 2 (25 mmol, 5.66 g) was dissolved in HOAc (25
mL), to which zinc powder (0.25 mol, 16.35 g) was slowly
added. The reaction mixture was stirred at room tempera-
ture and monitored by thin-layer chromatography (TLC).
After the reaction finished, the mixture was neutralized
1
-(2-hydroxy-4-methoxy-3-nitrophenyl)
ethanone (2)
Paeonol (1) (120 mmol, 19.94 g) was dissolved in conc. with a saturated sodium carbonate solution, extracted with
H SO (100 mL) and cooled to −15 °C. Then, conc. HNO
ethyl acetate, and dried (Na SO ). The residue was chroma-
2
4
3
2
4
(
120 mmol, 5.4 mL) was added dropwise to the above tographed over silica gel (petroleum/ethyl acetate=4/3) to

4
Journal of Chemical Research 00(0)
3
5
yield 3 (2.62 g, 58%) as a yellow solid. m.p. 115.0–115.6 were sequentially added into a 25-mL round flask. The
1
°
(
(
C; H NMR (400 MHz, CꢀCl ) δ 12.46 (s, 1H, OH), 7.19 reaction was stirred at room temperature and monitored by
3
d, J=8.9 Hz, 1H, ArH), 6.45 (d, J=8.9 Hz, 1H, ArH), 3.92 TLC. After the reaction finished, the mixture was evapo-
s, 4H, CH ), 3.84 (s, 2H, NH ), 2.56 (s, 3H, CH );
1
3
C
rated, extracted with CH Cl , dried (Na SO ), and concen-
3
2
3
2 2 2 4
NMR (100 MHz, CꢀCl ) δ 203.5, 151.9, 150.5, 124.3, trated. The residue was purified by column chromatography
3
−
1
1
20.6, 114.4, 102.1, 55.8, 26.3; IR (KBr) (vmax cm ): 3334, to afford the compounds 6a–r.
2
842, 1633, 1440, 1281, 1143, 1056, 764, 568; HRMS: m/z
+
calcd for C H NO (M+H) 182.0817, found 182.0823.
9
11
3
Antitumor activity
The logarithmic phase of human non-small cell lung cancer
NCI-H1299 cells in RPMI 1640 medium and human cervi-
cal carcinoma HeLa cells in ꢀulbecco’s Modified Eagle
8
3
-acetyl-5-methoxy-2H-1,4-benzoxazin-
(4H)-one (4)
To a solution of compound 3 (15 mmol, 2.72 g) in dichloro-
ethane (40 mL) was added chloroacetyl chloride (16.5
mmol, 1.23 mL) at 0 °C and the reaction was monitored by
TLC. After the reaction finished, the solvent was evapo-
rated. To the residue, dimethylformamide (ꢀMF) (30 mL)
and anhydrous K CO (18 mmol, 2.49 g) were successively
added. The mixture was reacted at room temperature and
monitored by TLC. The mixture was washed three times
with water, extracted with CH Cl , dried (Na SO ), and
4
Medium (ꢀMEM) was diluted into 5×10 cells/mL and
then vaccinated in 96-well plates at 37 °C in 5% CO envi-
2
ronment to cultivate for 24 h. And then after adding different
concentrations (NCI-H1299: 0.8 μM, 4 μM, 20 μM, 100 μM,
2
1
7
50μM, 500μM; HeLa: 0.16 μM, 0.8 μM, 4 μM, 20 μM,
00 μM, 500 μM) of the sample, each group 3 holes hatched
2
3
2 h. Before the end of the experiment of 4 h, to each hole
−1
was added a concentration of 0.5 mgmL determined by
2
2
2
4
2
0 μL MTT solution and continued to develop for 4 h. The
concentrated. The residue was purified by column chroma-
tography (petroleum/ethyl acetate=5/1) to give 4 (2.84 g,
supernatant fraction was discarded and 150 μL ꢀMSO was
added into each hole. The absorbance of each hole (A=562
nm) was determined by the enzyme calibration instrument.
After obtaining the inhibition rate, the IC50 value was cal-
culated by the logit method.
1
8
6%) as a white solid. m.p. 196.3–197.2 °C; H NMR (400
MHz, CꢀCl ) δ 7.98 (s, 1H, NH), 7.56 (d, J=8.9 Hz, 1H,
ArH), 6.63 (d, J=8.9 Hz, 1H, ArH), 4.69 (s, 2H, CH ), 3.94
3
2
1
3
(
s, 3H, CH ), 2.58 (s, 3H, CH ); C NMR (100 MHz,
3
3
8
-acetyl-5-methoxy-4-[(1-phenyl-1H-1,2,3-triazol-4-yl)
CꢀCl ) δ 196.3, 163.5, 149.8, 144.3, 125.4, 120.9, 115.8,
3
methyl]-2H-1,4-benzoxazin-3(4H)-one (6a): Yellow solid;
−
1
1
04.7, 67.1, 56.3, 31.6; IR (KBr) (vmax cm ): 3178, 2996,
1
m.p. 121.0–121.8 °C; H NMR (400 MHz, CꢀCl ) δ 7.94 (s,
3
1
681, 1448, 1361, 1284, 1106, 779, 543; HRMS: m/z calcd
1
H, CH), 7.67 (d, J=8.0 Hz, 2H, ArH), 7.61 (d, J=9.2 Hz,
+
for C H NO (M + H) 222.0766, found 222.0766.
11
11
4
1H, ArH), 7.47 (t, J=7.8 Hz, 2H, ArH), 7.39 (t, J=7.4 Hz,
1
H, ArH), 6.69 (d, J=8.8 Hz, 1H, ArH), 5.37 (s, 2H, CH ),
2
3
1
8
1
-acetyl-5-methoxy-4-(prop-2-yn-1-yl)-2H-
,4-benzooxazin-3(4H)-one (5)
4.61 (s, 2H, CH
2
), 3.94 (s, 3H, CH
) δ 196.3, 165.8, 153.5, 149.7,
45.3, 137.0, 129.7, 128.7, 127.3, 121.1, 121.0, 120.4, 118.9,
06.6, 68.7, 56.1, 40.8, 31.6; IR (KBr) (vmax cm ): 3020,
693, 1652, 1594, 1500, 1465, 1278, 1115, 807; HRMS: m/z
3 3
), 2.56 (s, 3H, CH ); C
NMR (100 MHz, CꢀCl
3
1
1
1
Compound 4 (10 mmol, 2.21 g), 3-bromopropyne (12
−1
mmol, 1.43 g), and anhydrous K CO (12 mmol, 1.66 g)
2
3
were suspended in ꢀMF (20 mL) and the reaction was
monitored by TLC. After the reaction finished, the mixture
was washed three times with water, extracted with ethyl
acetate, dried (Na SO ), and concentrated. The residue was
+
calcd for C H N O (M+H) 379.1406, found 379.1452.
20
18
4
4
8
-acetyl-5-methoxy-4-[(1-(3-nitrophenyl)-1H-1,2,3-tri-
azol-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one (6b):
Yellow solid; m.p. 162.9–163.4 °C; H NMR (400 MHz,
2
4
1
purified by column chromatography to afford 5 (2.51 g,
CꢀCl ) δ 8.58 (s, 1H, ArH), 8.28 (d, J=8.3 Hz, 1H, ArH),
3
1
9
7%) as a white solid. m.p. 104.6–105.3 °C; H NMR (400
8.13 (d, J=8.8 Hz, 1H, ArH), 8.11 (s, 1H, CH), 7.72 (t,
MHz, CꢀCl ) δ 7.66 (d, J=9.0 Hz, 1H, ArH), 6.74 (d,
3
J=8.2 Hz, 1H, ArH), 7.64 (d, J=8.9 Hz, 1H, ArH), 6.73 (d,
J=9.0 Hz, 1H, ArH), 5.36 (s, 2H, CH ), 4.64 (s, 2H, CH ),
J=9.0 Hz, 1H, ArH), 4.87 (d, J=2.4 Hz, 2H, CH ), 4.58 (s,
2
2
2
2
H, CH ), 3.96 (s, 3H, CH ), 2.59 (s, 3H, CH ), 2.12 (t,
2 3 3
13
3
.96 (s, 3H, CH ), 2.59 (s, 3H, CH ); C NMR (100 MHz,
3
3
1
3
J=2.4 Hz, 1H, CH); C NMR (100 MHz, CꢀCl ) δ 196.4,
3
CꢀCl ) δ 196.3, 165.9, 153.4, 149.6, 148.9, 146.2, 137.7,
3
1
6
2
65.0, 153.6, 149.9, 127.3, 121.3, 117.9, 106.6, 78.4, 71.5,
8.5, 56.3, 34.1, 31.7; IR (KBr) (vmax cm ): 3264, 3008,
1
1
1
30.9, 127.4, 125.7, 123.1, 121.2, 121.1, 118.9, 115.2,
06.6, 68.7, 56.1, 41.0, 31.5; IR (KBr) (vmax cm ): 3082,
−
1
−1
122, 1690, 1390, 1277, 1107, 810, 547; HRMS: m/z calcd
679, 1596, 1538, 1455, 1357, 1265, 1109, 821; HRMS: m/z
+
for C H NO (M + H) 260.0923, found 260.0912.
1
4
13
4
+
calcd for C H N O (M+H) 424.1257, found 424.1288.
20
17
5
6
8
-acetyl-5-methoxy-4-{[(1-(4-nitrophenyl)-1H-1,2,3-
triazol-4-yl]methyl}-2H-1,4-benzoxazin-3(4H)-one (6c):
Yellow granular solid; m.p. 179.2–180.7 °C; H NMR (400
General procedure for the
synthesis of the paeonol derivatives
containing 1,2,3-triazole (6a–r)
1
MHz, CꢀCl ) δ 8.39 (d, J=8.9 Hz, 2H, ArH), 8.11 (s, 1H,
3
CH), 7.95 (d, J=8.9 Hz, 2H, ArH), 7.64 (d, J=8.9 Hz, 1H,
Compound 5 (0.5 mmol, 130 mg), t-BuOH/H O (2.0 mL, ArH), 6.73 (d, J=9.0 Hz, 1H, ArH), 5.36 (s, 2H, CH
), 4.63
2
2
1
3
v/v=1/1), phenyl azide (0.75 mmol), sodium ascorbate (0.1 (s, 2H, CH
), 3.96 (s, 3H, CH
), 2.58 (s, 3H, CH
);
C
2
3
3
mmol, 20 mg), and Cu(OAc) ·H O (0.05 mmol, 10 mg) NMR (100 MHz, CꢀCl
) δ 196.3, 166.0, 153.4, 149.6,
2
2
3

Yang et al.
47.2, 146.4, 141.1, 127.4, 125.5, 121.2, 121.2, 120.4,
5
1
8-acetyl-5-methoxy-4-{[1-(2-methyl-5-nitrophenyl)-1H-
−1
118.9, 106.7, 68.7, 56.1, 41.0, 31.5; IR (KBr) (vmax cm ): 1,2,3-triazol-4-yl]methyl}-2H-1,4-benzoxazin-3(4H)-one
1
3
094, 1687, 1601, 1525, 1456, 1347, 1295, 1109, 821; (6h): Light yellow solid; m.p. 71.6–72.4 °C; H NMR (400
+
HRMS: m/z calcd for C H N O (M+Na) 446.1077, MHz, CꢀCl ) δ 8.25 (d, J=8.6 Hz, 1H, ArH), 8.20 (s, 1H,
found 446.1098.
2
0
17
5
6
3
ArH), 7.77 (s, 1H, CH), 7.63 (d, J=9.0 Hz, 1H, ArH), 7.54
8
-acetyl-4-[(1-(2-hydroxyphenyl)-1H-1,2,3-triazol- (d, J=8.4 Hz, 1H, ArH), 6.71 (d, J=9.0 Hz, 1H, ArH), 5.40
4
-yl]methyl)-5-methoxy-2H-1,4-benzoxazin-3(4H)-one (s, 2H, CH ), 4.62 (s, 2H, CH ), 3.95 (s, 3H, CH ), 2.58 (s,
2
2
13
3
1
(
6d): Orange solid; m.p. 220.0–220.6 °C; H NMR (400 3H, CH ), 2.27 (s, 3H, CH ).; C NMR (100 MHz, CꢀCl )
3
3
3
MHz, CꢀCl ) δ 9.88 (s, 1H, OH), 8.09 (s, 1H, CH), 7.64 (d, δ 196.3, 165.9, 153.5, 149.8, 146.5, 145.2, 141.4, 136.8,
3
J=8.9 Hz, 1H, ArH), 7.36 (d, J=8.1 Hz, 1H, ArH), 7.29 (d, 132.5, 127.4, 124.3, 124.3, 121.2, 121.2, 118.9, 106.6, 68.7
−1
J=7.9 Hz, 1H, ArH), 7.17 (d, J=8.2 Hz, 1H, ArH), 6.97 (t, 56.1, 40.9, 31.5, 18.5; IR (KBr) (vmax cm ): 3087, 1691,
J=7.7 Hz, 1H, ArH), 6.72 (d, J=9.0 Hz, 1H, ArH), 5.38 (s, 1598, 1527, 1502, 1456, 1353, 1283, 1283, 1109, 802;
+
2
H, CH ), 4.64 (s, 2H, CH ), 3.94 (s, 3H, CH ), 2.59 (s, 3H, HRMS: m/z calcd for C H N O (M+H) 438.1414,
2
3
2
3
21 19
5
6
1
CH ); C NMR (100 MHz, CꢀCl ) δ 196.5, 166.1, 153.7, found 438.1436.
1
1
3
3
49.8, 145.6, 144.6, 133.9, 130.8, 130.4, 127.9, 127.5,
8-acetyl-4-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]
(6i):
25.7, 124.1, 121.2, 118.9, 106.7, 68.8, 56.2, 41.3, 31.7; IR methyl}-5-methoxy-2H-1,4-benzoxazin-3(4H)-one
−1
1
(
KBr) (vmax cm ): 3364, 3058, 1693, 1665, 1507, 1234, Yellow viscous liquid; H NMR (400 MHz, CꢀCl ) δ 7.99
3
+
1
3
115, 809; HRMS: m/z calcd for C H N O (M+H)
(s, 1H, CH), 7.90 (t, J=7.7 Hz, 1H, ArH), 7.62 (d, J=9.0
Hz, 1H, ArH), 7.40 (q, J=7.3, 6.8 Hz, 1H, ArH), 7.31–7.23
2
0
18
4
5
95.1355, found 395.1355.
8
-acetyl-4{[(1-(5-acetyl-4-hydroxy-2-methoxyphenyl)- (m, 2H, ArH), 6.70 (d, J=9.0 Hz, 1H, ArH), 5.42 (s, 2H,
1
H-1,2,3-triazol-4-yl]methyl}-5-methoxy-2H-1,4-benzoxa- CH ), 4.62 (s, 2H, CH ), 3.94 (s, 3H, CH ), 2.58 (s, 3H,
2
2
3
1
3
zin-3(4H)-one (6e): Brick red solid; m.p. 191.9–192.8 °C; CH ); C NMR (100 MHz, CꢀCl ) δ 196.4, 165.8, 154.5,
3
3
1
H NMR (400 MHz, CꢀCl ) δ 12.83 (s, 1H, OH), 8.01 (s, 153.5, 152.0, 149.9, 144.9, 130.1 (d, J=7.7 Hz), 127.3,
3
1
6
2
H, ArH), 7.86 (s, 1H, CH), 7.61 (d, J=9.0 Hz, 1H, ArH), 125.2 (d, J=3.7 Hz), 124.8, 124.0 (d, J=8.2 Hz), 121.1,
.70 (d, J=9.0 Hz, 1H, ArH), 6.55 (s, 1H, ArH), 5.44 (s, 118.8, 117.0 (d, J=19.8 Hz), 106.6, 68.7, 56.1, 40.6, 31.6;
−1
H, CH ), 4.61 (s, 2H, CH ), 3.96 (s, 3H, CH ), 3.84 (s, 3H, IR (KBr) (vmax cm ): 3082, 1686, 1668, 1596, 1508, 1274,
2
2
1
3
3
+
CH ), 2.57 (s, 6H, CH ); C NMR (100 MHz, CꢀCl ) δ 1106, 815; HRMS: m/z calcd for C H FN O (M+H)
3
3
3
20 17
4
4
2
1
1
02.8, 196.4, 165.8, 165.1, 157.8, 153.6, 149.9, 143.9, 397.1312, found 397.1316.
28.1, 127.2, 124.9, 121.1, 118.7, 118.7, 113.2, 106.6,
8-acetyl-4-{[1-(4-chloro-2-nitrophenyl)-1H-1,2,3-tria-
00.8, 68.7, 56.5, 56.1, 40.3 31.5, 26.5; IR (KBr) (v
zol-4-yl]methyl}-5-methoxy-2H-1,4-benzoxazin-3(4H)-one
max
−
1
1
cm ): 3438, 3184, 1686, 1640, 1513, 1454, 1276, 1109, (6j): Yellow solid; m.p. 134.7–135.5 °C; H NMR (600
8
4
19; HRMS: m/z calcd for C H N O (M+Na)+ MHz, CꢀCl ) δ 8.03 (s, 1H, CH), 7.73 (d, J=11.2 Hz, 2H,
2
3
22
4
7
3
89.1386, found 489.1411.
ArH), 7.63 (d, J=8.8 Hz, 1H, ArH), 7.54 (d, J=8.3 Hz, 1H,
8
-acetyl-4-({1-[2-(2-hydroxy-4-methoxyphenyl)-2- ArH), 6.70 (d, J=8.8 Hz, 1H, ArH), 5.35 (s, 2H, CH ), 4.62
2
1
3
oxoethyl]-1H-1,2,3-triazol-4-yl}methyl)-5-methoxy-2H-1,4- (s, 2H, CH ), 3.89 (s, 3H, CH ), 2.58 (s, 3H, CH );
C
2
3
3
benzoxazin-3(4H)-one (6f): White solid; m.p. 175.4–176.3 NMR (150MHz, CꢀCl ) δ 196.4, 166.0, 153.5, 149.6,
3
1
°
(
1
C; H NMR (400 MHz, CꢀCl ) δ 11.87 (s, 1H, OH), 7.61 145.7, 144.6, 136.7, 133.8, 128.8, 128.7, 127.4, 125.8,
s, 1H, CH), 7.58 (d, J=4.6 Hz, 2H, ArH), 6.67 (d, J=9.0 Hz, 124.0, 121.1, 118.8, 106.6, 68.7, 56.1, 41.2, 31.5; IR (KBr)
H, ArH), 6.49 (dd, J=9.2, 2.4 Hz, 1H, ArH), 6.44 (d, J=1.8 (vmax cm ): 3097, 1694, 1670, 1598, 1506, 1358, 1264,
Hz, 1H, ArH), 5.69 (s, 2H, CH ), 5.36 (s, 2H, CH ), 4.60 (s, 1112, 834; HRMS: m/z calcd for C H ClN O (M+H)
H, CH ), 3.87 (d, J=16.1 Hz, 6H, CH ), 2.57 (s, 3H, CH ); 458.0867, found 458.0880.
8-acetyl-4-{[1-(5-chloro-2-nitrophenyl)-1H-1,2,3-tria-
65.8, 153.6, 149.8, 144.9, 130.3, 127.2, 124.5 121.0, 118.9, zol-4-yl]methyl}-5-methoxy-2H-1,4-benzoxazin-3(4H)-one
3
−1
+
2
2
20 16
5
6
2
2
3
3
13
C NMR (100 MHz, CꢀCl ) δ 196.4, 193.1, 167.2, 165.8,
3
1
1
1
11.2, 108.9, 106.6, 101.3, 68.7, 56.1, 55.8, 54.2, 40.9, 31.6; (6k): Yellow solid; m.p. 146.0–147.2 °C; H NMR (400
IR (KBr) (vmax cm ): 3438, 3088, 1690, 1598, 1506, 1456, MHz, CꢀCl ) δ 8.02 (d, J=8.7 Hz, 1H, ArH), 7.75 (s, 1H,
−
1
3
+
1
4
240, 1110, 812; HRMS: m/z calcd for C H N O (M+H)
67.1567, found 467.1568.
8
CH), 7.65–7.61 (m, 3H, ArH), 6.71 (d, J=9.0 Hz, 1H,
ArH), 5.35 (s, 2H, CH ), 4.63 (s, 2H, CH ), 3.89 (s, 3H,
2
3
22
4
7
2
2
1
3
-acetyl-4-{[1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl] CH ), 2.59 (s, 3H, CH ); C NMR (100 MHz, CꢀCl ) δ
3
3
3
methy})-5-methoxy-2H-1,4-benzoxazin-3(4H)-one
(6g): 196.4, 166.0, 153.5, 149.6, 145.8, 142.5, 140.1, 131.2,
1
Yellow solid; m.p. 202.7–203.4 °C; H NMR (400 MHz, 130.7, 128.0, 127.4, 126.8, 124.0, 121.1, 118.8, 106.6, 77.2,
CꢀCl ) δ 7.96 (s, 1H, CH), 7.61 (q, J=8.9 Hz, 5H, ArH), 77.0, 68.7, 56.1, 41.2, 31.6; IR (KBr) (vmax cm ): 3076,
.71 (d, J=9.0 Hz, 1H, ArH), 5.35 (s, 2H, CH ), 4.61 (s, 1702, 1669, 1560, 1501, 1362, 1286, 1111, 857; HRMS:
−1
3
6
2
(
1
1
1
2
1
3
+
H, CH ), 3.94 (s, 3H, CH ), 2.57 (s, 3H, CH ); C NMR m/z calcd for C H ClN O (M+H) 458.0867, found
2
3
3
20 16
5
6
100 MHz, CꢀCl ) δ 196.3, 165.9, 153.5, 149.7, 145.6, 458.0852.
36.0, 132.9, 127.3, 122.3, 121.8, 121.1, 121.0, 118.9,
3
8-acetyl-4-[(1-mesityl-1H-1,2,3-triazol-4-yl)methyl]-
06.6, 68.7, 56.1, 40.9, 31.5; IR (KBr) (vmax cm ): 3101, 5-methoxy-2H-1,4-benzoxazin-3(4H)-one (6l): Yellow
−
1
1
690, 1662, 1498, 1458, 1266, 1118, 808; HRMS: m/z solid; m.p. 134.9–135.3 °C; H NMR (600 MHz, CꢀCl ) δ
3
+
calcd for C H BrN O (M+H) 457.0511, found 7.60 (d, J=8.9 Hz, 1H, ArH), 7.36 (s, 1H, CH), 6.92 (s, 2H,
2
0
17
4
4
4
57.0475.
ArH), 6.64 (d, J=8.9 Hz, 1H, ArH), 5.48 (s, 2H, CH ), 4.61
2

6
Journal of Chemical Research 00(0)
1
(
3
s, 2H, CH ), 3.90 (s, 3H, CH ), 2.56 (s, 3H, CH ), 2.31 (s, Yellow powdery solid; m.p. 164.2–165.1 °C; H NMR (400
2
3
3
1
3
H, CH ), 1.78 (s, 6H, CH ); C NMR (100 MHz, CꢀCl ) MHz, CꢀCl ) δ 7.91 (s, 1H, CH), 7.69–7.59 (m, 3H, ArH),
3
3
3
3
δ 196.2, 165.8, 153.7, 150.2, 144.1, 140.0, 134.9, 133.3, 7.18 (t, J=8.4 Hz, 2H, ArH), 6.70 (d, J=9.0 Hz, 1H, ArH),
1
3
1
29.0, 127.3, 124.1, 120.9, 118.5, 106.4, 68.8, 56.1, 40.6, 5.35 (s, 2H, CH ), 4.61 (s, 2H, CH ), 3.94 (s, 3H, CH ),
2 2 3
−
1
13
1.6, 21.1, 17.0; IR (KBr) (vmax cm ): 3089; 1692, 1598, 2.57 (s, 3H, CH3); C NMR (100 MHz, CꢀCl ) δ 196.4,
499, 1456, 1283, 1108, 806; HRMS: m/z calcd for 165.9, 163.6, 161.1, 153.5, 149.7, 145.5, 133.3, 127.4,
3
+
C H N O (M+H) 421.1876, found 421.1864.
122.4(d, J=8.6 Hz), 121.3, 121.1, 118.9, 116.8, 116.6,
-acetyl-5-methoxy-4-[(1-o-tolyl-1H-1,2,3-triazol-4-yl) 106.7, 68.7, 56.1, 40.9, 31.6; IR (KBr) (vmax cm ): 3021,
2
3
24
4
4
−1
8
methyl]-2H-1,4-benzoxazin-3(4H)-one (6m): Yellow vis- 1705, 1653, 1593, 1460, 1234, 1114, 844; HRMS: m/z
1
+
cous liquid; H NMR (400 MHz, CꢀCl ) δ 7.64–7.62 (m, calcd for C H FN O
(M+H) 397.1312, found
3
20 17
4
4
2
7
2
H, CH, ArH), 7.38 (dd, J=6.3, 1.8 Hz, 1H, ArH), 7.33– 397.1307.
.26 (m, 3H, ArH), 6.69 (d, J=9.0 Hz, 1H, ArH), 5.44 (s,
H, CH ), 4.62 (s, 2H, CH ), 3.94 (s, 3H, CH ), 2.58 (s, 3H, methyl]-2H-1,4-benzoxazin-3(4H)-one (6r): Yellow solid;
CH ), 2.08 (s, 3H, CH ); C NMR (100 MHz, CꢀCl ) δ m.p. 137.3–138.3 °C; H NMR (400 MHz, CꢀCl ) δ 7.90
8-acetyl-5-methoxy-4-[(1-p-tolyl-1H-1,2,3-triazol-4-yl)
2
2
1
3
3
1
3
3
3
3
1
1
5
1
96.3, 165.8, 153.6, 149.9, 144.3, 136.4, 133.6, 131.4, (s, 1H, CH), 7.61 (d, J=9.0 Hz, 1H, ArH), 7.55 (d, J=8.3
29.8, 127.3, 126.8, 125.9, 124.2, 121.1, 118.8, 106.6, 68.7, Hz, 2H, ArH), 7.27 (d, J=8.2 Hz, 2H, ArH), 6.70 (d, J=9.0
−
1
6.1, 40.8, 31.6, 17.7; IR (KBr) (vmax cm ): 3124, 1682, Hz, 1H, ArH), 5.37 (s, 2H, CH ), 4.61 (s, 2H, CH ), 3.94 (s,
2
2
1
3
666, 1595, 1504, 1284, 1106, 818; HRMS: m/z calcd for 3H, CH ), 2.57 (s, 3H, CH ), 2.39 (s, 3H, CH ); C NMR
3
3
3
+
C H N O (M+H) 393.1563, found 393.1551.
(100 MHz, CꢀCl ) δ 196.3, 165.8, 153.6, 149.8, 145.1,
-acetyl-4-{[1-(2,6-diisopropylphenyl)-1H-1,2,3-tria- 138.8, 134.7, 130.2, 127.3, 121.1, 121.0, 120.3, 118.9,
2
1
20
4
4
3
8
−
1
zol-4-yl]methyl}-5-methoxy-2H-1,4-benzoxazin-3(4H)-one 106.6, 68.7, 56.1, 40.9, 31.5, 21.1; IR (KBr) (vmax cm ):
1
(
6n): Light pink solid; m.p. 140.0–141.1 °C; H NMR (600 3021, 1698, 1653, 1594, 1501, 1279, 1113, 823; HRMS:
MHz, CꢀCl ) δ 7.62 (d, J=8.8 Hz, 1H,ArH), 7.43 (t, J=7.5 m/z calcd for C H N O (M+H)+ 393.1563, found
3
21 20
4
4
Hz, 1H, ArH), 7.37(s, 1H, CH), 7.21 (d, J=7.6 Hz, 2H, 393.1559.
ArH), 6.64 (d, J=8.8 Hz, 1H, ArH), 5.55 (s, 2H, CH ), 4.61
2
(
s, 2H, CH ), 3.92 (s, 3H, CH ), 2.55 (s, 3H, CH ), 1.00 (dd,
2 3 3
Declaration of conflicting interests
1
3
J=34.6, 6.5 Hz, 12H, CH3); C NMR (150 MHz, CꢀCl3)
δ 196.0, 165.8, 153.7, 150.3, 145.9, 143.8, 133.1, 130.8,
1
3
1
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
27.4, 125.0, 123.7, 120.83, 118.2, 106.4, 68.8, 56.1, 40.1,
−
1
1.6, 28.3, 24.1, 23.8; IR (KBr) (vmax cm ): 2967, 1681,
662, 1597, 1456, 1283, 1107, 814; HRMS: m/z calcd for
Funding
+
C H N O (M+H) 463.2345, found 463.2330.
2
6
30
4
4
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported financially by Innovative Talents Program of
Henan Province (no. 174100510025), Foundation of Henan
Educational Committee (no. 18A150030), Scientific Research
Foundation for ꢀoctors (no. qd16106), and Youth Foundation (no.
8
-acetyl-5-methoxy-4-{[1-(naphthalen-1-yl)-1H-1,2,3-
triazol-4-yl]methyl}-2H-1,4-benzoxazin-3(4H)-one (6o):
Brown viscous liquid; H NMR (600 MHz, CꢀCl ) δ 7.99
1
3
(
(
d, J=7.1 Hz, 1H, ArH), 7.93 (d, J=8.1 Hz, 1H, ArH), 7.81
s, 1H, CH), 7.67 (d, J=8.9 Hz, 1H,ArH), 7.55 (dd, J=11.5,
6
.8 Hz, 3H, ArH), 7.46 (t, J=7.5 Hz, 1H, ArH), 7.31 (d,
J=8.4 Hz, 1H, ArH), 6.73 (d, J=8.9 Hz, 1H, ArH), 5.51 (s,
H, CH ), 4.63 (s, 2H, CH ), 3.97 (s, 3H, CH ), 2.58 (s, 3H,
2
016QK09) of Henan Normal University.
2
2
3
2
3
References
1
CH ); C NMR (150 MHz, CꢀCl ) δ 196.3, 165.9, 153.6,
3
3
1
2
3
4
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1
1
1
50.0, 144.4, 134.1, 133.6, 130.4, 128.4, 128.3, 127.9,
3
27.3, 127.1, 125.4, 125.0, 123.5, 122.0, 121.1, 118.7,
−
1
06.6, 68.8, 56.2, 40.7, 31.6; IR (KBr) (vmax cm ): 3058,
2
690, 1598, 1505, 1454, 1282, 1108, 803; HRMS: m/z
+
calcd for C H N O (M+H) 429.1563, found 429.1544.
2
4
20
4
4
8
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2
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2
1
1
3
1
.30 (s, 2H, CH ), 4.55 (s, 2H, CH ), 3.85 (s, 3H, CH ),
2 2 3
1
3
.54 (s, 3H, CH3); C NMR (150 MHz, CꢀCl ) δ 196.3,
3
9
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1.6; IR (KBr) (vmax cm ): 3137, 1688, 1598, 1501, 1456,
284, 1108, 804; HRMS: m/z calcd for C H N O
4
1
129.
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1
−
1
4
2
1
20
4
+
(
M+H) 393.1563, found 393.1556.
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1
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2
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