Hypervalent Iodine(III)-Promoted Radical Oxidative C-H Annulation of Arylamines with α-Keto Acids

Article abstract of DOI:10.1021/acs.joc.1c01424

A novel catalyst-free radical oxidative C-H annulation reaction of arylamines with α-keto acids toward benzoxazin-2-ones synthesis under mild conditions was developed. This hypervalent iodine(III)-promoted process eliminated the use of a metal catalyst or additive with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a radical initiator for this reaction. The synthetic utility of this method was confirmed by the synthesis of the natural product cephalandole A.

Full text of DOI:10.1021/acs.joc.1c01424

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Article
Hypervalent Iodine(III)-Promoted Radical Oxidative C−H Annulation
of Arylamines with α‑Keto Acids
Lipeng Long,* Jieyan Wang, Liuqing Gu, Shiguang Yang, Liang Qiao, Guotian Luo,
and Zhengwang Chen*
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ABSTRACT: A novel catalyst-free radical oxidative C−H
annulation reaction of arylamines with α-keto acids toward
benzoxazin-2-ones synthesis under mild conditions was developed.
This hypervalent iodine(III)-promoted process eliminated the use
of a metal catalyst or additive with high levels of functional group
tolerance. Hypervalent iodine(III) was both an oxidant and a
radical initiator for this reaction. The synthetic utility of this
method was confirmed by the synthesis of the natural product cephalandole A.
catalyzed,11 transition-metal-catalyzed,12 and hypervalent
iodine-facilitated decarboxylative radical acylation reactions,13
where the new C−C, C−N, and C−S bonds were formed.
Very recently, tandem condensation and decarboxylative
amination reactions between amines and α-keto acids have
attracted great attention. For example, Xu’s group described a
catalyst-free photocatalytic α-imino acids oxidative decarbox-
ylation followed by the hydrolysis approach to produce
amides14 (Scheme 1a). Takemoto’s group presented a
decarboxylative synthesis of amides via the nucleophilic
addition of tert-butyl hydroperoxide (TBHP) to imine
intermediate (Scheme 1b).15 They also reported using
nucleophilic sulfurizing species instead of the TBHP method
to afford thioamides (Scheme 1c).16 Although the decarbox-
ylative coupling of ketoacids as acyl radicals has achieved great
success, their binding as the ketoacid radicals has been less
explored.17 Herein we described the first metal-free hyper-
valent iodine(III)-promoted tandem condensation/radical
oxidative C−H annulation of arylamines with α-keto acids
for the synthesis of 2H-benzo[b][1,4]oxazin-2-ones (Scheme
1d).
INTRODUCTION
■
The benzoxazin-2-one nucleus represents a significant class of
lactone compounds1 that exhibits a broad spectrum of
biological and pharmacological activity.2 As a consequence, it
has received considerable attention to developing efficient
synthetic methods for their preparation. The current methods
toward benzoxazin-2-ones involve the use of o-aminophenols3
or its precursor4 in the presence of strong acids or bases at
elevated temperatures. However, the modern approaches from
the nonfunctionalized and more accessible anilines toward 2H-
benzoxazin-2-ones were still barely developed. Recently,
transition-metal-catalyzed oxidative C−H bond functionaliza-
tion proved to be a powerful tool to construct lactone
compounds.5 This strategy avoided the preinstallation of
functional groups with step and atom economy. Despite the
obvious advantages, some transition-metal catalysts still have
some shortcomings, such as high price, residual metallic
impurities, and generation of toxic waste. In the interest of
green and sustainable chemistry, further research into mild and
metal-free methods to access diverse benzoxazin-2-ones from
readily accessible precursors remains a great challenge.
On the other hand, C−H direct functionalization via a
radical process has been considered as one of the most
effective and straightforward method to form carbon−carbon
and carbon−heteroatom bonds from readily available starting
materials.6 The addition of oxygen-centered radicals to
aromatic rings is an efficient method for the construction of
complex molecules.7 The direct generation of oxygen-centered
radicals by the use of hypervalent iodine reagents (HIR)8 is
easy to handle and nontoxic under mild photoredox
conditions.9 α-Keto acids are cheap, readily available, stable,
and nontoxic, making them ideal precursors for the synthesis of
important compounds.10 In the past few years, they have
played an important role in the development of photoredox-
RESULTS AND DISCUSSION
■
We commenced our investigation with the reaction of 4-
methoxyaniline 1a and phenylglyoxylic acid 2a at room
temperature. As shown in Table 1, a variety of hypervalent
iodines including 1-hydroxy-1,2-benziodoxol-3-(1H)-one (IB−
Received: June 16, 2021
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A

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It was unfavorable when the reaction time was shortened to 6 h
(Table 1, entries 13 and 14). When the reaction was
performed at 40 °C, the yield of 3aa was slightly decreased
(Table 1, entry 15). In addition, the ratios of 1a to 2a were
tested, and it was found an excess of α-keto acid was beneficial
to the reaction (Table 1, entries 16 and 17). Furthermore, blue
LED irradition reduced the yield of 3aa, and shielded light did
not affect the yield (Table 1, entries 18 and 19). The optimal
conditions for 3aa are 1a/2a (1:1.5) with IB-OAc in CH2Cl2
solvent.
Scheme 1. Different Transformations of Amines and α-Keto
Acids
With the optimized conditions in hand, the substrate scope
was evaluated. As illustrated in Scheme 2, a variety of
a
Scheme 2. Scope of Arylamines
a
Table 1. Optimization of the Reaction Parameters
entry
oxidant
IB−OH
IB-OAc
IB-CF3
PhI(OAc)2
PhI(OOCCF3)2
solvent
additive
yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
52
80
35
40
10
nr
40
35
20
5
53
73
66
80
65
62
38
58
76
IB-OAc
IB-OAc
IBOAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
IB-OAc
9
b
10
11
12
Et3N
b
NaOAc
HOAc
b
c
13
d
14
e
15
f
16
g
17
h
18
19j
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), oxidant (0.1
mmol) in solvent (1.0 mL) for 8 h under air in an oil bath at room
b
c
temperature. The amount of additive was 0.10 mmol (1 equiv). 6 h.
d
e
f
a
10 h. In a preheated oil bath at 40 °C. The ratio of 1a to 2a is 1:1.
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), IB-OAc (0.1
g
h
The ratio of 1a to 2a is 1.5:1. 40 W blue LEDs (410−490 nm).
mmol) in DCM (1.0 mL) for 8 h under air in an oil bath at room
i
b
Light-shielded. nr = no reaction.
temperature. Two mmol scale.
OH), 1-acetoxy-1,2-benziodoxol-3-(1H)-one (IB-OAc), 1-
trifluoromethyl-1,2-benziodoxol-3-(1H)-one (IB-CF3), diace-
toxyiodo benzene (PhI(OAc)2), and [bis(trifluoroacetoxy)-
iodo]benzene (PhI(OOCCF3)2) were examined in the
reaction, among which IB-OAc was the most efficient with a
yield of 80% (Table 1, entries 1−5). Notably, the reaction
could not occur without an oxidant (Table 1, entry 6). The
screening of solvents showed that CH2Cl2 was an optimal
solvent (Table 1, entries 7−9). The addition of a base or an
acid would decrease the yield of 3aa (Table 1, entries 10−12).
arylamines were tolerated with 2-oxo-2-phenylacetic acid 2a
to generate the benzoxazin-2-one products in moderate to
excellent yields (3ba−3ra). Various aniline-bearing electron-
donating (3ba−3da) or electron-deficient groups (3fa−3ia)
were all suitable substrates for this transformation. It was found
that m-anisidine only produced para-cyclized product 3ca,
probably due to the steric hindrance. It is noteworthy that aryl
bromide and iodide could be further functionalized in metal-
catalyzed cross-coupling reactions (3ha−3ia). Strangely, ani-
line was carried out to give the desired product 3ea in a
B
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moderate yield. 1-Naphthylamine and 2-naphthylamine also
worked well to render the corresponding products 3ja and 3ka
in 86% and 75% yields, respectively. When 2-naphthylamine
was employed in this reaction, regioselective product 3ka was
obtained in a good yield. Fortunately, heteroaryl-substituted 2-
thienylamine was also compatible with this reaction (3la).
Moreover, disubstituted arylamines proved to be compatible
with the tandem annulation reaction, providing the corre-
sponding products in good to excellent yields (3ma−3ra).
Note that 3,4-dimethoxylbenzenamine delivered the product
3na in 90% yield, thus indicating the electronic effect was
essential for the reaction. The structure of 3fa was
unambiguously confirmed by X-ray crystal analysis.18 Luckily,
the reaction could be performed by large-scale synthesis and
yielded the product 3na in 72% yield.
for alkyl-substituted substrates and yielded the corresponding
3as and 3at in moderate yields. In addition, 4-chloroaniline
reacted successfully with phenylglyoxylic acid bearing am
electron-donating (3fh) or electron-withdrawing group (3fc).
These results implied that this annulation reaction can be
effective in elaborating the benzoxazin-2-one library.
Cephalandole A is known to be an important natural
product.4a,c The target molecule 3eu can be easily synthesized
in 80% yield from aniline 1e and 3-indolyloxoacetic acid 2u via
an HIR-promoted radical oxidative C−H annulation reaction
(Scheme 4a). Furthermore, the synthetic utility of the product
Scheme 4. Synthesis of Natural Product Cephalandole A
and Late-Stage Modifications of Benzoxazin-2-one
The scope of α-oxocarboxylic acids was then tested in the
reaction with 4-methoxyaniline or 4-chloroaniline, as shown in
Scheme 3. This reaction proceeded smoothly with electron-
a
Scheme 3. Scope of Arylamines and α-Keto Acids
was demonstrated for the construction of more highly
functionalized benzoxazin-2-one. The 4ae product was
prepared through the classic Sonogashira reaction with a
terminal alkyne in 87% yield (Scheme 4b).
Several control experiments were carried out to gain insight
into the reaction mechanism (Scheme 5). The control
Scheme 5. Control Experiments
a
Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), IB-OAc (0.1
mmol) in DCM (1.0 mL) for 8 h under air in an oil bath at room
temperature.
deficient groups such as fluoro, chloro, bromo, iodo, and
trifluoromethyl groups (3ab−3af, 3ai−3ak, 3am−3ao), like-
wise electron-rich groups (3ag, 3ah, 3al, 3ap). The reaction
was tolerable with various functional groups, whether p-
substituted phenylglyoxylic acids (3ab−3ah), m-substituted
phenylglyoxylic acids (3ai−3al), or o-substituted phenyl-
glyoxylic acids (3am−3ap), providing the corresponding
benzoxazin-2-ones in moderate to good yields. It indicated
that the steric hindrances of the substituents on the ketoacids
were negligible in the reaction. When α-naphthyloxoacetic acid
was employed in this reaction, the desired product 3aq was
achieved in 64% yield. While, in Duan’s work,4b only a trace
amount of product was detected. To our delight, the
heterocylic substituted 2-thienylglyoxylic acid was also
compatible in the reaction, albeit in a relatively low yield
(3ar). Apart from aryl groups, this reaction was also applicable
experiment indicated that HIR was necessary for this reaction
(Table 1, entry 6). When p-toluidine 1b was subjected to the
reaction with phenylglyoxylic acid 2a without IB-OAc in
methanol, imino intermediate 4a was obtained in 73% yield
(Scheme 5a). To our delight, 4a could be transformed into 3ba
product under the optimal conditions (Scheme 5b). These
results suggested that imino acetic acid was involved in the
reaction. Under the standard conditions, the formation of
C
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Scheme 6. Possible Reaction Mechanism
TMS as the internal standard unless otherwise noted. Mass spectra
were recorded on a GC−MS spectrometer at an ionization voltage of
70 eV equipped with a DB-WAX capillary column (internal diameter:
0.25 mm, length: 30 m). High-resolution mass spectra (HRMS)
(TOF) were measured using electrospray ionization (ESI) mass
spectrometry. Silica gel (300−400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with an ethyl
acetate/petroleum ether (PE) (60−90 °C) mixture.
The arylamines 1a−1r and α-ketoacids 2s and 2t were
commercially available from Sigma-Aldrich China. Substituted α-
ketoacids 2a−2r and 2u were prepared using the literature
procedure.20,11a The typical experimental procedures for the
preparation of starting materials and the characterization data for
new compounds are given below.
General Procedure for the Preparation of Substituted α-Keto
Acids (2a−2r and 2u)..20,11a Methyl ketones (5 mmol), SeO2 (6
mmol), and 20 mL of pyridine were added to a 50 mL round-bottom
flask. The reaction mixture was stirred at 110 °C for 1 h in an oil bath,
and then the temperature was reduce to 90 °C for 4 h. The desired
products were isolated by flash chromatography on silica gel to give α-
ketoacids 2 in 65−90% yields.
product 3ba was largely suppressed in the presence of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydrox-
ytoluene (BHT) as a radical scavenger (Scheme 5c).
Additionally, the yield of 3ba was still reduced to 18%, when
the free radical inhibitor TEMPO was added after the reaction
had proceeded for 2 h, as shown in Scheme 5d. These
experiments inferred that this transformation undergoes a
radical process.
Based on the mechanistic investigations above, a possible
reaction pathway for this radical oxidative C−H annulation
process was depicted in Scheme 6. Initially, the condensation
of primary amine 1a with α-keto acid 2a afforded the
intermediate α-iminoacid 4b.14 Next, transesterification of
BI-OAc with α-iminoacids 4b generated intermediate A with
the release of HOAc, and homolytic cleavage of A achieved
iodanyl radical B19 and carboxyl radical C.17 Subsequently,
intermediate D was afforded through the intramolecular free
radical addition of a carboxyl radical to a phenyl ring. Finally,
intermediate D oxidized to product 3aa via a hydrogen atom
abstraction (HAT) or SET/deprotonation processes, along
with the formation of o-iodobenzoic acid. It is important to
note that intermediate A was detected by HRMS.
In summary, we have explored an efficient tandem
condensation and C(sp2)−H lactonization reaction for the
synthesis of benzoxazin-2-ones from arylamines and α-keto
acids. A wide range of lactone compounds was constructed in
moderate to excellent yields via hypervalent iodine(III) as the
oxidant and radical initiator under room temperature. The
advantages of this transformation include catalyst and additive-
free, direct C(sp2)−H lactonization without decarboxylation,
readily accessible substrates, good functional group tolerance,
operational simplicity, etc. Further studies on the detailed
reaction mechanism and the application of HIRs are currently
ongoing in our laboratory.
General Procedure for the Synthesis of Hypervalent Iodine.21
Synthesis of 1-Hydroxy-1,2-benziodoxol-3-(1H)-one. NaIO4 (7.24 g,
33.8 mmol), 2-iodobenzene (I) (8 g, 32.2 mmol), and 50 mL of 30%
(v/v) AcOH were added to a 100 mL round-bottom flask. The
reaction mixture was refluxed for 4 h in a preheated oil bath with
vigorous stirring. The reaction mixture was then diluted with 180 mL
of cold water and cooled to room temperature, and the crude was
collected via suction filtration. The crude white solid was washed with
cold water (×3) and acetone (×3) and air-dried in the dark overnight
to afford 1-hydroxy-1,2-benziodoxol-3-(1H)-one (7.6 g, 90% yield).
Synthesis of 1-Acetoxy-1,2-benziodoxol-3-(1H)-one. 1-Hydroxy-
1,2-benziodoxol-3-(1H)-one (5.00 g, 18.9 mmol) and Ac2O were
refluxed in a preheated oil bath until the solution became clear. The
reaction mixture was then cooled slowly to −20 °C for 4 h using a dry
ice/ethylene glycol/ethanol (9:1) bath. The solution was decanted,
and the white solid (III) was dried under a vacuum with stirring for 24
h to afford 1-acetoxy-1,2-benziodoxol-3-(1H)-one (3.9 g, 67% yield).
Synthesis of 1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one. 1-
Acetoxy-1,2-benziodoxol-3-(1H)-one(5.0 g, 16.3 mmol) was dis-
solved in 50 mL of dry MeCN (under Ar). To the mixture were
added trimethyl(trifluoromethyl)silane (3.6 mL, 24.4 mmol) and
cesium fluoride (0.04 g, 0.26 mmol) under argon. The reaction
mixture was then stirred vigorously at room temperature for 22 h. The
solvent was removed using a rotovap, and the mixture was purified by
column chromatography (CH2Cl2/MeOH (15:1)) to afford 1-
EXPERIMENTAL SECTION
■
General Information. Melting points were investigated using a
melting point instrument and are uncorrected. 1H and 13C{1H} NMR
spectra were obtained on a 400 or 500 MHz for 1H NMR and 100 or
125 MHz for 13C{1H} NMR. The chemical shifts are referenced to
signals at 7.26 and 77.0 ppm, respectively, chloroform is solvent with
D
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trifluoromethyl-1,2-benziodoxol-3-(1H)-one as a pure white solid (3.6
g, 70% yield).
13C{1H} NMR (125 MHz, CDCl3) δ 163.6 (d, J = 252.5 Hz), 151.6,
149.5 (d, J = 3.7 Hz), 147.5 (d, J = 12.5 Hz), 133.9, 131.5, 130.9 (d, J
= 10.5 Hz), 129.4, 128.6 (d, J = 2.9 Hz), 128.4, 113.5 (d, J = 23.3
Hz), 103.7(d, J = 26.3 Hz); HRMS (ESI) m/z calcd for C14H9FNO2
[M + H]+ 242.0612, found 242.0623.
General Procedure for the Synthesis of 2H-Benzo[b][1,4]oxazin-
2-ones. A mixture of arylamine (0.1 mmol), α-keto acid (0.15 mmol),
and IB-OAc (30.6 mg, 1 equiv) in DCM (1.0 mL) was stirred in the
air in an oil bath at room temperature for 8 h. After the reaction was
finished, water (5 mL) was added, and the solution was extracted with
ethyl acetate (3 × 5 mL), and the combined extract was dried with
anhydrous MgSO4. The solvent was removed, and the residue was
separated by column chromatography to give the pure sample.
Large-Scale Synthesis. A mixture of 3,4-dimethoxyaniline (306
mg, 2 mmol), 2-oxo-2-phenylacetic acid (450 mg, 3 mmol), and IB-
OAc (612 mg, 1 equiv) in DCM (5.0 mL) was stirred in the air in an
oil bath at room temperature for 8 h. After the reaction was finished,
water (10 mL) was added, the solution was extracted with ethyl
acetate (3 × 10 mL), and the combined extract was dried with
anhydrous MgSO4. The solvent was removed, and the residue was
separated by column chromatography to give 3na (408 mg, 72%).
7-Methoxy-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3aa): yel-
low solid, 20.2 mg, 80% yield; mp 129−130 °C; Rf = 0.21 (petroleum
7-Bromo-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3ha): brown
solid, 22.3 mg, 74% yield; mp 121−122 °C; Rf = 0.52 (petroleum
1
ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.32−
8.27 (m, 2H), 7.63 (td, J = 8.1, 2.1 Hz, 1H), 7.54−7.49 (m, 1H),
7.48−7.39 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 151.3,
150.7, 146.7, 133.8, 131.7, 130.6, 130.4, 129.5, 129.0(d, J = 1.9 Hz),
128.4, 124.6, 119.4; HRMS (ESI) m/z calcd for C14H9BrNO2 [M +
H]+ 301.9811, found 301.9823.
7-Iodo-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3ia): yellow
solid, 27.6 mg, 79% yield; mp 136−137 °C; Rf = 0.43 (petroleum
ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3) δ 8.32 (dt,
J = 8.6, 2.0 Hz, 2H), 7.70 (dt, J = 4.8, 1.7 Hz, 2H), 7.56−7.46 (m,
4H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.4, 151.1, 146.5, 135.0,
133.9, 131.8, 131.2, 130.5, 129.5, 128.5, 125.3, 96.1; HRMS (ESI) m/
z calcd for C14H9INO2 [M + H]+ 349.9672, found 349.9678.
2-Phenyl-3H-naphtho[2,1-b][1,4]oxazin-3-one (3ja):22 yellow
solid, 23.5 mg, 86% yield; mp 168−169 °C; Rf = 0.39 (petroleum
ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J
= 8.4 Hz, 1H), 8.53 (dd, J = 7.6, 1.9 Hz, 2H), 7.96 (d, J = 9.0 Hz,
1H), 7.89 (d, J = 8.1 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.64−7.50 (m,
4H), 7.47−7.38 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 152.7,
148.4, 144.8, 134.5, 132.4, 131.4, 131.1, 130.5, 129.5, 128.4, 128.3,
128.1, 126.7, 126.4, 122.9, 115.7.
1
ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.32−
8.24 (m, 2H), 7.74 (d, J = 8.9 Hz, 1H), 7.47 (dd, J = 10.0, 5.0 Hz,
3H), 6.94 (dd, J = 8.9, 2.6 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 3.89 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 162.2, 152.5, 148.1, 147.2,
134.4, 130.8, 130.4, 129.1, 128.3, 126.3, 113.3, 100.1, 56.00; HRMS
(ESI) m/z calcd for C15H12NO3 [M + H]+ 254.0812, found 254.0824.
7-Methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3ba):4b yel-
low solid, 13.3 mg, 56% yield; mp 117−118 °C; Rf = 0.38 (petroleum
1
3-Phenyl-2H-naphtho[1,2-b][1,4]oxazin-2-one (3ka):22 yellow
solid, 20.5 mg, 75% yield; mp 157−158 °C; Rf = 0.53 (petroleum
ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.34−
8.29 (m, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.54−7.46 (m, 3H), 7.19 (dd,
J = 8.1, 1.1 Hz, 1H), 7.12 (s, 1H), 2.48 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 152.5, 149.6, 146.4, 142.6, 134.3, 131.2, 129.8, 129.3,
129.0, 128.3, 126.7, 116.2, 21.8.
1
ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 8.53−
8.46 (m, 1H), 8.43 (ddd, J = 5.5, 4.3, 2.6 Hz, 2H), 7.93−7.87 (m,
1H), 7.84 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.70−7.62
(m, 2H), 7.60−7.49 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
152.3, 149.8, 142.5, 134.2, 131.3, 129.4, 128.7, 128.4, 127.9, 127.8,
127.2, 125.6, 125.4, 122.4, 122.0; HRMS (ESI) m/z calcd for
C18H12NO2 [M + H]+ 274.0863, found 274.0866.
6-Methoxy-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3ca): yellow
solid, 15.2 mg, 60% yield; mp 121−122 °C; Rf = 0.25 (petroleum
1
ether/ethyl acetate = 20:1); H NMR (400 MHz, CDCl3) δ 8.36−
8.29 (m, 2H), 7.56−7.47 (m, 3H), 7.31 (d, J = 2.9 Hz, 1H), 7.26 (d, J
= 1.9 Hz, 1H), 7.10 (dd, J = 9.0, 3.0 Hz, 1H), 3.89 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 157.1, 152.5, 151.1, 140.8, 134.2, 132.1,
131.4, 129.5, 128.4, 119.4, 116.8, 111.2, 55.9; HRMS (ESI) m/z calcd
for C15H12NO3 [M + H]+ 254.0812, found 254.0813.
2-Phenyl-3H-thieno[2,3-b][1,4]oxazin-3-one (3la): yellow solid,
17.9 mg, 78% yield; mp 127−128 °C; Rf = 0.37 (petroleum ether/
ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3) δ 8.29−8.21 (m,
2H), 7.53−7.45 (m, 3H), 7.22 (d, J = 6.0 Hz, 1H), 7.01 (d, J = 5.9
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.3, 151.4, 146.3,
134.2, 132.1, 131.0, 128.9, 128.4, 122.6, 116.6; HRMS (ESI) m/z
calcd for C12H8NO2S [M + H]+ 230.0270, found 230.0279.
6,7-Dimethyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3ma):
yellow solid, 15.6 mg, 62% yield; mp 136−137 °C; Rf = 0.39
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 8.36−8.25 (m, 2H), 7.59 (s, 1H), 7.49 (d, J = 6.9 Hz, 3H), 7.09 (s,
1H), 2.37 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
152.8, 149.6, 144.6, 141.4, 134.5, 134.4, 131.0, 129.9, 129.4, 129.3
128.3, 116.5, 20.3, 19.3; HRMS (ESI) m/z calcd for C16H14NO2 [M
+ H]+ 252.1019, found 252.1021.
6,7-Dimethoxy-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3na):
yellow solid, 25.5 mg, 90% yield; m.p 155−156 °C; Rf = 0.29
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3)
δ 8.30 (t, J = 2.7 Hz, 2H), 7.49 (dd, J = 6.0, 4.6 Hz, 3H), 7.26 (d, J =
1.3 Hz, 1H), 6.81 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 152.8, 152.3, 147.5, 147.2, 142.0, 134.5, 130.8,
129.1, 128.3, 125.7, 109.8, 98.6, 56.6, 56.4; HRMS (ESI) m/z calcd
for C16H14NO4 [M + H]+ 284.0917, found 284.0929.
7-Phenoxy-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3da): yellow
solid, 17.6 mg, 56% yield; mp 121−122 °C; Rf = 0.30 (petroleum
1
ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.35−
8.27 (m, 2H), 7.78 (dd, J = 9.5, 5.1 Hz, 1H), 7.55−7.40 (m, 5H), 7.23
(dd, J = 4.8, 3.7 Hz, 1H), 7.14−7.09 (m, 2H), 7.01 (dd, J = 8.8, 2.6
Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 160.6, 155.2, 152.2, 148.2, 147.8, 134.3, 131.1, 130.6, 130.2,
129.2, 128.4, 127.4, 125.2, 120.4, 115.4, 104.3; HRMS (ESI) m/z
calcd for C20H14NO3 [M + H]+ 316.0968, found 316.0981.
3-Phenyl-2H-benzo[b][1,4]oxazin-2-one (3ea):4b white solid, 10.3
mg, 46% yield; mp 109−110 °C; Rf = 0.30 (petroleum ether/ethyl
acetate = 20:1); 1H NMR (400 MHz, CDCl3) δ 8.33 (dd, J = 8.1, 1.5
Hz, 2H), 7.83 (dd, J = 7.9, 1.4 Hz, 1H), 7.57−7.44 (m, 4H), 7.37 (td,
J = 7.8, 1.2 Hz, 1H), 7.31 (dd, J = 8.2, 1.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 152.2, 150.8, 146.5, 134.1, 131.7, 131.4, 131.1,
129.5, 129.4, 128.4, 125.6, 116.2.
7-Chloro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3fa): yellow
solid, 17.5 mg, 68% yield; mp 103−104 °C; Rf = 0.51 (petroleum
1
ether/ethyl acetate = 20:1); H NMR (500 MHz, CDCl3) δ 8.34−
8.29 (m, 2H), 7.77−7.72 (m, 1H), 7.56−7.51 (m, 1H), 7.48 (tt, J =
8.4, 1.5 Hz, 2H), 7.36−7.29 (m, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 151.4, 150.5, 146.7, 136.7, 133.8, 131.6, 130.2, 130.1, 129.4,
128.4, 126.1, 116.4; HRMS (ESI) m/z calcd for C14H9ClNO2 [M +
H]+ 258.0316, found 258.0325.
6-Fluoro-5-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one
(3oa): yellow solid, 14.0 mg, 55% yield; mp 140−141 °C; Rf = 0.51
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 8.44−8.36 (m, 2H), 7.56−7.48 (m, 3H), 7.21 (t, J = 8.8 Hz, 1H),
7.14 (d, J = 4.8 Hz, 1H), 2.62 (d, J = 2.3 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 158.0 (d, J = 240.1 Hz), 152.0, 149.7, 143.1,
134.2, 131.6, 130.7 (d, J = 9.2 Hz), 129.6, 128.4, 124.7 (d, J = 19.2
Hz), 117.9 (d, J = 26.0 Hz), 113.6 (d, J = 9.3 Hz), 9.2 (d, J = 3.5 Hz);
HRMS (ESI) m/z calcd for C15H11FNO2 [M + H]+ 256.0768, found
256.0771.
7-Fluoro-3-phenyl-2H-benzo[b][1,4]oxazin-2-one (3ga): yellow
solid, 13.7 mg, 57% yield; mp =142−143 °C; Rf = 0.65 (petroleum
1
ether/ethyl acetate = 10:1); H NMR (400 MHz, CDCl3) δ 8.34−
8.28 (m, 2H), 7.83 (dd, J = 8.9, 5.8 Hz, 1H), 7.57−7.46 (m, 3H), 7.12
(ddd, J = 8.8, 8.2, 2.7 Hz, 1H), 7.05 (dd, J = 8.4, 2.7 Hz, 1H);
E
https://doi.org/10.1021/acs.joc.1c01424
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
7-Chloro-6-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one
(3pa): yellow solid, 16.3 mg, 60% yield; mp 181−182 °C; Rf = 0.43
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3)
δ 8.35−8.28 (m, 2H), 7.83 (s, 1H), 7.57−7.45 (m, 3H), 7.19 (s, 1H),
2.49 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 152.0, 150.7,
144.9, 140.1, 133.9, 131.6, 131.1, 130.5, 129.5, 128.9, 128.4, 117.7,
20.6; HRMS (ESI) m/z calcd for C15H11ClNO2 [M + H]+ 272.0473,
found 272.0482.
7-Chloro-5-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one
(3qa): white solid, 14.9 mg, 55% yield; m.p 160−161 °C; Rf = 0.53
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 8.41−8.33 (m, 2H), 7.57−7.45 (m, 3H), 7.22 (d, J = 1.3 Hz, 1H),
7.16 (d, J = 1.9 Hz, 1H), 2.67 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 151.7, 148.5, 147.0, 140.1, 136.4, 134.2, 131.5, 129.5, 128.9,
128.4, 127.0, 114.0, 16.9; HRMS (ESI) m/z calcd for C15H11ClNO2
[M + H]+ 272.0473, found 272.0478.
7-Bromo-5-methyl-3-phenyl-2H-benzo[b][1,4]oxazin-2-one
(3ra): brown solid, 18.3 mg, 58% yield; mp 170−171 °C; Rf = 0.51
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 8.40−8.34 (m, 2H), 7.54−7.45 (m, 3H), 7.36 (dd, J = 1.9, 0.7 Hz,
1H), 7.30 (d, J = 1.6 Hz, 1H), 2.66 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 151.6, 148.7, 146.9, 140.3, 134.2, 131.5, 129.8, 129.5,
129.2, 128.4, 124.4, 117.0, 16.8; HRMS (ESI) m/z calcd for
C15H11BrNO2 [M + H]+ 315.9968, found 315.9971.
3-(4-Fluorophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ab): yellow solid, 13.6 mg, 50% yield; mp 149−150 °C; Rf = 0.20
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3)
δ 8.35 (ddd, J = 7.1, 5.3, 2.5 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.18−
7.11 (m, 2H), 6.94 (dd, J = 8.9, 2.7 Hz, 1H), 6.78 (d, J = 2.6 Hz, 1H),
3.89 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.5 (d, J = 250.8
Hz), 162.2, 152.5, 148.0, 145.8, 131.4 (d, J = 8.7 Hz), 130.6 (d, J =
3.0 Hz), 130.3, 126.2, 115.4(d, J = 21.4 Hz), 113.4, 100.1, 56.0;
HRMS (ESI) m/z calcd for C15H11FNO3 [M + H]+ 272.0718, found
272.0728.
3-(4-Chlorophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ac): yellow solid, 15.8 mg, 55% yield; mp 178−179 °C; Rf = 0.25
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 8.28 (d, J = 7.7 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.7
Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.76 (s, 1H), 3.88 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.4, 152.3, 148.1, 145.6,
137.0, 132.8, 130.4, 130.3, 128.5, 126.1, 113.5, 100.0, 56.0; HRMS
(ESI) m/z calcd for C15H11ClNO3 [M + H]+ 288.0422, found
288.0434.
3-(4-Bromophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ad): yellow solid, 19.2 mg, 58% yield; mp 141−142 °C; Rf = 0.40
(petroleum ether/ethyl acetate = 10:1); 1H NMR (500 MHz, CDCl3)
δ 8.26−8.19 (m, 2H), 7.73 (d, J = 8.9 Hz, 1H), 7.64−7.57 (m, 2H),
6.96 (dd, J = 8.9, 2.7 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.91 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 162.4, 152.4, 148.2, 145.8,
133.3, 131.6, 130.6, 130.4, 126.2, 125.7, 113.5, 100.1, 56.0; HRMS
(ESI) m/z calcd for C15H11BrNO3 [M + H]+ 331.9917, found
331.9930.
7-Methoxy-3-(p-tolyl)-2H-benzo[b][1,4]oxazin-2-one (3ag): yel-
low solid, 16.0 mg, 60% yield; mp 138−139 °C; Rf = 0.25 (petroleum
ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J
= 8.3 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 6.92
(dd, J = 8.9, 2.6 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 2.42
(s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.9, 152.6, 148.0,
147.1, 141.3, 131.7, 130.2, 129.1, 126.3, 113.2, 100.0, 56.0, 21.5;
HRMS (ESI) m/z calcd for C16H14NO3 [M + H]+ 268.0968, found
268.0971.
7-Methoxy-3-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-2-one
(3ah): yellow solid, 18.4 mg, 65% yield; m.p 137−138 °C; Rf = 0.30
(petroleum ether/ethyl acetate = 10:1); 1H NMR (500 MHz, CDCl3)
δ 8.35−8.32 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.00−6.97 (m, 2H),
6.93 (dd, J = 8.9, 2.7 Hz, 1H), 6.78 (d, J = 2.6 Hz, 1H), 3.89 (s, 3H),
3.88 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.9, 161.7,
152.7, 147.8, 146.5, 130.9, 130.0, 127.1, 126.4, 113.8, 113.2, 100.0,
56.0, 55.4; HRMS (ESI) m/z calcd for C16H14NO4 [M + H]+
284.0917, found 284.0929.
3-(3-Fluorophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ai): yellow solid, 16.0 mg, 59% yield; mp 126−127 °C; Rf = 0.39
(petroleum ether/ethyl acetate = 10:1); 1H NMR (500 MHz, CDCl3)
δ 8.14 (d, J = 7.9 Hz, 1H), 8.05 (dd, J = 10.5, 1.8 Hz, 1H), 7.70 (d, J
= 8.9 Hz, 1H), 7.51−7.35 (m, 1H), 7.17 (td, J = 8.2, 2.5 Hz, 1H),
6.93 (dd, J = 8.9, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 3.88 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 162.6 (d, J = 243.8 Hz), 162.5,
152.2, 148.2, 145.4 (d, J = 3.8 Hz), 136.4 (d, J = 7.5 Hz), 130.5, 129.8
(d, J = 7.5 Hz), 126.08, 124.8 (d, J = 3.8 Hz), 117.7 (d, J = 21.3 Hz),
116.0 (d, J = 23.8 Hz), 113.5, 100.0, 56.0; HRMS (ESI) m/z calcd for
C15H11FNO3 [M + H]+ 272.0718, found 272.0729.
3-(3-Chlorophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3aj): yellow solid, 18.1 mg, 63% yield; mp 137−138 °C; Rf = 0.40
(petroleum ether/ethyl acetate = 10:1); 1H NMR (500 MHz, CDCl3)
δ 8.31 (t, J = 1.7 Hz, 1H), 8.26−8.21 (m, 1H), 7.72 (d, J = 8.9 Hz,
1H), 7.49−7.36 (m, 2H), 6.94 (dd, J = 8.9, 2.6 Hz, 1H), 6.78 (d, J =
2.6 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
162.6, 152.2, 148.2, 145.4, 136.0, 134.4, 130.8, 130.5, 129.5, 129.0,
127.3, 126.1, 113.5, 100.1, 56.0; HRMS (ESI) m/z calcd for
C15H11ClNO3 [M + H]+ 288.0422, found 288.0433.
3-(3-Bromophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ak): yellow solid, 18.5 mg, 56% yield; mp 81−82 °C; Rf = 0.39
(petroleum ether/ethyl acetate = 10:1); 1H NMR (500 MHz, CDCl3)
δ 8.47 (t, J = 1.8 Hz, 1H), 8.33−8.26 (m, 1H), 7.74 (d, J = 8.9 Hz,
1H), 7.61 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H),
6.96 (dd, J = 8.9, 2.7 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 3.90 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 162.6, 152.2, 148.2, 145.3,
136.3, 133.7, 131.8, 130.6, 129.8, 127.8, 126.2, 122.5, 113.6, 100.1,
56.1; HRMS (ESI) m/z calcd for C15H11BrNO3 [M + H]+ 331.9917,
found 331.9930.
7-Methoxy-3-(m-tolyl)-2H-benzo[b][1,4]oxazin-2-one (3al): yel-
low oil, 13.4 mg, 50% yield; mp 152−153 °C; Rf = 0.27 (petroleum
ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J
= 6.8 Hz, 2H), 7.74 (d, J = 8.9 Hz, 1H), 7.33 (dd, J = 19.9, 7.9 Hz,
2H), 6.94 (dd, J = 8.9, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 3.89 (s,
3H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 152.5,
148.1, 147.4, 138.0, 134.4, 131.7, 130.3, 129.5, 128.2, 126.4, 126.3,
113.3, 100.1, 56.0, 21.5; HRMS (ESI) m/z calcd for C16H14NO3 [M
+ H]+ 268.0968, found 268.0976.
3-(2-Fluorophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3am): white solid, 17.1 mg, 63% yield; mp 174−175 °C; Rf = 0.59
(petroleum ether/ethyl acetate = 5:1); 1H NMR (400 MHz, CDCl3)
δ 7.75 (d, J = 8.9 Hz, 1H), 7.68 (td, J = 7.4, 1.7 Hz, 1H), 7.49 (tdd, J
= 8.2, 5.1, 1.8 Hz, 1H), 7.28 (dd, J = 5.8, 4.8 Hz, 1H), 7.23−7.16 (m,
1H), 6.96 (dd, J = 8.9, 2.7 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 3.92 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.7, 160.7 (d, J = 252.9
Hz), 152.0, 148.4, 146.7, 132.1 (d, J = 8.4 Hz), 131.0 (d, J = 2.5 Hz),
130.6, 126.2, 124.2 (d, J = 3.6 Hz), 123.2 (d, J = 13.6 Hz), 116.3(d, J
= 21.6 Hz), 113.4, 100.3, 56.1; HRMS (ESI) m/z calcd for
C15H11FNO3 [M + H]+ 272.0718, found 272.0725.
3-(4-Iodophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ae): yellow solid, 29.2 mg, 77% yield; mp 170−171 °C; Rf = 0.25
(petroleum ether/ethyl acetate = 20:1); 1H NMR (400 MHz, CDCl3)
δ 8.08−8.01 (m, 2H), 7.82−7.77 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H),
6.93 (dd, J = 8.9, 2.7 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 3.88 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.4, 152.3, 148.1, 145.9,
137.5, 133.8, 130.6, 130.4, 126.2, 113.5, 100.0, 98.1, 56.1; HRMS
(ESI) m/z calcd for C15H11INO3 [M + H]+ 379.9778, found
379.9782.
7-Methoxy-3-(4-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]-
oxazin-2-one (3af): yellow solid, 11.6 mg, 36% yield; mp 140−141
°C; Rf = 0.38 (petroleum ether/ethyl acetate = 10:1); 1H NMR (400
MHz, CDCl3) δ 8.44 (d, J = 8.2 Hz, 2H), 7.74 (dd, J = 12.3, 8.6 Hz,
3H), 6.97 (dd, J = 8.9, 2.7 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 3.91 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 152.3, 148.3, 145.4,
137.6, 132.2 (q, J = 32.0 Hz), 130.7, 129.4, 126.2, 125.2 (q, J = 4.0
Hz), 123.9 (q, J = 271.0 Hz), 113.7, 100.1, 56.1; HRMS (ESI) m/z
calcd for C16H11F3NO3 [M + H]+ 322.0686, found 322.0690.
3-(2-Chlorophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3an): yellow solid, 16.9 mg, 59% yield; mp 151−152 °C; Rf = 0.58
F
https://doi.org/10.1021/acs.joc.1c01424
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Article
(petroleum ether/ethyl acetate = 5:1); 1H NMR (500 MHz, CDCl3)
δ 7.74 (d, J = 8.9 Hz, 1H), 7.54 (dd, J = 7.3, 1.8 Hz, 1H), 7.49 (dd, J
= 7.9, 1.0 Hz, 1H), 7.41 (dtd, J = 16.2, 7.4, 1.5 Hz, 2H), 6.96 (dd, J =
8.9, 2.6 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 3.91 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 162.7, 152.0, 149.3, 148.6, 134.2, 133.4,
131.1, 130.8, 130.6, 130.0, 126.9, 125.9, 113.4, 100.5, 56.1; HRMS
(ESI) m/z calcd for C15H11ClNO3 [M + H]+ 288.0422, found
288.0434.
3-(2-Bromophenyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one
(3ao): white solid, 17.5 mg, 53% yield; mp 141−142 °C; Rf = 0.55
(petroleum ether/ethyl acetate = 5:1); 1H NMR (400 MHz, CDCl3)
δ 7.74 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 8.0, 0.9 Hz, 1H), 7.51 (dd, J
= 7.6, 1.7 Hz, 1H), 7.44 (d, J = 1.0 Hz, 1H), 7.34 (td, J = 7.8, 1.8 Hz,
1H), 6.96 (dd, J = 8.9, 2.7 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 3.91 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.7, 151.9, 150.4, 148.6,
136.0, 133.1, 131.2, 130.8, 130.6, 127.5, 125.8, 122.5, 113.4, 100.5,
56.1; HRMS (ESI) m/z calcd for C15H11BrNO3 [M + H]+ 331.9917,
found 331.9930.
7-Methoxy-3-(o-tolyl)-2H-benzo[b][1,4]oxazin-2-one (3ap):
white solid, 13.4 mg, 50% yield; mp 147−148 °C; Rf = 0.34
(petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, CDCl3)
δ 7.72 (d, J = 8.9 Hz, 1H), 7.52−7.48 (m, 1H), 7.37 (dd, J = 10.8, 4.1
Hz, 1H), 7.32−7.27 (m, 2H), 6.96 (dd, J = 8.9, 2.6 Hz, 1H), 6.83 (d, J
= 2.6 Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.3, 152.7, 151.2, 148.3, 137.1, 134.3, 130.9, 130.4, 129.9,
129.5, 126.1, 125.8, 113.2, 100.4, 56.1, 20.1; HRMS (ESI) m/z calcd
for C16H14NO3 [M + H]+ 268.0968, found 268.0971.
7-Methoxy-3-(naphthalen-1-yl)-2H-benzo[b][1,4]oxazin-2-one
(3aq): yellow solid, 19.4 mg, 64% yield; mp 193−194 °C; Rf = 0.58
(petroleum ether/ethyl acetate = 5:1); 1H NMR (500 MHz, CDCl3)
δ 8.08−8.01 (m, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.96−7.88 (m, 1H),
7.80 (dd, J = 21.1, 7.9 Hz, 2H), 7.64−7.47 (m, 3H), 7.01−6.95 (m,
1H), 6.87 (s, 1H), 3.92 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
162.5, 153.1, 150.0, 148.4, 133.9, 131.7, 131.2, 130.8, 130.5, 128.7,
128.3, 126.9, 126.2, 124.9 (d, J = 10 Hz), 113.3, 100.4, 56.1; HRMS
(ESI) m/z calcd for C19H14NO3 [M + H]+ 304.0968, found 304.0982.
7-Methoxy-3-(thiophen-2-yl)-2H-benzo[b][1,4]oxazin-2-one
(3ar): green solid, 15.0 mg, 58% yield; mp 167−168 °C; Rf = 0.25
(petroleum ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3)
δ 8.33 (dd, J = 3.8, 1.0 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.55 (dd, J
= 5.0, 1.0 Hz, 1H), 7.16 (dd, J = 5.0, 3.9 Hz, 1H), 6.94 (dd, J = 8.9,
2.7 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.7, 151.7, 147.6, 142.3, 138.9, 132.1, 131.3,
129.8, 128.4, 126.1, 113.4, 100.2, 56.0; HRMS (ESI) m/z calcd for
C13H10NO3S [M + H]+ 260.0376, found 260.0388.
116.3, 113.9, 55.5; HRMS (ESI) m/z calcd for C15H11ClNO3 [M +
H]+ 288.0422, found 288.0424.
7-Chloro-3-(4-chlorophenyl)-2H-benzo[b][1,4]oxazin-2-one
(3fc): yellow solid, 12.2 mg, 42% yield; mp 173−174 °C; Rf = 0.73
(petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, CDCl3)
δ 8.31 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.6
Hz, 2H), 7.40−7.28 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
151.3, 149.1, 146.7, 138.2, 137.1, 132.1, 130.8, 130.2, 130.1, 128.7,
126.3, 116.5; HRMS (ESI) m/z calcd for C14H8Cl2NO2 [M + H]+
291.9927, found 291.9938.
3-(1H-indol-3-yl)-2H-benzo[b][1,4]oxazin-2-one (3eu):4a yellow
solid, 21.0 mg, 80% yield; mp 248−249 °C; Rf = 0.38 (petroleum
ether/ethyl acetate = 5:1); 1H NMR (400 MHz, DMSO) δ 11.98 (s,
1H), 8.75 (dt, J = 6.3, 2.7 Hz, 1H), 8.70 (s, 1H), 7.89−7.79 (m, 1H),
7.57−7.50 (m, 1H), 7.49−7.38 (m, 3H), 7.30−7.23 (m, 2H);
13C{1H} NMR (100 MHz, DMSO) δ 152.5, 148.4, 145.3 137.1,
134.2, 132.4, 129.1, 128.2, 126.4, 125.8, 123.5, 123.3, 122.0, 116.4,
112.7, 111.1; HRMS (ESI) m/z calcd for C16H11N2O2 [M + H]+
263.0815, found 263.0821.
7-Methoxy-3-(4-(phenylethynyl)phenyl)-2H-benzo[b][1,4]-
oxazin-2-one (4ae): yellow solid, 30.7 mg, 87% yield; mp 168−169
°C; Rf = 0.33 (petroleum ether/ethyl acetate = 10:1); 1H NMR (400
MHz, CDCl3) δ 8.38−8.33 (m, 2H), 7.74 (d, J = 8.9 Hz, 1H), 7.64−
7.60 (m, 2H), 7.56 (dd, J = 6.5, 3.2 Hz, 2H), 7.39−7.34 (m, 3H), 6.95
(dd, J = 8.9, 2.7 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 3.90 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 152.5, 148.1, 146.0,
134.0, 131.7, 131.5, 130.4, 129.0, 128.6, 128.4, 126.3, 125.8, 123.0,
113.5, 100.0, 91.9, 89.2, 56.1; HRMS (ESI) m/z calcd for C23H16NO3
[M + H]+ 354.1125, found 354.1127.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01424.
1H and 13C NMR spectra, crystal data, and preparation
of starting materials (PDF)
Accession Codes
CCDC 2076545 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
3-(tert-Butyl)-7-methoxy-2H-benzo[b][1,4]oxazin-2-one (3as):
yellow solid, 10.5 mg, 45% yield; mp 87−88 °C; Rf = 0.38 (petroleum
ether/ethyl acetate = 20:1); 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J
= 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.5 Hz, 1H), 6.72 (d, J = 2.5 Hz,
1H), 3.86 (s, 3H), 1.43 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ
161.4, 159.0, 151.1, 148.1, 130.0, 125.4, 112.6, 99.9, 55.9, 39.0, 27.7;
HRMS (ESI) m/z calcd for C13H16NO3 [M + H]+ 234.1125, found
234.1136.
7-Methoxy-3-phenethyl-2H-benzo[b][1,4]oxazin-2-one (3at):
yellow solid, 10.1 mg, 36% yield; mp 106−107 °C; Rf = 0.33
(petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 4.6 Hz, 4H), 7.21 (d,
J = 4.2 Hz, 1H), 6.91 (dd, J = 8.9, 2.7 Hz, 1H), 6.75 (d, J = 2.7 Hz,
1H), 3.88 (s, 3H), 3.17 (ddd, J = 5.9, 5.3, 2.0 Hz, 2H), 3.10 (ddd, J =
9.0, 5.2, 1.9 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.6,
153.2, 153.1, 147.9, 141.0, 129.7, 128.6, 128.5, 126.2, 125.7, 112.9,
100.4, 56.0, 35.6, 32.3; HRMS (ESI) m/z calcd for C17H16NO3 [M +
H]+ 282.1125, found 282.1130.
AUTHOR INFORMATION
■
Corresponding Authors
Lipeng Long − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, P.R. China; Email: long_lipeng@
126.com
Zhengwang Chen − Key Laboratory of Organo-
Pharmaceutical Chemistry of Jiangxi Province, Gannan
Normal University, Ganzhou 341000, P.R. China;
orcid.org/0000-0002-6795-9625; Email: chenzwang@
126.com
Authors
Jieyan Wang − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, P.R. China
Liuqing Gu − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, P.R. China
8-Chloro-3-(4-methoxyphenyl)-2H-benzo[b][1,4]oxazin-2-one
(3fh): yellow solid, 14.4 mg, 50% yield; mp 156−157 °C; Rf = 0.55
(petroleum ether/ethyl acetate = 10:1); 1H NMR (400 MHz, CDCl3)
δ 8.40−8.34 (m, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.35−7.28 (m, 2H),
7.00−6.95 (m, 2H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 162.6, 151.7, 149.5, 146.5, 136.0, 131.4, 130.4, 129.8, 126.5, 126.0,
G
https://doi.org/10.1021/acs.joc.1c01424
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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1447−1450.
Shiguang Yang − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, P.R. China
Liang Qiao − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, P.R. China
Guotian Luo − Key Laboratory of Organo-Pharmaceutical
Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou 341000, P.R. China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01424
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSF of Jiangxi
Provincial Education Department (GJJ201422, GJJ190776,
and GJJ180776) and Science and Technology Project of
Ganzhou City. We acknowledge the Analytical & Testing
Center of Beijing Normal University for the high-resolution
mass spectrometry analyses.
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