pubs.acs.

org/joc Article

One Stone, Three Birds: One-Pot Synthesis of

Pyrido[3,2‑a]phenoxazin-5-one Derivatives from o‑Aminophenols
with Triple Roles, Paraformaldehyde, and Enaminones via the
Povarov Reaction
Shuang-Gui Lei,§ You Zhou,§ Li-Sheng Wang, Zhi-Cheng Yu, Ting Chen, Yan-Dong Wu, Meng Gao,*
and An-Xin Wu*
Downloaded via CHINESE UNIV OF HONG KONG SHENZHEN on August 5, 2023 at 05:32:48 (UTC).

Cite This: J. Org. Chem. 2023, 88, 11150−11160 Read Online

See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

ACCESS Metrics & More Article Recommendations *

sı Supporting Information

ABSTRACT: A novel multicomponent cascade cyclization reaction in one pot for the preparation of pyrido[3,2-a]phenoxazin-5-
ones from simple o-aminophenols, paraformaldehyde, and enaminones has been established. It is noteworthy that o-aminophenol
plays multiple roles serving as both a bis-nucleophile and an iminoquinone precursor, which can in situ generate
aminophenoxazinones to undergo the Povarov reaction for the first time to yield pyrido[3,2-a]phenoxazin-5-ones with a high
efficiency. Moreover, the photoluminescence of pyrido[3,2-a]phenoxazin-5-ones has polarity sensitivity and features aggregation-
induced emission (AIE) characteristics, which is promising for bioimaging and theranostic applications.

■ INTRODUCTION
Pyridophenoxazinones featuring four-annulated coplanar ar-
omatic rings have a wide range of pharmacological activities,
such as DNA intercalation and BACE1 and topoisomerase
inhibitors, which are promising for the treatment of cancer,
cataracts, and inflammation.1,2 Therefore, the development of
their synthetic methods has become a hot research topic.
According to a survey of the literature, only two main synthetic
strategies have been reported for their synthesis: the first
strategy is based on the self-dimerization of 3-hydroxykynur-
enine, and the other strategy is based on the cyclization
reaction between o-aminophenols and quinoline-5,8-dione
(Scheme 1a,b).3 Obviously, it is of great significance to
develop new synthetic methods with the advantages of easily
available raw materials, mild reaction conditions, and diverse
molecular skeletons of target compounds.
Over the past 10 years, our group has performed detailed
studies of the Povarov reactions of arylamines with two
reactive sites in an I2−DMSO system.4 However, the Povarov
reactions involving o-aminophenol with more active sites have
rarely been reported. Recently, it has been reported that o-
aminophenol underwent self-dimerization to obtain amino-
phenoxazinone.5 It is worth noting that self-dimer amino-
phenoxazinone is a potential Povarov reaction precursor. Based
on the above studies, we envisioned that the self-dimer formed
in situ from o-aminophenol under our system can subsequently
undergo the Povarov reaction, which is expected to capture
enaminones6 and paraformaldehyde to provide a novel
synthesis method for pyridophenoxazinone skeletons. The
envision faces great challenges: first, the self-dimerization of o-
aminophenol must be compatible with the Povarov reaction in
our system and the two processes must be performed in an
orderly fashion in one pot; second, many side reactions
between substrates of the multicomponent reaction must be
overcome.
In our continuing efforts, mediated by I2−DMSO, we
utilized multiple roles of o-aminophenol to generate a Povarov
reaction precursor in situ so as to construct the A and B rings
of pyrido[3,2-a] phenoxazin-5-one skeletons. In particular, the
Received: May 18, 2023
Published: July 18, 2023

© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.3c01118

11150 J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 1. Methods for Constructing Pyrido[3,2-a] phenoxazin-5-one Skeletons

Table 1. Optimization of the Reaction Conditionsa,b

entry I2 (equiv) additives (equiv) temp (°C) yield (%)b

1 1.0 100 41%
2 0.5 MnO2 (1.0) 100 35%
3 1.0 MnO2 (1.0) 100 52%
4 1.5 MnO2(1.0) 100 57%
5 2.0 MnO2(1.0) 100 63%
6 2.5 MnO2(1.0) 100 61%
7 3.0 MnO2(1.0) 100 60%
8 2.0 MnO2(0.5) 100 56%
9 2.0 MnO2(1.5) 100 67%
10 2.0 MnO2(2.0) 100 64%
11c 2.0 MnO2(1.5) 100 69%
12d 2.0 MnO2(1.5) 100 75%
13e 2.0 MnO2(1.5) 100 72%
14d 2.0 MnO2(1.5) 90 73%
15d 2.0 MnO2(1.5) 110 70%
16d 2.0 MnO2(1.5) 120 68%
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol), 3a (0.5 mmol), I2 (equiv), additive (equiv), indicated temperature, DMSO 2.5 mL, 4 h.
b
Isolated yields. c1a:2a:3a = 1: 6: 1. d1a:2a:3a = 2: 4: 1. e1a:2a:3a = 2: 6: 1.

11151 https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 2. Substrate Scope for the Synthesis of 4 and 5a,b

a
Reaction conditions: 1 (2.0 mmol), 2a (4.0 mmol), 3 (1.0 mmol), I2 (2.0 mmol), MnO2 (1.5 mmol), DMSO (5 mL), 100 °C, and 4 h. bIsolated
yields.

11152 https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
Scheme 3. Control Experiments
dimer of o-aminophenol is involved in the Povarov reaction,
which was developed for the first time. This single-step method
involving the three simple substrates has led to the develop-
ment of a facile, efficient one-pot system for the synthesis of
pyridophenoxazinone derivatives (Scheme 1c).
■ RESULTS AND DISCUSSION
At the beginning of this study, the reaction conditions were
investigated using o-aminophenol (1a), paraformaldehyde
(2a), and 3-(dimethylamino)-1-phenyl prop-2-en-1-one (3a)
as model substrates (Table 1). Using these compounds and in
the presence of I2 in DMSO at 100 °C, target product 4a was
obtained in 41% yield (entry 1). Attempts were made to
increase this yield by investigating the effects of various
additives, including acids, bases, metal salts, and oxidants (see
the Supporting Information for details). These trials indicated
that the yield of 4a was significantly increased following the
addition of MnO2. Considering that the equivalents of I2 and
MnO2 may affect the yield, the equivalents were optimized in
subsequent experiments, and 2.0 equiv I2 together with 1.5
equiv MnO2 was found to be optimal (entries 2−10). In other
trials, the optimal 1a:2a:3a equivalent ratio was determined to
be 2:4:1 (entries 11−13). Finally, the effect of temperature on
11153
pubs.acs.org/joc Article
the reaction yield was examined, and the best results were
obtained at 100 °C (entries 12 and 14−16).
With the optimal conditions in hand, the substrate scope
was assessed by examining different enaminones (3) and o-
aminophenols (1) (Scheme 2). Various alkyl-substituted
phenyl enaminones were found to be compatible with this
process (4a−4g, 69%−79%). In addition, when enaminones
were substituted with alkoxy groups, the target product was
obtained in good yields (4h−4l, 71%−80%). An enaminone
with a methylthio substituent provided a moderate yield (4m,
51%). Enaminones with halogen substituents were compatible
with the reaction (4n−4s, 54%−67%). In addition to good
yields of electron donor-substituted enaminones, enaminones
incorporating electron-withdrawing groups (-OCF3, -COOMe,
-CN, -NO2, -SO2Me) also reacted smoothly under the
optimized conditions (4t−4x, 70%−81%). It should also be
noted that substrates containing sterically bulky groups
afforded the corresponding products in good yields (4y−5a,
62%−70%). Heterocyclic enaminones such as pyridine,
thiophene, furan, and benzofuran were compatible under the
present reaction conditions and gave the target products in
49%−71% yields (5b−5f). The target product 5g was also
obtained in 70% yield from a styryl-substituted enaminone.
Furthermore, alkyl- and ester-substituted enaminones were
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
Scheme 4. Proposed Mechanism
converted into the corresponding products in good yields
(5h−5i, 72%−82%). Finally, o-aminophenols with methyl or
fluorine located at position 6 were found to be compatible
(5j−5l, 72%−84%). An enaminone substituted with an
−NMe2 group (5m) did not react to give the desired product.
To further investigate compatibility, this reaction was
conducted on the 8.0 mmol scale, affording target product
4a in 68% yield (1.92 g).
A series of control experiments was performed to elucidate
the mechanism of this reaction (Scheme 3). In the absence of
I2, the reaction generated only a trace of the expected product
4a, and the yield was decreased to 41% without MnO2
(Scheme 3a). Subsequently, o-aminophenol (1a) was con-
verted into III in excellent yield in the presence of I2 and
MnO2, while the yield of III was found to be greatly reduced in
the absence of either I2 or MnO2 (Scheme 3b). The reaction of
III with paraformaldehyde (2a) and enaminone (3a) under the
standard conditions subsequently afforded product 4a in 65%
yield. This product was not obtained when I2 was removed
from the reaction system, while removing MnO2 had only a
slight effect on the yield of 4a (Scheme 3c). To explore if air
plays a role in the reaction, several control experiments were
conducted under argon (Scheme 3a−c). These results suggest
that I2 plays a key role in the overall reaction process, while
MnO2 primarily affects the dimerization of o-aminophenol and
air acts as an oxidant in the final aromatization step. The trial
shown in Scheme 3c also demonstrated that III is a potential
intermediate in this reaction, and the experiment in Scheme 3d
11154
pubs.acs.org/joc Article
was conducted to further confirm the mechanism (see the SI
for details).
Based on the above results and on prior studies,7 a possible
reaction mechanism is proposed in Scheme 4. Initially, o-
aminophenol (1a) is converted into iminoquinone (1ab) in
the presence of I2 and MnO2.5a,c 1ab then undergoes two
consecutive 1,4-additions with another molecule of the bis-
nucleophile o-aminophenol; the first is an intermolecular aza-
Michael addition to obtain I, while the second is an
intramolecular oxa-Michael addition to obtain intermediate
II.5a,b The latter is converted to aminophenoxazinone
intermediate III by oxidation. Subsequently, intermediate III
reacts with paraformaldehyde (2a) to form diene intermediate
IV, and intermediate IV undergoes [4 + 2] cycloaddition with
enaminone (3a), acting as a dienophile, to generate
intermediate V.4a,b Finally, intermediate V loses HNMe2
molecules and is aromatized to obtain product 4a.
Intermediates II, III, IV, and V are all detected by HRMS.
As a consequence of the π-conjugated four-annulated
structures of these newly synthesized pyrido[3,2-a] phenox-
azin-5-one derivatives, these compounds exhibited bright
orange fluorescence when viewed under a 365 nm UV lamp.
To gain insights into the photophysical properties, UV/Vis
spectra and fluorescence emission of 5h was measured in
different solvents (see SI for details), and we found that 5h
presented a solvatochromic effect;8 with increasing solvent
polarity, a red-shift was observed (Figure 1a). Subsequently,
trials using 5h in a THF/water mixed system with excitation at
360 nm showed that increasing the proportion of water
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
Figure 1. (a) Normalized photoluminescence spectra of 5h in different solvents. (b) Photoluminescence (PL) spectra of 5h in THF/H2O mixtures
with different water fractions ( f w); [5h] =10−5 mol/L. (c) Plots of the maximum photoluminescence intensity change with different f w. (d) Photos
of different f w using UV irradiation (λ = 365 nm).
intensified the fluorescent emissions, demonstrating a typical
AIE feature (Figure 1b). Water proportions greater than 70%
caused the fluorescence intensity to increase rapidly up to a
maximum at 95% water (Figure 1c). Photographs of 5h in
different water fractions using 365 nm UV irradiation are also
provided in Figure 1d. These photophysical characteristics
suggest that such compounds may have potential applications
in biological imaging, medical diagnosis, and treatment and
environmental monitoring.9
■ CONCLUSIONS
In summary, we developed a simple yet efficient one-pot
method for the synthesis of pyrido[3,2-a] phenoxazin-5-ones.
In this process, o-aminophenol plays multiple roles, serving as a
bis-nucleophile and an iminoquinone precursor, which can
generate aminophenoxazinone in situ for further Povarov
reaction with paraformaldehyde and enaminone to yield
pyrido[3,2-a]phenoxazin-5-ones with a high efficiency. This
reaction has significant advantages in terms of readily
accessible substrates, mild operating conditions, and excellent
substrate compatibility. Pyrido[3,2-a]phenoxazin-5-ones also
feature with aggregation-induced emission (AIE) character-
istics, which are promising for imaging-guided theranostic
applications.
■ EXPERIMENTAL SECTION
General Methods. All substrates and reagents were commercially
available and used without further purification. TLC analysis was
performed using pre-coated glass plates. Column chromatography was
performed using silica gel (200−300 mesh). 1H, 13C, and 19F spectra
were recorded in CDCl3 and DMSO-d6 on Bruker 400 MHz NMR
(AVANCE III HD 400) spectrometers and chemical shifts of 1H
11155
pubs.acs.org/joc Article
NMR are reported in ppm, relative to the internal standard of
tetramethylsilane (TMS, δ = 0.00 ppm). Chemical shifts of 13C NMR
were reported in ppm with the solvent as the internal standard
(CDCl3, δ = 77.0 ppm, DMSO-d6, δ = 39.5 ppm). Data are reported
as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, m = multiplet), coupling constants (Hz) and integration. 13C
spectra were recorded in CDCl3 on 100 MHz NMR spectrometers,
and resonances (δ) are given in ppm. 19F spectra were recorded in
CDCl3 on 376 MHz NMR spectrometers, and resonances (δ) are
given in ppm. HRMS were obtained on an Agilent LC1290-TOF
6224 equipped with an electrospray source. The X-ray crystal-
structure determinations of 4a were obtained on a Bruker APEX
DUO CCD system. Melting points were determined using XT-4
apparatus and not corrected. UV/Vis spectra were recorded using a
Shimadzu Corporation UV-2600 UV/Vis spectrophotometer. Fluo-
rescence spectra were recorded using an Hitachi Corporation F-7000
fluorescence spectrophotometer.
General Procedures for the Synthesis of Enaminone (3). To
a stirred solution of aryl methyl ketone (5.0 mmol, 1.0 equiv) in
toluene (5.0 mL), 1,1-dimethoxy-N,N-dimethylmethanamine (7.0
mmol, 1.4 equiv) was added and stirred at 110 °C (metal heating
block). After completion of the reaction (monitored by TLC), we
used ethyl acetate to transfer the reaction solution to the eggplant
shaped bottle, rotated it, and evaporated it under vacuum and
pressure at 60 °C (metal heating block) to obtain a yellow oil, which
turns into a yellow solid after cooling. We washed the solid with
petroleum ether with the aid of ultrasound and discarded the
supernatant. In this way, enaminone (3) can be obtained after three
times of washing. As for the synthesis of 3h, to a stirred solution of 1-
(tetrahydro-2H-pyran-4-yl)ethan-1-one (5.0 mmol, 1.0 equiv) in 1,4-
dioxane (5.0 mL), Bredereck’s Reagent (6.0 mmol, 1.2 equiv) was
added and stirred at 70 °C (metal heating block). After 5 h of
reaction, ethyl acetate can be used to transfer the reaction solution to
the flask, and then the target product 3h can be obtained by vacuum
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
decompression rotary evaporation. It can be used for standby without
column chromatography separation and purification.10
General Procedures for the Synthesis of Substrates 4 and 5
(4a as an Example). 1.0 mmol Scale. The reactions did not require
the protection of inert gases. Into a 35 mL sealed tube were added 1a
(218 mg, 2.0 mmol), 2a (120 mg, 4.0 mmol), 3a (175 mg, 1.0 mmol),
iodine (508 mg, 2.0 mmol), MnO2 (131 mg, 1.5 mmol), and dimethyl
sulfoxide (5 mL), the resulting mixture was stirred at 100 °C (metal
heating block), and the reaction tube was removed after about 4 h
until substrate conversion was almost complete by TLC analysis. The
reaction mixture was quenched with saturated Na2S2O3 solution (50
mL) and NaCl solution (150 mL), then the mixture was extracted
with EtOAc (150 mL × 2), and the reddish brown layers were
separated and combined, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (eluent: petroleum ether/
EtOAc = 2:1) to afford the product 4a (264 mg, 75% yield).
8.0 mmol Scale. The reactions did not require the protection of
inert gases. Into a 100 mL round flask were added 1a (1744 mg, 16.0
mmol), 2a (960 mg, 32.0 mmol), 3a (1400 mg, 8.0 mmol), iodine
(4064 mg, 16.0 mmol), MnO2 (1044 mg, 12.0 mmol), and dimethyl
sulfoxide (40 mL), the resulting mixture was stirred at 100 °C (metal
heating block), and the reaction tube was removed after about 4 h
until substrate conversion was almost complete by TLC analysis. The
reaction mixture was quenched with saturated Na2S2O3 solution (150
mL) and NaCl solution (300 mL), then the mixture was extracted
with EtOAc (300 mL × 2), and the reddish brown layers were
separated and combined, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (eluent: petroleum ether/
EtOAc = 2:1) to afford product 4a (1915 mg, 68% yield).
Analytical Data. 2-Benzoyl-5H-pyrido[3,2-a]phenoxazin-5-one
(4a). Yield 75%; 264 mg; yellowish brown solid; column
chromatography, silica gel (PE:EA, 2:1); mp 276−278 °C. 1H
NMR (400 MHz, CDCl3) δ 9.40 (d, J = 8.4 Hz, 2H), 7.91−7.86 (m,
3H), 7.71 (d, J = 6.8 Hz, 1H), 7.62−7.54 (m, 3H), 7.40 (t, J = 10.0
Hz, 2H), 6.70 (s, 1H). 13C{1H} (100 MHz, CDCl3) δ 193.6, 181.4,
153.4, 151.3, 148.4, 145.6, 144.0, 136.1, 135.0, 134.5, 133.8, 132.9,
132.6, 130.3, 130.2, 128.9, 127.4, 125.8, 116.2, 109.0. HRMS (ESI):
m/z [M + H]+ calcd for C22H13N2O3+: 353.0921; found: 353.0916.
2-(4-Methylbenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4b).
Yield 77%; 282 mg; yellowish brown solid column chromatography,
silica gel (PE:EA, 2:1); mp 269−271 °C. 1H NMR (400 MHz,
CDCl3) δ 9.37 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J
= 8.0 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.42−7.37 (m, 4H), 6.69 (s,
1H), 2.50 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.2, 181.4,
153.3, 151.3, 148.2, 145.7, 145.0, 144.0, 135.3, 134.4, 133.5, 132.8,
132.6, 130.4, 130.3, 129.6, 127.4, 125.8, 116.1, 109.0, 21.8. HRMS
(ESI): m/z [M + H]+ calcd for C23H15N2O3+:367.1077; found:
367.1079.
2-(4-Ethylbenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4c). Yield
75%; 285 mg; yellowish brown solid; column chromatography, silica
gel (PE:EA, 2:1); mp 255−257 °C. 1H NMR (400 MHz, CDCl3) δ
9.39 (d, J = 11.2 Hz, 2H), 7.88−7.83 (m, 3H), 7.58 (t, J = 7.7 Hz,
1H), 7.43−7.38 (m, 4H), 6.70 (s, 1H), 2.79 (q, J = 7.6 Hz, 2H), 1.32
(t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.3,
181.4, 153.3, 151.3, 151.1, 148.3, 145.8, 144.1, 135.5, 134.4, 133.7,
132.8, 132.6, 130.5, 130.3, 128.4, 127.5, 125.8, 116.2, 109.0, 29.0,
15.1. HRMS (ESI): m/z [M + H]+ calcd for C24H17N2O3+: 381.1234;
found: 381.1236.
2-(4-Isopropylbenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4d).
Yield 76%; 299 mg; light yellowish brown solid; column
chromatography, silica gel (PE:EA, 2:1); mp 242−244 °C. 1H
NMR (400 MHz, CDCl3) δ 9.37 (d, J = 4.0 Hz, 2H), 7.85 (d, J = 7.6
Hz, 3H), 7.56 (t, J = 7.6 Hz, 1H), 7.44−7.36 (m, 4H), 6.67 (q, 1H),
3.08−3.02 (m, 1H), 1.34 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ 193.1, 181.3, 155.6, 153.2, 151.2, 148.1, 145.6, 143.9,
135.3, 134.3, 133.7, 132.8, 132.5, 130.5, 130.2, 127.3, 127.0, 125.8,
116.1, 108.9, 34.3, 23.6. HRMS (ESI): m/z [M + H]+ calcd for
C25H19N2O3+: 395.1390; found: 395.1390.
11156
pubs.acs.org/joc Article
2-(4-(tert-Butyl)benzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(4e). Yield 79%; 322 mg; light orange-brown solid; column
chromatography, silica gel (PE:EA, 2:1); mp 183−185 °C. 1H
NMR (400 MHz, CDCl3,CF3COOD) δ 10.01 (s, 1H), 9.65 (s, 1H),
8.09 (d, J = 7.6 Hz, 1H), 7.88−7.82 (m, 3H), 7.66−7.60 (m, 4H),
6.98 (s, 1H), 1.40 (s, 9H). 13C {1H}NMR (100 MHz, CDCl3,
CF3COOD) δ 190.1, 176.0, 159.9, 153.4, 147.3, 144.3, 141.5,
141.4, 140.7, 138.0, 136.0, 133.2, 131.6, 131.4, 130.5, 129.1, 127.6,
126.5, 116.8, 108.0, 35.5, 30.8. HRMS (ESI): m/z [M + H]+ calcd for
C26H21N2O3+: 409.1547; found: 409.1540.
2-(3-Methylbenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4f).
Yield 71%; 260 mg; black-brown solid; column chromatography,
silica gel (PE:EA, 2:1); mp 249−250 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.97 (s, 1H), 9.62 (s, 1H), 8.09 (d, J = 5.6 Hz,
1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.68−7.57 (m, 4H), 7.50 (s, 1H),
6.99 (s, 1H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
CF3COOD) δ 190.7, 175.7, 153.5, 147.2, 144.3, 141.9, 141.2,
140.5, 139.8, 137.9, 136.22, 136.16, 134.3, 133.2, 131.4, 130.6, 129.2,
127.7, 116.9, 108.0, 21.0. HRMS (ESI): m/z [M + H]+ calcd for
C23H15N2O3+:367.1077; found: 367.1075.
2-(3,5-Bimethylbenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(4g). Yield 69%; 262 mg; black-brown solid; column chromatography,
silica gel (PE:EA, 2:1); mp 266−268 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 10.07 (s, 1H), 9.63 (s, 1H), 8.13 (s, 1H), 7.88
(s, 1H), 7.66 (s, 2H), 7.54−7.40 (m, 3H), 7.06 (s, 1H), 2.41 (s, 6H).
13
C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 190.8, 174.9, 154.0,
146.3, 144.5, 143.0, 140.6, 139.8, 138.4, 137.5, 136.9, 134.1, 133.5,
131.6, 129.5, 128.2, 117.0, 107.9, 20.8. HRMS (ESI): m/z [M + H]+
calcd for C24H17N2O3+: 381.1234; found: 381.1230.
2-(4-Methoxybenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4h).
Yield 80%; 306 mg; brown solid; column chromatography, silica gel
(PE:EA, 1:1); mp 245−246 °C. 1H NMR (400 MHz, CDCl3) δ 9.35
(d, J = 3.6 Hz, 2H), 7.91−7.85 ( m, 3H), 7.58 (t, J = 7.6 Hz, 1H),
7.40 ( q, J = 8.0 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 3.6 Hz,
1H), 3.94 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 192.1, 181.4,
164.2, 153.1, 151.3, 148.1, 145.7, 144.0, 135.8, 134.2, 132.8, 132.7,
132.6, 130.3, 128.8, 127.4, 125.8, 116.1, 114.2, 108.9, 55.6. HRMS
(ESI): m/z [M + H]+ calcd for C23H15N2O4+: 383.1026; found:
383.1020.
2-(4-Ethoxybenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4i).
Yield 78%; 309 mg; brown solid; column chromatography, silica gel
(PE:EA, 1:1); mp 247−249 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.90 (s, 1H), 9.57 (s, 1H), 8.07 (d, J = 6.8 Hz,
1H), 7.91−7.81 (m, 3H), 7.63−7.57 (m, 2H), 7.06 (d, J = 7.6 Hz,
2H), 6.97 (s, 1H), 4.18 (q, J = 8.0 Hz, 2H), 1.49 (t, J = 4.0 Hz, 3H).
13
C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 188.9, 175.6, 165.2,
153.5, 146.7, 144.4, 141.9, 141.2, 140.1, 138.7, 136.2, 133.4, 131.4,
129.2, 127.7, 126.6, 116.9, 115.3, 107.9, 64.4, 14.4. HRMS (ESI): m/z
[M + H]+ calcd for C24H17N2O4+: 397.1183; found: 397.1181.
2-(3-Methoxybenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4j).
Yield 75%; 287 mg; orange-brown solid; column chromatography,
silica gel (PE:EA, 1:1); mp > 300 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.98 (s, 1H), 9.67 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H),
7.83 (d, J = 7.2 Hz, 1H), 7.63 (m, 2H), 7.51−7.45 (m, 2H), 7.37 (d, J
= 6.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 3.88 (s, 3H).
13
C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 190.4, 176.1, 160.2,
153.4, 147.6, 144.3, 141.4, 140.9, 137.6, 136.0, 135.6, 133.2, 131.3,
130.3, 129.0, 127.6, 123.2, 121.5, 116.8, 114.3, 107.9, 55.5. HRMS
(ESI): m/z [M + H]+ calcd for C23H15N2O4+: 383.1026; found:
383.1026.
2-(3,4-Bimethoxybenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(4k). Yield 73%; 301 mg; black brown solid; column chromatography,
silica gel (PE:EA, 1:2); mp 160−162 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.85 (s, 1H), 9.59 (s, 1H), 8.05 (d, J = 7.2 Hz,
1H), 7.78 (d, J = 7.2 Hz, 1H), 7.61−7.56 (m, 3H), 7.41 (d, J = 7.6
Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 4.00 (s, 3H), 3.98 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 189.6, 177.2,
155.1, 152.9, 149.7, 148.3, 144.2, 142.2, 142.0, 139.9, 138.0, 135.4,
133.0, 131.1, 128.8, 127.6, 127.2, 127.0, 116.7, 111.4, 110.4, 108.0,
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
56.2, 56.1. HRMS (ESI): m/z [M + H]+ calcd for C24H17N2O5+:
413.1132; found: 413.1131.
2-(Benzo[d][1,3]dioxole-5-carbonyl)-5H-pyrido[3,2-a]-
phenoxazin-5-one (4l). Yield 71%; 281 mg; brown solid; column
chromatography, silica gel (PE:EA, 1:1); mp 198−200 °C. 1H NMR
(400 MHz, CDCl3, CF3COOD) δ 9.87 (s, 1H), 9.57 (s, 1H), 8.07 (d,
J = 6.4 Hz, 1H), 7.81 (s, 1H), 7.64−7.57 (m, 2H), 7.43−7.38 (m,
2H), 6.98−6.93 (m, 2H), 6.14 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3, CF3COOD) δ 188.7, 176.0, 154.1, 153.3, 149.1, 147.2, 144.3,
141.4, 141.1, 140.6, 138.3, 136.0, 133.1, 131.3, 129.0, 128.8, 128.6,
127.6, 116.8, 109.0, 108.5, 107.8, 102.7. HRMS (ESI): m/z [M + H]+
calcd for C23H13N2O5+: 397.0819; found: 397.0817.
2-(4-(Methylthio)benzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(4m). Yield 51%; 203 mg; brown solid; column chromatography,
silica gel (PE:EA, 2:1); mp 272−274 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.47 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 7.6 Hz,
1H), 7.81 (d, J = 6.8 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.48−7.42 (m,
2H), 7.36 (d, J = 7.6 Hz, 2H), 6.75 (s, 1H), 2.57 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3, CF3COOD) δ 191.7, 180.7, 151.9, 148.2,
146.6, 144.5, 144.0, 136.1, 135.6, 133.6, 132.6, 131.5, 130.6, 130.5,
127.8, 126.3, 125.0, 116.3, 108.5, 14.5. HRMS (ESI): m/z [M + H]+
calcd for C23H15N2O3S+: 399.0798; found: 399.0799.
2-(4-Fluorobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4n).
Yield 67%; 248 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp 266−268 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.85 (s, 1H), 9.60 (s, 1H), 8.07−7.98 (m, 3H), 7.80 (t,
J = 7.2 Hz, 1H), 7.62−7.57 (m, 2H), 7.29 (t, J = 8.0 Hz, 2H), 6.95 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 189.8, 177.5,
166.8 (d, JCF = 258.0 Hz, 1JCF), 153.1, 148.7, 144.2, 142.6, 142.2,
139.8, 137.1, 135.5, 133.2 (d, JCF = 9.0 Hz, 3JCF), 133.1, 131.2, 131.1,
128.8, 127.3, 116.8, 116.7 (d, JCF = 22.0 Hz, 2JCF), 108.1. 19F NMR
(376 MHz, CDCl3, CF3COOD) δ −100.79. HRMS (ESI): m/z [M +
H]+ calcd for C22H12N2O3F+: 371.0826; found: 371.0829.
2-(3-Fluorobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4o).
Yield 64%; 237 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp 267−269 °C. 1H NMR (400 MHz, CDCl3) δ 9.39
(d, J = 8.0 Hz, 2H), 7.88 (d, J = 7.2 Hz, 1H), 7.66−7.55 (m, 4H),
7.44−7.39 (m, 3H), 6.71 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 192.4 (d, JCF = 3.0 Hz, 4JCF), 181.2, 162.8 (d, JCF = 248.0 Hz,1JCF),
153.2, 151.4, 148.5, 145.5, 144.0, 138.0 (d, JCF = 6.0 Hz, 3JCF), 134.5,
134.4, 133.0, 132.6, 130.6 (d, JCF = 7.0 Hz, 3JCF), 130.3, 127.4, 126.0
(d, JCF = 3.0 Hz, 4JCF), 125.9, 121.0 (d, JCF = 21.0 Hz, 2JCF), 116.7 (d,
JCF = 22.0 Hz, 2JCF), 116.2, 109.0. 19F NMR (376 MHz, CDCl3) δ
−110.50. HRMS (ESI): m/z [M + H]+ calcd for C22H12N2O3F+:
371.0826; found: 371.0821.
2-(4-Chlorobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4p).
Yield 63%; 243 mg; black brown solid; column chromatography,
silica gel (PE:EA, 2:1); mp 290−292 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.96 (s, 1H), 9.63 (s, 1H), 8.10 (d, J = 8.0 Hz,
1H), 7.89−7.83 (m, 3H), 7.66−7.59 (m, 4H), 7.01 (s, 1H). 13C{1H}
NMR (100 MHz, CDCl3, CF3COOD) δ 189.5, 176.2, 153.4, 147.6,
144.4, 142.2, 141.4, 141.2, 137.3, 136.1, 133.2, 132.7, 131.7, 131.4,
129.8, 129.2, 127.7, 116.9, 108.1. HRMS (ESI): m/z [M + H]+ calcd
for C22H12N2O3Cl+: 387.0531; found: 387.0535.
2-(2,4-Bichlorobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4q).
Yield 66%; 277 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp 285−287 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.70 (s, 1H), 9.45 (s, 1H), 8.05 (d, J = 8.0 Hz,
1H), 7.75 (t, J = 7.6 Hz, 1H), 7.60−7.57 (m, 3H), 7.55−7.52 (m,
2H), 6.92 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ
190.1, 178.6, 152.9, 149.9, 144.2, 142.7, 139.6, 138.6, 135.5, 135.2,
133.6, 133.0, 132.9, 131.7, 131.1, 130.8, 128.8, 128.3, 127.2, 116.7,
108.3. HRMS (ESI): m/z [M + H]+ calcd for C22H11N2O3Cl2+:
421.0141; found: 421.0139.
2-(4-Bromobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4r).
Yield 57%; 245 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp > 300 °C; 1H NMR (400 MHz, CDCl 3,
CF3COOD) δ 9.97 (s, 1H), 9.64 (s, 1H), 8.11 (d, J = 8.0 Hz,
1H), 7.86 (t, J = 7.6 Hz, 1H), 7.79−7.77 (m, 4H), 7.67−7.62 (m,
2H), 7.02 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ
11157
pubs.acs.org/joc Article
189.6, 176.1, 153.5, 147.5, 144.4, 141.4, 141.3, 141.0, 137.3, 136.2,
133.2, 133.1, 132.8, 131.6, 131.4, 131.0, 129.2, 127.7, 116.9, 108.0.
HRMS (ESI): m/z [M + H]+ calcd for C22H12N2O3Br+: 431.0026;
found: 431.0023.
2-(4-Iodobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4s). Yield
54%; 258 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp > 300 °C; 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 10.07 (s, 1H), 9.65 (s, 1H), 8.16 (d, J = 7.2 Hz,
1H), 8.02 (d, J = 7.2 Hz, 2H), 7.91 (s, 1H), 7.69−7.61 (m, 4H), 7.08
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 189.6,
175.0, 153.9, 146.5, 144.5, 142.6, 140.5, 139.7, 139.0, 137.6, 136.9,
133.4, 133.2, 131.7, 131.3, 129.4, 128.1, 117.1, 108.0, 104.5. HRMS
(ESI): m/z [M + H] + calcd for C22H12N2O3I+: 478.9887; found:
478.9883.
2-(4-(Trifluoromethoxy)benzoyl)-5H-pyrido[3,2-a]phenoxazin-5-
one (4t). Yield 74%; 323 mg; black brown solid; column
chromatography, silica gel (PE:EA, 2:1); mp 157−159 °C; 1H
NMR (400 MHz, CDCl3, CF3COOD) δ 9.97 (s, 1H), 9.64 (s, 1H),
8.10 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.87−7.83 (m,
1H), 7.66−7.60 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H).
13
C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ188.9, 175.7, 154.2,
153.7, 147.2, 144.4, 141.8, 141.1, 140.6, 137.4, 136.4, 133.3, 132.5,
132.3, 131.5, 129.3, 127.8, 121.5, 120.2 (q, JCF = 258.0 Hz,1JCF),
116.9, 108.0. 19F NMR (376 MHz, CDCl3, CF3COOD) δ −57.86.
HRMS (ESI): m/z [M + H]+ calcd for C23H12N2O4F3+: 437.0744;
found: 437.0741.
Methyl-4-(5-oxo-5H-pyrido[3,2-a]phenoxazine-2-carbonyl)-
benzoate (4u). Yield 70%; 287 mg; black brown solid; column
chromatography, silica gel (PE:EA, 1:1); mp > 300 °C; 1H NMR
(400 MHz, CDCl3, CF3COOD) δ9.97 (s, 1H), 9.66 (s, 1H), 8.28 (d,
J = 7.6 Hz, 2H), 8.10 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.2 Hz, 2H),
7.85 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 8.0 Hz, 2H), 7.03 (s, 1H), 4.04 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 190.2, 176.6,
167.1, 153.4, 148.2, 144.3, 141.6, 141.0, 138.1, 136.8, 136.0, 134.9,
133.2, 131.4, 130.6, 130.2, 127.6, 116.9, 108.2, 53.4. HRMS (ESI): m/
z [M + H]+ calcd for C24H15N2O5+: 411.0975; found: 411.0970.
4-(5-Oxo-5H-pyrido[3,2-a]phenoxazine-2-carbonyl)benzonitrile
(4v). Yield 79%; 298 mg; black brown solid; column chromatography,
silica gel (PE:EA, 1:1); mp 291−293 °C; 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 10.08 (s, 1H), 9.70 (s, 1H), 8.16−7.92 (m,
6H), 7.72−7.66 (m, 2H), 7.10 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3, CF3COOD) δ 188.8, 175.4, 153.8, 147.0, 144.4, 142.3, 140.7,
140.5, 137.8, 136.8, 136.6, 133.4, 133.3, 131.6, 130.5, 129.4, 128.0,
117.3, 117.0, 116.7, 108.1. HRMS (ESI): m/z [M + H]+ calcd for
C23H12N3O3+: 378.0873; found: 378.0874.
2-(4-Nitrobenzoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4w).
Yield 76%; 302 mg; orange brown solid; column chromatography,
silica gel (PE:EA, 1:1); mp > 300 °C; 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 10.07 (s, 1H), 9.70 (s, 1H), 8.46 (d, J = 8.0 Hz, 2H),
8.14−8.11 (m, 3H), 7.91 (t, J = 7.6 Hz, 1H), 7.70−7.61 (m, 2H),
7.09 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 188.8,
175.6, 153.8, 151.1, 147.3, 144.5, 142.1, 140.8, 139.0, 136.8, 136.5,
133.4, 131.6, 131.2, 129.4, 128.0, 124.5, 117.1, 108.1. HRMS (ESI):
m/z [M + H]+ calcd for C22H12N3O5+: 398.0771; found: 398.0773.
2-(4-(Methylsulfonyl)benzoyl)-5H-pyrido[3,2-a]phenoxazin-5-
one (4x). Yield 81%; 348 mg; brown solid; column chromatography,
silica gel (PE:EA, 1:2); mp > 300 °C; 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 10.09 (s, 1H), 9.70 (s, 1H), 8.15−8.11 (m, 5H), 7.89
(t, J = 7.6 Hz, 1H), 7.68−7.65 (m, 2H), 7.06 (s, 1H), 3.19 (s, 3H).
13
C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 188.7, 175.1, 153.9,
146.8, 144.5, 144.4, 142.7, 140.6, 140.2, 138.8, 136.8, 136.7, 133.4,
131.6, 131.1, 129.5, 128.3, 128.0, 117.0, 108.0, 43.8. HRMS (ESI): m/
z [M + H]+ calcd for C23H15N2O5S+: 431.0696; found: 431.0692.
2-([1,1’-Biphenyl]-4-carbonyl)-5H-pyrido[3,2-a]phenoxazin-5-
one (4y). Yield 62%; 265 mg; black brown solid; column
chromatography, silica gel (PE:EA, 2:1); mp 286−288 °C. 1H
NMR (400 MHz, CDCl3, CF3COOD) δ 9.64 (s, 1H), 9.52 (s, 1H),
8.00−7.96 (m, 3H), 7.82 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 7.2 Hz,
3H), 7.53−7.43 (m, 5H), 6.85 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3, CF3COOD) δ 192.0, 180.0, 152.3, 151.2, 147.2, 144.1, 139.1,
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
137.0, 136.4, 134.2, 133.9, 132.8, 130.9, 130.8, 129.1, 128.7, 128.2,
127.7, 127.3, 126.7, 116.5, 108.3. HRMS (ESI): m/z [M + H]+ calcd
for C28H17N2O3+: 429.1234; found: 429.1231.
2-(1-Naphthoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (4z). Yield
66%; 265 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp 176−178 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.75 (s, 1H), 9.55 (s, 1H), 8.39 (d, J = 7.6 Hz,
1H), 8.13 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.76−7.68
(m, 2H), 7.61−7.51 (m, 5H), 6.85 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3, CF3COOD) δ 192.6, 178.4, 152.7, 150.2, 144.1, 143.9,
142.8, 139.1, 137.8, 134.9, 134.5, 134.0, 132.9, 132.3, 131.0, 130.7,
128.8, 128.7, 128.5, 127.3, 127.0, 125.0, 124.3, 116.6, 108.2. HRMS
(ESI): m/z [M + H]+ calcd for C26H15N2O3+: 403.1077; found:
403.1078.
2-(2-Naphthoyl)-5H-pyrido[3,2-a]phenoxazin-5-one (5a). Yield
70%; 281 mg; black brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp 247−249 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.99 (s, 1H), 9.70 (s, 1H), 8.33 (s, 1H), 8.05−8.00
(m, 2H), 7.97−7.91 (m, 3H), 7.85−7.80 (m, 1H), 7.70−7.66 (m,
1H), 7.59 (d, J = 7.6 Hz, 3H), 6.97 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3, CF3COOD) δ 190.7, 176.2, 153.3, 147.6, 144.3, 141.4,
141.3, 141.0, 138.0, 136.2, 136.0, 133.5, 133.2, 132.2, 131.7, 131.4,
130.1, 129.8, 129.7, 129.0, 128.0, 127.8, 127.6, 124.5, 116.8, 108.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H15N2O3+: 403.1077;
found: 403.1076.
2-Nicotinoyl-5H-pyrido[3,2-a]phenoxazin-5-one (5b). Yield 71%;
251 mg; black brown solid; column chromatography, silica gel
(PE:EA, 1:2); mp 180−182 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 10.33 (s, 1H), 9.83 (s, 1H), 9.57 (s, 1H), 9.28−9.19
(m, 2H), 8.47−8.37 (m, 1H), 8.25−8.15 (m, 1H), 8.05−7.97 (m,
1H), 7.87−7.76 (m, 2H), 7.26 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3, CF3COOD) δ 184.3, 174.5, 155.1, 147.8, 146.3, 145.7, 145.0,
144.1, 143.4, 140.0, 139.7, 138.3, 135.7, 134.6, 134.2, 132.1, 130.4,
129.0, 117.4, 108.2. HRMS (ESI): m/z [M + H]+ calcd for
C21H12N3O3+: 354.0873; found: 354.0872.
2-(Furan-2-carbonyl)-5H-pyrido[3,2-a]phenoxazin-5-one (5c).
Yield 59%; 202 mg; brown solid; column chromatography, silica gel
(PE:EA, 1:1); mp 248−250 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.78 (s, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.88 (s,
1H), 7.68 (t, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.53−7.46 (m, 2H),
6.81−6.77 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, CF3COOD)
δ 176.8, 175.7, 153.2, 151.2, 149.8, 148.2, 144.3, 142.0, 141.2, 136.3,
135.7, 133.2, 131.4, 129.1, 127.5, 123.8, 116.9, 114.1, 108.2. HRMS
(ESI): m/z [M + H]+ calcd for C20H11N2O4+: 343.0713; found:
343.0711.
2-(Thiophene-2-carbonyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(5d). Yield 53%; 190 mg; brown solid; column chromatography, silica
gel (PE:EA, 1:1); mp 287−289 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.87 (s, 1H), 9.66 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H),
7.99 (d, J = 4.8 Hz, 1H), 7.82−7.76 (m, 2H), 7.61−7.55 (m, 2H),
7.32 (t, J = 4.0 Hz, 1H), 6.94 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3, CF3COOD) δ 181.7, 175.6, 153.6, 146.4, 144.4, 141.7, 141.0,
140.5, 139.2, 137.8, 136.5, 133.3, 131.6, 129.7, 129.4, 127.9, 117.0,
108.0, 104.1. HRMS (ESI): m/z [M + H]+ calcd for C20H11N2O3S+:
359.0485; found: 359.0483.
2-(Thiophene-3-carbonyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(5e). Yield 49%; 175 mg; black brown solid; column chromatography,
silica gel (PE:EA, 1:1); mp 173−175 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.85 (s, 1H), 9.62 (s, 1H), 8.21 (s, 1H), 8.03
(d, J = 7.6 Hz, 1H), 7.79−7.73 (m, 1H), 7.71−7.6 (m, 1H), 7.59−
7.55 (m, 3H), 6.89 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3,
CF3COOD) δ 184.5, 178.1, 152.9, 148.9, 144.2, 143.2, 142.5, 139.1,
138.8, 137.8, 137.0, 135.2, 133.0, 131.1, 128.8, 128.2, 127.9, 127.2,
116.7, 108.1. HRMS (ESI): m/z [M + H]+ calcd for C20H11N2O3S+:
359.0485; found: 359.0480.
2-(Benzofuran-2-carbonyl)-5H-pyrido[3,2-a]phenoxazin-5-one
(5f). Yield 60%; 235 mg; orange brown solid; column chromatog-
raphy, silica gel (PE:EA, 1:1); mp 185−187 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.95 (d, J = 18.8 Hz, 2H), 8.00 (s, 1H), 7.84−
7.76 (m, 3H), 7.61−7.55 (m, 4H), 7.36 (s, 1H), 6.83 (s, 1H).
11158
pubs.acs.org/joc Article
13
C{1H} NMR (100 MHz, CDCl3, CF3COOD) δ 178.4, 178.2, 156.5,
152.7, 150.8, 149.6, 144.1, 143.7, 142.6, 139.2, 135.7, 135.1, 132.9,
131.0, 130.1, 128.6, 127.1, 126.5, 124.8, 124.0, 118.9, 116.6, 112.5,
108.1. HRMS (ESI): m/z [M + H]+ calcd for C24H13N2O4+:
393.0870; found: 393.0869.
2-Cinnamoyl-5H-pyrido[3,2-a]phenoxazin-5-one (5g). Yield
70%; 265 mg; brown solid; column chromatography, silica gel
(PE:EA, 2:1); mp 341−243 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 10.20 (s, 1H), 9.92 (s, 1H), 8.15−8.06 (m, 2H),
7.88−7.57 (m, 6H), 7.51−7.44 (m, 3H), 6.97 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3, CF3COOD) δ 184.7, 175.3, 153.6, 151.0, 146.2,
144.3, 141.3, 141.0, 140.3, 137.6, 136.3, 133.4, 133.3, 132.6, 131.5,
129.5, 129.2, 127.8, 118.8, 116.9, 108.0. HRMS (ESI): m/z [M + H]+
calcd for C24H15N2O3+: 379.1077; found: 379.1074.
2-(Tetrahydro-2H-pyran-4-carbonyl)-5H-pyrido[3,2-a]-
phenoxazin-5-one (5h). Yield 72%; 259 mg; yellowish brown solid;
column chromatography, silica gel (PE:EA, 1:1); mp 247−249 °C. 1H
NMR (400 MHz, CDCl3) δ 9.51 (d, J = 9.2 Hz, 2H), 7.94 (d, J = 7.6
Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.47−7.39 (m, 2H), 6.69 (s, 1H),
4.11 (d, J = 11.2 Hz, 2H), 3.66 (t, J = 10.4 Hz, 3H), 2.00−1.88 (m,
4H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.9, 181.2, 152.3, 151.4,
148.9, 145.6, 144.1, 133.3, 133.0, 132.6, 132.5, 130.3, 127.7, 125.9,
116.2, 109.1, 67.0, 43.5, 28.6. HRMS (ESI): m/z [M + H]+ calcd for
C21H17N2O4+: 361.1183; found: 361.1182.
Ethyl-5-oxo-5H-pyrido[3,2-a]phenoxazine-2-carboxylate (5i).
Yield 82%; 262 mg; orange brown solid; column chromatography,
silica gel (PE:EA, 2:1); mp 259−261 °C. 1H NMR (400 MHz,
CDCl3) δ 9.61 (s, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz,
1H), 7.45−7.38 (m, 2H), 6.68 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.51
(t, J = 8.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 190.8,
181.4, 164.2, 153.6, 151.3, 149.0, 145.6, 144.0, 134.8, 132.8, 132.6,
130.3, 128.2, 127.4, 125.9, 116.2, 109.0, 62.2, 14.3. HRMS (ESI): m/z
[M + H]+ calcd for C18H13N2O4+: 321.0870; found: 321.0864.
2-Benzoyl-6,8-dimethyl-5H-pyrido[3,2-a]phenoxazin-5-one (5j).
Yield 78%; 296 mg; red brown solid; column chromatography, silica
gel (PE:EA, 2:1); mp 252−254 °C. 1H NMR (400 MHz, CDCl3,
CF3COOD) δ 9.81 (s, 1H), 9.58 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H),
7.77 (q, J = 8.0 Hz, 2H), 7.63−7.55 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H),
2.55 (s, 3H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
CF3COOD) δ 191.2, 176.8, 149.2, 148.5, 142.8, 142.0, 141.7, 139.7,
136.7, 136.0, 134.8, 132.6, 130.2, 129.3, 128.5, 128.1, 126.4, 126.1,
118.6, 14.6, 8.1. HRMS (ESI): m/z [M + H]+ calcd for C24H17N2O3+:
381.1234; found: 381.1236.
2-Benzoyl-6,8-difluoro-5H-pyrido[3,2-a]phenoxazin-5-one (5k).
Yield 72%; 279 mg; black brown solid; column chromatography,
silica gel (PE:EA, 2:1); mp 281−283 °C. 1H NMR (400 MHz,
CDCl3, CF3COOD) δ 9.78 (s, 1H), 9.57 (s, 1H), 7.91 (d, J = 8.0 Hz,
2H), 7.85 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.6
Hz, 2H), 7.59−7.50 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3,
CF3COOD) δ 192.5, 171.3 (d, JCF = 16.0 Hz, 2JCF), 150.8 (d, JCF =
255.0 Hz,1JCF), 143.1, 142.5 (d, JCF = 266.0 Hz,1JCF), 138.7, 137.5 (d,
JCF = 8.0 Hz, 3JCF), 137.2, 135.2, 134.7, 134.0, 131.9 (d, JCF = 12.0 Hz,
3
JCF), 130.4, 129.4, 127.2, 126.5, 126.4, 121.3 (d, JCF = 17.0 Hz, 2JCF).
19
F NMR (376 MHz, CDCl3, CF3COOD) δ −134.02, −150.16.
HRMS (ESI): m/z [M + H]+ calcd for C22H11N2O3F2+: 389.0732;
found: 389.0733.
Ethyl-6,8-dimethyl-5-oxo-5H-pyrido[3,2-a]phenoxazine-2-car-
boxylate (5l). Yield 84%; 292 mg; orange brown solid; column
chromatography, silica gel (PE:EA, 3:1); mp 242−244 °C. 1H NMR
(400 MHz, CDCl3) δ 9.49 (s, 1H), 9.35 (s, 1H), 7.53 (d, J = 6.8 Hz,
1H), 7.31−7.27 (m, 1H), 7.19−7.14 (m, 1H), 4.53 (q, J = 4.0 Hz,
2H), 2.38 (s, 3H), 2.20 (s, 3H), 1.51 (t, J = 6.8 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 180.4, 163.9, 152.9, 148.1, 147.1, 144.2,
142.0, 133.9, 133.5, 131.7, 127.4, 126.3, 125.3, 124.6, 117.9, 61.9,
14.4, 14.2, 8.1. HRMS (ESI): m/z [M + H]+ calcd for C20H17N2O4+:
349.1183; found: 349.1184.
2-Amino-3H-phenoxazin-3-one(III). Yield 86%; 182 mg; puce
solid; column chromatography, silica gel (PE:EA, 3:1); mp 250−252
°C. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.0 Hz, 1H),
7.50−7.43 (m, 2H), 7.38 (t, J = 7.2 Hz, 1H), 6.84 (s, 2H), 6.35 (s,
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry
2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 180.2, 148.9, 148.2,
147.4, 141.9, 133.7, 128.8, 128.0, 125.3, 115.9, 103.4, 98.3. HRMS
(ESI): m/z [M + H]+ calcd for C12H9N2O2+: 213.0659; found:
213.0655.
■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its Supporting Information.
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.3c01118.
Experimental procedures, product characterizations,
crystallographic data, and copies of the 1H, 13C and
19
F NMR spectra involved (PDF)
Accession Codes
CCDC 2243865 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.
■ AUTHOR INFORMATION
Corresponding Authors
Meng Gao − National Engineering Research Center for Tissue
Restoration and Reconstruction, Key Laboratory of
Biomedical Materials and Engineering of the Ministry of
Education, School of Materials Science and Engineering,
South China University of Technology, Guangzhou 510006,
China; orcid.org/0000-0001-8071-8079;
Email: msmgao@scut.edu.cn
An-Xin Wu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan, Hubei 430079, P. R.
China; orcid.org/0000-0001-7673-210X;
Email: chwuax@mail.ccnu.edu.cn
Authors
Shuang-Gui Lei − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan, Hubei 430079, P. R.
China
You Zhou − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan, Hubei 430079, P. R. China
Li-Sheng Wang − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan, Hubei 430079, P. R.
China
Zhi-Cheng Yu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan, Hubei 430079, P. R.
China
Ting Chen − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan, Hubei 430079, P. R. China
Yan-Dong Wu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan, Hubei 430079, P. R.
China; orcid.org/0000-0003-0589-7155
Complete contact information is available at:
11159
pubs.acs.org/joc Article
https://pubs.acs.org/10.1021/acs.joc.3c01118
Author Contributions
§
S.-G.L. and Y.Z. contributed equally.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (Grants 21971080, 21971079 and
22171098). This work was supported by “The Fundamental
Research Funds for the Central Universities”. This work was
also supported by the 111 Project B17019.
■ REFERENCES
(1) For selected examples, see: (a) Alberti, A.; Bolognese, A.;
Guerra, M.; Lavecchia, A.; Macciantelli, D.; Marcaccio, M.; Novellino,
E.; Paolucci, F. Antitumor Agents. 4. Characterization of Free Radicals
Produced During Reduction of the Antitumor Drug 5H-Pyridophe-
noxazin-5-one (PPH). An EPR Study. Biochemistry 2003, 42, 11924−
11931. (b) Bolognese, A.; Correale, G.; Manfra, M.; Lavecchia, A.;
Mazzoni, O.; Novellino, E.; Barone, V.; Pani, A.; Tramontano, E.; La
Colla, P.; Murgioni, C.; Serra, I.; Setzu, G.; Loddo, R. Antitumor
Agents. 1. Synthesis, Biological Evaluation, and Molecular Modeling
of 5H-Pyrido[3,2-a]phenoxazin-5-one, a Compound with Potent
Antiproliferative Activity. J. Med. Chem. 2002, 45, 5205−5216.
(2) (a) Luo, Y. Pyridine-containing Starch Protein front β Site
Decomposing Enzyme I (BACEL) Inhibitor. CN104513255A, 2015.
(b) Pedatella, S.; Cerchia, C.; Manfra, M.; Cioce, A.; Bolognese, A.;
Lavecchia, A. Antitumor Agents 7. Synthesis, Antiproliferative Activity
and Molecular Modeling of New L-lysine-conjugated Pyridophenox-
azinones as Potent DNA-binding Ligands and Topoisomerase IIα
Inhibitors. Eur. J. Med. Chem. 2020, 187, No. 111960. (c) Gu, L. Q.;
Ruan, J. W.; Fu, L. W.; Huang, Z. S.; Chen, X. Z.; Ma, L
Pyridophenoxazinone Compounds and its Preparation Method and
Application. ZL03146847.0, 2007. (d) Yao, R. S.; Wu, S. H.; Deng, S.
S.; Ming, Y. Q.; Lu, X. Q Preparation of Carboxylic Non-steroidal
Anti-inflammatory Drug Derivatives and Application.
CN102212057A, 2011.
(3) (a) Williams, T. L.; Lopez, S. A.; Deravi, L. F. A Sustainable
Route To Synthesize the Xanthommatin Biochrome via an Electro-
catalyzed Oxidation of Tryptophan Metabolites. ACS Sustainable
Chem. Eng. 2019, 7, 8979−8985. (b) Nisco, M. D.; Bolognese, A.;
Sala, M.; Pedatella, S.; Manfra, M. Microwave-Assisted Synthesis of
Pyridophenoxazinones, a Class of Antiproliferative Compounds.
ChemistrySelect 2016, 1, 1292−1295. (c) Bolognese, A.; Correale,
G.; Manfra, M.; Lavecchia, A.; Novellino, E.; Pepe, S. Antitumor
Agents. 5. Synthesis, Structure-Activity Relationships, and Biological
Evaluation of Dimethyl-5H-pyridophenoxazin-5-ones, Tetrahydro-
5H-benzopyridophenoxazin-5-ones, and 5H-Benzopyridophenoxazin-
5-ones with Potent Antiproliferative Activity. J. Med. Chem. 2006, 49,
5110−5118.
(4) (a) Zhao, P.; Wu, X.; Zhou, Y.; Geng, X.; Wang, C.; Wu, Y. D.;
Wu, A. X. Direct Synthesis of 2,3-Diaroyl Quinolines and Pyridazino-
[4,5-b] quinolines via an I2-Promoted One-Pot Multicomponent
Reaction. Org. Lett. 2019, 21, 2708−2711. (b) Zhou, Y.; Wang, L. S.;
Lei, S. G.; Gao, Y. X.; Ma, J. T.; Yu, Z. C.; Wu, Y. D.; Wu, A. X. I2-
Promoted Site-selective C−C Bond Cleavage of Aryl Methyl Ketones
as C1 Synthons for Constructing 5-acyl-1H-pyrazolo[3,4-b]pyridines.
Org. Chem. Front. 2022, 9, 4416−4420. (c) Gao, Q.; Liu, S.; Wu, X.;
Wu, A. Povarov-Type Reaction Using Methyl as New Input: Direct
Synthesis of Substituted Quinolines by I2-Mediated Formal [3 + 2 +
1] Cycloaddition. Org. Lett. 2014, 16, 4582−4585. (d) Yu, X. X.;
Zhao, P.; Zhou, Y.; Huang, C.; Wang, L. S.; Wu, Y. D.; Wu, A. X.
Employing Arylacetylene as a Diene Precursor and Dienophile:
Synthesis of Quinoline via the Povarov Reaction. J. Org. Chem. 2021,
86, 8381−8388. (e) Geng, X.; Wu, X.; Zhao, P.; Zhang, J.; Wu, Y. D.;
https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160
The Journal of Organic Chemistry pubs.acs.org/joc Article

Wu, A. X. Synergistic I2/Amine Promoted Povarov-Type Reaction for Zhao, Z.; White, J. M.; Yao, B.; Hong, Y. Development and
the Synthesis of 2-Acyl-3-aryl(alkyl)quinolines Using Aryl(alkyl)- Application of Diels-Alder Adducts Displaying AIE Properties. Cell
acetaldehydes as Alkene Surrogates. Org. Lett. 2017, 19, 4179−4182. Rep. Phys. Sci. 2022, 3, No. 100766.
(f) Wu, X.; Geng, X.; Zhao, P.; Zhang, J.; Gong, X.; Wu, Y. D.; Wu, A. (10) (a) Wang, F.; Sun, W.; Wang, Y.; Jiang, Y.; Loh, T. P. Highly
X. I2-Promoted Povarov-Type Reaction Using 1,4-Dithane-2,5-diol as Site-Selective Metal-Free C−H Acyloxylation of Stable Enamines.
an Ethylene Surrogate: Formal [4 + 2] Synthesis of Quinolines. Org. Org. Lett. 2018, 20, 1256−1260. (b) Ni, M.; Zhang, J.; Liang, X.;
Lett. 2017, 19, 1550−1553. (g) Zhao, P.; Yu, Z. C.; Wang, L. F.; Jiang, Y.; Loh, T. P. Directed C−C bond cleavage of a cyclopropane
Zhou, Y.; Wu, Y. D.; Ma, Y.; Wu, A. X. I2-Promoted In Situ intermediate generated from N-tosylhydrazones and stable enami-
Cyclization-Rethiolation Reaction: Synthesis of 2-Aliphatic- or nones: expedient synthesis of functionalized 1,4-ketoaldehydes. Chem.
Aromatic-Substituted Indolizines. J. Org. Chem. 2022, 87, 15197− Commun. 2017, 53, 12286−12289. (c) Bredereck, H.; Simchen, G.;
15209. (h) Huo, J.; Geng, X.; Li, W.; Zhang, P.; Wang, L. A Traceless Rebsdat, S.; Kantlehner, W.; Horn, P.; Wahl, R.; Hoffmann, H.;
Heterocyclic Amine Mediator in Regioselectivity−Switchable Formal Grieshaber, P. Darstellung und Eigenschaften der Amidacetale und
[1 + 2 + 2] Cycloaddition Reaction to 1,3,4- and 1,4,5-Trisubstituted Aminalester. Chem. Ber. 1968, 101, 41−50. (d) Schuda, P. F.; Ebner,
Pyrazoles. Org. Lett. 2023, 25, 512−516. C. B.; Morgan, T. M. The synthesis of mannich bases from ketones
(5) For selected examples, see: (a) Duan, W.; Li, W.; Tang, Q.; and esters via enaminones. Tetrahedron Lett. 1986, 27, 2567.
Zhao, Y.; Guo, X.; Yang, G. Laccase-Mimicking Syntheses of (e) Morera, E.; Pinnen, F.; Lucente, G. Synthesis of 1,2-Dithiolane
Phenoxazinones by Aerobic Oxidative Homo- and Hetero-Dimeriza- Analogues of Leucine for Potential Use in Peptide Chemistry. Org.
tions of Aminophenols. ChemistrySelect 2021, 6, 2504−2507. Lett. 2002, 4, 1139−1142.
(b) Dhara, A. K.; Maity, S.; Dhar, B. B. Visible-Light-Mediated
Synthesis of Substituted Phenazine and Phenoxazinone Using Eosin Y
as a Photoredox Catalyst. Org. Lett. 2021, 23, 3269−3273. (c) Sun, F.;
Qin, J.; Cao, X.; Zhang, X.; Tang, X.; Wan, T.; Zhao, J.; Ma, J.; Long,
Y. Cerium-Doped Manganese Oxide Catalyst for the Oxidative
Coupling Synthesis of Fluorescent 2-Amino-1,9-dimethyl-3H-phenox-
azin-3-one Using Atmospheric Oxygen. ACS Sustainable Chem. Eng.
2022, 10, 9087−9095.
(6) (a) Tian, S.; Liu, Y.; Wan, C.; Wan, J. P.; Hao, G. Catalyst-Free
Cascade Annulation of Enaminones and Aryl Diazonium Tetrafluor-
oboronates for Cinnoline Synthesis and the Anti-Inflammatory
Activity Study. J. Org. Chem. 2023, 88, 2433−2442. (b) Guo, H.;
Tian, L.; Liu, Y.; Wan, J.-P. DMSO as a C1 Source for [2 + 2 + 1]
Pyrazole Ring Construction via Metal-Free Annulation with
Enaminones and Hydrazines. Org. Lett. 2021, 24, 228−233.
(c) Wan, J.-P.; Cao, S.; Liu, Y. Base-Promoted Synthesis of N-
Substituted 1,2,3-Triazoles via Enaminone-Azide Cycloaddition
Involving Regitz Diazo Transfer. Org. Lett. 2016, 18, 6034−6037.
(d) Yang, L.; Wei, L.; Wan, J. P. Redox Neutral [4+2] Benzannulation
of Dienals and Tertiary Enaminones for Benzaldehyde Synthesis.
Chem. Commun. 2018, 54, 7475−7478. (e) Gao, H.; Zhou, L.; Wan, J.
P.; Liu, Y. Rongalite as C1 Synthon in the Synthesis of Divergent
Pyridines and Quinolines. J. Org. Chem. 2023, 88, 7188−7198.
(f) John, J. Inverse Electron Demand Diels Alder Reaction of Aza-o-
Quinone Methides and Enaminones: Accessing 3-Aroyl Quinolines
and Indeno[1,2-b]quinolinones. J. Org. Chem. 2022, 87, 13708−
13714. (g) Guo, Y.; Liu, Y.; Wan, J. P. Amine-catalyzed Synthesis of
N2-sulfonyl 1,2,3-triazole in Water and the Tunable N2-H 1,2,3-
triazole Synthesis in DMSO via Metal-free Enamine Annulation. Chin.
Chem. Lett. 2022, 33, 855−858.
(7) (a) Zhang, J.; Wu, X.; Gao, Q.; Geng, X.; Zhao, P.; Wu, Y.-D.;
Wu, A. Diamination/Oxidative Cross-Coupling/Bicyclization of
Anilines and Methyl Ketones: Direct I2-Promoted Synthesis of 1,2-
Fused Oxindoles. Org. Lett. 2017, 19, 408−411. (b) Wu, X.; Geng, X.;
Zhao, P.; Wu, Y. D.; Wu, A. X. Iodine-Catalyzed Oxidative Coupling
To Construct C−O Bonds for the Synthesis of 2,3-Dihydrooxepines.
Org. Lett. 2017, 19, 4584−4587.
(8) For selected examples, see: (a) Tian, Y.; Yang, H.; Li, X.; Wang,
Y.; Teng, Y.; Yin, D. Design of Nitroso-Modified Naphthylene-Based
Fluorophores as Photo activatable Bioorthogonal Turn-On Probes.
Org. Lett. 2021, 23, 3782−3787. (b) Yang, Z.; Li, X.; Yang, K.; Zhang,
Z.; Wang, Y.; Yu, N.; Baumgartner, T.; Ren, Y. Tailored
Solvatochromic NIR Phosphorus-Chromophores via Selective P−N
and P−C Chemistry in P-Heteropines. Org. Lett. 2022, 24, 2045−
2049.
(9) For selected examples, see: (a) Liu, B.; Tang, B. Z. Aggregation-
Induced Emission: More Is Different. Angew. Chem., Int. Ed. 2020, 59,
9788−9789. (b) Zhao, Z.; Zhang, H.; Lam, J. W. Y.; Tang, B. Z.
Aggregation-Induced Emission: New Vistas at the Aggregate Level.
Angew. Chem., Int. Ed. 2020, 59, 9888−9907. (c) Gialelis, T. L.;
Owyong, T. C.; Ding, S.; Li, W.; Yu, M.; O’Brien-Simpson, N. M.;

11160 https://doi.org/10.1021/acs.joc.3c01118
J. Org. Chem. 2023, 88, 11150−11160