Visible-Light-Induced C(sp2)-C(sp3) Cross-Dehydrogenative-Coupling Reaction of N-Heterocycles with N-Alkyl- N-methylanilines under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.1c01207

Disclosed herein is a cross-dehydrogenative-coupling reaction of N-heterocycles including 1,2,4-triazine-3,5(2H, 4H)-diones and quinoxaline-2(1H)-ones with N-methylanilines to form C(sp2)-C(sp3) under visible-light illumination and ambient air at room temperature. In this process, easily available Ru(bpy)3Cl2·6H2O serves as the catalyst, and air acts as the green oxidant. This method features high atom economy, environmental friendliness, and convenient operation and provides an efficient and practical access to aminomethyl-substituted N-heterocycles with extensive functional group compatibility in 40-86% yields.

Full text of DOI:10.1021/acs.joc.1c01207

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Article
Visible-Light-Induced C(sp2)−C(sp3) Cross-Dehydrogenative-
Coupling Reaction of N‑Heterocycles with N‑Alkyl‑N‑methylanilines
under Mild Conditions
Hong-Yu Zhang, Jianjun Chen, Cong-Cong Lu, Ya-Ping Han, Yuecheng Zhang,* and Jiquan Zhao*
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ABSTRACT: Disclosed herein is a cross-dehydrogenative-cou-
pling reaction of N-heterocycles including 1,2,4-triazine-3,5(2H,
4H)-diones and quinoxaline-2(1H)-ones with N-methylanilines to
form C(sp2)−C(sp3) under visible-light illumination and ambient
air at room temperature. In this process, easily available
Ru(bpy)3Cl2·6H2O serves as the catalyst, and air acts as the
green oxidant. This method features high atom economy,
environmental friendliness, and convenient operation and provides
an efficient and practical access to aminomethyl-substituted N-
heterocycles with extensive functional group compatibility in 40−
86% yields.
disclosed an elegant C−H difluoromethylation of heterocycles,
and 1,2,4-triazine-3,5(2H,4H)-dione was selected as a
substrate providing 6-(difluoromethyl)-1,2,4-triazine-3,5-
(2H,4H)-dione in a good yield (Scheme 1, equation b).6
Recently, the Kim group described a novel C−H methylation
of heterocycles with sulfur ylides and found that a range of
1,2,4-triazine-3,5(2H,4H)-diones matched well with the stand-
ard conditions (Scheme 1, equation c).7 In view of the conflict
between the significance of 1,2,4-triazine-3,5(2H,4H)-dione
derivatives and the scarcity of synthesis methods for them, it is
in urgent demand to develop the convenient and direct C−H
functionalization of 1,2,4-triazine-3,5(2H,4H)-diones.
In addition, over the past decade, various protocols for the
C−H functionalization of quinoxalin-2(1H)-ones, including
alkylation,8 arylation,9 acylation,10 amination,11 alkoxylation,12
phosphorylation,13 sulfenylation,14 and so forth,15 have been
accomplished, but the direct introduction of diverse amino-
methyl groups into quinoxalin-2(1H)-ones via C−H function-
alization is extremely rare. In 2020, Chen and Yu groups
cooperatively reported a visible-light-induced addition reaction
of quinoxalin-2(1H)-ones with N-aryl glycines achieving 3-
aminomethyl-substituted 3,4-dihydroquinoxalin-2(1H)-ones
(Scheme 1, equation d).16 This hydro-aminomethyl addition
transformation features the utilization of recyclable g-C3N4 as
INTRODUCTION
■
N-Heterocycles, such as 1,2,4-triazine-3,5(2H,4H)-dione (6-
azauracil) and quinoxalin-2(1H)-one, are privileged scaffolds
and commonly found in a wide range of biologically active
molecules, natural products, and synthetic pharmaceuticals.1,2
As shown in Figure 1, diclazuril is a broad-spectrum
anticoccidial drug on the market and applicable to treat
coccidiosis in chicken.2a Furthermore, 6-azauridine which is an
analogue of uridine shows effective antiviral activity and is
utilized in clinics against pathogenic flaviviruses.2b Other
examples shown in Figure 1 also exhibit distinct bioactivity and
medicinal properties, such as the c-MeT kinase inhibitor, 5-
HT2C receptor agonist, and cannabinoid CB2 receptor
agonist.2c−e
Although 1,2,4-triazine-3,5(2H,4H)-dione derivatives are of
interest in pharmaceutical chemistry, the direct and efficient
synthesis methods for 1,2,4-triazine-3,5(2H,4H)-dione deriva-
tives have not been well established. The traditional methods
are based on the nucleophilic substitution or cross-coupling
reactions of 3-halo-1,2,4-triazine-3,5(2H,4H)-dione, which
suffer from limitations such as the requirement of prefunction-
alized substrates, low atom economy, and harsh conditions.3
The newly developed C−H functionalization strategy shows its
superiority in short steps, high atom economy, and mild
conditions,4 but only a few of the examples of direct
functionalization of 1,2,4-triazine-3,5(2H,4H)-dione have
been achieved.5−7 In 2018, the Xu group gave a pioneering
example for the C−H functionalization of 1,2,4-triazine-
3,5(2H,4H)-dione to synthesize C(CH3)2CF3-substituted
1,2,4-triazine-3,5(2H,4H)-dione in a moderate yield (Scheme
1, equation a).5 In 2020, Meng and Li groups cooperatively
Received: May 24, 2021
https://doi.org/10.1021/acs.joc.1c01207
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© XXXX American Chemical Society
A

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Figure 1. Representation of 1,2,4-triazine-3,5(2H,4H)-dione and quinoxalin-2(1H)-one derivatives with bioactivity.
functional tolerance, this method offers an environmentally
benign and synthetically efficient protocol to potentially
pharmacoactive 3-aminomethyl-substituted 1,2,4-triazine-3,5-
(2H,4H)-dione or quinoxalin-2(1H)-one derivatives in mod-
erate to high yields.
Scheme 1. C−H Functionalization of 1,2,4-Triazine-
3,5(2H,4H)-diones and Hydro-aminomethyl Addition of
Quinoxalin-2(1H)-ones
RESULTS AND DISCUSSION
■
Our investigation was started by employing 1-methylquinox-
alin-2(1H)-one (1a) and N,N-dimethylaniline (2a) as the
model substrates to optimize the reaction conditions (Table
1). Initially, diverse solvents, such as CH3CN, dimethylforma-
mide (DMF), dimethyl ether (DME), acetone, and N-methyl-
2-pyrrolidone (NMP), were tested in the presence of rose
bengal (5 mol %) as the photocatalyst under blue light
irradiation and ambient air at room temperature (Table 1,
entries 1−5). Fortunately, DMF was found to be the effective
solvent, and the expected product (3a) was obtained in 18%
yield. Subsequently, a series of other photocatalysts including
eosin B, eosin Y, fac-Ir(ppy)3, and Ru(bpy)3Cl2·6H2O were
examined (Table 1, entries 6−9). Among them, Ru(bpy)3Cl2·
6H2O was proved to be the most suitable and delivered
product 3a in 24% yield. In addition, the yield of product 3a
increased to 32% in the presence of 3 equiv of N,N-
dimethylaniline, but a further increase in the amount of N,N-
dimethylaniline was slightly helpful (Table 1, entry 10). Next,
various oxidants, including O2, K2S2O8, di-tert-butyl peroxide
(DTBP), tert-butyl hydroperoxide (TBHP), and cumene
hydroperoxide (CHP), were employed instead of air (Table
1, entries 11−15). Fortunately, the reaction with CHP as the
oxidant provided the target product in a yield of 58%.
Changing the loading of CHP or Ru(bpy)3Cl2·6H2O did not
enhance the reaction efficiency (Table 1, entries 16−19).
Subsequently, we investigated the dosage of the solvent and
found that 1 mL of DMF was appropriate offering the desired
product in a yield of 64% (Table 1, entries 20−21). Next, a
number of bases including K2CO3, 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU), Et3N, and CH3COOK were investigated,
and DBU was found to be the best one with the yield of 3a
increasing from 64 to 72% (Table 1, entries 22−25). However,
the yield of 3a was not further increased by using 0.5 or 1.5
equiv of DBU (Table 1, entries 26 and 27). To our great
surprise, the yield of 3a dramatically increased to 83% under an
air atmosphere without CHP (Table 1, entry 28). Therefore,
the optimal reaction conditions were achieved, which are blue
light as the light source, 2 mol % of Ru(bpy)3Cl2·6H2O as the
photocatalyst, and 1.0 equiv of DBU as the additive in 1.0 mL
of DMF under ambient air at room temperature.
the catalyst, mild conditions, and easy operation. However,
compared with N-aryl glycines which have to undergo
decarboxylation to generate aminomethyl radicals, N-methyl-
aniline derivatives are regarded as more environmentally
friendly and higher atom-economic aminomethyl radical
precursors.17 Therefore, the exploration of C−H amino-
methylation of quinoxalin-2(1H)-ones with N-methylanilines
is still meaningful and challenging. Over the past years, the
visible-light-induced cross-dehydrogenative coupling (CDC)
reaction has emerged as a popular and ideal strategy for the
step- and atom-economical construction of C−C bonds due to
the advantages such as high efficiency, mild reaction
conditions, and low energy consumption.18 Herein, we disclose
the first visible-light-induced CDC reactions of N-heterocycles
including 1,2,4-triazine-3,5(2H,4H)-diones and quinoxalin-
2(1H)-ones with N-methylanilines (Scheme 1, equation e).
Thanks to the features of low catalyst loading, using molecular
oxygen in ambient air as an oxidant and a wide range of
B
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a
Next, we continued to explore the substrate range with a series
of N,N-dimethylanilines bearing the electron-donating or
electron-withdrawing groups on the benzene ring. N,N-
Dimethylanilines with electron-donating methyl, ethyl, or
methoxy groups at the para or meta position on the benzene
ring reacted well to give the target products in good to
excellent yields (3j−3m). On the other hand, N,N-
dimethylanilines with electron-withdrawing bromine atoms at
the para position on the benzene ring offered the
corresponding product 3n in a moderate yield of 49%. It was
assumed that the reaction became more challenging in the
cases where one methyl was replaced by ethyl, n-butyl, allyl, or
even benzyl in N,N-dimethylaniline. Fortunately, the reaction
exclusively took place on the N-methyl group and afforded the
corresponding in moderate yields (3o−3r). Other amino-
methyl sources including 4-dimethylaminopyridine, 2-phenyl-
1,2,3,4-tetrahydroisoquinoline, and so forth, were also tested in
the reaction with 1-methylquinoxalin-2(1H)-one, but no
corresponding products were detected (Figure S6, Supporting
Information).
In consideration of the significance of 1,2,4-triazine-3,5-
(2H,4H)-dione derivatives, we further verified the feasibility of
this methodology for the modification of 1,2,4-triazine-
3,5(2H,4H)-diones (Table 3). To our delight, 1,2,4-triazine-
3,5(2H,4H)-diones with diverse N-substituent groups includ-
ing methyl, benzyl, 4-fluorobenzyl, allyl, and acetophenone
groups matched with the present transformation well, and the
target products were received in good to high yields (5a−5e).
The reaction with 4b as the substrate could be readily scaled
up to 1.5 mmol, and the target product 5b was obtained in a
satisfactorily isolated yield of 78%. Subsequently, a variety of
N,N-dimethylanilines with electron-donating groups, such as
methyl, ethyl, or methoxy groups on the benzene ring,
progressed successfully under the optimal conditions and
afforded the corresponding products in good yields (5f−5i).
Furthermore, the reaction was also investigated with other
dialkylanilines having two different N-alkyl groups, for
instance, N-butyl-N-methylaniline, N-allyl-N-methylaniline,
and N-benzyl-N-methylaniline. Satisfyingly, C−C bond for-
mation highly selectively took place on the N-methyl carbon,
and the aminomethyl-substituted products were obtained in
moderate to good yields (5j−5l). Besides, N,N-dimethylnaph-
thalen-1-amine and N,N-diethylaniline were attempted as
special substrates and offered the corresponding products in
good yields of 75 and 78%, respectively (5m−5n). What
surprised us was the reaction of N-methylaniline with free NH
groups was also carried out smoothly under the standard
conditions and provided the corresponding C−C cross-
coupling product 5o in a satisfactory yield of 53%.
Table 1. Selected Reaction Condition Optimization
b
entry
cde
photocatalyst
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
eosin B
eosin Y
fac-Ir(ppy)3
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
oxidant
solvent
yield (%)
,
,
1
2
3
4
5
6
7
8
9
air
air
air
air
air
air
air
air
air
air
O2
K2S2O8
CH3CN
DMF
DME
acetone
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
17
18
13
15
trace
18
15
12
24
32(29 )
11
n.d.
trace
51(50 )
58
53
36
50
45
64
61
65
72
59
64
70
69
83
cde
, ,
cde
, ,
cde
, ,
cde
, ,
cde
, ,
cde
, ,
ce
,
ce
,
e
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
e
e
e
e
e
g
DTBP
h
i
TBHP
j
CHP
ek
,
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
air
el
,
em
,
ed
,
n
o
p
q
r
s
t
p
a
Unless specifically noted otherwise, reaction conditions are 1a (0.3
mmol), 2a (3.0 equiv), catalyst (2 mol %), oxidant (1.0 equiv., except
for an air or O2 atmosphere), and solvent (1.0 mL), stirring at room
b
temperature under an argon atmosphere about 12 h. Yield of the
c
d
e
isolated product. 2a (2.0 equiv). Photocatalyst (5 mol %). Solvent
f
g
h
(1.5 mL). stirring for 28 h. Di-tert-butyl peroxide. tert-Butyl
hydroperoxide (70% in water). TBHP 5.5 M in decane. CHP
(contains ca. 20% aromatic hydrocarbon). Oxidant (1.5 equiv).
Oxidant (0.5 equiv). Photocatalyst (1 mol %). Solvent (0.5 mL).
K2CO3 as the additive (1.0 equiv). DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene) as the additive (1.0 equiv). Et3N as the additive (1.0
equiv). CH3COOK as the additive (1.0 equiv). DBU as the additive
i
j
k
l
m
n
o
p
q
r
s
t
(0.5 equiv). DBU as the additive (1.5 equiv).
With the optimal reaction conditions established, the scope
of the present transformation was further investigated by
employing different quinoxalin-2(1H)-ones as substrates and
N-methylanilines as aminomethyl radical precursors (Table 2).
First, several quinoxalin-2(1H)-ones with different N-sub-
stituent groups such as ethyl, benzyl, allyl, and ester groups
were examined to react with N,N-dimethylaniline (3b−3f). As
expected, N-ethyl-substituted quinoxalin-2(1H)-one was also
well compatible with the optimal reaction conditions and gave
the corresponding product 3b in a good yield of 72%.
However, for the other N-substituted quinoxalin-2(1H)-ones,
CHP was utilized as the oxidant instead of ambient air in order
to obtain the corresponding products in moderate to good
yields. Quinoxalin-2(1H)-ones with electron-donating groups
could provide the expected products in good yields (3g−3i).
After studying the range of substrates, several control
experiments were carried out to clarify the mechanism of the
reaction (Scheme 2). When 3.0 equiv of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added under the standard
reaction conditions, the reaction was completely inhibited
and a TEMPO-adduct 6a was detected by high-resolution mass
spectrometry (HRMS) (Scheme 2, equation A). This result
suggested that the transformation might involve a single-
electron transfer. When 3.0 equiv of 1,4-diazabicyclo[2.2.2]-
octane as singlet oxygen scavengers was added in the model
reaction, the target product was obtained in 45% yield, which
excluded the possibility that the singlet oxygen might be a
reactive intermediate in this transformation (Scheme 2,
equation B). Besides, an iminium ion species 7a was observed
C
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a
Table 2. Substrate Scope of Various Quinoxalin-2(1H)-ones
a
General conditions: 1 (0.3 mmol), 2 (0.9 mmol), Ru(bpy)3Cl2·6H2O (2.0 mol %), and DBU (1.0 equiv) in 1.0 mL of DMF irradiated with a 25
b
W blue LED under an air atmosphere for 12 h; yield of the isolated product. CHP was used as the oxidant under an argon atmosphere.
when the model reaction was stopped at 4 h (Scheme 2,
equation C). When the reaction was performed in the absence
of the photocatalyst, hardly any desired product was detected,
suggesting that the photocatalyst played an important role in
the process of electron transfer (Scheme 2, equation D). In
addition, the formation of the product did not take place in the
dark (Scheme 2, equation E). This indicated that visible-light
irradiation was essential to initiate catalytic reactions. More-
over, the on/off visible-light irradiation experiments also
confirmed the great influence of continuous illumination
(Figure 2).
iminium ion species 7a.19c Next, the electrophilic addition of
7a to 1-methylquinoxalin-2(1H)-one (1a) provides the cation
intermediate 10a.19f Finally, the target product 3a is obtained
through H+ elimination from intermediate 10a with the aid of
DBU.
In conclusion, we have developed, for the first time, an
efficient and atom-economic visible-light-induced C(sp3)−
C(sp2) cross-dehydrogenation-coupling reaction between
1,2,4-triazine-3,5(2H,4H)-diones/quinoxalin-2(1H)-ones and
N,N-dimethylanilines. The method was also applicable to
other N-methylaniline derivatives such as N,N-diethylaniline,
dialkylanilines with two different N-alkyl groups, and even N-
methylaniline. This protocol had the advantages of cheap and
easily available starting materials and catalysts, ambient air as
the green oxidant, eco-friendly energy source, mild reaction
conditions, a broad functional-group tolerance in good yields,
high scalability, and operational simplicity, so it is promising to
provide an ideal method for organic synthesis and
pharmaceutical chemistry.
On the basis of the aforementioned results and previous
literature studies,19 a plausible mechanism pathway is proposed
2+
in Scheme 3. Initially, Ru(bpy)3 is photoexcited by visible-
light irradiation to generate excited *Ru(bpy)32+. Subse-
quently, a single-electron-transfer process between excited
2+
*Ru(bpy)3 and N,N-dimethylaniline (2a) takes place to
+
furnish Ru(bpy)3 and the cation radical of N,N-dimethylani-
line (8a).19b Then, Ru(bpy)3 is oxidized by aerial oxygen or
+
19e
2+
CHP to regenerate ground-state Ru(bpy)3
.
Meanwhile,
with the assistance of DBU, 8a undergoes deprotonation to
generate α-amino radical 9a which is sequentially oxidized to
D
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a
Table 3. Substrate Scope of Various 1,2,4-Triazine-3,5(2H, 4H)-diones
a
General conditions: 4 (0.3 mmol), 2 (0.9 mmol), Ru(bpy)3Cl2·6H2O (2.0 mol %), and DBU (1.0 equiv) in 1.0 mL of DMF irradiated with a 25
b
W blue LED under an air atmosphere for 12 h; yield of the isolated product. Scaled up to 1.5 mmol 4b.
Scheme 2. Control Experiments
E
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Figure 2. On/off visible-light irradiation experiments.
Scheme 3. Proposed Reaction Mechanism
triazine-3,5(2H,4H)-diones 4 were synthesized according to proce-
dures described in the previous literature studies.21
EXPERIMENTAL SECTION
■
General. All reactions involving air- and moisture-sensitive
General Procedure for the Preparation of Various N-
Methylanilines. To a stirred solution of N-methylaniline (30
mmol) and Et3N (75 mmol) in MeCN (30 mL), various
halogenoalkanes (51 mmol) were added, and the mixture was heated
to reflux for 16 h. Then, the solution was added with brine (50 mL)
and extracted with CH2Cl2 (3 × 50 mL). The organic layer was
separated, dried over anhydrous Na2SO4, and filtered. The solvent was
removed under reduced pressure to obtain a crude product, which
was purified by column chromatography on silica gel to afford the
alkylated N-methylanilines 2.
General Procedure of Aminomethylation of N-Heterocycles
(Condition for 3a−3b, 3h, 3j−3l, 3n−3r, and 5a−o). N-
Heterocycle derivatives (1 and 4) (0.3 mmol) and Ru(bpy)3Cl2·
6H2O (0.02 equiv., 0.006 mmol) were added to an oven-dried
reaction vessel (dimension: 20 mL) equipped with a magnetic stir bar.
Subsequently, anhydrous DMF (1.0 mL), DBU (1.0 equiv., 0.3
mmol), and N-methylaniline derivatives (2) (3.0 equiv., 0.9 mmol)
were added successively through respective syringes. The mixture was
stirred at room temperature under an air atmosphere and irradiated
with a 25 W blue light-emitting diode (LED) lamp until the substrate
was consumed completely (TLC monitoring, about 12 h). Then, the
reaction mixture was quenched with water (20 mL) and extracted
with ethyl acetate (20 mL × 3). The organic layer was separated,
dried over anhydrous Na2SO4, and filtered. The solvent was removed
under reduced pressure to obtain a crude product, which was purified
by column chromatography on silica gel using petroleum ether/ethyl
acetate as an eluent to afford the pure product.
reagents were carried out under an argon atmosphere. H, 13C{1H},
1
and 19F{1H} NMR spectra were recorded on a Bruker AC-P 400
spectrometer (400 MHz for 1H, 100 MHz for 13C{1H}, and 376 MHz
for 19F{1H}) in CDCl3 [with trimethylsilyl (TMS) as the internal
standard]. Chemical shifts (δ) were measured in parts per million
relative to TMS δ = 0 for 1H or to chloroform δ = 77.0 for 13C as the
internal standard. Coupling constants, J, are reported in Hertz. Mass
data were measured using a Thermo Scientific DSQ II mass
spectrometer. High-resolution mass spectra were recorded on a
quadrupole time-of-flight mass spectrometer using electrospray
ionization (ESI) as an ionization method. Melting points were
obtained using a Shanghai Inesa WRS-3 melting point apparatus. The
starting materials were purchased from Energy Chemical or J&K
Chemicals and used without further purification. Solvents were dried
and purified according to the procedure from the “Purification of
Laboratory Chemicals” book. The reaction procedure was monitored
through thin-layer chromatography (TLC), which was performed
using 0.25 mm silica gel plates (60 F254) and was visualized using a
UV lamp (254 nm). As for cyclic voltammetry experiments, a
CHI760E electrochemical workstation was used. The crude products
were purified by flash column chromatography on silica gel using
petroleum ether/ethyl acetate as an eluent, and the reported yields are
the actual isolated yields of pure products. The purity of products was
determined by high-performance liquid chromatography (HPLC)
with a Shimadzu LC-20AD system.
General Procedure for the Preparation of Various Quinox-
alin-2(1H)-ones. The substrates of various quinoxalin-2(1H)-ones 1
were synthesized according to procedures described in the previous
literature studies.9a,20
General Procedure for the Preparation of Various 1,2,4-
Triazine-3,5(2H,4H)-diones. The substrates of various 1,2,4-
General Procedure of Aminomethylation of Quinoxalin-
2(1H)-ones (Condition for 3c−3g, 3i, and 3m). Quinoxalin-
2(1H)-one derivatives (1) (0.3 mmol) and Ru(bpy)3Cl2·6H2O (0.02
equiv., 0.006 mmol) were added to an oven-dried reaction vessel
(dimension: 20 mL) equipped with a magnetic stir bar. Then, the
vessel was evacuated and backfilled with argon three times.
F
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Subsequently, anhydrous DMF (1.0 mL), DBU (1.0 equiv., 0.3
mmol), CHP (1.0 equiv., 0.3 mmol), and N-methylaniline derivatives
(2) (3.0 equiv., 0.9 mmol) were added successively through respective
syringes. The mixture was stirred at room temperature under an argon
atmosphere and irradiated with a 25 W blue LED lamp until the
substrate was consumed completely (TLC monitoring, about 12 h).
Then, the reaction mixture was quenched with water (20 mL) and
extracted with ethyl acetate (20 mL × 3). The organic layer was
separated, dried over anhydrous Na2SO4, and filtered. The solvent was
removed under reduced pressure to obtain a crude product, which
was purified by column chromatography on silica gel using petroleum
ether/ethyl acetate as an eluent to afford the pure product.
(2a) (3.0 equiv., 0.9 mmol) were added successively through
respective syringes. The mixture was stirred at room temperature
under an air atmosphere and irradiated with a 25 W blue LED lamp
for 12 h. The target product 3a was not detected by TLC (petroleum
ether/ethyl acetate = 4:1 as a spread solvent).
Control Experiment E. 1-Methylquinoxalin-2(1H)-one (1a) (0.3
mmol) and Ru(bpy)3Cl2·6H2O (0.02 equiv., 0.006 mmol) were added
to an oven-dried reaction vessel (dimension: 20 mL) which was
equipped with a magnetic stir bar and wrapped in tinfoil.
Subsequently, anhydrous DMF (1 mL), DBU (1.0 equiv., 0.3
mmol), and N,N-dimethylaniline (2a) (3.0 equiv., 0.9 mmol) were
added successively through respective syringes. The mixture was
stirred in the dark at room temperature under an air atmosphere for
12 h. The target product 3a was not detected by TLC (petroleum
ether/ethyl acetate = 4:1 as a spread solvent).
Characterization of the Products. 1-Methyl-3-((methyl-
(phenyl)amino)methyl)quinoxalin-2(1H)-one (3a). The crude prod-
uct was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1 as an eluent) to afford the
product 3a (83% yield, 69.3 mg) as a yellow solid, mp 86−88 °C. 1H
NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.51 (dd, J =
8.0 Hz, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0 Hz, J = 8.0 Hz, 2H), 7.20
(dd, J = 8.0 Hz, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.70 (dd, J
= 8.0 Hz, J = 8.0 Hz, 1H), 4.74 (s, 2H), 3.68 (s, 3H), and 3.20 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.5, 154.8, 149.7,
133.2, 132.6, 130.4, 130.2, 129.0, 123.6, 116.5, 113.6, 112.6, 55.3,
39.7, and 28.9; and HRMS (ESI) m/z: calcd for C17H18N3O+ [M +
H]+, 280.1444; found, 280.1444. Purity: 99% (HPLC: a Shim-pack
VP-ODS column, MeOH/H2O = 80:20, flow rate = 1 mL/min, λ =
254 nm, and tR = 7.369 min).
1-Ethyl-3-((methyl(phenyl)amino)methyl)quinoxalin-2(1H)-one
(3b). The crude product was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 4:1 as an eluent)
to afford the product 3b (73% yield, 64.3 mg) as a yellow solid, mp
106−107 °C. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8 Hz, 1H),
7.51 (dd, J = 8.0 Hz, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.0 Hz, J = 8.0 Hz,
2H), 7.24−7.19 (m, 2H), 6.90 (d, J = 8 Hz, 2H), 6.68 (dd, J = 8.0 Hz,
J = 8.0 Hz, 1H), 4.75 (s, 2H), 4.31 (q, J = 8.0 Hz, 2H), 3.20 (s, 3H),
and 1.38 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
156.5, 154.3, 149.7, 132.9, 132.1, 130.7, 130.2, 129.0, 123.4, 116.5,
113.5, 112.6, 55.2, 39.6, 37.2, and 12.5; and HRMS (ESI) m/z: calcd
for C18H20N3O+ [M + H]+, 294.1601; found, 294.1599. Purity: 98%
(HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 80:20, flow
rate = 1 mL/min, λ = 254 nm, and tR = 17.679 min).
Scaled-Up Reaction Condition for 5b. 2,4-Dibenzyl-1,2,4-
triazine-3,5(2H,4H)-dione (1.5 mmol) and Ru(bpy)3Cl2·6H2O (0.02
equiv., 0.03 mmol) were added to an oven-dried reaction vessel
(dimension: 120 mL) equipped with a magnetic stir bar.
Subsequently, anhydrous DMF (5.0 mL), DBU (1.0 equiv., 1.5
mmol), and N,N-dimethylaniline (3.0 equiv., 4.5 mmol) were added
successively through respective syringes. The mixture was stirred at
room temperature under an air atmosphere and irradiated with a 25
W blue LED lamp until the substrate was consumed completely (TLC
monitoring, about 12 h). Then, the reaction mixture was quenched
with water (100 mL) and extracted with ethyl acetate (100 mL × 3).
The organic layer was separated, dried over anhydrous Na2SO4, and
filtered. The solvent was removed under reduced pressure to obtain a
crude product, which was purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate = 15:1 as an eluent) to
afford the product 5b (78% yield, 483.1 mg) as a white solid.
Control Experiment A. 1-Methylquinoxalin-2(1H)-one (1a) (0.3
mmol), Ru(bpy)3Cl2·6H2O (0.02 equiv., 0.006 mmol), and 2,2,6,6-
tetramethyl-1-piperidinyloxy (3.0 equiv., 0.9 mmol) were added to an
oven-dried reaction vessel (dimension: 20 mL) equipped with a
magnetic stir bar. Subsequently, anhydrous DMF (1.0 mL), DBU (1.0
equiv., 0.3 mmol), and N,N-dimethylaniline (2a) (3.0 equiv., 0.9
mmol) were added successively through respective syringes. The
mixture was stirred at room temperature under an air atmosphere and
irradiated with a 25 W blue LED lamp for 12 h. However, no target
product 3a was detected by TLC (petroleum ether/ethyl acetate =
4:1 as a spread solvent). Compound 6a was detected by HRMS (ESI)
m/z: calcd for C17H28KN2O+ [M + K]+, 315.1833; found, 315.1837.
Control Experiment B. 1-Methylquinoxalin-2(1H)-one (1a) (0.3
mmol), Ru(bpy)3Cl2·6H2O (0.02 equiv., 0.006 mmol), and 1,4-
diazabicyclo[2.2.2]octane (3.0 equiv., 0.9 mmol) were added to an
oven-dried reaction vessel (dimension: 20 mL) equipped with a
magnetic stir bar. Subsequently, anhydrous DMF (1.0 mL), DBU (1.0
equiv., 0.3 mmol), and N,N-dimethylaniline (2a) (3.0 equiv., 0.9
mmol) were added successively through respective syringes. The
mixture was stirred at room temperature under an air atmosphere and
irradiated with a 25 W blue LED lamp for 12 h. Then, the reaction
mixture was quenched with water (20 mL) and extracted with ethyl
acetate (20 mL × 3). The organic layer was separated, dried over
anhydrous Na2SO4, and filtered. The solvent was removed under
reduced pressure to obtain a crude product, which was purified by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 4:1 as an eluent) to afford the product 3a in 45% yield.
Control Experiment C. 1-Methylquinoxalin-2(1H)-one (1a) (0.3
mmol) and Ru(bpy)3Cl2·6H2O (0.02 equiv., 0.006 mmol) were added
to an oven-dried reaction vessel (dimension: 20 mL) equipped with a
magnetic stir bar. Subsequently, anhydrous DMF (1.0 mL), DBU (1.0
equiv., 0.3 mmol), and N,N-dimethylaniline (2a) (3.0 equiv., 0.9
mmol) were added successively through respective syringes. The
mixture was stirred at room temperature under an air atmosphere and
irradiated with a 25 W blue LED lamp for 4 h. The target product 3a
was detected by TLC (petroleum ether/ethyl acetate = 4:1 as a spread
solvent). Compound 7a was detected by HRMS (ESI) m/z: calcd for
C8H10N+ [M]+, 120.0808; found, 120.0815.
1-Benzyl-3-((methyl(phenyl)amino)methyl)quinoxalin-2(1H)-
one (3c). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1
as an eluent) to afford the product 3c (50% yield, 53.4 mg) as a
1
yellow solid, mp 141−143 °C. H NMR (400 MHz, CDCl3): δ 7.82
(d, J = 8 Hz, 1H), 7.39 (dd, J = 8 Hz, J = 8 Hz, 1H), 7.33−7.22 (m,
9H), 6.93 (d, J = 8 Hz, 2H), 6.70 (dd, J = 8 Hz, J = 8 Hz, 1H), 5.49
(s, 2H), 4.81 (s, 2H), and 3.23 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.7, 154.9, 149.7, 135.1, 132.9, 132.5, 130.5, 130.19,
129.0, 129.0, 127.8, 126.9, 123.7, 116.6, 114.4, 112.6, 55.2, 45.8, and
39.7; and HRMS (ESI) m/z: calcd for C23H22N3O+ [M + H]+,
356.1757; found, 356.1755. Purity: 99% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 80:20, flow rate = 1 mL/min, λ = 254
nm, and tR = 11.958 min).
1-Allyl-3-((methyl(phenyl)amino)methyl)quinoxalin-2(1H)-one
(3d). The crude product was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 4:1 as an eluent)
to afford the product 3d (72% yield, 66.2 mg) as a yellow solid, mp
115−116 °C. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8 Hz, 1H),
7.48 (dd, J = 8 Hz, J = 8 Hz, 1H), 7.31−7.19 (m, 4H), 6.90 (d, J = 8
Hz, 2H), 6.69 (dd, J = 8 Hz, J = 8 Hz, 1H), 5.98−5.89 (m, 1H), 3.76
(s, 3H), 3.36 (s, 3H), and 2.45 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.6, 154.4, 149.7, 132.8, 132.4, 130.6, 130.5, 130.1,
129.0, 123.6, 118.2, 116.6, 114.2, 112.6, 55.2, 44.4, and 39.6; and
HRMS (ESI) m/z: calcd for C19H20N3O+ [M + H]+, 306.1601;
found, 306.1591. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
Control Experiment D. 1-Methylquinoxalin-2(1H)-one (1a) (0.3
mmol) was added to an oven-dried reaction vessel (dimension: 20
mL) equipped with a magnetic stir bar. Subsequently, anhydrous
DMF (1 mL), DBU (1.0 equiv., 0.3 mmol), and N, N-dimethylaniline
G
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Article
MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254 nm, and tR =
5.181 min).
C20H24N3O+ [M + H]+, 322.1914; found, 322.1919. Purity: 99%
(HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 70:30, flow
rate = 1 mL/min, λ = 254 nm, and tR = 36.525 min).
Methyl 2-(3-((methyl(phenyl)amino)methyl)-2-oxoquinoxalin-
1(2H)-yl)acetate (3e). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 4:1 as an eluent) to afford the product 3e (64% yield, 65.0 mg) as a
1-Methyl-3-((methyl(p-tolyl)amino)methyl)quinoxalin-2(1H)-
one (3j). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1
as an eluent) to afford the product 3j (85% yield, 74.6 mg)
1
yellow solid, mp 113−115 °C. H NMR (400 MHz, CDCl3): δ 7.84
1
(d, J = 8 Hz, 1H), 7.49 (dd, J = 8 Hz, J = 8 Hz, 1H), 7.31 (dd, J = 8
Hz, J = 8 Hz, 1H), 7.22 (dd, J = 8 Hz, J = 8 Hz, 2H), 7.05 (d, J = 8
Hz, 1H), 6.90 (d, J = 8 Hz, 2H), 6.69 (dd, J = 8 Hz, J = 8 Hz, 1H),
5.03 (s, 2H), 4.76 (s, 2H), 3.78 (s, 3H), and 3.19 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 167.6, 156.4, 154.3, 149.6, 132.7, 132.3,
130.8, 130.4, 129.0, 124.0, 116.6, 113.0, 112.6, 55.2, 53.0, 43.3, and
(conditionsb) as yellow oily liquid. H NMR (400 MHz, CDCl3): δ
7.81 (d, J = 8 Hz, 1H), 7.51 (dd, J = 8 Hz, J = 8 Hz, 1H), 7.32−7.25
(m, 2H), 7.01 (d, J = 8 Hz, 2H), 6.83 (d, J = 8 Hz, 2H), 4.70 (s, 2H),
3.68 (s, 3H), 3.16 (s, 3H), and 2.22 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 156.7, 154.7, 147.6, 133.2, 132.6, 130.3, 130.1,
129.5, 125.7, 123.5, 113.5, 112.9, 55.5, 39.7, 28.9, and 20.2; and
HRMS (ESI) m/z: calcd for C18H20N3O+ [M + H]+, 294.1601;
found, 294.1605. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254 nm, and tR =
5.555 min).
+
39.5; and HRMS (ESI) m/z: calcd for C19H20N3O3 [M + H]+,
338.1499; found, 338.1499. Purity: 99% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 80:20, flow rate = 1 mL/min, λ = 254
nm, and tR = 6.037 min).
tert-Butyl 2-(3-((methyl(phenyl)amino)methyl)-2-oxoquinoxalin-
1(2H)-yl)acetate (3f). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 4:1 as an eluent) to afford the product 3f (72% yield, 81.4 mg) as
yellow oily liquid. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8 Hz,
1H), 7.48 (dd, J = 8 Hz, J = 8 Hz, 1H), 7.29 (dd, J = 8 Hz, J = 8 Hz,
1H), 7.21 (dd, J = 8 Hz, J = 8 Hz, 2H), 7.03 (d, J = 8 Hz, 1H), 6.88
(d, J = 8 Hz, 2H), 6.68 (dd, J = 8 Hz, J = 8 Hz, 1H), 4.93 (s, 2H),
4.75 (s, 2H), 3.18 (s, 3H), and 1.46 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3): δ 166.1, 156.3, 154.2, 149.6, 132.6, 132.3, 130.6,
130.2, 129.0, 123.8, 116.5, 113.0, 112.5, 83.2, 55.1, 44.0, 39.5, and
1-Methyl-3-((methyl(m-tolyl)amino)methyl)quinoxalin-2(1H)-
one (3k). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1
as an eluent) to afford the product 3k (86% yield, 75.3 mg) as yellow
1
oily liquid. H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8 Hz, 1H),
7.53−7.49 (m, 1H), 7.31−7.24 (m, 2H), 7.09 (dd, J = 8 Hz, J = 8 Hz,
1H), 6.71 (d, J = 8 Hz, 2H), 6.51 (d, J = 8 Hz, 1H), 4.73 (s, 2H), 3.68
(s, 3H), 3.18 (s, 3H), and 2.29 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.6, 154.8, 149.7, 138.7, 133.2, 132.6, 130.4, 130.2,
128.9, 123.6, 117.5, 113.6, 113.3, 109.8, 55.3, 39.7, 28.9, and 22.0; and
HRMS (ESI) m/z: calcd for C18H20N3O+ [M + H]+, 294.1601;
found, 294.1595. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254 nm, and tR =
3.059 min).
+
28.0; and HRMS (ESI) m/z: calcd for C22H26N3O3 [M + H]+,
380.1969; found, 380.1969. Purity: 98% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 80:20, flow rate = 1 mL/min, λ = 254
nm, and tR = 9.773 min).
3-(((4-Ethylphenyl) (methyl)amino)methyl)-1-methylquinoxalin-
2(1H)-one (3l). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 as
an eluent) to afford the product 3l (79% yield, 69.7 mg) as yellow oily
1,7-Dimethyl-3-((methyl(phenyl)amino)methyl)quinoxalin-
2(1H)-one (3g). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 as
an eluent) to afford the product 3g (80% yield, 70.1 mg) as yellow
1
liquid. H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8 Hz, 1H), 7.50
1
oily liquid. H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8 Hz, 1H),
(dd, J = 8 Hz, J = 8 Hz, 1H), 7.31−7.24 (m, 2H), 7.05 (d, J = 8 Hz,
2H), 6.86 (d, J = 8 Hz, 2H), 4.70 (s, 2H), 3.67 (s, 3H), 3.17 (s, 3H),
2.52 (q, J = 8 Hz, 2H), and 1.17 (t, J = 8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 156.8, 154.8, 147.8, 133.2, 132.6, 132.4, 130.4,
130.2, 128.4, 123.6, 113.6, 55.6, 39.7, 28.9, 27.8, and 16.0; and HRMS
(ESI) m/z: calcd for C19H22N3O+ [M + H]+, 308.1757; found,
308.1759. Purity: 98% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254 nm, and tR =
8.447 min).
7.20 (dd, J = 8 Hz, J = 8 Hz, 2H), 7.12 (d, J = 8 Hz, 1H), 7.07 (s,
1H), 6.90 (d, J = 8 Hz, 2H), 6.68 (dd, J = 8 Hz, J = 8 Hz, 1H), 4.71
(s, 2H), 3.67 (s, 3H), 3.19 (s, 3H), and 2.49 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 155.2, 154.9, 149.7, 140.9, 133.1, 130.8, 130.0,
128.9, 124.9, 116.4, 113.7, 112.6, 55.3, 39.6, 28.8, and 22.1; and
HRMS (ESI) m/z: calcd for C18H20N3O+ [M + H]+, 294.1601;
found, 294.1593. Purity: 98% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 80:20, flow rate = 1 mL/min, λ = 254 nm, and tR =
9.120 min).
1,6,7-Trimethyl-3-((methyl(phenyl)amino)methyl)quinoxalin-
2(1H)-one (3h). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 as
an eluent) to afford the product 3h (86% yield, 79.2 mg) as yellow
oily liquid. 1H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 7.20 (dd, J =
8 Hz, J = 8 Hz, 2H), 7.04 (s, 1H), 6.90 (d, J = 8 Hz, 2H), 6.68 (dd, J
= 8 Hz, J = 8 Hz, 1H), 4.71 (s, 2H), 3.67 (s, 3H), 3.19 (s, 3H), 2.39
(s, 3H), and 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
155.1, 154.8, 149.7, 140.0, 132.5, 131.2, 131.0, 130.4, 128.9, 116.4,
114.1, 112.6, 55.3, 39.5, 28.8, 20.6, and 19.1; and HRMS (ESI) m/z:
calcd for C19H22N3O+ [M + H]+, 308.1757; found, 308.1751. Purity:
>99% (HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 90:10,
flow rate = 1 mL/min, λ = 254 nm, and tR = 6.298 min).
3-(((4-Methoxyphenyl)(methyl)amino)methyl)-1-methylquinox-
alin-2(1H)-one (3m). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 as
an eluent) to afford the product 3m (72% yield, 66.8 mg) as yellow
1
oily liquid. H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8 Hz, 1H),
7.54−7.51 (m, 1H), 7.33−7.26 (m, 2H), 6.92 (d, J = 8 Hz, 2H), 6.81
(d, J = 8 Hz, 2H), 4.65 (s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), and 3.11
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.8, 154.8, 151.8,
144.7, 133.2, 132.6, 130.4, 130.2, 123.6, 114.6, 114.6, 113.6, 56.4,
+
55.8, 39.9, and 29.0; and HRMS (ESI) m/z: calcd for C18H20N3O2
[M + H]+, 310.1550; found, 310.1540. Purity: 99% (HPLC: a Shim-
pack VP-ODS column, MeOH/H2O = 80:20, flow rate = 1 mL/min,
λ = 254 nm, and tR = 3.733 min).
3-(((4-Bromophenyl) (methyl)amino)methyl)-1-methylquinoxa-
lin-2(1H)-one (3n). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 as
an eluent) to afford the product 3n (49% yield, 52.3 mg) as yellow
1-Ethyl-6,7-dimethyl-3-((methyl(phenyl)amino)methyl)-
quinoxalin-2(1H)-one (3i). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 4:1 as an eluent) to afford the product 3i (63% yield, 60.9 mg) as a
1
oily liquid. H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8 Hz, 1H),
1
yellow solid, mp 133−135 °C. H NMR (400 MHz, CDCl3): δ 7.58
7.56−7.52 (m, 1H), 7.34−7.24 (m, 4H), 6.75 (d, J = 8 Hz, 2H), 4.72
(s, 2H), 3.70 (s, 3H), and 3.17 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.0, 154.7, 148.6, 133.2, 132.5, 131.6, 130.4, 130.4,
123.7, 114.2, 113.6, 108.4, 55.1, 39.8, and 29.0; and HRMS (ESI) m/
z: calcd for C17H17BrN3O+ [M + H]+, 358.0550; found, 358.0550.
Purity: 97% (HPLC: a Shim-pack VP-ODS column, MeOH/H2O =
90:10, flow rate = 1 mL/min, λ = 254 nm, and tR = 4.892 min).
(s, 1H), 7.20 (dd, J = 8 Hz, J = 8 Hz, 2H), 7.06 (s, 1H), 6.90 (d, J = 8
Hz, 2H), 6.68 (dd, J = 8 Hz, J = 8 Hz, 1H), 4.71 (s, 2H), 4.29 (q, J =
8 Hz, 2H), 3.19 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), and 1.37 (t, J = 8
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.2, 154.4, 149.8,
140.0, 132.4, 131.4, 130.7, 130.1, 129.0, 116.4, 113.9, 112.6, 55.3,
39.6, 37.1, 20.7, 19.1, and 12.6; and HRMS (ESI) m/z: calcd for
H
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3-((Ethyl(phenyl)amino)methyl)-1-methylquinoxalin-2(1H)-one
(3o). The crude product was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 4:1 as an eluent)
to afford the product 3o (58% yield, 51.1 mg) as yellow oily liquid. 1H
NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8 Hz, 1H), 7.50 (dd, J = 8
Hz, J = 8 Hz, 1H), 7.31−7.24 (m, 2H), 7.18 (dd, J = 8 Hz, J = 8 Hz,
2H), 6.83 (d, J = 8 Hz, 2H), 6.64 (dd, J = 8 Hz, J = 8 Hz, 1H), 4.72
(s, 2H), 3.69−3.64 (m, 5H), and 1.25 (t, J = 8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 156.6, 154.8, 148.4, 133.2, 132.7, 130.4,
130.1, 129.1, 123.6, 116.0, 113.6, 112.4, 52.6, 45.8, 28.9, and 12.1; and
HRMS (ESI) m/z: calcd for C18H20N3O+ [M + H]+, 294.1601;
found, 294.1608. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254 nm, and tR =
3.498 min).
3-((Butyl(phenyl)amino)methyl)-1-methylquinoxalin-2(1H)-one
(3p). The crude product was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 4:1 as an eluent)
to afford the product 3p (50% yield, 48.0 mg) as yellow oily liquid. 1H
NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8 Hz, 1H), 7.49 (dd, J = 8
Hz, J = 8 Hz, 1H), 7.27 (dd, J = 8 Hz, J = 8 Hz, 2H), 7.16 (dd, J = 8
Hz, J = 8 Hz, 2H), 6.80 (d, J = 8 Hz, 2H), 6.62 (dd, J = 8 Hz, J = 8
Hz, 1H), 4.73 (s, 2H), 3.68 (s, 3H), 3.58 (t, J = 8 Hz, 2H), 1.72−1.64
(m, 2H), 1.44−1.35 (m, 2H), and 0.96 (t, J = 8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 156.4, 154.7, 148.5, 133.0, 132.6, 130.3,
130.0, 129.0, 123.5, 115.8, 113.5, 112.2, 53.0, 51.5, 29.2, 28.8, 20.4,
and 14.1; HRMS (ESI) m/z: calcd for C20H24N3O+ [M + H]+,
322.1914; found, 322.1913. Purity: 99% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254
nm, and tR = 6.812 min).
3-((Allyl(phenyl)amino)methyl)-1-methylquinoxalin-2(1H)-one
(3q). The crude product was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 4:1 as an eluent)
to afford the product 3q (43% yield, 39.5 mg) as yellow oily liquid. 1H
NMR (400 MHz, CDCl3): δ 8.13−8.11 (m, 3H), 7.88−7.81 (m, 2H),
7.52−7.37 (m, 5H), 3.66 (s, 3H), 3.39 (s, 3H), and 2.44 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 156.5, 154.7, 148.8, 134.2,
133.1, 132.6, 130.4, 130.1, 128.9, 123.6, 116.4, 116.1, 113.5, 112.5,
53.9, 52.6, and 28.9; and HRMS (ESI) m/z: calcd for C19H20N3O+
[M + H]+, 306.1601; found, 306.1601. Purity: 98% (HPLC: a Shim-
pack VP-ODS column, MeOH/H2O = 70:30, flow rate = 1 mL/min,
λ = 254 nm, and tR = 21.005 min).
column chromatography on silica gel (petroleum ether/ethyl acetate
= 15:1 as an eluent) to afford the product 5b (75% yield, 92.8 mg) as
a white solid, mp 130−132 °C. 1H NMR (400 MHz, CDCl3): δ 7.47
(d, J = 8 Hz, 2H), 7.31−7.19 (m, 10H), 6.78 (dd, J = 8 Hz, J = 8 Hz,
3H), 5.04 (s, 2H), 4.99 (s, 2H), 4.45 (s, 2H), and 3.06 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 155.9, 148.8, 148.7, 140.9,
135.4, 135.3, 129.5, 129.1, 128.9, 128.6, 128.6, 128.2, 128.1, 116.9,
112.6, 55.4, 51.9, 44.2, and 39.5; and HRMS (ESI) m/z: calcd for
+
C25H25N4O2 [M + H]+, 413.1972; found, 413.1977. Purity: >99%
(HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 85:15, flow
rate = 1 mL/min, λ = 254 nm, and tR = 24.488 min).
2,4-Bis(4-fluorobenzyl)-6-((methyl(phenyl)amino)methyl)-1,2,4-
triazine-3,5(2H,4H)-dione (5c). The crude product was purified by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 15:1 as an eluent) to afford the product 5c (77% yield, 103.2
mg) as a white solid, mp 131−132 °C. 1H NMR (400 MHz, CDCl3):
δ 7.49−7.45 (m, 2H), 7.20 (dd, J = 8 Hz, J = 8 Hz, 2H), 7.16−7.14
(m, 2H), 7.01−6.96 (m, 2H), 6.91 (dd, J = 8 Hz, J = 8 Hz, 2H), 6.76
(dd, J = 8 Hz, J = 8 Hz, 3H), 5.00 (s, 2H), 4.94 (s, 2H), 4.47 (s, 2H),
and 3.07 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.77 (d, J
= 72 Hz), 161.31 (d, J = 68 Hz), 155.8, 148.7, 148.6, 140.9, 131.5 (d,
J = 80 Hz), 131.2 (d, J = 29 Hz), 131.0 (d, J = 35 Hz), 130.8 (d, J =
80 Hz), 129.1, 117.0, 115.6 (d, J = 89 Hz), 115.4 (d, J = 88 Hz),
112.5, 54.6, 51.7, 43.4, and 39.6; 19F{1H} NMR (376 MHz, CDCl3):
δ −113.5 (d, J = 13 Hz, 1F) and −113.6 (d, J = 14 Hz, 1F); and
+
HRMS (ESI) m/z: calcd for C25H23F2N4O2 [M + H]+, 449.1784;
found, 449.1781. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254 nm, and tR =
11.913 min).
2,4-Diallyl-6-((methyl(phenyl)amino)methyl)-1,2,4-triazine-3,5-
(2H,4H)-dione (5d). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 15:1 as
an eluent) to afford the product 5d (80% yield, 74.7 mg) as a white
solid, mp 113−115 °C. 1H NMR (400 MHz, CDCl3): δ 7.23 (dd, J =
8 Hz, J = 8 Hz, 2H), 6.86 (d, J = 8 Hz, 2H), 6.73 (dd, J = 8 Hz, J = 8
Hz, 1H), 5.90−5.81 (m, 1H), 5.32−5.21 (m, 2H), 4.53−4.50 (m,
4H), 4.44 (s, 2H), and 3.09 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 155.8, 148.9, 148.4, 141.2, 131.3, 130.3, 129.1, 119.4,
119.3, 117.1, 112.8, 54.0, 52.3, 43.0, and 39.5; and HRMS (ESI) m/z:
calcd for C17H21N4O2+ [M + H]+, 313.1659; found, 313.1655. Purity:
99% (HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 85:15,
flow rate = 1 mL/min, λ = 254 nm, and tR = 6.382 min).
3-((Benzyl(phenyl)amino)methyl)-1-methylquinoxalin-2(1H)-
one (3r). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 4:1
as an eluent) to afford the product 3r (40% yield, 42.1 mg) as a yellow
solid, mp 106−108 °C. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8
Hz, 1H), 7.52 (dd, J = 8 Hz, J = 8 Hz, 1H), 7.31−7.21 (m, 6H), 7.14
(dd, J = 8 Hz, J = 8 Hz, 2H), 6.81 (d, J = 8 Hz, 2H), 6.66 (dd, J = 8
Hz, J = 8 Hz, 1H), 4.89 (s, 2H), 4.86 (s, 2H), and 3.68 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 156.4, 154.7, 149.0, 139.2,
133.2, 132.7, 130.4, 130.2, 129.1, 128.6, 126.8, 123.7, 116.6, 113.6,
112.6, 55.4, 53.1, and 28.9; and HRMS (ESI) m/z: calcd for
C23H22N3O+ [M + H]+, 356.1757; found, 356.1752. Purity: 99%
(HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 80:20, flow
rate = 1 mL/min, λ = 254 nm, and tR = 13.461 min).
6-((Methyl(phenyl)amino)methyl)-2,4-bis(2-oxo-2-phenylethyl)-
1,2,4-triazine-3,5(2H,4H)-dione (5e). The crude product was purified
by flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 15:1 as an eluent) to afford the product 5e (64% yield, 89.5
mg) as a yellow solid, mp 67−69 °C. 1H NMR (400 MHz, CDCl3): δ
7.97 (dd, J = 8 Hz, J = 8 Hz, 4H), 7.62 (dd, J = 8 Hz, J = 8 Hz, 2H),
7.50(dd, J = 8 Hz, J = 8 Hz, 4H), 7.25−7.21 (m, 2H), 6.86 (d, J = 8
Hz, 2H), 6.74 (dd, J = 8 Hz, J = 8 Hz, 1H), 5.39−5.38 (m, 4H), 4.47
(s, 2H), and 3.03 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
191.4, 190.3, 155.8, 149.1, 149.1, 141.9, 134.5, 134.4, 134.2, 134.2,
129.1, 129.0, 128.9, 128.2, 128.1, 117.3, 112.9, 57.6, 52.4, 46.6, and
+
38.9; and HRMS (ESI) m/z: calcd for C27H25N4O4 [M + H]+,
469.1870; found, 469.1867. Purity: 99% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254
nm, and tR = 4.552 min).
2,4-Dimethyl-6-((methyl(phenyl)amino)methyl)-1,2,4-triazine-
3,5(2H,4H)-dione (5a). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 15:1 as an eluent) to afford the product 5a (73% yield, 57.6 mg) as
a white solid, mp 108−109 °C. 1H NMR (400 MHz, CDCl3): δ 7.23
(dd, J = 8 Hz, J = 8 Hz, 2H), 6.86 (d, J = 8 Hz, 2H), 6.73 (dd, J = 8
Hz, J = 8 Hz, 1H), 4.42 (s, 2H), 3.59 (s, 3H), 3.34 (s, 3H), and 3.09
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.4, 149.1, 148.9,
140.6, 129.1, 117.0, 112.6, 52.1, 39.7, 39.4, and 27.1; and HRMS
2,4-Dibenzyl-6-((methyl(p-tolyl)amino)methyl)-1,2,4-triazine-
3,5(2H,4H)-dione (5f). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 15:1 as an eluent) to afford the product 5f (80% yield, 102.1 mg) as
1
a yellow solid, mp 88−90 °C. H NMR (400 MHz, CDCl3): δ 7.46
(d, J = 7 Hz, 2H), 7.29−7.22 (m, 8H), 7.01 (d, J = 8 Hz, 2H), 6.72
(d, J = 8 Hz, 2H), 5.02 (s, 2H), 4.97 (s, 2H), 4.41 (s, 2H), 3.02 (s,
3H), and 2.26 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.9,
148.7, 146.7, 141.1, 135.5, 135.3, 129.6, 129.4, 128.8, 128.6, 128.5,
128.1, 128.1, 126.1 112.9, 55.3, 52.1, 44.1, 39.5, and 20.3; and HRMS
+
(ESI) m/z: calcd for C13H17N4O2 [M + H]+, 261.1346; found,
261.1343. Purity: >99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254 nm, and tR =
14.716 min).
2,4-Dibenzyl-6-((methyl(phenyl)amino)methyl)-1,2,4-triazine-
3,5(2H,4H)-dione (5b). The crude product was purified by flash
+
(ESI) m/z: calcd for C26H27N4O2 [M + H]+, 427.2129; found,
427.2122. Purity: >99% (HPLC: a Shim-pack VP-ODS column,
I
https://doi.org/10.1021/acs.joc.1c01207
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254 nm, and tR =
27.237 min).
ODS column, MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254
nm, and tR = 15.126 min).
2,4-Dibenzyl-6-((benzyl(phenyl)amino)methyl)-1,2,4-triazine-
3,5(2H,4H)-dione (5l). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 15:1 as an eluent) to afford the product 5l (54% yield, 78.4 mg) as a
2,4-Dibenzyl-6-((methyl(m-tolyl)amino)methyl)-1,2,4-triazine-
3,5(2H,4H)-dione (5g). The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 15:1 as an eluent) to afford the product 5g (72% yield, 91.9 mg) as
yellow oily liquid. 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 6 Hz,
2H), 7.32−7.22 (m, 8H), 7.09 (dd, J = 8 Hz, J = 8 Hz, 1H), 6.60 (dd,
J = 8 Hz, J = 8 Hz, 3H), 5.04 (s, 2H), 4.99 (s, 2H), 4.44 (s, 2H), 3.05
(s, 3H), and 2.28 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
156.0, 149.0, 148.8, 141.1, 138.8, 135.6, 135.4, 129.6, 129.1, 128.9,
128.7, 128.7, 128.3, 128.2, 118.0, 113.4, 109.9, 55.5, 51.9, 44.2, 39.6,
1
white solid, mp 113−115 °C. H NMR (400 MHz, CDCl3): δ 7.46
(d, J = 6 Hz, 2H), 7.31−7.26 (m, 10H), 7.21−7.14 (m, 5H), 6.76 (dd,
J = 8 Hz, J = 8 Hz, 3H), 5.03 (s, 2H), 5.01 (s, 2H), 4.69 (s, 2H), and
4.54 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.9, 148.7,
148.4, 141.1, 138.7, 135.5, 135.4, 129.5, 129.2, 129.0, 128.7, 128.6,
128.6, 128.3, 128.2, 126.9, 126.7, 117.2, 112.9, 55.4, 55.2, 50.2, and
+
44.2; and HRMS (ESI) m/z: calcd for C31H29N4O2 [M + H]+,
+
and 22.0; and HRMS (ESI) m/z: calcd for C26H27N4O2 [M + H]+,
489.2285; found, 489.2279. Purity: 98% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254
nm, and tR = 20.023 min).
427.2129; found, 427.2126. Purity: 98% (HPLC: a Shim-pack VP-
ODS column, MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254
nm, and tR = 14.372 min).
2,4-Dibenzyl-6-((methyl(naphthalen-1-yl)amino)methyl)-1,2,4-
triazine-3,5(2H,4H)-dione (5m). The crude product was purified by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 15:1 as an eluent) to afford the product 5m (75% yield,
2,4-Dibenzyl-6-(((4-ethylphenyl) (methyl)amino)methyl)-1,2,4-
triazine-3,5(2H,4H)-dione (5h). The crude product was purified by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 15:1 as an eluent) to afford the product 5h (74% yield, 97.3
mg) as yellow oily liquid. 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J =
6 Hz, 2H), 7.31−7.25 (m, 8H), 7.04 (d, J = 8 Hz, 2H), 6.75 (d, J = 8
Hz, 2H), 5.03 (s, 2H), 4.99 (s, 2H), 4.41 (s, 2H), 3.03 (s, 3H), 2.57
(q, J = 8 Hz, 2H), and 1.21 (t, J = 8 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 155.9, 148.7, 146.9, 141.2, 135.5, 135.3, 132.7,
129.4, 128.9, 128.6, 128.6, 128.4, 128.2, 128.1, 112.8, 55.3, 52.1, 44.1,
1
103.8 mg) as yellow oily liquid. H NMR (400 MHz, CDCl3): δ
8.31−8.29 (m, 1H), 7.83−7.81 (m, 1H), 7.56 (d, J = 8 Hz, 1H),
7.47−7.43 (m, 4H), 7.37−7.21 (m, 9H), 7.15 (d, J = 8 Hz, 1H), 5.04
(s, 2H), 5.00 (s, 2H), 4.30 (s, 2H), and 2.92 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 155.8, 149.0, 148.8, 141.6, 135.6, 135.5, 134.8,
129.6, 129.5, 128.8, 128.7, 128.6, 128.3, 128.2, 128.1, 125.9, 125.6,
125.6, 123.9, 123.9, 116.6, 55.5, 55.0, 44.2, and 43.1; and HRMS
+
39.5, 27.8, and 16.0; and HRMS (ESI) m/z: calcd for C27H29N4O2
+
(ESI) m/z: calcd for C29H27N4O2 [M + H]+, 463.2129; found,
[M + H]+, 441.2285; found, 441.2285. Purity: 98% (HPLC: a Shim-
pack VP-ODS column, MeOH/H2O = 85:15, flow rate = 1 mL/min,
λ = 254 nm, and tR = 19.486 min).
463.2128. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 85:15, flow rate = 1 mL/min, λ = 254 nm, and tR =
5.450 min).
2,4-Dibenzyl-6-(((4-methoxyphenyl) (methyl)amino)methyl)-
1,2,4-triazine-3,5(2H,4H)-dione (5i). The crude product was purified
by flash column chromatography on silica gel (petroleum ether/ethyl
acetate = 15:1 as an eluent) to afford the product 5i (78% yield, 103.8
mg) as a yellow solid, mp 76−78 °C. 1H NMR (400 MHz, CDCl3): δ
7.47 (d, J = 7 Hz, 2H), 7.32−7.23 (m, 8H), 6.80 (d, J = 4 Hz, 4H),
5.05 (s, 2H), 5.00 (s, 2H), 4.37 (s, 2H), 3.76 (s, 3H), and 2.99 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.0, 152.0, 148.8,
143.7, 141.3, 135.5, 135.4, 129.5, 128.9, 128.7, 128.6, 128.3, 128.2,
114.7, 114.6, 55.8, 55.4, 52.9, 44.2, and 39.8; and HRMS (ESI) m/z:
calcd for C26H27N4O3+ [M + H]+, 443.2078; found, 443.2075. Purity:
99% (HPLC: a Shim-pack VP-ODS column, MeOH/H2O = 85:15,
flow rate = 1 mL/min, λ = 254 nm, and tR = 9.756 min).
2,4-Dibenzyl-6-(1-(ethyl(phenyl)amino)ethyl)-1,2,4-triazine-3,5-
(2H,4H)-dione (5n). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 15:1 as
an eluent) to afford the product 5n (78% yield, 103.4 mg) as yellow
oily liquid. 1H NMR (400 MHz, CDCl3): δ 7.45−7.42 (m, 2H),
7.31−7.24 (m, 8H), 7.22−7.18 (m, 2H), 6.86 (d, J = 8 Hz, 2H), 6.72
(dd, J = 7 Hz, J = 7 Hz, 1H), 6.86 (q, J = 7 Hz, 1H), 5.16−5.00 (m,
4H), 3.39−3.22 (m, 2H), 1.44 (d, J = 7 Hz, 3H), and 0.98 (t, J = 7
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.5, 148.8, 147.8,
144.7, 135.6, 135.6, 129.4, 129.2, 128.8, 128.7, 128.6, 128.3, 128.1,
117.3, 114.1, 55.4, 52.3, 44.3, 39.3, 15.0, and 14.5; and HRMS (ESI)
+
m/z: calcd for C27H29N4O2 [M + H]+, 441.2285; found, 441.2285.
Purity: >99% (HPLC: a Shim-pack VP-ODS column, MeOH/H2O =
85:15, flow rate = 1 mL/min, λ = 254 nm, and tR = 15.515 min).
2,4-Dibenzyl-6-((phenylamino)methyl)-1,2,4-triazine-3,5-
(2H,4H)-dione (5o). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 10:1 as
an eluent) to afford the product 5o (53% yield, 63.8 mg) as a yellow
solid, mp 127−128 °C. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 2
Hz, 2H), 7.44−7.24 (m, 8H), 7.16 (dd, J = 8 Hz, J = 8 Hz, 2H), 6.74
(dd, J = 8 Hz, J = 8 Hz, 1H), 6.69−6.67 (m, 2H), 5.08 (s, 2H), 5.05
(s, 2H), 4.44 (t, J = 6 Hz, 1H), and 4.29 (d, J = 6 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 155.7, 148.8, 146.9, 141.6, 135.4, 135.4,
129.4, 129.3, 128.8, 128.8, 128.7, 128.3, 128.2, 118.3, 113.5, 55.4,
2,4-Dibenzyl-6-((butyl(phenyl)amino)methyl)-1,2,4-triazine-3,5-
(2H,4H)-dione (5j). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 15:1 as
an eluent) to afford the product 5j (76% yield, 104.2 mg) as a yellow
1
solid, mp 63−64 °C. H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 6
Hz, 2H), 7.32−7.23 (m, 8H), 7.18 (dd, J = 8 Hz, J = 8 Hz, 2H), 6.72
(dd, J = 8 Hz, J = 8 Hz, 3H), 5.05 (s, 2H), 4.99 (s, 2H), 4.44 (s, 2H),
3.42 (t, J = 8 Hz, 2H), 1.60 (m, 2H), 1.34 (m, 2H), and 0.93 (t, J = 8
Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.0, 148.8, 147.8,
141.0, 135.5, 135.3, 129.5, 129.2, 129.0, 128.7, 128.6, 128.2, 128.2,
116.4, 112.4, 55.4, 51.5, 50.1, 44.2, 29.4, 20.3, and 14.1; and HRMS
+
(ESI) m/z: calcd for C28H31N4O2 [M + H]+, 455.2442; found,
+
44.3, and 43.5; and HRMS (ESI) m/z: calcd for C24H23N4O2 [M +
455.2438. Purity: 99% (HPLC: a Shim-pack VP-ODS column,
MeOH/H2O = 90:10, flow rate = 1 mL/min, λ = 254 nm, and tR =
5.048 min).
H]+, 399.1816; found, 399.1816. Purity: 99% (HPLC: a Shim-pack
VP-ODS column, MeOH/H2O = 70:30, flow rate = 1 mL/min, λ =
254 nm, and tR = 31.705 min).
6-((Allyl(phenyl)amino)methyl)-2,4-dibenzyl-1,2,4-triazine-3,5-
(2H,4H)-dione (5k). The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 15:1 as
an eluent) to afford the product 5k (73% yield, 96.5 mg) as a yellow
ASSOCIATED CONTENT
■
sı
* Supporting Information
1
solid, mp 72−74 °C. H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 6
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01207.
Hz, 2H), 7.31−7.24 (m, 8H), 7.17 (dd, J = 8 Hz, J = 8 Hz, 2H),
6.77−6.71 (m, 3H), 5.87−5.78 (m, 1H), 5.16−5.02 (m, 6H), 4.45 (s,
2H), and 4.07 (d, J = 4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3):
δ 155.9, 148.7, 148.0, 141.1, 135.4, 135.3, 133.9, 129.5, 129.1, 128.9,
128.7, 128.6, 128.2, 128.1, 116.9, 116.2, 112.6, 55.3, 53.7, 49.7, and
Details of the photoreaction setup, cyclic voltammetry,
copies of 1H, 13C{1H}, and 19F{1H} NMR spectra for all
products, and copies of HPLC chromatograms for all
products (PDF)
+
44.2; and HRMS (ESI) m/z: calcd for C27H27N4O2 [M + H]+,
439.2129; found, 439.2137. Purity: 99% (HPLC: a Shim-pack VP-
J
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Article
Rev. Med. Chem. 2018, 18, 392−413. (d) Qin, X.; Hao, X.; Han, H.;
Zhu, S.; Yang, Y.; Wu, B.; Hussain, S.; Parveen, S.; Jing, C.; Ma, B.;
Zhu, C. Design and Synthesis of Potent and Multifunctional Aldose
Reductase Inhibitors Based on Quinoxalinones. J. Med. Chem. 2015,
58, 1254−1267.
AUTHOR INFORMATION
Corresponding Authors
■
Yuecheng Zhang − School of Chemical Engineering and
Technology, Hebei Provincial Key Lab of Green Chemical
Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety, Hebei University of
Technology, Tianjin 300130, P. R. China; orcid.org/
0000-0002-7071-6501; Email: yczhang@hebut.edu.cn
Jiquan Zhao − School of Chemical Engineering and
Technology, Hebei Provincial Key Lab of Green Chemical
Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety, Hebei University of
Technology, Tianjin 300130, P. R. China; orcid.org/
0000-0003-0913-6011; Email: zhaojq@hebut.edu.cn
(2) (a) Vanparijs, O.; Marsboom, R.; Desplenter, L. Diclazuril, a
New Broad Spectrum Anticoccidial Drug in Chickens. Poult. Sci.
1989, 68, 489−495. (b) Crance, J. M.; Scaramozzino, N.; Jouan, A.;
Garin, D. Interferon, ribavirin, 6-azauridine and glycyrrhizin: antiviral
compounds active against pathogenic flaviviruses. Antiviral Res. 2003,
58, 73−79. (c) Liu, J.; Gong, Y.; Shi, J.; Hao, X.; Wang, Y.; Zhou, Y.;
Hou, Y.; Liu, Y.; Ding, S.; Chen, Y. Design, synthesis and biological
evaluation of novel N-[4-(2-fluorophenoxy)pyridin-2-yl]-
cyclopropanecarboxamide derivatives as potential c-Met kinase
inhibitors. Eur. J. Med. Chem. 2020, 194, 112244. (d) Mosher, T.;
Hayes, D.; Greenshaw, A. Differential Effects of 5-HT2C Receptor
Ligands on Place Conditioning and Locomotor Activity in Rats. Eur. J.
Pharmacol. 2005, 515, 107−116. (e) Cowden, W. B.; March, D. R.;
Robertson, A.; Jenkins, N. Heterocyclic Cannabinoid CB2 Receptor
Antagonists. WO 2005021547 A2, 2005.
(3) (a) Pontillo, J.; Guo, Z.; Wu, D.; Struthers, R. S.; Chen, C.
Synthesis of Aryl-1,2,4-Triazine-3,5-Diones as Antagonists of the
Gonadotropin-Releasing Hormone Receptor. Bioorg. Med. Chem. Lett.
2005, 15, 4363−4366. (b) Hin, N.; Duvall, B.; Ferraris, D.; Alt, J.;
Thomas, A. G.; Rais, R.; Rojas, C.; Wu, Y.; Wozniak, K. M.; Slusher,
B. S.; Tsukamoto, T. 6-Hydroxy-1,2,4-Triazine-3,5(2H,4H)-Dione
Derivatives as Novel D-Amino Acid Oxidase Inhibitors. J. Med. Chem.
2015, 58, 7258−7272.
(4) (a) Liu, S.; Zhao, Z.; Wang, Y. Construction of N-Heterocycles
through Cyclization of Tertiary Amines. Chem.Eur. J. 2019, 25,
2423−2441. (b) Li, Z.-L.; Sun, K.-K.; Wu, P.-Y.; Cai, C. Iron-
Catalyzed Regioselective α-C-H Alkylation of N-Methylanilines:
Cross-Dehydrogenative Coupling between Unactivated C(sp3)-H
and C(sp3)-H Bonds via a Radical Process. J. Org. Chem. 2019, 84,
6830−6839. (c) Proctor, R. S. J.; Phipps, R. J. Recent Advances in
Minisci-Type Reactions. Angew. Chem., Int. Ed. 2019, 58, 13666−
13699. (d) Black, C. C.; Gorden, A. E. V. Oxidative Mannich
Reactions of Tertiary Amines Using a Cu(II) 2-Quinoxalinol Salen
Catalyst. J. Org. Chem. 2019, 84, 9806−9810. (e) Lin, H.-C.; Xie, P.-
P.; Dai, Z.-Y.; Zhang, S.-Q.; Wang, P.-S.; Chen, Y.-G.; Wang, T.-C.;
Hong, X.; Gong, L.-Z. Nucleophile-Dependent Z/E- and Regiose-
lectivity in the Palladium-Catalyzed Asymmetric Allylic C-H
Alkylation of 1,4-Dienes. J. Am. Chem. Soc. 2019, 141, 5824−5834.
(f) Lv, N.; Chen, Z.; Yu, S.; Liu, Z.; Zhang, Y. Nickel-catalyzed dual
C(sp2)-H activation of arenes: a new route to diaryl ethers. Org.
Chem. Front. 2020, 7, 2224−2229.
(5) Liu, S.; Huang, Y.; Qing, F.-L.; Xu, X.-H. Transition-Metal-Free
Decarboxylation of 3,3,3-Trifluoro-2,2-dimethylpropanoic Acid for
the Preparation of C(CF3)Me2-Containing Heteroarenes. Org. Lett.
2018, 20, 5497−5501.
(6) Zhang, W.; Xiang, X.-X.; Chen, J.; Yang, C.; Pan, Y.-L.; Cheng,
J.-P.; Meng, Q.; Li, X. Direct C-H Difluoromethylation of Hetero-
cycles via Organic Photoredox Catalysis. Nat. Commun. 2020, 11,
638−647.
(7) Ghosh, P.; Kwon, N. Y.; Kim, S.; Han, S.; Lee, S. H.; An, W.;
Mishra, N. K.; Han, S. B.; Kim, I. S. C−H Methylation of Iminoamido
Heterocycles with Sulfur Ylides. Angew. Chem., Int. Ed. 2021, 60,
191−196.
(8) (a) Zhao, L.; Wang, L.; Gao, Y.; Wang, Z.; Li, P. Visible-Light-
Induced Alkoxylation of Quinoxalin-2(1 H )-ones with Alcohols for
the Synthesis of Heteroaryl Ethers. Adv. Synth. Catal. 2019, 361,
5363−5370. (b) Xu, J.; Yang, H.; Cai, H.; Bao, H.; Li, W.; Zhang, P.
Transition-Metal and Solvent-Free Oxidative C-H Fluoroalkoxylation
of Quinoxalinones with Fluoroalkyl Alcohols. Org. Lett. 2019, 21,
4698−4702. (c) Yang, Q.; Han, X.; Zhao, J.; Zhang, H.-Y.; Zhang, Y.
Direct C3 Alkoxylation of Quinoxalin-2(1H)-Ones with Alcohols via
Cross-Dehydrogenative Coupling under Catalyst-Free Conditions. J.
Org. Chem. 2019, 84, 11417−11424.
Authors
Hong-Yu Zhang − School of Chemical Engineering and
Technology, Hebei Provincial Key Lab of Green Chemical
Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety, Hebei University of
Technology, Tianjin 300130, P. R. China; orcid.org/
0000-0002-1186-6614
Jianjun Chen − School of Chemical Engineering and
Technology, Hebei Provincial Key Lab of Green Chemical
Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety, Hebei University of
Technology, Tianjin 300130, P. R. China
Cong-Cong Lu − School of Chemical Engineering and
Technology, Hebei Provincial Key Lab of Green Chemical
Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety, Hebei University of
Technology, Tianjin 300130, P. R. China
Ya-Ping Han − School of Chemical Engineering and
Technology, Hebei Provincial Key Lab of Green Chemical
Technology & High Efficient Energy Saving, Tianjin Key
Laboratory of Chemical Process Safety, Hebei University of
Technology, Tianjin 300130, P. R. China; orcid.org/
0000-0002-5839-225X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01207
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the National
Natural Science Foundation of China (grant no. 21776056),
the Central Government Guides Local Science and Technol-
ogy Development Project (grant no. 206Z4001G), and the
Natural Science Foundation of Hebei Province (CN) (grant
nos. B2018202253 and B2020202010).
REFERENCES
■
(1) (a) Rankovic, Z.; Cai, J.; Fradera, X.; Dempster, M.; Mistry, A.;
Mitchell, A.; Long, C.; Hamilton, E.; King, A.; Boucharens, S.;
Jamieson, C.; Gillespie, J.; Cumming, I.; Uitdehaag, J.; Zeeland, M. v.
Dioxo-Triazines as a Novel Series of Cathepsin K Inhibitors. Bioorg.
Med. Chem. Lett. 2010, 20, 1488−1490. (b) Schön, A.; Kaminska, E.;
Schelter, F.; Ponkkonen, E.; Korytiaková, E.; Schiffers, S.; Carell, T.
Analysis of an Active Deformylation Mechanism of 5-Formyl-
deoxycytidine (fdC) in Stem Cells. Angew. Chem., Int. Ed. 2020, 59,
5591−5594. (c) Shi, L.; Hu, W.; Wu, J.; Zhou, H.; Zhou, H.; Li, X.
Quinoxalinone as a Privileged Platform in Drug Development. Mini-
K
https://doi.org/10.1021/acs.joc.1c01207
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(9) (a) Paul, S.; Ha, J. H.; Park, G. E.; Lee, Y. R. Transition Metal-
Free Iodosobenzene-Promoted Direct Oxidative 3-Arylation of
Quinoxalin-2(H)-ones with Arylhydrazines. Adv. Synth. Catal. 2017,
359, 1515−1521. (b) Jiang, Y. y.; Dou, G. y.; Zhang, L. s.; Xu, K.;
Little, R. D.; Zeng, C. c. Electrochemical Cross-Coupling of C( sp2)−
H with Aryldiazonium Salts via a Paired Electrolysis: an Alternative to
Visible Light Photoredox-Based Approach. Adv. Synth. Catal. 2019,
361, 5170−5175. (c) Paul, S.; Khanal, H. D.; Clinton, C. D.; Kim, S.
H.; Lee, Y. R. Pd(TFA)2-catalyzed direct arylation of quinoxalinones
with arenes. Org. Chem. Front. 2019, 6, 231−235. (d) Tian, M.; Liu,
S.; Bu, X.; Yu, J.; Yang, X. Covalent Organic Frameworks: A
Sustainable Photocatalyst toward Visible-Light-Accelerated C3
Arylation and Alkylation of Quinoxalin-2(1H)-ones. Chem.Eur. J.
2020, 26, 369−373. (e) Xu, J.; Zhang, H.; Zhao, J.; Ni, Z.; Zhang, P.;
Shi, B.-F.; Li, W. Photocatalyst-, Metal- and Additive-Free, Direct C-
H Arylation of Quinoxalin-2(1H)-Ones with Aryl Acyl Peroxides
Induced by Visible Light. Org. Chem. Front. 2020, 7, 4031−4042.
(10) (a) Bao, P.; Liu, F.; Lv, Y.; Yue, H.; Li, J.-S.; Wei, W. Visible-
light-promoted acridine red catalyzed aerobic oxidative decarbox-
ylative acylation of α-oxo-carboxylic acids with quinoxalin-2(1H)-
ones. Org. Chem. Front. 2020, 7, 492−498. (b) Yuan, J.-W.; Zhu, J.-L.;
Zhu, H.-L.; Peng, F.; Yang, L.-Y.; Mao, P.; Zhang, S.-R.; Li, Y.-C.; Qu,
L.-B. Transition-Metal Free Direct C-H Functionalization of
Quinoxalin-2(1H)-Ones with Oxamic Acids Leading to 3-Carbamoyl
Quinoxalin-2(1H)-Ones. Org. Chem. Front. 2020, 7, 273−285.
(c) Xie, L.-Y.; Bai, Y.-S.; Xu, X.-Q.; Peng, X.; Tang, H.-S.; Huang,
Y.; Lin, Y.-W.; Cao, Z.; He, W.-M. Visible-light-induced decarbox-
ylative acylation of quinoxalin-2(1H)-ones with α-oxo carboxylic acids
under metal-, strong oxidant- and external photocatalyst-free
conditions. Green Chem. 2020, 22, 1720−1725.
(11) (a) Wei, W.; Wang, L.; Bao, P.; Shao, Y.; Yue, H.; Yang, D.;
Yang, X.; Zhao, X.; Wang, H. Metal-Free C(sp2)-H/N-H Cross-
Dehydrogenative Coupling of Quinoxalinones with Aliphatic Amines
under Visible-Light Photoredox Catalysis. Org. Lett. 2018, 20, 7125−
7130. (b) Yang, Q.; Yang, Z.; Tan, Y.; Zhao, J.; Sun, Q.; Zhang, H. Y.;
Zhang, Y. Direct C( sp2)−H Amination to Synthesize Primary 3-
aminoquinoxalin-2(1H)-ones under Simple and Mild Conditions.
Adv. Synth. Catal. 2019, 361, 1662−1667. (c) Xie, L.-Y.; Hu, J.-L.;
Song, Y.-X.; Jia, G.-K.; Lin, Y.-W.; He, J.-Y.; Cao, Z.; He, W.-M.
Visible-Light-Initiated Cross-Dehydrogenative Coupling of Quinox-
alin-2(1H)-Ones and Simple Amides with Air as an Oxidant. ACS
Sustain. Chem. Eng. 2019, 7, 19993−19999.
(12) (a) Gu, Y.-R.; Duan, X.-H.; Chen, L.; Ma, Z.-Y.; Gao, P.; Guo,
L.-N. Iminyl Radical-Triggered Intermolecular Distal C(sp3)-H
Heteroarylation via 1,5-Hydrogen-Atom Transfer (HAT) Cascade.
Org. Lett. 2019, 21, 917−920. (b) Wang, L.; Liu, H.; Li, F.; Zhao, J.;
Zhang, H.-Y.; Zhang, Y. Copper-Catalyzed C3−H Difluoroacetylation
of Quinoxalinones with Ethyl Bromodifluoroacetate. Adv. Synth.
Catal. 2019, 361, 2354−2359.
(13) (a) Li, K.-J.; Jiang, Y.-Y.; Xu, K.; Zeng, C.-C.; Sun, B.-G.
Electrochemically dehydrogenative C-H/P-H cross-coupling: effective
synthesis of phosphonated quinoxalin-2(1H)-ones and xanthenes.
Green Chem. 2019, 21, 4412−4421. (b) Rawat, D.; Kumar, R.;
Subbarayappa, A. Visible-Light Induced Phosphonation of Quinoxa-
lines and Quinoxalin-2(1H)-Ones under Aerobic Metal-Free
Conditions. Green Chem. 2020, 22, 6170−6175.
(14) (a) Xie, L.-Y.; Chen, Y.-L.; Qin, L.; Wen, Y.; Xie, J.-W.; Tan, J.-
X.; Huang, Y.; Cao, Z.; He, W.-M. Visible-Light-Promoted Direct C-
H/S-H Cross-Coupling of Quinoxalin-2(1H)-Ones with Thiols
Leading to 3-Sulfenylated Quinoxalin-2(1H)-Ones in Air. Org.
Chem. Front. 2019, 6, 3950−3955. (b) Teng, Q.-H.; Yao, Y.; Wei,
W.-X.; Tang, H.-T.; Li, J.-R.; Pan, Y.-M. Direct C-H Sulfenylation of
Quinoxalinones with Thiols under Visible-Light-Induced Photo-
catalyst-Free Conditions. Green Chem. 2019, 21, 6241−6245.
(15) (a) Sekhar Dutta, H.; Ahmad, A.; Khan, A. A.; Kumar, M.;
Raziullah; Koley, D. Metal Free Benzylation and Alkylation of
Quinoxalin-2(1H)-ones with Alkenes Triggered by Sulfonyl Radical
Generated from Sulfinic Acids. Adv. Synth. Catal. 2019, 361, 5534−
5539. (b) Zhang, W.; Pan, Y.-L.; Yang, C.; Li, X.; Wang, B. Ring-
opening C(sp3)-C coupling of cyclobutanone oxime esters for the
preparation of cyanoalkyl containing heterocycles enabled by
photocatalysis. Org. Chem. Front. 2019, 6, 2765−2770. (c) Wang,
J.; Sun, B.; Zhang, L.; Xu, T.; Xie, Y.; Jin, C. Transition-Metal-Free
Direct C-3 Cyanation of Quinoxalin-2(1H)-Ones with Ammonium
Thiocyanate as the “CN” Source. Org. Chem. Front. 2020, 7, 113−
118. (d) Dai, C.; Zhan, Y.; Liu, P.; Sun, P. Organic Photoredox
Catalyzed C-H Silylation of Quinoxalinones or Electron-Deficient
Heteroarenes under Ambient Air Conditions. Green Chem. 2021, 23,
314−319.
(16) Si, Y.-F.; Chen, X.-L.; Fu, X.-Y.; Sun, K.; Song, X.; Qu, L.-B.;
Yu, B. Divergent G-C3N4-Catalyzed Reactions of Quinoxalin-2(1H)-
Ones with N-Aryl Glycines under Visible Light: Solvent-Controlled
Hydroaminomethylation and Annulation. ACS Sustain. Chem. Eng.
2020, 8, 10740−10746.
(17) (a) Huang, P.; Wang, P.; Wang, S.; Tang, S.; Lei, A.
Electrochemical oxidative [4 + 2] annulation of tertiary anilines and
alkenes for the synthesis of tetrahydroquinolines. Green Chem. 2018,
20, 4870−4874. (b) Hsu, C.-W.; Sundén, H. α-Aminoalkyl Radical
Addition to Maleimides via Electron Donor-Acceptor Complexes.
Org. Lett. 2018, 20, 2051−2054. (c) Döben, N.; Yan, H.; Kischkewitz,
M.; Mao, J.; Studer, A. Intermolecular Acetoxyaminoalkylation of α-
Diazo Amides with (Diacetoxyiodo)benzene and Amines. Org. Lett.
2018, 20, 7933−7936. (d) Mandal, T.; Das, S.; De Sarkar, S.
Nickel(II) Tetraphenylporphyrin as an Efficient Photocatalyst
Featuring Visible Light Promoted Dual Redox Activities. Adv. Synth.
Catal. 2019, 361, 3200−3209. (e) Hwang, J. Y.; Ji, A. Y.; Lee, S. H.;
Kang, E. J. Redox-Selective Iron Catalysis for α-Amino C-H Bond
Functionalization via Aerobic Oxidation. Org. Lett. 2020, 22, 16−21.
(f) Masuda, Y.; Ito, M.; Murakami, M. Dehydrative Allylation of α
C(sp3)-H Bonds of Alkylamines with Allylic Alcohols. Org. Lett. 2020,
22, 4467−4470.
(18) (a) Li, Y.-H.; Wang, C.-H.; Gao, S.-Q.; Qi, F.-M.; Yang, S.-D.
Visible photocatalysis of novel oxime phosphonates: synthesis of β-
aminophosphonates. Chem. Commun. 2019, 55, 11888−11891.
(b) Zhou, C.; Lei, T.; Wei, X.-Z.; Ye, C.; Liu, Z.; Chen, B.; Tung,
C.-H.; Wu, L.-Z. Metal-Free, Redox-Neutral, Site-Selective Access to
Heteroarylamine via Direct Radical-Radical Cross-Coupling Powered
by Visible Light Photocatalysis. J. Am. Chem. Soc. 2020, 142, 16805−
16813. (c) Cui, W.-J.; Wu, Z.-J.; Gu, Q.; You, S.-L. Divergent
Synthesis of Tunable Cyclopentadienyl Ligands and Their Application
in Rh-Catalyzed Enantioselective Synthesis of Isoindolinone. J. Am.
Chem. Soc. 2020, 142, 7379−7385. (d) Gao, Y.; Jing, Y.; Li, L.; Zhang,
J.; Chen, X.; Ma, Y.-N. Synthesis of Phenanthridines through Iodine-
Supported Intramolecular C-H Amination and Oxidation under
Visible Light. J. Org. Chem. 2020, 85, 12187−12198. (e) Kang, Q.-Q.;
Wu, W.; Li, Q.; Wei, W.-T. Photochemical strategies for C-N bond
formation via metal catalyst-free (hetero) aryl C(sp2)-H functional-
ization. Green Chem. 2020, 22, 3060−3068. (f) Xie, L.-Y.; Peng, S.;
Yang, L.-H.; Peng, C.; Lin, Y.-W.; Yu, X.; Cao, Z.; Peng, Y.-Y.; He,
W.-M. Aryl Acyl Peroxides for Visible-Light Induced Decarboxylative
Arylation of Quinoxalin-2(1H)-Ones under Additive-, Metal Cata-
lyst-, and External Photosensitizer-Free and Ambient Conditions.
Green Chem. 2021, 23, 374−378.
(19) (a) Zou, Y.-Q.; Xiao, W.-J. Visible Light Mediated α-Amino C-
H Functionalization Reactions. In Visible Light Photocatalysis in
Organic Chemistry; Stephenson, C., Yoon, T., MacMillan, D. W. C.,
Eds.; Wiley-VCH: Berlin, 2018; Chapter 4, pp 93−127. (b) Freeman,
D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Functionally
Diverse Nucleophilic Trapping of Iminium Intermediates Generated
Utilizing Visible Light. Org. Lett. 2012, 14, 94−97. (c) Rueping, M.;
Koenigs, R. M.; Poscharny, K.; Fabry, D. C.; Leonori, D.; Vila, C.
Dual Catalysis: Combination of Photocatalytic Aerobic Oxidation and
Metal Catalyzed Alkynylation Reactions-C-C Bond Formation Using
Visible Light. Chem.Eur. J. 2012, 18, 5170−5174. (d) Dai, X.;
Cheng, D.; Guan, B.; Mao, W.; Xu, X.; Li, X. The Coupling of
Tertiary Amines with Acrylate Derivatives via Visible-Light Photo-
redox Catalysis. J. Org. Chem. 2014, 79, 7212−7219. (e) Borra, S.;
Chandrasekhar, D.; Adhikary, S.; Rasala, S.; Gokulnath, S.; Maurya, R.
L
https://doi.org/10.1021/acs.joc.1c01207
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
A. Visible-Light Driven Photocascade Catalysis: Union of N,N-
Dimethylanilines and α-Azidochalcones in Flow Microreactors. J. Org.
Chem. 2017, 82, 2249−2256. (f) Kibriya, G.; Bagdi, A. K.; Hajra, A.
Visible-Light-Promoted C(sp3)-C(sp2) Cross-Dehydrogenative Cou-
pling of Tertiary Amine with Imidazopyridine. J. Org. Chem. 2018, 83,
10619−10626.
(20) (a) Jacobsen, E. J.; TenBrink, R. E.; Stelzer, L. S.; Belonga, K.
L.; Carter, D. B.; Im, H. K.; Im, W. B.; Sethy, V. H.; Tang, A. H.;
VonVoigtlander, P. F.; Petke, J. D. High-Affinity Partial Agonist
Imidazo[1,5-a]quinoxaline Amides, Carbamates, and Ureas at the γ-
Aminobutyric Acid A/Benzodiazepine Receptor Complex. J. Med.
Chem. 1996, 39, 158−175. (b) Carrër, A.; Brion, J.-D.; Messaoudi, S.;
Alami, M. Palladium(II)-Catalyzed Oxidative Arylation of Quinoxalin-
2(1H)-Ones with Arylboronic Acids. Org. Lett. 2013, 15, 5606−5609.
(c) Yin, K.; Zhang, R. Transition-Metal-Free Direct C-H Arylation of
Quinoxalin-2(1H)-ones with Diaryliodonium Salts at Room Temper-
ature. Lett 2017, 19, 1530−1533. (d) Yuan, J.; Liu, S.; Qu, L.
Transition Metal-Free Direct C-3 Arylation of Quinoxalin-2(1H
)-ones with Arylamines under Mild Conditions. Adv. Synth. Catal.
2017, 359, 4197−4207.
(21) (a) Huang, P.-J.; Lee, K.-H. Synthesis and antibacterial
evaluation of 6-azapyrimidines with α-methylene-γ-(4-substituted
phenyl)-γ-butyrolactone pharmacophores. Med. Chem. Res. 2011, 20,
1081−1090. (b) Hwang, L.-C.; Yang, S.-Y.; Chuang, C.-L.; Lee, G.-H.
An Optimized Synthesis, Molecular Structure and Characterization of
Benzylic Derivatives of 1,2,4-Triazin-3,5(2H,4H)-Dione. Molecules
2017, 22, 1924−1934.
M
https://doi.org/10.1021/acs.joc.1c01207
J. Org. Chem. XXXX, XXX, XXX−XXX