PIFA-promoted intramolecular oxidative C(aryl)-H amidation reaction: Synthesis of quinolino[3,4-b]quinoxalin-6(5H)-ones

Article abstract of DOI:10.1016/j.tet.2017.12.016

A facile and direct intramolecular oxidative C(aryl)-H amidation reaction was developed for the synthesis of quinolino[3,4-b]quinoxalin-6(5H)-ones in moderate to excellent yields starting from readily available materials by tethering the adjacent N-methoxyamide and aryl portions in the presence of phenyliodine(III) bis(trifluoroacetate) at room temperature. This metal-free approach is a valuable addition to the traditional methods already available for the preparation of these molecules.

Full text of DOI:10.1016/j.tet.2017.12.016

Accepted Manuscript
PIFA-promoted intramolecular oxidative C(aryl)-H amidation reaction: Synthesis of
quinolino[3,4-b]quinoxalin-6(5H)-ones
Chunfang Hu, Zhiguo Zhang, Wenjing Gao, Guisheng Zhang, Tongxin Liu, Qingfeng
Liu
PII:
S0040-4020(17)31267-X
10.1016/j.tet.2017.12.016
TET 29172
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 October 2017
Revised Date: 6 December 2017
Accepted Date: 8 December 2017
Please cite this article as: Hu C, Zhang Z, Gao W, Zhang G, Liu T, Liu Q, PIFA-promoted intramolecular
oxidative C(aryl)-H amidation reaction: Synthesis of quinolino[3,4-b]quinoxalin-6(5H)-ones, Tetrahedron
(2018), doi: 10.1016/j.tet.2017.12.016.
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ACCEPTED MANUSCRIPT
GA
3
1
2
1
2
A facile and direct intramolecular oxidative C(aryl)-H amidation reaction was
developed for the synthesis of quinolino[3,4-b]quinoxalin-6(5H)-ones in moderate to
excellent yields, starting from readily available materials by tethering the adjacent
N-methoxyamide and aryl portion in the presence of phenyliodine(III)
bis(trifluoroacetate) (PIFA) at room temperature. This metal-free approach is a
valuable addition to the traditional methods already available for the preparation of
these molecules.

ACCEPTED MANUSCRIPT
PIFA-Promoted Intramolecular Oxidative C(aryl)-H Amidation Reaction:
Synthesis of Quinolino[3,4-b]quinoxalin-6(5H)-ones
Chunfang Hu,a Zhiguo Zhang, a,b* Wenjing Gao,a Guisheng Zhang,a* Tongxin Liu,a
Qingfeng Liua
a
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, Henan Key laboratory of Organic Functional Molecule and Drug Innovation, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of
Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007,
China. Fax: (+86)-373-332-5250; E-mail: zhangzg@htu.edu.cn or zgs6668@yahoo.com
b
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Northeast Normal University, Jilin, Changchun 130024, China

ACCEPTED MANUSCRIPT
PIFA-Promoted Intramolecular Oxidative C(aryl)-H Amidation Reaction: Synthesis of
Quinolino[3,4-b]quinoxalin-6(5H)-ones
Chunfang Hu, Zhiguo Zhang,* Wenjing Gao, Guisheng Zhang,* Tongxin Liu, Qingfeng Liu
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan
a
Key laboratory of Organic Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China. Fax: (+86)-373-332-5250; E-mail: zhangzg@htu.edu.cn or
zgs6668@yahoo.com
b
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal
University, Jilin, Changchun 130024, China
Abstract: A facile and direct intramolecular oxidative C(aryl)-H amidation reaction was developed
for the synthesis of quinolino[3,4-b]quinoxalin-6(5H)-ones in moderate to excellent yields starting
from readily available materials by tethering the adjacent N-methoxyamide and aryl portions in the
presence of phenyliodine(III) bis(trifluoroacetate) at room temperature. This metal-free approach is a
valuable addition to the traditional methods already available for the preparation of these molecules.
Keywords: Quinolino[3,4-b]quinoxalin-6(5H)-ones; Pyrazino[2,3-c]quinolin-5(6H)-ones; C(aryl)-N
Formation; PIFA; Hypervalent organoiodine
1. Introduction
Quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones analogues
are interesting heterocycles of great importance. Quinolino[3,4-b]quinoxalin-6(5H)-ones and
quinolino[3,4-b]quinoxalines,
such
as
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5-(3-(dimethylamino)propyl)quinolino[3,4-b]quinoxalin-6(5H)-one
(I)
and
N1,N1-dimethyl-N4-(quinolino[3,4-b]quinoxalin-6-yl)butane-1,4-diamine (II) have shown interesting
topoisomerase IIα (Topo IIα) inhibition activity and G-quadruplex stabilization (Figure 1).1
Furthermore,
the
radioiodinated
compound
7-(iodo-125I)-5-((1-propylpiperidin-4-yl)methoxy)pyrazino[2,3-c]quinoline ([125I]III, Figure 1)
exhibited excellent binding affinity toward human 5-HT4R (Ki 5-HT4R = 0.094 nM) and a high
selectivity over other serotonin receptor subtypes (5-HTR),2 which could be used as a radiotracer for
brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed
tomography in the future.3 Interestingly, compounds I, II, and [125I]III can be obtained from the
derivatization of quinolino[3,4-b]quinoxalin-6(5H)-ones or pyrazino[2,3-c]quinolin-5(6H)-ones
through a N5- or C6-functionalization, respectively. This conversion indicates that the
quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones analogues are
important intermediates in organic synthetic chemistry.
Figure 1. Representative quinolino[3,4-b]quinoxalin-6(5H)-ones and their derivatives.
Although they have important applications in organic synthesis and pharmaceutical chemistry, a
systematic literature review revealed a limited number of existing works addressing the systematic
construction of quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones
analogues, and some of them were synthesized as key intermediates in these chemistry. Vanelle’s
and Pierre’s groups reported that the quinolino[3,4-b]quinoxalin-6(5H)-ones and their
pyrazino[2,3-c]quinolin-5(6H)-ones analogues can be obtained through a stepwise intermolecular
cross-coupling reaction of 3-halogenated quinoxaline-2-carboxylate esters with arylboronic acids by
a Suzuki–Miyaura reaction, and then an intramolecular coupling–lactamization reaction in the
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presence of a palladium catalyst (Scheme 1).4-6 A microwave-assisted post-Ugi cascade reaction was
developed by Xu and Chen et al. to access a series of quinolino[3,4-b]quinoxalin-6(5H)-ones in good
yields (Scheme 1).7 In addition, the cross-coupling of 3-chloro-2-cyanopyrazine with boronic species
resulted in biaryl derivatives, followed by an anionic ring closure route in the presence of 5
t
o
equivalents of KOH in a sealed tube containing BuOH at 150 C to obtain the target
pyrazino[2,3-c]quinolin-5(6H)-ones in a two-step reaction.8,9 Moreover, Catto’s and Gewald’s
groups reported that these types of angular multi-fused aza-heterocycles can also be prepared in low
to moderate yields by a condensation reaction of 1,3-dicarbonyl compounds with o-diamines under
heat conditions (Scheme 1).1,10-12 Despite the obvious progress that has been achieved, it is still
highly desirable to develop alternative and more flexible methods that lead to structurally diverse
libraries of quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones
analogues under mild and environmentally friendly conditions for high-throughput screening in
medicinal chemistry. Here, we present our recent efforts for the synthesis of
quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones analogues (2)
using the phenyliodine(III) bis(trifluoroacetate) (PIFA)-mediated C(aryl)–H bond oxidative
C(aryl)-N formation reaction.13 This highly efficient metal-free intramolecular reaction, which forms
a bond between the nitrogen atom of an amide with the carbon atom of a phenyl, can be performed
with readily available starting materials and a broad substrate scope and would further enlarged the
library of this type of angular fused heterocycle (Scheme 1).
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Scheme 1. Representative routes to quinolino[3,4-b]quinoxalin-6(5H)-ones.
Hypervalent organoiodine reagents have been widely used in organic transformations, especially
in C(sp2)-N formation reactions, serving as advanced oxidants that are readily available, nontoxic,
ease to handle and environmentally benign.14-16 It is well documented that the nitrogen atom of
N-methoxyl secondary amides can couple directly with the sp2 carbon atom of a phenyl by releasing
one molecule of H2 in formal, commonly through an intramolecular oxidative C(aryl)-H amidation
reaction in the presence of organoiodine reagents.17-31 This ring closure procedure proceeds in high
yields and allows access to various N-containing five-, six-, and seven-membered fused heterocycles
through the ipso-annulation reaction or ortho-cyclization reaction (Scheme 2).32-34 Combined with
our recent work on the synthesis of functional small organic molecules in the presence of
hypervalent organoiodine reagents through efficient, green oxidative C(aryl)–N bond formation
reactions,32,35-37 we intended to transfer this N-methoxyamide participation C(aryl)-N formation
strategy
to
synthesize
other
useful
fused
aza-heterocycles,
such
as
quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones analogues
starting from commercially available β-ketoamides in the presence of hypervalent organoiodine
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reagents.
Scheme 2. Direct oxidative C(aryl)-H amidation of adjacent N-methoxyamide and phenyl group
2. Results and discussion
We began our evaluation with N-methoxy-3-phenylquinoxaline-2-carboxamide (1a) as a model
substrate, which was readily prepared by the condensation reaction of o-diamines with
1,2,3-tricarbonyl compounds (generated in situ from the oxidation reaction of 1,3-dicarbonyl
compounds),38 under [bis-(trifluoroacetoxy)iodo]benzene (PIFA) as a model reaction (Table 1).
Acetonitrile (MeCN) was investigated first as
a
solvent; the desired product
5-methoxyquinolino[3,4-b]quinoxalin-6(5H)-one (2a) was formed in 95% yield in the presence of 1
equivalent of PIFA at room temperature after 1 h (Table 1, entry 1). When the solvent was switched
to tetrahydrofuran (THF), dichloromethane (DCM), DMSO and DMF, product 2a was obtained in
lower yields (19-78%) than that in MeCN (Table 1, entry 1 versus 2-5). However, when the reaction
was carried out in trifluoroethanol (TFE), a slightly higher yield of 96% was observed; however,
because of the significantly higher price of TFE compared with that of MeCN, we did not use TFE as
a solvent in subsequent reactions (Table 1, entry 6). Interestingly, when the PIFA loading was
reduced from 1 to 0.5 equivalents at room temperature, the yield of 2a dropped from 95% to 45%,
and starting material 1a was recovered in 47% yield (Table 1, entry 7). Other organoiodine reagents
including diacetoxyiodobenzene (PIDA), PhI(OPiv)2 and 2-iodosobenzoic acid were screened and
found to not be as efficient as PIFA (Table 1, entries 8-10). After screening, the optimal reaction
conditions were PIFA (1.1 equivalent) in MeCN (1.5 mL) at room temperature.
Table 1. Survey of the reaction conditionsa
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Entry
Catalyst (equiv)
PIFA (1.1)
Solvent
MeCN
THF
T (°C)
Time (h) Yield of 2a/%
1
2
3
4
5
6
7
8
rt
rt
rt
rt
rt
rt
rt
rt
rt
1
1
95
31
78
19
52
96
45b
26
PIFA (1.1)
PIFA (1.1)
DCM
DMSO
DMF
1
PIFA (1.1)
1
PIFA (1.1)
1
PIFA (1.1)
TFE
1
PIFA (0.5)
MeCN
MeCN
MeCN
1.5
1.5
1.5
PIDA (1.1)
PhI(OPiv)2 (1.1)
9
23
0c
10
2-Iodosobenzoic acid (1.1)
MeCN
rt
1.5
a Unless otherwise indicated, all reactions were carried out with 1a (0.3 mmol), PIFA (1.1 equiv) and
MeCN (1.5 mL) at room temperature.
b 47% of 1a was recovered. c 91% of 1a was recovered.
With the optimized conditions in hand (Table 1, entry 1), we investigated the substrate scope
( Table 2). Initially, various R2 substituents were investigated. The starting material 1b bearing a
-OMe at the meta position formed the desired ortho-cyclized product 2b in 99% yield. However, the
compounds 1c and 1d with the -OMe at the para and ortho positions, respectively, regiospecifically
afforded the ipso-annulated products 3c and 3d in 93% and 87% yield, respectively, without the
formation of the ortho-cyclized products 2c and 2d. All of the reactions in our protocol resulted in a
single product 2 or 3 instead of a mixture of ipso- and ortho-cyclized product, which is different
from some previous reports.17,23 We found the reaction was very unfavorable when a chloro
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substituent was present in the starting material. Only 16% of compound 2e was isolated, along with
an unidentified complex mixture, starting from 1e bearing the chloro- group at the -meta position. An
analogous result was obtained in the case of 1f and 1g; the desired products 2f and 2g were not
observed. Three kinds of heterocyclic substituents 2-pyridinyl, 2-thiophenyl and 2-furanyl were also
employed in the reaction. Good yields of 2h (76%) and 2i (72%) were achieved for the reactions
starting from 1h and 1i, respectively.
Next, we screened the reactions using substrates with various R1 substituents. A number of
functional groups bearing -OMe at the 6-position, and -Cl, -CF3, or -NO2 at the 7-position were
tolerated well, and the target products 2j–m were obtained in good yields (74−95%). Importantly,
starting material 1n derived from 1,2-cyclohexanediamine also showed high reactivity leading to 2n
in moderate yield (63%). Furthermore, the fused heterocycle starting material 1o was also reacted
under the optimized conditions to give the corresponding product 2o in 94% yield. These successful
examples prompted us to investigate additional modifications at these positions. Compounds 1p and
1q, as well as the unmodified starting material 1r were also viable for the construction of 2p−r in
satisfactory yields (47−92%).
Table 2. Reaction extensiona
2a: 1 h, 95%
2b: 50 min, 99%
3c: 50 min, 93%
3d: 40 min, 87%
O
N
N
O
N
Cl
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2e: 50 min, 16%
2i: 30 min, 72%
2f: 50 min, 0%
2g: 50 min, 0%
2h: 20 min, 76%
2l: 30 min, 74%
2j: 20 min, 79%
2k: 40 min, 95%
2o: 30 min, 94%
2m: 40 min, 84%
2q: 20 min, 92%
2n: 30 min, 63%
2r: 50 min, 47%
2p: 35 min, 80%
a
Unless otherwise indicated, all reactions were carried out with 1a (0.3 mmol), PIFA (1.1 equiv)
and MeCN (1.5 mL) at room temperature.
3. Conclusion
We developed
a
facile, metal-free
method
for the
direct
synthesis
of
quinolino[3,4-b]quinoxalin-6(5H)-ones and their pyrazino[2,3-c]quinolin-5(6H)-ones analogues by
tethering adjacent N-methoxyamide and aryl portions in the presence of phenyliodine(III)
bis(trifluoroacetate) (PIFA) at room temperature. The advantages of this intramolecular oxidative
C(aryl)-H amidation reaction include the use of readily available starting materials, moderate to good
yields and flexible substitution patterns. Moreover, as an alternative and valuable route, it allows
enlargement of the library of this type of angular, fused, heterocyclic compounds for biology and
pharmacology purposes.
4. Experimental section
4.1. General methods
All reactions were carried out under air atmosphere, unless otherwise indicated. Other all reagents
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were purchased from commercial sources and used without further treatment, unless otherwise
indicated. Petroleum ether (PE) used refers to the 60-90 °C boiling point fraction of petroleum. Ethyl
1
13
acetate is abbreviated as EA. H NMR and C NMR spectra were recorded on Bruker Avance/600
(1H: 600 MHz, 13C: 150 MHz at 25 °C) or Bruker Avance/400 (1H: 400 MHz, 13C: 100 MHz at 25 °C)
and TMS as internal standard. Data are represented as follows: chemical shift, integration,
multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m =
multiplet), coupling constants in Hertz (Hz). All high-resolution mass spectra (HRMS) were
measured on a mass spectrometer by using electrospray ionization (ESI-oa-TOF), and the purity of
1
all samples used for HRMS (>95%) were confirmed by H NMR and 13C NMR spectroscopic
analysis. Melting points were measured on a melting point apparatus equipped with a thermometer
and were uncorrected. All reactions were monitored by TLC with GF254 silica gel coated plates.
Flash chromatography was carried out on SiO2 (silica gel 200−300 mesh).
4.2. Typical Experimental Procedure For 2 (2a as an example):
To a round-bottom flask (25 mL) was added N-methoxy-3-phenylquinoxaline-2-carboxamide 1a
(84 mg, 0.3 mmol), PIFA (142 mg, 0.33 mmol), the mixture was well stirred for 1 h in MeCN (1.5
mL) at room temperature (the whole process was closely monitored by TLC). After completion,
water (10 mL) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (10
mL×3). The combined organic layer was dried over sodium sulphate. The solvent was evaporated,
and the residue was purified by a short flash silica gel column chromatography (eluent: PE/EA = 2/1)
to give 5-methoxyquinolino[3,4-b]quinoxalin-6(5H)-one 2a as a yellow solid (79 mg, 95%).
4.2.1. 5-methoxyquinolino[3,4-b]quinoxalin-6(5H)-one (2a)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (79 mg,
95%). mp: 200-201 oC; 1H NMR (600 MHz, CDCl3) δ 8.98 (d, J = 7.8 Hz, 1H), 8.47 (d, J = 8.4 Hz,
1H), 8.27 (d, J = 8.4 Hz, 1H), 7.96 (t, J = 7.5 Hz, 1H), 7.89 (t, J = 7.2 Hz, 1H), 7.79-7.64 (m, 2H),
7.47 (t, J = 6.9 Hz, 1H), 4.22 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 156.3, 144.7, 144.3, 142.8,
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138.2, 137.3, 133.1, 132.9, 131.1, 131.0, 129.4, 126.1, 124.3, 118.6, 112.7, 63.1. HRMS (ESI), m/z
calcd. for C16H12N3O2 ([M+H]+) 278.0924, found: 278.0926.
4.2.2. 2,5-dimethoxyquinolino[3,4-b]quinoxalin-6(5H)-one (2b)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (91 mg,
99%). mp: 202-204 oC; 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 2.8 Hz,
1H), 8.26 (d, J = 8.4 Hz, 1H), 7.95 (t, J = 7.4 Hz, 1H), 7.88 (t, J = 7.4 Hz, 1H), 7.61 (d, J = 9.2 Hz,
1H), 7.29 (dd, J = 8.8, 2.8 Hz, 1H), 4.20 (s, 3H), 4.01 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 156.5,
155.7, 144.2, 144.0, 142.7, 138.4, 133.0, 131.5, 131.0, 130.9, 129.3, 121.1, 119.4, 114.3, 107.9, 63.1,
56.1. HRMS (ESI), m/z calcd. for C17H13NaN3O3 ([M+Na]+) 330.0849, found: 330.0854.
4.2.3. 2’-methoxyspiro[cyclohexane-1,1’-pyrrolo[3,4-b]quinoxaline]-2,5-diene-3’,4(2’H)-dione (3c)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (82 mg,
o
1
93%). mp: 216-220 C; H NMR (600 MHz, CDCl3) δ 8.38 (dd, J = 9.0, 5.4 Hz, 1H), 8.17 (dd, J =
9.6, 4.8 Hz, 1H), 7.94 (dd, J = 9.6, 5.4 Hz, 2H), 6.75-6.65 (m, 4H), 4.10 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 184.2, 160.9, 152.0, 144.4, 144.3, 142.5, 142.4, 133.9, 132.9, 132.1, 131.0, 129.8, 66.6,
65.6. HRMS (ESI), m/z calcd. for C16H12N3O3 ([M+H]+) 294.0873, found: 294.0875.
4.2.4. 2’-methoxyspiro[cyclohexane-1,1’-pyrrolo[3,4-b]quinoxaline]-2,4-diene-3’,6(2’H)-dione (3d)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (76 mg,
o
1
87%). mp: 193-195 C; H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 6.0, 3.6 Hz, 1H), 8.09 (dd, J =
6.3, 3.3 Hz, 1H), 7.85 (dd, J = 6.3, 3.3 Hz, 2H), 7.35-7.30 (m, 1H), 6.79 (dd, J = 9.3, 6.3 Hz, 1H),
13
6.44 (d, J = 9.0 Hz, 1H), 6.27 (d, J = 10.2 Hz, 1H), 4.05 (s, 3H). C NMR (150 MHz, CDCl3) δ
193.5, 162.6, 152.1, 143.9, 143.6, 143.1, 142.9, 135.5, 132.4, 131.5, 130.9, 129.6, 128.5, 125.9, 72.7,
65.5. HRMS (ESI), m/z calcd. for C16H11NaN3O3 ([M+Na]+) 316.0693, found: 316.0706.
4.2.5. 2-chloro-5-methoxyquinolino[3,4-b]quinoxalin-6(5H)-one (2e)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (15 mg,
o
1
16%). mp: 240-241 C; H NMR (400 MHz, CDCl3) δ 8.98-8.92 (m, 1H), 8.48 (d, J = 8.4 Hz, 1H),
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8.29 (d, J = 8.8 Hz, 1H), 8.00 (t, J = 7.2 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.73-7.63 (m, 2H), 4.22 (s,
13
3H). C NMR (100 MHz, CDCl3) δ 156.0, 144.2, 143.6, 143.1, 138.1, 135.9, 133.4, 132.8, 131.6,
131.0, 130.2, 129.5, 125.7, 119.8, 114.4, 63.3. HRMS (ESI), m/z calcd. for C16H10ClNaN3O2
([M+Na]+) 334.0354, found: 334.0353.
4.2.6. 4-methoxythieno[2’,3’:5,6]pyrido[3,4-b]quinoxalin-5(4H)-one (2h)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (65 mg,
76%). mp: 213-214 oC; 1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz,
1H), 7.93 (t, J = 7.5 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.77-7.73 (m, 1H), 7.33-7.29 (m, 1H), 4.25 (s,
13
3H). C NMR (150 MHz, CDCl3) δ 156.7, 144.3, 143.5, 141.9, 140.8, 137.5, 133.4, 131.9, 131.2,
130.4, 128.7, 116.2, 116.1, 63.9. HRMS (ESI), m/z calcd. for C14H10N3O2S ([M+H]+) 284.0488,
found: 284.0496.
4.2.7. 4-methoxyfuro[2’,3’:5,6]pyrido[3,4-b]quinoxalin-5(4H)-one (2i)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (58 mg,
o
72%). mp: 209-210 C; 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 7.8 Hz, 1H), 8.21 (t, J = 6.9 Hz,
2H), 7.73 (t, J = 7.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.55 (q, J = 14.4 Hz, 7.2 Hz 2H), 7.31 (t, J =
13
7.2 Hz, 1H), 4.12 (s, 3H). C NMR (150 MHz, CDCl3) δ 157.3, 135.8, 132.9, 132.6, 129.9, 128.5,
128.1, 126.3, 123.2, 121.9, 118.6, 112.6, 62.7. HRMS (ESI), m/z calcd. for C14H9NaN3O3 ([M+Na]+)
290.0536, found: 290.0546.
4.2.8. 5,10-dimethoxyquinolino[3,4-b]quinoxalin-6(5H)-one (2j)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (73 mg,
o
1
79%). mp: 268-270 C; H NMR (600 MHz, CDCl3) δ 8.98-8.94 (m, 1H), 8.33 (d, J = 9.6 Hz, 1H),
7.74 (m, 2H), 7.54 (dd, J = 9.4, 2.6 Hz, 1H), 7.50-7.44 (m, 2H), 4.21 (s, 3H), 4.07 (s, 3H) . 13C NMR
(150 MHz, CDCl3) δ 163.5, 156.6, 146.4, 144.8, 139.7, 137.4, 135.8, 132.7, 132.0, 125.9, 124.0,
118.6, 112.7, 105.5, 63.1, 56.3. HRMS (ESI), m/z calcd. for C17H14N3O3 ([M+H]+) 308.1030, found:
308.1037.
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4.2.9. 9-chloro-5-methoxyquinolino[3,4-b]quinoxalin-6(5H)-one (2k)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (89 mg,
95%). mp: 207-209 oC; 1H NMR (600 MHz, CDCl3) δ 8.91 (d, J = 7.8 Hz, 1H), 8.42 (s, 1H), 8.19 (d,
J = 8.4 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.45 (t, J
= 7.2 Hz, 1H), 4.22 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 155.9, 144.7, 142.8, 142.8, 138.7, 137.4,
137.2, 134.3, 133.1, 130.6, 129.4, 126.1, 124.4, 118.2, 112.8, 63.2. HRMS (ESI), m/z calcd. for
C16H10ClNaN3O2 ([M+Na]+) 334.0354, found: 334.0357.
4.2.10. 5-methoxy-9-(trifluoromethyl)quinolino[3,4-b]quinoxalin-6(5H)-one (2l)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (77 mg,
o
74%). mp: 225-228 C; 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 7.8 Hz, 1H), 8.21 (t, J = 6.9 Hz,
2H), 7.73 (t, J = 7.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.55 (q, J = 14.4 Hz, 7.2 Hz 2H), 7.31 (t, J =
13
7.2 Hz, 1H), 4.12 (s, 3H). C NMR (150 MHz, CDCl3) δ 157.3, 135.8, 132.9, 132.6, 129.9, 128.5,
128.1, 126.3, 123.2, 121.9, 118.6, 112.6, 62.7. HRMS (ESI), m/z calcd. for C17H10F3NaN3O2
([M+Na]+) 368.0617, found: 368.0623.
4.2.11. 5-methoxy-9-nitroquinolino[3,4-b]quinoxalin-6(5H)-one (2m)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (81 mg,
o
1
84%). mp: 239-241 C; H NMR (400 MHz, CDCl3) δ 9.40-9.35 (m, 1H), 9.02-8.97 (m, 1H),
8.73-8.67 (m, 1H), 8.46-8.39 (m, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.53 (d, J =
6.4 Hz, 1H), 4.24 (d, J = 2.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 155.4, 148.5, 147.1, 146.1,
141.3, 140.1, 138.1, 134.4, 131.1, 127.4, 126.9, 126.1, 124.7, 117.8, 113.1, 63.3. HRMS (ESI), m/z
calcd. for C16H10NaN4O4 ([M+Na]+) 345.0594, found: 345.0607.
4.2.12. 5-methoxy-8,9,10,11-tetrahydroquinolino[3,4-b]quinoxalin-6(5H)-one (2n)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (53 mg,
63%). mp: 197-200 oC; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 4.0 Hz,
2H), 7.40 (m, 1H), 4.17 (s, 3H), 3.21 (d, J = 20.0 Hz, 4H), 2.03 (s, 4H). 13C NMR (150 MHz, CDCl3)
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δ 158.4, 156.7, 155.1, 143.2, 136.8, 134.9, 131.9, 125.2, 123.8, 118.3, 112.4, 63.1, 33.3, 32.7, 22.7,
22.6. HRMS (ESI), m/z calcd. for C16H15NaN3O2 ([M+Na]+) 304.1056, found: 304.1066.
4.2.13. 5-methoxypyrido[2’,3’:5,6]pyrazino[2,3-c]quinolin-6(5H)-one (2o)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a yellow solid (78 mg,
94%). mp: 187-189 oC; 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 9.14 (d, J = 7.6 Hz, 1H), 8.84 (d,
J = 6.4 Hz, 1H), 7.90-7.84 (m, 1H), 7.80 (d, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 4.27-4.21 (m,
3H). 13C NMR (150 MHz, CDCl3) δ 158.2, 155.6, 151.2, 147.6, 139.9, 139.3, 138.5, 137.9, 133.9,
127.2, 126.3, 124.7, 118.1, 112.9, 63.3. HRMS (ESI), m/z calcd. for C15H10NaN4O2 ([M+Na]+)
301.0696, found: 301.0691.
4.2.14. 6-methoxypyrazino[2,3-c]quinolin-5(6H)-one (2p)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (54 mg,
80%). mp: 202-204 oC; 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.93 (s, 1H), 8.79 (d, J = 8.0 Hz,
1H), 7.74 (m, 2H), 7.45 (t, J = 7.4 Hz, 1H), 4.19 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 156.3, 148.2,
146.1, 145.3, 137.7, 137.2, 132.9, 125.7, 124.2, 118.0, 112.6, 63.2. HRMS (ESI), m/z calcd. for
C12H10N3O2 ([M+H]+) 228.0768, found: 228.0772.
4.2.15. 5-methoxyphenanthridin-6(5H)-one (2q)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a white solid (62 mg,
o
92%). mp: 231-234 C; 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 7.8 Hz, 1H), 8.21 (t, J = 6.9 Hz,
2H), 7.73 (t, J = 7.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.55 (q, J = 14.4 Hz, 7.2 Hz 2H), 7.31 (t, J =
13
7.2 Hz, 1H), 4.12 (s, 3H). C NMR (150 MHz, CDCl3) δ 157.3, 135.8, 133.0, 132.6, 130.0 128.5,
128.1, 126.3, 123.2, 122.0, 118.6, 112.6, 62.7. HRMS (ESI), m/z calcd. for C14H11NaNO2 ([M+Na]+)
248.0682, found: 248.0686.
4.2.16. 1-methoxy-3,4-dihydroquinolin-2(1H)-one (2r)
The product was isolated by flash chromatography (eluent: PE/EA = 2/1) as a colorless oily liquid
(25 mg, 47%); 1H NMR (400 MHz, CDCl3) δ 7.25-7.22 (m, 1H), 7.20-7.15 (m, 1H), 7.13 (d, J = 7.2
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Hz, 1H), 7.00 (td, J = 7.4, 1.3 Hz, 1H), 3.87 (s, 3H), 2.89-2.83 (m, 2H), 2.66 (m, 2H). 13C NMR (100
MHz, CDCl3) δ 165.9, 137.9, 127.9, 127.9, 124.5, 123.7, 112.4, 62.7, 31.7, 25.0. HRMS (ESI), m/z
calcd. for C10H11NaNO2 ([M+Na]+) 200.0682, found: 200.0692.
Acknowledgments
We thank the NSFC (21272057, 21372065, 21772032, 21702051 and U1604285), Young
Backbone Teachers Fund of Henan (2014GGJS-049), Key Project of Henan Educational Committee
(15A150015 and 18A150009), Science & Technology Innovation Talents in Universities of Henan
Province (17HASTIT002), Outstanding Young Talent Cultivation Project Funding of Henan Normal
University (14YR002), and Jilin Province Key Laboratory of Organic Functional Molecular Design
& Synthesis (130028742). We thank Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for
editing the English text of a draft of this manuscript.
Supplementary data
Supplementary data associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2017.**.***.
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