Tandem C-N Bond Formation through Condensation and Metal-Free N-Arylation: Protocol for Synthesizing Diverse Functionalized Quinoxalines

Article abstract of DOI:10.1021/acs.joc.7b00011

Diverse functionalized quinoxalines were synthesized in good yields from arylamines and readily available β-keto oximes through condensation and metal-free N-arylation. The reaction was compatible with various functional groups, such as halides, cyano, and esters. A mechanism was proposed based on the experimental results. These quinoxalines were easily obtained on a gram scale and converted to various useful scaffolds. Compound LASSBio-1022 was prepared in 83% yield in two steps.

Full text of DOI:10.1021/acs.joc.7b00011

Note
pubs.acs.org/joc
Tandem C−N Bond Formation through Condensation and Metal-Free
N‑Arylation: Protocol for Synthesizing Diverse Functionalized
Quinoxalines
Yan-Xiao Jiao, Ling-Ling Wu, Hai-Miao Zhu, Jiang-Ke Qin, Cheng-Xue Pan,* Dong-Liang Mo,*
and Gui-Fa Su*
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of
China; School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China
S
* Supporting Information
ABSTRACT: Diverse functionalized quinoxalines were syn-
thesized in good yields from arylamines and readily available β-
keto oximes through condensation and metal-free N-arylation.
The reaction was compatible with various functional groups,
such as halides, cyano, and esters. A mechanism was proposed
based on the experimental results. These quinoxalines were
easily obtained on a gram scale and converted to various useful
scaffolds. Compound LASSBio-1022 was prepared in 83% yield in two steps.
uinoxaline derivatives are valuable synthetic targets
Although quinoxalines have been prepared by conventional
strategies using ortho-phenylenediamines or ortho-function-
alized arylamines, the nitrogen sources are not always
commercially available or easily obtained. Recently, Yu’s
group and Zeng’s group developed a novel protocol for the
synthesis of quinoxalines via copper-catalyzed cycloamination
of N-aryl enamines with TMSN3 or NaN3 as the nitrogen
sources, respectively (Scheme 1A).7,8 Although much progress
has been made in the copper-catalyzed synthesis of quinoxa-
lines using TMSN3 or NaN3 as the nitrogen sources, there are
safety and environmental issues associated with large-scale
performance of these reactions. The development of new
reagents for quinoxalines synthesis to avoid using TMSN3 or
NaN3 as the nitrogen sources is important. In 2014, Zhang and
co-workers reported a novel one-pot strategy for the synthesis
of 3-trifluoromethylquinoxalines from N-aryl enamines and
nitromethane under metal-free conditions (Scheme 1B).9 Jiao
and co-workers developed a novel transition-metal-free
approach to the synthesis of quinoxaline N-oxides using readily
available methyl imines and tert-butyl nitrite as the nitrogen
source (Scheme 1C).10 Our group studied metal-free arylation
of N−O bonds with diaryliodonium salts and found that the
direct N-arylation of oximes could be achieved because of the
ambident nucleophilicity of the N−O bond.11 We hypothesized
that the condensation of β-keto oximes with arylamines would
provide N-aryl β-keto oximes, which could be converted to
various functionalized quinoxalines through Lewis-acid-medi-
ated intramolecular N-arylation with production of water as a
byproduct (Scheme 1D). Herein, we report an efficient tandem
C−N bond formation strategy for synthesizing functionalized
Q because they are present in a range of compounds,
including pharmaceuticals,1a−g semiconductors,1h,i and photo-
electric materials.1j Since 2010, more than 8000 documents
related to quinoxalines have been published.2 About 50
pharmaceutical compounds contain the quinoxaline moiety,3
and some representative examples of drugs, bioactive quinoxa-
lines and their analogues are listed in Figure 1.4 Many synthetic
Figure 1. Examples of bioactive quinoxalines.
methods have therefore been developed for constructing
quinoxaline scaffolds. Traditionally, quinoxalines have been
prepared by condensation of ortho-phenylenediamines with
diketone derivatives,5 or ortho-functionalized arylamines with
various ketones, alkynes, or their equivalents.6
Received: January 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
amount of acid, and the reaction temperature were explored to
optimize the conditions for this transformation (Table 1).
POCl3 in MeCN gave the best result (Table 1, entry 6). The
optimal conditions for producing 4aa from 3aa were used in
the condensation and direct N-arylation of ethyl 2-(hydrox-
yimino)-3-oxobutanoate (1a) and p-methoxyaniline (2a).
Compound 3aa, without further purification after condensa-
tion, afforded the corresponding product 4aa in 78% overall
yield (Table 1, entry 6). This suggests that quinoxaline 4aa can
be synthesized in a one-pot reaction from ethyl 2-(hydrox-
yimino)-3-oxobutanoate (1a) and p-methoxyaniline (2a) using
POCl3 as a Lewis acid. Quinoxaline 4aa was prepared as
follows: ethyl 2-(hydroxyimino)-3-oxobutanoate (1a) and p-
methoxyaniline (2a) were refluxed in benzene with HOAc as an
additive for 2 h, POCl3 in MeCN was added and the reaction
was performed at 100 °C, providing quinoxaline in a one-pot
reaction.
Scheme 1. Strategies for Synthesis of Quinoxalines Using
Various Nitrogen Sources
The scope of quinoxaline synthesis using this condensation
and arylation protocol was investigated. As shown in Table 2, a
series of quinoxalines were prepared from various substituted
arylamines in moderate to good yields. Arylamines containing
electron-donating or electron-withdrawing groups with ortho-,
meta-, or para-substituents in the aryl ring, proceeded smoothly
to provide the desired products 4. When arylamine 2n was
used, quinoxaline 4an was obtained in 70% yield; its structure
was determined unambiguously by X-ray diffraction.12 When
unsymmetrical arylamines, such as meta-halo (F, Cl, Br), meta-
isopropyl, meta-methoxy, or 3,4-dimethoxy aniline, were used in
the reaction, the desired products were obtained regioselec-
tively, as single isomers, in high yields (Table 2, 4af, 4ag, 4ah,
4ao, and 4ak). However, the meta-methyl and 3,4-dimethyl
substituted arylamines 2i and 2l gave two regioisomers in 1:1
ratios. These regioisomers were purified by using flash
chromatography (Table 2, 4ai and 4al). The experimental
results indicate that electronic and steric effects both play key
roles in the regioselectivity of this C−N bond formation. In
addition, meta-halo anilines gave the corresponding quinoxa-
lines only in acceptable total yields, possibly because the
condensation step was difficult (Table 2, 4af and 4ag). When
the para-position of arylamines with strong electron-with-
drawing groups, such as nitro, cyano, carbonyl, or trifluor-
omethyl, were tested, the intermediate 3 was not formed by
condensation with 1a, therefore the corresponding quinoxalines
were not obtained.
Various β-keto oximes were used to determine their effect on
the synthesis of functionalized quinoxalines via this con-
densation and metal-free arylation process. The reactions of β-
keto oximes 1b−k with 2a provided the corresponding
quinoxalines 4ba−ka in good yields (Table 3). The R1 group
was compatible with alkyl, aryl, and heteroaryl groups. Electron-
withdrawing groups (EWG), such as esters, ketone, and cyano
group, can be used. Pleasingly, when unsymmetrical oxime 1j
was used, product 4ja was obtained in 64% yield with high
selectivity (Table 3, entry 10). Functionalized qunioxalines with
ester, ketone, and cyano groups increase the range of potential
applications of these compounds in organic synthesis.
quinoxalines using an oxime as the nitrogen source under mild
conditions.
Initially, compound 3aa (Table 1) was chosen as a model
substrate for investigating the key step in C−N bond formation.
Table 1. Optimization of Conditions for Quinoxaline
a
Synthesis from Oxime
b
entry
solvent
acid
T (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
THF
conc-H2SO4
BF3·Et2O
PPA
70
52
47
42
30
43
THF
70
THF
70
THF
POCl3
70
MeCN
MeCN
MeCN
DCE
conc-H2SO4
POCl3
100
100
100
85
c
87 (78)
45
BF3·Et2O
POCl3
21
DCM
POCl3
50
27
POCl3
110
trace
a
Reaction conditions: 3aa (1.0 mmol), acid (2.0 mmol), and solvent
b
c
(5 mL), 0.5−24 h. Isolated yield. 3aa was not purified and the yield
was based on 2a.
Additional experiments (Scheme 2) were performed to
clarify the reaction mechanism. When oxime 3da was reacted
with 2.0 equiv of TEMPO under the optimal conditions, the
quinoxaline was obtained in 64% yield. This suggests that N-
arylation is not a radical process (Scheme 2-1). No desired
product was observed in the reaction of the methyl-protected
oxime 5da under the optimal conditions and only the oxime
3aa was prepared in 96% yield by the condensation of ethyl 2-
(hydroxyimino)-3-oxobutanoate (1a) and p-methoxyaniline
(2a). When H2SO4 was used to promote the arylation reaction
in THF, the desired product 4aa was obtained in 52% yield
(Table 1, entry 1). A series of acids in different solvents, the
B
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a,b
Table 2. Scope of Arylamines for Synthesis of Product 4
a
b
c
Reaction conditions: 1a (1.2 mmol), 2 (1.0 mmol), POCl3 (2 mmol), and MeCN (5 mL), 0.5−2 h. Isolated yield. Total yield of two isomers.
a
Table 3. Scope of Oximes for Synthesis of Product 4
Scheme 2. Mechanistic Study
b
entry
1
R1
EWG
4
yield (%)
1
1a
1b
1c
1d
1e
1f
Me
Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
COPh
CN
4aa
4ba
4ca
4da
4ea
4fa
78
79
83
59
49
53
47
61
82
64
66
2
3
n-Pr
Ph
4
Scheme 3. Plausible Mechanism
5
4-MeOC6H4
4-BrC6H4
2-MeC6H4
2-pyridinyl
Me
6
7
1g
1h
1i
4ga
4ha
4ia
8
9
10
11
1j
Me
4ja
1k
Ph
4ka
a
Reaction conditions: 1 (1.2 mmol), 2a (1.0 mmol), POCl3 (2 mmol),
b
and MeCN (5 mL), 0.5−2 h. Isolated yield.
was recovered (Scheme 2-2). This result shows that the
hydroxyl group was the leaving group during N-arylation.
Although the mechanism has not been completely
elucidated, a possible mechanism for quinoxaline formation is
shown in Scheme 3, based on the experimental results and
literature reports.13 The oxime 3 initially reacts with POCl3 to
provide intermediate A. The phosphoryl group of intermediate
A serves as the leaving group, forming nitrogen ion
intermediate B, which goes through an electrophilic amination
to afford intermediate C. Alternatively, removal of the
C
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Applications of Quinoxalines
refluxed for 2 h. The solvent was removed under reduced pressure to
provide the crude product. The crude product was recrystallized from
the solution of ethyl acetate and petroleum ether to afford compound
phosphoryl group and cyclization might be a concerted process.
Finally, aromatization of intermediate C furnishes the qunioxa-
line 4.
1
3a, a gray solid, 0.253 g, 96% yield. mp: 123−124 °C; H NMR (500
To explore the practical applications of these functionalized
quinoxalines, we found that the reaction could be performed
using 2.0 g of arylamine 2a to give 3.74 g of quinoxaline 4aa in
76% yield (Scheme 4-1). Oxidation of 4ac with m-CPBA at
room temperature provided the N4-oxides quinoxaline 5ac in
78% yield while 1,4-dioxides quinoxaline 6ac was obtained in
64% yield under reflux conditions (Scheme 4-2).14 Treatment
of 4ac with NaBH4 in MeOH afforded alcohol 7ac in 92% yield
(Scheme 4-3). The reaction of 4ac with hydrazine gave
hydrazide 8ac, which was converted to 9ac in 90% yield by
reaction with salicylaldehyde. Compound 9ac, named LASS-
Bio-1022, is a potential lead compound for developing novel
cruzain inhibitors.4c
In summary, we have developed an efficient one-pot protocol
for the synthesis of structurally diverse functionalized quinoxa-
lines via condensation and metal-free N-arylation. This method
provides a metal-free and green route for preparation of
functionalized quinoxalines from readily available common
arylamines and β-keto oximes as the nitrogen source. The
reaction can be easily performed on the gram scale and various
useful scaffolds can be obtained from the obtained function-
alized quinoxalines.
MHz, DMSO-d6) δ 12.51 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.78 (d, J
= 8.8 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 2.04 (s, 3H),
1.24 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 163.6,
161.9, 156.8, 153.9, 142.4, 121.8, 114.6, 61.3, 55.6, 15.4, 14.5; IR (thin
film) 3540, 3106, 2980, 2913, 1724, 1610, 1090, 758 cm−1; HRMS
(ESI) m/z calcd for C13H17N2O4 (M+H)+ 265.1183; found: 265.1180.
General Procedure for Synthesis of Product 4 (Table 2 and
Table 3). A round-bottle flask connected with water separator was
charged with oxime 1 (1.2 mmol), aniline 2 (1.0 mmol), and AcOH
(0.05 mL) in benzene (5 mL). The mixture was refluxed for 2 h. Then
the solution of POCl3 in MeCN (0.4 mol/L) was added to the
reaction mixture at 0 °C and heated to reflux until the oxime
intermediate was completely disappeared (monitored by TLC). At this
time, the reaction mixture was poured into cool saturated aqueous
NaHCO3 (30 mL). The organic layer was separated and the water
phase was extracted with ethyl acetate (25 mL × 2). The combined
organic layers were washed with saturated aqueous NaHCO3 (25 mL
× 1) and brine (25 mL × 1), dried over anhydrous Na2SO4, filtered,
and concentrated. Purification by silica gel chromatography (petro-
leum ether/ethyl acetate, V:V = 1:4) afforded product 4.
Ethyl 7-Methoxy-3-methylquinoxaline-2-carboxylate (4aa). Yel-
1
low solid, 0.191 g, 78% yield. mp: 59−60 °C; H NMR (500 MHz,
CDCl3) δ 7.94 (d, J = 9.4 Hz, 1H), 7.51−7.28 (m, 2H), 4.57 (q, J = 7.1
Hz, 2H), 3.97 (s, 3H), 2.94 (s, 3H), 1.51 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 165.8, 160.6, 150.3, 144.0, 141.5, 138.9,
129.3, 125.5, 106.7, 62.4, 55.9, 23.4, 14.3; IR (thin film) 3106, 2989,
2921, 1725, 1621, 1449, 1379, 1089, 839 cm−1; HRMS (APCI) m/z
calcd for C13H15N2O3 (M+H)+ 247.1083; found: 247.1079.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under an air
atmosphere. Commercially available reagents were used without
further purification. The NMR spectra were recorded in CDCl3 or
DMSO-d6 on 400, 500, or 600 MHz instrument with TMS as the
internal standard. NMR data are represented as follows: chemical shift
(ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet), coupling constants in hertz (Hz), and integration. IR
spectra were recorded on FT-IR spectrometer, and only major peaks
are reported in cm−1. HRMS were measured in ESI mode and the
mass analyzer of the HRMS was TOF. Flash column chromatography
was performed on silica gel (300−400 mesh).
Ethyl 3,7-Dimethylquinoxaline-2-carboxylate (4ab). Yellow solid,
1
0.168 g, 73% yield. mp: 40−41 °C; H NMR (500 MHz, CDCl3) δ
7.96 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.6 Hz, 1.6 Hz,
1H), 4.57 (q, J = 7.1 Hz, 2H), 2.94 (s, 3H), 2.58 (s, 3H), 1.49 (t, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.8, 151.9, 144.2,
141.0, 140.4, 139.9, 134.2, 128.5, 127.9, 62.4, 23.6, 21.8, 14.3; IR (thin
film) 3104, 2978, 2914, 1723, 1635, 1380, 1234, 1088, 835 cm−1;
HRMS (APCI) m/z calcd for C13H15N2O2 (M+H)+ 231.1133; found:
231.1123.
Ethyl 3-Methylquinoxaline-2-carboxylate (4ac). Yellow solid,
1
Synthesis of Product 3a. A round-bottle flask connected with
water separator was charged with oxime 1a (1.2 mmol), aniline 2a (1.0
mmol), and AcOH (0.05 mL) in benzene (5 mL). The mixture was
0.162 g, 75% yield, mp: 65−66 °C; H NMR (500 MHz, CDCl3) δ
8.18 (dd, J = 8.4 Hz, 0.9 Hz, 1H), 8.05 (dd, J = 8.4 Hz, 0.9 Hz, 1H),
7.83 (ddd, J = 8.4 Hz, 6.9 Hz, 1.4 Hz, 1H), 7.80−7.73 (m, 1H), 4.56
D
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(q, J = 7.1 Hz, 2H), 2.96 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 165.7, 152.8, 144.4, 142.5, 139.9, 131.8, 129.8,
129.7, 128.4, 62.5, 23.8, 14.3; IR (thin film) 3207, 2971, 2916, 1718,
1632, 1371, 1081, 851, 772, 701 cm−1; HRMS (APCI) m/z calcd for
C12H13N2O2 (M+H)+ 217.0972; found: 217.0973.
Ethyl 7-Bromo-3-methylquinoxaline-2-carboxylate (4ad). Yellow
solid, 0.185 g, 63% yield, mp: 63−65 °C; 1H NMR (500 MHz,
CDCl3) δ 8.34 (d, J = 1.1 Hz, 1H), 8.00−7.76 (m, 2H), 4.54 (q, J = 7.1
Hz, 2H), 2.91 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 165.3, 153.2, 145.1, 141.2, 140.4, 135.3, 132.0, 129.8, 123.7,
62.6, 23.7, 14.2; IR (thin film) 3132, 2982, 2925, 1725, 1641, 1475,
1274, 1092, 840 cm−1; HRMS (APCI) m/z calcd for C12H12N2O2Br
(M+H)+ 295.0082; found: 295.0069.
Ethyl 7-Fluoro-3-methylquinoxaline-2-carboxylate (4ae). Pale
yellow solid, 0.152 g, 65% yield, mp: 62−63 °C; 1H NMR (500
MHz, CDCl3) δ 8.10−8.04 (m, 1H), 7.89−7.74 (m, 1H), 7.64−7.59
(m, 1H), 4.70−4.49 (m, 2H), 2.94 (s, 3H), 1.52−1.48 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 165.4, 163.5 (d, JC−F = 252.4 Hz), 152.1
(d, JC−F = 3.0 Hz), 145.2, 140.5 (d, JC−F = 13.2 Hz), 139.8, 130.5 (d,
JC−F = 9.9 Hz), 122.2 (d, JC−F = 26.2 Hz), 113.1 (d, JC−F = 21.7 Hz),
62.6, 23.5, 14.2; IR (thin film) 3068, 2988, 1723, 1623, 1378, 1118,
1089, 836, 753 cm−1; HRMS (ESI) m/z calcd for C12H12N2O2F (M
+H)+ 235.0877; found: 235.0877.
Ethyl 6-Chloro-3-methylquinoxaline-2-carboxylate (4af). Yellow
solid, 0.110 g, 44% yield, mp: 75−76 °C; 1H NMR (500 MHz,
CDCl3) δ 8.11 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.70 (dd,
J = 9.0 Hz, 2.3 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 2.95 (s, 3H), 1.50 (t,
J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.4, 154.0, 144.5,
142.8, 138.4, 137.8, 131.0, 130.9, 127.5, 62.6, 23.8, 14.3; IR (thin film)
3108, 2972, 1723, 1269, 1171, 1084, 866, 831, 802, 729 cm−1; HRMS
(APCI) m/z calcd for C12H12N2O2Cl (M+H)+ 251.0582; found:
251.0581.
Ethyl 3,6,8-Trimethylquinoxaline-2-carboxylate (4aj). White solid,
0.197 g, 81% yield, mp: 109−110 °C; 1H NMR (500 MHz, CDCl3) δ
7.64 (s, 1H), 7.42 (s, 1H), 4.54 (q, J = 7.1 Hz, 2H), 2.92 (s, 3H), 2.78
(s, 3H), 2.55 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.2, 152.0, 142.8, 142.5, 142.3, 137.8, 132.1, 132.0, 125.1,
62.0, 23.5, 22.1, 16.9, 14.2; IR (thin film) 3011, 2982, 2929, 2856,
1715, 1621, 1274, 1235, 1104, 866, 787 cm−1; HRMS (APCI) m/z
calcd for C14H17N2O2 (M+H)+ 245.1285; found: 245.1276.
Ethyl 6,7-Dimethoxy-3-methylquinoxaline-2-carboxylate (4ak).
1
Yellow solid, 0.218 g, 79% yield, mp: 115−116 °C; H NMR (500
MHz, CDCl3) δ 7.45 (s, 1H), 7.31 (s, 1H), 4.55 (q, J = 7.1 Hz, 2H),
4.07 (s, 3H), 4.04 (s, 3H), 2.94 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 165.9, 154.6, 152.8, 151.2, 141.0, 140.4,
137.1, 107.1, 105.8, 62.2, 56.5, 56.5, 23.8, 14.4; IR (thin film) 3019,
2973, 2853, 1720, 1621, 1500, 1220, 1087, 846, 609 cm−1; HRMS
(ESI) m/z calcd for C14H16N2O4Na (M+Na)+ 299.1002; found:
299.1004.
Ethyl 3,6,7-Trimethylquinoxaline-2-carboxylate (4al-a). Yellow
solid, 0.088 g, 36% yield, mp: 74−75 °C; 1H NMR (500 MHz,
CDCl3) δ 7.93 (s, 1H), 7.79 (s, 1H), 4.55 (q, J = 7.1 Hz, 2H), 2.94 (s,
3H), 2.51 (s, 3H), 2.45 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 165.9, 152.0, 143.2, 142.9, 141.6, 140.4, 138.9,
128.7, 127.5, 62.3, 23.8, 20.6, 20.3, 14.3; IR (thin film) 3011, 2980,
2853, 1725, 1610, 1376, 1204, 1091, 877, 752 cm−1; HRMS (ESI) m/z
calcd for C14H17N2O2 (M+H)+ 245.1285; found: 245.1286.
Ethyl 3,7,8-Trimethylquinoxaline-2-carboxylate (4al-b). Yellow
solid, 0.081 g, 33% yield, mp: 51−52 °C; 1H NMR (500 MHz,
CDCl3) δ 7.80 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 4.55 (q, J
= 7.1 Hz, 2H), 2.93 (s, 3H), 2.76 (s, 3H), 2.53 (s, 3H), 1.51 (t, J = 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.3, 150.9, 143.2, 141.2,
139.1, 137.7, 135.5, 134.8, 125.1, 62.1, 23.3, 20.4, 14.3, 13.0; IR (thin
film) 3058, 2981, 2928, 1721, 1261, 1101, 839, 786, 674 cm−1; HRMS
(ESI) m/z calcd for C14H17N2O2 (M+H)+ 245.1285; found: 245.1281.
Ethyl 3,5-Dimethylquinoxaline-2-carboxylate (4am). Yellow solid,
Ethyl 6-Fluoro-3-methylquinoxaline-2-carboxylate (4ag). Yellow
1
oil, 0.107 g, 46% yield; H NMR (500 MHz, CDCl3) δ 8.21 (dd, J =
1
9.2 Hz, 5.7 Hz, 1H), 7.69 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.57 (ddd, J =
9.2 Hz, 8.2 Hz, 2.8 Hz, 1H), 4.58 (q, J = 7.1 Hz, 2H), 2.98 (s, 3H),
1.51 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.5, 165.0
0.140 g, 61% yield, mp: 63−65 °C; H NMR (500 MHz, CDCl3) δ
7.92−7.88 (m, 1H), 7.54−7.51 (m, 2H), 4.48 (q, J = 7.0 Hz, 1H), 2.86
(s, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 165.9, 151.6, 143.8, 141.7, 139.9, 136.9, 131.6, 129.4, 127.6,
62.4, 23.9, 17.1, 14.3; IR (thin film) 3013, 2979, 2929, 1721, 1274,
1196, 1124, 862, 798, 765, 664 cm−1; HRMS (APCI) m/z calcd for
C13H15N2O2 (M+H)+ 231.1128; found: 231.1121.
(d, JC−F = 255.1 Hz), 154.0, 143.7 (d, JC−F = 3.6 Hz), 143.5 (d, JC−F
=
13.6 Hz), 137.1, 132.1 (d, JC−F = 10.3 Hz), 120.5 (d, JC−F = 26.2 Hz),
112.1 (d, JC−F = 21.7 Hz), 62.5, 23.8, 14.3; IR (thin film) 3014, 2986,
1725, 1637, 1601, 1194, 1081, 868, 784, 696 cm−1; HRMS (ESI) m/z
calcd for C12H12N2O2F (M+H)+ 235.0877; found: 235.0871.
Ethyl 6-Isopropyl-3-methylquinoxaline-2-carboxylate (4ah).
White solid, 0.212 g, 82% yield, mp: 63−64 °C; 1H NMR (500
MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 1H), 7.77−7.72 (m, 1H), 7.60 (d,
J = 7.2 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.24 (dt, J = 13.9 Hz, 6.9 Hz,
1H), 2.91 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H), 1.37 (s, 3H), 1.36 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 166.2, 151.7, 148.6, 143.3, 142.6,
138.0, 131.6, 125.9, 125.4, 62.0, 27.4, 23.5, 23.3, 14.2; IR (thin film)
3050, 2958, 1720, 1271, 1137, 1105, 1087, 834, 781, 558 cm−1; HRMS
(APCI) m/z calcd for C15H19N2O2 (M+H)+ 259.1441; found:
259.1433.
Ethyl 2-Methylbenzo[f]quinoxaline-3-carboxylate (4an). Pale
1
yellow solid, 0.186 g, 70% yield, mp: 105−106 °C; H NMR (500
MHz, CDCl3) δ 9.30−9.27 (m, 1H), 8.06−8.02 (m, 2H), 7.99−7.94
(m, 1H), 7.83−7.78 (m, 2H), 4.61 (q, J = 7.1 Hz, 2H), 3.10 (s, 3H),
1.54 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 151.1,
142.0, 140.6, 138.4, 133.0, 130.5, 129.1, 128.6, 127.0, 126.6, 125.6,
124.1, 61.3, 22.9, 13.3; IR (thin film) 3033, 2987, 2918, 1721, 1636,
1378, 1237, 1110, 845, 761, 639 cm−1; HRMS (ESI) m/z calcd for
C16H14N2O2Na (M+Na)+ 289.0948; found: 289.0944.
Ethyl 6-Methoxy-3-methylquinoxaline-2-carboxylate (4ao). Yel-
1
low solid, 165 mg, 67% yield. mp: 89−90 °C; H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 9.2, 2.7 Hz, 1H), 7.29
(d, J = 2.6 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 2.90 (s,
3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7,
162.7, 153.4, 144.2, 141.3, 136.2, 131.0, 123.6, 105.5, 62.3, 56.0, 23.9,
14.3; IR (thin film) 2973, 2941, 2838, 1795, 1604, 1491, 1223, 1090,
838 cm−1; HRMS (APCI) m/z calcd for C13H15N2O3 (M+H)+
247.1083; found: 247.1080.
Ethyl 3,6-Dimethylquinoxaline-2-carboxylate (4ai-a). White solid,
1
0.087 g, 38% yield, mp: 88−89 °C; H NMR (500 MHz, CDCl3) δ
8.08 (d, J = 8.6 Hz, 1H), 7.83 (s, 1H), 7.60 (dd, J = 8.6 Hz, 1.7 Hz,
1H), 4.57 (q, J = 7.1 Hz, 2H), 2.96 (s, 3H), 2.62 (s, 3H), 1.51 (t, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.8, 152.9, 143.4,
142.8, 142.6, 138.4, 132.2, 129. 3, 127.3, 62.3, 23.8, 22.1, 14.3; IR (thin
film) 3078, 2982, 2932, 1720, 1370, 1276, 1197, 1100, 804, 792, 777
cm−1; HRMS (APCI) m/z calcd for C13H15N2O2 (M+H)+ 231.1128;
found: 231.1123.
Ethyl 3-Ethyl-7-methoxyquinoxaline-2-carboxylate (4ba). White
solid, 0.205 g, 79% yield, mp: 50−51 °C; 1H NMR (600 MHz,
CDCl3) δ 7.92 (d, J = 9.1 Hz, 1H), 7.44 (dd, J = 9.1, 2.8 Hz, 1H), 7.42
(d, J = 2.7 Hz, 1H), 4.53 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.20 (q, J =
7.5 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.5 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 166.2, 160.7, 154.6, 144.5, 141.5, 139.1,
129.6, 125.3, 106.8, 62.5, 56.0, 29.2, 14.4, 13.6; IR (thin film) 3089,
2988, 2924, 1728, 1620, 1492, 1216, 1085, 836, 771, 623 cm−1; HRMS
(APCI) m/z calcd for C14H17N2O3 (M+H)+ 261.1234; found:
261.1226.
Ethyl 3,8-Dimethylquinoxaline-2-carboxylate (4ai-b). White solid,
1
0.085 g, 37% yield, mp: 82−83 °C; H NMR (500 MHz, CDCl3) δ
7.89 (d, J = 8.4 Hz, 1H), 7.74−7.68 (m, 1H), 7.59 (d, J = 7.0 Hz, 1H),
4.56 (d, J = 7.1 Hz, 2H), 2.94 (s, 3H), 2.83 (s, 3H), 1.51 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 166.1, 151.9, 143.5, 142.6,
139.2, 138.4, 131.4, 129.6, 126.2, 62.1, 23.4, 17.0, 14.2; IR (thin film)
3103, 2983, 2924, 1715, 1618, 1190, 1085, 841, 824, 753 cm−1; HRMS
(ESI) m/z calcd for C13H15N2O2 (M+H)+ 231.1128; found: 231.1106.
E
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Ethyl 7-Methoxy-3-propylquinoxaline-2-carboxylate (4ca). White
solid, 0.227 g, 83% yield, mp: 113−115 °C; H NMR (600 MHz,
2986, 1670, 1621, 1219, 1025, 903, 831 cm−1; HRMS (ESI) m/z calcd
for C17H15N2O2 (M+H)+ 279.1128; found: 279.1127.
1
CDCl3) δ 7.89 (d, J = 9.1 Hz, 1H), 7.43−7.37 (m, 2H), 4.50 (q, J = 7.1
Hz, 2H), 3.90 (s, 3H), 3.14−3.10 (m, 2H), 1.84−1.75 (m, 2H), 1.43
(d, J = 7.1 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 166.1, 160.7, 153.5, 144.6, 141.4, 139.0, 129.6, 125.3, 106.7,
62.4, 55.9, 37.8, 23.0, 14.3, 14.2; IR (thin film) 3088, 2978, 2939, 1642,
1512, 1245, 1182, 1086, 835, 805, 768 cm−1; HRMS (APCI) m/z
calcd for C15H19N2O3 (M+H)+ 275.1390; found: 275.1378.
7-Methoxy-3-phenylquinoxaline-2-carbonitrile (4ka). Yellow
1
solid, 0.172 g, 66% yield, mp: 184−185 °C; H NMR (500 MHz,
CDCl3) δ 8.09 (d, J = 9.3 Hz, 1H), 8.07−8.02 (m, 2H), 7.63−7.58 (m,
4H), 7.43 (d, J = 2.8 Hz, 1H), 4.04 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 161.9, 152.1, 142.5, 139.1, 135.3, 130.5, 130.4, 129.1, 128.9,
128.1, 127.6, 116.9, 105.9, 56.1; IR (thin film) 3011, 2974, 2511, 1621,
1333, 1219, 1023, 835, 758, 692 cm−1; HRMS (ESI) m/z calcd for
C16H12N3O (M+H)+ 262.0975; found: 262.0970.
Ethyl 7-Methoxy-3-phenylquinoxaline-2-carboxylate (4da). Yel-
low oil, 0.181 g, 59% yield; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J =
8.9 Hz, 1H), 7.75−7.72 (m, 2H), 7.55−7.51 (m, 5H), 4.35 (q, J = 7.1
Hz, 2H), 4.02 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.8, 161.3, 149.9, 145.5, 141.7, 138.6, 138.0, 130.3, 129.2,
128.6, 128.5, 125.4, 106.5, 62.3, 56.0, 13.8; IR (thin film) 3098, 2965,
1730, 1619, 1260, 1111, 1019, 804, 669 cm−1; HRMS (ESI) m/z calcd
for C18H16N2O3Na (M+Na)+ 331.1053; found: 331.1047.
Synthesis of 3-(Ethoxycarbonyl)-2-methylquinoxaline 1-Oxide
(5ac). A mixture of ethyl 3-methylquinoxaline-2-carboxylate 4ac (1.0
mmol), m-CPBA (4.0 mmol) in CH2Cl2 (3 mL) was stirred for 3 h at
room temperature. The solvent was removed under reduced pressure
and the crude product was purified by flash chromatography with
eluents (petroleum ether/ethyl acetate, V:V = 1:6) to provide product
1
5ac (0.181 g, 78%). A white solid, mp: 85−86 °C; H NMR (500
MHz, CDCl3) δ 8.60−8.57 (m, 1H), 8.19−8.18 (m, 1H), 7.82−7.80
(m, 2H), 4.58 (q, J = 7.1 Hz, 2H), 2.80 (s, 3H), 1.50 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 164.7, 147.3, 142.5, 140.1,
137.1, 131.6, 131.2, 130.7, 118.8, 62.9, 14.2; IR (thin film) 3077, 2990,
1717, 1341, 1255, 1063, 887, 773, 603 cm−1; HRMS (APCI) m/z
calcd for C12H13N2O3 (M+H)+ 233.0921; found: 233.0912.
Ethyl 7-Methoxy-3-(4-methoxyphenyl)quinoxaline-2-carboxylate
1
(4ea). Yellow oil, 0.165 g, 49% yield; H NMR (500 MHz, CDCl3) δ
8.02 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.51−7.43 (m, 2H),
7.01 (d, J = 8.7 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.86
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.1, 161.0, 160.7, 149.3,
145.4, 141.3, 138.7, 130.0, 129.9, 125.2, 114.2, 114.1, 106.5, 62.3, 55.9,
55.4, 13.9; IR (thin film) 3111, 2964, 1721, 1610, 1213, 1106, 1026,
835, 793 cm−1; HRMS (ESI) m/z calcd for C19H19N2O4 (M+H)+
339.1339; found: 339.1354.
Ethyl 3-(4-Bromophenyl)-7-methoxyquinoxaline-2-carboxylate
(4fa). White solid, 0.204 g, 53% yield, mp: 97−98 °C; 1H NMR
(500 MHz, CDCl3) δ 8.04 (d, J = 9.2 Hz, 1H), 7.65−7.62 (m, 2H),
7.61−7.58 (m, 2H), 7.52 (dd, J = 9.2, 2.8 Hz, 1H), 7.49 (d, J = 2.7 Hz,
1H), 4.37 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 166.6, 161.5, 148.7, 145.0, 141.8,
Synthesis of 2-(Ethoxycarbonyl)-3-methylquinoxaline 1,4-Diox-
ide (6ac). A mixture of ethyl 3-methylquinoxaline-2-carboxylate 4ac
(1.0 mmol) and m-CPBA (4.0 mmol) in DCE (5 mL) was refluxed for
4 h. The solvents were removed under reduced pressure and the crude
product was purified by flash chromatography with eluents (petroleum
ether/ethyl acetate, V:V = 1:2) to provide product 6ac (0.159 g, 64%).
1
A white solid, mp: 133−134 °C; H NMR (500 MHz, CDCl3) δ
8.65−8.53 (m, 2H), 7.92−7.82 (m, 2H), 4.58 (q, J = 7.1 Hz, 2H), 2.59
(s, 3H), 1.47 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
159.8, 139.0, 137.9, 136.9, 135.6, 132.6, 131.5, 120.4, 120.1, 63.7, 14.4,
14.0; IR (thin film) 3098, 2947, 1741, 1636, 1335, 1247, 1064, 772,
634 cm−1; HRMS (APCI) m/z calcd for C12H13N2O4 (M+H)+
249.0870; found: 249.0861.
138.6, 136.9, 131.7, 130.2, 130.2, 125.7, 123.9, 106.5, 62.5, 56.0, 13.9;
IR (thin film) 3121, 2986, 1728, 1620, 1251, 1103, 1028, 829, 751
cm−1; HRMS (APCI) m/z calcd for C18H16N2O3Br (M+H)+
387.0344; found: 387.0324.
Synthesis of (3-Methylquinoxalin-2-yl)methanol (7ac). A mixture
of ethyl 3-methylquinoxaline-2-carboxylate 4ac (1.0 mmol) and
NaBH4 (3.0 mmol) in MeOH (5 mL) was stirred for 15 min at
room temperature. The solvent was removed under reduced pressure
and the crude product was purified by flash chromatography with
eluents (petroleum ether/ethyl acetate, V:V = 1:1) to provide product
Ethyl 7-Methoxy-3-(o-tolyl)quinoxaline-2-carboxylate (4ga). Yel-
low oil, 0.151 g, 47% yield; 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J =
9.0 Hz, 1H), 7.55−7.50 (m, 2H), 7.37−7.33 (m, 1H), 7.30 (d, J = 7.5
Hz, 1H), 7.28−7.25 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H),
2.22 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
165.9, 161.5, 151.5, 145.5, 142.0, 138.7, 138.1, 136.3, 130.4, 130.3,
129.0, 128.9, 125.8, 125.8, 106.8, 62.2, 56.1, 19.9, 13.7; IR (thin film)
3097, 2979, 2856, 1737, 1620, 1246, 1103, 837, 741, 647 cm−1; HRMS
(APCI) m/z calcd for C19H19N2O3 (M+H)+ 323.1390; found:
323.1384.
1
7ac (0.160 g, 92%). A yellow solid, mp: 109−110 °C; H NMR (500
MHz, CDCl3) δ 8.13−7.96 (m, 2H), 7.72 (dd, J = 6.5 Hz, 2.7 Hz, 2H),
4.91 (s, 2H), 4.59 (s, 1H), 2.65 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 152.7, 151.3, 141.5, 139.5, 129.5, 129.3, 128.5, 128.2, 62.0, 20.7; IR
(thin film) 3455, 2896, 1640, 1382, 1163, 1060, 775, 682 cm−1; HRMS
(APCI) m/z calcd for C10H11N2O (M+H)+ 175.0866; found:
175.0860.
Ethyl 7-Methoxy-3-(pyridin-2-yl)quinoxaline-2-carboxylate (4ha).
1
White solid, 0.155 mg, 61% yield, mp: 175−176 °C; H NMR (500
MHz, CDCl3) δ 8.65−8.62 (m, 1H), 8.40−8.34 (m, 1H), 8.06−8.01
(m, 1H), 7.90−7.85 (m, 1H), 7.51−7.45 (m, 2H), 7.38−7.33 (m, 1H),
4.49 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 167.3, 161.6, 154.6, 148.4, 146.7, 146.5,
142.3, 137.9, 136.9, 130.3, 124.9, 124.0, 122.4, 106.7, 62.1, 55.9, 14.0;
IR (thin film) 3093, 2977, 1731, 1619, 1248, 1111, 1025, 828, 783, 747
cm−1; HRMS (APCI) m/z calcd for C17H16N3O3 (M+H)+ 310.1186;
found: 310.1177.
Synthesis of LAssBio-1022 (9ac). A mixture of ethyl 3-
methylquinoxaline-2-carboxylate 4ac (1.0 mmol) and hydrazine
hydrate (85%, 20 mmol) in EtOH (5 mL) was refluxed for 0.5 h.
When the 4ac was completely consumed (monitored by TLC), the
mixture was cooled to room temperature and a colorless needle crystal
was precipitated. The precipitate was filtered to give 8ac (0.200 g,
99%), mp: 171−172 °C.4b A round-bottle flask was charged with 8ac
(0.2 g, 1.0 mmol) and EtOH (10 mL). Salicyaldehyde (0.122 g, 1.0
mmol) was added in one portion. The mixture was stirred for 1 h. At
this time, the solvent was removed under reduced pressure to afford
the crude product, which was crystallized from EtOH to give product
1-(7-Methoxy-3-methylquinoxalin-2-yl)ethanone (4ia). Yellow
solid, 0.177 g, 82% yield, mp: 92−93 °C; 1H NMR (500 MHz,
CDCl3) δ 7.90 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 7.35
(d, J = 2.8 Hz, 1H), 3.99 (s, 3H), 2.92 (s, 3H), 2.83 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 201.5, 160.4, 150.3, 147.0, 141.3, 138.9, 129.3,
125.5, 106.6, 55.8, 28.0, 24.0; IR (thin film) 3111, 2962, 1697, 1620,
1217, 1029, 940, 837, 653, 606 cm−1; HRMS (APCI) m/z calcd for
C12H13N2O2 (M+H)+ 217.0972; found: 217.0973.
9ac (0.2 g, 90% yield).4c A white solid, mp: 228−229 °C; H NMR
1
(400 MHz, CDCl3) δ 11.02 (s, 1H), 10.90 (s, 1H), 8.48 (s, 1H), 8.02
(d, J = 8.8 Hz, 2H), 7.82−7.77 (m, 1H), 7.75−7.70 (m, 1H), 6.96 (d, J
= 8.1 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 3.12 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 158.7, 157.7, 153.6, 150.2, 142.2, 140.6, 137.8, 131.2,
131.1, 130.0, 129.1, 128.0, 127.7, 118.4, 116.4, 23.7.
(7-Methoxy-3-methylquinoxalin-2-yl) (phenyl)methanone (4ja).
1
White solid, 0.178 g, 64% yield, mp: 171−172 °C; H NMR (500
MHz, CDCl3) δ 7.97 (t, J = 9.4 Hz, 3H), 7.66 (t, J = 7.4 Hz, 1H),
7.53−7.48 (m, 3H), 7.38 (s, 1H), 3.95 (s, 3H), 2.77 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 194.3, 160.6, 150.7, 149.4, 141.0, 138.4, 135.7,
134.0, 130.6, 129.5, 128.7, 124.6, 106.7, 55.8, 22.3; IR (thin film) 3201,
General Procedure for Synthesis of Oxime 1. A solution of ethyl
acetoacetate (44 mL, 4.1 g, 31.5 mmol) in glacial acetic acid (5.2 mL)
was cooled to 5 °C and a solution of sodium nitrite (3.2 g, 46.2 mol)
in water (7 mL) was added dropwise at 5−10 °C. The mixture was
F
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
stirred for 1 h, then 18% solution of sodium chloride (15 mL) was
added and the mixture was stirred for additional 20 min. Then it was
extracted with chloroform (75 mL × 2); the extracts were sequentially
washed with 18% solution of sodium chloride, 10% solution of sodium
bicarbonate, 18% solution of sodium chloride; and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure to give 1a as yellow oil (4.5 g, 97%). All 2-oxime-1, 3-
diketone derivatives 1a15, 1b16, 1c17, 1d18, 1e19, 1f20, 1g21, 1h22, 1i23,
1j18a, 1k24 were obtained in a similar method and the data matched the
literature.
Natarajan, A. Bioorg. Med. Chem. Lett. 2011, 21, 1929. (d) Wurz, R. P.;
Sastri, C.; D’Amico, D. C.; Herberich, B.; Jackson, C. L. M.; Pettus, L.
H.; Tasker, A. S.; Wu, B.; Guerrero, N.; Lipford, J. R.; Winston, J. T.;
Yang, Y.; Wang, P.; Nguyen, Y.; Andrews, K. L.; Huang, X.; Lee, M. R.;
Mohr, C.; Zhang, J. D.; Reid, D. L.; Xu, Y.; Zhou, Y.; Wang, H.-L.
Bioorg. Med. Chem. Lett. 2016, 26, 5580.
(5) For some selected recent examples, see: (a) Xie, F.; Zhang, M.;
Jiang, H.; Chen, M.; Lv, W.; Zheng, A.; Jian, X. Green Chem. 2015, 17,
279. (b) Schmidt, B.; Krehl, S.; Hauke, S. J. Org. Chem. 2013, 78, 5427.
(c) Nguyen, T. B.; Retailleau, P.; Al-Mourabit, A. Org. Lett. 2013, 15,
5238. (d) Huang, A.; Chen, Y.; Zhou, Y.; Guo, W.; Wu, X.; Ma, C.
Org. Lett. 2013, 15, 5480. (e) Okumura, S.; Takeda, Y.; Kiyokawa, K.;
Minakata, S. Chem. Commun. 2013, 49, 9266. (f) Yang, Y.; Ni, F.; Shu,
W.-M.; Wu, A.-X. Chem. - Eur. J. 2014, 20, 11776. (g) Shi, S.; Wang,
T.; Yang, W.; Rudolph, M.; Hashmi, A. S. K. Chem. - Eur. J. 2013, 19,
6576. (h) Ammermann, S.; Hrib, C.; Jones, P. G.; du Mont, W.-W.;
Kowalsky, W.; Johannes, H.-H. Org. Lett. 2012, 14, 5090. (i) Wang, L.;
Guo, W.; Zhang, X.-X.; Xia, X.-D.; Xiao, W.-J. Org. Lett. 2012, 14, 740.
(j) Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen, Y.; Chen, B. Org.
Lett. 2011, 13, 4514. (k) Ghorai, M. K.; Sahoo, A. K.; Kumar, S. Org.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00011.
■
S
Spectra of 3a, 4, 5ac, 6ac, 7ac, 9ac, and X-ray crystal
structure of 4an (CIF) (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: panchx@gxnu.edu.cn
*E-mail: moeastlight@mailbox.gxnu.edu.cn
*E-mail: gfysglgx@163.com
■
́
Lett. 2011, 13, 5972. (l) Vidal-Albalat, A.; Rodríguez, S.; Gonzalez, F.
V. Org. Lett. 2014, 16, 1752. (m) Zhang, F.; Xi, Y.; Lu, Y.; Wang, L.;
Liu, L.; Li, J.; Zhao, Y. Chem. Commun. 2014, 50, 5771. (n) Jeena, V.;
Sithebe, S.; Robinson, R. S. Synth. Commun. 2015, 45, 1484. (o) Xie,
C.; Zhang, Z.; Yang, B.; Song, G.; Gao, H.; Wen, L.; Ma, C.
Tetrahedron 2015, 71, 1831. (p) Shen, J.; Wang, X.; Lin, X.; Yang, Z.;
Cheng, G.; Cui, X. Org. Lett. 2016, 18, 1378.
ORCID
Dong-Liang Mo: 0000-0002-4005-2249
Gui-Fa Su: 0000-0003-3128-2381
Notes
(6) For some selected recent examples, see: (a) Meyer, C.; Zapol’skii,
V. A.; Adam, A. E. W.; Kaufmann, D. E. Synthesis 2008, 2008, 2575.
̈
(b) Ozpinar, G. A.; Erdem, S. S.; Meyer, C.; Kaufmann, D. E. J. Org.
Chem. 2009, 74, 4727. (c) Maichrowski, J.; Gjikaj, M.; Hubner, E. G.;
̈
The authors declare no competing financial interest.
Bergmann, B.; Muller, I. B.; Kaufmann, D. E. Eur. J. Org. Chem. 2013,
̈
2013, 2091. (d) Xekoukoulotakis, N. P.; Hadjiantoniou-Maroulis, C.
P.; Maroulis, A. J. Tetrahedron Lett. 2000, 41, 10299.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21162002, 21462008), the Guangxi
Natural Science Foundation (2014GXNSFAA118053,
2015GXNSFDA139009, 2016GXNSFFA380005), the “Over-
seas 100 Talents Program” of Guangxi Higher Education, State
Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology of
China (CMEMR2011-17, CMEMR2012-A014, CMEMR2014-
A01).
(7) Ma, H.; Li, D.; Yu, W. Org. Lett. 2016, 18, 868.
(8) Chen, T.; Chen, X.; Wei, J.; Lin, D.; Xie, Y.; Zeng, W. Org. Lett.
2016, 18, 2078.
(9) Yang, Z.-J.; Liu, C.-Z.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G. Chem.
Commun. 2014, 50, 14554.
(10) Chen, F.; Huang, X.; Li, X.; Shen, T.; Zou, M.; Jiao, N. Angew.
Chem., Int. Ed. 2014, 53, 10495.
(11) Ma, X.-P.; Shi, W.-M.; Mo, X.-L.; Li, X.-H.; Li, L.-G.; Pan, C.-X.;
Chen, B.; Su, G.-F.; Mo, D.-L. J. Org. Chem. 2015, 80, 10098.
(12) CCDC: 1484740 (4an) contains the supplementary crystallo-
graphic data for this article. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
(13) For some recent reports, see: (a) Venkatesh, C.; Singh, B.;
Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169.
(b) Kobayashi, Y.; Kuroda, M.; Toba, N.; Okada, M.; Tanaka, R.;
Kimachi, T. Org. Lett. 2011, 13, 6280. (c) Narasaka, K.; Kitamura, M.
Eur. J. Org. Chem. 2005, 2005, 4505. (d) Kitamura, M.; Yoshida, M.;
Kikuchi, T.; Narasaka, K. Synthesis 2003, 2003, 2415.
(14) Bartoszek, M.; Salzwedel, D.; Stumm, G.; Niclas, H.-J. Org. Mass
Spectrom. 1987, 22, 259.
(15) Fershtat, L. L.; Kulikov, A. S.; Ananyev, I. V.; Struchkova, M. I.;
Makhova, N. N. J. Heterocyclic Chem. 2016, 53, 102.
(16) Shibata, Y.; Kagechika, K.; Yamaguchi, M.; Yoshikawa, K.;
Chiba, K.; Takano, H.; Akiyama, C.; Ono, M.; Nishi, M.; Kubo, H.;
Kobayashi, Y.; Usui, H. Chem. Pharm. Bull. 2013, 61, 1248.
(17) Dong, J.; Chen, S.; Li, R.; Cui, W.; Jiang, H.; Ling, Y.; Yang, Z.;
Hu, W. Eur. J. Med. Chem. 2016, 108, 605.
REFERENCES
■
(1) For some selected reviews, see: (a) Mamedov, V. A.; Zhukova, N.
A. Prog. Heterocycl. Chem. 2012, 24, 55. (b) Mamedov, V. A.; Zhukova,
N. A. Prog. Heterocycl. Chem. 2013, 25, 1. (c) Nageswar, Y. V. D.;
Reddy, K. H. V.; Ramesh, K.; Murthy, S. N. Org. Prep. Proced. Int.
2013, 45, 1. (d) Fultz, M.; Rollyson, W. Pyrazines and Quinoxalines.
In Heterocyclic Chemistry in Drug Discovery; Li, J. J. Ed.; Wiley & Sons,
Inc.: Hoboken, New Jersey, 2013, 536−567. (e) Bharagava, D.; Garg,
G. J. Pharm. Res. 2012, 5, 130. (f) Kamal, A.; Reddy, K. L.; Devaiah, V.;
Shankaraiah, N.; Rao, M. V. Mini-Rev. Med. Chem. 2006, 6, 71.
(g) Ajani, O. O. Eur. J. Med. Chem. 2014, 85, 688. (h) Marin, L.;
Lutsen, L.; Vanderzande, D.; Maes, W. Org. Biomol. Chem. 2013, 11,
5866. (i) Gawrys, P.; Marszalek, T.; Bartnik, E.; Kucinska, M.; Ulanski,
J.; Zagorska, M. Org. Lett. 2011, 13, 6090. (j) Gers, C. F.; Nordmann,
J.; Kumru, C.; Frank, W.; Muller, T. J. J. J. Org. Chem. 2014, 79, 3296.
̈
(2) This number is based on a survey of the SciFinder database used
the “quinoxalines” as research topic.
(18) (a) Zolfigol, M. A. Molecules 2001, 6, 694. (b) Mordant, C.;
Dunkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J. Eur. J. Org.
Chem. 2004, 2004, 3017.
(3) Negwer, M.; Scharnow, H. G. Organic Chemical Drugs and Their
Synonyms; Wiley-VCH: Weinheim, 2001; Vols. 2−3.
(4) (a) Edwards, M. L.; Bambury, R. E.; Ritter, H. W. J. Med. Chem.
̈
(19) Fan, S.; Liu, S.; Zhang, H.; Liu, Y.; Yang, Y.; Jin, L. Eur. J. Org.
Chem. 2014, 2014, 5591.
(20) Albaugh, P. A.; Dominguez-Manzanares, E.; Hong, J. E.;
Hornback, W. J.; Jiang, D.; Ornstein, P. L.; Thompson, M. L.;
Tromiczak, E. G.; Wu, Z.; Zarrinmayeh, H.; Zimmerman, D. M.;
1975, 18, 637. (b) Romeiro, N. C.; Aguirre, G.; Hernan
́
dez, P.;
Gonzalez, M.; Cerecetto, H.; Aldana, I.; Perez-Silanes, S.; Monge, A.;
́
́
Barreiro, E. J.; Lima, L. M. Bioorg. Med. Chem. 2009, 17, 641.
(c) Chen, Q.; Bryant, V. C.; Lopez, H.; Kelly, D. L.; Luo, X.;
G
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Castano Mansanet, A. M.; Huffman, L. G.; Miller, W. D. WO
2005040110, May 6, 2005.
(21) Yamamoto, K.; Kondoh, K.; Horiuchi, K.; Matsui, Y.; Nagamine,
M. EP 761658, March 12, 1997.
(22) Altaf, M.; Wang, Y.; Socorro, I. M.; Stoeckli-Evans, H. Inorg.
Chim. Acta 2012, 383, 204.
(23) Mloston
2011, 2011, 2542.
́ ́
, G.; Jasinski, M.; Heimgartner, H. Eur. J. Org. Chem.
(24) Mo, K.; Kang, S. B.; Kim, Y.; Lee, Y. S.; Lee, J. W.; Keum, G.
Eur. J. Org. Chem. 2015, 2015, 1137.
H
DOI: 10.1021/acs.joc.7b00011
J. Org. Chem. XXXX, XXX, XXX−XXX