Efficient synthesis of quinoxalines with hypervalent iodine as a catalyst

Article abstract of DOI:10.1016/j.tet.2013.09.027

Various biologically important quinoxalines were efficiently synthesized in excellent yields via one-pot reaction between 1,2-diaminobenzenes and internal alkynes. The method utilizes inexpensive and readily available hypervalent iodine source, such as (diacetoxyiodo)benzene (PhI(OAc)₂) and proved to be a better alternative as compared to expensive transition metal catalysts. Quinoxaline 4i [(2-phenyl-3-(3,4,5-trimethoxy phenyl)quinoxaline)] was evaluated for leukemia cancer cell lines and turned out to be a good candidate.

Full text of DOI:10.1016/j.tet.2013.09.027

Tetrahedron xxx (2013) 1e7
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Tetrahedron
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Efficient synthesis of quinoxalines with hypervalent iodine as
a catalyst
,
Chung-Yu Chen b, Wan-Ping Hu c, Mei-Chun Liu a, Pi-Cheng Yan a, Jeh-Jeng Wang a
,
*
,
Mei-Ing Chung b
*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
c Department of Biotechnology, Kaohsiung Medical University, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2013
Received in revised form 4 September 2013
Accepted 5 September 2013
Available online xxx
Various biologically important quinoxalines were efficiently synthesized in excellent yields via one-pot
reaction between 1,2-diaminobenzenes and internal alkynes. The method utilizes inexpensive and
readily available hypervalent iodine source, such as (diacetoxyiodo)benzene (PhI(OAc)2) and proved to be
a better alternative as compared to expensive transition metal catalysts. Quinoxaline 4i [(2-phenyl-3-
(3,4,5-trimethoxy phenyl)quinoxaline)] was evaluated for leukemia cancer cell lines and turned out to be
a good candidate.
Keywords:
Quinoxaline
PhI(OAc)2
Ó 2013 Elsevier Ltd. All rights reserved.
Combretastatin A4
One-pot reaction
Anti-cancer
1. Introduction
Previous report
O
Diversely substituted quinoxalines are important biological
agents and therefore a significant development of research has
been directed towards the synthesis of this class of compounds.1 In
particular, they are used as anti-tumor,2 antibacterial,3 antifungal,4
antiviral,5 anti-inflammatory,6 anti-tubercular,7 anticonvulsant,8
antimalarial,9 antileishanial,10 and trypanocidal11 agents. A num-
ber of reliable synthetic strategies have been developed in the re-
cent past for the synthesis of various substituted quinoxalines12,13
The most common method is the condensation of 1,2-diamino
benzenes with 1,2-dicarbonyl compounds.14 However, most of
these methods suffer from harsh reaction conditions, tedious iso-
lation procedures, and unsatisfactory yields. Moreover, recent re-
port of one-pot strategy has been developed to construct
quinoxalines from internal alkyne with 1,2-diaminobenzene
using expensive metal catalysts, such as PdI2 or PdCl2/CuCl2
(Scheme 1a).15 Therefore, these disadvantages and the cost effec-
tiveness of the methodology brought us an attention to develop an
affordable alternative catalyst system for this conversion.
NH2
NH2
N
N
PdI2,PdCl2/CuCl2
ref 15
(a)
+
O
Our work
R3
C
B
PhI(OAc)2 10mol%
N
N
R1
A
NH2
NH2
(b)
R
+
C
R2
3
DMSO, O2
140oC 12hrs
A
B
R1
R2
1.Low catalysis loading
2.High reaction yield
Scheme 1. Synthesis of 2,3-diphenylquinoxaline derivatives.
In recent years, hypervalent iodine reagents have received con-
siderable attention due to their low toxicity, ready availability, easy
handling, and reactivity similar to those of heavy metal reagents.16
To the best of our knowledge, there is no literature precedence
to synthesize quinoxaline derivatives in one-pot using hypervalent
iodine as a catalyst. Herein we report a novel one-pot transition
metal free approach to construct quinoxaline derivatives with
high structural diversity using PhI(OAc)2 as a catalyst under mild
reaction condition. Mechanistically, the 1,2-diketo compound
* Corresponding authors. Fax: þ886
7 312 5339; e-mail address: jjwang@
kmu.edu.tw (J.-J. Wang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.027
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C.-Y. Chen et al. / Tetrahedron xxx (2013) 1e7
would be generated in situ from internal alkynes in the presence of
hypervalent iodine reagent and the subsequent reaction with 1,2-
diaminobenzenes leading to the formation of target product in
one-pot fashion (Scheme 1b).
product (entries 8 and 9). When the reaction was carried out at
140 ꢀC with ICl, NIS, and PIFA produced the desired product in 51%,
77%, and 60%, respectively (entries 10e12). The stoichiometric
amount of PhI(OAc)2 afforded the desired compound 4a in 39%
yield when AcOH was used as an additive (entry 13). Among vari-
ous solvents used to check the feasibility of the reaction, (entries
14e17) DMSO was found to be the better solvent to obtain the
desired product in excellent yield (entry 7).
2. Results and discussion
At first, we initiated the optimization of reaction conditions with
the model substrates of alkyne 1a and diaminobenzene 2a to fur-
nish the corresponding product 4a. The effect of various oxidants,
additives at different temperature was studied and the results are
summarized in Table 1. The reaction of alkyne 1a with dia-
minobenzene 2a was carried out using stoichiometric amounts of
different oxidants viz., PhI(OAc)2, KMnO4, and CAN in the presence
of an additive PivOH in DMSO at room temperature (entries 1e3).
The use of PhI(OAc)2 afforded the desired compound 4a in 27% yield
(entry 1); whereas, KMnO4 and ceric (IV) ammonium nitrate (CAN)
did not produce the desired product (entries 2 and 3). We thought if
iodine coupled with an oxidizing reagent might exhibit anticipated
product. We, therefore tested the reaction using stoichiometric
amounts of N-iodosuccinamide (a mild source of molecular iodine)
ICl and PIFA (phenyliodine bis(trifluoroacetate)), which produced
the required product in low yields (entries 4e6). Further studies
were conducted with PhI(OAc)2 at elevated temperatures and the
formation of compound 4a was obtained in 93% yield (entry 7).
Furthermore, the reaction of 1a and 2a in the presence of KMnO4
and CAN at 140 ꢀC was unsuccessful in generating the desired
Since the reaction was successful with stoichiometric amount of
PhI(OAc)2, our next efforts were devoted for making this reaction
catalytic in nature. Interestingly, it was found that the loading of
PhI(OAc)2 had an important effect on reaction yield at different
concentrations. Thus, the product 4a was obtained in 89% yield,
when 50 mol % of PhI(OAc)2 was used. Even 10 mol % of PhI(OAc)2
worked well to furnish 4a in 90% yield (entries 19 and 20). How-
ever, further decrease in the catalyst loading to 5 mol % has an
adverse effect on the reaction yield of 4a (67%, entry 21). The effect
of O2 also had a significant effect on reaction yield. Thus, the for-
mation of product in 63% and 11% was obtained under air and N2,
respectively (entries 22 and 23). Therefore, the reaction condition
described in entry 20 (10 mol % of PhI(OAc)2 in DMSO) can be
considered as a standard protocol for this transformation.
With the optimized reaction conditions, we have studied the
reaction scope and limitations. Various 1,2-diaminobenzenes and
internal alkynes (Fig. 1) were selected to execute this one-pot ap-
proach for the synthesis of wide range of quinoxalines bearing
various substituents, including electron-withdrawing and electron-
donating on the aromatic core moiety of compounds 4aeg. Non
aromatic diamines, such as cis-1,2-ethyldiamine also underwent
smooth conversion under the standard reaction condition afforded
the corresponding substituted pyrazine 4h in good yield. The cy-
clization reactions proceeded smoothly irrespective of the electron-
donating or electron-withdrawing substituents at R2 and R3 along
with the ring A bearing 3,4,5-trimethoxy groups to furnish prod-
ucts 4iez in moderate to good yields. These products (4iez) were
made with this strategy because the structural activity relationship
of Combretastatin A4 (CA-4)17 indicates that the presence of the
3,4,5-trimethoxy phenyl group is fundamental for antitubulin and
its anticancer activity (vide infra). It is remarkable that the aryl
fluorinated product 4m was a compatible substrate given its im-
portant synthetic application since it could be further functional-
ized via metal-catalyzed cross-coupling reactions. We were
delighted to observe that the replacement of ring B with cyclo-
propane also worked well under the standard conditions to afford
corresponding product 4s in 72% yield. Our additional attempts
to expand the scope of our methodology by replacing 1,2-diamino
benzenes with cyclohexyl- and pyridinyl diamino compounds was
successful to produce various quinoxaline analogues (4e and 4y)
and pyridoepyrazine derivative 4z in moderate to good yields. The
structure of 4i was unambiguously confirmed by single crystal X-
ray analysis (Fig. 2).
Table 1
Optimization of reaction conditions to synthesize compound 4aa
N
N
NH2
NH2
catalysis
solvent
4a
1a
2a
Entry
Catalysis
Solvent
Additive
T (ꢀC)
Yieldb
1
2
3
4
5
6
7
8
PhI(OAc)2
KMnO4
CAN
NIS
ICl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
AcOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
rt
rt
rt
rt
rt
rt
4a, 27%
n.r.
n.r.
4a, 13%
4a, 21%
n.r.
4a, 93%
n.r.
PIFA
PhI(OAc)2
KMnO4
CAN
NIS
ICl
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
100 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
140 ꢀC
9
Trace
10
11
12
13
14
15
16
17
18
19c
20d
21e
22f
23g
4a, 51%
4a, 77%
4a, 6%
4a, 39%
4a, 33%
n.r.
PIFA
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
MeCN
PhCl
n.r.
n.r.
CHCl3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
We could also able to construct bis-quinoxaline skeleton from
1,4-bis(phenylethynyl)benzene 5 and 1,2-diaminobenzene 2a to
furnish 1,4-bis(3-phenylquinoxalin-2-yl)benzene (6) in 88% yield
(Scheme 2).
4a, 60%
4a, 88%
4a, 90%
4a, 67%
4a, 63%
4a, 11%
In order to gain insight into the reaction mechanism, we carried
out few control experiments. Initially, we performed a reaction
between diphenylacetylene 1a and diaminobenzene 2a in presence
of PIDA (10 mol %) and PivOH in DMSO for 6 h. We observed the
formation of 4a as a major product and the benzil product 3 as
a minor component (Scheme 3, reaction A). Formation of the benzil
product 3 was further evidenced by performing a control experi-
ment with alkyne 1a in the absence of diaminobenzene 2a (Scheme
3, reaction B). Based on these observations, we confirmed that the
benzil product 3 might be an intermediate during this trans-
formation. Based on the previous literature,18 we envision that the
The bold value signifies the reaction condition described in entry 20 (10 mol % of
PhI(OAc)2 in DMSO) and can be considered as
a standard protocol for this
transformation.
a
Reactions were performed with 1a (1.0 mmol), oxidant (1.0 mmol), additive
(3.0 mmol), solvent (5 ml) at 140 ꢀC under 1 atm O2 for 12 h.
b
Isolated yield.
Catalysis (50 mol %).
Catalysis (10 mol %).
Catalysis (5 mol %).
Under air.
Under N2.
c
d
e
f
g
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C.-Y. Chen et al. / Tetrahedron xxx (2013) 1e7
3
R3
R2
C
B
N
N
NH2
NH2
PhI(OAc)2 10mol%
C
DMSO, O2
140oC
A
R3
A
B
R1
R2
R1
1
2
4
N
N
N
N
N
N
N
N
O
O
4d, 81%
4c, 83%
4a, 90%
O
4b, 85%
NO2
CH3
N
N
N
N
N
N
N
N
4h, 80%
4g, 89%
4f, 85%
O
4e, 91%
N
N
N
N
N
N
N
N
Fig. 2. ORTEP diagram of 4i.
O
O
O
O
OCH3
O
O
O
O
CH3
O
O
NH2
O
O
4j, 90%
4k, 87%
4l, 73%
4i, 89%
N
N
NH
N
N
PhI(OAc)
N
N
N
N
N
N
N
N
DMSO, O
140 C 24h
NH
5
2a
CH3
O
NH2
O
OCH3
O
O
6, 88%
O
O
O
O
O
O
F
O
O
aReaction were performed with 5 (1.0 mmol), 2a (2.0 mmol), PhI(OAc)2 (0.1 mmol),
4n, 91%
4o, 85%
4p, 85%
COOH
4m, 80%
PivOH (3.0 mmol), DMSO (5 ml) at 140oC under O2 for 24hrs.b Isolated yield.
Scheme 2. Synthesis of bis-quinoxaline derivative.a,b
N
N
N
N
N
N
N
N
CH3
OCH3
O
O
O
O
O
O
O
O
O
O
O
O
4s, 72%
4t, 69%
CH3
4q, 87%
4r, 83%
NO2
PIDA 10mol%
N
N
O
NH
NH
PivOH 3eq
CH3
CH3
+
DMSO 5ml
(A)
1a
N
N
N
N
O
N
N
140 C,6h
N
N
2a
under O
3, 33%
4a,51%
O
O
O
PIDA 10mol%
PivOH 3eq
O
O
O
O
CH3
O
O
O
O
O
---
O
O
O
(B)
DMSO 5ml
1a
O
3, 83%
4x, 89%
4u, 81%
140 C,12h
4w, 87%
4v, 75%
under O
N
I
N
N
NH
PivOH 3eq
DMSO 5ml
N
N
N
N
+
(C)
NH
140 C,18h
1a
under O
O
O
7,30 mol%
2a
4a,75%
O
O
O
O
4y, 80%
4z, 83%
aReactions were performed with 1 (1.0 mmol), 2 (1.0mmol),
NH
NH
N
N
PIDA 10mol%
PhI(OAc)2 (10 mol%) and PivOH (3.0 mmol) in DMSO (5 ml) at
+
DMSO 5ml
(D)
140oC under O2.b Isolated yield.
140 C,12h
1a
under O
2a
4a,6%
Fig. 1. The series of quinoxaline derivatives.a,b
Scheme 3. Control experiments.
iodobenzene might be a byproduct during the reaction. To our
delight, when 30 mol % iodobenzene was used instead of PIDA,
desired compound 4a was obtained in 75% yield (Scheme 3, re-
action C). Furthermore, in absence of PivOH the reaction was un-
successful (Scheme 3, reaction D).
DMSO
DMS
O
NH
NH
N
N
-2H
O
O
3
Based on our observations and previous literature reports,15a,19
a plausible mechanism was outlined in Scheme 4. Initially formed
PhI(OPiv)2 from PIDA and PivOH20 react with compound 1a to
produce oxidized compound 3 with the expulsion of iodobenzene.
The compound 3 will then undergo subsequent condensation
with 1,2-diaminobenzene to afford desired compound 3a. The
2a
1a
4a
PhI(OPiv)
PhI
PivOH
DMSO
O
PIDA
Scheme 4. Proposed reaction mechanism for the PIDA-promoted construction of
quinoxaline.
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4
C.-Y. Chen et al. / Tetrahedron xxx (2013) 1e7
iodobenzene will then undergo oxidation18 in presence of oxygen
in DMSO followed by the reaction with pivalic acid to regenerate
PhI(OPiv)2 in the catalytic cycle.
4.2. Instrumentation
1H NMR and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, using CDCl3 as a solvent. 1H NMR chemical
shifts are referenced to TMS or CDCl3 (0; 7.26 ppm). 13C NMR was
referenced to CDCl3 (77.0 ppm). Mass spectra and high-resolution
mass spectra (HRMS) were measured using the Electrospray Ioni-
zation (ESI, 70 eV, ion trap) technique. Flash chromatography
was carried out on silica gel 60 (40e63 mesh). Spectral data are
represented in the following order: chemical shift; multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, dd¼doublet of dou-
blets, td¼triplet of doublets, m¼multiplet); coupling constant
(J, Hertz); number of protons.
After examining scope and limitation of this method we
thought of evaluating the biological potential of the synthesized
quinoxaline products. In particular, we have chosen 4i as a model
substrate for evaluating its activity against various cancel lines
because of its structural similarity with CA-4. Since the cis con-
figuration21 of the olefinic bridge and the presence of 3,4,5-
trimethoxy phenyl group at ring A are fundamental for anti-
tubulin activity,22 we envisioned compound 4i would serve as
a potential candidate. Accordingly, 4i was submitted to NCI for
screening against 60 cancer cell lines. Indeed, the compound
showed promising results with leukemia cancer cell lines (HL-60)
in a highly selective manner (Fig. 3).
4.3. Materials
Unless otherwise noted, all reagents, and catalysts were pur-
chased from commercial sources. Dimethyl sulfoxide was purified
by distillation under nitrogen immediately prior to use. All other
solvents were used as supplied without further purification.
4.4. General procedure for the synthesis of quinoxaline
derivatives
The starting material 1,2-diphenylalkyne derivatives
(1.0 mmol) was dissolved in dry dimethyl sulfoxide (DMSO, 5 ml),
followed by 10 mol % of PhI(OAc)2, then the 1,2-diaminobenzene
derivatives (1.0 mmol) were charged to the reaction mixture and
stirred at 140 ꢀC for 8e24 h under O2. Reaction was monitored by
TLC and the reaction mixture was poured into a rapidly stirred ice
cooled saturated NaHCO3 solution (10 ml) and the aqueous phase
was extracted with ethylacetate (2ꢁ200 ml), and the combined
organic layers were washed with water (2ꢁ200 ml), brine
(1ꢁ200 ml) and dried over Na2SO4, filtered and the volatiles were
removed under reduced pressure. The product was purified by
column chromatography over silica gel 40e63 mesh (gradient el-
uent ethylacetate/hexane). Purified quinoxaline derivatives 4aez,
6 (yield 69e91%).
Fig. 3. NCI screening against human cancer cell line.a,b
3. Conclusion
In conclusion, we described a simple, efficient, and one-pot
methodology for the synthesis of quinoxaline analogues from vari-
ous internal alkynes and 1,2-diaminobenzenes using inexpensive and
readilyavailablePhI(OAc)2 asanoxidant.Highreactionrates, excellent
product yields, and easy work up procedures made this methodology
asanalternative platform toreplacethe conventionaltransition metal
catalyzed processes. Biological evaluation was carried out for the
compound 4i against 60 cancer cell lines, which showed promising
resultswithleukemiacancer(HL-60). Thisstudyexhibitedthatproper
structureeactivity relationship studies of this structure might gen-
erate a compound useful for therapeutic applications. Further bi-
ological work is in progress and will be reported in due course.
4.4.1. 2,3-Diphenylquinoxaline (4a).23 The title compound was
prepared according to the general procedure and purified by col-
umn chromatography to obtain a white solid 142.6 mg (90%).
Mp¼125e128 ꢀC. 1H NMR (CDCl3, 400 MHz): dH 8.19 (d, J¼7.2 Hz,
2H), 7.79 (d, J¼7.2 Hz, 2H), 7.53 (d, J¼7.6, 1.6 Hz, 4H), 7.38e7.31 (m,
6H). 13C NMR (CDCl3, 100 MHz): dC 153.4 (2C), 141.2 (2C), 139.0 (2C),
129.9 (2C), 129.8 (4C), 129.1 (2C), 128.7 (2C), 128.2 (4C). HRMS (ESI-
ion trap, m/z): [MþH]þ calcd for C20H15N2 283.1230; found
283.1234.
4. Experimental section
4.4.2. 2-(4-Methoxyphenyl)-3-phenylquinoxaline (4b).24 The title
compound was prepared according to the general procedure and
purified by column chromatography to obtain a yellow solid
127.4 mg (85%). Mp¼120e122 ꢀC. 1H NMR (CDCl3, 400 MHz): dH
8.02 (d, J¼7.2 Hz, 2H), 7.58 (d, J¼7.2 Hz, 2H), 7.42e7.40 (m, 2H), 7.35
(d, J¼8.8 Hz, 2H), 7.21e7.20 (m, 3H), 6.71 (d, J¼8.8 Hz, 2H), 3.63 (s,
3H). 13C NMR (CDCl3, 100 MHz): dC 160.4, 153.6 (2C), 153.2, 141.2
(2C), 139.6, 131.9, 131.6, 131.6, 130.1, 130.0, 129.8, 129.3, 129.2,
129.0, 128.5 (2C), 113.9 (2C), 55.5. HRMS (ESI-ion trap, m/z):
[MþH]þ C21H17N2O 313.1335; found 313.1344.
4.1. General experimental procedures
PhI(OAc)2 oxidant annulation reactions were performed in mild
condition. All other reactions, unless otherwise indicated, were
carried out underambient atmosphere in single-neck, round bottom
flasks fitted with a stopcock or condenser, equipped with a magnetic
stir bar. Air-or water- sensitive solvents weretransferredviasyringe.
When required, solvents were degassed by bubbling of nitrogen
through a needle. Organic solutions were concentrated by rotary
evaporation at 25e40 ꢀC under reduced pressure (15e30 Torr, house
vacuum). Analytical Thin Layer Chromatography (TLC) was per-
formed using pre-coated UV 254 plates (0.2 mm) from EM Separa-
tions. Visualization of the spots was rendered visible either by
shining with a 254 nm UV light source, or bycharring the plates with
potassium permanganate (KMnO4) or anisaldehyde solutions.
4.4.3. 2-(3-Methoxyphenyl)-3-phenylquinoxaline (4c). The title
compound was prepared according to the general procedure and
purified by column chromatography to obtain a colorless oil
124.4 mg (83%). 1H NMR (CDCl3, 400 MHz): dH 8.09 (d, J¼7.2 Hz,
2H), 7.66 (d, J¼7.2 Hz, 2H), 7.44e7.42 (m, 2H), 7.25e7.23 (m, 3H),
7.12 (t, J¼8.0 Hz, 1H), 6.99e6.97 (m, 2H), 6.81 (d, J¼8.0 Hz, 1H), 3.57
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C.-Y. Chen et al. / Tetrahedron xxx (2013) 1e7
5
(s, 3H). 13C NMR (CDCl3, 100 MHz): dC 159.2, 153.1 (2C), 141.1, 141.0,
140.1 (2C), 139.0 (2C), 129.9, 129.8, 129.6 (2C), 129.2, 129.0, 128.7,
128.1, 122.3, 115.1, 114.7, 55.1. HRMS (ESI-ion trap, m/z):
[MþH]þ calcd for C21H17N2O 313.1335; found 313.1340.
107.6 (2C), 61.1, 55.8 (2C). HRMS (ESI-ion trap, m/z): [MþH]þ calcd
for C23H21N2O3 373.1474; found 373.1553.
4.4.10. 2-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)quinoxaline
(4j). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain a light
yellow solid 121.4 mg (90%). Mp¼114e118 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 8.16 (d, J¼7.2 Hz, 2H), 7.76 (d, J¼7.2 Hz, 2H), 7.48 (d,
J¼8.8 Hz, 2H), 6.88 (d, J¼9.2 Hz, 2H), 6.77 (s, 2H), 3.86 (s, 3H), 3.82
(s, 3H), 3.71 (s, 6H). 13C NMR (CDCl3,100 MHz): dC 160.4,153.3,153.2
(2C), 141.4, 141.1, 138.9, 134.5 (2C), 131.8, 131.3 (2C), 130.1, 129.9,
129.2 (2C),114.0 (2C),107.5 (2C), 61.1, 56.2 (2C), 55.6. HRMS (ESI-ion
trap, m/z): [MþNa]þ calcd for C24H22N2O4Na 425.1425; found
425.1475.
4.4.4. 2-(2-Methoxyphenyl)-3-phenylquinoxaline (4d).25 The title
compound was prepared according to the general procedure and
purified by column chromatography to obtain a white solid
121.4 mg (81%) Mp¼91e95 ꢀC. 1H NMR (CDCl3, 400 MHz): dH 8.20
(d, J¼7.2 Hz, 2H), 7.76 (d, J¼7.2 Hz, 2H), 7.66 (dd, J¼7.6, 2.0 Hz, 1H),
7.50e7.47 (m, 2H), 7.39 (t, J¼8.2 Hz, 1H), 7.28e7.25 (m, 3H), 7.13 (t,
J¼8.0 Hz, 1H), 6.70 (d, J¼8.4 Hz, 1H), 3.20 (s, 3H). 13C NMR (CDCl3,
100 MHz): dC 156.3, 154.6, 152.2 (2C), 141.2, 141.1, 139.1, 130.9, 130.6,
129.6, 129.4, 129.1, 129.0, 128.7, 128.5, 128.3, 127.6 (2C), 121.2, 110.9,
54.6. HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C21H17N2O
313.1335; found 313.1342.
4.4.11. 2-p-Tolyl-3-(3,4,5-trimethoxyphenyl)quinoxaline (4k). The
title compound was prepared according to the general procedure
and purified by column chromatography to obtain a light yellow
solid 119.0 mg (87%). Mp¼116e120 ꢀC. 1H NMR (CDCl3, 400 MHz):
dH 8.17 (d, J¼7.2 Hz, 2H), 7.77 (d, J¼7.2 Hz, 2H), 7.41 (d, J¼8.4 Hz, 2H),
7.16 (d, J¼8.0 Hz, 2H), 6.76 (s, 2H), 3.86 (s, 3H), 3.68 (s, 6H), 2.37 (s,
3H). 13C NMR (CDCl3, 100 MHz): dC 153.8, 153.2, 153.1, 141.4, 141.2,
139.0 (2C), 138.9, 136.7, 134.3, 130.0, 129.7, 129.3, 129.2, 129.2, 129.0,
128.5, 111.0, 107.6 (2C), 61.1, 56.1 (2C), 21.5. HRMS (ESI-ion trap, m/
z): [MþH]þ C24H23N2O3 387.4431; found 387.1706.
4.4.5. 2,3-Diphenyl-4a,5,6,7,8,8a-hexahydroquinoxaline (4e).26 The
title compound was prepared according to the general procedure
and purified by column chromatography to obtain a white solid
147.2 mg (91%). Mp¼170e176 ꢀC. 1H NMR (CDCl3, 400 MHz): dH 7.40
(d, J¼6.0 Hz, 4H), 7.25 (d, J¼2.8 Hz, 4H), 7.24 (t, J¼1.2 Hz, 2H),
3.05e3.04 (m, 4H),1.96e1.95 (m, 4H). 13C NMR (CDCl3,100 MHz): dC
150.3 (2C), 149.3 (2C), 138.8 (2C), 129.4 (4C), 128.0 (4C), 127.9 (2C),
31.6 (2C), 22.6 (2C). HRMS (ESI-ion trap, m/z): [MþH]þ calcd for
C
20H19N2 287.1543; found 287.1548.
4.4.12. 4-(3-(3,4,5-Trimethoxyphenyl)quinoxalin-2-yl)benzenamine
(4l). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain
a brown solid 99.8 mg (73%). Mp¼170e180 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 8.11 (d, J¼7.2 Hz, 2H), 7.73 (d, J¼7.2 Hz, 2H), 7.34 (d,
J¼8.8 Hz, 2H), 6.80 (s, 2H), 6.62 (d, J¼8.8 Hz, 2H), 3.87 (s, 3H), 3.73
(s, 6H). 13C NMR (CDCl3, 100 MHz): dC 153.4 (2C), 152.9, 152.9, 147.2
(2C), 141.2, 140.6, 138.5, 134.6, 131.0 (2C), 129.7, 129.3, 128.9, 128.9,
114.5, 114.1, 107.1 (2C), 60.9, 55.9 (2C). HRMS (ESI-ion trap, m/z):
[MþH]þ calcd for C23H22N3O3 388.1661; found 388.1662.
4.4.6. 3-(4-Methoxyphenyl)-5-methyl-2-phenylquinoxaline
(4f). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain
a colorless oil 133.2 mg (85%). 1H NMR (CDCl3, 400 MHz): dH 7.88 (d,
J¼8.4 Hz, 1H), 7.52e7.49 (m, 2H), 7.48e7.37 (m, 5H), 7.27e7.23 (m,
2H), 6.76e6.73 (m, 2H), 3.70 (s, 3H), 2.75 (s, 3H). 13C NMR (CDCl3,
100 MHz): dC. 160.0, 152.6, 151.2, 140.8, 140.0, 139.6 (2C), 137.3 (2C),
131.6, 131.5, 131.2, 129.9, 129.6, 129.4 (2C), 126.8 (2C), 113.5 (2C),
55.2, 17.0. HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C22H19N2O
327.1492; found 327.1498.
4.4.13. 2-(4-Fluorophenyl)-3-(3,4,5-trimethoxy phenyl)quinoxaline
(4m). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain light
yellow solid 109.0 mg (80%). Mp¼88e96 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 8.07 (d, J¼7.2 Hz, 2H), 7.67 (d, J¼7.2 Hz, 2H), 7.45e7.41
(m, 2H), 6.98 (d, J¼8.4 Hz, 2H), 6.64 (s, 2H), 3.76 (s, 3H), 3.60 (s, 6H).
13C NMR (CDCl3, 100 MHz): dC 164.5, 162.0, 153.2, 152.5, 141.3, 141.2,
139.0, 135.5, 135.5, 134.0, 131.9, 131.8, 130.3, 130.3, 129.2, 129.0,
115.7, 115.4, 107.5 (2C), 61.1, 56.2 (2C). HRMS (ESI-ion trap, m/z):
[MþH]þ calcd for C23H20FN2O3 391.1380; found 391.1372.
4.4.7. 6-Nitro-2,3-diphenylquinoxaline (4g).27 The title compound
was prepared according to the general procedure and purified by
column chromatography to obtain a light brown solid 163.4 mg
(89%). Mp¼190e196 ꢀC. 1H NMR (CDCl3, 400 MHz): dH 8.97 (s, 1H),
8.43 (d, J¼9.2 Hz, 1H), 8.23 (m, J¼8.8 Hz, 1H), 7.55e7.52 (m, 4H),
7.39 (dt, J¼7.2, 6.8 Hz, 6H). 13C NMR (CDCl3, 100 MHz): dC 155.9,
155.3, 147.5, 143.2, 139.6, 137.8, 137.7, 130.5 (2C), 129.7, 129.6, 129.5,
129.4, 129.1, 128.4, 128.2, 127.8 (2C), 125.3, 122.9. HRMS (ESI-ion
trap, m/z): [MþH]þ calcd for C20H14N3O2 328.1081; found
328.1083.
4.4.14. 2-(3-Methoxyphenyl)-3-(3,4,5-trimethoxy phenyl)quinoxa-
line (4n). The title compound was prepared according to the gen-
eral procedure and purified by column chromatography to obtain
a yellow solid 122.7 mg (91%). Mp¼102e108 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 8.19 (d, J¼7.2 Hz, 2H), 7.79 (d, J¼7.2 Hz, 2H), 7.28 (s,
1H), 7.11e7.09 (m, 2H), 6.94 (d, J¼8.0 Hz, 1H), 6.78 (s, 2H), 3.86 (s,
3H), 3.73 (s, 3H), 3.70 (s, 6H). 13C NMR (CDCl3, 100 MHz): dC 159.4,
153.2, 152.8, 152.8, 141.0, 140.9, 140.5, 138.7, 133.8 (2C), 130.0, 129.9,
129.4, 129.1, 129.0, 122.0, 114.8, 114.6, 107.2 (2C), 60.8, 55.9 (2C),
55.2. HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C24H23N2O4
403.1580; found 403.1586.
4.4.8. 2,3-Diphenylpyrazine (4h).28 The title compound was pre-
pared according to the general procedure and purified by column
chromatography to obtain
a white solid 104.2 mg (80%).
Mp¼120e122 ꢀC. 1H NMR (CDCl3, 400 MHz): dH 8.58 (s, 2H),
7.46e7.43 (m, 4H), 7.33 (dt, J¼7.2, 6.8 Hz, 6H). 13C NMR (CDCl3,
100 MHz): dC 152.6 (2C), 141.9 (2C), 138.4 (2C), 129.5 (4C), 128.5
(4C), 128.1 (2C). HRMS (ESI-ion trap, m/z): [MþH]þ calcd for
C
16H13N2 233.1073; found 233.1081.
4.4.9. 2-Phenyl-3-(3,4,5-trimethoxyphenyl)quinoxaline (4i). The ti-
tle compound was prepared according to the general procedure
and purified by column chromatography to obtain a light yellow
solid 123.5 mg (89%). Mp¼150e152 ꢀC. 1H NMR (CDCl3, 400 MHz):
dH 8.19 (d, J¼7.2 Hz, 2H), 7.78 (d, J¼7.2 Hz, 2H), 7.55 (d, J¼3.2 Hz,
2H), 7.38e7.37 (m, 3H), 6.76 (s, 2H), 3.85 (s, 3H), 3.67 (s, 6H) 13C
NMR (CDCl3, 100 MHz): dC 153.7 (2C), 152.8 (2C), 141.1, 141.0, 139.3,
138.7, 133.8, 130.0 (2C), 129.9, 129.5, 129.1, 129.0, 128.7 (2C), 128.3,
4.4.15. 2-m-Tolyl-3-(3,4,5-trimethoxy phenyl)quinoxaline (4o). The
title compound was prepared according to the general procedure
and purified by column chromatography to obtain a light yellow
solid 116.3 mg (85%). Mp¼84e92 ꢀC. 1H NMR (CDCl3, 400 MHz): dH
8.18 (d, J¼7.2 Hz, 2H), 7.74 (d, J¼7.2 Hz, 2H), 7.42 (s, 1H), 7.25e7.19
(m, 3H), 6.79 (s, 2H), 3.86 (s, 3H), 3.68 (s, 6H), 2.34 (s, 3H). 13C NMR
Please cite this article in press as: Chen, C.-Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.027

6
C.-Y. Chen et al. / Tetrahedron xxx (2013) 1e7
(CDCl3, 100 MHz): dC 153.4 (2C), 152.5 (2C), 140.8 (2C), 139.0, 138.5,
137.8, 133.6 (2C), 129.8 (2C), 129.6 (2C), 128.8, 127.9, 126.5, 107.2
(2C), 60.6, 55.6 (2C), 21.1. HRMS (ESI-ion trap, m/z): [MþH]þ calcd
for C24H23N2O3 387.1703; found 387.1710.
to the general procedure and purified by column chromatography
to obtain a yellow oil 113.0 mg (81%). 1H NMR (CDCl3, 400 MHz):
dH 7.98 (d, J¼8.4 Hz, 1H), 7.64 (t, J¼4.0 Hz, 1H), 7.59 (d, J¼8.4 Hz,
2H), 7.50 (d, J¼8.4 Hz, 1H), 6.94 (d, J¼6.0 Hz, 2H), 6.84 (s, 2H), 3.87
(s, 3H), 3.82 (s, 3H), 3.71 (s, 6H), 2.85 (s, 3H). 13C NMR (CDCl3,
100 MHz): dC 160.1 (2C), 152.8 (2C), 151.2, 140.8 (2C), 140.0, 137.3,
137.2, 134.6, 131.7, 131.3, 129.6, 129.5 (2C), 129.3, 126.7, 113.7, 107.4
(2C), 60.8, 55.2 (2C), 17.0. HRMS (ESI-ion trap, m/z): [MþH]þ calcd
for C25H25N2O4 417.1809; found 417.1814.
4.4.16. 3-(3-(3,4,5-Trimethoxyphenyl)quinoxalin-2-yl)benzenamine
(4p). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain a light
yellow solid 116.2 mg (85%). Mp¼167e172 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 8.17 (d, J¼7.2 Hz, 2H), 7.78 (d, J¼7.2 Hz, 2H), 7.25 (s,
1H), 7.14 (t, J¼8.2 Hz, 1H), 6.92e6.91 (m, 1H), 6.83 (s, 2H), 6.71e6.68
(m, 1H), 3.86 (s, 3H), 3.72 (s, 6H). 13C NMR (CDCl3, 100 MHz): dC
153.9, 153.0 (2C), 146.8 (2C), 141.3, 141.2, 140.6 (2C), 134.1, 130.2,
130.1, 129.5, 129.3, 129.3, 120.3, 116.0, 115.6, 107.6 (2C), 61.1, 56.2
(2C). HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C23H22N3O3
388.1583; found 388.1585.
4.4.22. 3-(4-Methoxyphenyl)-6-nitro-2-(3,4,5-trimethoxy
phenyl)
quinoxaline (4v). The title compound was prepared according to
the general procedure and purified by column chromatography to
obtain a yellow oil 108.7 mg (75%). 1H NMR (CDCl3, 400 MHz): dH
9.02 (s, 1H), 8.49 (d, J¼9.2 Hz, 1H), 8.25 (d, J¼9.2 Hz, 1H), 7.57 (d,
J¼8.8 Hz, 2H), 6.93 (d, J¼8.8 Hz, 2H), 6.83 (s, 2H), 3.89 (s, 3H), 3.85
(s, 3H), 3.73 (s, 6H). 13C NMR (CDCl3, 100 MHz): dC 160.9, 160.7,
155.6, 155.1, 153.0, 147.6, 143.5, 143.1, 139.8, 139.4, 133.1, 131.3, 131.2,
130.4, 125.2, 123.0, 122.8, 113.8, 107.2 (2C), 60.9 (2C), 55.9, 55.3.
HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C24H22N3O6 448.1503;
found 448.1502.
4.4.17. 2-(2-Methoxyphenyl)-3-(3,4,5-trimethoxy phenyl)quinoxa-
line (4q). The title compound was prepared according to the gen-
eral procedure and purified by column chromatography to obtain
a light yellow oil 117.3 mg (87%). 1H NMR (CDCl3, 400 MHz): dH 8.12
(d, J¼7.2 Hz, 2H), 7.74 (d, J¼7.2 Hz, 2H), 7.62 (d, J¼5.4 Hz,1H), 7.32 (t,
J¼4.4 Hz, 1H), 7.08 (t, J¼4.2 Hz, 1H), 6.77 (s, 2H), 6.64 (s, 1H), 3.76 (s,
3H), 3.56 (s, 6H), 3.20 (s, 3H). 13C NMR (CDCl3, 100 MHz): dC 156.4,
153.8, 152.3 (2C), 151.9, 141.0 (2C), 140.9, 138.2, 134.4, 130.5 (2C),
129.7, 129.4, 129.0, 128.9, 121.5, 110.9, 105.9 (2C), 60.7, 55.6 (2C),
54.8. HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C24H23N2O4
403.1580; found 403.1590.
4.4.23. 5-Methyl-3-p-tolyl-2-(3,4,5-trimethoxy phenyl)quinoxaline
(4w). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain
a yellow solid 123.4 mg (87%). Mp¼140e144 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 7.99 (d, J¼8.0 Hz, 1H), 7.65 (t, J¼8.4 Hz, 1H), 7.58
(d, J¼6.8 Hz, 1H), 7.43 (d, J¼8.0 Hz, 2H), 7.19 (d, J¼7.8 Hz, 2H),
6.82 (s, 2H), 3.87 (s, 3H), 3.67 (s, 6H), 2.86 (s, 3H), 2.37 (s, 3H).
13C NMR (CDCl3, 100 MHz): dC 152.9, 152.7 (2C), 151.2 (2C), 141.0,
140.1, 138.6 (2C), 137.3, 136.7, 134.3, 129.7, 129.5, 129.4 (2C),
129.0, 126.8, 107.6 (2C), 60.9, 55.8 (2C), 21.2, 17.0. HRMS (ESI-ion
trap, m/z): [MþH]þ calcd for C25H25N2O3 401.1860; found
401.1872.
4.4.18. 2-o-Tolyl-3-(3,4,5-trimethoxy phenyl)quinoxaline (4r). The
title compound was prepared according to the general procedure
and purified by column chromatography to obtain a yellow solid
113.6 mg (83%). Mp¼132e134 ꢀC. 1H NMR (CDCl3, 400 MHz): dH
8.23 (d, J¼7.2 Hz, 2H), 7.82 (d, J¼7.2 Hz, 2H), 7.41 (d, J¼8.8 Hz, 1H),
7.34e7.28 (m, 2H), 7.21 (d, J¼8.4 Hz, 1H), 6.80 (s, 2H), 3.84 (s, 3H),
3.66 (s, 6H), 1.99 (s, 3H). 13C NMR (CDCl3, 100 MHz): dC 154.1, 152.6
(2C), 141.2 (2C), 140.6, 139.3, 138.6, 135.8, 133.2, 130.4, 130.0, 129.7,
129.5, 129.0, 129.0, 128.7, 126.1, 106.8 (2C), 60.7, 55.7 (2C), 19.5.
HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C24H23N2O3 387.1630;
found 387.1624.
4.4.24. 5-Methyl-3-phenyl-2-(3,4,5-trimethoxy phenyl)quinoxaline
(4x). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain
a yellow solid 128.1 mg (89%). Mp¼180e184 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 8.00 (d, J¼8.8 Hz, 1H), 7.66 (t, J¼7.2 Hz, 1H), 7.61 (d,
J¼7.8 Hz, 1H), 7.55e7.53 (m, 2H), 7.38e7.37 (m, 3H), 6.82 (s, 2H),
3.87 (s, 3H), 3.66 (s, 6H), 2.87 (s, 3H). 13C NMR (CDCl3, 100 MHz): dC
152.8, 152.7, 151.0 (2C), 140.9, 140.2, 139.6, 138.6, 137.3 (2C), 134.0,
129.8, 129.6, 129.5, 128.5 (2C), 128.3, 126.8, 107.6 (2C), 60.8, 55.8
(2C), 17.0. HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C24H23O3N2
387.1703; found 387.1715.
4.4.19. 2-Cyclopropyl-3-(3,4,5-trimethoxy phenyl)quinoxaline (4s). The
title compound was prepared according to the general procedure and
purified by column chromatography to obtain a yellow oil 104.2 mg
(72%). 1H NMR (CDCl3, 400 MHz): dH 8.09 (d, J¼8.0 Hz, 1H), 7.97 (d,
J¼8.0 Hz, 1H), 7.69e7.65 (m, 2H), 7.02 (s, 2H), 3.94 (s, 6H), 3.92 (s, 3H),
1.42e1.40 (m, 2H), 1.25 (s, 1H), 1.09e1.06 (m, 2H). 13C NMR (CDCl3,
100 MHz): dC 156.6, 154.4, 153.4 (2C), 141.6 (2C), 140.3, 134.4, 129.7,
129.2, 128.8, 128.5, 106.9 (2C), 61.1, 56.4 (2C), 15.8, 12.0 (2C). HRMS
(ESI-ion trap, m/z): [MþH]þ calcd for C20H21N2O3 337.1547; found
337.1555.
4.4.25. 2-Phenyl-3-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydroquin
oxaline (4y). The title compound was prepared according to the
general procedure and purified by column chromatography to ob-
tain a yellow oil 98.2 mg (70%). 1H NMR (CDCl3, 400 MHz): dH 7.39
(d, J¼8.0 Hz, 2H), 7.31e7.24 (m, 3H), 6.62 (s, 2H), 3.81 (s, 3H), 3.63 (s,
6H), 3.06e3.05 (m, 4H), 1.99e1.98 (t, J¼5.6 Hz, 4H). 13C NMR (CDCl3,
100 MHz): dC 152.8 (2C), 150.4 (2C), 149.5, 149.0, 139.2, 138.1, 133.9,
129.4 (2C), 128.2 (2C), 128.0, 107.0 (2C), 60.8, 55.8 (2C), 31.8 (2C),
22.7 (2C). HRMS (ESI-ion trap, m/z): [MþH]þ calcd for C23H25N2O3
377.1860; found 377.1868.
4.4.20. 3-Phenyl-2-(3,4,5-trimethoxyphenyl)quinoxaline-6-carboxylic
acid (4t). The title compound was prepared according to the
general procedure and purified by column chromatography to
obtain
a
light yellow oil 107.1 mg (69%). 1H NMR (CDCl3,
400 MHz): dH 8.90 (s, 1H), 8.38 (d, J¼8.8 Hz, 1H), 8.19 (d, J¼8.4 Hz,
1H), 7.53e7.51 (m, 2H), 7.37e7.35 (m, 3H), 6.75 (s, 2H), 3.83 (s,
3H), 3.64 (s, 6H). 13C NMR (CDCl3, 100 MHz): dC 168.6, 155.0, 154.3,
153.6, 152.7 (2C), 142.9, 140.1, 138.7 (2C), 133.1, 132.0, 131.4, 129.6
(2C), 129.4, 128.9, 128.3 (2C), 107.3 (2C), 60.8, 55.8 (2C). HRMS
(ESI-ion trap, m/z): [MþH]þ calcd for C24H21N2O5 417.1445; found
417.1453.
4.4.26. 3-Phenyl-2-(3,4,5-trimethoxyphenyl)pyrido[3,4-b]pyrazine
(4z). The title compound was prepared according to the general
procedure and purified by column chromatography to obtain
a yellow solid 115.5 mg (83%). Mp¼156e164 ꢀC. 1H NMR (CDCl3,
400 MHz): dH 9.62 (s, 1H), 8.92e8.76 (m, 1H), 8.03e7.91 (m, 1H),
7.55 (d, J¼7.6 Hz, 2H), 7.45e7.38 (m, 3H), 6.79 (s, 2H), 3.87 (s, 3H),
3.68 (s, 6H). 13C NMR (CDCl3, 100 MHz): dC 158.0, 157.3, 155.5, 154.8,
153.0, 152.9 (2C), 147.1, 143.5, 139.5, 138.6, 132.8, 129.6, 129.5, 129.3,
4.4.21. 3-(4-Methoxyphenyl)-5-methyl-2-(3,4,5-trimethoxyphen
yl)quinoxaline (4u). The title compound was prepared according
Please cite this article in press as: Chen, C.-Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.027

C.-Y. Chen et al. / Tetrahedron xxx (2013) 1e7
7
10. (a) Croft, S. L.; Coombs, G. H. Trends Parasitol. 2003, 19, 502; (b) Guillon, J.;
Forfar, I.; Mamani-Matsuda, M.; Desplat, V.; Saliege, M.; Thiolat, D.; Massip, S.;
Tabourier, A.; Leger, J.; Dufaure, B.; Haumont, G.; Jarry, C.; Mossalayi, D. Bioorg.
Med. Chem. 2007, 15, 194; (c) Burguete, A.; Estevez, Y.; Castillo, D.; Gonzalez, G.;
Villar, R.; Solano, B.; Vicente, E.; Silanes, S. P.; Aldana, I.; Monge, A.; Sauvain, M.;
Deharo, E. Mem. Inst. Oswaldo Cruz 2008, 103, 778.
128.5, 121.4, 107.5 (2C), 60.9, 55.9 (2C). HRMS (ESI-ion trap, m/z):
[MþH]þ calcd for C22H20N3O3 374.1499; found 374.1509.
4.4.27. 1,4-Bis(3-phenylquinoxalin-2-yl)benzene(1,4-quinoxaline-di-
mer) (6). The title compound was prepared according to the
general procedure and purified by column chromatography to
obtain a light yellow oil 153.8 mg (88%). 1H NMR (CDCl3, 400 MHz):
dH 8.20 (d, J¼7.2 Hz, 4H), 7.82 (d, J¼7.2 Hz, 4H), 7.54e7.52 (m, 4H),
7.51e7.50 (m, 4H), 7.33e7.30 (m, 6H). 13C NMR (CDCl3, 100 MHz):
dC 153.3 (4C), 152.6 (4C), 141.1 (4C), 139.3 (2C), 138.8 (2C), 130.0
(4C), 129.8 (2C), 129.7 (4C), 129.1 (4C), 128.8 (2C), 128.2 (2C). HRMS
(ESI-ion trap, m/z): [MþH]þ calcd for C34H22N4 487.1844; found
487.1846.
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Acknowledgements
We thank the National Science Council of the Republic of China
for financial support. This work was also supported by a grant from
the Kaohsiung Medical University Research Foundation.
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Supplementary data
Experimental details, spectra data for the products, and X-ray
crystallographic data (CIF file of 4i: CCDC 897279) are available.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.027.
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Please cite this article in press as: Chen, C.-Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.09.027