N-Bromosuccinimide-Mediated Synthesis of Substituted Quinoxalines

Article abstract of DOI:10.1055/s-0035-1561472

An efficient and simple N-bromosuccinimide-mediated two-step synthesis of substituted quinoxalines from 1,2-diarylacetylenes and 1,2-diaminobenzenes in boiling AcOH, during a one-pot procedure has been developed. All the structures of the substituted quinoxalines were confirmed, some by single-crystal X-ray crystallography. Possible reaction pathways were discussed, and some data were matched with the previous work.

Full text of DOI:10.1055/s-0035-1561472

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
C.-K. Chan, M.-Y. Chang
Paper
Synthesis
N-Bromosuccinimide-Mediated Synthesis of Substituted Quinox-
alines
Chieh-Kai Chan
√ one-pot
Ar1
Meng-Yang Chang*
N
N
NBS, AcOH
then
√ open air
Ar1
Ar2
R
Department of Medicinal and Applied Chemistry,
Kaohsiung Medical University, Kaohsiung 80708,
Taiwan, Republic of China
√ metal-free
√ high yields
Ar2
NH2
R
29 examples
79–96% yields
mychang@kmu.edu.tw
NH2
Ar1, Ar2 = Ph, 3-MeOCH2C6H4, 3-CF3C6H4, 4-PhC6H4, 4-MeO2CC6H4, 4-ClC6H4, 2-thienyl
R = H, 3,4-Me2, 3,4-Cl2, naphthyl, 3-CO2Me, 3-pyridyl, 3,3',4,4'-tetraaminobiphenyl
Received: 25.03.2016
Accepted after revision: 13.05.2016
Published online: 24.06.2016
ortho-carbon units, such as aldehydes,10 ketones,11 1,2-di-
ketones,12 epoxides,13 vicinal diols,14 diazoketones,15
alkenes,16 and alkynes.17
DOI: 10.1055/s-0035-1561472; Art ID: ss-2016-h0124-op
Recently, several research groups have used 1,2-phenyl-
Abstract An efficient and simple N-bromosuccinimide-mediated two-
step synthesis of substituted quinoxalines from 1,2-diarylacetylenes
and 1,2-diaminobenzenes in boiling AcOH, during a one-pot procedure
has been developed. All the structures of the substituted quinoxalines
were confirmed, some by single-crystal X-ray crystallography. Possible
reaction pathways were discussed, and some data were matched with
the previous work.
diamines and alkynes, the latter being oxidized to carbonyl
or hydroxyl groups like ketones11,12 or vicinal diols14 for the
preparation of quinoxalines. For this purpose, a variety of
oxidants and catalytic systems were employed, including
KMnO4/NaHCO3,18 PdX2/DMSO,17b,c,19 PdBr2/CuBr2/1,4-diox-
ane,20 O2/Cu,21 Ga(OTf)3,22 SO3/1,4-dioxane,23 and PdCl2/
CuCl2/PEG.24 Despite the fact that these methods are effec-
tive in synthesizing substituted quinoxalines, we explored a
novel one-pot, metal-free, rapid reaction to synthesize
quinoxaline with cheaper reagents from alkynes.
Key words one-pot synthesis, N-bromosuccinimide, acetic acid, phe-
nylacetylene, quinoxalines
Quinoxalines are ubiquitous nitrogen-containing het-
erocyclic compounds that play important roles in the or-
ganic field, such as efficient intermediates of some synthet-
ic routes,1 polymers,2 and useful dyes.3 In addition to these
meaningful features, quinoxalines and their derivatives
have a wide range of pharmaceutical uses, such as antimi-
crobial,4 anticancer,5 antiprotozoal,6 antibacterial,7 antima-
larial,8 and antileishmanial.9 On the basis of these signifi-
cant characteristics, many protocols have been developed
for the synthesis of quinoxalines. According to relevant
studies, the most popular procedures are derived from the
condensation of 1,2-diamines with a number of polar
Even if many efficient approaches for preparing substi-
tuted quinoxalines from alkynes using halogenated oxi-
dants such as I2/DMSO,25 I2/TBHP/DMSO,26 IBX/DMSO,27 and
Au(I)/Selectflour28 have been well developed (Scheme 1),
we envisioned that other halogen-containing reagents may
also promote the one-pot condensation of alkynes with 1,2-
diaminobenzenes. In particular, only few reports on the
condensation of alkynes with 1,2-diaminobenzenes medi-
ated by bromine-containing reagents are known. After fur-
ther comparison of literature on the halogenated reagent-
mediated synthesis of quinoxalines, no report on the sys-
tem NBS/AcOH was found for this transformation.
PhI(OAc)2/DMSO, Wang25
I2/TBHP/DMSO, Chaskar26
I2/DMSO, Bathula27
N
N
Ar
R
halogenated reagents
Ar
R
then
NH2
Au(I)/Selectfluor, Liu28
NH2
Scheme 1 Halogenated-reagent-mediated synthesis of quinoxalines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
C.-K. Chan, M.-Y. Chang
Paper
Synthesis
In 2011, we developed a synthetic strategy from cyclo-
hexanone (1) and 1,2-diaminobenzene (2a) toward substi-
tuted quinoxalines 3.11d Herein, we conducted bromination
of alkynes 4 followed by condensation of 2 using the expe-
rience of our previous work for the synthesis of quinoxaline
analogues (Scheme 2).
Table 1 Reaction Conditions of 4a with NXS (X = Br, Cl, I)a
OAc
NXS (X = Br, Cl, I)
AcOH, reflux
X
O
N
4a
6
NBS, AcOH
then
previous
work
Entry
Additive
Equiv
6, Yield (%)b
N
NH2
NH2
1
4
3
1
2
3
4
5
6
7
NBS
NBS
NBS
NCS
NCS
NIS
1.0
1.2
1.5
1.2
1.5
1.2
1.5
6a, 80
2a
6a, 95
6a, 85c
6b, 60d
6b, 55c,d
6c, 30d
6c, 35d
N
Ar1
Ar2
NBS, AcOH
then
Ar1
Ar2
this work
R
N
NH2
NH2
R
5
2
NIS
a The reactions were conducted on a 1.0 mmol scale with 4a.
b Isolated yields.
Scheme 2 NBS-mediated synthesis of quinoxalines
c Trace amounts (<5%) of unknown products were obtained.
d Recovered 4a: entry 4, 20%; entry 5, 18%, entry 6, 55%, entry 7, 60%.
Initially, 1,2-diphenylacetylene (4a) and 1,2-diamino-
benzene (2a) were chosen as the model substrates to exam-
ine this one-pot transformation via NBS-mediated bromi-
nation. Other NXS (X = Cl or I) and equivalents were investi-
gated on a 1.0 mmol scale of 4a in acetic acid at reflux, and
the results are summarized in Table 1. Obviously, 1.2 equiv-
alents of NBS was an efficient additive in this step, and the
yield of 6a was 92% after 2 hours (Table 1, entries 1–3). NCS
was also examined with 1.2 and 1.5 equivalents, but the re-
action time was more than 6 hours for conducting chlorina-
tion (entries 4 and 5). NIS was not appropriate in this step,
because the yields were 30% and 35%, with numerous re-
covered starting materials (entries 6 and 7). The structure
of 6a was determined by single-crystal X-ray crystallogra-
phy (Figure 1).29
As expected, the reaction between 6a and 1.1 equiva-
lents of 2a smoothly afforded the corresponding quinoxal-
ine 5a in AcOH at reflux in good yield. To our delight, this
two-step strategy produced 5a in 90% total yield in 5 hours
(Scheme 3, eq. 1). Owing to acetic acid acting as a solvent in
both the bromination and condensation reactions of syn-
thesizing substituted quinoxaline 5a, the combined reac-
tion deserved further exploration. However, considering
the convenience of the NBS-mediated synthesis of substi-
tuted quinoxaline 5a, we wished to develop a convenient,
one-pot protocol to elevate efficiency and shorten the reac-
tion time.
OAc
N
N
NH2
NH2
AcOH
reflux
(1)
+
Br
6a (1.0 mmol)
2a (1.0 mmol)
5a (95%)
NBS (1.2 mmol)
AcOH
N
(2)
then
2a (1.1 mmol)
reflux
N
4a (1.0 mmol)
5a (92%)
Scheme 3 Synthesis of 5a
Subsequently, 4a was first investigated via NBS-mediat-
ed bromination in acetic acid at reflux, until the reaction
was terminated after 2 hours. Then 2a was added directly
Figure 1 X-ray crystal structure of compound 6a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
C.-K. Chan, M.-Y. Chang
Paper
Synthesis
to the reaction mixture and the progress of the reaction
was followed by TLC. Fortunately, the above-mentioned
one-pot reaction strategy was complete in four hours, and
5a was obtained in high yield (Scheme 3, eq. 2).
N
Ar1
Ar2
NBS, AcOH
then
Ar1
Ar2
R
N
5
NH2
4
R
NH2
2
N
Cl
Cl
N
N
Me
Me
N
N
N
N
N
5a (92%)
5b (87%)
5c (84%)
5d (85%)
N
N
N
N
Me
Me
N
N
N
Me
CF3
CF3
N
N
O
5e (83%)
5f (79%)
5g (95%)
5h (92%)
N
N
N
N
N
Me
Me
N
N
MeO
CF3
CF3
O
N
5ja (92%)
5i (91%)
5k (88%)
5l (86%)
Cl
Cl
N
N
N
N
N
N
MeO
O
N
N
CO2Me
5oa (81%)
5n (87%)
5m (82%)
5p (86%)
N
N
Me
Me
N
N
N
N
N
N
OMe
CO2Me
5rb (88%)
5q (88%)
5s (93%)
Cl
N
N
S
N
N
Cl
5t (93%)
5u (93%)
Scheme 4 Synthesis of 5. Reagents and conditions: 1,2-diarylacetylene 4 (1.0 mmol), NBS (1.2 mmol) in AcOH (8 mL) at reflux for 2 h, then 1,2-diami-
nobenzenes 2 (1.1 mmol) was added and the mixture was stirred another 2 h. The isolated products were >95% pure as determined by 1H NMR analysis.
a Two isomers (5j, 1:1; 5o, 1:1). b1,2-Diphenylacetylene 4a (2.0 mmol), NBS (2.4 mmol) in AcOH (10 mL) at reflux for 2 h, then 3,3′,4,4′-tetraaminobi-
phenyl 2g (1.1 mmol) was added and the mixture was stirred for another 2.5 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
C.-K. Chan, M.-Y. Chang
Paper
Synthesis
On the basis of the optimized reaction conditions, a
study on the substrate scope was carried out, and is shown
in Scheme 4. Initially, a variety of symmetric diamines 2a–d
with a range of substituents were used in the reaction, fol-
lowed by the NBS-mediated bromination of 4a. The corre-
sponding quinoxalines 5a–d were isolated in 84–92% yields.
Asymmetric methyl 3,4-diaminobenzoate (2e) and hetero-
cyclic 2,3-diaminopyridine (2f) were also used in this reac-
tion to give the products 5e and 5f in good isolated yields
(83% and 79%, respectively). Asymmetric 4b was tested in
this reaction with 1,2-diamines 2 and the desired products
5g–i were obtained in high yields between 91–95%. When
methyl 3,4-diaminobenzoate (2e) was used in this reaction
with 4b, the product 5j was obtained in 90% yield as two
isomers in a 1:1 ratio. The reactions of 1-phenyl-4-(2-
phenylethynyl)benzene (4c) with 2a–e afforded substituted
quinoxalines 5k–n in good yields (82–88%) and 5o in 81%
yield in a 1:1 ratio. 1-(4-Methoxycarbonylphenyl)-2-phenyl-
acetylene (4d) also reacted with 2a and 2b; the desired 5p
and 5q were isolated in high yields (86% and 88%, respec-
tively). It is noteworthy that 3,3′,4,4′-tetraaminobiphenyl
(2g), tested in this condensation with 4a afforded 5r in good
to excellent yield of 88%. The reaction of 1-(methoxymeth-
yl)-3-(phenylethynyl)benzene (4e) with 2b gave 5s in 93%
yield. The reaction of 1,2-bis(4-chlorophenyl)ethyne (4f)
with 2a was also examined, and 5t was obtained in 93%
yield. Much to our satisfaction, 2-(phenylethynyl)thiophene
(4g), which contains a thiophene ring, was tested with 2b
and produced the quinoxaline 5u in 93% yield. The struc-
tures of substituted quinoxalines 5d, 5f, and 5r were deter-
mined by single-crystal X-ray crystallography,29 and that of
5r is shown in Figure 2.
sults of this two-step one-pot synthetic route toward mo-
nosubstituted quinoxalines 7a–h are shown in Scheme 5. In
particular, monosubstituted quinoxaline derivatives 7b and
7d have shown the ability to selectively block EGFR ki-
nase.30
N
Ar
NBS, AcOH
then
Ar
H
R
N
NH2
4h–k
7
R
NH2
2
Me
N
N
N
N
Me
7a (94%)
7b (96%)
Cl
Cl
N
N
N
N
7c (93%)
7d (95%)
Me
N
N
MeO
O
N
N
7ea (96%)
7f (95%)
OMe
N
N
N
N
7g (93%)
7h (94%)
Scheme 5 Synthesis of 7. Reagents and conditions: 4h–k (1.0 mmol),
NBS (1.2 mmol) in AcOH (8 mL) at reflux, 2 h, then 2 (1.1 mmol), reflux,
2 h. The isolated products were >95% pure as determined by 1H NMR
analysis. a Two isomers with a ratio 1:1.
According to the aforementioned results, a plausible re-
action pathway is proposed in Scheme 6. First, bromination
of 1,2-diphenylacetylene (4a) in the presence of NBS afford-
ed the intermediate A, and acetic acid underwent a nucleo-
philic substitution to furnish acetate 6a. Then, 2a was add-
ed to form enol B-1 and acetamide C. By the enol-keto tau-
tomerism, B-1 gets transformed to B-2. Finally, the desired
quinoxaline 5a was obtained via a condensation of B-2 with
C followed by a sequential aromatization.
In summary, a facile one-pot strategy for the synthesis
of substituted quinoxalines has been successfully devel-
oped from 1,2-diarylacetylenes with 1,2-diaminobenzenes
in high yields. This convenient protocol goes through a bro-
mination step via NBS in boiling AcOH giving intermediate
Figure 2 X-ray crystal structure of 5r
From the above observation, the substrate scope of
alkynes 4 was further investigated from 1,2-diarylacety-
lenes 4a–g to monoarylacetylenes 4h–k. Phenylacetylene
(4h) was reacted with 2a under the above optimized reac-
tion conditions and the corresponding 7a was obtained in
94% yield. Based on the success of obtaining 7a, other 1,2-
diamines 2b–e were also tested with 4h and provided the
desired quinoxalines 7b–e in high yields (93–96%). Subse-
quently, 4i–k were reacted with 2a affording the desired
quinoxalines 7f–h in yields ranging from 93–95%. The re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
C.-K. Chan, M.-Y. Chang
Paper
Synthesis
H2N
H2N
Ph
Ph
Br
OAc
Ph
Ph
Br
OH
Ph
2a
NBS
OAc
Br
4a
Ph
A
B-1
6a
H2N
+
HN
Ac
Ph
Br
O
C
5a
Ph
B-2
Scheme 6 Plausible reaction pathway
acetates, which are then condensed with 1,2-diaminoben-
zenes smoothly affording substituted quinoxaline deriva-
tives in good to excellent yields. A possible reaction path-
way was also discussed using the single-crystal X-ray crys-
tallography of the intermediate acetate 6a. Some
quinoxaline data matched with the previous literature.
HRMS (ESI): m/z (M+ + H) calcd for C20H15N2: 283.1235; found:
283.1229.
6,7-Dimethyl-2,3-diphenylquinoxaline (5b)31
Yield: 270 mg (87%); colorless solid; mp 174–175 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.93 (s, 2 H), 7.51–7.49 (m, 4 H), 7.34–
7.29 (m, 6 H), 2.52 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 152.45 (2 ×), 140.50 (2 ×), 140.16 (2 ×),
139.33 (2 ×), 129.80 (4 ×), 128.49 (4 ×), 128.14 (4 ×), 20.38 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C22H19N2: 311.1548; found:
311.1544.
All reagents and solvents were obtained from commercial sources
and used without further purification. Reactions were routinely car-
ried out under an atmosphere of dry N2 with magnetic stirring. Prod-
ucts in organic solvents were dried with anhyd MgSO4 before concen-
tration in vacuum. Melting points were determined with a SMP3
melting point apparatus. 1H and 13C NMR spectra were recorded on a
Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, re-
spectively. Chemical shifts (δ) are reported in parts per million (ppm)
and the coupling constants (J) are given in hertz. High-resolution
mass spectra (HRMS) were recorded on a Bruker microTOF-Q mass
spectrometer. X-ray crystal structures were obtained with an Enraf-
Nonius FR-590 diffractometer (CAD4, Kappa CCD).
6,7-Dichloro-2,3-diphenylquinoxaline (5c)32
Yield: 294 mg (84%); colorless solid; mp 111–112 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.29 (s, 2 H), 7.52–7.49 (m, 4 H), 7.41–
7.33 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 154.49 (2 ×), 139.95 (2 ×), 138.39 (2 ×),
134.43 (2 ×), 130.26 (2 ×), 129.78 (4 ×), 129.28 (2 ×), 128.35 (4 ×).
HRMS (ESI): m/z (M+ + H) calcd for C20H13Cl2N2: 351.0456; found:
351.0452.
Quinoxalines 5 and 7; General Procedure
2,3-Diphenylbenzo[g]quinoxaline (5d)33
NBS (214 mg, 1.2 mmol) was added to a solution of the appropriate
alkyne 4 (1.0 mmol) in AcOH (8 mL) at r.t. The reaction mixture was
stirred at reflux for 2 h, then the respective diamine 2 (1.1 mmol) was
added to the reaction mixture directly. The mixture was stirred at
120 °C for 2 h continuously, cooled to r.t., and the solvent was concen-
trated. The residue was diluted with aq NaHCO3 (95%, 10 mL) and the
mixture was extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine, dried, filtered and evaporated to af-
ford the crude product. Purification on silica gel (hexanes/EtOAc: 10:1
to 6:1) afforded quinoxaline 5 or 7.
Yield: 282 mg (85%); colorless solid; mp 183–184 °C (hexanes/EtOAc)
1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 2 H), 8.13–8.11 (m, 2 H), 7.59–
7.57 (m, 6 H), 7.42–7.34 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 154.17 (2 ×), 139.10 (2 ×), 137.92 (2 ×),
134.07 (2 ×), 129.83 (4 ×), 129.01 (2 ×), 128.54 (2 ×), 128.24 (4 ×),
127.52 (2 ×), 126.73 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C24H17N2: 333.1392; found:
333.1388.
2,3-Diphenylquinoxaline (5a)17b
X-ray Crystallographic Data29
Yield: 260 mg (92%); colorless solid; mp 120–121 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.21–8.18 (m, 2 H), 7.80–7.75 (m, 2 H),
7.55–7.52 (m, 4 H), 7.39–7.32 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.39 (2 ×), 141.15 (2 ×), 138.99 (2 ×),
Single-crystal of 5d was grown by slow diffusion of EtOAc into a solu-
tion of 5d in CH2Cl2 to give colorless prisms. The compound crstal-
lized in the monoclinic crystal system, space group C 2/c, a =
25.127(2) Å, b = 7.7380(7) Å, c = 21.2747(19) Å, V = 3436.0(5) Å3, Z = 8,
dcalcd= 1.285 g/cm3, F(000) = 1392, 2θ range 1.95–26.44°, R indices (all
data) R1 = 0.0561, wR2 = 0.1009.
129.92 (2 ×), 129.80 (4 ×), 129.13 (2 ×), 128.76 (2 ×), 128.21 (4 ×).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
C.-K. Chan, M.-Y. Chang
Paper
Synthesis
Methyl 2,3-Diphenylquinoxaline-6-carboxylate (5e)34
1H NMR (400 MHz, CDCl3): δ = 8.77 (s, 1 H), 8.76 (s, 1 H), 8.14–8.11
(m, 2 H), 7.93 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H),
7.61–7.57 (m, 2 H), 7.55–7.53 (m, 2 H), 7.47–7.37 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 153.75, 152.38, 139.71, 138.51,
137.83, 137.76, 134.30, 134.14, 133.14, 129.74 (4 ×), 129.27, 128.55 (4
×), 128.44, 127.71, 127.60, 126.99, 126.92, 126.86 (q, J = 3.8 Hz),
125.64 (q, J = 3.8 Hz).
Yield: 282 mg (83%); colorless solid; mp 115–116 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.90 (d, J = 2.0 Hz, 1 H), 8.36 (dd, J = 2.0,
8.8 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 7.56–7.53 (m, 4 H), 7.41–7.32 (m,
6 H), 4.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.28, 155.08, 154.37, 143.10,
140.36, 138.57, 131.87 (2 ×), 131.16, 129.83 (4 ×), 129.79 (2 ×),
129.42, 129.36, 129.21, 129.09, 128.29 (2 ×), 52.54.
HRMS (ESI): (M+
401.1261.
+ H) calcd for C25H16F3N2: 401.1266; found:
HRMS (ESI): m/z (M+ + H) calcd for C22H17N2O2: 341.1290; found:
341.1287.
Methyl 2-Phenyl-3-[3-(trifluoromethyl)phenyl]quinoxaline-6-car-
boxylate and Methyl 3-Phenyl-2-[3-(trifluoromethyl)phenyl]qui-
noxaline-6-carboxylate (5j)
2,3-Diphenylpyrido[3,4-b]pyrazine (5f)35
Yield: 224 mg (79%); colorless solid; mp 180–181 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.61 (s, 1 H), 8.83 (d, J = 5.6 Hz, 1 H),
8.01 (dd, J = 0.8, 5.6 Hz, 1 H), 7.56–7.53 (m, 4 H), 7.44–7.34 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.08, 155.49, 154.23, 147.00,
143.68, 138.21 (2 ×), 136.30, 129.87 (2 ×), 129.78 (2 ×), 129.74,
129.46, 128.43 (4 ×), 121.50.
Two isomers, ratio = 1:1; yield: 376 mg (92%); colorless solid; mp
159–160 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.92–8.91 (m, 1 H), 8.41–8.38 (m, 1 H),
8.24–8.21 (m, 1 H), 7.89–7.87 (m, 1 H), 7.70–7.63 (m, 2 H), 7.52–7.36
(m, 6 H), 4.031–4.029 (m, 3 H).
HRMS (ESI): m/z (M+ + H) calcd for C23H16N2O2: 409.1164; found:
409.1159.
HRMS (ESI): m/z (M+ + H) calcd for C19H14N3: 284.1188; found
284.1181.
2-([1,1′-Biphenyl]-4-yl)-3-phenylquinoxaline (5k)36
X-ray Crystallographic Data29
Yield: 315 mg (88%); colorless solid; mp 116–117 °C (hexanes/EtOAc).
Single-crystal of 5f was grown by slow diffusion of EtOAc into a solu-
tion of 5f in CH2Cl2 to give colorless prisms. The compound crstallized
in the monoclinic crystal system, space group P 21/n, a = 13.9951(9)
1H NMR (400 MHz, CDCl3): δ = 8.22–8.17 (m, 2 H), 7.80–7.75 (m, 2 H),
7.64–7.56 (m, 8 H), 7.45–7.42 (m, 2 H), 7.39–733 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 153.39, 152.99, 141.50, 141.18,
141.11, 140.30, 138.98, 137.80, 130.30 (2x), 130.01, 129.99, 129.83 (2
×), 129.12 (2 ×), 128.87, 128.78 (2 ×), 128.35 (2 ×), 127.59, 127.05 (2
×), 126.92 (2 ×).
Å, b = 7.1280(4) Å, c = 14.7290(9) Å, V = 1435.17(15) Å3, Z = 4, dcalcd
=
1.311 g/cm3, F(000) = 592, 2θ range 2.27–26.47°, R indices (all data)
R1 = 0.0531, wR2 = 0.0943.
HRMS (ESI): m/z (M+ + H) calcd for C26H19N2: 359.1548; found:
2-Phenyl-3-[3-(trifluoromethyl)phenyl]quinoxaline (5g)
359.1540.
Yield: 333 mg (95%); colorless solid; mp 107–108 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.23–8.18 (m, 2 H), 7.87 (s, 1 H), 7.84–
7.79 (m, 2 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.62 (d, J = 7.6 Hz, 1 H), 7.51–
7.48 (m, 2 H), 7.45–7.34 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 153.30, 151.70, 141.39, 141.21,
139.72, 138.51, 133.17, 130.48, 130.27, 129.76 (2 ×), 129.26 (2 ×),
129.24 (2 ×), 129.11, 128.60, 128.50 (2 ×), 126.90 (q, J = 3.8 Hz),
125.48 (q, J = 3.8 Hz).
2-([1,1′-Biphenyl]-4-yl)-6,7-dimethyl-3-phenylquinoxaline (5l)
Yield: 332 mg (86%); colorless solid; mp 147–148 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 2 H), 7.63–7.54 (m, 8 H), 7.47–
7.42 (m, 2 H), 7.38–7.34 (m, 4 H), 2.53 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 152.39, 151.96, 141.26, 140.72, 140.39
(2 ×), 140.11, 140.05, 139.18, 138.01, 130.01 (2 ×), 129.85 (2 ×),
128.78 (2 ×), 128.65, 128.29 (2 ×), 128.08, 128.07, 127.54, 127.05 (2
×), 126.86 (2 ×), 20.45 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C21H14F3N2: 351.1109; found:
351.1102.
HRMS (ESI): m/z (M+ + H) calcd for C28H23N2: 387.1861; found:
387.1857.
6,7-Dimethyl-2-phenyl-3-[3(trifluoromethyl)phenyl]quinoxaline
(5h)
2-([1,1′-Biphenyl]-4-yl)-6,7-dichloro-3-phenylquinoxaline (5m)
Yield: 348 mg (92%); colorless solid; mp 96–97 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.94 (s, 1 H), 7.84 (s, 1 H),
7.64 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.48–7.45 (m, 2 H),
7.42 (d, J = 7.6 Hz, 1 H), 7.40–7.32 (m, 3 H), 2.53 (br s, 6 H).
Yield: 349 mg (82%); transparent gel.
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 8.30 (s, 1 H), 7.65–7.55
(m, 9 H), 7.47–7.35 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 152.27, 150.70, 141.25, 141.00,
140.30, 140.21, 139.96, 138.71, 133.17, 129.77 (4 ×), 128.85, 128.50,
128.42 (2 ×), 128.17 (2 ×), 126.87 (q, J = 3.8 Hz), 125.21 (q, J = 3.8 Hz),
20.48, 20.44.
13C NMR (100 MHz, CDCl3): δ = 154.46, 154.05, 142.00, 140.13,
139.98, 139.88, 138.41, 137.17, 134.45, 134.40, 130.28 (2 ×), 129.77 (2
×), 129.75 (2 ×), 129.34, 128.85 (2 ×), 128.46 (2 ×), 127.77, 127.08 (2
×), 126.99 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C23H18F3N2: 379.1422; found:
HRMS (ESI): m/z (M+ + H) calcd for C26H17Cl2N2: 427.0769; found:
379.1417.
427.0764.
2-Phenyl-3-[3-(trifluoromethyl)phenyl]benzo[g]quinoxaline (5i)
2-([1,1′-Biphenyl]-4-yl)-3-phenylbenzo[g]quinoxaline (5n)
Yield: 364 mg (91%); colorless solid; mp 161–162 °C (hexanes/EtOAc).
Yield: 355 mg (87%); colorless solid; mp 168–169 °C (hexanes/EtOAc).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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C.-K. Chan, M.-Y. Chang
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.78 (s, 1 H), 8.77 (s, 1 H), 8.15–8.11
X-ray Crystallographic Data29
(m, 2 H), 7.68–7.57 (m, 10 H), 7.48–7.36 (m, 6 H).
Single-crystal of 5r was grown by slow diffusion of EtOAc into a solu-
tion of 5r in CH2Cl2 to yield colorless prisms. The compound crstalliz-
es in the monoclinic crystal system, space group P 21/c, a = 6.2940(7)
Å, b = 7.6457(9) Å, c = 29.753(4) Å, V = 1426.6(3) Å3, Z = 2, dcalcd= 1.310
g/cm3, F(000) = 588, 2θ range 1.37–26.36°, R indices (all data) R1 =
0.0658, wR2 = 0.1592.
13C NMR (100 MHz, CDCl3): δ = 154.12, 153.71, 141.75 (2 ×), 140.29 (2
×), 139.04, 137.82, 134.10, 134.09, 130.34 (2 ×), 129.85 (2 ×), 129.12,
128.83 (2 ×), 128.55 (2 ×), 128.35 (2 ×), 127.67, 127.50, 127.47, 127.09
(2 ×), 126.91 (2 ×), 126.79 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C30H21N2: 409.1705; found:
409.1696.
2-[3-(Methoxymethyl)phenyl]-3-phenylquinoxaline (5s)
Yield: 303 mg (93%); colorless solid; mp 76–77 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.23–8.19 (m, 2 H), 7.81–7.77 (m, 2 H),
7.53–7.51 (m, 3 H), 7.42–7.29 (m, 6 H), 4.43 (s, 2 H), 3.28 (s, 3 H).
Methyl 3-([1,1′-Biphenyl]-4-yl)-2-phenylquinoxaline-6-carboxyl-
ate and Methyl 2-([1,1′-Biphenyl]-4-yl)-3-phenylquinoxaline-6-
carboxylate (5o)
13C NMR (100 MHz, CDCl3): δ = 153.43, 153.23, 141.05, 138.86,
138.83, 138.42, 130.09 (2 ×), 129.83 (2 ×), 129.18, 129.15, 129.09 (2
×), 129.08, 128.84, 128.34, 128.29 (2 ×), 128.15, 74.23, 57.93.
Two isomers, ratio = 1:1; yield: 337 mg (81%); colorless solid; mp
153–154 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.92–8.91 (m, 1 H), 8.39–8.36 (m, 1 H),
HRMS (ESI): m/z (M+ + H) calcd for C22H19N2O: 327.1497; found:
327.1491.
8.24–8.22 (m, 1 H), 7.65–7.58 (m, 8 H), 7.47–7.35 (m, 6 H), 4.03 (s, 3
H).
HRMS (ESI): m/z (M+ + 1) calcd for C28H21N2O2: 417.1603; found:
2,3-Bis(4-chlorophenyl)quinoxaline (5t)12c
417.1601.
Yield: 326 mg (93%); colorless solid; mp 188–189 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.19–8.14 (m, 2 H), 7.82–7.78 (m, 2 H),
7.47 (d, J = 8.8 Hz, 4 H), 7.35 (d, J = 8.8 Hz, 4 H).
Methyl 4-(3-Phenylquinoxalin-2-yl)benzoate (5p)17b
Yield: 292 mg (86%); colorless solid; mp 151–152 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.24–8.20 (m, 2 H), 8.01 (d, J = 8.4 Hz, 2
H), 7.84–7.79 (m, 2 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.52–7.49 (m, 2 H),
7.41–7.32 (m, 3 H), 3.93 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.71, 153.21, 152.31, 143.28,
141.16, 141.06, 138.33, 130.57, 130.33, 130.22, 129.92 (2 ×), 129.83 (2
×), 129.50 (2 ×), 129.18, 129.14, 129.11, 128.46 (2 ×), 52.25.
13C NMR (100 MHz, CDCl3): δ = 151.92 (2 ×), 141.21 (2 ×), 137.20 (2 ×),
135.35 (2 ×), 131.17 (4 ×), 130.40 (2 ×), 129.18 (2 ×), 128.73 (4 ×).
HRMS (ESI): m/z (M+ + H) calcd for C20H13Cl2N2: 351.0456; found:
351.0452.
2-Phenyl-3-(thiophen-2-yl)quinoxaline (5u)
HRMS (ESI): m/z (M+ + H) calcd for C22H17N2O2: 341.1290; found:
341.1284.
Yield: 268 mg (93%); colorless solid; mp 97–98 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.14–8.10 (m, 2 H), 7.78–7.70 (m, 2 H),
7.63–7.60 (m, 2 H), 7.52–7.48 (m, 3 H), 7.41 (dd, J = 0.8, 5.2 Hz, 1 H),
6.88 (dd, J = 3.6, 5.2 Hz, 1 H), 6.77 (dd, J = 0.8, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 152.51, 146.88, 142.68, 141.11,
139.34, 132.62, 130.20, 129.93, 129.75, 129.32, 129.24, 129.12 (2 ×),
129.02, 128.82, 127.74, 128.71 (2 ×).
Methyl 4-(6,7-Dimethyl-3-phenylquinoxalin-2-yl)benzoate (5q)
Yield: 324 mg (88%); colorless solid; mp 91–92 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.8 Hz, 2 H), 7.95 (s, 1 H),
7.93 (s, 1 H), 7.58 (d, J = 8.8 Hz, 2 H), 7.48–7.46 (m, 2 H), 7.35–7.31 (m,
3 H), 3.92 (s, 3 H), 2.53 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.81, 152.33, 151.31, 143.80,
141.22, 140.95, 140.31, 140.12, 138.83, 129.91 (2 ×), 129.81 (2 ×),
129.44 (2 ×), 128.80, 128.37 (2 ×), 128.18 (2 ×), 121.37, 52.21, 20.50,
20.47.
HRMS (ESI): m/z (M+ + H) calcd for C18H13N2S: 289.0800; found:
289.0794.
2-Phenylquinoxaline (7a)38
Yield: 194 mg (94%); colorless solid; mp 75–76 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.31 (s, 1 H), 8.19–8.10 (m, 4 H), 7.78–
7.70 (m, 2 H), 7.57–7.48 (m, 3 H).
HRMS (ESI): m/z (M+ + H) calcd for C24H21N2O2: 369.1603; found:
369.1596.
13C NMR (100 MHz, CDCl3): δ = 151.70, 143.21, 142.18, 141.42,
136.63, 130.19, 130.09, 129.51, 129.45, 129.05 (2 ×), 128.99, 127.45 (2
×).
HRMS (ESI): m/z (M+ + H) calcd for C14H11N2: 207.0922; found:
207.0916.
2,2′,3,3′-Tetraphenyl-6,6′-biquinoxaline (5r)37
Yield: 495 mg (88%); colorless solid; mp 253 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.60 (d, J= 2.0 Hz, 2 H), 8.33 (d, J = 8.8
Hz, 2 H), 8.24 (dd, J = 2.0, 8.4 Hz, 2 H), 7.59–7.56 (m, 8 H), 7.41–7.34
(m, 12 H).
13C NMR (100 MHz, CDCl3): δ = 154.16 (2 ×), 153.73 (2 ×), 141.42 (2 ×),
141.23 (2 ×), 140.91 (2 ×), 138.90 (2 ×), 133.61 (2 ×), 130.14 (2 ×),
129.90 (2 ×), 129.86 (8 ×), 129.52 (2 ×), 128.96 (2 ×), 128.30 (8 ×),
127.43 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C40H27N4: 563.2236; found:
563.2228.
6,7-Dimethyl-2-phenylquinoxaline (7b)39
Yield: 225 mg (96%); colorless solid; mp 130–131 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.21 (s, 1 H), 8.17–8.14 (m, 2 H), 7.90
(s, 1 H), 7.85 (s, 1 H), 7.57–7.47 (m, 3 H), 2.50 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 150.96, 142.22, 141.19, 140.86,
140.35, 140.19, 137.01, 129.83, 129.04 (2 ×), 128.58, 127.99, 127.34 (2
×), 20.36, 20.33.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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C.-K. Chan, M.-Y. Chang
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Synthesis
HRMS (ESI): m/z (M+ + H) calcd for C16H15N2: 235.1235; found:
235.1232.
1H NMR (400 MHz, CDCl3): δ = 9.35 (s, 1 H), 8.26 (d, J = 8.4 Hz, 2 H),
8.16 (dd, J = 1.6, 8.0 Hz, 1 H), 8.12 (dd, J = 1.6, 8.0 Hz, 1 H), 7.77 (d, J =
8.4 Hz, 2 H), 7.75–7.65 (m, 4 H), 7.50–7.45 (m, 2 H), 7.42–7.37 (m, 1
H).
6,7-Dichloro-2-phenylquinoxaline (7c)32
13C NMR (100 MHz, CDCl3): δ = 151.19, 143.09, 142.76, 142.21,
141.43, 140.04, 135.39, 130.17, 129.49, 129.37, 129.00, 128.80 (2 ×),
127.80 (2 ×), 127.74, 127.65 (2 ×), 127.02 (2 ×).
HRMS (ESI): m/z (M+ + H) calcd for C20H15N2: 283.1235; found:
283.1230.
Yield: 255 mg (93%); colorless solid; mp 155–156 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.32 (s, 1 H), 8.28 (s, 1 H), 8.24 (s, 1 H),
8.20–8.17 (m, 2 H), 7.61–7.54 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.64, 144.27, 141.09, 140.24,
135.97, 134.93, 134.01, 130.77, 130.18, 129.77, 129.27 (2 ×), 127.57 (2
×).
HRMS (ESI): m/z (M+ + H) calcd for C14H9Cl2N2: 275.0143; found:
(E)-2-Bromo-1,2-diphenylethenyl Acetate (6a)
NBS (214 mg, 1.2 mmol) was added to a solution of 1,2-diphenylacet-
ylene (4a; 178 mg, 1.0 mmol) in AcOH (8 mL) at r.t. The reaction mix-
ture was stirred at reflux for 2 h, cooled to r.t., and the solvent was
concentrated. The residue was diluted with aq NaHCO3 (95%, 10 mL)
and the mixture was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine, dried, filtered, and evaporat-
ed to afford crude product. Purification on silica gel (hexanes/EtOAc:
10:1 to 6:1) afforded compound 6a; yield: 303 mg (96%); colorless
solid; mp 113–114 °C (hexanes/EtOAc).
275.0135.
2-Phenylbenzo[g]quinoxaline (7d)10
Yield: 243 mg (95%); colorless solid; mp 158–159 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.40 (s, 1 H), 8.79 (s, 1 H), 8.75 (s, 1 H),
8.29–8.26 (m, 2 H), 8.15–8.11 (m, 2 H), 7.63–7.56 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 151.68, 143.62, 138.48, 136.89,
136.20, 134.43, 133.84, 130.79, 129.29 (2 ×), 128.56, 128.52, 127.86,
127.75 (2 ×), 127.27, 127.14, 126.99.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.68 (m, 2 H), 7.52–7.49 (m, 2 H),
7.45–7.31 (m, 6 H), 1.91 (s, 3 H).
HRMS (ESI): m/z (M+ + H) calcd for C18H13N2: 257.1079; found:
257.1072.
13C NMR (100 MHz, CDCl3): δ = 168.54, 144.52, 137.62, 135.26,
129.18, 129.14 (2 ×), 128.72, 128.61 (2 ×), 128.25 (2 ×), 128.05 (2 ×),
114.02, 20.53.
Methyl 2-Phenylquinoxaline-6-carboxylate and Methyl 3-Phenyl-
quinoxaline-6-carboxylate (7e)40
HRMS (ESI): m/z (M+ + Na) calcd for C16H13BrO2Na: 338.9997; found:
338.9989.
Two isomers, ratio = 1:1; yield: 254 mg (96%); colorless solid; mp
159–160 °C (hexanes/EtOAc).
X-ray Crystallographic Data29
1H NMR (400 MHz, CDCl3): δ = 9.40–9.38 (m, 1 H), 8.86–8.80 (m, 1 H),
8.37–8.30 (m, 1 H), 8.23–8.14 (m, 3 H), 7.60–7.52 (m, 3 H), 4.01 (br s,
3 H).
HRMS (ESI): m/z (M+ + Na) calcd for C16H12N2O2Na: 287.0797; found:
287.0793.
Single-crystal of 6a was grown by slow diffusion of EtOAc into a solu-
tion of 6a in CH2Cl2 to afford colorless prisms. The compound crstal-
lizes in the triclinic crystal system, space group P-1, a = 8.1329(3) Å,
b = 8.9362(3) Å, c = 10.0140(4) Å, V = 700.17(4) Å3, Z = 2, dcalcd= 1.504
g/cm3, F(000) = 320, 2θ range 2.11–26.47°, R indices (all data) R1 =
0.0318, wR2 = 0.0605.
2-(p-Tolyl)quinoxaline (7f)32
Yield: 209 mg (95%); colorless solid; mp 92–93 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.29 (s, 1 H), 8.14–8.07 (m, 4 H), 7.78–
7.69 (m, 2 H), 7.35 (d, J = 0.8, 8.4 Hz, 2 H), 2.43 (s, 3 H).
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 151.70, 143.17, 142.22, 141.30,
140.42, 133.85, 130.12, 129.80 (2 ×), 129.44, 129.21, 128.98, 127.34 (2
×), 21.35.
We thank the Ministry of Science and Technology of the Republic of
China for financial support (MOST 104-2113-M-037-012).
HRMS (ESI): m/z (M+ + H) calcd for C15H13N2: 221.1079; found:
221.1075.
Supporting Information
Supporting information for this article is available online at
2-(4-Methoxyphenyl)quinoxaline (7g)32
http://dx.doi.org/10.1055/s-0035-1561472.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Yield: 220 mg (93%); colorless solid; mp 95–96 °C (hexanes/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 9.27 (s, 1 H), 8.15 (d, J = 9.2 Hz, 2 H),
8.12–8.07 (m, 2 H), 7.76–7.67 (m, 2 H), 7.06 (d, J = 9.2 Hz, 2 H), 3.88 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 161.41, 151.34, 142.93, 142.21,
141.05, 130.15, 129.29, 129.14, 129.02, 128.94, 128.92 (2 ×), 114.52 (2
×), 55.36.
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2-([1,1′-Biphenyl]-4-yl)quinoxaline (7h)32
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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C.-K. Chan, M.-Y. Chang
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I