Copper-catalyzed aerobic oxidative coupling of o-phenylenediamines with 2-aryl/heteroarylethylamines: direct access to construct quinoxalines

Article abstract of DOI:10.1039/c7ob00122c

A copper-catalyzed oxidative coupling reaction of o-phenylenediamines with 2-aryl/heteroarylethylamines using molecular oxygen as an oxidant has been developed. This approach provides a practical and direct access to construct quinoxalines in excellent yields at room temperature. The reaction has a broad substrate scope and exhibits excellent functional-group tolerance. This method could be easily scaled up and applied to the synthesis of biologically active molecules bearing a quinoxaline structural scaffold.

Full text of DOI:10.1039/c7ob00122c

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Copper-Catalyzed Aerobic Oxidative Coupling of o-Phenylenediamines
with 2-Aryl/Heteroarylethylamines: Direct Access to Construct
Quinoxalines
Kovuru Gopalaiah,*,† Anupama Saini,† Sankala Naga Chandrudu,† Devarapalli Chenna
Rao,† Harsh Yadav,‡ Binay Kumar‡
† Organic Synthesis and Catalysis Laboratory, Department of Chemistry, University of
Delhi, Delhi 110007, India
‡ Crystal Lab, Department of Physics & Astrophysics, University of Delhi, Delhi 110007,
India
ABSTRACT
A copper-catalyzed oxidative coupling reaction of o-phenylenediamines with 2-
aryl/heteroarylethylamines using molecular oxygen as an oxidant has been developed.
This novel approach provides a practical and direct access to construct quinoxalines in
excellent yields at room temperature. The reaction has broad substrate scope and exhibits
excellent functional-group tolerance. This method could be easily scaled up and applied
to the synthesis of biologically active molecules bearing quinoxaline structural scaffold.
Dedicated to Professor Sosale Chandrasekhar on the occasion of his 65th
birthday
----------------------------------------------------------------------------------------------------------
Corresponding Author: Dr. Kovuru Gopalaiah
Email: gopal@chemistry.du.ac.in

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Introduction
In recent years, oxidative cross-coupling reactions received great attention for their
exemplary potential in carbon-carbon and carbon-heteroatom bond formation.1
Conventionally, organometallic compounds can be used as one of the reaction partners in
these transformations, but recent findings revealed that amines, alcohols, and
hydrocarbons can directly be used as well.2 Comparing with organometallic compounds,
amines are ideal reactants to construct nitrogen-heterocycles in view of atom economy
and green chemical synthesis. Until now, selection of amines and exploiting them in
different oxidative C-H/N-H coupling remains a challenge.
Quinoxaline, which is one of the well-known and important classes of nitrogen
heterocyclic compounds, exhibits extensive biological and pharmaceutical properties
(Figure 1).3 This scaffold is also an active core unit of several antibiotics,4 pesticides,5
herbicides,6 fungicides,7 and advanced functional materials.8 In consequent to these
important applications, a large number of synthetic methods have been developed to
construct quinoxalines.9-14Among these methods, condensation of α-diketones with 1,2-
diamines,9 oxidative trapping of α-hydroxy ketones or vicinal diols with 1,2-
diamines,10,11 oxidative cyclisation of phenacyl bromides with 1,2-diamines,12 and
reaction of alkynes or ketones with 1,2-diamines via an oxidation process,13 have widely
been used. In addition, oxidative cyclization of o-phenylenediamines was studied to
obtain quinoxalines through the metal/enzyme-catalyzed or photochemical dimerization
process.15 Despite these significant approaches toward the synthesis of quinoxalines, the
development of mild, efficient and environmentally friendly methods are still desired
because: 1) Precursors should be readily available or easily prepared and handled; 2)

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Instead of stoichiometric oxidants such as peroxides and toxic metal compounds,
environmentally friendly molecular oxygen or air is desirable as an ideal oxidant; 3)
More attention should be given to minimize the environmentally hazardous by-products.
Recently, a few elegant examples of copper-catalyzed oxidative C-N bond
formations to construct quinoxalines have been disclosed. Yu and co-workers reported a
copper-catalyzed tandem oxidative azidation/cyclization of enamine esters with TMSN3
(Scheme 1A, a).16 Lin, Zeng and co-workers described a copper-catalyzed
cycloamination of α-Csp3-H bond of N-phenyl ketimines with sodium azide (Scheme 1A,
b).17 However, these methods suffer from certain drawbacks, such as the need of large
amount of nitrogen sources, usage of non-renewable oxidants/additives, narrow substrate
scope, and lower yields. The groups of Chen18 and Hwang19 independently reported the
synthesis of quinoxalines by copper-catalyzed C-N coupling between o-
phenylenediamines and terminal alkynes using large quantity of organic and/or inorganic
bases under thermal (Scheme 1B, a) and blue-LED light irradiation (Scheme 1B, b)
conditions, respectively.

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Figure 1. Representative Examples of Bioactive Quinoxaline Compounds.
In the perspective of sustainable chemistry, oxidative C(sp3)-H bond
functionalization is one of the most appealing and powerful strategies in organic
synthesis.20 For these transformations, air or molecular oxygen could be ideal oxidants.
Remarkably, activation of dioxygen by copper enzymes has been explored in some
biological oxygenase systems, namely dopamine β-monooxygenase and monooxygenase
tyrosinase that effect hydroxylation of unactivated C-H bonds.21 Recently, copper
catalyzed reactions that implicate dioxygen activation and use rather simple models to
twig biomimetic syntheses have been given much attention.22,23 Herein, we report an
efficient synthesis of 2-aryl/heteroarylquinoxalines using readily available o-
phenylenediamines and 2-aryl/heteroarylethylamines (Scheme 1C). This transformation
proceeds through Cu-catalyzed direct aerobic oxidative C-H/N-H coupling of C(sp3)-H
bonds at room temperature. Compared to the conventional methods, this procedure is

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distinguished by using clean O2 as an oxidant, avoiding the use of harmful peroxides and
hypervalent iodine reagents.16,17,24 This method provides a totally convenient and
environmentally friendly direct access to construct a variety of functionalized
quinoxalines under mild conditions.
Scheme 1. Copper-catalyzed C-N bond formation for synthesis of quinoxalines

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Results and discussion
Our study commenced with the reaction of o-phenylenediamine (1a) and 2-
phenylethylamine (2a) catalyzed by copper salts (Table 1). Under the atmosphere of air,
the 2-phenylquinoxaline (3a) was obtained in 73% isolated yield upon treatment of 1:1.2
mixture of 1a and 2a with 20 mol % CuBr in chlorobenzene at room temperature for 12 h
(Table 1, entry 1). Other Cu salts, regardless of their oxidation state (either I or II), also
showed catalytic activity, but they were found to be less effective (see, Table 1, entries 2-
6 and Supporting Information). The reaction failed to give any desired product in the
absence of copper catalyst (Table 1, entry 7). We then examined the effect of different
solvents, and it was observed that the reactions proceeded with low yields in toluene,
DMSO, and other solvents (Table 1, entries 8 and 9; also see the Supporting
Information). Furthermore, various ligands were tested, but the results were
unsatisfactory (see the Supporting Information). On increasing the reaction temperature
o
o
from 25 C to 50 C or higher, the yields of desired product were not improved
considerably (Table 1, entries 10 and 11). However, when we performed the reaction
under the atmosphere of molecular oxygen at room temperature, to our delight, the yield
of 3a was remarkably improved to 92% (Table 1, entry 12). The yield remains the same
when catalyst loading was decreased from 20 mol % to 10 mol % (Table 1, entry 13).
However, a further decrease of catalyst loading resulted in relatively low yield of 3a
(Table 1, entry 14). When the reaction was conducted under argon, no desired product
was observed (Table 1, entry 15). Finally, the reaction conditions described in entry 13
were chosen as the standard conditions for further exploration.

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Table 1. Optimization of Reaction Conditionsa
NH2
NH2
Ph
N
Ph
Cu Catalyst
air, rt
+
NH2
N
1a
2a
3a
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
CuBr
CuCl
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
12
12
12
12
12
12
73
62
40
51
43
35
Cu2O
CuBr2
CuCl2
Cu(OAc)2
none
7
chlorobenzene
toluene
12
12
12
12
12
0
8
CuBr
60
9
CuBr
DMSO
trace
73
10c
11d
12e
CuBr
chlorobenzene
chlorobenzene
CuBr
75
CuBr
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
6
92
13e,f
14e,g
15h
CuBr
CuBr
CuBr
6
92
79
0
12
24
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), catalyst (20 mol %), solvent (2 mL),
b
air atmosphere, room temperature,12 h. Yields of the isolated product. c The reaction
d
e
was carried out at 50 oC. The reaction was carried out at 90 oC. The reaction was
f
g
performed under molecular oxygen (O2 balloon). Using 10 mol % of CuBr. Using 5
mol % of CuBr. h The reaction was performed under argon atmosphere.

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With the optimized experimental conditions in hand, we then investigated the
generality of the synthetic approach. First, 2-arylethylamines with various substituents on
the phenyl ring were subjected to the reaction with 1a (Table 2, entries 1-11). Both
electron-donating and electron-withdrawing substituents on the phenyl ring of 2-
arylethylamines were well tolerated, affording the desired quinoxaline products in
excellent yields. Most of the electron-withdrawing substituents have led to higher yields
than electron-donating groups (2b-2d vs. 2f-2j). However, a lower yield was observed for
the reaction of 2-(4-nitrophenyl)ethylamine (2e) (Table 2, entry 5). Apparently,
substitution at the ortho and meta positions were not detrimental to the reaction yield
(Table 2, entries, 2, 7, and 8). Furthermore, the bulky substituent viz., 2-(1-
naphthyl)ethylamine (2k) afforded the desired product in 85 % yield (Table 2, entry 11).
In addition to the arylethylamines, a variety of 2-heteroarylethylamines could react well
with 1a to give the corresponding quinoxaline compounds in high yields (Table 2, entries
12 to 14). It is worth mentioning that the products of this transformation, namely 2-(4-
bromophenyl)quinoxaline (3c) and 2-(4-hydroxyphenyl)quinoxaline (3j) (Table 2, entries
3 and 10) are used as key precursors for the synthesis of biologically active compounds as
well as organic electroluminescent devices.25

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Table 2: Copper-catalyzed aerobic oxidative cross-coupling of 1a with a range
of 2-aryl/heteroarylethylamines 2.a
NH2
NH2
Ar(Het)
N
Ar(Het)
CuBr (10 mol %)
+
chlorobenzene
O2, rt
NH2
N
1a
Entry
2
3
3
2
Ar(Het)
Time (h)
Yield (%)b
92
6
3a
3b
3c
3d
3e
3f
1
2a
C6H5
93
2
2-ClC6H4
7
2b
2c
2d
2e
2f
97
3
4-BrC6H4
5
95
4
4-CF3C6H4
4-NO2C6H4
4-OMeC6H4
3-OMeC6H4
2-OMeC6H4
3,4-(OMe)2C6H3
4-OHC6H4
1-naphthyl
2-pyridyl
7
5
83
10
8
88
6
7
2g
2h
2i
8
3g
3h
3i
89
85
8
10
8
86
9
81
10
11
12
13
14
9
3j
2j
2k
2l
3k
3l
10
16
13
14
85
83
2m
2n
3m
3n
85
3-indolyl
78
2-thienyl
a Reaction conditions: 1a (1.0 mmol), 2 (1.2 mmol), CuBr (10 mol %), chlorobenzene
(2 mL), room temperature, O2 balloon. b Isolated yield.

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To further explore the scope of this approach, several 4-substituted and 4,5-
disubstituted o-phenylenediamines 1 were employed to react with 2-phenylethylamine
(2a) under the optimized conditions (Table 3). In fact, symmetrical diamines gave the
corresponding products as sole compounds in high yields (Table 3, entries 1-4), whereas
unsymmetrical diamines resulted in a mixture of two possible regioisomers (Table 3,
entries 5-9). All these regioisomers were easily separated by column chromatography,
and characterized by single crystal X-ray diffraction and/or spectroscopic methods. In
addition to the 4-substituted and 4,5-disubstituted o-phenylenediamines, heteroaryl
diamine was also examined for this transformation. For instance, 2,3-diaminopyridine
(1k) could react well with 2a to give the corresponding regioisomers (Table 3, entry 10).
A series of functional groups such as methoxy, methyl, chloro, nitro, and benzoyl
substituents on the aryl ring of diamine were well tolerated under the optimized reaction
conditions.

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Table 3: Copper-catalyzed aerobic oxidative cross-coupling of a range of o-phenylenediamines 1
with 2aa
NH2
NH2
Ph
N
Ph
CuBr (10 mol %)
+
R
R
chlorobenzene
O2, rt
NH2
N
1
2a
4
Entry
1
Substrate (1)
Time (h)
4, Yield (%)b
Ratioc
MeO
NH2
NH2
MeO
N
5
MeO
MeO
N
Ph
1b
4b, 90
Me
Me
NH2
NH2
Me
Me
N
2
3
4
6
N
4c, 87
Ph
Ph
Ph
1c
1d
1e
NH2
NH2
N
8
N
4d, 86
Cl
Cl
NH2
NH2
Cl
Cl
N
10
N
4e, 81
Cl
NH2
NH2
Cl
N
N
Cl
N
Ph
Ph
5
6
8
1:1.3
1:1
Ph
N
1f
4f, 39
4f'
, 44
O2N
NH2
NH2
O2N
N
O2N
N
14
N
Ph
N
1g
4g
4g'
, 37
, 35
O
O
O
NH2
NH2
N
N
N
N
Ph
Ph
Ph
Ph
Ph
7
8
11
7
1:1.1
1.2:1
Ph
Ph
1h
1i
4h, 37
4h', 42
Me
NH2
NH2
Me
N
Me
N
N
N
4i, 45
4i'
, 39
MeO
NH2
NH2
MeO
N
MeO
N
Ph
9
6
1.6:1
1:1
N
4j, 53
Ph
Ph
N
4j', 34
1j
NH2
NH2
N
N
10
16
N
N
N
N
N
Ph
1k
4k, 33
4k', 32
a Reaction conditions: 1 (1 mmol), 2a (1.2 mmol), CuBr (10 mol %), chlorobenzene (2 mL), room
temperature, O2 balloon. b Isolated yield.c Determined by 1H NMR.

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It is worth noting that the reaction could be effectively scaled up with excellent
efficiency under the optimized conditions. Notably, the oxidative cross-coupling between
2-(4-bromophenyl)ethylamine (2c) and o-phenylenediamine (1a) is operationally simple
and amenable to gram-scale synthesis with 94% yield (Scheme 2). Moreover, due to the
high selectivity and efficiency, this aerobic copper-catalyzed oxidative coupling strategy
offers promising synthetic routes for the construction of a library of medicinal
compounds having quinoxaline structural scaffold. For instance, 2-(4-
hydroxyphenyl)quinoxaline (3j) acts as butyrylcholinesterase inhibitor.26 Furthermore,
6,7-dimethoxy-2-phenylquinoxaline (4b) and 6,7-dimethyl-2-phenylquinoxaline (4c) are
selective inhibitors of the platelet derived growth factor (PDGF) receptor kinase and the
PDGF dependent DNA synthesis in Swiss 3T3 cells,27 and 2-phenylbenzo[g]quinoxaline
(4d) used for treatment of platelet derived growth factor-related disorders such as
cancers28.
Scheme 2. Gram-Scale Reaction of the Synthesis of 2-Phenylquinoxaline

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To understand the possible reaction mechanism, the following control
experiments were performed under standard conditions as shown in Scheme 3. We found
that phenylacetaldehyde (5) was formed in 26% yield along with the quinoxaline 3a
when the reaction of 2-phenylethylamine (2a) and o-phenylenediamine (1a) was
performed under standard conditions for 3h. Moreover, the 2-phenylethylamine (2a) with
the present catalytic system produced the corresponding aldehyde 5 in 93% yield.
Gratifyingly, the desired product 3a was obtained smoothly in 93% yield by the reaction
of phenylacetaldehyde (5) and o-phenylenediamine (1a) under the standard conditions. In
addition, the condensation reaction between phenylglyoxal (6) and diamine 1a was
carried out to obtain the quinoxaline compound 3a in 96% yield.
NH2
NH2
Ph
N
Ph
Ph
CuBr (10 mol %)
+
+
chlorobenzene
O2, rt, 3h
O
NH2
N
3a
1a
2a
5
Ph
Ph
CuBr (10 mol %)
chlorobenzene
O2, rt, 3h
O
NH2
2a
5
NH2
Ph
N
Ph
Ph
CuBr (10 mol %)
+
+
chlorobenzene
O2, rt, 6h
O
NH2
N
1a
5
3a
NH2
NH2
O
O
Ph
N
CuBr (10 mol %)
chlorobenzene
O2, rt, 1h
N
1a
6
3a
Scheme 3. Control Experiments

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On the basis of the above experiments and relevant reports in the literature,29a
plausible mechanism is proposed for the formation of quinoxalines (Scheme 4). The first
step may involve the aerobic oxidation of 2-phenylethylamine (2a) leading to 2-
phenylethylimine (7) by the use of CuBr/O2 catalytic system. The Imine 7 may hydrolyze
to generate the phenylacetaldehyde (5), which on further condensation with o-
phenylenediamine (1a) form cross-imine 8. Concomitantly, the 2-phenylethylimine (7)
may undergo direct transimination with 1a to produce cross-imine 8. In the presence of
copper catalyst and oxygen, the imine 8 may generate the keto-imine 11 via benzyl
radical intermediate 9 and hydroperoxide 10. Jiao et al., recently reported the formation
of 11 from imine 8 using Et3N/O2 catalytic system.29a Moreover, copper-catalyzed
benzylic oxidation of C(sp3)-H bonds to keto-group under aerobic conditions is well
documented.30 Finally, intramolecular condensation of 11 may takes place to produce the
quinoxaline 3a.

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Ph
O
1a
5
NH2
NH2
H2O
NH2
NH2
H
CuBr
Ph
Ph
Ph
Ph
H
H
1a
-NH3
NH2
NH
N
N
1/2O2
H2O
8
9
transimination
2a
7
HO2
O2
O2
N
N
Ph
CuI
CuII
3a
-H2O
OH
O
NH2
NH2
NH2
NH2
O
Ph
Ph HO2
Ph
Ph
H
H
H
-H2O
N
N
N
N
11
10
9
Scheme 4. A Plausible mechanism for the formation of quinoxaline
Conclusions
In summary, we have demonstrated an efficient copper-catalyzed oxidative
coupling reaction of o-phenylenediamines with 2-aryl/heteroarylethylamines at room
temperature under molecular oxygen atmosphere, which provides facile access to
functionalized quinoxalines in excellent yields. This method is practical and
straightforward as it can be easily scaled up by using readily available starting materials.
Further studies are currently under investigation to explore the reaction mechanism and
the scope of its synthetic applications.

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Experimental
General Information
All commercially obtained materials were used directly without further purification
unless otherwise noted. Chlorobenzene was dried over P2O5 and distilled before use.
Reactions were carried out in oven-dried round-bottom flask. Melting points were
determined on a Büchi melting point apparatus and were uncorrected. NMR spectra were
recorded on a 400 MHz spectrometer (1H at 400 MHz, 13C at 100 MHz). Chemical shifts
are reported in ppm, relative to the internal standard of tetramethylsilane (TMS). Proton
coupling patterns are described as singlet (s), doublet (d), doublet of doublet (dd), triplet
(t), multiplet (m). High-resolution mass spectra (HRMS) were obtained using an
electrospray quadrupole time-of-flight (ESI-Q-TOF) mass spectrometer.
Typical experimental procedure for the copper-catalyzed synthesis of quinoxalines
(3 and 4)
o-Phenylenediamine 1 (1.0 mmol), 2-aryl/heteroarylethylamine 2 (1.2 mmol), CuBr (10
mol %), and dry chlorobenzene (2.0 mL) were charged into an oven-dried round-bottom
flask. The flask was equipped with oxygen balloon and stirred at room temperature, until
complete consumption of o-phenylenediamine as monitored by TLC. After the
completion of reaction, it was diluted with CH2Cl2 and adsorbed on silica gel. The
products were purified by silica gel (100-200 mesh) column chromatography by using
hexane/EtOAc as mobile phase.

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Products Characterization
o
o
1
2-Phenylquinoxaline (3a)31: White solid; yield: 92%; mp: 68-69 C (Lit. mp: 70 C); H
NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.21-8.12 (m, 4H), 7.81-7.73 (m, 2H), 7.59-7.51
(m, 3H); 13C NMR (100 MHz, CDCl3): δ 151.8, 143.3, 142.2, 141.5, 136.7, 130.2, 130.1,
129.6, 129.5, 129.1, 129.0, 127.5; HRMS: m/z [M+ H]+ calcd for C14H10N2: 207.0917;
found: 207.0918.
2-(2-Chlorophenyl)quinoxaline (3b)32: Light yellow solid; yield: 93%; mp: 135-
136 oC; 1H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 8.19-8.17 (m, 2H), 7.84-7.81 (m, 2H),
7.75-7.73 (m, 1H), 7.58-7.55 (m, 1H), 7.48-7.46 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
152.4, 146.1, 142.2, 141.3, 136.5, 132.6, 131.9, 130.8, 130.3, 130.2, 130.1, 129.6, 129.2,
127.5; HRMS: m/z [M + H]+ calcd for C14H9ClN2: 241.0527; found: 241.0522.
2-(4-Bromophenyl)quinoxaline (3c)31: Pale yellow solid; yield: 97%; mp: 135-
136 oC (Lit. mp: 134-137 oC); 1H NMR (400 MHz, CDCl3): δ 9.29 (s, 1H), 8.15-8.10 (m,
2H), 8.08 (d, J = 8.4 Hz, 2H), 7.81-7.74 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3): δ 150.6, 142.7, 142.1, 141.6, 135.5, 132.3, 130.5, 129.8, 129.5, 129.1,
128.9, 124.9; HRMS: m/z [M + H]+ calcd for C14H9BrN2: 285.0022; found: 285.0025.
2-(4-(Trifluoromethyl)phenyl)quinoxaline (3d)33: Light brown solid; yield: 95%;
mp: 140-141oC (Lit. mp: 142 oC); 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.33 (d, J =
7.6 Hz, 2H), 8.19-8.14 (m, 2H), 7.84-7.78 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 150.2,
142.9, 142.2, 141.9, 140.0, 130.6, 130.2, 129.7, 129.2, 127.8, 126.1, 126.0; HRMS: m/z
[M + H]+ calcd for C15H9F3N2: 275.0791; found: 275.0799.
2-(4-Nitrophenyl)quinoxaline (3e)34: Light brown crystals; yield: 83%; mp: 190-
191.6 oC (Lit. mp: 190-192 oC); 1H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H), 8.43-8.38 (m,

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4H), 8.20-8.16 (m, 2H), 7.86-7.83 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 149.2, 148.7,
142.6, 142.4, 142.2, 142.0, 130.9, 130.7, 129.8, 129.2, 128.3, 124.2; HRMS: m/z [M + H]+
calcd for C14H9N3O2: 252.0768; found: 252.0784.
2-(4-Methoxyphenyl)quinoxaline (3f)31: Pale yellow solid; yield: 88%; mp: 97-99
o
1
oC (Lit. mp: 97-98 C); H NMR (400 MHz, CDCl3): δ 9.29 (s, 1H), 8.18 (d, J = 9.2 Hz,
2H), 8.11 (t, J = 9.2 Hz, 2H), 7.78-7.69 (m, 2H), 7.08 (d, J = 9.2 Hz, 2H), 3.91 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 161.4, 151.4, 143.0, 142.2, 141.1, 130.1, 129.3, 129.2, 129.0,
128.9, 114.5, 55.4; HRMS: m/z [M + H]+ calcd for C15H12N2O: 237.1022; found:
237.1029.
2-(3-Methoxyphenyl)quinoxaline (3g)35: Pale yellow solid; yield: 89%; mp: 88-90
o
1
oC (Lit. mp: 87-88 C); H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.18-8.12 (m, 2H),
13
7.82-7.74 (m, 4H), 7.51-7.47 (m, 1H), 7.08 (dd, J = 7.6, 1.2 Hz, 1H), 3.95 (s, 3H); C
NMR (100 MHz, CDCl3): δ 160.2, 151.6, 143.4, 142.2, 141.6, 138.1, 130.2, 130.1, 129.6,
129.5, 129.1, 119.8, 116.2, 112.6, 55.4 ; HRMS: m/z [M + H]+ calcd for C15H12N2O:
237.1022; found: 237.1019.
2-(2-Methoxyphenyl)quinoxaline (3h)36: Yellow solid; yield: 85%; mp: 110-112
oC (Lit. mp: 109-110 oC); 1H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.18-8.11 (m, 2H),
7.91-7.88 (m, 1H), 7.79-7.74 (m, 2H), 7.51-7.47 (m, 1H), 7.18-7.14 (m, 1H), 7.07 (d, J =
13
8.4 Hz, 1H), 3.91 (s, 3H); C NMR (100 MHz, CDCl3): δ 157.3, 152.2, 147.2, 142.6,
140.9, 131.6, 131.4, 129.8, 129.5, 129.4, 128.9, 126.4, 121.5, 111.3, 55.6; HRMS: m/z [M
+ H]+ calcd for C15H12N2O: 237.1022; found: 237.1029.
2-(3,4-Dimethoxyphenyl)quinoxaline (3i)34: Brown solid; yield: 86%; mp: 116-
118 oC (Lit. mp: 113-115 oC); 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.17-8.10 (m,

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2H), 7.88-7.87 (m, 1H), 7.80-7.73 (m, 3H), 7.04 (d, J = 8.0 Hz, 1H), 4.06 (s, 3H), 3.99 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 151.3, 151.1, 149.7, 143.0, 142.2, 141.2, 130.2,
129.5, 129.3, 129.1, 129.0, 120.4, 111.1, 110.1, 56.0; HRMS: m/z [M + H]+ calcd for
C16H14N2O2: 267.1128; found: 267.1132.
2-(4-Hydroxyphenyl)quinoxaline (3j)31: Orange solid; yield: 81%; mp: 206-207
o
1
oC (Lit. mp: 208-209 C); H NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H, OH), 9.16 (s,
1H), 7.89 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4Hz, 2H), 7.55-7.45 (m, 2H), 6.66 (d, J = 8.4
13
Hz, 2H); C NMR (100 MHz, DMSO-d6): δ 159.9, 151.1, 143.4, 141.6, 140.6, 130.5,
129.2, 128.9, 128.8, 126.9, 116.1; HRMS: m/z [M + H]+ calcd for C14H10N2O: 223.0866;
found: 223.0868.
2-(Naphthalen-1-yl)quinoxaline (3k)31: Light brown solid; yield: 85%; mp: 135-
136 oC (Lit. mp: 136 oC); 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.25-8.20 (m, 2H),
8.17 (d, J = 7.6 Hz, 1H), 8.03-7.97 (m, 2H), 7.86-7.83 (m, 2H), 7.78 (d, J = 6.8 Hz, 1H),
7.65 (t, J = 7.6 Hz, 1H), 7.59-7.54 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 154.2, 146.6,
142.2, 141.3, 135.1, 133.9, 131.1, 130.4, 130.1, 129.9, 129.6, 129.2, 128.6, 128.5, 127.2,
126.3, 125.4, 125.0; HRMS: m/z [M + H]+ calcd for C18H12N2: 257.1073; found:
257.1083.
2-(Pyridin-2-yl)quinoxaline (3l)33: Pale yellow solid; yield: 83%; mp: 117-118 oC
1
(Lit. mp: 116 oC); H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 8.80 (s, 1H), 8.61 (d, J =
8.0 Hz, 1H), 8.19-8.16 (m, 2H), 7.93-7.89 (m, 1H), 7.82-7.76 (m, 2H), 7.44-7.41 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 154.4, 150.0, 149.3, 144.1, 142.6, 141.8, 137.3, 130.2,
130.1, 129.7, 129.3, 124.7, 122.1; HRMS: m/z [M + H]+ calcd for C13H9N3: 208.0876;
found: 208.0869.

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2-(1H-Indol-3-yl)quinoxaline (3m)31: Pale yellow solid; yield: 85%; mp: 206-207
oC (Lit. mp: 206-208 oC); 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 8.94 (br s, 1H, NH),
8.79 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 2.8
Hz, 1H), 7.77-7.73 (m, 1H), 7.68-7.64 (m, 1H), 7.45-7.43 (m, 1H), 7.38-7.30 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 150.3, 143.8, 142.6, 140.2, 136.8, 129.9, 129.0, 128.9, 128.2,
125.7, 125.6, 123.5, 122.3, 121.8, 115.0, 111.5; HRMS: m/z [M + H]+ calcd for C16H11N3:
246.1011; found: 246.1030.
2-(Thiophen-2-yl)quinoxaline (3n)31: Pale yellow solid; yield: 78%; mp: 118-119
oC (Lit. mp: 116-117 oC); 1H NMR (400 MHz, CDCl3): δ 9.18 (s, 1H), 8.04-8.01 (m, 2H),
7.81 (d, J = 3.6 Hz, 1H), 7.72-7.63 (m, 2H), 7.50 (d, J = 6.0 Hz, 1H), 7.16-7.14 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 147.4, 142.1, 141.9, 141.0, 130.5, 129.9, 129.3, 129.1,
128.9, 128.5, 127.1; HRMS: m/z [M + H]+ calcd for C12H8N2S: 213.0481; found:
213.0485.
6,7-Dimethoxy-2-phenylquinoxaline (4b)37: White solid; yield: 90%; mp: 130-
o
1
132 C; H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.70-7.69
(m, 1H), 7.59-7.46 (m, 1H), 7.43-7.39 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.24 (m, 2H), 4.10
13
(s, 3H), 4.09 (s, 3H); C NMR (100 MHz, CDCl3): δ 152.9, 152.6, 149.8, 140.7, 138.9,
131.4, 128.8, 128.7, 128.5, 127.1, 126.8, 126.6, 106.9, 106.5, 56.2; HRMS: m/z [M + H]+
calcd for C16H14N2O2: 267.1128; found: 267.1132.
6,7-Dimethyl-2-phenylquinoxaline (4c)31: Pale yellow solid; yield: 87%; mp: 130-
132 oC (Lit. mp: 130-131 oC); 1H NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 8.15 (d, J = 8.4
Hz, 2H), 7.85 (s, 1H), 7.83 (s, 1H), 7.56-7.46 (m, 3H), 2.49 (s, 6H); 13C NMR (100 MHz,

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CDCl3): δ 150.9, 142.3, 141.1, 140.7, 140.5, 140.0, 137.0, 129.8, 128.9, 128.6, 128.0,
127.3, 20.3, 20.2; HRMS: m/z [M + H]+ calcd for C16H14N2: 235.1230; found: 235.1238.
o
2-Phenylbenzo[g]quinoxaline (4d)38: Orange solid; yield: 86%; mp: 145-149 C
o
1
(Lit. mp: 162 C); H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H), 8.75-8.69 (m, 2H), 8.29-
8.27 (m, 2H), 8.14-8.12 (m, 1H), 8.01-7.99 (m, 1H), 7.63-7.54 (m, 4H) 7.47-7.45 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 151.7, 144.5, 138.7, 138.1, 136.7, 134.1, 133.6, 130.4,
129.2, 128.7, 128.5, 128.4, 127.9, 127.6, 127.5, 126.9, 126.7; HRMS: m/z [M + H]+ calcd
for C18H12N2: 257.1073; found: 257.1072.
6,7-Dichloro-2-phenylquinoxaline (4e)31: Pale yellow solid; yield: 81%; mp: 156-
o
o
1
158 C (Lit. mp: 155-157 C); H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.28 (s, 1H),
8.24 (s, 1H), 8.20-8.18 (m, 2H), 7.61-7.56 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 152.6,
144.2, 141.1, 140.2, 135.9, 134.9, 133.9, 130.7, 130.1, 129.7, 129.2, 127.5; HRMS: m/z
[M + H]+ calcd for C14H8Cl2N2: 275.0137; found: 275.0138.
6-Chloro-2-phenylquinoxaline (4f)39: Less polar regioisomer; Yellow solid;
o
1
yield: 39%; mp: 143-145 C ; H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.19 (d, J =
13
7.6 Hz, 2H), 8.12-8.09 (m, 2H), 7.73 (dd, J = 9.2, 2.4 Hz, 1H), 7.60-7.53 (m, 3H); C
NMR (100 MHz, CDCl3): δ 151.9, 144.1, 141.7, 140.8, 136.3, 135.2, 131.3, 130.8, 130.4,
129.2, 128.0, 127.5; HRMS: m/z [M + H]+ calcd for C14H9ClN2: 241.0523; found:
241.0523.
7-Chloro-2-phenylquinoxaline (4fʹ)39: More polar regioisomer; Pale yellow
o
1
solid; yield: 44%; mp: 118-119 C ; H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.21-
8.17 (m, 3H), 8.08 (d, J = 9.2 Hz, 1H), 7.72-7.68 (m, 1H), 7.61-7.55 (m, 3H); 13C NMR

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(100 MHz, CDCl3): δ 152.4, 143.3, 142.6, 140.0, 136.2, 136.0, 130.5, 130.4, 130.3, 129.2,
128.4, 127.5; HRMS: m/z [M + H]+ calcd for C14H9ClN2: 241.0507; found: 241.0507.
6-Nitro-2-phenylquinoxaline (4g)39: Less polar regioisomer; Pale yellow solid;
o
1
yield: 35%; mp: 207-210 C; H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 9.03 (m, 1H),
8.56 (dd, J = 9.2, 2.0 Hz, 1H), 8.30-8.26 (m, 3H), 7.65-7.61 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 153.9, 147.1, 145.5, 144.9, 140.3, 135.6, 131.4, 131.2, 129.4, 127.9, 125.6,
123.8; HRMS: m/z [M + H]+ calcd for C14H9N3O2: 252.0768; found: 252.0782.
7-Nitro-2-phenylquinoxaline (4g')39: More polar regioisomer; Pale yellow solid;
o
yield: 37%; mp: 175-177.2 C; 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 9.07-9.06 (m,
1H), 8.51 (dd, J = 8.8, 2.8 Hz, 1H), 8.29-8.24 (m, 3H), 7.63-7.56 (m, 3H); 13C NMR (100
MHz, CDCl3): δ 153.7, 148.2, 146.1, 143.8, 141.3, 135.5, 131.2, 130.8, 129.4, 127.7,
125.9, 122.8; HRMS: m/z [M + H]+ calcd for C14H9N3O2: 252.0768; found: 252.0757.
Phenyl(2-phenyl-6-quinoxalinyl)methanone (4h)40: Less polar regioisomer; Pale
o
o
1
yellow solid; yield: 37%; mp: 142-143 C (Lit. mp: 144-145 C); H NMR (400 MHz,
CDCl3): δ 9.42 (s, 1H), 8.50 (s, 1H), 8.27-8.25 (m, 4H), 7.91 (d, J = 7.6 Hz, 2H), 7.68-7.53
(m, 6H); 13C NMR (100 MHz, CDCl3): δ 195.6, 153.3, 144.4, 144.1, 140.6, 137.8, 137.0,
136.2, 132.9, 132.3, 130.8, 130.2, 130.1, 130.0, 129.3, 128.5, 127.7; HRMS: m/z [M + H]+
calcd for C21H14N2O: 311.1179; found: 311.1177.
Phenyl(3-phenyl-6-quinoxalinyl)methanone (4h')41: More polar regioisomer;
Pale yellow solid; yield: 42%; mp: 134-136 oC (Lit. mp: 132-133 oC); 1H NMR (400 MHz,
CDCl3): δ 9.35 (s, 1H), 8.43 (s, 1H), 8.20-8.12 (m, 4H), 7.83 (d, J = 7.6 Hz, 2H), 7.60-7.43
(m, 6H); 13C NMR (100 MHz, CDCl3): δ 195.6, 153.3, 144.4, 144.1, 140.6, 137.8, 137.0,

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136.2, 132.9, 132.3, 130.8, 130.2, 130.1, 130.0, 129.3, 128.5, 127.7; HRMS: m/z [M + H]+
calcd for C21H14N2O: 311.1179; found: 311.1186.
6-Methyl-2-phenylquinoxaline (4i)39: More polar regioisomer; Reddish brown
solid; yield: 45%; mp: 138-140 oC; 1H NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 8.17 (d,
J = 7.6 Hz, 2H), 8.05-7.99 (m, 1H), 7.93-7.89 (m, 1H), 7.62-7.51 (m, 4H), 2.61 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 151.10, 143.2, 141.6, 140.8, 140.1, 136.9, 132.6, 131.8,
130.0, 129.9, 129.1, 127.9, 127.5, 127.4, 21.8; HRMS: m/z [M + H]+ calcd for C15H12N2:
221.1073; found: 221.1075.
7-Methyl-2-phenylquinoxaline (4i')39: Less polar regioisomer; Brown solid;
o
1
yield: 39%; mp: 92-95 C; H NMR (400 MHz, CDCl3): δ 9.24 (s, 1H), 8.18-8.16 (m,
2H), 8.04-7.98 (m, 1H), 7.92-7.87 (m, 1H), 7.61-7.49 (m, 4H), 2.59 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 150.9, 143.1, 142.3, 141.5, 140.7, 140.0, 136.8, 132.5, 131.8, 129.9,
129.0, 128.5, 127.9, 127.3, 21.8; HRMS: m/z [M + H]+ calcd for C15H12N2: 221.1073;
found: 221.1072.
6-Methoxy-2-phenylquinoxaline (4j)39: More polar regioisomer; Yellow solid;
o
1
yield: 53%; mp: 115-117 C; H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 8.15 (d, J =
7.2 Hz, 2H), 8.04 (d, J = 9.2 Hz, 1H), 7.58-7.49 (m, 3H), 7.46-7.41 (m, 2H), 3.99 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 160.7, 149.7, 142.6, 138.6, 136.8, 130.6, 129.8, 129.1,
127.2, 123.8, 106.2, 55.8; HRMS: m/z [M + H]+ calcd for C15H12N2O: 237.1022; found:
237.0993.
7-Methoxy-2-phenylquinoxaline (4j')39: Less polar regioisomer; Yellow solid;
yield: 34%; mp: 82-84 oC; 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.17 (dd, J = 8.4,
1.2 Hz, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.59-7.52 (m, 3H), 7.47-7.46 (m, 1H), 7.41 (dd, J =

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9.2, 2.4 Hz, 1H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.1, 151.9, 143.8, 140.5,
137.6, 136.8, 130.1, 129.9, 129.1, 127.5, 123.0, 106.7, 55.8; HRMS: m/z [M + H]+ calcd
for C15H12N2O: 237.1022; found: 237.1028.
2-Phenylpyrido[2,3-b]pyrazine (4k)42: Less polar regioisomer; Brown solid;
o
1
yield: 32%; mp: 125-128 C; H NMR (400 MHz, CDCl3): δ 9.48 (s, 1H), 9.21 (s, 1H),
8.51 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 7.6 Hz, 2H), 7.75-7.72 (m, 1H), 7.62-7.55 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 154.7, 154.4, 150.7, 144.5, 138.4, 136.8, 135.6, 131.1,
129.2, 128.1, 124.8; HRMS: m/z [M + H]+ calcd for C13H9N3: 208.0869; found: 28.0874.
3-Phenylpyrido[2,3-b]pyrazine (4k')42: More polar regioisomer; Brown solid;
o
1
yield: 33%; mp: 90-92.3 C; H NMR (400 MHz, CDCl3): δ 9.47 (s, 1H), 9.07 (s, 1H),
8.44 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.69-7.66 (m, 1H), 7.53-7.46 (m, 2H),
7.18-7.13 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 153.4, 153.0, 150.2, 146.4, 138.8,
137.6, 135.8, 130.8, 129.3, 127.7, 125.7; HRMS: m/z [M + H]+ calcd for C13H9N3:
208.0869; found: 208.0868.
1
2-Phenylacetaldehyde (5)43: Colourless liquid; yield: 26%; H NMR (400 MHz,
CDCl3): δ 9.75-9.7 (m, 1H), 7.41-7.21 (m, 5 H), 3.69 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 199.4, 131.7, 130.1, 129.5, 128.9, 127.9, 127.3, 50.4; HRMS: m/z [M + H]+
calcd for C8H8O: 121.0648; found: 121.0646.
Acknowledgments
The authors sincerely thank the University of Delhi for R&D grant support to carry out
this work. A.S, S.N.C and H.Y thanks the UGC/CSIR for research fellowships. We are
grateful to Prof. Pavan Mathur for his valuable suggestions on the reaction mechanism.

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