Nucleophilic substitution on 2-monosubstituted quinoxalines giving 2,3-disubstituted quinoxalines: Investigating the effect of the 2-Substituent

Article abstract of DOI:10.3390/molecules21101304

An investigation on the effect of substituent at the 2-position of mono-substituted quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution reactions, is reported. Di-substituted quinoxalines bearing aryl-Alky

Full text of DOI:10.3390/molecules21101304

molecules
Communication
Nucleophilic Substitution on 2-Monosubstituted
Quinoxalines Giving 2,3-Disubstituted Quinoxalines:
Investigating the Effect of the 2-Substituent
Ndumiso Thamsanqa Ndlovu and Winston Nxumalo *
Department of Chemistry, Faculty of Science and Agriculture, University of Limpopo, Private Bag X 1106,
Sovenga 0727, South Africa; nthami001@gmail.com
* Correspondence: winston.nxumalo@ul.ac.za; Tel.: +27-015-268-2331
Academic Editor: Philippe Belmont
Received: 30 August 2016; Accepted: 23 September 2016; Published: 30 September 2016
Abstract: An investigation on the effect of substituent at the 2-position of mono-substituted
quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution
reactions, is reported. Di-substituted quinoxalines bearing aryl-alky, aryl-aryl, aryl-heteroaryl,
aryl-alkynyl, and amino-alkyl substituents were prepared in moderate to good yields.
2-Monosubstituted quinoxalines bearing a phenyl and butyl substituent reacted readily with alkyl-,
aryl-, heteroaryl- and alkynyl- nucluephiles, giving di-substituted quinoxalines. 2-Monosubstituted
quinoxalines bearing an amine and alkynyl substituent only reacted with alkyl nucleophiles.
Oxidative rearomatization to give 2,3-disubstituted quinoxaline products occurred in atmospheric O2.
Keywords: 2,3-disubsituted quinoxaline; nucleophilic substitution; oxidative rearomatization
1. Introduction
Quinoxaline derivatives possess extensive applications in medicinal chemistry, due to their
broad spectrum of biological activity [
1,
2]. A large number of synthetic quinoxalines have been
reported to exhibit anti-tubercular [ ], anti-viral [
3
4,
5
], anti-microbial [ ], and neuroprotective [
6
,
7
8,9]
activity. Quinoxaline derivatives have been reported to be prepared, but not limited, by intramolecular
cyclisation of N-substituted aromatic ortho-diamines [10], ring transformation of benzofurazans [11],
and condensation of benzofuran-1-oxide to form quinoxaline-N-oxides [12]. The most common method
for the preparation of quinoxaline derivatives relies on the condensation of an aryl 1,2-diamine with a
1,2-dicarbonyl compound, of which this type of reaction has limitations due to the use of pre-defined
starting materials [13–16], which limit the number of substituents that can be added.
A more convenient approach for the synthesis of quinoxaline derivatives is the substitution
of hydrogen at the 2- or 3-position of quinoxaline by C-nucleophiles. Substitution of hydrogen by
C-nucleophiles on electron deficient arenes has been reported extensively [17
quinoxaline derivatives with aryl and alkyl nucleophiles has been investigated [20
have been shown to add to 6-aminoquinoxaline [ 20] affording alkyl- and aryl-substituted
–
19]. The reaction of
–26]. C-nucleophiles
9,
quinoxalines in low to high yields. Although efficient, these reactions require the use of an oxidising
agent to afford aromatic substitution products. Azev et al. [21], reported formation of resorcinol
derivative, 2-(2,4-dihydroxyphenyl)quinoxaline after reacting quinoxaline and resorcinol in refluxing
ethanol (EtOH) in the presence of an acid. The reaction of quinoxaline with this nucleophile continues to
oxidative rearomatization of the compound without the need of having an oxidizing agent, but requires
the use of concentrated HCl and high temperature. The use of nucleophilic substitution has been
extended to other functional groups like aromatic amines and heteroaryls, but examples of quinoxaline
derivatives containing these groups are limited. The reaction of 2-chloro-3-methylquinoxaline with
Molecules 2016, 21, 1304; doi:10.3390/molecules21101304
www.mdpi.com/journal/molecules

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aromatic amines as nucleophilic reagents in the presence of anhydrous potassium carbonate and
potassium iodide, forming the corresponding 2-arylamino-3-methylquinoxalines, has been described
by Badr et al. [22]. This method only describes 2-arylaminoquinoxaline derivatives containing a
methyl-substituent at the 3-position. A more recent strategy by Zhou entails direct heteroarylation
of N-heteroarenes by heteroaryl Grignard reagents. Although this method gives high yields and
is efficient, it focuses solely on heterobiaryl preparation for double functionalization [23,25,26].
Phenylacetylide nucleophile was also reported to add to quinoxaline via nucleophilic substitution,
affording mono-substituted and di-substituted quinoxaline [24]. The influence of substituents at the
2-position on nucleophilic substitution by C-nucleophiles has not been fully investigated. Herein,
we wish to report nucleophilic substitution reactions on mono-substituted quinoxalines, bearing an
aryl, alkyl, alkynyl, and amino substituents at the 2-position.
By starting with quinoxaline bearing a benzenesulfonyloxy leaving group, which we previously
reported to be an efficient leaving group in coupling of pteridines [27,28], we envisaged that we
can prepare mono-substituted quinoxaline derivatives, employing the Negishi [29], Sonogashira [30],
and Buchwald coupling conditions [31].
2. Results
Our investigation began with the preparation of 2-benzensulfonyloxyquinoxaline
prepared from our previously reported method [27]. 2-Phenylquinoxaline was prepared via
Negishi coupling of and 1.14 M solution of phenyl-ZnCl, in 75% yield (Scheme 1). Treating 2 with
1 which was
2
1
0.5 equivalents of n-BuLi gave 3-butyl-2-phenylquinoxaline 2a in 12% yield. The oxidative elimination
of H2 occurs in atmospheric oxygen, to exclusively provide the aromatic product. Increasing the amount
n-BuLi to 1.5 equivalents gave 2a in 66% yield, which is a significant improvement. This method was
extended to other; aryl-, heteroaryl-, alkynyl-, and alkyl-nucleophiles on compound 2, of which the
compounds 2a–2g were synthesised (Table 1).
Ph-ZnCl
Pd(PPh3)2Cl2
Et3N
N
N
SO2Ph
N
N
THF, RT, 18hrs
76%
1
2
Scheme 1. Negishi Coupling.
Table 1. Nucleophilic substitution on 2-phenylquinoxaline.
R
Metal
N
N
THF, RT, 18 hrs
N
N
R
2a-g
2
Entry
Product
R-Metal
R
% Yield
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
n-BuLi
Isopropyl-MgCl
Phenyl-MgBr
-Butyl
-Isopropyl
-Phenyl
66
54
22
47
14
22
46
2-Phenylethynyl-Li -2-Phenylethynyl
Oct-1-ynyl-Li
Thiopen-2-yl-Li
Furan-2-yl-Li
-Oct-1-ynyl
-Thiophen-2-yl
-furan-2-yl
2g
A solution of Li- or Mg-aryl/alkyl was treated with 2-phenylquinoxaline
2 (100 mg, 0.485 mmol), and the
solution allowed to stir at room temperature for 18 h. The final solution was diluted with EtOAc (10 mL),
quenched with sat. NaHCO3 (10 mL). The organic layers were combined and dried over Na2SO4, filtered,
concentrated, and purified by flash column chromatography on silica gel.

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Alkyl nucleophiles afforded 2,3-disubstituted quinoxalines in higher yields compared to the aryl
and alkynyl nucleophiles (entries 1, 2 vs. entries 3–7). The high electron density found on the aryl and
alkynyl nucleophiles could be responsible for the low to moderate yields observed.
We also envisaged that the phenyl group attached at the 2-position could be affecting the yields,
presumably due to steric hindrance. We then synthesised 2-butylquinoxaline
3, which contain a less
bulky substituent, by Negishi coupling of 1a and butyl-ZnCl. Reacting compound
3
with 1.5 eq of
n-BuLi, gave 2,3-dibutylquinoxaline 3a in 76% yield. When the number of equivalents of n-BuLi
was increased to 3.0 eq, the target compound 3a was isolated in 97% yield. We were also able to
synthesize 2-butyl-3-(furan-2-yl)quinoxaline 3b in 91% yield, 3-butyl-2-phenylquinoxaline 2a in 95%
yield and 3-butyl-2-(2-phenylethynyl)quinoxaline 3c in 65% yield. The use of 2-butylquinoxaline
3 for
the synthesis of 3a and 2a (Table 2) further supports the assumption that the low yields are due to
–c
the phenyl-group. The use of a less bulky substituent, in this case, makes nucleophilic substitution
occur readily, affording products in good yields.
Table 2. Nucleophilic substitution on 2-butylquinoxaline.
N
N
R1 Li
THF, RT, 18 hrs
N
N
R1
3
Entry
Product
R1
% Yield
1
2
3
4
3a
3b
2a
3c
-Butyl
-Furan-2-yl
-Phenyl
97
91
95
65
-Phenylacetylene
The successful synthesis of compounds 2a–2g, and 3a–c, encouraged us to further investigate
the possibilities of nucleophilic addition on compounds with a different functional group on the
2-position of the quinoxaline moiety. We wanted to investigate the possibilities for nucleophilic
substitution if the quinoxaline moiety at the 2-position had a Csp2-Csp bond. We thus employed
Sonogashira cross-coupling conditions to synthesise 2-(2-phenylethynyl)quinoxaline 4. Treating 4 with
3.0 equivalents of n-BuLi gave 3-butyl-2-(2-phenylethynyl)quinoxaline 3c in 20% yield. Increasing the
reaction time from 18 h to 36 h improved the percentage yield to 56% (Scheme 2).
N
N
n-BuLi
N
THF, RT, 36 hrs
56%
N
4
3c
Scheme 2. Nucleophilic substitution on 2-(2-phenylethynyl)quinoxaline.
Attempts to extend the scope to other C-nucleophiles employed on quinoxaline 2, were
unsuccessful as only the starting material was recovered. We postulate that nucleophilic substitution on
2-(2-phenylethynyl)quinoxaline was difficult due to the electron donating nature of the phenylalkynyl
4
attached at the 2-position of the quinoxaline moiety. This is possibly due to the high electron density
caused by highly delocalized pi-electrons from the phenyl ring and the acetynyl moiety, which could
make the –N=C–H site less electrophilic. This suggests that only very strong nucleophiles, such as
n-BuLi, can work efficiently. We then proceeded to investigate the possibility of nucleophilic attack
if the bonding atom on the 2-position of the quinoxaline was C–N. We used Buchwald-Hartwig
cross-coupling reaction to synthesize quinoxaline derivatives containing an arylamine.
The coupling reaction between 2-benzenesulfonyloxyquinoxaline
conditions, formed N-phenylquinoxalin-2-amine . When we extended nucleophilic substitution on the
compounds synthesized by Buchwald-Hartwig coupling, we found that the results were similar to
1 and aniline, under Buchwald-Hartwig
5

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those on the Sonogashira coupled product
4. When N-phenylquinoxalin-2-amine
5
was reacted with
n-BuLi (3.0 eq) and left to stir for 18 h, the target compound 3-butyl-N-phenylquinoxalin-2-amine 5a
was isolated in 15% yield and there was also recovery of the starting material . When the reaction
time was increased to 36 h, compound 5a was isolated in 32% yield (Table 3), and there was
still recovery of the starting material. Reacting with a less bulky nucleophile, Me-MgCl, gave
5
5
3-methyl-N-phenylquinoxalin-2-amine 5b in 42% yield. The low yields could be due to the competition
between deprotonation of the free N–H and nucleophilic substitution at the –N=C–H site. The N–H
group on compound 5, was methylated to give N-methyl-N-phenylquinoxalin-2-amine 6.
Table 3. Nucleophilic substitution on N-benzylquinoxalin-2-amine.
R1
N
R1
N
N
N
n-BuLi/Me-MgCl
THF, r.t, 36 hrs
N
N
R2
5: R1 = H
6: R1 = CH3
5a-b
6a
Entry
Product
R1
R2
% Yield
1
2
3
5a
5b
6a
-H
-H
-CH3
-Butyl
-Methyl
-Butyl
32
42
62
Reacting quinoxaline
92% yield and no starting material was recovered. With the protecting group (methyl-) on the nitrogen,
the n-BuLi was able to fully react with the starting material with no other competing reactions
(Table 3). Attempts to use other nucleophiles on the mono-substituted Buchwald-Hartwig coupled
products were not successful. Similarly to the Sonogashira coupled product , only strong alkyl
6 with n-BuLi gave 3-butyl-N-methyl-N-phenylquinoxalin-2-amine 6a in
6
4
nucleophiles can readily react at the 3-position of the quinoxaline moiety. This could be due to steric
hindrance accompanied by electron density on nitrogen atom, making the –N=C–H site less reactive
towards nucleophiles.
In conclusion, nucleophilic substitution on 2-phenylquinoxaline
2 and 2-butylquinoxaline 3,
proceeded smoothly to give 2,3-disubstituted quinoxalines. Di-substituted quinoxalines bearing
aryl-alky, aryl-aryl, aryl-heteroaryl, and aryl-alkynyl substituents were prepared in moderate to good
yields. Nucleophilic substitutions on 2-acetylene and 2-amine quinoxaline, were only possible with
strong alkyl nucleophiles (n-BuLi and Me-MgCl). This could be due to steric and electronic properties
associated with these substituents. Molecular modelling studies are being conducted to understand
the influence of the substituent attached at the 2-position, and the nature of the nucleophile.
3. Experimental Section
3.1. General Information
Reagents were purchased from Sigma-Aldrich (Johannesburg, South Africa) and were used
without further purification. Melting points were obtained using Lasec/SA-melting point apparatus
1
from Lasec Company, SA (Johannesburg, South Africa). H- and 13C-NMR spectra were recorded at
400 MHz and 100 MHz, respectively, on Bruker Avance-400 spectrometer (Johannesburg, South Africa).
Spectra were recorded in deuterated chloroform (CDCl3) unless otherwise specified. Chemical shifts
are reported in parts per million (ppm) relative to tetramethylsilane as an internal standard at zero
ppm. The 1H-NMR chemical shifts are reported: value (number of hydrogens, description of signal,
assignment) and the 13C-NMR chemical shifts are reported: value (assignment). Abbreviations used:
s = singlet, d = doublet, dd = doublet of doublets, t = triplet, and m = multiplet.

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3.2. Synthetic Procedure
3.2.1. 2-Benzensulfonyloxyquinoxaline (1)
In a round bottom flask, quinoxalinone (5 g, 34 mmol), DMAP (0.416 g, 3.4 mmol) and
benzenesulfonyl chloride (8.72 mL, 68 mmol) were dissolved in DCM (100 mL), cooled to 0 ◦C and
stirred for 5 min. Et3N (12 mL, 88 mmol) was added drop-wise over 5 min, the solution allowed to stir
at room temperature for 1 h, and the reaction quenched with aqueous NaHCO3 (80 mL). The two layers
were separated and the aqueous layer washed twice with DCM (2
×
60 mL). The combined organic
layers were dried over MgSO4, filtered, concentrated, and dissolved in EtOAc (15 mL). The filtrate was
concentrated to give 2-benzenesulfonyloxyquinoxaline as a brown solid (8.23 g, 85%); m.p. 90–91 ◦C;
δH (400 MHz, CDCl3) 7.58–7.63 (2H, m), 7.69–7.77 (3H, m), 7.87–7.90 (1H, m), 8.09–8.17 (3H, m)
and 8.67 ppm (1H, s); δC (100 MHz, CDCl3) 128.51, 128.80, 129.01, 129.22, 129.51, 131.20, 134.74,
136.41, 139.10, 139.71, 141.32 and 150.90; HRMS (ES): MH+ calcd for [C14H10N2SO3]+: 286.04212,
found: 286.0421.
3.2.2. 2-Phenylquinoxaline (2)
ZnCl2 (0.95 g, 6.99 mmol, 2.0 eq, taken directly from the oven) was added to an oven dried 2-neck
flask with a stirrer bar, which was further dried under vacuum for 15 min. Dry THF (10 mL) was
added to the flask under dry nitrogen. The solution was left to stir until all dried ZnCl2 was dissolved.
Phenyl-MgBr (6.3 mL, 6.29 mmol, 1 M) was added to the solution and left to stir for 1 h. To a solution
of Phenyl-ZnCl (6.29 mmol), 2-benzenesulfonyloxyquinoxaline 1 (1 g, 3.49 mmol) and PdCl2(PPh3)2
(122.6 mg, 0.18 mmol, 5 mol %) were added and set to reflux while stirring under nitrogen for 20 h.
The solution was allowed to cool to room temperature, diluted with EtOAc (25 mL), quenched with sat.
NaHCO3 (15 mL). The two layers were separated and the aqueous layer diluted with EtOAc (15 mL).
The combined organic layers were dried over Na2SO4, filtered and concentrated, and purified on silica
gel eluting with 20% EtOAc/Hexane to give 2-phenylquinoxaline as a yellow solid (0.537 g, 75%); m.p.
73–74 ◦C (Lit. 74–75 ◦C); δH (400 MHz, CDCl3) 7.46–7.52 (3H, m), 7.69–7.77 (2H, m), 8.12–8.15 (4H, m)
and 9.27 (1H, s); δC (100 MHz, CDCl3) 127.63, 128.54, 129.32, 129.51, 129.65, 130.58, 138.87, 132.16,
136.24, 140.41, 142.51 and 152.00; m/z (ES-API, +ve) 207.1 (M + 1100). Physical and spectroscopic data
agree with those reported in literature [32].
General Methods for Nucleophilic Substitution on 2-Phenylquinoxaline
Method 1: A solution of n-BuLi or Mg-aryl/alkyl was treated with 2-phenylquinoxaline 2 (100 mg,
0.485 mmol), and the solution allowed to stir at room temperature for 18 h. The final solution was
diluted with EtOAc (10 mL), quenched with sat. NaHCO3 (10 mL). The organic layers were combined
and dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on
silica gel.
Method 2: A solution of either an alkyne or hetero-aromatic substrate (0.97 mmol) in THF (5 mL)
was lithiated with n-BuLi (0.4 mL, 0.97 mmol, 2 eq, 2.5 M) and left to stir for 15 min under a nitrogen
atmosphere. 2-Phenylquinoxaline
2 (100 mg, 0.485 mmol) was added to the flask, and the solution
allowed to stir at room temperature for 18 h. The final solution was diluted with EtOAc (10 mL),
quenched with sat. NaHCO3 (10 mL). The organic layers were combined and dried over Na2SO4,
filtered, concentrated, and purified by flash column chromatography on silica gel.
3.2.3. 3-Butyl-2-phenylquinoxaline (2a)
Following general method 1, 2-phenylquinoxaline 2 (100 mg, 0.485 mmol) was treated with n-BuLi
(0.3 mL, 0.728 mmol, 1.5 eq, 2.5 M) at
−
78 ◦C under nitrogen atmosphere. The solution was left to
stir for 18 h at room temperature, followed by aqueous work-up and purification by flash column
chromatography on silica gel, eluting with 5% EtOAc/hexane to give 3-butyl-2-phenylquinoxaline as
tan oil (84 mg, 66%); δH (400 MHz, CDCl3) 0.75–0.79 (3H, t, J = 7.4 Hz); 1.18–1.27 (2H, m), 1.62–1.65

Molecules 2016, 21, 1304
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(2H, m), 2.96–2.99 (2H, t, J = 7.8 Hz), 7.44–7.54 (5H, m), 7.65–7.68 (2H, m) and 8.01–8.06 (2H, m);
δC (100 MHz, CDCl3) 13.83, 22.62, 29.72, 31.25, 35.76, 128.45, 128.57, 128.86, 129.22, 129.27, 129.73,
139.11, 140.72, 141.32, 146.38, 155.12 and 156.35; m/z (ES-API, +ve) 263.1 (M + 1100). Physical and
spectroscopic data agree with those reported in literature [14].
3.2.4. 3-Isopropyl-2-phenylquinoxaline (2b)
Following general method 1, 2-phenylquinoxaline
2 (100 mg, 0.485 mmol) was treated with
iPrMgCl (0.8 mL, 0.728 mmol, 1.5 eq, 0.9 M) at 0 ◦C under nitrogen atmosphere. The solution was left
to stir for 18 h, followed by aqueous work-up and purification by flash column chromatography on
silica gel, eluting with 5% EtOAc/hexane to give 2-isopropyl-3-phenylquinoxaline as yellowish solid
(65.28 mg, 54%); m.p. 97–98 ◦C (Lit. 98–99 ◦C); δH (400 MHz, CDCl3) 1.17–1.25 (6H, d, J = 6.8 Hz),
3.39–3.46 (1H, m), 7.41–7.51 (5H, m), 7.61–7.68 (2H, m) and 8.03–8.05 (2H, m); δC (100 MHz, CDCl3)
21.80, 30.99, 127.50, 127.66, 127.71, 127.79, 128.07, 128.18, 128.51, 138.12, 139.42, 140.66, 153.53 and
159.74; m/z (ES-API, +ve) 249.1 (M + 1100). Physical and spectroscopic data agree with those reported
in literature [33].
3.2.5. 2,3-Diphenylquinoxaline (2c)
Following general method 1, 2-phenylquinoxaline
2 (100 mg, 0.485 mmol) was treated with
Phenyl-MgBr (0.64 mL, 0.728 mmol, 1.5 eq, 1.14 M) at 0 ◦C under nitrogen atmosphere. The solution
was left to stir for 18 h, followed by aqueous work-up and purification by flash column chromatography
on silica gel, eluting with 5% EtOAc/hexane to give 2,3-diphenylquinoxaline as orange solid (29.8 mg,
22%); m.p. 126–128 ◦C (Lit. 127–129 ◦C); δH (400 MHz, CDCl3) 7.27–7.29 (6H, m), 7.44–7.52 (4H, d,
J = 7.4 Hz), 7.62–7.73 (2H, dd, J = 8.7 and 2.3 Hz) and 8.05–8.13 (2H, dd, J = 8.7 and 2.3 Hz); δC
(100 MHz, CDCl3) 126.88, 127.47, 127.91, 128.05, 129.12, 137.73, 140.01 and 152.38; m/z (ES-API, +ve)
283.1 (M + 1100). Physical and spectroscopic data agree with those reported in literature [34].
3.2.6. 2-Phenyl-3-(2-phenylethynyl)quinoxaline (2d)
Following general method 2, the resulting solution from phenylacetylene (0.1 mL, 0.97 mmol,
2.0 eq) and n-BuLi, was treated with
2. After normal work-up and purification, eluting with 10%
EtOAc/hexane gave 2-phenyl-3-(2-phenylethynyl)quinoxaline as light brown solid (69.2 mg, 47%);
◦
◦
m.p. 110–112 C (Lit. 109–111 C); δH (400 MHz, CDCl3) 7.33–7.39 (3H, m), 7.48–7.50 (2H, d, J = 6.8 Hz),
7.56–7.57 (3H, m), 7.77–7.79 (2H, m) and 8.09–8.15 (4H, m); δC (100 MHz, CDCl3) 87.31, 94.06, 120.66,
127.15, 127.44, 127.74, 128.29, 128.60, 128.67, 128.71, 129.31, 129.69, 131.11, 136.60, 137.08, 139.70, 139.99
and 154.10; m/z (ES-API, +ve) 307.1 (M + 1100). Physical and spectroscopic data agree with those
reported in literature [35].
3.2.7. 3-(Oct-1-ynyl)-2-phenylquinoxaline (2e)
Following general method 2, the resulting solution from 1-octyne (0.14 mL, 0.97 mmol, 2.0 eq) and
n-BuLi was treated with 2. After normal work-up and purification, eluting with 10% EtOAc/hexane
gave 2-(oct-1-ynyl)-3-phenylquinoxaline as orange oil (20.5 mg, 14%); δH (400 MHz, CDCl3) 0.86–0.89
(3H, t, J = 6.8 Hz), 1.25–1.32 (4H, m), 1.52–1.60 (4H, m), 2.42–2.46 (2H, t, J = 7.1 Hz), 7.50–7.52 (3H, m),
7.74–7.76 (2H, m) and 8.02–8.03 (4H, m); δC (100 MHz, CDCl3) 14.10, 19.76, 22.53, 27.81, 28.64, 29.72,
31.35, 97.92, 128.08, 128.64, 129.23, 129.53, 129.58, 130.13, 130.36, 137.75, 138.50, 140.60,140.93 and 154.92.
HRMS (ES): MH+ calcd for [C22H22N2]+: 315.1783, found: 315.1861.
3.2.8. 2-Phenyl-3-(thiophen-2-yl)quinoxaline (2f)
Following general method 2, the resulting solution from thiophene (0.08 mL, 0.97 mmol,
2.0 eq) and n-BuLi was treated with
2. After normal work-up and purification, eluting with
10% EtOAc/hexane gave 2-phenyl-3-(thiophen-2-yl)quinoxaline as a lime solid (30.5 mg, 22%);

Molecules 2016, 21, 1304
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m.p. 126–128 ◦C (Lit. 128 ◦C); δH (400 MHz, CDCl3) 6.75–6.76 (1H, d, J = 3.6 Hz), 6.86–6.88 (1H, m),
7.40–7.41 (1H, d, J = 4.8 Hz), 7.48–7.54 (3H, m), 7.59–7.61 (2H, m), 7.70–7.79 (2H, m) and 8.08–8.12
(2H, m); δC (100 MHz, CDCl3) 127.78, 128.76, 128.85, 129.07, 129.14, 129.25, 129.34, 129.77, 129.95,
130.23, 139.42, 140.45, 141.14, 142.74, 146.91 and 152.58; m/z (ES-API, +ve) 289.1 (M + 1100). Physical
and spectroscopic data agree with those reported in literature [36].
3.2.9. 2-(Furan-2-yl)-3-phenylquinoxaline (2g)
Following general method 2, the resulting solution from furan (0.08 mL, 0.97 mmol, 2.0 eq) and
n-BuLi was treated with
2. After normal work-up and purification, eluting with 10% EtOAc/hexane
gave 2-(furan-2-yl)-3-phenylquinoxaline as brown solid (60.6 mg, 46%); m.p. 102–103 ◦C (Lit. 103–104 ◦C)
;
δH (400 MHz, CDCl3) 6.14–6.15 (1H, d, J = 3.5 Hz), 6.35–6.36 (1H, m), 7.50–7.59 (6H, m), 7.71–7.79
(2H, m), 8.10–8.12 (1H, dd, J = 8.0 and 1.1 Hz) and 8.20–8.28 (1H, dd, J = 8.0 and 1.1 Hz); δC (100 MHz,
CDCl3) 111.79, 114.88, 128.70, 128.82, 129.07, 129.13, 129.25, 129.96, 130.35, 139.28, 140.35, 141.01, 143.09,
144.74, 150.88 and 152.57; m/z (ES-API, +ve) 273.1 (M + 1100). Physical and spectroscopic data agree
with those reported in literature [37].
3.2.10. 2-Butylquinoxaline (3)
ZnCl2 (475.7 mg, 3.49 mmol, 2.0 eq, taken directly from the oven) was added to a pre-oven dried
round bottom flask with a stirrer bar. Dry THF (20 mL) was added to the flask and left to stir until
all ZnCl2 was dissolved, under nitrogen. n-BuLi (1.4 mL, 3.49 mmol, 2.0 eq, 2.5 M) was added to
the flask at
−
78 ◦C, left to stir for 1 h at
−
78 ◦C. To the solution, 2-benzenesulfonyloxyquinoxaline
1
(500 mg, 1.75 mmol) and PdCl2(PPh3)3 (61.3 mg, 0.0874 mmol, 5 mol %) were added and set to reflux
while stirring under nitrogen for 18 h. The solution was allowed to cool to room temperature, diluted
with EtOAc (12.5 mL) and quenched with sat. NaHCO3 (2
×
15 mL). The two layers separated and
the aqueous layer diluted with EtOAc (8 mL). The combined organic layers were dried over Na2SO4,
concentrated, and purified on silica gel eluting with 10% EtOAc/Hexane to give 2-butylquinoxaline
as an orange oil (200 mg, 61%); δH (400 MHz, CDCl3) 1.00 (3H, t, J = 7.4 Hz), 1.44–1.49 (2H, m),
1.79–1.86 (2H, m), 3.02 (2H, t, J = 7.8 Hz), 7.70–7.74 (2H, m), 8.03–8.08 (2H, m) and 8.75 (1H, s); δC
(100 MHz, CDCl3) 14.13, 22.62, 31.61, 36.37, 128.94, 129.16, 129.29, 139.99, 141.26, 142.20, 145.84 and
157.73; m/z (ES-API, +ve) 188 (M + 1100). Physical and spectroscopic data agree with those reported in
literature [38].
3.2.11. 2,3-Dibutylquinoxaline (3a)
Following general method 1, 2-butylquinoxaline
3 (50 mg, 0.269 mmol) was treated with n-BuLi
(0.32 mL, 0.807 mmol, 3.0 eq, 2.5 M) at
−
78 ◦C under nitrogen atmosphere. The solution was left to
stir for 18 h at room temperature, followed by aqueous work-up and purification by flash column
chromatography on silica gel, eluting with 10% EtOAc/hexane to give 2,3-dibutylquinoxaline as
brown oil (63 mg, 97%); δH (400 MHz, CDCl3) 0.89–1.11 (6H, t, J = 7.4 Hz), 1.49–1.53 (4H, m), 2.99–3.03
(4H, t, J = 7.4 Hz), 7.63–7.66 (2H, m) and 7.98–8.00 (2H, m); δC (100 MHz, CDCl3) 14.01, 22.91, 31.05,
35.21, 128.47, 128.69, 140.99 and 156.72. Physical and spectroscopic data agree with those reported in
literature [39].
3.2.12. 2-Butyl-3-(furan-2-yl)quinoxaline (3b)
Furan (0.06 mL, 0.807 mmol, 3.0 eq) was treated with n-BuLi (0.32 mL, 0.807 mmol, 3.0 eq,
2.5 M) at
−
78 ◦C under nitrogen atmosphere. The resulting solution was treated with
3 and
the solution was left to stir for 18 h at room temperature, followed by aqueous work-up and
purification by flash column chromatography on silica gel, eluting with 10% EtOAc/hexane to give
2-butyl-3-(furan-2-yl)quinoxaline as brown oil (62 mg, 91%); δH (400 MHz, CDCl3) 0.97–1.01 (3H, t,
J = 7.4 Hz), 1.48–1.54 (2H, m), 1.78–1.84 (2H, m), 3.29–3.33 (2H, t, J = 7.8 Hz), 6.63–6.64 (1H, m),
7.22–7.23 (1H, d, J = 3.5 Hz), 7.68–7.71 (3H, m) and 8.01–8.10 (2H, m); δC (100 MHz, CDCl3) 14.01,

Molecules 2016, 21, 1304
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22.87, 30.81, 36.69, 112.12, 113.96, 128.41, 128.93, 129.41, 129.62 and 144.49. HRMS (ES): MH+ calcd for
[C16H16N2O]+: 253.1263, found: 253.1339.
3.2.13. 3-Butyl-2-(2-phenylethynyl)quinoxaline (3c)
Following general method 2, the resulting solution from phenylacetylene (0.1 mL, 0.97 mmol,
2.0 eq) and n-BuLi, was treated with 3. After normal work-up and purification, eluting with 10%
EtOAc/hexane gave 3-butyl-2-(2-phenylethynyl)quinoxaline as orange solid (90.1 mg, 65%); m.p.
◦
76–78 C; δH (400 MHz, CDCl3) 0.93–0.96 (3H, t, J = 7.4 Hz), 1.44–1.50 (2H, m), 1.82–1.89 (2H, m),
3.19–3.23 (2H, t, J = 7.8 Hz), 7.35–7.37 (3H, m), 7.60–7.66 (4H, m) and 7.95–8.97 (2H, m); δC (100 MHz,
CDCl3) 14.02, 22.90, 29.72, 30.93, 36.34, 86.87, 94.90, 121.74, 128.62, 128.84, 129.51, 129.70, 130.34, 132.24,
139.52, 140.73,140.85 and 158.86. HRMS (ES): MH+ calcd for [C20H18N2]+: 287.1470, found: 287.1545.
3.2.14. 2-(2-Phenylethynyl)quinoxaline (4)
Under a nitrogen atmosphere, in a round bottom flask equipped with a stirrer bar,
2-benzenesulfonyloxyquinoxaline
Et3N (0.2 mL, 2.1 mmol, 2 eq) and phenylacetylene (154
1
(0.301 g, 1.05 mmol), PdCl2(PPh3)2 (38.0 mg, 0.052 mmol, 5 mol %),
L, 1.26 mmol, 1.2 eq) were dissolved in
µ
THF (10 mL). The solution was refluxed for 18 h under nitrogen, followed by aqueous work-up and
purification by flash column chromatography on silica gel, eluting with 1:9 EtOAc/n-hexane to give
2-(2-phenylethynyl)quinoxaline as a yellowish solid (0.178 g, 61%); m.p. 65–66◦C (Lit. 65–66 ◦C); δH
(400 MHz, CDCl3) 7.42–7.45 (3H, m), 7.69–7.71 (2H, m), 7.78–7.82 (2H, m), 8.11–8.12 (2H, m) and 8.99
(1H, s); δC (100 MHz, CDCl3) 121.41, 128.58, 129.05, 129.19, 129.23, 129.27, 129.80, 130.45, 130.73, 132.40,
139.14, 139.62, 140.92, 142.22 and 147.36; m/z 231 (M + 1100). Physical and spectroscopic data agree
with those reported in literature [40].
3.2.15. N-Phenylquinoxalin-2-amine (5)
In a 50 mL 2-neck round bottom flask equipped with a stirrer bar under nitrogen,
2-benzenesulfonyloxyquinoxaline 1 (100 mg, 0.349 mmol), Pd(OAc)2 (4 mg, 0.0175 mmol, 5 mol %),
Brett-Phos (9.4 mg, 0.0175 mmol, 5 mol %) and aniline (0.1 mL, 1.047 mmol, 3.0 eq) were dissolved in
1,4-dioxane (5 mL). Pyridine (0.08 mL, 1.047 mmol, 3.0 eq) was added to the solution, and refluxed
for 18 h. The solution was diluted with EtOAc (10 mL), and quenched with sat. NaHCO3 (10 mL).
The organic layers were combined and dried over Na2SO4, filtered then concentrated and purified by
flash column chromatography on silica gel eluting with 40% EtOAc/hexane and on prep TLC with 5%
MeOH/DCM to give N-phenylquinoxalin-2-amine as yellowish solid (40 mg, 52%); m.p. 135–137 ◦C
◦
(Lit. 137 C); δH (400 MHz, CDCl3) 7.08 (1H, s), 7.14–7.17 (1H, m), 7.40–7.45 (2H, m), 7.48–7.52 (1H, m),
7.64–7.68 (1H, m), 7.76–7.97 (3H, m) and 8.47 (1H, s); δC (100 MHz, CDCl3) 119.85, 123.59, 125.65, 126.95,
128.83, 129.32, 130.37, 137.84, 138.48, 139.21, 141.19 and 149.32. m/z (ES-API, +ve) 222.1 (M + 1100).
Physical and spectroscopic data agree with those reported in literature [41].
3.2.16. 3-Butyl-N-phenylquinoxalin-2-amine (5a)
2-Quinoxalineamine
5
(50 mg, 0.226 mmol) was treated with n-BuLi (0.3 mL, 0.678 mmol, 3 eq,
◦
2.5 M) at
−
78 C under nitrogen atmosphere. The solution was left to stir for 36 h at room temperature,
followed by aqueous work-up and purification by flash column chromatography on silica gel eluting
with 10% EtOAc/hexane to give 3-butyl-N-phenylquinoxalin-2-amine as orange solid (22 mg, 32%);
◦
m.p. 99–102 C; δH (400 MHz, CDCl3) 0.95–0.98 (3H, t, J = 7.4 Hz), 1.46–1.51 (2H, m), 1.81–1.89 (2H, m),
2.87–2.91 (2H, t, J = 7.8 Hz), 6.68 (1H, s), 7.03–7.06 (1H, m), 7.32–7.41 (3H, m), 7.48–7.52 (1H, m) and
7.72–7.83 (4H, m); δC (100 MHz, CDCl3) 14.03, 22.78, 28.91, 33.94, 119.85, 123.17, 125.45, 126.68, 128.17,
129.07, 137.51, 138.25, 139.44, 140.25, 147.58 and 148.01. HRMS (ES): MH+ calcd for [C18H19N3]+:
278.1579, found: 278.1659.

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3.2.17. 3-Methyl-N-phenylquinoxalin-2-amine (5b)
2-Quinoxalineamine 5 (50 mg, 0.226 mmol) was treated with Me-MgCl (0.3 mL, 3 eq, 3.0 M) at
0 ◦C under nitrogen atmosphere. The solution was left to stir for 36 h at room temperature, followed
by aqueous work-up and purification by flash column chromatography on silica gel eluting with
10% EtOAc/hexane to give 3-methyl-N-phenylquinoxalin-2-amine as orange oil (22 mg, 42%); δH
(400 MHz, CDCl3) 2.43 (3H, s), 6.61 (1H, s), 7.39–7.41 (2H, m), 7.45–7.48 (2H, m), 7.53–7.57 (3H, m),
7.94–7.97 (1H, m) and 8.09–8.12 (1H, m); δC (100 MHz, CDCl3) 15.32, 116.36, 119.22, 124.82, 125.44,
128.34, 128.82, 129.63, 136.44, 140.28, 143.62, 145.99 and 160.32. Physical and spectroscopic data agree
with those reported in literature [23].
3.2.18. N-Methyl-N-phenylquinoxalin-2-amine (6)
2-Quinoxalineamine
5 (200 mg, 0.904 mmol) was dissolved in THF (20 mL) and was treated
with NaH (43 mg, 1.81 mmol, 2.0 eq) at 0 ◦C and left to stir for 1 h at room temperature.
Iodomethane (0.2 mL, 0.712 mmol, 3.0 eq) was added to the solution under nitrogen. The solution
was left to stir for 5 h at room temperature. The solution was quenched with sat. NH4Cl and
purified by flash column chromatography on silica gel eluting with 5% MeOH/DCM to give
N-methyl-N-phenylquinoxalin-2-amine as orange oil (165 mg, 78%); δH (400 MHz, CDCl3) 3.60 (3H, s),
7.32–7.34 (3H, m), 7.38–7.43 (1H, m), 7.45–7.49 (2H, m), 7.58–7.62 (1H, m), 7.76–7.88 (2H, m) and 8.27
(1H, s); δC (100 MHz, CDCl3) 36.68, 124.83, 126.42, 126.57, 126.82, 128.76, 128.76, 130.02, 130.23, 136.92,
141.67, 144.96 and 152.20. HRMS (ES): MH+ calcd for [C15H13N3]+: 236.1109, found: 236.1191.
3.2.19. 3-Butyl-N-methyl-N-phenylquinoxalin-2-amine (7a)
N-Methyl-N-phenylquinox◦alin-2-amine
6 (50 mg, 0.213 mmol) was treated with n-BuLi (0.26 mL,
78 C under nitrogen atmosphere. The solution was left to stir for 36 h at
0.639 mmol, 3 eq, 2.5 M) at
−
room temperature, followed by aqueous work-up and purification by flash column chromatography
on silica gel eluting with 10% EtOAc/hexane to give 3-butyl-N-methyl-N-phenylquinoxalin-2-amine as
yellow oil (52.2 mg, 62%); δH (400 MHz, CDCl3) 0.75–0.79 (3H, t, J = 7.4 Hz), 1.09–1.19 (2H, m), 1.52–1.58
(2H, m), 2.36–2.40 (2H, t, J = 7.8 Hz), 3.55 (1H, s), 6.97–6.99 (2H, m), 7.10–7.14 (1H, m), 7.28–7.34 (2H,
m), 7.51–7.56 (1H, m), 7.60–7.63 (1H, m), 7.86–7.89 (1H, d, J = 7.6 Hz) and 7.92–7.94 (1H, d, J = 7.4 Hz);
δC (100 MHz, CDCl3) 13.84, 22.56, 29.78, 35.44, 41.73, 122.96, 124.33, 126.66, 127.05, 127.97, 128.81,
129.62, 138.83, 140.29, 148.92, 153.34 and 154.28. HRMS (ES): MH+ calcd for [C19H21N3]+: 292.1735,
found: 292.1817.
Acknowledgments: We gratefully acknowledge the South African National Research Foundation Thuthuka grant
(Grant no. TTK1205280912) and Sasol-Inzalo Foundation (SaIF) for financial support.
Author Contributions: Winston Nxumalo conceived and designed the experiments; Ndumiso T. Ndlovu
performed the experiments; Winston Nxumalo and Ndumiso T. Ndlovu analyzed the data.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
Singh, D.P.; Deivedi, S.K.; Hashim, S.R.; Singhal, R.G. Synthesis and antimicrobial activity of some
new quinoxaline derivatives. Pharmaceuticals 2010, 3, 2416–2425. [CrossRef]
Selvam, P.; Chandramohan, M.; Pannecouque, C.; de Clercq, E. Studies on antiviral activity of
2,3-diphenylquinoxaline. Int. J. Pharm Ind. Res. 2011, 1, 138–140.
Ramalingam, P.; Ganapaty, S.; Rao, C.B. In vitro antitubercular and antimicrobial activities of 1-substituted
quinoxaline-2,3(1H,4H)-diones. Biorg. Med. Chem. Lett. 2010, 20, 406–408. [CrossRef] [PubMed]
1
Patel, N.; Bergman, J.; Graslund, A. H-NMR studies of the interaction between a self-complementary
deoxyoligonucleotide duplex and indolo[2,3-b]quinoxaline derivatives active against herpes virus.
Eur. J. Biochem. 1991, 197, 597–604. [CrossRef] [PubMed]

Molecules 2016, 21, 1304
10 of 11
5.
Balasubramanian, S.; Sasikumar, P.; Velmurugan, D. In-vitro evaluation and molecular docking calculation of
tricyclic phthalimide quinoxaline analogues as novel inhibitors of hiv-1 integrase using GLIDE and GOLD.
Int. J. Pharm. Sci. Drug Res. 2014, 6, 60–66.
6.
7.
Potey, L.C.; Kosalge, S.B.; Hadke, M.A. Synthesis and antimicrobial activity of quinoxaline sulfonamide.
Int. J. Adv. Sci. Technol. 2013, 2, 126–134.
Agboke, A.; Attama, A.; Qkoye, C.; Jackson, C. Evaluation of effectiveness of various combinations of
penicillin groups commonly used in Nigeria clinics on selected microorganisms. Innov. J. Med. Health. Sci.
2014, 4, 93–98.
8.
9.
Le Douaron, G.; Ferrié, L.; Sepulveda-Diaz, J.E.; Amar, M.; Harfouche, A.; Séon-Méniel, B.;
Raisman-Vozari, R.; Michel, P.P.; Figadère, B. New 6-aminoquinoxaline derivatives with neuroprotective
effect on dopaminergic neurons in cellular and animal Parkinson disease models. J. Med. Chem. 2016, 59,
6169–6186. [CrossRef] [PubMed]
Le Douaron, G.; Schmidt, F.; Amar, M.; Kadar, H.; Debortoli, L.; Latini, A.; Séon-Méniel, B.; Ferrié, L.;
Michel, P.P.; Touboul, D.; et al. Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in
cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease. Eur. J. Med. Chem.
2015, 89, 467–479. [CrossRef] [PubMed]
10. Söderberg, B.C.G.; Wallace, J.M.; Tamariz, J. A novel palladium-catalyzed synthesis of 1,2-dihydroquinoxalines
and 3,4-dihydroquinoxalinones. Org. Lett. 2002, 4, 1339–1342. [CrossRef] [PubMed]
11. Issidorides, C.H.; Haddadin, M.J. Benzofurazan oxide. II. reactions with enolate anions. J. Org. Chem. 1966
31, 4067–4068. [CrossRef]
,
12. Abu-Hashem, A.A. Synthesis, reactions and biological activity of quinoxaline derivatives. Am. J. Org. Chem.
2015, 5, 14–56.
13. Noorulla, S.M.P.; Sreenivasulu, N.; Khan, A.; Sayeed, A. Antibacterial activity of novel substituted
quinoxaline heterocycles. Pharmanest 2011, 2, 229–238.
14. Cho, C.S.; Ren, W.X. A recyclable copper catalysis in quinoxaline synthesis from α-hydroxyketones and
o-phenylenediamines. J. Organomet. Chem. 2009, 694, 3215–3217. [CrossRef]
15. Khaksar, S.; Rostamnezhad, F. A novel one-pot synthesis of quinoxaline derivatives in fluorinated alcohols.
Korean Chem. Soc. 2012, 33, 2581–2584. [CrossRef]
16. Soleymani, R.; Niakan, N.; Tayeb, S.; Hakimi, S. Synthesis of novel aryl quinoxaline derivatives by
new catalytic methods. Oriental J. Chem. 2012, 28, 687–701. [CrossRef]
17. Makosza, M. Nucleophilic substitution of hydrogen in electron-deficient arenes, a general process of great
practical value. Chem. Soc. Rev. 2010, 39, 2855–2868. [CrossRef] [PubMed]
18. Makosza, M. Vicarious nucleophilic substitution of hydrogen. Russ. Chem. Rev. 1989, 58, 1298–1317.
[CrossRef]
19. Kovalev, I.S.; Kopchuk, D.S.; Zyryanov, G.V.; Rusinov, V.L.; Chupakhin, O.N.; Charushin, V.N. Organolithium
compounds in the nucleophilic substitution of hydrogen in arenes and hetarenes. Russ. Chem. Rev. 2015, 84,
1191–1225. [CrossRef]
20. Hui, X.; Schmidt, F.; Fakhfakh, M.F.; Franck, X.; Figadère, B. Novel highly regioselective syntheses of
unsymmetrical 2,3-disubstituted quinoxalines. Heterocycles 2007, 72, 353–361.
21. Azev, Y.A.; Oprina, E.D.; Golomolzin, B.V.; Ermakova, O.S.; Bakulev, V.S. A simple means of preparing
quinoxaline derivatives: Direct introduction of C-nucleophiles into the quinoxaline nucleus by substituting a
hydrogen atom. Pharm. Chem. J. 2013, 47, 172–175. [CrossRef]
22. Badr, M.Z.A.; El-Naggar, G.M.; El-Sherief, H.A.H.; Abdel-Rahman, A.E.; Aly, M.F. Reaction of quinoxaline
derivatives with nucleophilic reagents. Bull. Chem. Soc. Jpn. 1983, 56, 326–330. [CrossRef]
23. Zhuo, F.; Xie, W.; Yang, Y.; Zhang, L.; Wang, P.; Yuan, R.; Da, C. TMEDA-assisted effective direct ortho
arylation of electron-deficient N-heteroarenes with aromatic Grignard reagents. J. Org. Chem. 2013, 78,
3243–3249. [CrossRef] [PubMed]
24. Prokhorov, A.M.; Makosza, M.; Chupakhin, O.N. Direct introduction of acetylene moieties into azines by
H
SN methodology. Tetrahedron Lett. 2009, 50, 1444–1446. [CrossRef]
25. Epifani, E.; Florio, S.; Ingrosso, G.; Sgarra, R.; Stasi, F. Reaction of quimoxalines with β,γ-unsaturated
grignard reagents: Synthesis of allyl-, allenyl-, propargyl-quinoxaline derivatives. Tetrahedron 1987, 43,
2767–2778. [CrossRef]

Molecules 2016, 21, 1304
11 of 11
26. Wienhöfer, E.; Kauffmann, T. Lineare verknüpfung von 5 und 6 verschiedenen arenen (1). Tetrahedron Lett.
1974, 15, 2347–2350. [CrossRef]
27. Nxumalo, W.; Dinsmore, A. Preparation of 6-ethynylpteridine derivatives by Sonogashira coupling.
Heterocycles 2013, 87, 78–79. [CrossRef]
28. Nxumalo, W.; Dinsmore, A.S. Negishi coupling of pteridine-O-sulfonates. S. Afr. J. Chem. 2013, 66, 42–46.
29. Negishi, E.; King, A.O.; Okukado, N. Selective carbon-carbon bond formation via transition metal
catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel-
or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides. J. Org. Chem. 1977, 42,
1821–1823. [CrossRef]
30. Sonogashira, K. Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon
halides. J. Organomet. Chem. 2002, 653, 46–49. [CrossRef]
31. Guram, A.S.; Buchwald, S.L. Palladium-catalyzed aromatic aminations with in situ generated
aminostannanes. J. Am. Chem. Soc. 1994, 116, 7901–7902. [CrossRef]
32. Darabantu, M.; Boully, L.; Turck, A.; Ple, N. Synthesis of new polyaza heterocycles. Part 42: Diazines.
Tetrahedron 2005, 61, 2897–2905. [CrossRef]
33. Cho, C.S.; Ren, W.X.; Shim, S.C. Ketones as a new synthon for quinoxaline synthesis. Tetrahedron Lett. 2007
48, 4665–4667. [CrossRef]
,
34. Rekha, M.; Kathyayini, H.; Nagaraju, N. Catalytic activity of manganese oxide supported on alumina in the
synthesis of quinoxalines. Front. Chem. Sci. Eng. 2013, 7, 415–421. [CrossRef]
35. Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen, Y.; Chen, B. Copper-catalyzed synthesis of quinoxalines with
o-phenylenediamine and terminal alkyne in the presence of bases. Org. Lett. 2011, 13, 4514–4517. [CrossRef]
[PubMed]
36. Wilhelm, S.; Georg, B.E. Thiophene series. XLVII. 2-Thienyl phenyl diketone and its oxime. Eur. J. Org. Chem.
1939, 540, 14–24.
37. Gomez-Sanchez, A.; Antinolo, M.Y.; Gonzalez, F.G. The influence of the aromatic nucleus on the dehydration
of polyhydroxy chains. V. The structure of Maurer’s glucazidone. Span. Roya. Soc. Chem. 1954, 50B, 431–440.
38. Das, B.; Venkateswarlu, K.; Suneel, K.; Majhi, A. An efficient and convenient protocol for the synthesis
of quinoxalines and dihydropyrazines via cyclization-oxidation processes using HClO4/SiO2 as a
heterogeneous recyclable catalyst. Tetrahedron Lett. 2007, 48, 5371–5374. [CrossRef]
39. Fontana, F.; Minisci, F.; Barbosa, M.C.N.; Vismara, E. Homolytic alkylation of heteroaromatic bases: the
problem of monoalkylation. Tetrahedron 1990, 46, 2525–2538. [CrossRef]
40. Supabphol, A.; Muangman, V.; Chavasiri, W.; Supabphol, R.; Gritsanapan, W. N-acetylcysteine inhibits
proliferation, adhesion, migration and invasion of human bladder cancer cells. J. Med. Ass. Thail. 2009, 92,
1171–1177.
41. Saari, R.; Törmä, J.; Nevalainen, T. Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and
quinazoline derivatives as CB2 receptor agonists. Bioorg. Med. Chem. 2011, 19, 939–950. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are available from the authors.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).