Bromination of quinoxaline and derivatives: Effective synthesis of some new brominated quinoxalines

Article abstract of DOI:10.1016/j.tet.2017.02.014

The synthesis of brominated quinoxaline derivatives starting from several kinds of quinoxaline by different bromination strategies was studied. First the synthesis of some brominated quinoxalines was accomplished along with the development of an alternative and effective synthesis of some known compounds. A new, clean, and effective synthetic method for selective reduction of quinoxaline to 1,2,3,4-tetrahydroquinoxaline was also developed. The products obtained were characterized by means of NMR spectroscopy, elemental analyses, and mass spectrometry.

Full text of DOI:10.1016/j.tet.2017.02.014

Accepted Manuscript
Bromination of quinoxaline and derivatives: Effective synthesis of some new
brominated quinoxalines
Sefa Uçar, Selçuk Eşsiz, Arif Daştan
PII:
S0040-4020(17)30139-4
10.1016/j.tet.2017.02.014
TET 28455
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 October 2016
Revised Date: 25 January 2017
Accepted Date: 6 February 2017
Please cite this article as: Uçar S, Eşsiz S, Daştan A, Bromination of quinoxaline and derivatives:
Effective synthesis of some new brominated quinoxalines, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.02.014.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Bromination of Quinoxaline and Derivatives:
Effective Synthesis of Some New Brominated
Quinoxalines
Leave this area blank for abstract info.
Sefa Uçar, Selçuk Eşsiz and Arif Daştan

ACCEPTED MANUSCRIPT
Bromination of Quinoxaline and Derivatives: Effective Synthesis
†
of Some New Brominated Quinoxalines
Sefa Uçar,a Selçuk Eşsiza,b and Arif Daştana*
Abstract— The synthesis of brominated quinoxaline derivatives starting from several kinds of
quinoxaline by different bromination strategies was studied. First the synthesis of some brominated
quinoxalines was accomplished along with the development of an alternative and effective synthesis of
some known compounds. A new, clean, and effective synthetic method for selective reduction of
quinoxaline to 1,2,3,4-tetrahydroquinoxaline was also developed. The products obtained were
characterized by means of NMR spectroscopy, elemental analyses, and mass spectrometry.
Keywords: quinoxaline, tetrahydroquinoxaline, bromination, Birch reduction, aromatization
1. Introduction
The chemistry of benzenoid hydrocarbons such as naphthalene goes back to the 19th century.1 Although
many investigations have been performed on this kind of molecule, benzenoid hydrocarbons are still
valuable due to their importance in both material sciences and medicinal chemistry. Two nitrogen-
containing heteroaromatic naphthalene derivatives, called diazanaphthalene and naphthyridines or
diazines, are important structures found in many natural and synthetic compounds.2
aAtatürk University, Science Faculty, Department of Chemistry, TR-25240 Erzurum, Turkey
bHakkari University, Engineering Faculty, Department of Chemical Engineering, TR-30000 Hakkari,
Turkey
†Electronic supplementary information (ESI) available. See DOI: 10.1039 xxxxxxx
1

ACCEPTED MANUSCRIPT
Br
H
N
N
N
N
N
NH
N
N
Quinoxaline
1
HN
N
Varenicline
Brimonidine
2
3
Figure 1 Quinoxaline and its derivatives
Among them, 1,4-diazanaphthalene, that is to say quinoxaline (1), is a crucial core structure of various
macrocyclic antibiotics such as echinomycin,3 levomycin,4 and actinoleutin5 that are known to inhibit
growth of Gram-positive bacteria, and are active against various transplantable tumors. Even small
analogues such as varenicline (2)6 and brimonidine (3)7 have valuable pharmaceutical effects. (Figure
1). In addition to biological and pharmaceutical effects, molecules consisting of a quinoxaline unit, have
many important applications in material sciences. For example, quinoxaline derivatives are useful as
electroluminescent materials,8 organic semiconductors,9 dyes,10 and electrical/photochemical
materials.11 Their ability to harvest both singlet and triplet energy for emission improves device
efficiency. For example, a few compounds with quinoxaline unit are used for dye-sensitized solar
cells.10b,12
Consequently, significant efforts have been made to develop efficient methods for the synthesis of
quinoxalines and their derivatives. The traditional method relies on condensation of 1,2-diamines with
1,2-dicarbonyl compounds,13 while oxidative cyclization of α-hydroxy ketones or α-halide ketones with
1,2-diamines has also been widely used.14 Although these methods work well for a few derivatives at
routine positions, quinoxalines substituted in more specific positions suffer when the substituted 1,2-
diamines and 1,2-dicarbonyl compounds are used as starting materials.
Furthermore, brominated compounds are versatile key compounds and starting materials for many
organic transformations. Halogens may be reductively or permutationally replaced by lithium or
magnesium, and the organometallic intermediate converted into a functionalized derivative by reaction
with an appropriate electrophile. In addition, the C-Br bond formed in arenes can be easily transformed
into a C-C bond and C–hetero atom bond via Ullmann, Heck, Stille, Suzuki etc. reactions.15 For this
reason, the synthesis of halogenated arenes is extremely important in organic chemistry and material
science.
In our previous works, we examined the bromination of naphthalene and its derivatives and we obtained
many new naphthalene derivatives.16 Cakmak and co-workers also studied the bromination and
2

ACCEPTED MANUSCRIPT
functionalization of benzenoid aromatic compounds such as naphthalene, anthracene, and quinoline.17
Due to our sustained interest in the bromination of aromatic compounds and derivatives, we aimed to
study quinoxalines to find a regioselective bromination method for the parent compounds. Although
bromination of naphthalene has been investigated in detail by many groups,16-18, direct bromination of
diazanaphthalenes is not common, owing to the lower activity of these compounds in electrophilic
reactions. Diazanaphthalenes are electron-deficient in nature, and N-bromo complexes form easily
during the bromination reaction. For this reason, direct bromination of quinoxaline has not been reported
in the literature to achieve brominated products as key compounds for other kinds of functionalization.
Brominated quinoxalines 9,19 10,20 11,21 and 1222 have been obtained by condensation of benzene-1,2-
diamines 4-7 with glyoxal (8) (Scheme 1). Although the last step works well, synthesis of halogenated
benzene-1,2-diamines in specific positions is not easy and consequently there are no practical and
general methods for the synthesis of many halogenated derivatives. In addition, most of this conversion
was patented.20,21 Continuing our work on the bromine functionalization of hydrocarbons, herein we
describe the halogenation of quinoxaline and derivatives under different conditions.
Scheme 1 Synthesis of some bromoquinoxalines
2. Results and Discussion
Our work in this study is based on three main strategies: i) bromination of quinoxaline (1) with different
reagents, solvents, and temperatures, ii) reduction of one ring of quinoxaline (1), and bromination of the
tetrahydroquinoxalines with different reagents, solvents, and temperatures to access brominated
quinoxalines, iii) synthesis of N-oxides of quinoxalines and bromination of them to obtain quinoxalines
with bromine atoms in specific positions.
3

ACCEPTED MANUSCRIPT
2.1 Bromination of quinoxaline (1) under different conditions
We first investigated the bromination of quinoxaline (1) under various conditions described in Table 1
and Scheme 2, and from this reaction the formation of different kinds of brominated product 9-14 was
observed. Under the conditions in entries 5, 8, and 9, monobromide 10 was obtained exclusively in 51-
65% yield. The reaction of 1 at 82 °C with 8 equiv. bromine in acetonitrile resulted in formation of only
dibromide 12 in considerably high yield (entry 3). The photobromination reaction of 1 with molecular
bromine (entry 7) gave us monobromide 9 in 70% yield as well as the dibromides 12 (10%) and 11
(3%). Synthesis of 9 starting from 1 using NBS in the presence of H2SO4 was first studied by Brown and
Gouliaev23 and they obtained 9 in only 12% yield. In the present work, thus, we have developed a good
method for monobromide 9. As is well known,16,20 in the bromination reaction of hydrocarbons at high
temperature, especially supported by photochemical conditions, the process proceeds via a radical
intermediate. In some cases there is competition between the radical and the ionic reactions. In view of
these points, we assumed that the reaction took place via addition of a bromine radical to a double bond,
and elimination of the formed tetrabromide.16,17,24 In other reaction conditions (entries 1, 2, 4, 6, 10, and
11) the formation of different product mixtures was observed. The reaction mixtures in that case were
easily separated by column chromatography using SiO2 with n-hexane/AcOEt. From this reaction, the
dibromide 13 was synthesized in low yield. A better synthetic method was developed for dibromide 14,25
by photochemical bromination of 1 (entry 6) and bromination of 1 with molecular bromine in the
presence of barium carbonate (entry 4) (Scheme 2).
Scheme 2 Bromination of quinoxaline at different conditions
4

ACCEPTED MANUSCRIPT
Method
Entry
Reagents
Br2 (6.6 eq.)
Solvent
T (°C)
Time, h
24
9
-
10
46
11
-
12
-
13
11
14
-
CH3CO2H
∆, 118
1
2
3
4
Br2 (12 eq.)
Br2 (8 eq.)
H2SO4
∆, 200
∆, 82
∆, 82
40
25
25
-
-
-
28
-
-
-
-
75
5
9
-
-
-
CH3CN
Br2 (8 eq.)/BaCO3 (2 eq.) CH3CN
Br2 (3 eq.)/BaCO3 (2 eq.) CH3CN
31
14
6
28
∆, 82
72
18
45
20
18
45
20
-
-
-
-
-
30
10
-
-
-
-
25
-
5
6
65
-
Br2 (8 eq.)
CCl4
hν
Br2 (2 eq.)
CCl4
-
3
-
7
70
-
hν
NBS (6 eq.)/BPO
NBS (6 eq.)/BPO
NBS (7 eq.)/BPO
NBS (6 eq.)/BPO
CH3CO2H
DMF
∆, 118
∆, 153
∆, 62
∆, 82
-
-
-
8
50
51
29
55
-
-
-
-
-
9
CHCl3
CH3CN
-
29
15
3
10
5
-
10
11
-
-
-
Table 1: Bromination of quinoxaline (1) under different conditions with bromination agents.
(BPO: Benzoyl peroxide, NBS: N-Bromosuccinimide, hv: A 150 W projector lamp).
2.2 Reduction of quinoxaline (1) and bromination of tetrahydroquinoxalines (15 and 19) under
different conditions
In our previous work we showed that bromination of saturated naphthalene, i.e. decalin, gave us a new
kind of brominated naphthalene derivative in high yield.16a Similarly Cakmak and co-workers
successfully brominated 1,2,3,4-tetrahydronaphthalene, tetralin.17 Those methods encouraged us to study
the bromination of reduced quinoxalines 15 and 19 under different reaction conditions. The compound
19 is commercially available, but isomeric 15 is expensive. Therefore, we first aimed to synthesize 15
starting from 1. Many effective methods for reduction of quinoxaline 1 to 15 exist in the literature and
few of them are patented.26 In addition, although Birch reduction is one of the best methods for
controlled reduction of aromatic rings, to the best of our knowledge, Birch reduction of 1 has not been
reported in the literature. Reduction of 1 with metallic sodium in liquid ammonia gave the target
compound 15 as the sole product in moderate yield (65%). Alternatively reduction of 1 was tried with
metallic lithium, and compound 15 was obtained in excellent yield (100%) (Scheme 3). Thus, a new and
effective method was developed for reduction of 1 to 15.
H
N
N
N
Birch Reduction
a or b
a) Na, NH3, t-BuOH, 65%
b) Li, NH3, t-BuOH, 100%
N
H
1
15
Scheme 3 Synthesis of 1,2,3,4-tetrahydroquinoxaline
5

ACCEPTED MANUSCRIPT
After the successful synthesis of 15, this compound is prone to bromination under different reaction
conditions, the results are reported in Scheme 4 and Table 2. As seen in Table 2, the bromination
reaction of 15 with molecular bromine or NBS in chloroform or carbon tetrachloride results in only
formation of aromatized compound 1 (entries 1-6). In addition, when the solvent was changed to
acetonitrile, the bromination reaction of 15 with bromine gave brominated products 9, 10, 11, 13, 16, 17,
and 18 as well as 1. This method gave us the synthesis of monobromide 16, dibromide 17, and
tetrabromide 18 in moderate yield. The first synthesis of tetrabromide 18 in up to 99% yield (entries 9-
12) is particularly valuable for us as it may be a key compound for many kinds of functionalized
quinoxaline derivatives for many applications.
Scheme 4 Bromination of 1,2,3,4-tetrahydroquinoxaline at different conditions
Method
Compounds / Yield (%)
Entry
Reagent
Solvent
T (°C) Time (h)
1
16
17
10
13
9
11
18
NBS (1 eq.)
NBS (1 eq.)
Br2 (1 eq.)
Br2 (1 eq.)
Br2 (2 eq.)
Br2 (1 eq.)
Br2 (1 eq.)
Br2 (2 eq.)
Br2 (6 eq.)
Br2 (6 eq.)
Br2 (12 eq.)
Br2 (30 eq.)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CCl4
∆, 62
2
2
35
35
38
30
55
45
50
35
35
50
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
-
-
1
2
hν, 62
∆, 62
h, 62
∆, 62
2
-
-
-
-
-
-
3
2
-
-
-
-
-
-
4
2
-
-
-
-
-
-
5
2
-
-
-
-
-
-
6
hν
∆, 82
∆, 82
∆, 82
∆, 82
25
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
-
2.5
2.5
2.5
10
15
48
30
15
-
20
10
-
-
-
-
-
7
7
11
-
5
6
-
5
5
-
-
8
17
50
65
99
9
-
-
10
11
12
-
-
-
-
-
-
25
-
-
-
4, dark
-
Table 2: Bromination of 1,2,3,4-tetrahydroquinoxaline (15) at different condition with
bromination agents. (BPO: Benzoyl peroxide, NBS: N-Bromosuccinimide, hv: A 150 W
projector lamp).
6

ACCEPTED MANUSCRIPT
The bromination reaction of isomeric tetrahydroquinoxaline 19 with molecular bromine was also studied
and the results are reported in Table 3 and Scheme 5. Depending on the reaction conditions, such as
solvent, reagent, temperature, light, and quantities of bromination agents, the formation of different
kinds of bromination product was observed. The reaction of 19 with 1.0 equiv. bromine at 82 °C (entry
1) in acetonitrile gave monobromide 2027 in 82% yield. When we used 2.0 equiv. bromine (entry 3) the
formation of dibromide 21 was observed as a major product in 86% yield. We showed that tetrabromide
23 was formed as the sole product in nearly quantitative yield by the bromination reaction of 19 with 6.0
equiv. bromine at 82 °C in acetonitrile (entry 7). When 3.0 equiv. bromine was used, tribromide 22 was
obtained in high yield (85%). These experiments are valuable for us because tribromide 22 and
tetrabromide 23 are starting compounds for the monobromide 9 and the dibromide 12, respectively, as
shown in Scheme 6.
Scheme 5 Bromination of 5,6,7,8-tetrahydroquinoxaline at different conditions
Method
Solvent
Compounds / Yield (%)
Entry
Reagent
Br2 (1 eq.)
Br2 (1 eq.)
Br2 (2 eq.)
Br2 (2 eq.)
Br2 (3 eq.)
Br2 (3 eq.)
Br2 (6 eq.)
Br2 (6 eq.)
Br2 (1.1 eq.)
Br2 (2.1 eq.)
Br2 (3.1 eq.)
Br2 (4.1 eq.)
T (°C)
∆, 82
∆, 62
∆, 82
∆, 62
∆, 82
∆, 62
∆, 82
∆, 62
Time
2
20
82
55
10
5
21
9
22
-
23
-
12
-
9
-
CH3CN
CHCl3
CH3CN
CHCl3
CH3CN
CHCl3
CH3CN
CHCl3
CCl4
1
2
2
7
-
-
-
-
2
4
-
-
-
3
86
70
8
2
-
-
-
-
4
2.5
2.5
3
-
5
-
2
-
5
85
60
-
-
15
-
5
-
6
-
-
-
7
99
75
-
3
-
-
10
-
-
-
8
0.5
0.5
0.75
0.75
70
-
15
85
14
-
-
-
9
hν
hν
hν
hν
CCl4
-
-
-
12
24
5
10
11
12
CCl4
-
43
-
-
-
CCl4
-
53
32
7

ACCEPTED MANUSCRIPT
NBS (6 eq.)/BPO
NBS (6 eq.)/BPO
NBS (6 eq.)/BPO
CH3CN
CHCl3
CCl4
∆, 82
∆, 62
hν
2
2
2
35
20
18
55
40
42
-
-
-
-
-
-
-
-
-
-
-
-
13
14
15
Table 3: Bromination of 5,6,7,8-tetrahydroquinoxaline (19) under different conditions with
bromination agents. (BPO: Benzoyl peroxide, NBS: N-Bromosuccinimide, hv: A 150 W
projector lamp).
Unlike isomer 15, which gave mainly aromatic compounds during bromination reactions, it is
noteworthy that bromination of 19 mostly results in the formation of saturated bromine functionalized
products as described in Scheme 5 and Table 3. This showed that the nitrogen-containing ring is easily
oxidized under the reaction conditions, while the other ring is more stable under those conditions. This
assumption was proved during the aromatization reaction of this kind of product with DDQ, and we
observed that while the nitrogen ring is easily aromatized with DDQ, the other ring shows resistance to
the oxidation reaction. For example, the aromatization reaction of saturated compound 20 and 21 with
DDQ under mild conditions does not work.
As saturated compounds 22 and 23 are formed in high yield (entries 5 and 7 in Table 3), these
compounds were treated with base and alternative and effective synthetic protocols were developed for
monobromide 9 and dibromide 12 in nearly quantitative yield (Scheme 6).
Br
N
N
DBU (2.2 eq)
N
N
THF, 25°C
99%
Br Br
Br
9
22
Br
Br Br
N
N
DBU (2.2 eq)
THF, 25°C
99%
N
N
Br Br
Br
23
12
Scheme 6 Synthesis of brominated quinoxalines by elimination reaction
Furthermore, the reaction of monobromide 20, formed in 82% yield (entry 1, in Table 3), was also
studied to access brominated quinoxalines to discover effective or alternative methods. For this purpose,
monobromide 20 was converted to alkene 24 by a base supported elimination reaction. Addition of
bromine to 24 gave trans dibromide 25. The aromatization reaction of 25 with DDQ resulted in the
formation of 9. Bromination of 24 with excess bromine at 82 °C gave monobromide 9, dibromide 12,
8

ACCEPTED MANUSCRIPT
and parent compound quinoxaline 1 in 44%, 22%, and 15% yield, respectively (Scheme 7).
Br
Br
Br
Br
DDQ (3 eq)
N
N
N
N
N
N
N
N
DBU (3 eq)
Br (6 eq)
PhH, 80°C
7 h, 12%
THF, 66°C
90%
CHCl3, 25°C
96%
20
9
24
25
CH3CN
82°C
Br (6 eq)
3 h
Br
N
Br
N
N
N
+
+
N
N
Br
12
1
15%
9
44%
22%
Scheme 7 Synthesis of brominated quinoxalines
2.3 Synthesis of N-oxides of quinoxalines and bromination of N-oxides
As shown in Schemes 2, 4, and 5, the direct bromination of quinoxaline (1) and saturated derivatives 15
and 19 gave only products derived on the benzene ring due to electron deficiency in the heterocyclic
ring. For derivatives on the heterocyclic ring, we also studied the bromination of N-oxide derivatives, as
oxygen atoms increase the electron density of the heterocyclic ring by a resonance effect. For this
purpose, quinoxaline (1) was oxidized to bis N-oxide 2628 by meta-chloroperbenzoic acid (m-CPBA) in
nearly quantitative yield. Bromination of 26 with POBr3 (2.9 eq.) in the presence of NEt3 in methylene
chloride at 40 °C gave the target compound dibromide 2729 in 82% yield as well as deoxygenated
compound 1 in 18% yield. Under the same reaction conditions, when we used POBr3 in lower quantity
(1.0 eq.), we obtained monobromide 28 in 25% yield along with dibromide 27 (20%) and mono N-oxide
2930 (45%). We also noticed that the reaction temperature has a dramatic effect on product distribution.
Reaction at 25 °C produced monobromo N-oxide 30 as the major product as well as dibromide 27 and
deoxygenated compound 1 in 20% and 24% yields, respectively.
9

ACCEPTED MANUSCRIPT
N
N
N
Br
Br
N
N
Br
+
+
N
O
27
28
29
20%
25%
45%
POBr3 (1 eq.)
Et3N (1.2 eq.)
CH2Cl2, 40°C
O
POBr3 (2.9 eq.)
Et3N (2.5 eq.)
N
N
Br
Br
N
N
N
N
N
m-CPBA (3 eq)
+
CHCl3, 25°C
48 h
CH2Cl2, 40°C
N
O
27
82%
1
1
26
99%
18%
POBr3 (1 eq)
Et3N (1.2 eq)
CH2Cl2, 25°C
N
Br
N
N
Br
N
N
+
+
N
O
Br
1
27
24%
30
47%
20%
Scheme 8 Synthesis of brominated quinoxalines via its N-oxide derivatives
After the successful synthesis of the dibromide 27, we turned our attention towards the synthesis of
monobromide 2831 via mono N-oxide 2929 obtained by the reaction of 1 with m-CPBA (1.1 eq.) in
77% yield in addition to bis N-oxide 26 (9%). From the reaction of N-oxide 26 with POBr3 (1.45 eq.),
target compound 2831 was successfully obtained in 99% yield (Scheme 9).
N
N
N
N
N
Br
POBr3 (1.45 eq)
m-CPBA (1.1 eq)
Et3N (1.3 eq)
CH2Cl2, r.t.
CHCl3, 25°C
48 h
N
O
29
28
1
99%
77%
+
26 (9%)
Scheme 9 Synthesis of 2-bromoquinoxaline via its N-oxide derivative
10

ACCEPTED MANUSCRIPT
Similar transformation of compound 9 to compound 32 was accomplished via N-oxide 31 in nearly
quantitative yield (Scheme 10). This reaction allowed the first and effective synthesis of the dibromide
32.
O
N
N
Br
N
N
N
POBr3 (2 eq), Et3N (1.5 eq)
m-CPBA (3 eq)
CH2Cl2, 25°C
overnight, 99%
CH2Cl2, 25°C, 2 d
99%
N
Br
Br
Br
32
9
31
Scheme 10 Synthesis of 2,6-dibromoquinoxaline via its N-oxide derivative
2.4 Structural analyses
1
13
The structures of these compounds were elucidated on the basis of H- and C-NMR spectral data and
elemental analyses, and by comparison of some spectral data of related systems reported in the
literature. The position of substituents in quinoxaline units is easily determined by vicinal and allylic
coupling constants. As compounds 12 and 13 are symmetrical in structure, it is not easy to determine
1
13
which one is which as both of them give two singlets in the H-NMR and four lines in the C-NMR
spectra. As physical data for compound 12 exists in the literature,22 it is easy to identify this compound
by means of its physical and spectral data. It is clear that the other compound should be structure 13. In
addition, H5 and H8 protons in compound 13 resonate at a higher field than H6 and H7 protons of
dibromide 12. These confirm the assigned structure. The other symmetric dibromide 27 also has four
lines in the 13C-NMR spectrum due to its symmetrical structure. Unlike the other symmetric dibromides
12 and 13, the typical AA’BB’ system of the benzene ring in the 1H-NMR spectra exactly confirms the
1
13
structure of dibromide 27. Only one singlet in the H-NMR spectrum and four lines in the C-NMR
spectrum confirm the structure of tetrabromide 18 by assistance from elemental analyses.
It is not easy to find the exact configuration of substituents in compound 21 because of its symmetrical
1
structure and highly complex second order spin system in the H-NMR spectra. However, we assumed
that the substituents should be trans in this compound, as bulky groups should be in equatorial-equatorial
orientations, which are typical for 1,2-, and 1,4- substituted cyclohexane and cyclohexene rings, which
are sterically more favorable.
11

ACCEPTED MANUSCRIPT
Because of the similar Rf values and solubility in solvents, monobromide 16 and dibromide 17 could not
be isolated as pure compounds. However, NMR analysis of a mixture provided us with enough
information for assignment of all signals of the proposed structures. For further support of the structures,
the mixture of these compounds was subjected to oxidation with DDQ. Monobromide 10 and dibromide
13 were obtained in quantitative yield, and this mixture could be easily separated by a combination of
sublimation and column chromatography. This transformation both supports the proposed structures and
also allows an alternative synthesis of monobromide 10 and dibromide 13 (Scheme 14).
H
N
H
N
Br
Br
Br
Br
N
N
N
N
DDQ (3 eq)
+
+
PhH, 80°C
5h
Br
N
H
N
H
Br
100%
10
13
16
17
Scheme 14 Aromatization of saturated quinoxalines
3. Conclusion
We have described an efficient and convenient synthesis of brominated quinoxalines. We showed that
bromination of a parent compound under different conditions results in the formation of several new
compounds in high yield along with the known derivatives. The bromination reaction of
tetrahydroquinoxaline generally produced aromatization of the ring and formed parent compound 1
along with a few halogenated compounds, whereas bromination of isomeric tetrahydroquinoxaline gave
a bromination product over the saturated ring. Bromination of N-oxides gave us a brominated product on
the ring with nitrogen atoms. An alternative and effective synthetic method is developed also for
reduction of quinoxaline to tetrahydroquinoxaline. These compounds are potential starting points for
polyfunctionalization to quinoxaline derivatives that are important for many applications such as
materials chemistry or for synthesis of biomaterials. Some transformation and functionalization
reactions of this compound are in progress.
4. Experimental
4.1 General remarks
All reactions were carried out under nitrogen and monitored by TLC and/or 1H-NMR spectroscopy.
All solvents were dried and distilled before use. Column chromatography was performed on silica gel
(60 mesh, Merck). TLC was carried out on Merck 0.2 mm silica gel 60 F254 anal. aluminum plates.
1
Melting points are uncorrected. The H- and 13C-NMR spectra were recorded on 400 MHz NMR
12

ACCEPTED MANUSCRIPT
spectrometers. Apparent splittings are given in all cases in ppm and coupling constants J in Hz. All new
compounds gave satisfactory HRMS or elemental analyses.
4.1.1 General methods for high temperature bromination of quinoxaline and derivatives
Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or
tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at
1
reflux temperature. The reaction was monitored by TLC or H-NMR spectroscopy. After the desired
time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was
removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate
(10 mL) and the mixture was extracted with ethyl acetate (2x25 mL). Combined organic layers were
washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method
described in below.
4.1.2 General methods for photochemical bromination of quinoxaline and derivatives
A solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in CCl4 (10 mL) was irradiated with a
500-W lamp in a 25-mL flask equipped with a reflux condenser. Bromine was added dropwise to the
refluxing solution and the solution was irradiated at reflux temperature. The reaction was monitored by
1
TLC or H-NMR spectroscopy. The resulting reaction mixture was allowed to warm to room
temperature and diluted with a saturated solution of sodium carbonate (10 mL). The mixture was
extracted with methylene chloride (2x25 mL) and the combined organic layers were washed with water,
dried over Na2SO4 and concentrated.
4.2 Bromination of Quinoxaline (1) with Bromine in AcOH
The reaction was carried out by the general procedure described in section 4.1.1 using quinoxaline (1)
(390 mg, 3.0 mmol), bromine (3.16 g, 19.8 mmol) and glacial acetic acid (10 mL). The resulting
reaction mixture was kept at reflux temperature for 24 h.
6,7-Dibromoquinoxaline (13) was separated by crystallization from methanol (400 mg, 46%). White
solid, mp 200-202 °C (lit20e mp= 210-212 °C). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 8.45 (s, 2H).
13C NMR (100 MHz, CDCl3) δ 146.0, 142.2, 133.6, 126.9. IR (KBr, cm-1): 3061s, 3036s, 2964m,
1575w, 1454w, 1421w, 1329w, 1184m, 915s. MS (EI, 70 eV): m/z 291/289/287(M+, 100), 236/234 (25),
13

ACCEPTED MANUSCRIPT
210/208 (M+ -Br, 50), 155 (5). Anal. Calcd. for C8H4Br2N2: C, 33.37, H, 1.40, N, 9.73%. Found: C,
33.41, H, 1.42, N, 9.58.
6-Bromoquinoxaline (10)20 was obtained by sublimating of the remaining part of residue at 125 °C (70
mg, 11%). White solid, mp 49-51 °C (lit20f mp= 48-49 °C). 1H NMR (400 MHz, CDCl3) δ 8.88-8.84 (m,
2H), 8.31 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (dd, J = 8.9 and 2.0 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 145.7, 145.2, 143.6, 141.8, 133.7, 131.8, 130.9, 124.1. IR (KBr, cm-1) 3059w, 1592w,
1482s, 1356m, 1204m, 1170m, 1127m, 1020s, 822s. MS (EI, 70 eV): m/z 210/209(M+, 100), 156(15),
130(M+ -Br, 10). Anal. Calcd. for C8H5BrN2: C, 45.97, H, 2.41, N, 13.40%. Found: C, 45.45, H, 2.29,
N, 13.35.
4.3 Bromination of Quinoxaline (1) with Bromine in Sulfuric Acid
The reaction was carried out by the general procedure described in section 4.1.1 using quinoxaline (1)
(390 mg, 3.0 mmol), bromine (2.43 g, 15.2 mmol) and sulfuric acid (10 mL). The resulting reaction
mixture was kept at 200 °C for 24 h.
6,7-Dibromoquinoxaline (13) (80 mg, 9%) data as above.
6-Bromoquinoxaline (10) (175 mg, 28%). data as above
4.4 Bromination of Quinoxaline (1) with Bromine in Acetonitrile
The reaction was carried by the general procedure described in section 4.1.1 using quinoxaline (1) (390
mg, 3.0 mmol), bromine (3.84 g, 24.0 mmol) and acetonitrile (20 mL). The resulting reaction mixture
was kept at reflux temperature for 25 h. The residue was purified via column chromatography on silica
gel (30 g) by eluting with 15% EtOAc/n-hexane. 5,8-Dibromoquinoxaline (12) was obtained as a sole
product.
1
5,8-Dibromoquinoxaline (12)22 (650 mg, 75%). Brown solid, decom. 225 °C (lit22d mp= 229 °C). H
NMR (400 MHz, CDCl3) δ 9.02 (s, 2H), 8.00 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 146.0, 141.6,
14

ACCEPTED MANUSCRIPT
133.7, 124.0. IR (KBr, cm-1) 3048w, 1449m, 1374m, 1170m, 1110w, 1025w, 972s. Anal. Calcd. for
C8H4Br2N2: C, 33.37, H, 1.40, N, 9.73%. Found: C, 33.42, H, 1.54 , N, 9.66.
4.5 Bromination of Quinoxaline (1) with Bromine (8 eq) in CCl4
The reaction was carried out by the general procedure described in section 4.1.2 using quinoxaline (1)
(390 mg, 3.0 mmol), bromine (3.84 g, 24.0 mmol) and carbon tetrachloride (20 mL). The resulting
reaction mixture was kept at reflux temperature for 18 h. The residue was purified via column
chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromoquinoxaline (12) (260 mg, 30%) data as before.
The second fraction was 5,6-dibromoquinoxaline (14)25 (215 mg, 25%). White solid, mp 182-184°C
(lit25 mp 182-184.3 °C, decomposition). 1H NMR (400 MHz, CDCl3) δ 8.98-8.95 (m, 1H), 8.90-8.88 (m,
1H), 8.00-7.97 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 146.0, 145.4, 142.6, 142.0, 134.5, 129.7, 128.1,
127.1. IR (KBr, cm-1): 3012m, 1589w, 1471m, 1396m, 1351m, 1112s, 1030s, 966s. Anal. Calcd. for
C8H4Br2N2: C, 33.37, H, 1.40, N, 9.73%. Found: C, 33.66, H, 1.65, N, 9.79.
4.6 Bromination of Quinoxaline (1) with Bromine (2 eq) in CCl4
The reaction was carried out by the general procedure described in section 4.1.2 using quinoxaline (1)
(390 mg, 3.0 mmol), bromine (960 mg, 6.0 mmol) and carbon tetrachloride (15 mL). The resulting
reaction mixture was kept at reflux temperature for 45 h. The residue was purified via column
chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5-bromoquinoxaline (9)19 (440 mg, 70%). White solid, mp 68-69 °C (lit19b mp 65-
1
67 °C). H NMR (400 MHz, CDCl3) δ 8.97-8.95 (m, 1H), 8.89-8.87 (m, 1H), 8.10 (bd, J=8.0 Hz, 1H),
8.09 (dd, J=8.0 Hz, J = 2.3 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 145.6,
145.4, 144.0 140.7, 133.6, 130.3, 129.5, 124.1. IR (KBr, cm-1): 3060w, 1601w, 1554w, 1485m, 1458w,
1057m, 1025m, 967s, 767s. MS (EI, 70 eV): m/z /210/208(M+, 60), 181 (20), 156 (20), 130 (M+ -Br,
15), 102 (20), 75 (100). Anal. Calcd. for C8H5BrN2: C, 45.97, H, 2.41, N, 13.40%. Found: C, 46.36, H,
2.65, N, 12.92.
15

ACCEPTED MANUSCRIPT
The second fraction was 5,8-dibromoquinoxaline (12) (85 mg, 10%) data as before.
The third fraction was 5,7-dibromoquinoxaline (11)21 (25 mg, 3%). White solid, mp 162-164 °C (lit21
mp, it is not given). 1H NMR (400 MHz, CDCl3) δ 8.96 (d, A-part of AB system, J = 1.7 Hz, 1H), 8.88
(d, B-part of AB system, J = 1.7 Hz, 1H), 8.29 (d, A-part of AB system, J = 2.0 Hz, 1H), 8.22 (d, B-part
of AB system, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 146.3, 145.6, 144.1, 139.7, 136.6, 131.7,
125.2, 123,8. IR (KBr, cm-1): 3064w, 3048w, 3036w, 2917w, 1634b, 1548w, 1466w, 1363w, 1095b,
1031w, 967w, 883m. Anal. Calcd. for C8H4Br2N2: C, 33.37, H, 1.40, N, 9.73%. Found: C, 33.69, H,
1.51, N, 9.82.
4.7 Bromination of Quinoxaline (1) with NBS in AcOH or DMF
A solution of quinoxaline (1) (390 mg, 3.0 mmol), NBS (390 mg, 3.0 mmol), and benzoyl peroxide
(catalytic amount) in glacial acetic acid (10 mL) was heated at reflux temperature for 20h. The reaction
was monitored by TLC or 1H-NMR spectroscopy. The resulting reaction mixture was allowed to cool to
room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a
saturated solution of sodium carbonate (10 mL) and the mixture was extracted with ethyl acetate (2x25
mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. 6-
Bromoquinoxaline (10) (315 mg, 50%) was obtained as a sole product. The reaction was repeated using
DMF as a solvent at the same reaction condition and monobromide 10 was obtained in 51% yield.
4.8 Bromination of Quinoxaline with NBS in CHCl3
The reaction was carried out by the procedure described in section 4.7 using quinoxaline (1) (390 mg,
3.0 mmol), NBS (3.74 g, 21.0 mmol) and chloroform (20 mL). The resulting reaction mixture was kept
at reflux temperature for 45 h. The residue was purified via column chromatography on silica gel (100 g)
by eluting with 15% EtOAc/n-hexane.
The first fraction was 6-bromoquinoxaline (10) (180 mg, 29%) data as before.
The second fraction was 5,8-dibromoquinoxaline (12) (25 mg, 3%) data as before.
16

ACCEPTED MANUSCRIPT
The third fraction was 6,7-dibromoquinoxaline (13) (85 mg, 10%) data as before.
The fourth fraction was 5,7-dibromoquinoxaline (11) (250 mg, 29%) data as before.
4.9 Bromination of Quinoxaline (1) with NBS in CH3CN
The reaction was carried out by the procedure described in section 4.7 using quinoxaline (1) (390 mg,
3.0 mmol), NBS (3.20 g, 18.0 mmol) and acetonitrile (20 mL). The resulting reaction mixture was kept
at reflux temperature for 20 h. The residue was purified via column chromatography on silica gel (100 g)
by eluting with 15% EtOAc/n-hexane.
The first fraction was 6-bromoquinoxaline (10) (345 mg, 55%) data as before.
The second fraction was 5,8-dibromoquinoxaline (12) (45 mg, 5%) data as before.
The third fraction was 6,7-dibromoquinoxaline (13) (130 mg, 15%) data as before.
4.10 Bromination of Quinoxaline (1) with Bromine (8 eq) and Barium Carbonate
Bromine (3.84 g, 24 mmol) was added dropwise to a magnetically stirred refluxing mixture of
quinoxaline (1) (390 mg, 3.0 mmol) and barium carbonate (1.20 g, 6.1 mmol) in acetonitrile (20 mL).
The resulting reaction mixture was heated at reflux temperature for 25 h and allowed to warm to room
temperature. The solvent was evaporated and the mixture was diluted with a saturated solution of
sodium carbonate (10 mL). The mixture was extracted with ethyl acetate (3x25 mL) and combined
organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was purified
via column chromatography on silica gel (100 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 6-bromoquinoxaline (10) (195 mg, 31%) data as before.
The second fraction was 5,8-dibromoquinoxaline (12) (45 mg, 5%) data as before.
The third fraction was 6,7-dibromoquinoxaline (13) (50 mg, 6%) data as before.
17

ACCEPTED MANUSCRIPT
The fourth fraction was 5,7-dibromoquinoxaline (11) (120 mg, 14%) data as before.
The fifth fraction was 5,6-dibromoquinoxaline (14) (240 mg, 28%) data as before.
4.11 Bromination of Quinoxaline (1) with Bromine (3 eq) and Barium Carbonate
Bromine (1.44 g, 9.0 mmol) was added (partly as three portions in 48h) to a magnetically stirred
refluxing mixture of quinoxaline (1) (390 mg, 3.0 mmol) and barium carbonate (1.20 g, 6.1 mmol) in
acetonitrile (20 mL) at reflux temperature. The resulting reaction mixture was heated at reflux
temperature for 72h and allowed to cool to room temperature. The solvent was evaporated and the
mixture was diluted with saturated solution of sodium carbonate (10 mL). The mixture was extracted
with ethyl acetate (3x25 mL) and combined organic layers were washed with water, dried over Na2SO4
and concentrated. The residue was purified via column chromatography on silica gel (20 g) by eluting
with 15% EtOAc/n-hexane and 6-bromoquinoxaline (10) (410 mg, 65%) was obtained.
4.12 Birch reduction of quinoxaline (1) with sodium in ammonia:
A two-necked round-bottomed flask (1 L) was immersed in an acetone–dry ice bath and fitted with a dry
ice condenser. Ammonia (100 mL) was condensed into the flask at -78 °C and sodium (4.60 g, 200.0
mmol) was added in small portions, with vigorous stirring, over a period of 15 min. The mixture was
stirred at -40 °C for 30 min. and a solution of quinoxaline (1) (2.60, 20 mmol) in THF (20 mL) was
added dropwise to the blue solution at -78 °C over 15 min. The reaction mixture was stirred at -78 °C for
1 hour and t-butyl alcohol (14.82 g, 200.0 mmol) was added dropwise to the reaction mixture. After the
addition was complete, the reaction mixture was stirred at -78 °C for another 1 hour. The cooling bath
was removed and the ammonia was allowed to evaporate overnight. A solution of ammonium chloride
(20 mL) was added to the mixture and the mixture was extracted with ethyl acetate (3x50 mL).
Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was
purified via column chromatography on silica gel (100 g) by eluting with 10% EtOAc/n-hexane and
1,2,3,4-tetrahydroquinoxaline 1526 was obtained as a brown solid (1.75 g, 65%, mp 91-93 °C (lit26j mp
95.5-97 °C)).
18

ACCEPTED MANUSCRIPT
1H NMR (400 MHz, CDCl3) δ 6.59 (AA’ part of AA’BB’ system, 2H), 6.50 (BB’ part of AA’BB’
system, 2H), 3.42 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 133.6, 118.7, 114.6, 41.3. IR (KBr, cm-1):
3245s, 3048w, 2980m, 2922m, 1600m, 1506m, 1356w, 1309w, 1270w, 1242w, 1104w, 1049w, 735s. (EI,
70 eV): m/z 136/135 (M+, 100). Anal. Calcd. for C8H10N2: C, 71.61, H, 7.51, N, 20.88%. Found: C,
71.47, H, 7.73, N, 20.61.
4.13 Birch reduction of quinoxaline (1) with lithium in ammonia:
Lithium (2.64 g, 380.0 mmol) was added to a magnetically stirred solution of quinoxaline (1) (2.6 g,
20.0 mmol) in dry ether at 0°C under Ar atm over 15 min. t-Butyl alcohol (20.16 g, 272.0 mmol) was
added slowly to the reaction mixture and the mixture was stirred at 0°C under ammonia atm for 7 h and
overnight at room temperature. A solution of ammonium chloride (30 mL) was added to the mixture and
the mixture was extracted with ether (3x50 mL). Combined organic layers were washed with water,
dried over Na2SO4 and concentrated. The residue was purified via column chromatography on silica gel
(100 g) by eluting with 10% EtOAc/n-hexane and tetrahydroquinoxaline 15 was obtained as a brown
solid (2.65 g, 99%).
4.14 Bromination of Tetrahydroquinoxaline 15 with Bromine (1 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 15 (270 mg, 2.0 mmol), bromine (350 mg, 2.2 mmol) and acetonitrile (10 mL).
The resulting reaction mixture was kept at reflux temperature for 2.5 h. Quinoxaline was purified via
column chromatography on silica gel (50 g) by eluting with 20% EtOAc/n-hexane.
Quinoxaline (1): 130 mg, 50% data as before.
6-Bromo-1,2,3,4-tetrahydroquinoxaline (16),26g (130 mg, 30%) was isolated as a mixture with 17 in a
ratio of (3:2).
1H NMR (400 MHz, CDCl3) δ 6.64 (dd, J = 8.2 Hz and J = 2.1 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 6.34
13
(d, J = 8.2 Hz, 1H), 3.61 (bs, 2H), 3.38 (s, 4H). C NMR (100 MHz, CDCl3) δ 135.0, 132.5, 120.8,
116.6, 115.5, 110.1, 41.0 (2C).
19

ACCEPTED MANUSCRIPT
6,7-Dibromo-1,2,3,4-tetrahydroquinoxaline (17): 120 mg, 20%
1H NMR (400 MHz, CDCl3) δ 6.67 (s, 2H), 3.61 (bs, 2H), 3.36 (s, 4H). 13C NMR (100 MHz, CDCl3) δ
134.0, 117.7, 111.3, 40.7.
4.15 Bromination of Tetrahydroquinoxaline 15 with Bromine (2 eq):
The reaction was carried by the general procedure described in section 4.1.1 using tetrahydroquinoxaline
15 (270 mg, 2.0 mmol), bromine (675 mg, 4.2 mmol) and acetonitrile (10 mL). The resulting reaction
mixture was kept at reflux temperature for 2.5 h. The solvent was removed, and then methanol was
added to the mixture, the insoluble dibromide 11 (30 mg, 5%) was collected by filtration. The residue
was filtered via column including silica gel and products were analyzed by 1H-NMR spectroscopy.
Quinoxaline (1): 92 mg, 35% data as before.
6-Bromo-1,2,3,4-tetrahydroquinoxaline (16): 65 mg, 15% data as before.
6,7-Dibromo-1,2,3,4-tetrahydroquinoxaline (17): 60 mg, 10% data as before.
6-Bromoquinoxaline (10): 30 mg, 7% data as before.
6,7-Dibromoquinoxaline (13): 30 mg, 5% data as before.
4.16 Bromination of Tetrahydroquinoxaline 15 with Bromine (6 eq):
The reaction was carried by the general procedure described in section 4.1.1 using tetrahydroquinoxaline
15 (270 mg, 2.0 mmol), bromine (2.0 g, 12.5 mmol) and acetonitrile (10 mL). The resulting reaction
mixture was kept at reflux temperature for 2.5 h. The residue was filtered via column including silica gel
and products were analyzed by 1H-NMR spectroscopy.
Quinoxaline (1): 92 mg, 35% data as before.
6-Bromoquinoxaline (10): 48 mg, 11% data as before.
20

ACCEPTED MANUSCRIPT
6,7-Dibromoquinoxaline (13): 35 mg, 6% data as before.
5-Bromoquinoxaline (9): 15 mg, 4% data as before.
5,7-Dibromoquinoxaline (11): 30 mg, 5% data as before.
5,6,7,8-Tetrabromoquinoxaline (18): 150 mg, 17%, brown solid, mp >300 °C.
1H NMR (400 MHz, CDCl3) δ 9.00 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 146.3, 140.4, 136.9, 125.6.
IR (KBr, cm-1): 3031w, 1687w,1425w, 1333w, 1030w, 983w. Anal. Calcd. for C8H2Br4N2: C, 21.56, H,
0.45, N, 6.28%. Found: C, 22.03, H, 0.67, N, 6.10.
4.17 Bromination of Tetrahydroquinoxaline 15 with Bromine (6 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 15 (135 mg, 1.0 mmol), bromine (1.0 g, 6.3 mmol) and acetonitrile (10 mL). The
resulting reaction mixture was kept at reflux temperature for 10 h. 5,6,7,8-tetrabromoquinoxaline (18)
(225 mg, 50%) was separated by crystallization from ethyl acetate.
Quinoxaline (1): 65 mg, 50%.
4.18 Bromination of Tetrahydroquinoxaline 15 with Bromine (12 eq):
Bromine (1.0 g, 6.3 mmol) was added dropwise to a magnetically stirred solution of
tetrahydroquinoxaline 15 (135 mg, 1.0 mmol) in methylene chloride at room temperature. The resulting
reaction mixture was stirred for 15 h. The mixture was diluted with a saturated solution of sodium
carbonate (10 mL) and the mixture was extracted with methylene chloride (3x25 mL). The combined
organic layers were washed with water, dried over Na2SO4 and concentrated. Methanol was added to the
mixture, the insoluble tetrabromide 18 (290 mg, 65%) was collected by filtration. Methanol was
removed, and then the residue was recrystallized from methylene chloride and 6,7-dibromoquinoxaline
(13) (72 mg, 25%) was obtained.
21

ACCEPTED MANUSCRIPT
4.19 Bromination of Tetrahydroquinoxaline 15 with Bromine (30 eq):
A mixture of 1,2,3,4-tetrahydroquinoxaline (15) (135 mg, 1.0 mmol) and bromine (4.82 g, 30.2 mmol)
was stirred in dark at 4 °C for 4 day. After bromine was removed, 5,6,7,8-tetrabromoquinoxaline (18)
(445 mg, 99%) was obtained in quantitative yield.
4.20 Bromination of Tetrahydroquinoxaline 19 with Bromine (1 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (350 mg, 2.2 mmol) and acetonitrile (10 mL).
The resulting reaction mixture was kept at reflux temperature for 2 h. The residue was purified via
column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (55 mg, 9%), white solid,
decom.>130°C. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 2H), 5.58 (bd, J = 2.9 Hz, 2H), 2.87 (bd, A-part
of AB system, J = 10.6 Hz, 2H), 2.46 (bd, B-part of AB system, J = 10.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 150.1, 144.7, 48.7, 28.1. IR (KBr, cm-1): 3047w, 2964m, 2912w, 2846w, 1434s, 1407s, 1341w,
1233w, 1199s, 1175m, 1085w, 1047m, 1007m, 932s. MS (EI, 70 eV): m/z 291/290/289 (M+, 5), 213/212
(M+ -Br, 10), 131 (M+ -2Br, 100). Anal. Calcd. for C8H8Br2N2: C, 32.91, H, 2.76, N, 9.59%. Found: C,
33.40, H, 2.95, N, 9.47.
1
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20)27 (350 mg, 82%), brown oil. H
NMR (400 MHz, CDCl3) δ 8.44-8.40 (m, 2H), 5.52-5.49 (m, 1H), 3.21-310 (m, 1H), 3.09-2.96 (m, 1H),
2.53-2.44 (m, 1H), 2.41-2.22 (m, 2H), 2.09-2.00 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 152.3, 151.3,
143.9, 142.4, 50.1, 32.4, 31.1, 18,2. IR (KBr, cm-1): 3046w, 2949m, 2874w, 1646b, 1456m, 1428m,
1403s, 1194m, 1182m, 1169m, 1143m, 1080w, 1054m, 1042m, 934m. MS (EI, 70 eV): m/z 214/212 (M+,
10), 168(4), 134(M+ -Br, 100). Anal. Calcd. for C8H9BrN2: C, 45.10, H, 4.26, N, 13.15%. Found: C,
45.41 , H, 4.25, N,12.91.
4.21 Bromination of Tetrahydroquinoxaline 19 with Bromine (1 eq.):
22

ACCEPTED MANUSCRIPT
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (350 mg, 2.2 mmol) and chloroform (10 mL).
The resulting reaction mixture was kept at reflux temperature for 2h. The residue was purified via
column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (42 mg, 7%) data as before.
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (235 mg, 55%) data as before.
4.22 Bromination of Tetrahydroquinoxaline 19 with Bromine (2 eq.):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (650 mg, 4.1 mmol) and acetonitrile (10 mL).
The resulting reaction mixture was kept at reflux temperature for 2 h. The residue was purified via
column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,5,8-tribromo-5,6,7,8-tetrahydroquinoxaline (22) (30 mg, 4%), white solid,
decom. > 75 °C. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.55 (s, 1H), 5.51-5.47 (m, 1H), 3.62-3.50
(m, 1H), 3.27-3.18 (m, 1H), 2.80-2.68 (m, 1H), 2.43-2.34 (m, 1H). 13C NMR (100 MHz, CDCl3) δ
151.3, 146.4, 145.7, 145.2, 61.4, 47.7, 43.8, 30.9. IR (KBr, cm-1): 3044w, 2965w, 2923w, 2848w,
1433m, 1400s, 1204m, 1176w, 1003w, 930s, 727s. MS (EI, 70 eV): m/z 291/290/289 (M+ -Br, 10),
210/209/208 (M+ -2Br, 45), 132/131(M+ -3Br, 100), 104(30), 78(45). Anal. Calcd. for C8H7Br3N2: C,
25.91, H, 1.90, N, 7.55%. Found: C, 26.13 , H, 1.84 , N, 7.78 .
The second fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (505 mg, 86%) data as before.
The third fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (38 mg, 9%) data as before.
4.23 Bromination of Tetrahydroquinoxaline 19 with Bromine (2 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (650 mg, 4.1 mmol) and chloroform (10 mL).
23

ACCEPTED MANUSCRIPT
The resulting reaction mixture was kept at reflux temperature for 2 h. The residue was purified via
column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (410 mg, 70%).
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (20 mg, 5%).
4.24 Bromination of Tetrahydroquinoxaline 19 with Bromine (3 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (1.00 g, 6.3 mmol) and acetonitrile (10 mL). The
resulting reaction mixture was kept at reflux temperature for 2.5 h. The residue was purified via column
chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,5,8,8-tetrabromo-5,6,7,8-tetrahydroquinoxaline (23) (45 mg, 5%), white solid,
mp 156-157 °C.
13
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 2H), 3.27 (s, 4H). C NMR (100 MHz, CDCl3) δ 147.2, 146.1,
59.6, 45.7. IR (KBr, cm-1): 3054w, 2972w, 2914w, 2846w, 1436m, 1393m, 1343w, 1202m,1107w,
1033w, 931s, 749s. MS (EI, 70 eV): m/z 289/287/285 (M+ -2Br, 55), 233 (20), 153 (15), 100 (20), 75
(100). Anal. Calcd. for C8H6Br4N2: C, 21.36, H, 1.34, N, 6.23%. Found: C, 21.66 , H, 1.50, N, 5.97.
The second fraction was 5,5,8-tribromo-5,6,7,8-tetrahydroquinoxaline (22) (635 mg, 85%).
The third fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (45 mg, 8%).
The fourth fraction was 5-bromoquinoxaline (9) (10 mg, 2%).
4.25 Bromination of Tetrahydroquinoxaline 19 with Bromine (3 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (1.00 g, 6.3 mmol) and chloroform (10 mL). The
24

ACCEPTED MANUSCRIPT
resulting reaction mixture was kept at reflux temperature for 2.5 h. The residue was purified via column
chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,5,8,8-tetrabromo-5,6,7,8-tetrahydroquinoxaline (23) (45 mg, 5%) data as before.
The second fraction was 5,5,8-tribromo-5,6,7,8-tetrahydroquinoxaline (22) (450 mg, 60%) data as
before.
The third fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (90 mg, 15%) data as before.
4.26 Bromination of Tetrahydroquinoxaline 19 with Bromine (6 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (135 mg, 1.0 mmol), bromine (1.00 g, 6.3 mmol) and acetonitrile (10 mL). The
resulting reaction mixture was kept at reflux temperature for 3 h. The residue was purified via column
chromatography on silica gel (20 g) by eluting with 15% EtOAc/n-hexane. 5,5,8,8-Tetrabromo-5,6,7,8-
tetrahydroquinoxaline (23) (450 mg, 99%) was obtained as a sole product.
4.27 Bromination of Tetrahydroquinoxaline 19 with Bromine (6 eq):
The reaction was carried out by the general procedure described in section 4.1.1 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (2.00 g, 12.5 mmol) and chloroform (10 mL).
The resulting reaction mixture was kept at reflux temperature for 3 h. The residue was purified via
column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The second fraction was 5,5,8,8-tetrabromo-5,6,7,8-tetrahydroquinoxaline (23) (680 mg, 75%) data as
before.
The third fraction was 5,5,8-tribromo-5,6,7,8-tetrahydroquinoxaline (22) (75 mg, 10%) data as before.
25

ACCEPTED MANUSCRIPT
4.28 Photochemical Bromination of Tetrahydroquinoxaline 19 with Bromine (1.1 eq):
The reaction was carried out by the general procedure described in section 4.1.2 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (350 mg, 2.2 mmol) and carbon tetrachloride
(10 mL). The resulting reaction mixture was kept at reflux temperature for 2 h. The residue was purified
via column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (90 mg, 15%) data as before.
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (300 mg, 70%) data as before.
4.29 Photochemical Bromination of Tetrahydroquinoxaline 19 with Bromine (2.1 eq):
The reaction was carried out by the general procedure described in section 4.1.2 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (650 mg, 4.1 mmol) and carbon tetrachloride
(10 mL). The resulting reaction mixture was kept at reflux temperature for 30 min. The residue was
purified via column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (500 mg, 85%) data as before.
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (50 mg, 12%) data as before.
4.30 Photochemical Bromination of Tetrahydroquinoxaline 19 with Bromine (3.1 eq):
The reaction was carried out by the general procedure described in section 4.1.2 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (1.00 g, 6.3 mmol) and carbon tetrachloride (10
mL). The resulting reaction mixture was kept at reflux temperature for 45 min. The residue was purified
via column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,5,8-tribromo-5,6,7,8-tetrahydroquinoxaline (22) (320 mg, 43%) data as before.
The second fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (80 mg, 14%) data as before.
26

ACCEPTED MANUSCRIPT
The third fraction was 5-bromoquinoxaline (9) (100 mg, 24%) data as before.
4.31 Photochemical Bromination of Tetrahydroquinoxaline 19 with Bromine (4.1 eq):
The reaction was carried out by the general procedure described in section 4.1.2 using
tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), bromine (1.32 g, 8.3 mmol) and carbon tetrachloride (10
mL). The resulting reaction mixture was kept at reflux temperature for 45 min. The residue was purified
via column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,6,7,8-tetrabromo-5,6,7,8-tetrahydroquinoxaline (23) (480 mg, 53%) data as
before.
The second fraction was 5,8-dibromoquinoxaline (12) (185 mg, 32%) data as before.
The third fraction was 5-bromoquinoxaline (9) (20 mg, 5%) data as before.
4.32 Bromination of Tetrahydroquinoxaline 19 with NBS (6 eq):
The reaction was carried out by the procedure described in section 4.7 using tetrahydroquinoxaline 19
(270 mg, 2.0 mmol), NBS (4.48 g, 12.5 mmol) and acetonitrile (10 mL). The resulting reaction mixture
was kept at reflux temperature for 2 h. The residue was purified via column chromatography on silica
gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (320 mg, 55%) data as before.
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (150 mg, 35%) data as before.
4.33 Bromination of Tetrahydroquinoxaline 19 with NBS (6 eq):
The reaction was carried out by the procedure described in section 4.7 using tetrahydroquinoxaline 19
(270 mg, 2.0 mmol), NBS (4.48 g, 12.5 mmol) and chloroform (10 mL). The resulting reaction mixture
27

ACCEPTED MANUSCRIPT
was kept at reflux temperature for 2 h. The residue was purified via column chromatography on silica
gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (235 mg, 40%) data as before.
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (85 mg, 20%) data as before.
4.34 Bromination of Tetrahydroquinoxaline 19 with NBS (6 eq):
A solution of tetrahydroquinoxaline 19 (270 mg, 2.0 mmol), NBS (4.48 g, 12.5 mmol) and benzoyl
peroxide (catalytic amount) in CCl4 (10 mL) was irradiated with a 500-W lamp in a 25-mL flask
equipped with a reflux condenser. The reaction was monitored by TLC or 1H-NMR spectroscopy. After
2h, the resulting reaction mixture was allowed to cool to room temperature and diluted with a saturated
solution of sodium carbonate (10 mL). The mixture was extracted with methylene chloride (2x25 mL)
and combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue
was purified via column chromatography on silica gel (50 g) by eluting with 15% EtOAc/n-hexane.
The first fraction was 5,8-dibromo-5,6,7,8-tetrahydroquinoxaline (21) (245 mg, 42%) data as before.
The second fraction was 5-bromo-5,6,7,8-tetrahydroquinoxaline (20) (78 mg, 18%) data as before.
4.35 Reaction of Tetrabromide 23 with DBU:
DBU (170 mg, 165 mmL, 1.1 mmol) was added dropwise to a solution of the tetrabromide 23 (225 mg,
0.5 mmol), in dry THF (20 mL) in dark and the resulting reaction mixture was stirred for overnight at
room temperature. The solvent was evaporated, the mixture was diluted with a solution of sodium
hydroxide (10%, 10 mL) and the aqueous solution was extracted with methylene chloride (3x25 mL).
Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was
purified via column chromatography on silica gel (20 g) by eluting with 15% EtOAc/n-hexane. 5,8-
Dibromoquinoxaline (12) (142 mg, 99%) was obtained as a sole product.
4.36 Reaction of Tribromide 22 with DBU:
28