Molecular iodine: A powerful catalyst for the easy and efficient synthesis of quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2005.07.026

Various biologically important quinoxaline derivatives were efficiently synthesized in excellent yields using inexpensive, nontoxic, and readily available bench top chemical, iodine in catalytic amount (10 mol %). Besides this, a systematic study was carried out to evaluate parameters such as solvent and catalyst loading. Several aromatic as well as aliphatic 1,2-diketones and aromatic 1,2-diamines, such as substituted phenylene diamines, tetra amines were further subjected to condensation using catalytic amounts of iodine to afford the products in excellent yield.

Full text of DOI:10.1016/j.tetlet.2005.07.026

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6345–6348
Molecular iodine: a powerful catalyst for the easy and
efficient synthesis of quinoxalines
Shivaji V. More, M. N. V. Sastry, Chieh-Chieh Wang and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, ROC
Received 13 May 2005; revised 24 June 2005; accepted 8 July 2005
Abstract—Various biologically important quinoxaline derivatives were efficiently synthesized in excellent yields using inexpensive,
nontoxic, and readily available bench top chemical, iodine in catalytic amount (10mol%). Besides this, a systematic study was car-
ried out to evaluate parameters such as solvent and catalyst loading. Several aromatic as well as aliphatic 1,2-diketones and aromatic
1
,2-diamines, such as substituted phenylene diamines, tetra amines were further subjected to condensation using catalytic amounts
of iodine to afford the products in excellent yield.
2005 Published by Elsevier Ltd.
ꢀ
1
. Introduction
suffer from unsatisfactory product yields, critical prod-
uct isolation procedures, expensive and detrimental
metal precursors, and harsh reaction conditions, which
limit their use under the aspect of environmentally
benign processes.
Among the various classes of nitrogen containing
heterocyclic compounds, quinoxaline derivatives are
important components of several pharmacologically
1
active compounds. Although rarely described in nature,
synthetic quinoxaline ring is a part of a number of anti-
biotics such as echinomycin, leromycin, and actinomycin,
which are known to inhibit the growth of Gram-positive
bacteria and are also active against various transplant-
The use of molecular iodine in organic synthesis has
been known for a long time. In recent years, molecular
iodine has received considerable attention as an inexpen-
sive, nontoxic, readily available catalyst for various
2
14
able tumors. Besides this, it has been reported for their
organic transformations under mild and convenient
3
application in dyes, efficient electroluminescent materi-
conditions to afford the corresponding products in excel-
lent yields with high selectivity. However, there is no
example of quinoxaline synthesis using molecular iodine
as a catalyst. As part of our on going interest, in the use
of cheap and ecofriendly materials as catalysts for vari-
ous organic transformations, we had the opportunity to
look into the synthesis of quinoxalines using molecular
iodine.
4
5
als, organic semiconductors, building blocks for the
6
7
synthesis of anion receptor, cavitands, dehydroannul-
8
9
enes, and DNA cleaving agents. A number of synthetic
strategies have been developed for the synthesis of
substituted quinoxalines and the most common
method is the condensation of an aryl 1,2-diamine with
1
,2-dicarbonyl compounds in refluxing ethanol or acetic
10
acid. However, many improved methods have been
reported for the synthesis of quinoxalines using catalytic
amounts of various metal precursors, acids, and
zeolites. In addition to the above catalytic methods,
reports were also known with microwave and solid
2. Results and discussion
1
1
1
2
In the beginning, a systematic study was carried out for
the catalytic evaluation of iodine toward the synthesis
of quinoxalines. Initially, a blank reaction was con-
ducted using benzil and o-phenylenediamine in boiling
ethanol, which resulted in the formation of a condensa-
tion product after 45 min (60% Y). With the same sub-
strates, the reaction in ethanol, using catalytic amount
of iodine at room temperature afforded the products in
1
3
phase synthesis. Nevertheless, most of these methods
Keywords: 1,2-Diketones; Quinoxalines; Iodine; Catalytic amount;
Ecofriendly process.
*
Corresponding author. Tel.: +886 229309092; fax: +886
29324249; e-mail: cheyaocf@scc.ntnu.edu.tw
2
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.026

6346
S. V. More et al. / Tetrahedron Letters 46 (2005) 6345–6348
extent, but needs a little longer reaction times (>1 h).
In the absence of iodine, the reaction takes more than
2
I (10 mol%)
Solvent
O
O
NH2
NH2
N
N
2
1
4 h to complete. In an optimized reaction condition,
,2-diketone (1 mmol) and 1,2-diamine (1.2 mmol) in
+
o
2
5 C
acetonitrile (0.5 mL) were mixed with iodine
0.10 mmol) and stirred at room temperature for 3–
0min. After the completion of the reaction (monitored
by TLC), a simple work up affords the products in excel-
(
3
1
2
3
Scheme 1.
1
5
lent yield (Scheme 2).
In order to evaluate the efficiency of this methodology, a
number of 1,2-diketones and 1,2-diamines were further
subjected to condensation using catalytic amount of
iodine (Table 2).
quantitative yield during 15 min. Thus, in the absence
of iodine, the reaction was slow and also requires
refluxing conditions with unsatisfactory yields. We next
investigated the effect of different solvents on the reac-
tion rate as well as the yields of products. Almost all
the solvents afforded the products in excellent yield
with a variation in time period. Protic solvents like
methanol and ethanol afforded the products in high
yield within 15–20min.
With symmetrical aromatic diamines the reaction
showed good product yields. Diamine, such as naph-
thalene-1,2-diamine, steric factors played a key role in
affecting the rate of reaction and the reaction requires
a longer time. With electron donating substituents in
the amine part, increased yields of products were
obtained, whereas the effect is reverse with electron
with drawing substituents. On the other hand, electron
donating substituents associated with aromatic 1,2-
diketone decreased the product yields and the effect is
reverse with electron with drawing groups. However,
the variations in the yields were very little and both
substituted aromatic diamines such as 4-chloro and
After screening different solvents, acetonitrile came out
as the solvent of choice, which not only afforded the
products in good yield, but also with higher reaction
rates. In general, for polar solvents the reaction rate is
high, whereas for nonpolar solvents it is little low
(
Scheme 1 and Table 1).
The method of iodine catalyzed synthesis of quinoxa-
lines is very simple, efficient, clean, and without any
other side products. We also evaluated the amount of
iodine required for this transformation. As less as,
3
-methyl gave the condensed products in excellent
yields with different substituted 1,2-diketones. To check
the versatility of this method, we have also subjected
other than symmetrical 1,2-diketones, such as furil
and 1-phenyl-1,2-propanedione, and obtained the
products in excellent yields. In the case of unsymmetri-
cal 1,2-diketones such as 1-phenyl-1,2-propanedione,
different aromatic diamines delivered a 1:1 ratio of
regioisomers in almost quantitative yield (Table 3,
entries 7 and 8). In another variation, tetra amines
5
mol% of iodine can catalyze the reaction to the same
Table 1. Effect of solvents for the iodine catalyzed synthesis of
quinoxalines
0
0
0
a
b
such as 3,3 ,4,4 -tetraamino-1,1 -biphenyl underwent
condensation with diketone (benzil) in the presence of
catalytic amount of iodine (10mol%) and afforded
Entry
Solvent
CH C1
MeOH
EtOH
Et O
2
THF
Time
Yield (%)
1
2
3
4
5
6
7
8
9
2
2
15 min
20min
15 min
30min
30min
15 min
2–3 min
30min
3 h
95
92
90
91
94
89
98
85
93
1
6
the product 5 in 85% yield (Scheme 3).
This methodology is very useful for the synthesis of a
sterically hindered amine such as 2,3,2 ,3 -tetraphenyl-
[6,6 ] biquinoxalinyl 5.
0
0
DMF
0
CH
EtOAc
PhCH
4.5 h
3
CN
3
Though the role of iodine is not clearly known, but it
can act as a mild Lewis acid. A part from its acidity
iodine plays a complex role in accelerating the dehydra-
tive steps, and thus promotes the formation of
1
0PhH
91
a
All reactions were performed at 1 mmol scale using 10mol% of
iodine in 0.5 mL of solvent.
Column isolated yields.
b
17
products.
R1
R
R
1
1
I2 (10 mol%)
O
O
NH2
NH2
N
N
CH CN
3
+
o
2
5 C
3
-30 min.
R2
R2
R1
1
2
3
Scheme 2.

S. V. More et al. / Tetrahedron Letters 46 (2005) 6345–6348
6347
Table 2. Synthesis of different quinoxalines using symmetrical aro-
Table 3. Synthesis of different quinoxalines using heterocyclic and
matic 1,2-diketones
unsymmetrical 1,2-diketones
a
b
c
a
b
c
Entry Product
Time (min) Yield (%)
Entry
Product
Time (min)
5
Yield (%)
N
N
N
O
O
1
3a
3b
3
98
1
31
95
N
N
N
2
2096
H C
N
N
3
O
O
2
3
3m
1096
2092
H C
N
3
3
3c
3d
5
95
N
N
O
3n
O
Cl
N
N
4
1090
Cl
N
N
N
O
CH3
4
5
6
3o
3p
3q
3092
O
N
5
3e
3f
4
5
94
92
N
CH3
CH3
CH3
N
N
3
95
H C
N
3
6
CH
3
N
CH3
N
N
1093
N
7
3g
3h
15
90
CH3
Cl
N
CH3
CH3
H C
N
N
3
8
3090
CH3
N
N
d
7
3r
5
93
CH3
N
N
CH3
OCH3
H C
3
N
9
3i
3
94
96
N
OCH3
OCH3
N
H C
N
3
Cl
Cl
CH3
CH3
N
1
1
0
1
3j
5
d
8
3s
15
90
N
OCH3
OCH3
N
N
N
3k
1092
Cl
N
a
b
c
All reactions were performed at 1 mmol scale using 10mol% of
iodine in 0.5 mL of CH CN.
All products were well characterized using H, C NMR, and
OCH3
3
a
b
c
1
13
All reactions were performed at 1 mmol scale using 10mol% of
iodine in 0.5 mL of CH CN.
All products were well characterized using H, C NMR, and
elemental analysis.
3
1
13
Isolated yields of pure products after passing through a small bed of
elemental analysis.
Isolated yields of pure products after passing through a small bed of
silica.
silica.
d
The yield belongs to the overall yield of two regioisomers which are
formed in 1:1 ratio.
O
I
2
(10 mol%)
N
N
H N
NH2
NH2
2
CH CN
Ph
Ph
3
+
25oC
N
N
O
H N
2
Ph
Ph
4
0 min, 85%
1
4
5
Scheme 3.

6348
S. V. More et al. / Tetrahedron Letters 46 (2005) 6345–6348
3
. Conclusion
Jory, J. W.; Joseph, P. B. J. Org. Chem. 2003, 68,
179.
0. (a) VOGELÕs Textbook of Practical Organic Chemistry,
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4
1
1
In summary, we describe a simple, efficient, and eco-
friendly method for the synthesis of quinoxalines from
various 1,2-diketones and 1,2-diamines using cheap
and readily available molecular iodine as a catalyst.
The ambient conditions, high reaction rates, excellent
product yields, and easy workup procedure not only
make this methodology an alternative platform to the
conventional acid/base catalyzed thermal processes,
but also makes it significant under the umbrella of envi-
ronmentally greener and safer processes.
5
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Financial support of this work was provided by the
National Science Council of the Republic of China
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(
1
The Procter and Gamble Company, USA) WO 9951688,
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1
(0.276 g 98% Y). Mp 126–127 ꢁC; H NMR (CDCl
3
,
4
5
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13
(m, 6H); C NMR (CDCl
139.15, 130.01, 129.93, 129.27, 128.87, 128.33. Anal. Calcd
for C20 : C, 85.08; H, 5.00; N, 9.92. Found: C, 84.98;
H, 5.12; N, 9.90.
3
, 100 MHz): 153.50, 141.29,
H N
14 2
0
0
0
16. 2,3,2 ,3 -Tetraphenyl-[6,6 ] biquinoxalinyl (5): yellow
1
6
color solid, mp >295 ꢁC; H NMR (CDCl
d 8.6 (s, 2H), 8.33 (d, J = 8.6 Hz, 2H), 8.2 (dd, J = 8.7 Hz,
J = 1.7 Hz, 2H), 7.58 (m, 8H), 7.41 (m, 12H); C NMR
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139.00, 129.98, 129.92, 129.55, 129.01, 128.35, 127.50.
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3
, 400 MHz):
1
3
7
3
1
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26 4
8
9
Found: C, 85.02; H, 4.79; N, 10.19.
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