An environmentally friendly, cost effective synthesis of quinoxalines: The influence of microwave reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2013.11.100

A convenient, environmentally friendly and novel synthesis of quinoxalines using silica gel as the catalyst is described. The choice of microwave conditions has been shown to have a substantial impact on the reaction outcome with closed-vessel microwave irradiation resulting in the formation of quinoxalines in high yields and short reaction times. Preliminary mechanistic investigations have indicated that a slight build-up in pressure has a major impact on the reaction outcome.

Full text of DOI:10.1016/j.tetlet.2013.11.100

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Tetrahedron Letters 55 (2014) 642–645
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Tetrahedron Letters
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An environmentally friendly, cost effective synthesis of quinoxalines:
the influence of microwave reaction conditions
⇑
Vineet Jeena, Ross S. Robinson
Department of Chemistry, University of KwaZulu-Natal, Scottsville, Pietermaritzburg, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient, environmentally friendly and novel synthesis of quinoxalines using silica gel as the catalyst
is described. The choice of microwave conditions has been shown to have a substantial impact on the
reaction outcome with closed-vessel microwave irradiation resulting in the formation of quinoxalines
in high yields and short reaction times. Preliminary mechanistic investigations have indicated that a
slight build-up in pressure has a major impact on the reaction outcome.
Received 20 September 2013
Revised 7 November 2013
Accepted 26 November 2013
Available online 4 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Silica gel
Microwave-assisted synthesis
various
oxidants
Quinoxalines have emerged as a vital structural unit within syn-
thetic organic chemistry as they form the backbone of many bacte-
ricides, fungicides and non nucleosidic HIV inhibitors.1
Consequently, there are a number of methods available to con-
struct this valuable moiety with the most common being the reac-
tion between a 1,2-dicarbonyl compound and a 1,2-diamine in
refluxing acetic acid.2 In addition, a number of reagents have been
shown to catalyse this coupling reaction such as acidic alumina,3
citric acid,4 magnetic Fe3O4 nanoparticles in water,5 silica-bonded
sulfonic acid,6 gallium triflate7 and bismuth(III) triflate in water,8
to name but a few. An alternative strategy to develop quinoxalines
involved the use of a one-pot tandem oxidation process (TOP).9 Un-
R
O
O
R
O
R
N
N
R''
H2N
H2N
R'
R'
OH
R'
R''
Scheme 1. Tandem oxidation process (TOP) mediated quinoxaline synthesis.
Within this context, the application of open or closed vessel micro-
wave conditions has been shown to have a significant impact on
the reaction outcome.16 In continuation of our interest in tandem
coupling reactions,17 we wanted to assess the effect of this simple
operational change, using a one-pot tandem oxidation quinoxaline
synthesis, by monitoring the coupling of 2-hydroxyacetophenone
and 1,2-phenylenediamine under various microwave conditions.
The results of this study are illustrated in Figure 1.
The coupling reaction was attempted under various microwave
conditions in a variety of solvents including CH2Cl2, THF and H2O.
In all cases, the yield of the desired product was disappointing
(trace to 10% range) (Fig. 1, experiments 1–6). The use of an acid
or base to catalyse the coupling reaction also failed to have a
significant impact on the yield10 (Fig. 1, experiments 7–10). Micro-
wave-mediated reactions are known to proceed efficiently under
solvent-free conditions,18 however, these conditions also failed to
influence the yield of the reaction significantly (Fig. 1, experiments
11–12). Next, we sought to probe the effect of silica gel as a
catalyst on the coupling reaction under solvent-free conditions.
While the yield remained poor under the open vessel conditions,
there was a noticeable increase under closed vessel conditions
(Fig. 1, experiments 13–14). Increasing the reaction time failed to
der these conditions, an
dant resulting in the formation of
a
-hydroxy ketone is mixed with an oxi-
diketone, which is
a
immediately trapped in situ, by the 1,2-diamine in a one-pot pro-
cedure (Scheme 1).
This protocol displays a number of advantages such as short
reaction times, high yields as well as a decrease in the number of
synthetic steps. Accordingly, a number of TOP-mediated quinoxa-
line syntheses have been developed using a variety of oxidants
such as manganese dioxide,10 mercuric iodide,11 RuCl2(PPh3)3 in
diglyme12 and ferric chloride/morpholine.13
Microwave-assisted organic synthesis (MAOS) has gained wide-
spread popularity in chemical reactions due to its positive effects
such as decreased reaction times and improvements in reaction
yields.14 The advent of specific pressure and temperature-con-
trolled scientific reactors over commercial reactors has further en-
hanced this field resulting in reproducible and clean reactions.15
⇑
Corresponding author.
E-mail address: robinsonr@ukzn.ac.za (R.S. Robinson).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.100

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643
(a)
(b)
H2N
H2N
O
N
microwave
conditions
OH
N
1a
2a
3a
Figure 1. (a) Optimisation of the reaction conditions for the one-pot quinoxaline synthesis (b) Optimisation experiments for the formation of 2-phenylquinoxaline. Reaction
conditions: Alcohol (0.5 mmol), diamine (0.5 mmol). Experiments: (1) Microwave conditions: Open vessel, Solvent: CH2Cl2, Temp: 40 °C, Time: 5 min; (2) Closed vessel,
CH2Cl2, 40 °C, 5 min; (3) Open vessel, THF, 70 °C, 5 min; (4) Closed vessel, THF, 70 °C, 5 min; (5) Open vessel, H2O, 70 °C, 5 min; (6) Closed vessel, H2O, 70 °C, 5 min; (7) Open
vessel, 1% AcOH (catalyst), THF, 70 °C, 5 min, (8) Closed vessel, 1% AcOH, THF, 70 °C, 5 min, (9) Open vessel, 1% K2CO3, THF, 70 °C, (10) Closed vessel, 1% K2CO3, THF, 70 °C,
5 min, (11) Open vessel, No solvent, 70 °C, 5 min; (12) Closed vessel, No solvent, 70 °C, 5 min; (13) Open vessel, 5 mg silica gel, No solvent, 70 °C, 5 min; (14) Closed vessel,
5 mg silica gel, No solvent, 70 °C, 5 min; (15) Open vessel, 5 mg silica gel, No solvent, 70 °C, 10 min; (16) Closed vessel, 5 mg silica gel, No solvent, 70 °C, 10 min.
improve the yield significantly under the open vessel conditions
(Fig. 1, experiment 15) but, to our delight, the desired product
was isolated in a yield of 81% using closed vessel microwave con-
ditions in just 10 min (Fig. 1, experiment 16), with the remaining
compounds being the unreacted starting materials. This result
was of utmost significance as unlike previously reported proce-
dures (which commence from the diketone), the silica gel required
no pre-treatment or particle size specifications and was used in a
significantly smaller amount (in previously reported cases up to
1 g of silica gel was used).6,19 In addition, silica gel is inexpensive
and readily available in most chemical laboratories further enhanc-
ing its utility. Thus, the application of just 5 mg of silica gel under
solvent-free conditions is more attractive than the previously re-
ported methods (vide supra). With this optimised procedure in
hand, we next explored the scope and limitations of this system
using a series of alcohols and diamines (Table 1). In order to high-
light the important role of closed vessel conditions, the reactions
were conducted in open and closed vessels at the same tempera-
ture to evaluate the effect of this simple operational change. In
all cases, care was taken to choose a reaction temperature that
was below the boiling point of aldehyde in order to prevent loss
of the reactant under the open vessel conditions.
alcohol/diamine combinations produced the desired products in
good to excellent yields in 10–20 min.
Protein kinase B or Akt plays an important role in the develop-
ment and progression of a wide variety of cancers by promoting
the proliferation, survival and metabolic capacity of these cells.21
Thus, the development of Akt inhibitors is of utmost importance
as a possible route for the successful treatment of cancers.22 The
2,3-diphenylpyrazine moiety, as an Akt inhibitor, has been shown
to exhibit promising activity against cancer cell lines.23 We thus
envisioned a synthetic route to the 2,3-diphenylpyrazine moiety
based on the above mentioned closed vessel-silica gel system.
Since the formation of 2,3-dihydro-5,6-diphenylpyrazine (3g)
was effected in excellent yield (Table 1, entry 14), we needed to de-
velop a procedure to successfully execute the aromatisation of this
compound. There are a number of reagents available to effect these
transformations which include p-chloroaniline24 and MnO2/KOH in
methanol.25 However, in keeping with our ideology of a simple,
cost-effective and green route towards these heterocyclic com-
pounds, elemental sulfur was chosen to effect the aromatisation.
Elemental sulfur offers a number of advantages as it is non-toxic,
easy to handle and readily available.26 Thus, we investigated the
synthesis of 2,3-diphenylpyrazine by conducting the coupling of
benzoin and ethylendiamine in the presence of silica gel under
closed vessel microwave irradiation for 20 min. After this period,
elemental sulfur was added to the crude mixture and subsequent
irradiation under closed vessel microwave conditions for a further
10 min produced the desired pyrazine 4 in an isolated yield of 77%,
while under open vessel conditions only a 41% yield of the product
was obtained (Scheme 2).
The coupling reaction between hydroxyacetone 1b and o-phen-
ylenediamine (2a) was examined (Table 1, entries 3 and 4). This
reaction was of particular interest as the corresponding keto–
aldehyde is known to be ‘hyper-reactive’ and is difficult to iso-
late.20 However, using the above one-pot coupling conditions, the
desired quinoxaline was isolated in 85% yield under closed vessel
conditions and in a disappointing yield of 31% under open vessel
conditions. The silica gel-closed vessel system was also effective
on a secondary hindered alcohol with the quinoxaline formed in
a 77% yield in 20 min as opposed to 34% under the open vessel
system (Table 1, entries 5 and 6). The yields obtained are compara-
The superior results obtained under closed vessel conditions
have been proposed to be due to oxygen from the air acting as
the stoichiometric oxidant.9 While our studies into the mechanism
of this coupling reaction are still in their infancy, we aimed to con-
duct a series of simple tests to lend credibility to the aforemen-
tioned proposal. Firstly, our test coupling reaction was conducted
under an atmosphere of dry nitrogen, to exclude the presence of
oxygen and, to our surprise, the desired product was formed in a
10
17a
ble with those in the literature using the MnO2 or Pd(OAc)2
mediated systems, however, the reaction time is noticeably
decreased from 45 min and 24 h, respectively, to 15 min. Further
examination of the microwave-silica gel system using a range of

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644
V. Jeena, R. S. Robinson / Tetrahedron Letters 55 (2014) 642–645
Table 1
Silica gel catalysed one pot synthesis of quinoxalinesa
Entry
a-Hydroxy ketone
Diamine
Quinoxaline
Microwave conditions
Temp (oC)
Time (min)
Yieldb (%)
H2N
1
2
Open vessel
Closed vessel
70
70
10
10
38
81 (97)cc
O
N
N
H2N
OH
2a
1a
3a
O
H2N
H2N
N
3
4
Open vessel
Closed vessel
70
70
10
10
31
85
OH
N
1b
3b
2a
H2N
5
6
Open vessel
Closed vessel
150
150
15
15
34
77
N
N
O
H2N
OH
2a
3c
1c
H2N
7
8
Open vessel
Closed vessel
70
70
10
10
29
89
O
N
H2N
OH
2b
N
3d
1a
H2N
H2N
9
10
Open vessel
Closed vessel
150
150
20
20
41
70
O
N
N
OH
2b
3e
1c
H2N
H2N
11
12
Open vessel
Closed vessel
150
150
15
15
31
73
O
N
N
Cl
2c
OH
Cl
1c
3f
H2N
13
14
Open vessel
Closed vessel
100
100
20
20
49
83
O
N
N
H2N
OH
2d
3g
1c
a
Reaction conditions: the alcohol (0.5 mmol), diamine (0.5 mmol) and silica gel (5 mg) (or 15 mg in the case of secondary alcohols) were stirred under microwave
conditions as highlighted above.
b
Isolated yield.
c
Estimated yield in parentheses using 1H NMR spectroscopy.
atmosphere, and a decrease in the yield was observed with the de-
sired product formed in 12% yield (Table 2, entry 3). These results
suggested that oxygen was not the stoichiometric oxidant as previ-
ously postulated. Preceding research reported that silica gel alco-
hol oxidations are effective on substrate specific keto–alcohols
using solvent-free conditions, however, in these cases 0.5 g of silica
gel is used.27 In our case, only 5 mg of silica gel is used implying
that other factors are contributing to the successful quinoxaline
synthesis.
Kappe and co-workers have reported a microwave-assisted
Diels–Alder reaction using a solvent free, pre-pressurised (10 bar)
reaction vessel approach.28 During our studies, it was noticed that
a slight increase in pressure (up to 5 psi) was recorded by the
instrument. Based on these observations, we were intrigued by
the possibility of this minor pressure increase having a significant
effect on the reaction outcome. In order to test this hypothesis, the
microwave vessel was charged with the reactants, surrounding
O
N
N
H2N
H2N
N
N
sulfur
silica gel
microwave
microwave
OH
1c
2d
4
Open vessel: 41%
Closed vessel: 77%
Scheme 2. Synthesis of Akt using the silica gel/closed vessel system.
yield of 41% (Table 2, entry 1). This result was comparable to the
yield obtained in an open vessel, air atmosphere (Table 2, entry
2). If oxygen was indeed the stoichiometric oxidant, its absence
should result in minimal product formation. To validate this pro-
posal we then conducted the test reaction under an oxygen

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V. Jeena, R. S. Robinson / Tetrahedron Letters 55 (2014) 642–645
645
Table 2
decreases the product output), but rather an air-mediated pressure
build-up has a major influence on the reaction outcome. Further
mechanistic studies are underway into pressurised microwave
synthesis as well as an expansion of this approach to other one-
pot tandem coupling reactions.
a
Synthesis of 2-phenylquinoxaline under various atmospheric conditions
H2N
5 mg silica gel
70 oC, 10 min
N
N
O
H2N
OH
Supplementary data
Entry
Conditions
Yieldb (%)
1
2
3
4
5
6
Microwave/N2
Microwave/air (open vessel)
Microwave/O2
Microwave/evacuated/closed vessel
Microwave/closed vessel
Microwave/evacuated/100 ll MeOH (Induced pressure)
41
38
12
8
81
85
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013. 11.100.
References and Notes
a
Reaction conditions.
Isolated yield.
b
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