Surfactant micelles as microreactors for the synthesis of quinoxalines in water: Scope and limitations of surfactant catalysis

Article abstract of DOI:10.1039/c3ra41038b

The scope and limitations of surfactants as catalysts for the synthesis of quinoxalines using microreactors made of the surfactants in water has been assessed. The catalytic potential followed the order: non-ionic surfactants > anionic surfactants > Bronsted acid surfactants > cationic surfactants. The non-ionic surfactant, Tween 40, is the most effective catalyst affording excellent yields within a short reaction time at room temperature and is compatible with different variations of the 1,2-diketones and 1,2-diamines. The reaction medium (spent water) containing the catalyst, as well as the catalyst itself (recovered Tween 40) can be reused for five consecutive reactions. The better catalytic efficiency of the surfactant (Tween 40) compared to the various Lewis/Bronsted acids, as well as the surfactant combined Lewis acid, suggests that surfactants, which generate microreactor assemblies at the interface, are better suited as catalytic aids to promote organic reactions in water. The inferior results obtained in organic solvents, which provide a homogeneous reaction mixture compared to those obtained in water, indicate the specific role of water. This has been depicted as a synergistic dual activation through the hydrogen bond mediated formation of supramolecular assemblies involving a water dimer and the reactants. The catalytic assistance of the surfactant could be ascribed to the ability of the surfactant molecule to undergo hydrophobic and hydrogen bond forming interactions with water and the reactants in orienting the reactants at the water interface and encapsulating inside the microreactors to facilitate the cyclocondensation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41038b

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PAPER
Surfactant micelles as microreactors for the synthesis of
quinoxalines in water: scope and limitations of
surfactant catalysis3{
Cite this: DOI: 10.1039/c3ra41038b
Dinesh Kumar, Kapileswar Seth, Damodara N. Kommi, Srikant Bhagat and Asit
K. Chakraborti*
The scope and limitations of surfactants as catalysts for the synthesis of quinoxalines using microreactors
made of the surfactants in water has been assessed. The catalytic potential followed the order: non-ionic
surfactants . anionic surfactants . Brønsted acid surfactants . cationic surfactants. The non-ionic
surfactant, Tween 40, is the most effective catalyst affording excellent yields within a short reaction time at
room temperature and is compatible with different variations of the 1,2-diketones and 1,2-diamines. The
reaction medium (spent water) containing the catalyst, as well as the catalyst itself (recovered Tween 40)
can be reused for five consecutive reactions. The better catalytic efficiency of the surfactant (Tween 40)
compared to the various Lewis/Brønsted acids, as well as the surfactant combined Lewis acid, suggests that
surfactants, which generate microreactor assemblies at the interface, are better suited as catalytic aids to
promote organic reactions in water. The inferior results obtained in organic solvents, which provide a
homogeneous reaction mixture compared to those obtained in water, indicate the specific role of water.
This has been depicted as a synergistic dual activation through the hydrogen bond mediated formation of
supramolecular assemblies involving a water dimer and the reactants. The catalytic assistance of the
surfactant could be ascribed to the ability of the surfactant molecule to undergo hydrophobic and
hydrogen bond forming interactions with water and the reactants in orienting the reactants at the water
interface and encapsulating inside the microreactors to facilitate the cyclocondensation.
Received 10th March 2013,
Accepted 30th May 2013
DOI: 10.1039/c3ra41038b
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chemicals such as transition/heavy metal based oxidants, (iii)
expensive and moisture sensitive reagents/catalysts, (iv)
Introduction
The quinoxaline-based compounds exhibit a broad spectrum
of biological activities1 and find applications as useful
materials.2 These have inspired synthetic organic/medicinal
chemists to develop new and more efficient synthetic
methodologies for the preparation of quinoxaline derivatives.
The various approaches (Scheme 1) involve the Lewis/Brønsted
acid or Lewis base promoted reaction of o-phenylenediamine
(commercially available or prepared in situ through the
reduction of the corresponding o-nitroaniline) with (i) 1,2-
diketone/1,2-ketomonoxime (Route A);3 (ii) a-hydroxyketone/
a-haloketone/1,2-diol or a-methyleno ketone (Route B);4 (iii) an
appropriately substituted epoxide (Route C);5 (iv) substituted
alkynes (Route D)6 under heating or microwave irradiation.
These routes are associated with the necessity/use of (i)
special efforts for the preparation of the starting material or
catalyst system, (ii) potentially hazardous additional/auxiliary
volatile organic solvents, (v) stringent reaction conditions
such as high temperature, and (vi) a laborious and complex
work-up procedure. In some of the methods, acidic/metallic
wastes are generated that are mixed with the effluent water
and are a matter of concern since they may cause serious
environmental pollution. The contamination of the products
with trace amounts of metallic impurities during the metal-
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
E-mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
Scheme 1 Synthetic strategies for the construction of the quinoxaline scaffold.
c3ra41038b
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catalyzed reactions poses a serious problem in cell/enzyme-
based biological evaluation. Therefore, there is a need to
develop an efficient and environmentally friendly protocol for
the synthesis of quinoxaline derivatives as the generation of
new hits/leads for potential therapeutic applications requires a
convenient, selective and high yielding synthetic method to
meet the needs for a timely supply of the designed molecules
for biological evaluation.7 The considerable influence of green
chemistry tools on medicinal chemistry and chemistry
research based organisations8 drives the requirement to
enrich the medicinal chemist’s tool box through the improve-
ment of existing transformations for a more general applica-
tion and making them amenable to parallel chemistry, as well
as potentially broadening the diversity of compounds for use
in medicinal chemistry purposes.9
The development of eco-friendly/green approaches (sustain-
able development) is an ongoing demand and a subject of
current interest due to the adverse effect of the manufacturing
processes of drugs and pharmaceuticals on the environment.10
The major drive towards this initiative is the replacement of
volatile organic solvents (VOSs) by green reaction media,11 as
VOSs are the major contributors to environmental pollution
due to their abundant use (more than 85% of the total mass
utilization of a chemical process) and incomplete recovery
efficiency (50–80%).12 In this regard, water is the most
preferred solvent8,13 and the use of water as a non-classical
medium for organic reactions has received increasing popu-
larity.14 However, the poor solubility of most organic com-
pounds in water often makes an adverse impact on water
mediated organic synthesis and this has brought to light the
use of surfactants15 in aqueous organic reactions. Herein we
describe an extremely efficient and green protocol for the
synthesis of functionalized quinoxalines in water using Tween
40 as a catalyst.
{ Experimental section: The glassware to be used in the reactions was
thoroughly washed and dried in an oven and the experiments were carried out
with the required precautions. Chemicals and all solvents were commercially
available and used without further purification. The 1H and 13C NMR spectra
were recorded on a 400 MHz NMR spectrometer in CDCl3 with residual
undeuterated solvent (CHCl3: 7.26/77.0) using Me4Si as an internal standard.
The chemical shift (d) values are given in ppm and J values are given in Hz. The
13C NMR spectra were fully decoupled and were referenced to the middle peak of
the solvent CDCl3 at 77.00 ppm. Splitting patterns were designated as s, singlet;
bs, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; and m, multiplet.
The mass spectra (MS) were recorded under atmospheric pressure chemical
ionization (APCI). The infra-red (IR) spectra were recorded in the range of 4000–
600 cm21 either as neat samples or using KBr for preparing pellets for solid
samples. The compounds prepared were routinely checked for their purity on
the silica gel GF-254 and visualized under UV light at a wavelength of 254 nm.
Melting points were measured using a melting point apparatus and were
uncorrected. Evaporation of solvents was performed at reduced pressure, using a
rotary evaporator.Preparation of pure water (15 MV cm resistivity at 25 uC): The
pure water was prepared by subjecting tap water to reverse osmosis and ensuring
ionic/organic removal by passing it through a pre-packed cartridge.Preparation
of ultrapure water (18.2 MV cm resistivity at 25 uC): The ultrapure water was
prepared by subjecting the pure water to UV treatment (185/254 nm UV lamp), as
well as deionization by passing it through a deionization cartridge, followed by
ultra membrane filtration (0.01 mm) under pressures up to 145 psi (10 bar).
Ultrapure water (UPW) is generally considered to have a resistivity ¢18.2 MV cm
at 25 uC, low amounts (ppt) in metals, less than 50 ppt in inorganic anions and
ammonia, less than 0.2 ppb in organic anions, and below 1 ppb total organic
carbon (TOC) and silica (dissolved and colloidal).General procedure for the
synthesis of 2,3-diphenylquinoxaline 3 from the reaction of 1 and 2 in water
using Tween 40 as the catalyst (Entry 1, Table 6). To the magnetically stirred
solution of Tween 40 (0.32 g, 0.25 mmol, 10 mol%) in water (5 mL), 1a (0.27 g,
2.5 mmol) and 2a (0.52 g, 2.5 mmol, 1 equiv.) were added and the mixture was
stirred magnetically at rt until completion (5 min, TLC). The reaction mixture
was filtered and the solid residue was washed with water (3 6 1 mL) and dried
under rotary vacuum evaporation to obtain analytically pure 3a (0.69 g, 98%) as a
white solid; mp = 125–127 uC; IR (neat) nmax = 3401, 1442, 1345, 1261, 1056, 767
cm21 1H NMR (400 MHz, CDCl3): d = 7.77–7.80 (2H, m), 7.50–7.55 (2H, m), 7.32–
;
7.40 (10H, m); 13C NMR (100 MHz, CDCl3): d = 153.5, 141.2, 139.1, 129.9, 129.8,
129.2, 128.8, 128.2; MS (APCI) m/z 283.32 (M + H)+ identical with an authentic
sample.3a The remaining compounds were prepared following this general
procedure except for 2,3-bis(4-methoxyphenyl)-6-nitroquinoxaline (entry 12,
Table 6) and the physical and spectral data were in conformity with the reported
data.General procedure for the synthesis of 2,3-bis(4-methoxyphenyl)-6-
nitroquinoxaline from the reaction of 1b and 2b in water using Tween 40 as the
catalyst (Entry 12, Table 6): To the magnetically stirred solution of Tween 40
(0.32 g, 0.25 mmol, 10 mol%) in water (5 mL), 1b (0.38 g, 2.5 mmol) and 2b (0.67
g, 2.5 mmol, 1 equiv.) were added and the mixture was heated under reflux (oil
bath, 110 uC) until the completion of the reaction (6 h, TLC). The reaction
mixture was filtered and the solid residue was washed with water (3 6 1 mL) and
dried under rotary vacuum evaporation to obtain analytically pure 3a (0.92 g,
95%) as a yellow solid; mp = 193–194 uC; IR (KBr) nmax = 3412, 1765, 1556, 1345,
Results and discussion
Although the use of surfactants in aqueous organic reactions is
popularly correlated with the beneficial effect of the surfac-
tants as solubility aids for the water insoluble organic
reactants, the specific role of the surfactants may extend
beyond the scope as solubility enhancers.16 Surfactants often
form microreactors at the oil–water interface and find various
applications such as ion trapping,17 size-controlled synthesis
of metallic nanoparticles,18 and solubilising reservoirs for
drugs, nutraceuticals, anti-oxidants and other compounds.19
The utility of the microreactors has also been demonstrated in
1035, 750 cm21 1H NMR (400 MHz, CDCl3): d = 9.01 (d, J = 2.4 Hz, 1H), 8.47 (dd,
;
J = 2.3 Hz & 9.1 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 7.54–7.58 (m, 4H), 6.89–6.91 (m,
4H); MS (APCI) m/z 343.41 (M + H)+, identical with an authentic
sample.24cProcedure for higher scale synthesis of 3a, recyclability of the spent
water containing the catalyst (Tween 40), and catalyst recovery after end use
(Table 10): To the solution of Tween 40 (1.3 g, 1 mmol, 10 mol%) in water (40
mL), 1a (1.1 g, 10 mmol) and 2a (2.1 g, 10 mmol, 1 equiv.) were added and the
mixture was stirred magnetically at rt until the completion of the reaction (10
min, TLC). The reaction mixture was filtered and the solid residue was washed
with water (3 6 5 mL) and dried under rotary vacuum evaporation to obtain
analytically pure 3a (2.76 g, 98%) as a white solid.3a The aqueous filtrate (spent
water) was successively used for further reactions (four consecutive fresh
batches/runs) to afford 3a in excellent yields (2.67 g, 95%; 2.7 g, 96%, 2. 67 g,
95%, and 2.59 g, 92%, respectively). After the 4th recycling, the spent water was
extracted with EtOAc (3 6 5 mL) to remove the traces of organic contaminants
and was subjected to freeze drying to recover the Tween 40 (1.0 g, 82%), which
was found to be identical (1H NMR) to the authentic sample.
performing organic reactions.20 In
a model study, 1,2-
diaminobenzene 1a was treated with benzil 2a in water in
the absence of any additional agent at rt for 1 h (Scheme 2).
However, a poor conversion (32% yield) to the desired product
of 2,3-diphenylquinoxaline 3a was observed. Therefore, var-
ious neutral, anionic, cationic and Brønsted acid surfactants
were used to investigate whether they had any beneficial effect
on the formation of 3a (Table 1).
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Table 1 Catalytic efficiency of various surfactants for the synthesis of 3a from 1a
and 2a in watera
Entry
1
Surfactant
Yield (%)b
32c
Scheme 2 Comparison of the catalytic efficiency of Tween 40 with that of the
catalysts reported for quinoxaline formation in aqueous media.
None
Anionic
2
3
4
5
Sodium dodecylsulfate (SDS)
Sodium dioctylsulfosuccinate (SDOSS)
Sodium N-lauroylsarcosine (SNLS)
Sodium deoxycholate (SDC)
Brønsted acid
Dodecylbenzenesulfonic acid (DBSA)
Cationic
Benzalkonium chloride
Cetyl trimethyl ammonium bromide
Hexadecyl pyridinium chloride
Tetrabutylammonium fluoride
Tetrabutylammonium chloride
Tetrabutylammonium bromide
Tetrabutylammonium iodide
Adogen-464
Non-ionic
Triton X 100
Triton X 110
Triton X 114
Triton SP 135
Triton SP 190
Tween 20
Tween 40
91
90
72
67
The presence of a suitable surfactant as a catalytic aid was
found to be essential, as in the absence of any surfactant a
poor result was obtained (entry 1).21 Amongst the anionic
surfactants, the best results were obtained with sodium
dodecylsulfate SDS and sodium dioctylsulfosuccinate SDOSS
(entries 2 and 3). Many non-ionic surfactants (entries 15–23)
exhibited very good catalytic activities. However, the cationic
surfactants (entries 7–14), as well as the Brønsted22 acid type
surfactant (entry 6), gave moderate results. Although the
reported procedure used the non-ionic surfactant PEG-600 as a
cosolvent with water (5 mL of 1 : 1 PEG-600 and water for 1
mmol of 1,2-diketone) for quinoxaline synthesis,23 lesser
yields are obtained when using various PEGs in a catalytic
amount (entries 40–48).
In order to determine the most effective catalyst from the
panel of the surfactants (e.g., SDS, SDOSS, Triton X 100, Triton
X 110, Triton X 114, Triton SP 135, Triton SP 190, Tween 20,
Tween 40, Tween 60, and Tween 80) that afforded very good
yields (.80%) (Table 1), the electron deficient 1,2-diamine-4-
nitrobenzene 1b was used as a less nucleophilic, diamine
representative, treated with 2a in the presence of these
surfactants in water at rt for 5 h (Table 2).
The initial study of performing the reaction for 5 h (Table 2)
clearly demonstrated the better catalytic potential of the non-
ionic surfactants. Tween 40, Triton SP 135, and Triton SP 190
are found to be the most effective catalysts, affording the
desired product, 6-nitro-2,3-diphenylquinoxaline 3b, in 88, 80,
and 76% yields, respectively. To have a clear distinction, the
reactions were performed for 1 h and Tween 40, Triton SP 135,
and Triton SP 190 emerged as the most effective catalysts
affording 88, 78, and 75% yields, respectively. Further lowering
the reaction time to 0.5 h also could not distinguish between
the catalytic potential of these three surfactants.
To distinguish the catalytic potential of Tween 40, Triton SP
135, and Triton SP 190, the reaction of 1b was carried out with
4,49-dimethoxybenzil 2b, which has fewer electrophilic carbo-
nyl groups compared to those in 2a, in the presence of the
selected catalysts (Table 3).
6
68
7
8
9
10
11
12
13
14
58
62
60
58
53
50
42
49
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
85
95
90
92
95
92
96
90
85
62
65
63
62
45
40
56
62
52
55
52
58
50
52
56
64
55
52
55
58
53
50
52
53
41
Tween 60
Tween 80
Span 20
Span 40
Span 60
Span 80
Myrj 49
Brij1 93
Brij S 100
Labrasol
Gelucire1 44/14
Compritol1 888
Capryol
Labrafil1 M2125CS
Igepal CO-630
Merpol HCS
Tetronic 90R4
b-Cyclodextrin
PEG-200
PEG-400
PEG-600
PEG-1000
PEG-2000
PEG-4600
PEG-8000
PEG-10000
PEG-20000
a
1a (0.10 g, 1 mmol) was treated with 2a (0.21 g, 1 mmol, 1 equiv.)
in water (5 mL) for 1 h at rt in the presence of different surfactants
(20 mol%). The isolated yield of 3a. The reaction was carried out
without any surfactant.
b
c
The desired product, 2,3-bis(4-methoxyphenyl)-6-nitroqui-
noxaline 3c, was not formed at room temperature in the
presence of these surfactants (Table 3, entries 1–3). However,
3c was obtained in 68, 55, and 92% yields, respectively, when
the reactions were carried out under reflux (Table 3, entries 4–
6). The requirement for catalytic assistance by the surfactants
was clearly demonstrated, since 3c was not obtained in the
absence of the surfactant either at rt or under reflux (Table 3,
entries 7 and 8).
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Table 3 The comparison of the catalytic potential of a few selected surfactants
during the reaction of 1b with 2b to form 3c in watera
Table 2 Comparison of the catalytic potential of a few selected surfactants for
quinoxaline synthesis in water from 1b with 2aa
Yield (%) afterb
Entry
Surfactant
Solvent
Yield (%)b
Entry
Surfactant
5 h
1 h
0.5 h
1
2
3
4
5
6
7
8
Triton SP 135
Triton SP 190
Tween 40
Triton SP 135
Triton SP 190
Tween 40
None
None
SDS
SDOSS
SDS
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
PhMe
Dioxane
DCM
EtOAc
DMF
MeOH
t-BuOH
neat
PhMe
Dioxane
DCM
EtOAc
DMF
MeOH
t-BuOH
PhMe
Dioxane
DCM
EtOAc
DMF
MeOH
t-BuOH
PhMe
Dioxane
DCM
EtOAc
DMF
MeOH
t-BuOH
PhMe
Dioxane
DCM
EtOAc
DMF
nil
nil
1
2
3
4
5
6
7
8
SDS
SDOSS
55
45
52
80
76
56
62
66
88
60
71
nil
31
24
30
78
75
28
35
46
88
41
52
nil
Triton X 114
Triton SP 135
Triton SP 190
Triton X 100
Triton X 110
Tween 20
Tween 40
Tween 60
Tween 80
None
68c
77
75
55c
92c
nil
nilc
nil
9
9
81
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
43
44
45
46
47
48
49
nil
10
11
12
62c
SDOSS
56c
Tween 40
Tween 40
Tween 40
Tween 40
Tween 40
Tween 40
Tween 40
Tween 40
Triton SP 135
Triton SP 135
Triton SP 135
Triton SP 135
Triton SP 135
Triton SP 135
Triton SP 135
Triton SP 190
Triton SP 190
Triton SP 190
Triton SP 190
Triton SP 190
Triton SP 190
Triton SP 190
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDOSS
SDOSS
SDOSS
SDOSS
SDOSS
SDOSS
32c
a
1b (0.15 g, 1 mmol) was treated with 2a (0.21 g, 1 mmol, 1 equiv.)
tracec
18c
in the presence of the surfactant (20 mol%) in water (5 mL) at rt for
different time intervals. Isolated yield of 3b.
20c
b
nilc
25c
31c
traced
30c
tracec
15c
The catalytic potential of SDS and SDOSS was assessed
further for the formation of 3c (Table 3). Not surprisingly, no
product formation was observed when using either SDS or
SDOSS during the reaction of 1b with 2b in water at rt for 5 h
(Table 3, entries 9 and 10). However, 3c was obtained in 62 and
56% yields when the reactions were performed in water under
reflux for 5 h in the presence of catalytic amounts of SDS and
SDOSS, respectively (Table 3, entries 11 and 12). Thus, Tween
40 was found to be the most effective catalyst for the
preparation of quinoxaline in water. It was observed that
apart from its distinctly superior catalytic potential compared
to other surfactants, the use of Tween 40 offers advantages in
many other aspects. The Tween surfactants are stable, possess
a relatively non-toxic profile and are widely used as detergents,
emulsifiers and excipients in a number of domestic, scientific,
pharmacological and pharmaceutical applications or pro-
ducts, because of its stability.
The reaction of 1b with 2b was performed in the presence
of Tween 40 in different organic solvents (non-polar, weakly
polar, polar, aprotic polar and a few alcohols as protic polar) in
which the reactants, as well as the surfactant, are soluble and a
homogeneous reaction mixture is formed. However, these led
to poor yields and in fact no product formation took place in
some of these solvents (Table 3, entries 14, 17, 22, 25, 29, 32,
39, 44, 47) indicating that when the reaction is run in aqueous
media, water also plays a role in promoting the reaction. Thus,
the role of the surfactant (e.g. Tween 40) could be not only to
help solubilize the water insoluble organics (the substrates/
reactants) in the aqueous medium, but it may also play some
specific role in promoting the reaction in the aqueous
medium. The observation that the use of surfactants may
20c
nilc
22c
25c
26c
tracec
15c
22c
nilc
26c
24c
22c
tracec
16c
18c
tracec
26c
25c
24c
tracec
15c
18c
tracec
20c
MeOH
t-BuOH
SDOSS
23c
a
1b (0.15 g, 1 mmol) was treated with 2b (0.27 g, 1 mmol, 1 equiv.)
in the presence of the selected surfactants (20 mol%) in different
solvent (5 mL) at rt (unless otherwise specified) for 5 h. Isolated
yield of 3c. The reaction was carried out under reflux conditions
(oil bath 110 uC). The reaction was carried out neat at 110 uC (oil
bath).
b
c
d
not be limited only to their role as solubility aids was
highlighted earlier in a communication from this laboratory.
This communication describes a non-heme model for oxygen
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Table 4 Evaluation of various reaction parameters for the Tween 40 catalysed
reaction of 1a and 2a to form 3a in aqueous media at rta
Table 5 The effect of the water/surfactant ratio on quinoxaline formation
during the Tween 40 catalysed reaction of 1b with 2a to form 3ba
Entry Reaction medium Amt (mol%)b Time (min) Yield (%)c
1
2
3
4
5
6
7
8
9
10
Normal water
Distilled waterd
Pure watere
20
20
20
20
20
2
60
60
60
60
60
60
5
5
5
5
98
98
97
97
98
45
72
95
95
96
Ultrapure waterf
Degassed waterg
Normal water
Normal water
Normal water
Normal water
Normal water
Entry
Water/surfactant ratio (w/w)
Yield (%)b
5
10
15
20
1
2
3
4
5
6
1 : 1
28
56
80
38
65
81
1 : 0.5
1 : 0.25
1 : 0.01
1 : 0.02
1 : 0.03
a
1a (0.10 g, 1 mmol) was treated with 2a (0.21 g, 1 mmol, 1 equiv.)
in the presence of Tween 40 in the specified reaction medium (5
mL) at rt. The amount of Tween 40 used with respect to 1. The
isolated yield of 3a. Glass distilled water. The pure water was
obtained by purification of normal/tap water through reverse
osmosis and ionic/organic removal and has the resistivity of 15 MV
cm at 25 uC. The ultrapure water was obtained by further
subjecting pure water to UV treatment (185/254 nm), deionization
b
c
d
e
a
1b (0.15 g, 1 mmol) was treated with 2a (0.21 g, 1 mmol, 1 equiv.)
in the presence of Tween 40 (20 mol%), in different amounts of
water so that the water/surfactant varies, at rt for 1 h. Isolated
yield of 3b.
b
f
and ultra membrane filtration (0.01 mm under pressure up to 145
g
psi (10 bar) and has the resistivity of 18.2 MV cm at 25 uC. The
degassed water was obtained by bubbling N2 gas into the glass
distilled water with sonication.
1 : 0.03 to 1 : 0.25. The product yield decreased when using a
larger amount of water (water/surfactant value , 1 : 0.03). A
decrease in product yield was also observed with lesser
quantities of water (water/surfactant value 1 : 1).
The catalytic potential of Tween 40 was explored for the
diversified synthesis of quinoxalines in water (Table 6). The
reactions were carried out with different variations of the 1,2-
diamine substrate (aromatic, hetroaromatic, alicyclic and
aliphatic 1,2-diamines), as well as of the 1,2 diketone system
(1,2-diaryl-, 1,2-heteroaryl-, aryl alkyl-, and 1,2-dialkyl-1,2-
diketones).
activation, a fact that has brought a new dimension to the field
of surfactant catalysis.16 The distinct advantages in rate
acceleration (in terms of product yields) in aqueous media
compared to organic solvents was further revealed/established
when the results of the reactions catalyzed by other surfactants
such as Triton SP-135, Triton SP-190, SDS, and SDOSS in
aqueous media were compared with those performed in
organic solvents (Table 3, entries 20–44).
The reaction proceeded smoothly with differently substi-
tuted 1,2-diaminobenzenes containing electron donating
groups (methyl, methoxy), electron withdrawing groups (nitro,
cyano), and halogen substituents (fluorine, chlorine, bro-
mine), affording excellent yields (85–95%) in a short time (5–
20 min). The exceptions are o-phenylenediamines with
electron withdrawing groups (entries 7 and 8, Table 6) that
require a longer reaction time (30–45 min). In the case of
heteroaromatic 1,2-diamines such as 2,3-diamino- and 3,4-
diamino-pyridines, excellent yields were obtained but after
longer reaction times (entries 14–16, Table 6) than those
required for 1,2-diaminobenzene for similar 1,2-dicarbonyl
substrates. The reactions also worked well with aliphatic-1,2-
diamines such as ethylenediamine and cyclohexane-1,2-dia-
mine. With respect to the 1,2-diketone system, benzil and its
substituted analogues such as 4,49-dimethoxybenzil, a hetero-
aromatic 1,2-diketone such as furil, a 1-alkyl-2-aryl-1,2-dike-
tone such as 3-phenylpropane-2,3-dione, as well as aliphatic
diketones such as hexane-3,4-dione and butane-2,3-dione were
used and excellent results were obtained. The product
isolation/purification is simple and straightforward. After the
completion of the reaction (TLC), the solid mass was filtered
off and washed with water to afford the quinoxaline. In most
of the cases the product obtained after filtration was pure
The influence of the various reaction parameters such as
the amount of catalyst, reaction time, and the source of water
(e.g., normal/tap, double glass distilled, pure, ultrapure and
degassed) as the reaction medium was studied to derive the
optimal operational conditions during the reaction of 1a with
2a to form 3a (Table 4). In order to avoid any catalytic
influence/assistance, due to the presence of traces of metal
ions, dissolved gases or any organic impurities, the reactions
were performed in normal/tap water, double glass distilled
water, pure water, ultrapure water, and degassed water
(Table 4, entries 1–5). As comparable results were obtained
when using water from various sources, subsequent studies
were performed in normal water. A 10 mol% of Tween 40 was
found to be the optimal amount required, affording a 95%
yield of 3a in 5 min. The use of lower amounts (2 or 5 mol%)
afforded lower yields.
The water/surfactant value18b,c has a significant influence
in controlling the size of the microreactor and is expected to
have implications on the rate of organic reactions. Thus, the
effect of the amount of water, used as the reaction medium, on
the product yield was evaluated during the Tween 40 catalysed
reaction of 1b with 2a to form 3b (Table 5).
The water/surfactant ratio significantly altered the product
yield and the best results were obtained for values from
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Table 6 Tween 40 catalysed synthesis of different quinoxaline derivatives in watera
Entry
1,2-Diamine
1,2-Diketone
Product
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
R1 = H; R2 = H
R1 = Me; R2 = H
R1 = OMe; R2 = H
R1 = Cl; R2 = H
R1 = Br; R2 = H
R1 = F; R2 = H
R1 = NO2; R2 = H
R1 = CN; R2 = H
R1 = R2 = Me
R3 = H
R3 = H
R3 = H
R3 = H
R3 = H
R3 = H
R3 = H
R3 = H
R3 = H
R3 = H
R3 = OMe
R3 = OMe
R1 = R2 = R3 = H
5
5
5
5
5
5
30
45
5
98
95
95
96
95
96
80
85
95
91
90
95c
91
R1 = Me; R2 = R3 = H
R1 = OMe; R2 = R3 = H
R1 = Cl; R2 = R3 = H
R1 = Br; R2 = R3 = H
R1 = F; R2 = R3 = H
R1 = NO2; R2 = R3 = H
R1 = CN; R2 = R3 = H
R1 = R2 = Me; R3 = H
R1 = R2 = Cl; R3 = H
R1 = R2 = H; R3 = OMe
R1 = NO2; R2 = H; R3 = OMe
9
10
11
12
13
R1 = R2 = Cl
5
R1 = R2 = H
20
6 h
20
R1 = NO2; R2 = H
R1 = R2 = H
14
15
16
17
2 h
2 h
2 h
15
88
86
85
85
18
19
1 h
1 h
92
92
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Table 6 (Continued)
Entry
20
1,2-Diamine
1,2-Diketone
Product
Time (min)
30
Yield (%)b
85
21
30
90
a
The 1,2-diamine (2.5 mmol) was treated with the 1,2 diketone (2.5 mmol, 1 equiv.) in the presence of Tween 40 (10 mol%) in water (5 mL)
b
c
at rt for the stipulated time. Isolated yield of the quinoxaline. The reaction was carried out under reflux condition (oil bath, 110 uC).
(NMR, MS) and purification was done through crystallisation
in EtOH or EtOH–water.
acids or metal Lewis acids, as well as the surfactant combined
Lewis acid in aqueous media.
As various Lewis acid catalysts are known to be tolerated in
aqueous media, it was decided to use Lewis acid catalysts
instead of the surfactant (Tween 40), so as to derive a
comparative catalytic potential between Tween 40 and the
water tolerant Lewis acids for the quinoxaline formation in
water. Hence, acidic catalysts with different water tolerances
were tested against Tween 40 for the synthesis of 3a by the
reaction of 1a with 2a in water (Table 7). The water tolerant
acidic catalysts were chosen from different classes such as
heterogeneous/solid acids (silica, alumina, clay and zeolite)
and metal Lewis acids [Sc(OTf)3, Ln(OTf)3, Yb(OTf)3 and InF3].
Tween 40 was found to be superior to all of the tested catalysts
as it gave an excellent yield in a short time, whereas with the
other catalysts tested, they either gave an inferior yield or
required a longer reaction time.
The results (Table 3) of the present study revealed that for
the Tween 40 catalysed reactions, inferior yields are obtained
when replacing water with organic solvents, indicating that for
reactions in water the surfactant may play a specific role in
promoting the reaction (Table 3). Therefore, it generated
curiosity as to whether there could be a similar advantage in
using water over organic solvents for the reported Lewis/
Brønsted acid-catalyzed procedures.24
Table 7 The comparison of the catalytic potential of Tween 40 and a few water
tolerant acidic catalysts for quinoxaline formation in water from the reaction of
1a with 2aa
Entry
Catalyst
Yield (%)b
It was observed that there are a few reports on the use of
acid catalysts for quinoxaline formation in an aqueous
medium.21 However, these involve the use of different Lewis
acids as catalysts which raises the query of whether these are
generalised Lewis-acid catalysed reactions or they have any
specific advantage in using water as the reaction medium.
Hence, three sets of reactions were designed (Scheme 2) for
quinoxaline formation in water involving the cyclo-condensa-
tion of (i) 1a and 2a, (ii) 1b and 2a, and (iii) 1a and 2b and the
efficiencies of these reported catalysts21 were compared with
that of Tween 40 (Table 8).
In each case, the reactions were performed following the
conditions (reaction time and temperature) mentioned in the
reported procedure,24 as well as for the conditions developed
under the present study for the Tween 40 catalysed reaction
(Table 8). In all of these three model reactions, the present
methodology using Tween 40 in water was found to be
distinctly superior to all of the reported procedures using solid
1
2
3
4
5
6
7
8
SiO2 (60–120)
SiO2 (100–200)
SiO2 (230–400)
Al2O3 (Acidic)
Al2O3 (Neutral)
Al2O3 (Basic)
KSF
35
35
38
36
35
35
45
46
42
44
40
36
35
65
68
65
66
98
Zeolite Y
9
Zeolite K L21
Zeolite ZSM 5
Zeolite K L21
Zeolite Na/Fau
Zeolite NH4-Y
Sc(OTf)3
10
11
12
13
14
15
16
17
18
Ln(OTf)3
Yb(OTf)3
InF3
Tween 40
a
1a (0.10 g, 1 mmol) was treated with 2a (0.21 g, 1 mmol, 1 equiv.)
in the presence of different catalysts (10% w/w for solid acids or 10
mol% for metal salt derived Lewis acids) in water (5 mL) at rt for 5
b
min. Isolated yield of 3a.
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Table 8 Comparison of the efficiency of the reported Lewis/Brønsted acid-catalysed procedures of quinoxaline formation in water with that of the Tween 40
catalysed reactionsa
Entry
Cat.
1,2-Diamine
1,2-Diketone
Quinoxaline
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
CAN24a
CAN
CAN
CAN
CAN
CAN
InCl3
InCl3
InCl3
InCl3
1a
1a
1a
1a
1b
1b
1a
1a
1a
1a
1b
1b
1a
1a
1a
1a
1b
1a
1a
1a
1a
1b
1b
1a
1a
1a
1a
1b
1b
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1b
2a
2a
2b
2b
2a
2a
2a
2a
2b
2b
2a
2a
2a
2a
2b
2b
2a
2a
2a
2b
2b
2a
2a
2a
2a
2b
2b
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2a
2a
2a
2a
2a
2b
2a
3a
3a
3d
3d
3b
3b
3a
3a
3d
3d
3b
3b
3a
3a
3d
3d
3b
3a
3a
3d
3d
3b
3b
3a
3a
3d
3d
3b
3b
3a
3a
3a
3a
3d
3d
3d
3d
3b
3b
3b
3b
3a
3d
3b
10
5
82c (98)d
68e
10
20
60
30
30
5
60
20
60
30
15
5
12
20
30
2.5 h
5
2.5 h
20
6 h
30
30
5
65c (88)d
72e
70
52
85c (98)d
55e
24a
9
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
60e
InCl3
InCl3
70
58e
CuSO4?5H2O24a
CuSO4?5H2O
CuSO4?5H2O
CuSO4?5H2O
CuSO4?5H2O
K 1024a
K 10
85 (96)d
65e
70 (90)d
75e
79e (94)d
72c (100)d
35e
K 10
K 10
K 10
K 10
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
68
35e
62 (70)d
35e
79 (94)d
52e
24a
35
20
90
30
20
20
5
75 (93)d
50e
Zr(DS)4
Zr(DS)4
72 (86)d
35e
Amberlyst 1524a
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Tween 40
82c,f (99)d,f
52g
56c,f
5
24g
60
60
20
20
60
60
30
30
5
60c,f
traceg
35c,f
traceg
62c,f
traceg
30c,f
traceg
98
Tween 40
Tween 40
20
30
88
80
a
b
The 1,2-diamine (1 mmol) was treated with 1,2-diketone (1 mmol, 1 equiv.) in water (5 mL) at rt in the presence of the catalyst. Isolated
c
yield of the corresponding quinoxaline. The yield obtained in the present study by performing the reaction following the reported procedure.
d
e
The figure in the parenthesis is the yield as reported in the respective literature. The yield obtained in performing the reaction using the
f
reported catalyst for the time period required for the Tween 40 catalysed reaction under the present study. In the reported procedure using
this catalyst the reactions were carried out at 70 uC. The reaction was performed at rt under the present study.
g
Hence, we performed two sets of reaction (Scheme 3) for
quinoxaline formation in various organic solvents involving
the reaction of (i) 1a and 2a, and (ii) 1b and 2a, in the presence
of these reported catalysts21 and compared the results with
those obtained when performing the reaction in water in the
presence of the said catalyst (Table 9).
hand, the better/equal catalytic potency of the Lewis/Brønsted
acids and surfactant combined Lewis acids in organic solvents
over those in water suggests that perhaps the Lewis/Brønsted
Surprisingly all of these catalysts performed better/equally
in organic solvents (particularly MeOH and MeCN) compared
to water. These results imply that the surfactants are best
suited as a catalytic aid in promoting organic reactions in
water rather than in organic solvents, implying the fact that
solubility is not the sole reason for the observed advantages of
using surfactants in aqueous organic reactions. On the other
Scheme 3 The comparative catalytic efficiency of a few Lewis/Brønsted acids
for quinoxaline formation in water and in organic solvents.
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Table 9 The efficiency of the catalysts, reported for quinoxaline formation in
water, in various organic solvents as well as in water for the reaction of the 1,2-
diamines 1a or 1b with the 1,2-diketone 2a to form 3a or 3ba
Table 9 (Continued)
Entry Cat
Diamine Product Solvent Time (h) Yield (%)b
Entry Cat
Diamine Product Solvent Time (h) Yield (%)b
Water 2.5
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
Amberlyst 15 1b
Amberlyst 15 1b
Amberlyst 15 1b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3a
3b
3a
3a
3a
3a
3a
3a
Dioxane 1
Toluene 1
46c
35c
32c
1
2
K10
K10
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
72
85
76
65
60
46
52
62
70
65
35
41
30
41
72
68
65
43
40
21
20
72
62
55
32
30
14
15
85
90
88
65
70
52
61
79
85
75
50
46
36
40
85
96
84
61
68
60
72
70
81
71
55
65
62
65
DMF
Water
1
MeOH 2.5
MeCN 2.5
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
1a
1a
10 min 72
3
4
K10
K10
MeOH 10 min 91
MeCN 10 min 80
DCM
2.5
5
6
K10
K10
Dioxane 2.5
Toluene 2.5
DCM
10 min 62
Dioxane 10 min 68
Toluene 10 min 48
7
8
K10
K10
DMF
2.5
6
6
6
6
Water
MeOH
MeCN
DCM
DMF
10 min 52
9
K10
K10
Water
MeOH
MeCN
DCM
1
1
1
1
70
84
71
51
65
30
46
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
K10
K10
K10
K10
Dioxane 6
Toluene 6
Dioxane 1
Toluene 1
DMF
Water
6
0.5
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
Zr(DS)4
CuSO4?5H2O 1a
CuSO4?5H2O 1a
CuSO4?5H2O 1a
CuSO4?5H2O 1a
CuSO4?5H2O 1a
CuSO4?5H2O 1a
CuSO4?5H2O 1a
CuSO4?5H2O 1b
CuSO4?5H2O 1b
CuSO4?5H2O 1b
CuSO4?5H2O 1b
CuSO4?5H2O 1b
CuSO4?5H2O 1b
CuSO4?5H2O 1b
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
Amberlyst 15 1a
Amberlyst 15 1a
Amberlyst 15 1a
Amberlyst 15 1a
Amberlyst 15 1a
Amberlyst 15 1a
Amberlyst 15 1a
Amberlyst 15 1b
Amberlyst 15 1b
Amberlyst 15 1b
Amberlyst 15 1b
DMF
1
MeOH 0.5
MeCN 0.5
a
The 1,2-diamine (1 mmol) was treated with 2a (0.21 g, 1 mmol, 1
equiv.) in the presence of the catalyst (10% w/w or 10 mol%,
whichever is applicable) in the specified solvent (5 mL) at rt (unless
DCM
0.5
Dioxane 0.5
Toluene 0.5
b
otherwise mentioned). Isolated yield of the corresponding
quinoxaline. The reaction was carried out at 70 uC (oil bath).
c
DMF
Water
0.5
1.5
MeOH 1.5
MeCN 1.5
DCM
1.5
Dioxane 1.5
Toluene 1.5
acids are better suited for applications in organic solvents. It
may further be concluded that without any distinct compar-
ison of the catalytic efficiency in organic solvents vs. water, a
mere use of an aqueous medium may not reflect the projected
greener advantage.
DMF
Water
1.5
0.25
MeOH 0.25
MeCN 0.25
DCM
0.25
Dioxane 0.25
Toluene 0.25
The recyclability of the spent water containing the
surfactant, as well as the surfactant (Tween 40) itself was
studied for the model reaction of 1a with 2a. After each
reaction the product was isolated by filtration. The filtrate
(aqueous layer containing the Tween 40) was reused for four
subsequent fresh reaction batches. Excellent results were
obtained without any significant loss of product yield
(Table 10). After the final use, the spent water containing the
catalyst (Tween 40) was subjected to freeze drying to recover
the Tween 40 (recovery 82%) and was found to be identical
(NMR) with the authentic (unused) sample of Tween 40.
The better performances of the surfactant (e.g., Tween 40)
in aqueous media rather than that in organic solvents
DMF
Water
0.25
0.5
MeOH 0.5
MeCN 0.5
DCM
0.5
Dioxane 0.5
Toluene 0.5
DMF
Water
MeOH 0.5
MeCN 0.5
DCM
Dioxane 0.5
Toluene 0.5
DMF
Water
MeOH
MeCN
DCM
Dioxane 1
Toluene 1
0.5
0.5
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
0.5
0.5
1
1
1
1
Table 10 Recyclability of the spent water containing the catalyst (Tween 40)
during the Tween 40 catalysed reaction of 1a with 2a to form 3a in watera
DMF
Water
1
20 min 82c
MeOH 20 min 88c
MeCN 20 min 80c
Entry
Run
Yield (%)b
DCM
20 min 68c
1
2
3
4
5
Fresh
98
95
96
Dioxane 20 min 65c
1st recycle
2nd recycle
3rd recycle
4th recycle
Toluene 20 min 42c
DMF
20 min 50c
95
92 (91)c
Water
MeOH
MeCN
DCM
1
1
1
1
62c
70c
68c
50c
a
1a (1.1 g, 10 mmol) was treated with 2a (2.1 g, 10 mmol, 1 equiv.)
in the presence of Tween 40 (1.3 g, 1 mmol, 10 mol%) in water (40
mL) at rt. Isolated yield of 3a. Isolated yield of 3a using the
b
c
recovered Tween 40.
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advantages such as (i) no requirement of an additional
reagent, (ii) non-flammable and non-toxic reaction medium,
(iii) high yields, (iv) short reaction time, (v) room temperature
reaction, (vi) virtually no waste generation, (vii) use of cheap,
readily available and non-toxic Tween 40 as the catalyst, and
(viii) ease of product isolation/purification fulfils the ‘triple
bottom line philosophy’34 of green chemistry and makes the
present methodology environmentally benign. In general, the
catalytic potential of Tween 40 was found to be superior
compared to some of the water tolerant Lewis/Brønsted acid
catalysts, as well as the reported methods of quinoxaline
synthesis in water in the presence of Lewis/Brønsted acid
catalysts and surfactant combined Lewis acids. From this
study it can be concluded that surfactants are the best suited
agents/catalysts to promote or accelerate organic reactions in
water and that Lewis or Brønsted acid catalysts are better
suited to promote reactions in organic solvents. The super-
iority of water as the reaction medium is attributed to its role
in hydrogen bond mediated synergistic activation of the 1,2-
diamine and the 1,2-dicarbonyl in facilitating the condensa-
tion, wherein the surfactant (Tween 40) also plays a critical
role in forming hydrogen bonds with the dangling OH groups
of the interfacial water, providing a close proximity to the
reactants in encapsulating them inside the microreactor
through hydrogen bond formation. Since the concern is to
develop environmentally benign protocols, the various fea-
tures such as stability, cost and toxicity profile of the
surfactants were looked into.
Fig. 1 The role of water during quinoxaline formation in aqueous media.
highlighted the distinct rate acceleration by water.
Understanding the role of water in promoting organic
reactions is yet to be fully recognised. Various factors such
as enforced hydrophobic interactions, high cohesive energy
density of water and the hydrogen bond (HB) effect have been
attributed to water for its unique ability to enhance the rate of
an organic reaction.25 Amongst the various factors, the HB
effect has gained popularity to account for ‘‘on water’’
catalysis.26,27 However, the non-HB effect has also been
invoked.28 The advantage of using water as the reaction
medium may be attributed to its superior HB donor (HBD)
ability29 in facilitating the condensation between the amine
group of the 1,2-diamine and the carbonyl group of the 1,2-
diketone, through the formation of the hydrogen bonded
supramolecular assembly I (Fig. 1). The intermittently formed
imine II may in turn undergo intramolecular condensation
between the adjacent amine and carbonyl groups through a
hydrogen bond mediated supramolecular assembly involving
the water dimer akin to I to form the quinoxaline.
The hydrogen bond induced formation of the supramole-
cular clusters involving the reactants and water molecule(s)
have been postulated in various water-mediated organic
reactions,26 water catalysis of radical-molecule gas-phase
reactions30 and epoxide-opening cascades.31 The poor results
in the organic solvents could be due to their inferior HBD
values. Thus, water accelerates the cyclocondensation process
through HB-assisted synergistic dual activation.32
Acknowledgements
Financial support from CSIR, New Delhi, India is thankfully
acknowledged for the award of Research Associateship to DK
and Senior Research Fellowship to KS and DNK.
The specific catalytic effect exhibited by Tween 40 could be
due its HB formation ability both in the form of HBDs
(through the terminal/free hydroxyl groups) and HB acceptors
(HBAs) (through the carbonyl and polyoxyethylene ethereal
oxygen atoms). The surfactant molecule undergoes HB
formation with the dangling OH groups33 of the interfacial
water and encapsulates, through HB, the reactants (the 1,2-
diamine and 1,2-dicarbonyl substrates) inside the microreac-
tor for acceleration of the cyclocondensation leading to the
formation of quinoxalines.
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In summary, we describe in this study a simple, extremely
efficient, and green protocol for the synthesis of quinoxalines
from various 1,2-diketones and 1,2-diamines in water at room
temperature catalysed by a surfactant. The catalytic potential
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