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K. Pradhan et al. / Tetrahedron Letters 54 (2013) 3105–3110
O
OH
CHO
NO2
O
O
catalyst
Solvent, 70 °C
O
O
O
O
O
NO2
Scheme 1. Synthesis of chromeno[4,3-b]chromene derivative.
Table 1
FeCl3/sodium dodecyl sulfate catalyst combination to enhance the
rate of the reaction. But very little improvement of the yield of the
desired product was noticed by using the catalyst combination (Ta-
ble 1, entry 11, bold).
Screening of different catalysts for the synthesisa of chromeno[4,3-b]chromene
derivative
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
In comparison with different acid catalysts, FeCl3 proved to be
the most efficient catalyst which gave higher yield (42%) within
6 h (Table 1, entry 10, bold). Probably due to the lower solubility
of the reactants, the product was not produced efficiently under
the above mentioned reaction conditions. Again in the presence
of a surfactant, activity of the catalyst was not as pronounced as
expected which may be due to water labile character of FeCl3.
The yield of the desired product was almost same when the exper-
iments 7–9 were repeated in the presence of FeCl3/sodium dodecyl
sulfate combo-catalyst (Table 1, entries 12–14). The above results
(Table 1, entries 10 and 11) encouraged us to think about a
water-stable catalyst having both the surfactant property and
strong Lewis acidity to promote the three-component reaction.
We have examined a wide spectrum of ‘Lewis acid-surfactant-
combined catalyst (LASC)’ such as Cu(dodecyl sulfate)2 [Cu(DS)2],
Ni(dodecyl sulfate)2 [Ni(DS)2], Ti(dodecyl sulfate)4 [Ti(DS)4],
Zn(dodecyl sulfate)2 [Zn(DS)2], and Fe(dodecyl sulfate)3 [Fe(DS)3]
in search of a suitable condition to synthesize the heterocyclic scaf-
fold in aqueous media. It is pertinent to mention that the addition
of LASC converted the initially floating reaction mass into a homo-
geneous mixture, which on stirring became a turbid emulsion
(Fig. 4). This observation implies that there was formation of mi-
celles or colloidal aggregates. After extensive studies this reaction
is optimized in aqueous media (Table 2, entry 5, bold) by using col-
loidal aggregates of Fe(DS)3 (characterized by IR and elemental
analysis). The average sizes of the colloidal particles formed from
[Fe(DS)3] and the reaction mixture in water were measured by dy-
namic light scattering (DLS), and shape of the colloidal aggregates
was nearly spherical with around 240 nm in diameter (Fig. 1b).
Formation of emulsion droplets in the present reaction system
was also confirmed by optical microscopy (Fig. 1a). Our studies re-
veal that the reaction rate depends on the size of colloidal aggre-
gates. The colloidal aggregates formed by the Cu(DS)2, Ni(DS)2,
Ti(DS)4, Zn(DS)2 are either very large or too small and thus these
LASCs were not effective to catalyze the MCR.
1
2
3
4
5
6
7
8
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
DMF
H2O
H2O
CH3CN
DCM
20
8
8
6
6
6
6
6
6
6
4
6
6
6
6
6
Trace
10
10
20
15
18
40
25
35
42
56
42
24
36
30
33
p-Toluene sulfonic acid
PEG–SO3H
ZnCl2
MgCl2
SiO2
FeCl3
FeCl3
FeCl3
9
10
11
12
13
14
15
16
FeCl3
FeCl3/sodium dodecyl sulfate
FeCl3/sodium dodecyl sulfate
FeCl3/sodium dodecyl sulfate
FeCl3/sodium dodecyl sulfate
Sodium dodecyl sulfate (SDS)
Dodecyl sulfonic acid (DSA)
DMF
H2O
H2O
a
4-Nitrobenzaldehyde (1 mmol), cyclohexane-1,3-dione (1 mmol), and 4-
hydroxycoumarin (1 mmol) were stirred in 2.5 ml solvent in presence of 10 mol %
catalyst at 70 °C.
b
Isolated yield of the pure product.
To develop a clean three component protocol for the formation
of only chromeno[4,3-b]chromene, we have installed a large num-
ber of Brønsted and Lewis acid catalysts for the optimization of the
reaction condition. In a pilot experiment, 4-nitrobenzaldehyde
(1 mmol), cyclohexane-1,3-dione (1 mmol), and 4-hydroxycouma-
rin (1 mmol) were stirred in CH3CN at 70 °C temperature
(Scheme 1). It was evident that the three component coupling
product, chromeno[4,3-b]chromene derivative was obtained in
trace amount after 20 h (Table 1, entry 1). To accelerate the
three-component reaction, we have applied a wide spectrum of
Brønsted and Lewis acid catalysts like p-toluene sulfonic acid,
PEG–SO3H, ZnCl2, MgCl2, SiO2, and FeCl3 (Table 1). We found that
for the three-component coupling protocol, Brønsted acids were
not very much efficient as compared to the Lewis acid catalysts
desiring the synthesis of the heterocyclic scaffold under the partic-
ular experimental condition. Again sodium dodecyl sulfate (SDS)
and dodecyl sulfonic acid (DSA) were unable to show significant
improvement of the desired product yield under the particular
experimental condition (Table 1, entries 15 and 16). It was also evi-
dent that FeCl3 responded well in comparison to other Lewis acid
catalysts. Various solvents such as CH3CN, DCM, DMF, and water
were screened for the three-component coupling reaction. CH3CN
was taken as the primary choice of the solvent as in this solvent
all the reactants remained as a homogeneous mixture. Table 1 also
revealed that the efficiency of FeCl3 was almost same in CH3CN and
water. One important facet of green chemistry is the eradication of
solvents in chemical processes or the replacement of hazardous
solvents with relatively benign solvents. Developing environmen-
tally benign and economical syntheses is an area of research that
is being vigorously pursued, and avoiding the use of harmful or-
ganic solvents is a fundamental strategy to achieving this. Hence,
we have tried to synthesize the heterocyclic scaffold in aqueous
media applying suitable catalyst combination and we have applied
To find the optimized amount of catalyst (as shown in Fig. 2),
the reaction was carried out by varying the amount of the catalyst
on the model reaction. The conversion of chromeno[4,3-b]chro-
mene derivative increased linearly with the catalyst weight up to
10 mol % and became almost steady when the amount of catalyst
was further increased beyond this. As the amount of the surfac-
tant-type catalyst increases, the size of each droplet may decrease,
because the emulsion system may become a microemulsion sys-
tem. The smaller the droplets, the larger the sum of the surface
area of the droplets and as a result, the organic phase and water
can contact each other decreasing the solubility of the organic mol-
ecules in water. Therefore 10 mol % catalyst is sufficient to catalyze
the reaction leading to expected coumarin fused heterocycle in
excellent yield.
Initializing the optimal conditions of this new multicomponent
domino process20 we embarked on the library construction with
1,3-diketo compounds and 4-hydroxycoumarin with various aro-