R. Sarkar, C. Mukhopadhyay / Tetrahedron Letters 55 (2014) 2618–2624
2619
Table 1
Thus, an efficient, environmentally benign, one pot transforma-
tion is always desirable to synthesize this bioactive heterocyclic
molecule with high yield and selectivity under mild reaction
conditions. Within the past few decades or so, studies on green
chemistry have led to the development of cleaner and relatively
benign chemical processes and the main portion of effort has been
devoted to the use of nontraditional solvents for chemical synthe-
sis. These unconventional media include no solvent, water, ionic
liquids and some others.14 Generally, water is considered as a
benign solvent due to its non toxicity and abundant natural occur-
rence. In view of the above perceptions, previously many organic
reactions were successfully studied in aqueous medium with good
to excellent yields.15 In continuation of our work, we aimed to
develop a facile, multicomponent, and sustainable green method
to synthesize this potent molecule and thus chose water as the
reaction medium. Multicomponent reactions are convergent
chemical processes that involve the fast assembly of poly-substi-
tuted systems without the isolation of unstable intermediates.
Due to both step and atom-economy, less waste production multi-
component condensation reactions (MCRs) have an advantageous
position among other reactions.16 Optimized reaction condition
Effect of various catalysts on the formation of 4a in aqueous SDS (10 mM) solution
Entry
Catalyst
Amout
(mol %)
Time
(h)
Yielda
(%)
1
2
3
4
5
6
7
8
9
None
SiO2
Alumina (acidic)
MgSO4
p-TsOH
InCl3
H3BO3
Acetic acid
Chloroacetic acid
Pyrrolidine
Glycine
—
15
15
15
15
15
15
15
15
15
15
15
15
No reaction
15
20
22
68
24
25
30
10
10
10
10
10
10
10
10
10
10
5
45
10
11
12
No reaction
72
45
L
L
L
L
L
-proline
-proline
-proline
-proline
-proline
13
14
15
16
8
15
12
15
15
78
80
85
85
10
10
15
17
18
TiO2
Nano TiO2
10
10
15
15
35
58
a
Isolated yield.
was obtained by using L-proline as an organocatalyst. Organocatal-
ysis emerged as an area of very rapid growth for organic transfor-
mations due to its lower toxicity, operational simplicity, and high
environmental compatibility as compared to the use of heteroge-
neous catalysts as well as metal catalysts.17 The application of
enantiomerically pure ‘small’ organic molecules, particularly
Table 2
Effects of different solvents with 10 mM SDS on the formation of 4a
Entry
Solvent
Temperature (°C)
Time (h)
Yielda (%)
L
-Proline as an organocatalyst was intensely investigated due to
1
2
3
4
5
6
7
8
9
EtOH
CH3CN
H2O
H2O
H2O
78.3
82
30
50
80
100
118
110.6
140
140
15
15
15
15
15
15
15
15
15
15
32
68
5
20
45
85
45
55
50
48
its dual role as a ligand and catalyst.18 Previously,
L-proline has
been used in asymmetric Aldol,19 Diels–Alder,20 Mannich,21
Michael,22 unsymmetric Biginelli reactions23 as well as in domino
reactions.24 Herein, we wish to report a practical, multicomponent,
green synthesis of fused N-substituted-2-pyridone derivatives
H2O
AcOH
Toluene
DMF
catalyzed by
L-proline in aqueous sodium dodecyl sulfate
(SDS) medium. To the best of our knowledge, this is the first
convenient procedure for the synthesis of fused N-substituted
2-pyridone derivatives in aqueous medium using
organocatalyst.
10
DMSO
a
Isolated yield.
L-proline as the
In order to derive a green and benign practice to synthesize
fused N-substituted-2-pyridone derivatives, we started to investi-
gate the reaction between cyclic 1,3-diketones, primary amines,
and dialkylacetylenedicarboxylates in aqueous medium. Since,
organic compounds are soluble in aqueous medium to a limited
extent, we choose an aqueous surfactant solution for this purpose.
The reaction was initially standardized with 1,3-cyclohexanedione,
diethylacetylenedicarboxylate and 3,4-dimethylaniline. They were
taken in a 25 ml round-bottomed flask containing 10 ml aqueous
SDS solution (SDS: CMC value 8.1 mM) and the mixture was
refluxed for 15 h in the absence of any catalyst. After 15 h, there
was no conversion of the starting materials to the product. Then,
our next attempt was done with different homogeneous and heter-
ogeneous catalysts for the said organic transformation in the same
conditions. We examined several catalysts for that purpose, but it
was observed that among all the catalysts, p-TsOH in aqueous
medium can catalyze the reaction to some extent though in poor
yield. Therefore, we focused our attention to study the organocat-
alytic effect in our stated organic transformation. A tremendous
increase in the yield of the reported transformation was noticed
Table 3
Effect of different surfactants on the formation of 4a, in aqueous medium containing
10 mol % L-proline.
Entry
Surfactant
Concentration (mM)
Yielda (%)
1
2
3
4
5
6
7
8
9
None
SDS
SDS
SDS
SDS
—
3
8
No reaction
20
35
85
85
80
5
20
25
10
25
40
10
12
20
0.8
1.0
10
3.0
4.0
10
SDS
CTAB
CTAB
CTAB
TTAB
TTAB
TTAB
10
11
12
a
Isolated yield.
effects of all catalysts including
product, 4a are illustrated in Table 1. We further examined the
catalytic activity of -proline in different solvents, where water
was found to be the best choice for our desired transformation
(Table 2). In addition, the effect of many surfactants such as cetyl-
trimethylammonium bromide (CTAB), tetradecyltrimethylammoni
um bromide (TTAB) were also studied to increase the yield of the
desired product, though the maximum yield was obtained with
10 mM SDS solution (Table 3).
L-proline for the formation of the
by introducing L-proline as an organocatalyst. All the starting
materials, 1,3-cyclohexanedione (1 mmol), 3,4-dimethylaniline
(1 mmol) and diethylacetylenedicarboxylate (1 mmol) were taken
L
in a 10 ml aqueous SDS (10 mM) solution containing L-proline
(10 mol %) in a 25 ml round-bottomed flask. The mixture was then
refluxed for 15 h and the reaction progress monitored by TLC. After
completion of the reaction work-up, the product was purified by
column chromatography to produce 4a in almost 85% yield. The