A green and highly efficient protocol for catalyst-free Knoevenagel condensation and Michael addition of aromatic aldehydes with 1,3-cyclic diketones in PEG-400

Article abstract of DOI:10.1002/cjoc.201100005

A convenient, highly efficient and green approach for synthesis of tetraketones from aromatic aldehydes with dimedone and 1,3-indanedione at room temperature in PEG-400 is described. The use of PEG-400 as the reaction medium and avoiding the use of any ca

Full text of DOI:10.1002/cjoc.201100005

FULL PAPER
A Green and Highly Efficient Protocol for Catalyst-free Kno-
evenagel Condensation and Michael Addition of Aromatic Al-
dehydes with 1,3-Cyclic Diketones in PEG-400
Firouzeh, Nemati*
Hossein, Kiani
Department of Chemistry, Faculty of Science, Semnan University, Semnan, Iran
A convenient, highly efficient and green approach for synthesis of tetraketones from aromatic aldehydes with
dimedone and 1,3-indanedione at room temperature in PEG-400 is described. The use of PEG-400 as the reaction
medium and avoiding the use of any catalyst makes the process environmentally benign. Seven new compounds are
reported.
Keywords Michael addition, green chemistry, polyethelene glycol, Knoevenagel condensation, dimedone,
1,3-Indanedione
Introduction
water, gave good results with different arylaldehydes in
terms of yield and time under these conditions.
The search for environmentally benign synthetic
procedures is one of the major focus areas of green
chemistry. Recently attention has been drawn to the re-
placement of volatile and often toxic solvents with al-
ternative reaction media such as ionic liquids,1 water,2
supercritical media,3 and polyethylene glycol.4
Polyethylene glycol promoted reactions have at-
tracted organic chemists. This solvent possesses unique
properties such as recyclability, ease of work up, ther-
mal stability, no flammability and economical cost. In
addition, numerous solvating ability of PEG-400, makes
the system homogeneous so allowing molecular interac-
tions to be more efficient.
The tetraketones and their enol forms, were com-
monly synthesized through the Knoevenagel condensa-
tions and Michael additions of aldehydes with dimedone
or other types of 1,3-cyclic diketones. They are key in-
termediates for the preparation of some heterocylic
compounds 5 and various acridindions as laser dyes.6
Several methods have already been reported for the
preparation of tetraketones such as use of NaOH,7
KOH,8 piperidine,5 proline,9 SDS,10 cetyltrimethyl am-
monium bromide (CTMAB),11 L-lysine in H2O,12
L-histidine in ionic liquid,13 grinding,14 and in solid
state.15 Very recently, the synthesis of tetraketones in
water was reported, which produced 2,2'-(arylmethyl-
ene) dicyclohexane-1,3-diones in 64%—99% yields at
room temperature for 0.5—4 h.16 The protocol provides
several features including use of water without any
catalyst. Compared with the related procedure in water,
PEG could reduce the time of the reaction. More impor-
tantly, 1,3-indanedione, which has little solubility in
Experimental
General procedure for the synthesis of 2-((2,3-dihy-
dro-1,3-dioxo-1H-inden-2-yl)(4-nitrophenyl)methyl)-
2H-indene-1,3-dione (16B)
A mixture of 1,3-indanedione (0.292 g, 2 mmol) and
4-nitro benzaldehyde (0.151 g, 1 mmol) was taken in 5
mL of polyethylene glycol 400, and stirred for 45 min at
room temperature (Table 2). After the completion of the
reaction (monitored by TLC), the reaction mixture was
poured into water. The precipitated solid was filtered
and the crude product was crystallized with ethanol to
afford the pure product (16B). Yellow crystals, yield
97%, 0.4 g, m.p. 197—199 ℃.
PEG-400 could be recycled by this procedure: after
the completion of reaction, the reaction mixture was
extracted with diethyl ether and the retained PEG-400
phase was reused. The ether layer was washed with wa-
ter (2 mL) and dried over MgSO4. The organic solvent
was removed under reduced pressure to give the crude
product. Crystallization from EtOH provided the pure
product.
1
Spectral (IR, H NMR, 13C NMR) and analytical
data for new compounds
2-((4-Fluorophenyl)(4,4-dimethyl-2,6-dioxocyclohex-
yl)methyl)-5,5-dimethylcyclohexane-1,3-dione
(13A)
(Entry 13, Table 2): Colorless crystals, yield 72%, 0.27
1
g, m.p. 185—187 ℃; H NMR (CDCl3, 300 MHz) δ:
1.11 (s, 6H), 1.23 (s, 6H), 2.50—2.18 (m, 8H), 5.49 (s,
*
E-mail: fnemati_1350@yahoo.com; fnemati@semnan.ac.ir; Tel.: 0098 (231) 3334201; Fax: 0098 (231) 3338847
Received June 10, 2011; revised July 16, 2011; accepted July 18, 2011.
Project supported by the Department of Chemistry and Office of Gifted Student at Semnan University.
Chin. J. Chem. 2011, 29, 2407— 2410
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Firouzeh & Hossein
FULL PAPER
1H), 6.98—6.93 (m, 2H), 7.07—7.03 (m, 2H), 11.12 (s,
br, 0.6H), 11.90 (s, br, 1H); 13C NMR (CDCl3, 75 MHz)
δ: 27.39, 29.62, 29.70, 31.40, 32.22, 46.42, 47.04,
114.87, 115.15, 115.54, 128.21, 128.31, 133.59, 133.64,
159.40, 162.64, 189.41, 190.57; IR (KBr) ν: 3047, 2962,
2H), 7.31 (t, J＝8.44 Hz, 2H), 7.85—7.79 (m, 4H), 7.93
—7.89 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ: 41.55,
54.28, 123.30, 128.51, 130.38, 133.24, 135.38, 135.66,
135.83, 137.38, 141.82, 142.00, 198.087, 199.07; IR
(KBr) ν: 1743, 1704 cm . Anal. calcd for C23H27ClO4:
C 68.57, H 6.70; found C 68.80, H 6.81.
－
1
－
1
1589 cm . Anal. calcd for C23H27FO4: C 71.50, H 6.99;
found C 71.43, H 6.81.
5,5-Dimethyl-2-((4,4-dimethyl-2,6-dioxocyclohexyl)-
(thiophen-2-yl)methyl)cyclohexane-1,3-dione
2-((2-Chlorophenyl)(2,3-dihydro-1,3-dioxo-1H-in-
de-n-2-yl)methyl)-2H-indene-1,3-dione (20B) (Entry 20,
Table 2): Crystals, yield 80%, 0.32 g, m.p. 165—167
℃; 1H NMR (CDCl3, 300 MHz) δ: 3.95 (d, J＝6.96 Hz,
2H), 4.70 (t, J＝6.99 Hz, 2H), 7.40—7.19 (m, 3H), 7.96
—7.79 (m, 9H); 13C NMR (CDCl3, 75 MHz) δ: 35.81,
54.75, 122.92, 123.23, 123.33, 127.19, 128.45, 129.50,
129.84, 133.93, 135.45, 135.70, 138.29, 141.58, 141.64,
197.11, 198.73; IR (KBr) ν: 1743, 1704, 1589, 1342,
(14A)
(Entry 14, Table 2): White crystals, yield 71%, 0.26 g,
m.p. 156—158 ℃; 1H NMR (CDCl3, 300 MHz) δ: 1.11
(s, 6H), 1.23 (s, 6H), 2.59—2.28 (m, 8H), 5.64 (s, 1H),
6.65 (d, br, J＝1.32 Hz, 1H), 6.88 (t, br, J＝3.75 Hz,
1H), 7.12 (d, br, J＝4.59 Hz, 1H), 11.62 (s, br, 0.6H),
12.34 (s, br, 1H); 13C NMR (CDCl3, 75 MHz) δ: 26.75,
29.99, 30.41, 31.17, 46.23, 47.00, 115.97, 123.50,
124.56, 126.37, 143.70, 189.51, 189.94; IR (KBr) ν:
－
1
756 cm . Anal. calcd for C23H27ClO4: C 68.57, H 6.70;
found C 68.69, H 6.59.
－
1
2592, 1589 cm . Anal. calcd for C21H26O4S: C 67.37,
H 6.95; found C 67.29, H 6.71.
Results and discussion
2-((2,3-Dihydro-1,3-dioxo-1H-inden-2-yl)(4-nitro-
phenyl)methyl)-2H-indene-1,3-dione (16B) (Entry 16,
Table 2): Yellow crystals, yield 97%, 0.4 g, m.p. 197—
199 ℃; 1H NMR (CDCl3, 300 MHz) δ: 4.03 (t, J＝7.41
Hz, 1H), 4.31 (d, J＝7.35 Hz, 2H), 7.60 (d, J＝8.61 Hz,
2H), 7.93—7.89 (m, 4H), 7.87—7.81 (m, 4H), 8.12 (d,
br, 1H); 13CNMR (CDCl3, 75 MHz) δ: 41.22, 53.98,
123.38, 123.61, 123.68, 130.00, 134.25, 135.86, 136.02,
141.64, 142.68, 146.75, 147.07, 197.61, 198.53; IR
(KBr) ν: 1704, 1512, 1350 cm－ 1. Anal. calcd for
C23H27NO6: C 66.82, H 6.53, N 3.38; found C 66.90, H
6.64, N 3.42.
In our pursuit of improved synthetic method for the
preparation of organic compounds17 here in we want to
report a simple, mild and highly efficient procedure for
the synthesis of tetraketones that employs only PEG-400
as a solvent at room temperature (Scheme 1).
Scheme 1 Knoevenagel condensation and Michael addition of
aromatic aldehydes with dimedone and 1,3-indanedione in
PEG-400 at room temperature
Ar
O
O
O
Ar-CHO
+
PEG-400
2-((3-Bromophenyl)(2,3-dihydro-1,3-dioxo-1H-inden-
2-yl)methyl)-2H-indene-1,3-dione (17B) (Entry 17, Ta-
ble 2): Light brown crystals, yield 90%, 0.4 g, m.p. 169
OH
HO
54__180 min
r.t.
A
O
O
1
—170 ℃; H NMR (CDCl3, 300 MHz) δ: 3.86 (t, J＝
Ar
O
O
7.31 Hz, 1H), 4.18 (dd, J＝7.22, 3.31 Hz, 2H), 7.38—
7.11 (m, 3H), 7.57 (s, br, 1H), 7.93—7.80 (m, 8H); 13C
NMR (CDCl3, 75 MHz) δ: 41.30, 54.46, 122.40, 123.30,
127.65, 129.88, 130.54, 132.01, 135.62, 135.82, 141.73,
PEG-400
Ar-CHO
+
45__349 min
r.t.
OO
B
O
－
1
141.90, 197.68, 198.87; IR (KBr) ν: 1743, 1704 cm .
Anal. calcd for C23H27BrO4: C 61.74, H 6.04; found C
61.81, H 6.11.
When benzaldehyde and dimedone in different sol-
vents, were allowed to react at room temperature, the
expected product was obtained whose ratio depends on
the nature of the solvent (Table 1). As can be seen in
Table 1, the most satisfactory result was obtained in
PEG-400 at room temperature.
2-((2,3-Dihydro-1,3-dioxo-1H-inden-2-yl)(p-tolyl)-
methyl)-2H-indene-1,3-dione (18B) (Entry18, Table 2):
Green crystals, yield 92%, 0.35 g, m.p. 172—174 ℃.
1H NMR (CDCl3, 300 MHz) δ: 2.3 (s, 3H), 3.72 (d, J＝
6.77, 1H), 3.85 (d, J＝6.92, 1H), 4.71 (t, J＝6.8 Hz, 1H),
7.41—7.20 (m, 3H), 7.97—7.82 (m, 9H); 13C NMR
(CDCl3, 75 MHz) δ: 24.3, 35.95, 54.82, 123.28, 123.38,
127.23, 128.50, 129.57, 129.92, 134.02, 135.48, 135.73,
138.35, 141.68, 141.74, 197.15, 198.75; IR (KBr) ν:
Based on the above results, we examined the sub-
strate scope of this reaction. First the reaction was car-
ried out using various substituted arylaldehydes and di-
medone. The results are presented in Table 2 (Entries 1
—15).
－
1
A variety of arylaldehydes including both elec-
tron-deficient and electron-rich groups were employed
and participated well to give the corresponding products
in good to excellent yields and no undesirable side reac-
tions were observed, although the yield and the time of
the reaction were dependent on the substituent.
PEG-400 is a sufficient solvent and helps in the eno-
1743, 1704 cm . Anal. calcd for C24H30O4: C 75.39, H
7.85; found C 75.44, H 7.71.
2-((4-Chlorophenyl)(2,3-dihydro-1,3-dioxo-1H-inden-
2-yl)methyl)-2H-indene-1,3-dione (19B) (Entry 19, Ta-
ble 2): Yellow crystals, yield 91%, 0.36 g, m.p. 153—
155 ℃; 1H NMR (CDCl3, 300 MHz) δ: 3.90 (t, J＝7.40
Hz, 1H), 4.26 (d, J＝7.45 Hz, 2H), 7.21 (d, J＝8.45 Hz,
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Chin. J. Chem. 2011, 29, 2407— 2410

A Green and Efficient Protocol for Catalyst-free Knoevenagel Condensation and Michael Addition
Table 1 Synthesis of 2,2'-[(phenyl)methylene]bis(3-hydroxy-
Scheme 2 A plausible mechanism
5,5-dimethylcyclohex-2-enone) in different conditions
H
O
H
O
O
OH
O
O
Entry
Solvent
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
H2O
Time/min T/℃ Yield/%
n
n OH
1
2
3
4
5
6
7
8
60
r.t.
r.t.
r.t.
50
70
r.t.
r.t.
r.t.
81
85
H
O
O
HO
O
80
100
100
100
240
240
240
97
Knoevenagel
codensation
91
84
9616
8016
9416
H
O
O
nOH
EtOH
EtOH/H2O (1∶1)
O
OH
O
-H2O
O
O
O
Table 2 The reaction of dimedone or 1,3-indanedione and ary-
laldehydes in PEG-400 at room temperature
O
HO
OH
intermediate
precipitate in PEG
Entrya Ar-CHO Time/minYieldb/%
m.p. (Lit.)/℃
Michael
addition
1A
2A
3A
C6H5
100
118
71
97 194—195 (194—195)16
77 172—173 (172—174)13
90 197—198 (184—186)13
98 183—185 (185—186)16
96 185—186 (181—183)16
97 190—191 (188—190)15
98 196—198 (196—198)16
74 141—142 (141—142)14
79 144—146 (145—146)15
98 204—205 (203—205)14
91 202—204 (203—204)14
95 208—209 (205—206)14
studied the reaction of 1,3-indanedione with variety of
arylaldehydes. Interestingly, 1,3-indanedione was also
effective for this reaction. However, reaction of
1,3-indanedion needs longer time due to lower activity
than dimedone (Table 2, Entries 16—21). The ortho-
and para-methoxy benzaldehydes only produced the
Knoevenagel condensation products with 1,3-indanedi-
one. Spectroscopic data support the chemical structure
of this intermediates.18
We have also successfully applied this new method-
ology on a larger scale. For example up to 20 mmol
benzaldehyde could produce 5,5-dimethyl-2-((4,4-di-
methyl-2-oxocyclohexyl)(phenyl)methyl)cyclohexanone
with yield up to 80%.
4-Br-C6H4
3-Br-C6H4
4A 4-MeO-C6H4
5A 2-MeO-C6H4
6A 4-NO2-C6H4
7A 3-NO2-C6H4
54
81
71
150
130
102
54
8A
9A
4-Me-C6H4
4-Cl-C6H4
2-Cl-C6H4
10A
11A 2,4-Cl2-C6H3
12A 2-OH-C6H4
75
116
108
94
13A
4-F-C6H4
72
71
185—187
156—158
Conclusions
14A 2-Thiophen
15A 4-(Me2N)-C6H4 180
59 193—194 (194—195)16
In summary, we have established a green and simple
method for the preparation of tetraketones. The proce-
dure offers several merits including high reaction yields,
broad application scope, simple experimental process
and avoidance of any catalyst and volatile organic sol-
vents. On the other hand, these advantages could make
this process available on an industrial scale.
16B 4-NO2-C6H4
17B 3-Br-C6H4
18B 4-Me-C6H4
45
97
90
92
91
80
93
197—199
169—170
349
322
250
338
186
172—174
19B
20B
21B
4-Cl-C6H4
2-Cl-C6H4
C6H5
153—155
165—167
163—164 (162)16
Supporting information
a
Reaction condition: aldehyde (1 mmol), A: Dimidone (2 mmol)
Supporting information for this article is available on
or B: 1,3-indanedion (2 mmol) and PEG (5 mmol) at r.t. b Isolated
the
www
under
http://dx.doi.org/10.1002/cjoc.
yield.
201100005 or from the author.
lization and increase of nucleophilic character of the
methylene carbon of 1,3-cyclic diketone by making hy-
drogen bonds with OH groups. In addition, it could in-
crease the electrophilic character of the carbonyl carbon
of arylaldehydes. After the Knoevenagel condensation,
the intermediate is transformed to the product (Scheme
2).16
References and notes
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Chin. J. Chem. 2011, 29, 2407— 2410
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Firouzeh & Hossein
FULL PAPER
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1H), 8.0—7.96 (m, 2H), 7.81—7.77 (m, 2H), 7.52 (td, J＝
7.13, 1.66 Hz, 1H), 7.07 (t, J＝7.44 Hz, 1H), 6.94 (d, J＝
8.35 Hz, 1H), 3.93 (s, 3H); 13CNMR (CDCl3, 75 MHz) δ:
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(td, J＝7.84, 1.58 Hz, 1H), 7.08 (t, J＝7.65 Hz, 1H), 6.95 (d,
J＝8.36 Hz, 1H), 3.94 (s, 3H); 13C NMR (CDCl3, 75 MHz)
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135.17, 135.01, 133.96, 128.26, 123.18, 123.17, 122.02,
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