Synthesis of tetraketones in water and under catalyst-free conditions

Article abstract of DOI:10.1039/b913816a

A simple, environmentally friendly, tandem Knoevenagel condensation and Michael addition procedure is reported. The reactions between cyclic-13-diketones and a variety of aldehydes were carried out in water to afford tetraketones (64-99%). In this green synthetic protocol, the solvent water itself catalysed the reaction by hydrogen bonding, thus avoiding the use of any other catalysts to make the work up procedure easier.

Full text of DOI:10.1039/b913816a

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www.rsc.org/greenchem | Green Chemistry
Synthesis of tetraketones in water and under catalyst-free conditions†
Jian-Jun Yu, Li-Min Wang,* Jin-Qian Liu, Feng-Lou Guo, Ying Liu and Ning Jiao
Received 13th July 2009, Accepted 17th November 2009
First published as an Advance Article on the web 9th December 2009
DOI: 10.1039/b913816a
A simple, environmentally friendly, tandem Knoevenagel
condensation and Michael addition procedure is reported.
The reactions between cyclic-13-diketones and a variety of
aldehydes were carried out in water to afford tetraketones
(64–99%). In this green synthetic protocol, the solvent water
itself catalysed the reaction by hydrogen bonding, thus
avoiding the use of any other catalysts to make the work
up procedure easier.
class of laser dyes.3 4H-1-Benzopyrans are an important class of
naturally occurring compounds with biological activities.7,8
Tetraketones were synthesized through Knoevenagel conden-
sations and Michael additions of aldehydes with cyclohexane-
1,3-diones, dimedones or other types of 1,3-cyclic diketones.
They were first reported by Merling in 1894 by synthesizing the
cyclohexane-1,3-dione from resorcinol.9 Vorlander and Kalkow
reported the practical synthesis of tetraketones in 1899.10 Several
reports of the attempts to carry out an efficient synthesis of
tetraketones have appeared in the literature. Many of these
methods involve the use of NaOH,13 KOH,2 piperidine1,11a,11c
and proline14 as catalyst, the use of cetyltrimethyl ammonium
bromide (CTMAB) as surfactant,12 and the use of aqueous
organic solvent as cosolvent.1,2,3b,11
In modern organic chemistry, the improvement of reaction
efficiency, the avoidance of toxic reagents, the reduction of waste,
and the responsible utilization of our resources have become
critical objectives.14,15 By keeping these ideas in mind, a simple
and green approach for the synthesis of tetraketones (I) has
been developed. Pure water as solvent, catalyst free and room
temperature conditions are enough to afford the tetraketones in
nearly quantitative yields. Most important of all, the purification
procedure is just followed by filtration, washing and drying and
the water can be reused for the next cycle, so the waste can be
reduced effectively.
Introduction
Tetraketones (I), which have four carbonyl functionalities along
with their tautomeric, that is, keto-enol-forms, have some tyrosi-
nase inhibitory properties and some are even better than both the
standards kojic acid and L-mimosine.1 The dimeric intermediate
(I) is a key intermediate for the preparation of heterocyclic three-
ring systems—either xanthendione (II), acridindione (III),3
or 4H-1-benzopyran (IV) derivatives (Scheme 1).2 Acridin-
dione (III) derivatives have been used as electron donors and
acceptors4 and in the photoinitiated polymerization of acrylates
and methacrylates.5 They are also interesting because they have
similar properties to those of 1,4-dihydropyridines, which are
similar in structure to biologically important compounds such
as NADH and NADPH.6 Recently they have been used as a new
Results and discussion
First, the reaction conditions were optimized in the reaction
of benzaldehyde and dimedone (Table 1). By comparing the
reaction yields of Entries 1 to 5 in Table 1, it was found that
4 h was enough for this reaction. Room temperature gave
excellent yields. However, the high temperature decreased the
yields (Entries 4, 6 and 7, Table 1). Ethanol and aqueous ethanol
were the solvents used mainly for this reaction, however, it is
exciting to find that water can also afford the product in good
yield even better than ethanol (Entries 4, 8 and 9, Table 1).
This may be because the polarity of water is higher than that
of ethanol and the effect of ethanol in this reaction is just to
increase the solubility of the substrates. Among the various
reaction conditions used in Table 1, those indicated in Entry
4 were the most promising conditions.
With the optimal conditions in hand, the range of the
substrates was checked. First, the Knoevenagel condensation
and Michael addition reaction were carried out by using a
series of different aldehydes with cyclohexane-1,3-dione. The
results are summarized in Table 2 (Entries 1–14). It was
found that both electron-rich and electron-deficient aromatic
aldehydes were suitable for this reaction. For benzaldehydes with
Scheme 1
Laboratory for Advanced Materials & Institute of Fine Chemicals, East
China University of Science and Technology, 130 Meilong Road,
Shanghai, 200237, China. E-mail: wanglimin@ecust.edu.cn
† Electronic supplementary information (ESI) available: Experimental
and spectra. See DOI: 10.1039/b913816a
216 | Green Chem., 2010, 12, 216–219
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Table 1 Synthesis of tetraketones under various reaction conditions
As well as its action as a solvent, water also helps in the
enolization of 1 by making hydrogen bonds with the OH of 1¢
and, thus, it increases the nucleophilic character of the methylene
carbon (C-2) of 1. Meanwhile, it also increases the electrophilic
character of the carbonylcarbon of 2 byforming hydrogen bonds
with the carbonyl oxygen of aldehyde 2.15a After the Knoevenagel
condensation reaction, the intermediate 4 is afforded. By the
nucleophilic attacking of 1¢, 4 is transformed to the tetraketone
5 (Scheme 3).
Entrya
Time/h
T/◦C
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
0.5
1
2
4
6
4
4
4
4
rt
rt
rt
rt
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
64
72
88
96
94
90
86
81
80
94
rt
40
60
80
rt
9
10
Ethanol
4
rt
Ethanol/H2O = 1 : 1c
a Reaction conditions: benzaldehyde (1 mmol), dimedone (2 mmol), and
water (5 mL) at rt. b Isolated yield. c Aqueous solution of ethanol: ethanol
(2.5 mL) and water (2.5 mL).
electron-donating groups such as 4-(dimethylamino) benzalde-
hyde, 4-methoxybenzaldehyde and piperonal, the desired prod-
ucts could be afforded in good yields (Entries 4, 5, 10, Table 2).
However, all of the electron-deficient aromatic aldehydes inves-
tigated in this way could give excellent yields without obvious
steric hindrance effects (Entries 1–3, 6–8, Table 2). A heterocyclic
aromatic aldehyde such as 2-furaldehyde could also react with
cyclohexane-1,3-dione to afford the tetraketone compound with
a yield up to 98% (Entry 11, Table 2). Just as reported pre-
viously, when the 2-hydroxybenzaldehyde was used as starting
material, the product was totally 2-(1-oxo-2,3,4,9-tetrahydro-
1H-xanthen-9-yl) cyclohexane-1,3-dione (5¢ja) instead of the
tetraketone (5ja) (Scheme 2).
Scheme 3 Plausible mechanism for the Knoevenagel condensation and
Michael addition leading to tetraketones.
The reaction procedure is very simple (Fig. 1). After the
benzaldehyde and 1,3-cyclohexanedione were added to water,
a nearly homogeneous system was formed at the beginning of
the reaction (Fig. 1(a)). After the reaction was completed, the
product precipitated (Fig. 1(b)). The product could be afforded
after filtration, washing and drying.
Scheme 2 The Knoevenagel condensation, Michael addition and
dehydration reaction of salicylaldehyde and 1,3-cyclohexanedione.
Besides cyclic-1,3-diketones (cyclohexane-1,3-dione and
dimedione), heterocyclo-1,3-diones and cyclopent-1,3-diones
were also investigated in these conditions. 4-Hydroxy-6-
methylpyran-2-one, spirolactone and 2,2-tetramethylene-4,6-
dioxo-1,3-dioxane were used to react with benzaldehyde and
afforded the target products in good yields (Entries 16–18,
Table 2). Cyclopent-1,3-dione was first reported to take part in
this reaction and the yield was excellent (Entry 19, Table 2). More
importantly, 1,3-indandione also gave a good result under these
conditions (Entry 20, Table 2). However, under these conditions,
dimethyl malonate and acetylacetone gave no reaction or just a
Knoevenagel condensation product, respectively (Entry 21, 22
Table 2).
Fig. 1 The phenomenon of the reaction between benzaldehyde and
1,3-cyclohexanediones. (a) The homogeneous phase at the beginning of
the reaction. (b) The product precipitated after reaction completion.
Conclusions
In summary, we report an effective, green and mild method for
the synthesis of tetraketones. To the best of our knowledge,
it is the first example of using water as a solvent without
catalyst, surfactant or ionic liquid. This process provides an
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Table 2 The synthesis of tetraketones 5 in water
Entrya
R-CHO (1)
1,3-cyclic diketones (2)
Time/h
Yield (%)b
Mp (lit.)/◦C
1
2
3
4
5
6
7
8
4-Br-C6H4 (1b)
3-Br-C6H4 (1c)
2-Br-C6H4 (1d)
4-MeO-C6H4 (1e)
4-(NMe2)-C6H4 (1f)
4-NO2-C6H4 (1g)
3-NO2-C6H4 (1h)
2-NO2-C6H4 (1i)
2-OH- C6H4 (1j)
3,4-OCH2O–C6H3 (1k)
2-Furyl (1l)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
4
4
4
4
91
96
85
225–227 (240–241)16
206–208 (248–249)17
241–243 (199–200)1
190–191 (199–201)1
142 (150)11a
93
4
70c
91
1/2
1/2
4
4
4
4
4
4
4
1/2
4
4
4
4
4
4
4
210–212 (218)11a
204–205 (209–211)1
204–206 (212–213)11a
228–230 (234)18
204–206 (212)11a
142–144 (146)11a
130–132 (134)11a
97–98 (97–98)11a
207–208 (217–218)1
194–195 (190–192)3b
167–169 (176)13
115–117
99
90
9
90d
80
10
11
12
13
14
15
16
17
18
19
20
21
22
98
96
64
94
96
85
80
95
85
95
trace
trace
H (1m)
n-Pr (1n)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
157–159
C6H5 (1a)
222–223
C6H5 (1a)
2g
2h
2i
156–158 (162)19
/
C6H5 (1a)
C6H5 (1a)
/
a Reaction conditions: benzaldehyde (1 mmol), dimedone (2 mmol), and water (5 mL) at rt. b Isolated yield. c The product was recrystallized from
ethanol. d The 4H-benzopyran derivative (5¢ja) was afforded.
opportunity to avoid organic solvents and resource consumption
compared to the traditional reaction system. The simplicity
of the methodology, ease of the product isolation and mild
conditions could make this process available on an industrial
scale.
Experimental procedure for the synthesis of compound 5aa
In a 20 mL flask was placed benzaldehyde (1 mmol/106 mg),
cyclohexane-1,3-dione (2 mmol/224 mg) and water (5 mL).
The resulting yellow solution was stirred at room temperature
for 4 h (TLC monitored/Rf: 0.6 (CH2Cl2–EtOAc, 4 : 1), white
precipitate was formed and the resultant precipitates were
filtered, washed by cold water and dried in vacuum affording
2,2¢-(phenylmethylene) dicyclohexane-1,3-dione (5aa) as white
solid. 0.294 g, yield: 94%.1HNMR (CDCl3, 400 MHz): d 1.99-
2.09 (4H, m, H-5/H-5¢), 2.35-2.52 (4H, m, H-4/H-4¢), 2.54-
2.70(4H, m, H-6/H-6¢), 5.48 (1H, s, H-7), 7.12 (2H, d, J =
8.0 Hz, H-2/H-6), 7.18 (1H, t, J = 7.2 Hz, H-4), 7.27 (2H, t, J =
7.8 Hz, H-3/H-5), 12.36 (2H, br s, -OH); 13CNMR (CDCl3, 100
MHz): d 20.1(C-5/C-5¢), 32.9 (C-4/C-4¢), 33.0 (C-7), 33.5 (C-
6/C-6¢), 116.4 (C-2/C-2¢), 125.8 (C-4), 126.5 (C-2/C-6), 128.1
(C-3/C-5), 137.8 (C-1), 190.7 (-COH), 192.1 (CO); EIMS: m/z
312.1 (M+, 45).
Experimental
General
Melting points were determined with an X-4 apparatus and
1
were uncorrected. H (400 MHz) and 13C (100 MHz) NMR
spectra were recorded on a Bruker Avance 400 spectrometer
in CDCl3 using TMS as internal reference. Mass (EI) spectra
were recorded on a Micromass GCTTM mass spectrometer. All
chemicals used were reagent grade and were used as received
without further purification.
218 | Green Chem., 2010, 12, 216–219
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Experimental procedure for the synthesis of compound 5fa
References
In a 20 mL flask was placed 4-(dimethylamino) benzaldehyde
(1 mmol/149 mg), cyclohexane-1,3-dione (2 mmol/224 mg)
and water (5 mL). The red solution was stirred at room
temperature for 4 h (TLC monitored/Rf: 0.3 (CH2Cl2–EtOAc,
4 : 1), red precipitate was formed and the resultant precipitates
were filtered to afford the raw product. Recrystallization from
ethanol afforded the pure product 2,2¢-((4-(dimethylamino)
phenyl)methylene)dicyclohexane-1,3-dione (5fa) 0.246 g. Red
solid; Yield: 94%. 1HNMR (CDCl3, 400 MHz): d 1.98-2.07 (4H,
m, H-5/H-5¢), 2.30-2.50 (4H, m, H-4/H-4¢), 2.52-2.68 (4H, m,
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Experimental procedure for the synthesis of compound 5ja¢
In a 20 mL flask was placed salicylaldehyde (1 mmol/122 mg),
cyclohexane-1,3-dione (2 mmol/224 mg) and water (5 mL).
The yellow solution was stirred at room temperature for 4 h
(TLC monitored/Rf: 0.45 (CH2Cl2–EtOAc, 4 : 1). A creamy
white solid was formed and the resultant precipitates were
filtered, washed by cold water and dried in vacuum affording
2-(1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl) cyclohexane-1,3-
dione (5¢ja) as creamy white solid. 0.278 g, yield: 90%. 1HNMR
(CDCl3, 400 MHz): d 1.71-2.82 (12H, m, 6CH2), 4.65 (1H, s,
CH), 7.00-7.05 (3H, m, ArH), 7.13-7.20 (1H, m, ArH), 10.85 (b,
1H, OH); 13CNMR (CDCl3, 100 MHz): d 20.7, 20.8, 25.8, 25.9,
27.7, 37.1, 112.4, 115.7, 124.7, 126.2, 127.3, 128.9, 150.0, 167.1,
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Acknowledgements
This work was financially supported by the Natural Science
Foundation of China (NO. 20672035).
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