An efficient synthesis of 2,2′-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) and 1,8-dioxooctahydroxanthenes using ZnO and ZnO-acetyl chloride

Article abstract of DOI:10.1016/j.cclet.2010.02.005

2,2′-Arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) 4l-s produced from reaction between dimedone with various aldehydes in acetonitrile using ZnO as a catalyst; whereas in the presence of ZnO-acetyl chloride catalysts the reaction is limite

Full text of DOI:10.1016/j.cclet.2010.02.005

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Chinese Chemical Letters 21 (2010) 686–689
www.elsevier.com/locate/cclet
An efficient synthesis of 2,20-arylmethylene bis
(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) and
1,8-dioxooctahydroxanthenes using ZnO and ZnO–acetyl chloride
*
Malek Taher Maghsoodlou , Sayyed Mostafa Habibi-Khorassani,
Zahra Shahkarami, Nariman Maleki, Mohsen Rostamizadeh
Department of Chemistry, The University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran
Received 21 October 2009
Abstract
2,20-Arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) 4l-s produced from reaction between dimedone with
various aldehydes in acetonitrile using ZnO as a catalyst; whereas in the presence of ZnO–acetyl chloride catalysts the reaction is
limited to give only 1,8-dioxo-octahydroxanthenes 3a-k in very good yields.
# 2010 Malek Taher Maghsoodlou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: ZnO; ZnO–acetyl chloride; Dimedone; Aldehyde; 1,8-Dioxooctahydroxanthene; 2,20-Arylmethylene bis(3-hydroxy-5,5-dimethyl-2-
cyclohexene-1-one)
Xanthenes are an important class of organic compounds that find use as dyes, fluorescent material for visualization
of biomolecules and in laser technologies due to their useful spectroscopic properties [1,2]. Xanthenes have also
received significant attention from many pharmaceutical and organic chemists essentially because of the broad
spectrum of their biological and pharmaceutical properties such as antiviral [3], antibacterial [4]. There are several
reports in the literature for the synthesis of xanthene and 1,8-dioxooctahydroxanthene derivatives [5–10]. Each of
these methods have their own advantages but also suffer from one or more disadvantages such as prolonged reaction
time, tedious work-up processes, low yield, lack of easy availability, preparation of starting materials and hazardous
reaction conditions. Zinc oxide is an inexpensive, moisture stable, reusable, commercially available and
environmentally benign catalyst used in Beckmann rearrangements [11], Friedel–Crafts acylation [12], and
synthesis of cyclic ureas [13]. In continuation of our work [14,15], we examined ZnO and ZnO–acetyl chloride for
synthesis of 2,20-arylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) and 1,8-dioxooctahydroxanthenes.
Initially we examined ZnO as heterogeneous catalyst in the condensation of 5,5-dimethyl-1,3-cyclohexanedione 1
with benzaldehyde 2a refluxing in acetonitrile. Surprisingly, contrary to our expectation, only intermediate 2,20-
phenylmethylenebis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) 4l is obtained in 92% yield. Cyclized product 3a
was not obtained. Prolonging the reaction time and increase in catalyst amount ZnO (80 mol%) did not yield the
* Corresponding author.
E-mail address: mt_maghsoodlou@yahoo.com (M.T. Maghsoodlou).
1001-8417/$ – see front matter # 2010 Malek Taher Maghsoodlou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.02.005

M.T. Maghsoodlou et al. / Chinese Chemical Letters 21 (2010) 686–689
687
Scheme 1. Synthesis of 9-aryl-1,8-dioxooctahydroxanthene derivatives 3 and 2,20-arylmethylene bis(3-hydroxy-2-cyclohexene-1-one) derivatives 4
in acetonitrile.
Table 1
Synthesis of 9-aryl-1,8-dioxooctahydroxanthene derivatives 3 and 2,20-arylmethylene bis(3-hydroxy-2-cyclohexene-1-one) derivatives 4 in
acetonitrile.
Entry
Ar
Product
Time (h)
Yield (%)
M.P. (8C) [16–21]
1
2
C6H5
3a
3b
3c
3d
3e
3f
5
2
86
96
94
94
92
92
88
82
96
89
95
92
92
89
90
86
85
90
92
203–204
224–226
171–173
180–182
226–228
117–119
224–225
224–226
216–218
184–186
245–246
187–189
187–189
131–133
141–143
182–184
202–204
179–181
190–192
4-(NO2)–C6H5
3-(NO2)–C6H5
3-(Cl)–C6H5
3
2.5
4
4
5
2-(Cl)–C6H5
4.5
3
6
2-(Cl), 6-(F)–C6H5
3-(OMe), 4(OH)–C6H5
4-(NMe2)–C6H5
4-(Me)–C6H5
3,4-(OCH3)2–C6H5
4-(OH)–C6H5
C6H5
7
3g
3h
3i
6
8
6
9
5
10
11
12
13
14
15
16
17
18
19
3j
6
3k
4l
5
12
6
4-(NO2)–C6H5
4-(Me)–C6H5
4-(Cl)–C6H5
4m
4n
4o
4p
4q
4r
15
8
4-(NMe2)–C6H5
4-(OH)–C6H5
3-(Cl)–C6H5
10
10
8
2,4-(Cl2)–C6H5
4s
8
cyclized product 3a. We have chosen ZnO–acetyl chloride for further study. When ZnO–acetyl chloride is used, the
condensation of dimedone 1 with benzaldehyde 2a proceeds smoothly to give 1,8-dioxooctahydroxanthene 3a in
excellent yield in acetonitrile as well as under reflux (Scheme 1). The amount of zinc oxide was optimized in the
reaction and the optimum amount of ZnO was found to be 30 mol%.
It is also noticed that the condensation using ZnO–acetyl chloride proceeds rapidly and is superior to the reported
procedures with respect to reaction time, temperature and yield (Table 1).
The spectral data and physical properties of 1,8-dioxooctahydroxanthene and 2,20-phenylmethylenebis(3-hydroxy-
5,5-dimethyl-2-cyclohexene-1-one) derivatives were in agreement with those of literatures reported [16–21]. It is
evident that the catalyst plays crucial role in limiting the reaction to the desired level, to yield products 3 or 4. The
hypothesis supported the fact that reaction proceeds via one-pot Knoevenagel condensation, Michael addition and
cyclodehydration (Scheme 2). Furthermore, the reaction was also performed in the presence of ZnCl2 as catalyst, as a
result, the product was same but the 1,8-dioxooctahydroxant generated in longer time with low yield. Nevertheless,
there is no clear evidence for just proceeding the reaction with formation of ZnCl2 in reaction media.
Under the reaction conditions several aromatic aldehydes containing electron donating as well as electron
withdrawing groups with diverse substitution pattern were effectively cyclized to give 1,8-dioxooctahydro-xanthenes.
In conclusion, we have represent ZnO–acetyl chloride as a highly and efficient catalyst in one-pot Knoevenagel
condensation, Michael addition for cyclodehydration synthesis of 9-aryl-1,8-dioxooctahydro-xanthene derivatives
(3a-k) by the condensation of an aromatic aldehydes and dimedone under reflux conditions in excellent yields. When
ZnO catalyst used in our research works, the reaction is limited to give only 2,20-arylmethylenebis(3-hydroxy-5,5-
dimethyl- 2-cyclohexene-1-one) derivatives (4l-s) in very good yields.

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M.T. Maghsoodlou et al. / Chinese Chemical Letters 21 (2010) 686–689
Scheme 2. Mechanism for the synthesis of compounds 3 and 4 in acetonitrile.
1. Experimental
1.1. General procedure for the synthesis of octahydroxanthenes 3a-k
The aldehyde (2) (1 mmol), 5,5-dimethyl-1,3-cyclohexanedione (1) (2 mmol), ZnO (30 mol%) and acetyl chloride
(2 mmol) were mixed in 20 mL acetonitrile at reflux condition (80 8C). The reaction mixture was refluxed for the time
indicated in Table 1. Completion of the reaction was monitored by TLC. After completion of the reaction, the mixture
was cooled and poured into 50 mL of ice water. The solid residue was separated and dissolved in dichloromethane. The
solution was filtered and zinc oxide was isolated and could be reused. The organic phase was evaporated and the
reaction mixture was recrystallized in ethanol to generate pure crystalline product. The obtained solid product washed
with cold water (20 mL) and dried for generation of the pure crystalline product.
1.2. General procedure for the synthesis of 2,20-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one)
4l-s
The aldehyde (2) (1 mmol), 5,5-dimethyl-1,3-cyclohexanedione (1) (2 mmol), ZnO (30 mol%) were mixed in
20 mL acetonitrile at reflux condition (80 8C). The reaction mixture was refluxed for the time indicated in Table 1.
Completion of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled and
poured into 50 mL of ice water. The solid residue was separated and dissolved in dichloromethane. The solution was
filtered and zinc oxide was isolated and could be reused. The organic phase was evaporated and the reaction mixture
was recrystallized in ethanol to obtain pure crystalline product. The obtained solid product washed with cold water
(20 mL) and dried for generation of the pure crystalline product.
Selected spectral data:
1
Compound 3a: H NMR (300 MHz, CDCl3): d 1.00 (s, 6H, CMe2); 1.11 (s, 6H, CMe2); 2.14–2.27 (q, 4H,
J = 16.3 Hz, 2ꢀ CH2); 2.47 (s, 4H, 2ꢀ CH2); 4.76 (s, 1H, CH); 7.01–7.32 (m, 5H, Ar). Anal. Calcd. for C23H26O3:
C, 78.83; H, 7.48. Found: C, 78.80; H, 7.52.
1
Compound 3h: H NMR (300 MHz, CDCl3): d 1.01 (s, 6H, CMe2); 1.10 (s, 6H, CMe2); 2.14–2.27 (q, 4H,
J = 16.2 Hz, 2ꢀ CH2); 2.46 (s, 4H, 2ꢀ CH2); 2.88 (s, 6H, NMe2); 4.67 (s, 1H, CH); 6.63–7.14 (m, 4H, Ar). Anal.
Calcd. for C25H31NO3: C, 76.30; H, 7.94; N, 3.56. Found: C, 76.35; H, 7.90; N, 3.50.
Compound 4m: 1H NMR (80 MHz, CDCl3): d 1.07 (s, 12H, 4ꢀ CH3); 2.34 (s, 8H, 4ꢀ CH2); 5.47 (s, 1H, CH); 7.11–
9.11 (m, 4H, Ar); 11.69 (brs, 2H, 2ꢀ OH). Anal. Calcd. for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C,
66.77; H, 6.60; N, 3.36.
Compound 4n: 1H NMR (80 MHz, CDCl3): d 1.09 (s, 12H, 4ꢀ CH3); 2.23 (s, 4H, 2ꢀ CH2); 2.32 (s, 4H, 2ꢀ CH2);
5.44 (s, 1H, CH); 6.64–7.19 (m, 4H, Ar); 11.69 (brs, 2H, 2ꢀ OH). Anal. Calcd. for C24H30O4: C, 75.36; H, 7.91.
Found: C, 75.40; H, 7.88.
Acknowledgment
We gratefully acknowledge financial support from the Research Council of University of Sistan and Baluchestan,
Iran.

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