Cyanuric chloride-catalyzed synthesis of 10-aryl-6,8-dimethyl-6,10-dihydro- 5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-diones

Article abstract of DOI:10.1016/j.cclet.2011.01.020

An environmentally friendly procedure for the preparation of 10-aryl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7, 9-diones under thermal solvent-free conditions in the presence of cyanuric chloride as heterogeneous catalyst was de

Full text of DOI:10.1016/j.cclet.2011.01.020

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 811–814
www.elsevier.com/locate/cclet
Cyanuric chloride-catalyzed synthesis of 10-aryl-6,8-dimethyl-6,10-
dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-diones
b
a
Wei Lin Li a, , Qiu Yan Luo , Fu Lin Yan
*
a School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
b Department of Gynecological and Obstetric, Third Affiliated Hospital to Xinxiang Medical University, Xinxiang 453003, China
Received 26 October 2010
Available online 17 April 2011
Abstract
An environmentally friendly procedure for the preparation of 10-aryl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-
d][1,3]dioxole-7,9-diones under thermal solvent-free conditions in the presence of cyanuric chloride as heterogeneous catalyst was
developed.
# 2011 Wei Lin Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Benzo[1,3]dioxoles; 3,4-Methylenedioxyphenol; 1,3-Dimethylbarbituric acid; Cyanuric chloride; Solvent-free
Benzo[1,3]dioxoles have been attractive to synthetic organic chemists and biochemists over the last two decades
since, these compounds have shown interesting biological properties such as antitumor [1], antimicrobial [1a], anti-
proliferative [2], antioxidant [3], anti-inflammatory [3], anti-HIV [4], antineoplastic and antiviral activities [5]. The
methylenedioxy unit, present in these compounds, can be identified in the clinical antitumor agents etoposide and
teniposide [6] and lignan lactone podophylotoxin [7]. Therefore, much attention has been focused on the efficient
synthesis of benzo[1,3]dioxole derivatives [8].
Cyanuric chloride (TCT), an inexpensive, easily available reagent, of low toxicity and less corrosive than other
similar reactants, has been widely used in organic reactions [9]. In the present research, we wish to describe a simple
and efficient protocol for the rapid preparation of 10-aryl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d]-
[1,3]dioxole-7,9-diones using a catalytic amount of TCT under solvent-free conditions (Scheme 1). To the best of our
knowledge, there are no reports on three-component coupling of aldehyde, 3,4-methylenedioxyphenol and 1,3-
dimethylbarbituric acid to produce a new class of 3,4-methylenedioxyphenol derivatives.
To optimize reaction conditions, the reaction of 3,4-methylenedioxyphenol (1 mmol), benzaldehyde (1 mmol), and
1,3-dimethylbarbituric acid (1 mmol) was selected as a model reaction to provide the desired 10-phenyl-6,8-dimethyl-
6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-dione. At first, the reaction was examined using various
amounts of TCT at different temperatures. The results are displayed in Table 1. As Table 1 indicates, higher yield and
shorter reaction time were obtained when the reaction was carried out in the presence of 0.05 mol catalyst at 120 8C.
* Corresponding author.
E-mail address: linweilin1977@163.com (W.L. Li).
1001-8417/$ – see front matter # 2011 Wei Lin Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.020

[()TD$FIG]
812
W.L. Li et al. / Chinese Chemical Letters 22 (2011) 811–814
R
O
O
N
O
O
O
O
N
TCT
N
+
+ RCHO
O
neat, 120 ºC
O
OH
O
N
O
1
2
3
4
Scheme 1.
Table 1
Synthesis of 10-phenyl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-dione under various conditions.
Entry
TCT (mol%)
Temperature (8C)
Time (h)
Yield (%)
1
2
3
4
5
6
0
1
4
5
5
6
120
120
120
110
140
120
6
<5
49
81
82
87
85
4
1.5
1.5
1
1.5
When reactions were carried out in the absence of catalyst for long period of time (4–6 h), the yield of product was low
(<5%). Thus, we applied these optimal conditions for all other reactions.
With these results in hand, we turned our attention to the scope of the aromatic aldehydes in the reaction. The results
were summarized in Table 2. Aromatic aldehydes containing electron-donating as well as electron-withdrawing
groups smoothly underwent the conversion. The reaction proceeded at 120 8C within 2.5 h in excellent yields after the
addition of the catalyst TCT (5 mol%) (Table 2). The structures of the products were established from their spectral
properties (1H NMR, 13C NMR, MS and elemental analysis).
The plausible mechanism of the reaction is as shown Scheme 2. The adventitious moisture reacts with TCT to
release 3 mol of HCl, and cyanuric acid (removable by water washing) as by-product [9]. The in situ generated HCl
acts as a protic acid to activate the carbonyl oxygen to form the 10-aryl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-
diazaanthra[2,3-d][1,3]dioxole-7,9-diones. In order to verify the role of HCl which is probably generated upon
Table 2
Preparation of 10-aryl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-diones.
Entry
R
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
C6H5
1.5
1.5
1
4a
4b
4c
4d
4e
4f
89
91
94
85
96
88
89
86
82
4-Cl-C6H4
4-F-C6H4
4-Me-C6H4
4-NO2-C6H4
3-NO2-C6H4
2,4-Cl2-C6H3
2-Cl-C6H4
2,4-MeO2-C6H3
2.5
1
2
2
4g
4h
4i
2
2.5
[()TD$FIG]
H
N
H
Cl
OH
N
O
Cl
OH
2
N
N
N
N
+ 3HCl
OH
N
Cl
N
Cl
HO
Cl
N
Cl
Scheme 2.

W.L. Li et al. / Chinese Chemical Letters 22 (2011) 811–814
813
moisturizing the TCT with water, we conducted the reaction under the similar conditions by directly using HCl in the
absence of TCT. A test reaction was performed between 3,4-methylenedioxyphenol (1 mmol), benzaldehyde
(1 mmol), and 1,3-dimethylbarbituric acid (1 mmol) in the presence of HCl (one drop) at 120 8C without solvent. It
was found that the generation of 10-phenyl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-
dione occurred in 56% after 3 h.
In conclusion, we developed a simple one-step method for the preparation of 10-aryl-6,8-dimethyl-6,10-dihydro-5-
oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-diones from the corresponding commercially available aldehyde, 3,4-
methylenedioxyphenol and 1,3-dimethylbarbituric acid. The method offers several advantages including high yield of
products, short reaction times, and ease of work-up procedure.
1. Experimental
NMR spectra were recorded on Bruker AV-400 spectrometer at room temperature using TMS as an internal
standard, coupling constants (J) were measured in Hz; mass spectra were taken on a macro mass spectrometer (waters)
by electro-spray method (ES); elemental analysis were performed by a Vario-III elemental analyzer; melting points
were determined on a XT-4 binocular microscope and were uncorrected.
General procedure for the preparation of 4: A mixture of 3,4-methylenedioxyphenol (1 mmol), aldehyde
(1 mmol), and 1,3-dimethylbarbituric acid (1 mmol) and TCT (0.05 mmol) was stirred at 120 8C for the appropriate
time (Table 2). Completion of the reaction was monitored by TLC. The material was cooled to 25 8C, after addition of
20 mL water; the mixture was stirred for 5 min. The solid so obtained was filtered off and recrystallized from ethanol.
The spectral data of 4a–4b are given below, spectral data for 4c–4i can be found in Supporting information.
10-Phenyl-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-dione (4a): White powder,
mp 245–246 8C; 1H NMR (CDCl3, 400 MHz): d 7.26–7.16 (m, 5H), 6.68 (s, 1H), 6.52 (s, 1H), 5.95 (d, 1H, J = 0.8 Hz),
5.91 (d, 1H, J = 0.8 Hz), 5.03 (s, 1H), 3.55 (s, 3H), 3.28 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 161.9, 152.6, 150.7,
147.2, 145.6, 145.1, 143.1, 128.6, 127.8, 127.7, 126.9, 116.8, 108.2, 101.8, 98.0, 90.0, 39.2, 29.0, 28.1; MS (ESI): m/z
365 [M+H]+; Anal. Calcd. for C20H16N2O5: C 65.93, H 4.43, N 7.69; found: C 65.90, H 4.48, N 7.74.
10-(4-Chlorophenyl)-6,8-dimethyl-6,10-dihydro-5-oxa-6,8-diazaanthra[2,3-d][1,3]dioxole-7,9-dione (4b): White
powder, mp 254–255 8C; 1H NMR (CDCl3, 400 MHz): d 7.22 (d, 2H, J = 6.4 Hz), 7.18 (d, 2H, J = 6.8 Hz), 6.67 (s,
1H), 6.47 (s, 1H), 5.97 (d, 1H, J = 0.8 Hz), 5.92 (d, 1H, J = 0.8 Hz), 5.00 (s, 1H), 3.54 (s, 3H), 3.28 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 161.8, 152.6, 150.6, 147.4, 145.7, 143.6, 143.0, 132.7, 129.3, 128.8, 128.7, 116.1, 108.0, 101.9,
98.1, 89.6, 38.6, 29.0, 28.1; MS (ESI): m/z 399 [M+H]+; Anal. Calcd. for C20H15ClN2O5: C 60.23, H 3.79, N 8.89;
found: C 60.19, H 3.85, N 8.95.
Acknowledgment
We are pleased to acknowledge the financial support from Xinxiang Medical University.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/
j.cclet.2011.01.020.
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