An efficient synthesis of 3-(guaiazulene-1-yl)succinimides by addition of guaiazulene to maleimides

Article abstract of DOI:10.1016/j.cclet.2011.01.003

A facile, efficient synthesis of 3-(guaiazulen-1-yl)succinimides was developed by Michael-type addition of guaiazulene to maleimides in the presence of p-toluenesulfonic acid under mild reaction conditions.

Full text of DOI:10.1016/j.cclet.2011.01.003

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 789–792
www.elsevier.com/locate/cclet
An efficient synthesis of 3-(guaiazulene-1-yl)succinimides
by addition of guaiazulene to maleimides
*
Dao Lin Wang , Shao Fei Li, Wei Li, Yuan Feng Li, Li Nan Lin
Key Laboratory of Synthesis & Application of Functional Compound, College of Chemistry & Chemical Engineering,
Bohai University, Jinzhou 121001, China
Received 11 October 2010
Available online 19 April 2011
Abstract
A facile, efficient synthesis of 3-(guaiazulen-1-yl)succinimides was developed by Michael-type addition of guaiazulene to
maleimides in the presence of p-toluenesulfonic acid under mild reaction conditions.
# 2011 Dao Lin Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Guaiazulene; Succinimides; Michael-type addition; p-Toluenesulfonic acid
Succinimides (pyrrolidine-2, 5-diones) are an important class of heterocyclic compounds with numerous
applications in different fields [1]. In organic synthesis they have been used as valuable reagents and intermediates for
the synthesis of natural and non-natural compounds [2]. In medicine, they have been used as irreversible protease
inhibitors [3], 3-substituted succinimides have been show potent anticonvulsants activity [4]. It is noteworthy to
specify that the 3-aryl derivatives are shown to be more biologically important.
The azulene constitute was the best known of polycyclic nonbenenoid aromatic compounds and has long fascinated
chemists with their beautiful colors and unusual electronic properties [5]. Azulenes have attracted interest in medicine
as antiulcer drugs [6], anticancer agents [7], and as antioxidant therapeutics for neurode-generative conditions [8]. A
variety of heterocycle-fused and substituted azulenes have so far been obtained on the viewpoints of chemical
properties and physiological activities by several methods [9]. Recently, our group has developed several synthesis
methods of heterocycle-substituted azulenes [10].
In continuation of our ongoing interest in heterocycle-substituted azulenes, we herein report the use of p-
toluenesulfonic acid ( p-TsOH) as a catalyst in the Michael-type addition of guaiazulene (1,4-dimethyl-7-iso-
propylazulene) to maleimides under mild reaction conditions (Scheme 1).
To optimize the conditions, we studied the effects of molar ratio, temperature, reaction time, and solvent. In a
typical experiment, a mixture of guaiazulene 1 and N-phenylmaleimide 2a was reacted and monitored by HPLC, and
the results are summarized in Table 1.
The initial reaction of guaiazulene 1 and N-phenylmaleimide 2a at an ambient temperature in CH2Cl2 did not give
any product until p-TsOH was added into the reaction mixture and stirred for 12 h. After the reaction was completed,
* Corresponding author.
E-mail address: wangdaolin@sina.com (D.L. Wang).
1001-8417/$ – see front matter # 2011 Dao Lin Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.003

[()TD$FIG]
790
D.L. Wang et al. / Chinese Chemical Letters 22 (2011) 789–792
O
O
N
O
N
O
R
+
p-TsOH
R
1
2
3
R = Alkyl, Aryl
Scheme 1. p-Toluenesulfonic acid-catalyzed Michael addition of guaiazulene.
Table 1
Optimization of reaction conditions on the p-TsOH catalyzed Michael addition of guaiazulene 1 and N-phenylmaleimide 2a
O
O
p-TsOH
N
+
N
O
2 a
O
1
3 a
.
Entry
Solvent
Molar ratio
Amount of p-TsOH (mol%)
Temp. (8C)
Time (h)
Yielda (%)
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2ClCH2Cl
EtOH
1:1
0
10
10
10
15
20
5
25
25
12
12
5
0
38
72
73
76
75
47
70
59
68
57
31
29
1:1
3
1:1
40
4
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
40
4
5
40
3
6
40
3
7
40
6
8
15
15
15
15
15
15
80
7
9
75
12
4
10
11
12
13
AcOH
90
CH3CN
Toluene
THF
100
100
50
8
10
12
aIsolated yields.
the mixture was purified by ash column chromatography to give pure product 3-(guaiazulen-1-yl)-succinimide 3a,
1
whose structure was characterized by IR and H NMR.
The reaction of 1 and 2a was optimized by screening the solvent such as CH2Cl2, CH2ClCH2Cl, EtOH, CH3CN,
AcOH, Toluene and THF, changing the amount of p-TsOH and the ratio of guaiazulene (1)/N-phenyl-maleimide 2a. It
was found that the reaction best proceeded with 15 mol% p-TsOH, in ratio of guaiazulene/N-phenyl maleimide 1:1.2
to give 3a in CH2Cl2 at 40 8C in 76% yield (Table 1, entry 5). Increasing the amount of p-TsOH to 20 mol%, the yield
of 3a was not further improved (Table 1, entry 6). However, if p-TsOH was used in less than 5 mol%, the yield of 3a
was significantly reduced to 47% (Table 1, entry 7). Furthermore, we also tested the catalytic activity of different
catalysts such as H3PO4, TFA, H2SO4, MeSO3H and HClO4 in CH2Cl2, the Michael adducts were detected, but in
lower yields.
Under the optimized conditions described above, guaiazulene reacted with maleimides to produce the correspond
ding 3-(guaiazulen-1-yl)succinimides in good yields. It was observed that N-aromatic substituted maleimides with
electron-withdrawing substitutents (Table 2, entries 6–11) were converted to the corresponding Michael adducts in
higher yields and shorter reaction times than those with electrodonating substituents (Table 2, entries 1–4). Also, N-
aliphatic substituted maleimides were employed and the corresponding Michael adducts products were obtained in
good yields with longer reaction time (Table 2, entries 12 and 13).

D.L. Wang et al. / Chinese Chemical Letters 22 (2011) 789–792
791
Table 2
Synthesis of 3-(guaiazulen-1-yl)succinimides 3
O
O
N
O
N
R
+
p-TsOH
R
O
1
2
3
.
Entry
Maleimides
Time (h)
Producta
Yieldb (%)
1
2a
2b
2c
2d
2e
2f
C6H5
3
4
4
5
4
4
3
2
4
4
2
8
6
3a
3b
3c
3d
3e
3f
76
74
60
73
72
83
85
87
80
83
90
64
70
2
2-CH3C6H4
3
2-CH3OC6H4
4-CH3OC6H4
4
5
2-F-4-CH3C6H3
2-FC6H4
6
7
2g
2h
2i
4-FC6H5
3g
3h
3i
8
2,4-F2C6H3
4-ClC6H4
9
10
11
12
13
2j
4-C6H4CO2CH3
4-NO2C6H4
C6H5CH2
3j
2k
2l
3k
3l
2m
Cyclohexyl
3m
aAll products were characterized by 1H NMR and IR spectral data [11].
bIsolated yields.
In conclusion, we have developed a facile and efficient method to preparation of 3-(guaiazulen-1-yl)succinimides
of potential and biological interest. Prominent among the advantages of this method are novelty, good yields, and easy
work-up.
Acknowledgment
The authors thank the Foundation of Innovation Team Project of Liaoning Education Department (No. 2008T001)
for financial support.
References
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D.L. Wang et al. / Chinese Chemical Letters 22 (2011) 789–792
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[11] General procedure: p-Toluenesulfonic acid (0.075 mmol) was added to mixture of guaiazulene (0.5 mmol) and the appropriate maleimide
(0.6 mmol) and CH2Cl2 (10 mL). Then the mixture was stirred at ambient temperature for the stipulated time (Table 2). After completion of the
reaction, was cooled and diluted with water (10 mL). The precipitate was quenched with aqueous saturated NaHCO3 solution, and the mixture
was extracted with EtOAc, washed with water and dried, the solvent was removed under the reduced pressure and the residue was purified by
1
column chromatography on silica gel using n-hexane–EtOAc (4:1) as eluent to afford 3a-m. Selected physical and spectral (IR, H NMR,
Anal.) data: 3a: mp: 78À80 8C. IR (KBr) n: 1706 cmÀ1 (C O). 1H NMR (400 MHz, CDCl3): d 1.34 (d, 6H, J = 6.6 Hz, CH(CH3)2), 2.67 (s,
3H, CH3), 3.01À3.04 (m, 2H, CH2), 3.05 (s, 3H, CH3), 3.42À3.46 (m, 1H, CH(CH3)2), 5.25À5.28 (m, 1H, CH), 6.96 (d, 1H, J = 10.2 Hz),
7.35À7.346 (m, 4H,), 7.40 (s, 1H,), 7.43À7.49 (m, 2H), 8.14 (s, 1H). Anal. Calcd. for C25H25NO2: C 80.83, H 6.78, N 3.77; Found C 80.98, H
6.87, N 3.84. 3g: mp: 133À135 8C. IR (KBr) n: 1702 cmÀ1 (C O). 1H NMR (400 MHz, CDCl3): d 1.24 (d, 6H, J = 6.6 Hz, CH(CH3)2), 2.50 (s,
3H, CH3), 2.90À2.94 (m, 2H, CH2), 2.96 (s, 3H, CH3), 3.34À3.41 (m, 1H, CH(CH3)2), 5.19À5.22 (m, 1H, CH), 6.84 (d, 1H, J = 10.4 Hz),
7.05À7.09 (m, 2H), 7.27À7.30 (m, 3H), 7.32 (s, 1H), 8.04 (s, 1H). Anal. Calcd. for C25H24FNO2: C 77.10, H 6.21, N 3.60; Found C 77.32, H
6.35, N 3.72. 3m: mp: 132À133 8C. IR (KBr) n: 1697 cmÀ1 (C O). 1H NMR (400 MHz, CDCl3): d 0.89À0.92 (m, 2H), 0.98À1.02 (m, 1H),
1.27À1.31 (m, 2H), 1.36 (d, 6H, J = 6.8 Hz, CH(CH3)2), 1.54À1.56 (m, 2H), 1.77À1.79 (m, 1H), 2.60 (s, 3H, CH3), 2.83À2.86 (m, 1H), 2.94
(s, 3H, CH3), 3.05À3.08 (m, 1H), 3.34À3.39 (m, 1H, CH(CH3)2), 3.75À3.77 (m, 1H), 4.98À4.99 (m, 1H), 5.41À5.47 (m, 1H, CH), 6.97 (d, 1H,
J = 10.2 Hz), 7.38 (d, 1H, J = 10.2 Hz), 7.42 (s, 1H), 8.16 (s, 1H). Anal. Calcd. for C25H31NO2: C, 79.54; H, 8.28; N, 3.71. Found: C, 79.67; H,
8.35; N, 3.87.