Review Article
Austin J Anal Pharm Chem.2015;2(2): 1039.
The Asymmetric Darzens Reaction Catalyzed by the Novel Chiral Phase Transfer Catalysts Derived from Cinchona Alkaloids
Pei Xu1, Xueyan Zhang1, Ziyu Wang1, Daorui Huang1, Xiaolong Wang2 and Zhenya Dai1*
1Department of Pharmaceutical Chemistry, School of Pharmacy, China Pharmaceutical University, China
2Yangzhou Tianhe Pharmaceutical Company
*Corresponding author: Dai Zhenya*, Department of Pharmaceutical Chemistry, School of Pharmacy, China Pharmaceutical University, China.
Received: April 06, 2015; Accepted: April 22, 2015; Published: April 24, 2015
Abstract
Herein a serial of asymmetric Darzens reactions catalyzed by the novel chiral phase transfer catalysts derived from cinchona alkaloids were reported with moderate to high diastereoselectivity and with moderate enantioselectivity.
Keywords: Chiral phase transfer catalysts; Cinchona alkaloid; Darzens reaction; Diastereoselectivity; Enantioselectivity
Introduction
The development of asymmetric phase transfer catalysis has become more and more significant in both economic and environmental fields [1,2,3]. Until recently, there have been three main generations of the catalysts derived from cinchona alkaloids. The first generation: R=H, Ar= Phenyl; the second generation: R=Allyl, Ar=Phenyl; and the third generation: R=Alkyl, Ar=Anthracyl. The first generation of catalysts were developed by Dolling’s group in 1984 [4,5], which were successfully applied in the asymmetric alkylation of glycine Schiff base by O’Donnell’s group with good enantioselectivity [6,7]. The second generation of the catalysts was applied by Deng et al. in the asymmetric Darzens reaction with high yield and good enantioselectivity [8]. The third generation of the catalysts were developed by E.J. Corey’s group (Figure 1) [9]. Until recently, only few chiral phase transfer catalysts have been reported to be applied in the asymmetric Darzens reaction. Deng et al. reported that the second generation of the catalysts derived from cinchona alkaloids could catalyze the asymmetric Darzens reaction with high yield and good enantioselectivity [8]. Shioiri’s group reported the diastereoselective Darzens reaction catalyzed by tetrahexylammonium bromide [10]. Macromolecular phase transfer catalysts were reported by Wang’s group and were applied in diastereoselective Darzens reaction (Figure 2) [11]. Jonczyk’s group and Murugan’s group also reported the asymmetric Darzens reaction with different kinds of chiral phase transfer catalysts [12,13].
Figure 1: Three main generations of cinchona alkaloid based catalysts.
Figure 2: The catalyst synthesized by Wang’s group.
Till now, we have reported three novel chiral phase transfer catalysts derived from cinchona alkaloids with cycle structure (Figure 3). The asymmetric alkylation reaction and sulfenylation reactions of glycine derivatives catalyzed by these catalysts were also investigated with high yields and moderate to good ee values (44- 88%) [14]. In continuation of our studies on the asymmetric phase transfer catalysis, herein we report the asymmetric Darzens reaction with the novel chiral phase transfer catalysts 4a to 4c. We began our investigation with non-chiral phase transfer catalyst, we tried TEBAC (triethyl benzyl ammonium chloride) and TBAB (tetrabutyl ammonium bromide) in the Darzens reaction between benzaldehyde and chloroacetonitrile in THF and we found only TBAB could catalyze the Darzens reaction, then we applied the reaction to different aldehydes and chloroacetonitrile in THF (Figure 4) and the results were listed in Table 1.
Entry
R
Catalyst
Time(h)
Yielda
cis:trans
1
H
TBAB
23
70%
1.2:1
2
p-Cl
TBAB
24
13%
1.4:1
3
p-Br
TBAB
12
30%
1.4:1
4
p-Me
TBAB
12
20%
0.9:1
5
m-Me
TBAB
12
31%
0.8:1
a. Isolated yields including cis-product and trans-product.
Table 1: The Darzens reaction between aldehydes and chloroacetonitrile under non-chiral phase transfer catalyst.
Figure 3: Three novel cinchona alkaloids based catalysts [14].
Figure 4: The reaction with different aldehydes and chloroacetonitrile in THF.
As was shown in Table 1, the rates between cis-product and transproduct were nearly 1:1. Only poor diastereoselectivity of the normal non-chiral phase transfer catalyst of TBAB was achieved and further work should be done to enhance the diastereoselectivity.
Having realized the non-chiral Darzens reaction between aldehydes and chloroacetonitrile, we turned our attention to its asymmetric version. We tried to investigate the novel chiral phase transfer catalysts 4a to 4c developed by our group in the asymmetric Darzens reaction. Firstly, we chose the Darzens reaction between benzaldehyde and chloroacetonitrile as the model reaction and different reaction conditions were investigated and the results were listed in Table 2 [15].
Entry
Catalyst
Solvent
Base
Yielda
Cis:trans
Ee of majorb
1
4a
THF
KOH
67%
2.1:1
60%
2
4b
THF
KOH
60%
2.1:1
51%
3
4c
THF
KOH
56%
1.5:1
45%
4
4a
toluene
KOH
0%
n.d.
n.d.
5
4a
DMSO
KOH
76%
1.4:1
50%
6
4a
toluene
KOH
(50% in water)
0%
n.d.
n.d.
7
4a
THF
NaOH
50%
1.5:1
54%
8
4a
THF
CsOH
53%
1.4:1
55%
a. Isolated yields including cis-product and trans-product.
b. Enantiopurity was determined by HPLC analysis using chiral column (DAICEL Chiralcel OD-H) with hexanes/ i-PrOH as a solvent.
Table 2: The asymmetric Darzens reaction between benzaldehyde and chloroacetonitrile under different reaction conditions.
In Table 2, we found that 4a was the best catalyst and could give the best result both in cis/trans value and ee value, while catalyst 4b and 4c gave relatively lower cis/trans value and lower ee values. Of all the solvents we investigated, THF gave the best yield, cis/trans value and ee value, the more dipolar solvent gave out a better yield but very low cis/trans rate and enantioselectivity (entry 5), the less polar solvent toluene gave no product whether with the solid or aqueous solution of KOH as the base (entry 6 and 7). Of all the bases we investigated, solid KOH gave the best yield, the cis/trans rate and the best enantioselectivity. So the optimal reaction condition was with 4a as the catalyst, with THF as the solvent, and with solid KOH as the base (entry 1). Under the optimal reaction condition, the Darzens reaction between different aldehydes and chloroacetonitrile were investigated, and the results were collected in Table 3.
Entry
R
Yielda
cis:trans
ee of majorb
1
H
67%
2.2:1
60%
2
p-Cl
63%
3.8:1
35%
3
p-Br
66%
4.1:1
50%
4
p-Me
68%
5.8:1
17%
5
m-Me
55%
6.9:1
30%
a. Isolated yields including cis-product and trans-product.
b. Enantiopurity was determined by HPLC analysis using chiral column (DAICEL Chiralcel OD-H) with hexanes/ i-PrOH as a solvent.
Table 3: The asymmetric Darzens reaction between different aldehydes and chloroacetonitrile.
As was shown in Table 3, the reaction catalyzed by 4a was much faster than common non-chiral phase transfer catalysts such as TBAB and higher diastereoselectivities were also achieved. The highest rate (cis:trans) was achieved as 6.9:1 with 3-methylbenzaldehyde as the substrate (entry 5). For the reactions catalyzed by 4a, low to moderate ee values were also achieved, and the highest ee value was achieved to be 60% with benzaldehyde as the substrate (Entry 1).
In all, we successfully applied the newly-designed chiral phase transfer catalysts 4a to 4c in the asymmetric Darzens reactions and satisfying and interesting results were achieved. Further work is under way to understand the mechanism and improve the diastereoselectivity and the enantioselectivity of the reaction.
Acknowledgment
We were thankful to the National Natural Science Foundation of China for their financial support (No. 21102180).
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- Typical procedure of the asymmetric Darzens reactions: To a mixture of benzaldehyde (0.106 g, 1 mmol), chloroacetonitrile (0.091 g, 1.2 mmol) and THF (5 ml), 4a (0.035 g, 0.1 mmol) was added and stirred for 20minutes. Solid KOH (0.067 g, 1.2 mmol) was added and stirring continued for 16 hours. The mixture was filtered and purified by TLC (PE: EA = 50:1) to give the cis-product (0.067 g) and trans-product (0.03 g) as colorless oil. Cis-product 1H NMR (500 MHz, CDCl3):7.408~7.388(3H, m), 7.282~7.263(2H, m), 4.278~4.275(1H, m), 3.410~3.405(1H, m) [a] D 25 = 36o (major product). Trans-product 1H NMR (500 MHz, CDCl3):7.245~7.260(5H, m), 4.248~4.237(1H, m), 3.778~3.766(1H, m).
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