Solvent-free, one-pot synthesis of α,β-unsaturated esters in the presence of a C3-symmetric arsine

Article abstract of DOI:10.1080/00397911.2016.1186698

An efficient synthesis of α, β-unsaturated esters is achieved via a one-pot reaction in the presence of a C₃-symmetric arsine. The key advantages are the short reaction time, simple workup, mild reaction conditions, and high yields.

Full text of DOI:10.1080/00397911.2016.1186698

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Solvent-Free, One-Pot Synthesis of α, β-
Unsaturated Esters in the Presence of a C3-
Symmetric Arsine
Changqing Wang, Liu Yang, Rong Zhou & Guangquan Mei
To cite this article: Changqing Wang, Liu Yang, Rong Zhou & Guangquan Mei (2016): Solvent-
Free, One-Pot Synthesis of α, β-Unsaturated Esters in the Presence of a C3-Symmetric Arsine,
Synthetic Communications, DOI: 10.1080/00397911.2016.1186698
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1186698
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Date: 09 June 2016, At: 03:26

Solvent-free, One-pot Synthesis of α,β-Unsaturated Esters in the Presence of a
C3-Symmetric Arsine
Changqing Wang1,2, Liu Yang1, Rong Zhou2, Guangquan Mei2
1Jiangxi Province Engineering Research Center of Ecological Chemical Industry, College
of Chemical and Environmental Engineering, Jiujiang University, Jiujiang, China, 2Key
Laboratory of Jiangxi University for Applied Chemistry and Chemical Biology, Yichun
University, Yichun, China
Corresponding Author to Changqing Wang: E-mail: wangyoungsea@gmail.com
Abstract
An efficient synthesis of α,β-unsaturated esters is achieved via a one-pot reaction in the
presence of a C3-symmetric arsine. The key advantages are the short reaction time, simple
workup, mild reaction conditions and high yields.
KEYWORDS: solvent-free, one-pot, C3-symmetric arsine, wittig-type olefination
INTRODUCTION
The Wittig reaction is a well-known classical reaction and has been acknowledged as
powerful and versatile tool in organic synthesis for the formation of carbon-carbon
double bond.1 Conventionally, this reaction requires three steps, i.e., preparation of salts,
ylide formation, and subsequent reaction with carbonyl compounds to give olefinic
1

products. The time-consuming and tedious steps make it difficult to handle and generate a
large volume of solvent waste. From the standpoint of environmental sustainability and
minimising pollution, the one-pot process of the Wittig reaction has been receiving
increasing attention.2 Until now, a number of variations on the reaction conditions have
been reported and the most impressive variant is the replacement of the three step-process
with a one-pot synthesis.3 Typical simplified methods that have been used include the
reaction of an aldehyde with ethyl bromoacetate using n-Bu3P/Zn4 or catalytic amounts of
tributylarsine in the presence of triphenyl phosphite in stoichiometric amounts.5
Choudary et al. reported the one-pot Wittig reaction catalyzed by using nanocrystalline
magnesium oxide (NAP-MgO) in the above protocol.6 Other advances also include the
use of ethyl diazoacetate (EDA) instead of α-bromo esters by catalytic amounts of iron,
ruthenium, or cobalt porphyrin complexes.7 Although great progress has been achieved,
the use of an excess of organic solvent, an inert atmosphere, expensive metal catalysts
and long reaction times all limit the applications of these methods. Therefore, a search for
a better method for carbon-carbon double bond formation is being continued.
Recently, great strides have been made in solvent-free reactions because of their high
efficiency, operational simplicity, low cost, and environmentally benign processes. A
limited number of reports have also appeared on Wittig olefination reactions in a
solventless system.8 For the most part, however, these have been limited to reactions for
which ylide salts have been employed.
2

Recently, we have reported a C3-symmetric tertiary arsine 1, which could be synthesized
from readily available and low-toxicity p-arsanilic acid in a 3-step reduction - Grignard
reaction - amidation sequence in 54% overall yield (Figure 1). By using this catalyst,
stereoselective cyclopropanation of electron-deficient olefins take place to give
cyclopropane derivatives in one-pot synthesis.9 During the course of this study, we
observed that the solid arsine 1 was reactive enough to react with ethyl bromoacetate and
form the corresponding ylide in the presence of weak bases. The ylide reacted
exothermally when mixed with aldehydes and these reactions could be performed with
short reaction times in solventless system. Herein, we report our recent studies on
preparing α,β-unsaturated esters with excellent yields and good stereoselectivity in the
presence of the arsine 1 under solvent-free conditions. As compared with reported
methods, the experimental procedure for this reaction is remarkably simple and does not
require the use of organic solvents or inert atmospheres.
RESULTS AND DISCUSSION
We first examined the reaction of benzaldehyde with ethyl bromoacetate in the presence
of arsine 1 with a variety of bases (Table 1). In the initial model experiment, a mixture of
arsine 1 (0.36 equiv), ethyl bromoacetate (1.2 equiv), benzaldehyde (1.0 equiv) and
K2CO3 (3.0 equiv) were taken in a flask, mixed thoroughly at room temperature. The
problem in the grinding reaction is that the starting materials soon become a tough waxy
substance that is hard to be ground. To overcome this, we add water to the mixture until
3

the substrates form a paste-like product that is easily ground. The process of the reaction
was detected by TLC, after 360 min, the desired product 3a was obtained in 57% yield,
but the olefination reaction was not completed and the starting material was observed on
the TLC analysis (Table 1, entry 1). Further experiments showed that the yield of the
reaction increased and the time of the reaction decreased when the temperature was
raised from room temperature to 80 °C, while the yield decreased when reaction was
carried out at 100 °C (entries 2-4). When NaOH was used as the base, the color of the
reaction mixture became deep brown and only 13% of the desired product was formed
(entry 5). The results also showed that NaHCO3 was less effective (entry 6). We have
also tested Et3N as the base for the deprotonation of the in situ formed arsonium salt, the
results show that the yield of the reaction increased and the time of the reaction decreased
when the temperature was raised from room temperature to 60 °C, but the yield decreased
when reaction was carried out at 80 °C (Table 1, entries 7 - 9). This was deemed to be an
effect of the volatility of Et3N in the reaction conditions, meanwhile, some deep color
by-products were produced when Et3N was used, thus reducing the yield and increasing
the difficulty of the separation and purification. In order to make this olefination practical
and environmentally friendly, we decided to use K2CO3 as base in the reactions. It is
worth noting that the reaction was very easy to carry out, and the work-up was
straightforward, which considerably reduce the risk of toxicity of arsines in practical
terms. Further, the arsine 1 proved to be more reactive for the Wittig olefination reaction
of the benzaldehyde 2a when compared to triphenylarsine under identical reaction
4

conditions ( 92% vs. 86% yield ), and higher stereoselectivity was also observed ( > 99 :
1).
To explore the generality of this reaction, a variety of substrates were submitted to this
reaction condition. As shown in Table 2, a variety of substrates 2, both electron-donating
and electron-withdrawing substituents on the aromatic ring were well tolerated and all
gave the desired products in high yields (Table 2, entries 2-14). Aromatic aldehydes with
electronwithdrawing groups afforded α,β-unsaturated esters stereoselectively in excellent
yields (entries 2 - 9). The results also showed that the presence of an electron-donating
group on the benzene ring decreased the reactivity and required longer reaction times
(entries 10-14). Moreover, while substitution at the ortho position of the phenyl ring of a
substrate led to a slightly lower yield, probably due to steric effects (entry 7). Aliphatic
aldehydes were also favorable substrates affording the corresponding unsaturated esters
in high yields (entry 15-17).
On the basis of experimental observation and the literature,8c the mechanism of this
reaction is likely to proceed via a reaction pathway involving the formation of arsonium
salt from arsine 1 and bromide followed by the production of ylide in the presence of
K2CO3, and the ylide and aldehydes generating the observed olefin products. This process
is depicted in Scheme 1.
5

It should be noted that this condensation occurs with high stereoselectivities. In most
cases described above, the stereoselectivity was excellent and the E/Z ratio was > 99/1, as
established by 1H NMR analysis of the crude reaction mixtures. The E-isomer structures
of compounds 3 are confirmed by the coupling constants of alkenyl protons and
compared with literatures. It has been reported that the alkenyl protons with an
E-configuration have a larger coupling constant (12 - 18 Hz), whereas those with a
Z-configuration have a smaller coupling constant (7 - 11 Hz). The coupling constants of
acrylates 3 are 15.0 - 16.0 Hz.10
CONCLUSION
In summary, we have achieved a one-step procedure for the preparation of
α,β-unsaturated esters from ethyl bromoacetate, aldehyde and K2CO3 in the presence of
arsine 1. Our approach greatly simplifies the traditional three steps of a Wittig reaction
into a one-pot solvent-free synthesis. Its advantages are the short reaction time, simple
workup, mild reaction conditions, high stereoselectivities and yields.
EXPERIMENTAL
All reagents and solvents were purified according to standard methods unless otherwise
noted. Melting points are uncorrected. Melting points were determined on WRS-1 digital
melting-point apparatus made by Shanghai Physical Instrument Factory (SPOIF), NMR
spectra were recorded on a Bruker AM-400 spectrometer, using CDCl3 as solvent. The
6

chemical shifts were reported in ppm downfield from tetramethylsilane (TMS) with the
solvent resonance as the internal standard. Coupling constants (J) are reported in Hz and
refer to apparent peak multiplications. Flash chromatography was performed on columns
of silica gel (20-30 μm).
General Procedure For Preparing Α,Β-Unsaturated Esters 3
The general process for synthesis of α,β-unsaturated esters 3a – 3q was as follows: A
mixture of 1 (0.402 g, 0.36 mmol), ethyl bromoacetate (0.200 g, 1.2 mmol), aldehyde 2
(1 mmol) and K2CO3 (0.414 g, 3 mmol) and three drops of water was mixed thoroughly
in a flask and then heated at 80 oC. The progress of reaction was monitored by TLC. After
completion, water was added and the product was extracted with CH2Cl2. The organic
layer was separated, dried over anhydrous sodium sulphate and the solvent evaporated
under reduced pressure to afford the crude product. The crude product was subjected to
column chromatography over silica gel using hexane/ethyl acetate as eluent to obtain
pure product.
ACKNOWLEDGMENT
The author thanks the National Natural Science Foundation of China (No. 21261024), the
Natural Science Foundation of Jiangxi Province (No. 20142BAB203006,
20132BAB203002) for financial support.
7

SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra. This material can be found via the
“Supplemental materials” section of this article’s webpage.
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10

Table 1. Optimization of reaction conditions for Wittig olefination with ethyl
bromoacetate and benzaldehyde a
Entry
Base
Temp. (oC)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
NaHCO3
Et3N
r.t.
60
80
100
80
80
r.t.
60
80
360
60
57
84
30
92 (86)c
87
30
30
13
120
360
60
69
41
Et3N
49
Et3N
60
33
a The reaction was carried out with arsine 1 (0.36 equiv), ethyl bromoacetate (1.2 equiv),
benzaldehyde (1.0 equiv) and base (3.0 equiv).
b Reaction yield resulted from arsine 1.
c Reaction yield resulted from triphenylarsine (1.0 equiv).
11

Table 2. Wittig reaction of different aldehydes with ethyl bromoacetate in the presence of
arsine 1a
Entry
1
Product
3a
R
Time (min)
Yield (%)b,c
Ph
30
30
30
30
30
30
30
30
30
60
60
60
60
60
92
89
91
93
94
96
87
92
93
95
90
94
91
96
2
4-NO2C6H4
3-NO2C6H4
4-FC6H4
3b
3c
3
4
3d
3e
5
4-BrC6H4
6
4-ClC6H4
3f
7
2-ClC6H4
3g
8
3-ClC6H4
3h
3i
9
3,4-Cl2C6H3
4-CH3C6H4
3,4-(CH3)2C6H3
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4-OCH2OC6H3
10
11
12
13
14
3j
3k
3l
3m
3n
12

15
16
17
n-C6H13
n-C8H17
n-C11H23
60
60
60
84
83
81
3o
3p
3q
a The reaction was carried out with arsine 1 (0.36 equiv), ethyl bromoacetate (1.2 equiv),
aldehyde (1.0 equiv) and K2CO3 (3.0 equiv) at 80 °C.
b Yield of isolated product after silica gel chromatography.
c Determined by 400 MHz 1H NMR, E/Z > 99/1.
13

Scheme 1. A plausible mechanism for the process
14

Figure 1. C3-symmetric tertiary arsine 1
15