Synthesis of a novel C3-symmetric arsine and its application in stereoselective cyclopropanation of electron-deficient olefins

Article abstract of DOI:10.1016/j.tetlet.2012.10.070

A novel C₃-symmetric arsine was synthesized from p-arsanilic acid in three steps. It was employed in the one-pot cyclopropanation of olefins with carbonyl-stabilized arsonium ylides formed in situ from methyl bromoacetate in the presence of NaH

Full text of DOI:10.1016/j.tetlet.2012.10.070

Tetrahedron Letters 53 (2012) 7003–7005
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Tetrahedron Letters
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Synthesis of a novel C3-symmetric arsine and its application in stereoselective
cyclopropanation of electron-deficient olefins
⇑
Changqing Wang
Key Laboratory of Jiangxi University for Applied Chemistry and Chemical Biology, College of Chemistry and Bio-Engineering, Yichun University, Yichun 336000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel C3-symmetric arsine was synthesized from p-arsanilic acid in three steps. It was employed in the
one-pot cyclopropanation of olefins with carbonyl-stabilized arsonium ylides formed in situ from methyl
bromoacetate in the presence of NaHCO3. This new arsine demonstrates good stereoselectivity and activ-
ity in the one-pot cyclopropanation of arylidenemalononitrile.
Received 31 July 2012
Revised 8 October 2012
Accepted 18 October 2012
Available online 24 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Arsine
One-pot
Cyclopropanation
Stereoselectivity
Ylide
Cyclopropane and its derivatives play an important role in the
total synthesis of complex compounds, natural products, and the-
oretically interesting molecules.1 Due to the strain associated with
the cyclopropane system, they can easily undergo a variety of
chemical transformations, such as electrophilic reaction, reduction
reaction, rearrangement reaction, radical reaction, and nucleo-
philic reaction to give many useful building blocks.2–6 Among the
synthetic methods of cyclopropanation reported, the reaction
involving arsonium ylides and electron-deficient olefins, Michael-
initiated ring closure (MIRC) is known for their high reactivity
and high diastereoselectivity.7 So far, a variety of arsonium ylides
have been investigated, but their corresponding precursors are al-
most exclusively prepared from triphenylarsine and reports
regarding other organoarsines are still lacking.8 In addition, despite
the fact that there has been much attention regarding C3-symmet-
ric molecules in the area of molecular recognition, chiral ligands,
and material science,9,10 successful applications to organocatalysts
are rare.11 Thus, it is conceptually interesting to design a class of
C3-symmetric organoarsines and investigate its reactivity in cyclo-
propanation. To our knowledge, such a class of arsines remains
unexplored in the course of development of arsonium ylides.
As part of our continued efforts to develop a stereoselective
cyclopropanation with arsonium salts and olefins,12 we report here
on our results from studies on cis-selective cyclopropanation of
bromides and acyclic olefins using a novel C3-symmetric tertiary
arsine 1 (Scheme 1). The use of 1 has several advantages over tri-
phenylarsine. First, the C3-symmetric arsine 1 can be readily pre-
pared from the less toxic precursor, p-arsanilic acid, a widely
used animal feed additive. Additionally; the amido groups at the
para-position of the arsine fragments might change the negative
charge density on the carbon center of the corresponding arsonium
ylides and, as a result, the arsine 1 might display a higher reactivity
toward particular substrates than triphenylarsine.7b
Our synthetic approach to C3-symmetric tertiary arsine 1 is
depicted in Scheme 1. Reduction of the commercially available
p-arsanilic acid with SO2 furnished 2 almost quantitatively, reac-
tion of 2 with phenylmagnesium bromide gave (p-aminophe-
nyl)diphenylarsine 3 as an oil, thus, a slight excess of 3 cleanly
reacted with benzene-1,3,5-tricarboxylic acid trichloride affording
the C3-symmetric tertiary arsine 1 in good yield after chromato-
graphic purification (see Supplementary data).
To gain an insight as to the behavior of the C3-symmetric ter-
tiary arsine 1 in cyclopropanation, the one-pot procedure for the
preparation of cyclopropane 5a using methyl bromoacetate and
phenylidenemalononitrile 4a as the starting material was chosen
as a model reaction. The phenylidenemalononitrile 4a was sub-
jected to a cyclopropanation reaction using C3-symmetric arsine
1 (0.15 equiv) and NaHCO3 (3 equiv) in CHCl3 (60 °C, 12 h) to give
5a in 54% yield (Table 1, entry 1). As a comparison, the same reac-
tion was performed using AsPh3 as catalyst, only 23% yield was ob-
tained even after 60 h. Since the reaction using arsine 1 appeared
to proceed more speedily than the reaction using triphenylarsine,
solvent effects were carefully examined. Of all solvents screened,
CH3CN was found to be the best in terms of the reaction time
and the yield. When the reaction was run in CH3CN with NaHCO3
⇑
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0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.070

7004
C. Wang / Tetrahedron Letters 53 (2012) 7003–7005
Cl
Cl
AsO3H2
As
MeO H, HCl, SO2, KI, rt, 1h
98%
NH2
NH2 HCl
2
Ph2As
AsPh2
PhM gBr, THF
rt, 4h
O
O
58%
N
H
N
H
benzene-1,3,5-tricarbonyl trichloride
Et3N, CH2Cl2, rt, 24h
As
HN
O
95%
NH2
AsPh2
1
3
Scheme 1. Synthesis of C3-symmetric tertiary arsine 1.
Table 1
Optimization of reaction conditions for cyclopropanation with methyl bromoacetate and phenylidenemalononitrilea
H
CN
CN
CO2Me
H
H
1
arsine
O
CN
CN
4a
Ph
Br
Ph
Base, Solvent
O
5a
Entry
Base
Solv.
Temp (°C)
Timeb (h)
Yieldb (%)
Timec (h)
Yieldc (%)
1
2
3
4
5
6
7
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
CHCl3
THF
DME
CH3CN
CH3CN
CH3CN
CH3CN
60
60
60
60
40
60
60
12
10
12
8
24
12
12
54
43
59
72
61
19
37
60
48
56
48
72
68
48
23
19
33
41
37
8
KFÁ2H2O
25
a
b
c
The reaction was carried out with arsine 1 or triphenylarsine (0.15 equiv), methyl bromoacetate (1.2 equiv), phenylidenemalononitrile (1.0 equiv), and base (3.0 equiv).
Reaction time and yield resulted from arsine 1.
Reaction time and yield resulted from triphenylarsine.
at 60 °C, 5a could be isolated in 72% yield (entry 4). Entry 5 showed
that by reducing the reaction temperature from 60 °C to 40 °C,
reaction rate and yield were decreased (entry 5). The effect of base
was also investigated and it has been observed that NaHCO3 was
the best base (entries 6 and 7).
Table 2
Arsine involved cyclopropanation with methyl bromoacetate and olefinsa
H
H
CN
CN
H
1
arsine
O
CN
CN
4a - 4m
Ar
Br
Ar
NaHCO3, CH3CN
O
CO2Me
Under the optimized conditions, the scope and limitation of the
current cyclopropanation were investigated by employing various
arylidene derivatives as substrates (see Supplementary data). As
exhibited in Table 2, both electron-donating and electron-
withdrawing substituents on the benzene ring were well tolerated
and all gave the desired products in high yields (Table 2, entries
2–13). For example, cyclopropanation product with 81% yield
was obtained for para-substituted 5d (entry 4). When an elec-
tron-donating group was introduced into the benzene ring of
phenylidenemalononitrile, the reaction rate became slow (entries
3–6). The result showed that increasing the electron density of
the arylidene derivatives was unfavorable to the reactivity of the
reaction.
On the basis of the experimental observation and the litera-
ture,12c the mechanism of this reaction is likely to proceed via a
catalytic cycle involving the formation of arsonium salt from arsine
and bromide followed by the production of ylide in the presence of
NaHCO3, and the MIRC of ylide and olefin generating the cis-
cyclopropane and arsine (Scheme 2). The beneficial effect of arsine
1 was assumed to create a stronger nucleophilic ylide than that of
triphenylarsine due to the electron-releasing substituent at the
5a - 5m
Ar = Ph; 4-CH3C6H4; 3,4-(CH3)2C6H3; 4-OCH3C6H4; 3,4-OCH2OC6H3;
3,4-(OCH3)2C6H3; 4-ClC6H4; 3-ClC6H4; 2-ClC6H4; 3,4-(Cl)2C6H3;
4-FC6H4; 4-BrC6H4; 4-NO2C6H4.
Entry
Product
Ar
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
8
10
12
12
12
12
8
8
8
8
8
72
74
78
81
77
79
73
71
57
74
67
77
69
4-CH3C6H4
3,4-(CH3)2C6H3
4-OCH3C6H4
3,4-OCH2OC6H3
3,4-(OCH3)2C6H3
4-ClC6H4
3-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
4-FC6H4
4-BrC6H4
9
10
11
12
13
5j
5k
5l
8
8
5m
4-NO2C6H4
a
The reaction was carried out with arsine 1 (0.15 equiv), methyl bromoacetate
(1.2 equiv), arylidenemalononitrile (1.0 equiv), and base (3.0 equiv) at 60 °C.
b
Yield of isolated product.

C. Wang / Tetrahedron Letters 53 (2012) 7003–7005
7005
H
H
CN
CN
References and notes
BrCH2CO2Me
Ar
R
AsPh2
CO2Me
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NaHCO3
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para-position of the arsine fragment, though the details need to be
investigated.
In summary, we have designed and synthesized the first
example of a C3-symmertric tertiary arsine from inexpensive and
low-toxicity bulk materials in high yield. The new arsine was dem-
onstrated to be a more effective reagent than triphenylarsine in the
cyclopropanation of olefins. Further detailed mechanism studies
are currently under investigation in our laboratories.
11. (a) Han, J.; Wu, H.; Teng, M.; Li, Z.; Wang, Y.; Wang, L.; Pan, Y. Synlett 2009, 933;
(b) Murai, K.; Fukushima, S.; Hayashi, S.; Takahara, Y.; Fujioka, H. Org. Lett.
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Acknowledgment
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85; (b) Tong, W.; Wang, C.; Zhao, W.; Chen, J.; Wu, X.; Zhang, M.; Deng, H.;
Shao, M.; Ren, Z.; Cao, W. Synth. Commun. 2009, 39, 3471; (c) Ren, Z.; Cao, W.;
Ding, W.; Wang, Y. Synthesis 2005, 2718.
The author thanks the Science Foundation of Jiangxi Provincial
Office of Education (GJJ11706) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
070.