Facile synthesis of spirosubstituted cyclopropanes through reaction of electron-deficient olefins and 1,3-indandione

Article abstract of DOI:10.1016/j.tetlet.2019.151417

An efficient and facile approach for the synthesis of spirosubstituted cyclopropane derivatives has been described. The reaction of 1,3-indandione with arylidenemalononitrile in the presence of molecular iodine and dimethylaminopyridine occurred to give c

Full text of DOI:10.1016/j.tetlet.2019.151417

Journal Pre-proofs
Facile Synthesis of Spiro-substituted Cyclopropanes Through Reaction of Elec-
tron-Deficient Olefins and 1,3-Indandione
Jiamin Huang, Wenli Liu, Changqing Wang, Liu Yang, Xiaohua Cao
PII:
S0040-4039(19)31208-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151417
TETL 151417
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
15 September 2019
7 November 2019
18 November 2019
Please cite this article as: Huang, J., Liu, W., Wang, C., Yang, L., Cao, X., Facile Synthesis of Spiro-substituted
Cyclopropanes Through Reaction of Electron-Deficient Olefins and 1,3-Indandione, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.151417
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Tetrahedron Letters
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Facile Synthesis of Spiro-substituted Cyclopropanes Through Reaction of Electron-Deficient Olefins
and 1,3-Indandione
Jiamin Huang, Wenli Liu, Changqing Wang,* Liu Yang, Xiaohua Cao
Jiangxi Province Engineering Research Center of Ecological Chemical Industry, College of Chemistry and Environment Engineering, Jiujiang University
Jiujiang, Jiangxi, China,332005
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and facile approach for the synthesis of spiro-substituted cyclopropane derivatives
has been described. The reaction of 1,3-indandione with arylidenemalononitrile in the presence
of molecular iodine and dimethylaminopyridine occurred to give cyclopropanes in moderate to
excellent yields. The structures of the products were characterized by NMR and X-ray
diffraction analysis. A possible mechanism of this reaction process is proposed.
Commented [l1]: Original text:
Available online
An efficient approach of facile synthesis of spiro-substituted
cyclopropane derivatives has been described. Promoted by
molecular iodine, 1,3-indandione 1 reacted smoothly with the
electron-deficient alkenes 2 to give cyclopropanes 3 in good
to excellent yields.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Spirocyclopropyl compound
1,3-indandione
iodine
alkenes
Recently, there has been an increasing use of the cyclopropyl
ring in both organic synthesis and medicinal chemistry.1 Due to
the strain associated with the cyclopropane systems, they can be
employed as building blocks for construction of more complex
compounds that exhibit biological and pharmaceutical activities.2
CH3CN at room temperature. It was found that DMAP was the
best base for this reaction (Table 1, entry 9). With 1.2 equiv of
Commented [l2]: Original text:
molecular
iodine
and
3
equiv
of
DMAP,
The cyclopropyl moiety plays an important role in many
synthetic and naturally occurring compounds for their
intrinsic utility of key intermediates for further
transformations
phenylidenemalononitrile was able to react with 1.05 equiv of
1,3-indandione at 40 °C to afford product 3a in good yield (Table
1, entry 10).
Among the synthetic methods of cyclopropanation reported,
the Simmons-Smith-type reaction has attracted much attention.3
Metal-catalyzed cyclopropanation of alkenes with diazo
compounds is also widely used.4 The cyclopropanation reaction
involving ylides and electron-deficient olefins, Michael-initiated
ring closure (MIRC) has been reported.5 However, these reported
procedures often required severe reaction conditions or transition
metal catalysts, an operationally simple, mild and competent
strategy using less toxic reagents is still rare and highly
desirable.6
Table 1. Optimization of reaction conditions for cyclopropanation
with 1,3-indandione and phenylidenemalononitrile a
O
O
H
H
CN
XHal
CN
CN
2a
Ph
Base, Solvent
NC
O
O
Commented [l3]: Original text: heavy metal catalysts
1
3a
XHal = I , Br , NBS
2
2
As part of our continued efforts to develop stereoselective
cyclopropanation with olefins,7 we report here a new approach
for synthesis of spiro-substituted cyclopropane derivatives from
1,3-indandione and the electron-deficient alkenes in the presence
of molecular iodine.
Commented [l4]: Original text: our continued efforts to
develop of stereoselective
Entry
Base
Solv.
DCM
XHal Temp.(oC) Time (h) Yield (%)
1
2
Et3N
Et3N
I2
I2
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
6
6
34
47
24
11
40
27
8
CH3CN
EtOH
The experiment began with the reaction of 1,3-indandione,
phenylidenemalononitrile, Et3N and molecular iodine in DCM at
room temperature. After simple workup, the main product was
isolated in a low yield. Further analysis of the NMR spectra
3
Et3N
I2
6
Commented [l5]: Original text: one main product
4
Et3N
benzene
THF
I2
6
5
Et3N
I2
6
revealed that the structure of this new compound was
a
spiro-substituted cyclopropane derivative 3a. Encouraged by the
result, we further optimized the reaction conditions. The results
are listed in Table 1. Of all solvents screened, CH3CN was found
to be the best in terms of the reaction time and the yield. Other
halogen sources such as Br2, NBS were also screened, the results
indicated that the reaction using Br2 appeared to proceed more
rapidly than the reaction using molecular iodine. However, all of
them gave the final product in low yields (Table 1, entries 6 - 7).
Furthermore, the screening for a suitable base was performed in
6
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
NBS
Br2
I2
6
7
Et3N
0.5
6
8
C5H5N
DMAP
DMAP
31
67
69
9
I2
6
Commented [l6]: Original text: proceed more speedily
than
10
I2
4
Commented [l7]: Original text: Further

11
12
13
14
15
16
DMAP
DMAP
DMAP
K2CO3
CH3CN
THF
I2
I2
I2
I2
I2
I2
60
rt
2
6
4
4
6
6
54
52
13
14
15
3m
3n
3o
3,4-OCH2OC6H3
2-ClC6H4
6
4
2
69
67
45
Commented [l8]: Original text:
Commented [l9]: Original text:
Commented [l15]: Original text:
THF
40
rt
57
3-pyridinyl
a
CH3CN
CH3CN
CH3CN
59
The reaction was carried out with 1,3-indandione (1.05 equiv),
Na2CO3
NaHCO3
rt
16
arylidenemalononitrile (1.0 equiv), iodine (1.2 equiv) and DMAP (3
equiv) at 40 °C.
rt
trace
b Yield of isolated product.
a
The reaction was carried out with 1,3-indandione (1.05 equiv),
phenylidenemalononitrile (1.0 equiv), and base (3.0 equiv).
Under the optimized conditions, the scope and limitation of
the current cyclopropanation were investigated by employing
various arylidene derivatives as substrates. In all cases, the
spiro-substituted cyclopropane 3 was obtained as the sole product.
The structures of compounds (3a-3o) were characterized by 1H
NMR, 13C NMR and X-ray diffraction analysis (Fig. 1).8 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 good yields (Table
2, entries 2 - 14). For example, cyclopropanation product with
94% yield was obtained for para-substituted 3c (entry 3).
Surprisingly, the result showed that increasing the electron
density of the arylidene derivatives was unfavorable to the
reactivity of the reaction. When an electron-donating group was
introduced into the benzene ring of phenylidenemalononitrile, the
reaction rate became slow (Table 2, entries 9 - 13). 3-Pyridinyl
group also afforded corresponding cyclopropane in moderate
yield (Table 2, entry 15). Moreover, it should be mentioned that
aliphatic aldehydes afforded corresponding cyclopropanes mainly
in low yields at the present reaction conditions.
Commented [l10]: Original text: 3a-n
Figure 1. X-ray crystal structure of 3h.
Commented [l11]: Original text: (Table 2, entries 2 - 14)
On the basis of experimental observation and the literature,9
possible reaction mechanism is proposed (Scheme 1). Michael
addition of 1,3-indandione to arylidenemalononitrile led to
a
intermediate
A and followed by the generation of B or D
respectively in the presence of DMAP. Then, the reaction of B or
D with iodine provided iodide E or F as the key intermediate.
Finally, the nucleophilic C-attack via G or H gave cyclopropanes
3.
Commented [l12]: Original text: (entry 9-13)
Commented [l16]: Original text:
On the basis of experimental observation and the literature,9
a possible reaction mechanism is proposed (Scheme 1).
Addition of the anion of 1,3-indandione to
O
CN
O
Michael Addition
CN
CN
Ar
O
Table 2. Synthesis of spiro-substituted cyclopropanes from
1,3-indandione and arylidenemalononitrile a
O
Ar
CN
arylidenemalononitrile leads to anion A, which exist in the
equilibrium with the anion B. The reaction of anion B with
iodine gave iodide C as the key intermediate, and then an
intramolecular nucleophilic C-attack with an elimination of
iodide ion gave product 3.
1
2
A
O
O
b
a
e
s
s
e
H
a
b
H
I
2
CN
CN
CN
2a - 2o
Ar
Ar
DMAP, CH CN
3
O
O
O
NC
3a - 3o
Ar = Ph; 4-FC H ; 4-ClC H ; 4-BrC H ; 4-NO C H ; 3-ClC H ; 3-NO C H ;
O
O
I
I
CN
CN
CN
CN
Commented [l13]: Original text:
O
CN
O
O
1
I
I
Ar
Moreover, it should be mentioned that aliphatic aldehydes
and heteroaromatic aldehydes afforded corresponding
cyclopropanes mainly in low yields at the present reaction
conditions.
Ar
Ar
CN
C
B
D
6
4
6
4
6
4
2
6
4
6
4
2 6 4
3,4-Cl C H ; 4-OCH C H ; 4-CH C H ; 3,4-(CH O) C H ; 3,4-(CH ) C H ;
2
6
3
3
6
4
3
6
4
3
2
6
3
3 2 6 3
3,4-OCH OC H ; 2-ClC H ; 3-pyridinyl.
2
6
3
6 4
O
I
O
I
CN
CN
CN
CN
Commented [l14]: Original text:
Arsine involved cyclopropanation with methyl bromoacetate
and olefinsa
Yield (%)b
O
O
Entry
Product
Ar
Ph
Time (h)
Ar
Ar
E
F
1
2
3a
3b
3c
3d
3e
3f
4
2
2
2
2
2
2
2
6
6
6
6
69
91
94
93
87
93
89
94
59
71
57
62
base
base
4-FC6H4
4-ClC6H4
O
O
I
H
O
CN
-
-
- I
3
I
- I
CN
CN
CN
CN
Ar
O
O
O
NC
Ar
4
4-BrC6H4
Ar
G
3
H
5
4-NO2C6H4
3-ClC6H4
Scheme 1. Proposed mechanism of the formation of 3.
In summary, we have presented novel reaction of
1,3-indandione with arylidene derivatives to selectively afford
spiro cyclopropanes in moderate to excellent yields under mild
conditions. This iodine-mediated oxidative cycloaddition
provides a unique and facile protocol for the preparation of
cyclopropane derivatives.
6
a
7
3g
3h
3i
3-NO2C6H4
3,4-Cl2C6H3
Commented [l17]: Original text: in good yields
8
Commented [l18]: Original text: protocol to the preparation
of
9
4-OCH3C6H4
4-CH3C6H4
10
11
12
3j
Acknowledgments
3k
3l
3,4-(OCH3)2C6H3
3,4-(CH3)2C6H3
The author thanks the National Natural Science Foundation of
China (Nos. 21662019 and 21864015) for financial support.

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4
Figure 1. X-ray crystal structure of 3h.
Table 1. Optimization of reaction conditions for cyclopropanation with 1,3-indandione and
phenylidenemalononitrile a
O
O
H
H
CN
XHal
CN
CN
2a
Ph
Base, Solvent
NC
O
O
1
3a
XHal = I2, Br2, NBS
Entry
Base
Solv.
DCM
XHal Temp.(oC) Time (h) Yield (%)
1
2
3
4
5
6
7
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
I2
I2
rt
rt
rt
rt
rt
rt
rt
6
6
34
47
24
11
40
27
8
CH3CN
EtOH
I2
6
benzene
THF
I2
6
I2
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
NBS
Br2
6
0.5
8
C5H5N
DMAP
DMAP
DMAP
DMAP
DMAP
K2CO3
Na2CO3
I2
I2
I2
I2
I2
I2
I2
I2
I2
rt
rt
6
6
4
2
6
4
4
6
6
31
67
9
10
11
12
13
14
15
16
40
60
rt
69
54
52
THF
40
rt
57
CH3CN
CH3CN
CH3CN
59
rt
16
NaHCO3
rt
trace
a
The reaction was carried out with 1,3-indandione (1.05 equiv), phenylidenemalononitrile (1.0 equiv), and base (3.0
equiv).

5
Table 2. Synthesis of spiro-substituted cyclopropanes from 1,3-indandione and arylidenemalononitrile a
O
O
H
H
I2
CN
NC
3a - 3o
CN
CN
Ar
Ar
DMAP, CH3CN
O
O
1
2a - 2o
Ar = Ph; 4-FC6H4; 4-ClC6H4; 4-BrC6H4; 4-NO2C6H4; 3-ClC6H4; 3-NO2C6H4;
3,4-Cl2C6H3; 4-OCH3C6H4; 4-CH3C6H4; 3,4-(CH3O)2C6H3; 3,4-(CH3)2C6H3;
3,4-OCH2OC6H3; 2-ClC6H4; 3-pyridinyl.
Entry
Product
Ar
Time (h)
Yield (%)b
1
2
3a
3b
3c
3d
3e
3f
Ph
4
2
2
2
2
2
2
2
6
6
6
6
6
4
2
69
91
94
93
87
93
89
94
59
71
57
62
69
67
45
4-FC6H4
3
4-ClC6H4
4
4-BrC6H4
5
4-NO2C6H4
3-ClC6H4
6
7
3g
3h
3i
3-NO2C6H4
3,4-Cl2C6H3
4-OCH3C6H4
4-CH3C6H4
3,4-(OCH3)2C6H3
3,4-(CH3)2C6H3
3,4-OCH2OC6H3
2-ClC6H4
8
9
10
11
12
13
14
15
3j
3k
3l
3m
3n
3o
3-pyridinyl
a
The reaction was carried out with 1,3-indandione (1.05 equiv), arylidenemalononitrile (1.0 equiv), iodine (1.2 equiv)
and DMAP (3 equiv) at 40 °C.
b Yield of isolated product.
Facile synthesis of spirocyclopropanes by 1,3-indandione and arylidenemalononitrile
The reaction occurred in the presence of molecular iodine and dimethylaminopyridine
Various substituents on the benzene ring were well tolerated and gave good yields

6
The structures of products were confirmed by NMR and X-ray diffraction analysis
A possible mechanism of this reaction process is proposed
Declaration of interests
√ The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this
paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:

7
Graphical Abstract
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Facile Synthesis of Spiro-substituted cyclopropanes
Through Reaction of Electron-Deficient Olefins
and 1,3-Indandione
Leave this area blank for abstract info.
Jiamin Huang, Wenli Liu, Changqing Wang,* Liu Yang, Xiaohua Cao
Jiangxi Province Engineering Research Center of Ecological Chemical Industry, College of Chemistry and
Environment Engineering, Jiujiang University, Jiujiang, Jiangxi, China,332005
O
O
H
H
I
2
CN
NC
3a - 3o
Ar = Ph; 4-FC H ; 4-ClC H ; 4-BrC H ; 4-NO C H ; 3-ClC H ; 3-NO C H ;
CN
CN
Ar
Ar
DMAP, CH CN
3
O
O
1
2a - 2o
6
4
6
4
6
4
2
6
4
6
4
2 6 4
3,4-Cl C H ; 4-OCH C H ; 4-CH C H ; 3,4-(CH O) C H ; 3,4-(CH ) C H ;
2
6
3
3
6
4
3
6
4
3
2
6
3
3 2 6 3
3,4-OCH OC H ; 2-ClC H ; 3-pyridinyl.
2
6
3
6 4