Cyclopropanation of active methylene compounds with β-alkoxycarbonyl vinylsulfonium salts

Article abstract of DOI:10.1016/j.cclet.2018.08.021

An efficient synthesis of β-alkoxycarbonyl vinylsulfonium salts had been developed. Their reaction with indene-1,3-diones and other active methylene compounds provided cyclopropane carboxylates in good yields. A tentative reaction mechanism was proposed.

Full text of DOI:10.1016/j.cclet.2018.08.021

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CCLET 4642 No. of Pages 3
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Cyclopropanation of active methylene compounds with
β-alkoxycarbonyl vinylsulfonium salts
Shenquan Guoa, Niuniu Zhangb, Xiangzheng Tangb, Zhifeng Maob, Xuejing Zhangb,
a,
Ming Yanb, , Yining Xuan
*
*
a
College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient synthesis of β-alkoxycarbonyl vinylsulfonium salts had been developed. Their reaction with
indene-1,3-diones and other active methylene compounds provided cyclopropane carboxylates in good
yields. A tentative reaction mechanism was proposed.
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 26 June 2018
Received in revised form 17 July 2018
Accepted 31 August 2018
Available online xxx
Keywords:
Vinylsulfonium salt
Active methylene compound
Cyclopropanation
Vinylsulfonium salts are a class of special Michael acceptors
with diversified reactivities. They had been used as efficient
ethylene transfer reagents for the synthesis of various valuable
products. Their reactions with amino aldehydes or ketones
generated heterocyclic epoxides [1]. They were also used to react
with bisheteroatomic nucleophiles for the preparation of hetero-
cyclic compounds [2]. The reaction of vinylsulfonium salts with
active methylene compounds or primary amines provided cyclo-
propanes and aziridines [3]. In addition, 1-butadienyl-sulfonium
salts were applied for the synthesis of epoxides via the conjugate
addition and subsequent intramolecular cyclization [4]. Huang and
co-workers explored the applications of allenic sulfonium salts for
the synthesis of fused heterocycles [5]. Recently, we developed an
annulation reaction of vinylsulfonium salts with β-naphthols and
1,4-hydroxycoumarins. A series of dihydrofuran derivatives were
prepared in moderate to good yields [6]. Despite these progresses,
only few functionalized vinylsulfonium salts were prepared and
applied to new synthetic reactions [1f,3b,3c]. Their reactivities and
synthetic potentials remain to be explored. As a continuous effort
to explore the new synthetic applications of vinylsulfonium salts,
herein we report the first synthesis of β-alkoxycarbonyl vinyl-
sulfonium salts and their application for the cyclopropanation of
active methylene compounds. A variety of cyclopropane carbox-
ylates could be prepared in good yields.
The synthesis of β-alkoxycarbonyl vinylsulfonium salts 1a-1c is
showed in Scheme 1. The conjugate addition of thiophenol to
propiolates provided 3-(phenylthio)acrylates in good yields [7].
The further phenylation with diphenyliodonium triflate gave β-
alkyloxycarbonyl vinylsulfonium salts 1a-1c [8]. Only Z-isomers
were detected for 1a-1b, but a small amount of E-isomer was
observed for 1c. The experiment details please see Supporting
information.
The reaction of 1a with 1,3-indenedione 2a was examined and
the results are summarized in Table 1. The reaction underwent
smoothly in the presence of organic bases DBU (1,5-diazabicyclo
[4.3.0]non-5-ene), TMG (tetramethylguanidine) and Et3N, but
lower yields were obtained with DABCO (1, 4-diazabicyclo[2.2.2]
octane) and DMAP ((4-dimethylamino-pyridine) (Table 1, entries
1–5). Inorganic bases are also efficient (Table 1, entries 6–10).
Considering the yield and convenient work-up, Et3N was selected
for the further study. The optimal amount of Et3N was identified as
2 equiv. More or less amount of Et3N led to decreased yields
(Table 1, entries 11 and 12). The effect of reaction solvent was also
examined (Table 1, entries 13–22). The reaction occurred in various
organic solvents. The best yield was achieved in CHCl3.
The reactions of 1b and 1c with 2a were also examined
(Scheme 2). The good reactivity was observed for 1b, but 1c is less
reactive probably due to the increased steric hindrance. The
product 3ac was obtained in 49% yield as a mixture of trans/cis
isomers.
The reaction of a series of 1,3-indene-diones 2a-h with 1a were
examined and the results are summarized in Table 2. The
substitutions on the benzene ring with 4-Cl and 4-F were tolerated
* Corresponding authors.
E-mail addresses: yanming@mail.sysu.edu.cn (M. Yan),
xuanyn@mail3.sysu.edu.cn (Y. Xuan).
https://doi.org/10.1016/j.cclet.2018.08.021
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: S. Guo, et al., Cyclopropanation of active methylene compounds with β-alkoxycarbonyl vinylsulfonium salts,
Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.08.021

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2
S. Guo et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Table 2
The reaction of 1,3-indene-diones 2a-h with 1a.a
Entry
R3
R4
R5
R6
Product
Yield (%)b,c
1
2
3
4
5
6
7
8
H
Cl
F
NO2
H
H
H
H
H
H
Cl
Br
Me
Cl
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
3a
3b
3c
3d
3e
3f
94
90 (1:1.3)
92 (1:1.1)
62 (1:1.3)
82 (1:1)
80 (1:1)
88 (1:1)
81
Scheme 1. Synthesis of β-alkoxycarbonyl vinylsulfonium salts 1a-1c.
Table 1
Optimization of reaction conditions.a
H
Cl
3 g
3 h
a
Conditions: the reactions were performed with 1a (0.24 mmol), 2a-h
(0.2 mmol), Et3N (0.4 mmol), CHCl3 (4 mL).
b
Isolated yields.
c
The diastereoisomeric ratios in the brackets were determined by 1H NMR.
direction of the ester group with 4- or 5-substituent, products 3b-g
consisted of two diastereoisomers. The ratios were determined by
1H NMR spectra. The reaction of 4,5,6,7-tetrachcloro-1,3-indene-
dione 2h provided the product 3h in a good yield.
Furthermore, the reactions of 1a with a series of active
methylene compounds 4a-g were examined and the results are
summarized in Table 3. 1,3-Cyclohexanedione 4a afforded the
expected product 5a in an excellent yield. 1,3-Diphenylpropane-
1,3-dione 4b showed low reactivity. The reaction of acetoacetone
Entry
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
DBU
TMG
Et3N
DABCO
DMAP
K2CO3
Na2CO3
Cs2CO3
Na3PO4
KOH
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CHCl3
82
86
86
64
48
79
76
67
54
64
61
85
55
94
90
72
83
84
85
76
70
56
9
10
11c
12d
13
14
15
16
17
18
19
20
21
22
4c provided the product 5c in
a moderate yield. α-Cyano
acetophenone 4d showed good reactivity. The product 5d was
obtained in an excellent yield. The reaction of diethyl malonate 4e
is not satisfactory. The product 5e was obtained in a poor yield. On
the other hand, the reaction of coumarin 4f and its analogue 4g did
not afford the expected products, instead O-vinyl products 5f and 5
g were obtained in low yields. Ethyl α-cyanoacetate 4h and the
substrate 4i were found to be unreactive (For the details of
synthetic procedures, see Supporting information).
A tentative reaction mechanism was proposed (Scheme 3). The
deprotonation of 1,3-indenedione 2a with Et3N gives the enolate
anion. The conjugate addition of the anion to 1a generates the
sulfur ylide A. After the second deprotonation of 1,3-indenedione,
the intermediate B is formed. Subsequent cyclization provides the
product 3a and eliminates diphenylsulfide.
ClCH2CH2Cl
Et2O
THF
EtOAc
Et3N
Et3N
Et3N
Et3N
Acetone
CH3CN
DMSO
DMF
a
Conditions: the reactions were performed with 1a (0.24 mmol), 2a (0.2 mmol),
base (0.4 mmol), solvent (4 mL).
b
Isolated yields.
Et3N (0.2 mmol) was used.
Et3N (0.6 mmol) was used.
c
d
The reduction of the product 3a was studied (Scheme 4). The
reactionwith NaBH4 afforded the complicated stereoisomers of the
alcohols. The treatment with Et3SiH gave selectively the mono-
decarbonyl product 6 [9]. The ester group obviously shielded the
carbonyl group on the same side. Only the carbonyl group on the
opposite was reduced. The further reduction of 6 with NaBH4
provided the alcohol 7 as a mixture of two diastereoisomers
(details in Supporting information).
well. Excellent yields were obtained for the products 3b-3c. The 4-
NO2 substituted 2d afforded a lower yield. The substitutions with
5-Cl, 5-Br and 5-Me led to slightly lower yields. Due to the different
We have developed an efficient synthetic route of β-alkox-
ycarbonyl vinylsulfonium salts. Their reactions with indene-1,3-
diones and other active methylene compounds were studied. A
series of cyclopropane carboxylates were prepared in good yields.
The characterization data of all products are posited in Supporting
information. A tentative reaction mechanism was proposed.
Further applications of β-alkoxycarbonyl vinylsulfonium salts to
new synthetic reactions are currently underway.
Scheme 2. The reactions of 1b or 1c with 2a. Conditions: 1b/1c (0.24 mmol), 2a
(0.2 mmol), Et3N (0.4 mmol), and CHCl3 (4 mL). Isolated yields.
Please cite this article in press as: S. Guo, et al., Cyclopropanation of active methylene compounds with β-alkoxycarbonyl vinylsulfonium salts,
Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.08.021

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S. Guo et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
Table 3
The reaction of 1a with active methylene compounds 4a-i.a
Scheme 3. Proposed reaction mechanism.
Scheme 4. Reduction of the product 3a.
References
[1] (a) Y.F. Wang, W.H. Zhang, V.J. Colandrea, L.S. Jimenez, Tetrahedron 55 (1999)
10659–10672;
(b) Z. Wang, L.S. Jimenez, J. Am. Chem. Soc. 116 (1994) 4977–4978;
(c) K.H. Kim, L.S. Jimenez, Tetrahedron Asymmetry 12 (2001) 999–1005;
(d) M.G. Unthank, N. Hussain, V.K. Aggarwal, Angew. Chem. Int. Ed. 45 (2006)
7066–7069;
(e) M.G. Unthank, B. Tavassoli, V.K. Aggarwal, Org. Lett. 10 (2008) 1501–1504;
(f) S.P. Fritz, T.H. West, E.M. McGarrigle, V.K. Aggarwal, Org. Lett.14 (2012) 6370–
6373.
aConditions: the reactions were performed with 4a-4i (0.2 mmol), 1a (0.24 mmol),
Et3N (0.4 mmol), CHCl3 (4 mL).
bIsolated yields.
cDetermined by 1H NMR.
[2] (a) M. Yar, E.M. McGarrigle, V.K. Aggarwal, Angew. Chem. Int. Ed. 47 (2008)
3784–3786;
(b) M. Yar, E.M. McGarrigle, V.K. Aggarwal, Org. Lett. 11 (2009) 257–260;
(c) E.M. McGarrigle, S.P. Fritz, L. Favereau, M. Yar, V.K. Aggarwal, Org. Lett. 13
(2011) 3060–3063;
Acknowledgements
(d) J. An, N.J. Chang, L.D. Song, et al., Chem. Commun. 47 (2011) 1869–1871;
(e) C.S. Xie, D.Y. Han, Y. Hu, J.H. Liu, T. Xie, Tetrahedron Lett. 51 (2010) 5238–
5241.
We thank the National Natural Science Foundation of China
(Nos. 21772240, 21472248), National Science and Technology
Major Project of the Ministry of Science and Technology of China
(No. 2017ZX09305010), Guangzhou Science Technology and
Innovation Commission (No. 201707010210), Department of
Science and Technology of Guangdong Province (Nos.
2017A020211011, 2017A020211027) and China Scholarship Council
(No. 201608440090) for the financial support of this study.
[3] (a) H. Braun, G. Huber, Tetrahedron Lett. 17 (1976) 2121–2124;
(b) K. Takaki, T. Agawa, J. Org. Chem. 42 (1977) 3303–3304;
(c) R. Maeda, K. Oyama, R. Anno, et al., Org. Lett. 12 (2010) 2548–2550;
(d) H. Lin, Q.L. Shen, L. Lu, J. Org. Chem. 76 (2011) 7359–7369.
[4] (a) M.E. Garst, J. Org. Chem. 44 (1979) 1578–1580;
(b) M.E. Garst, P. Arrhenius, J. Org. Chem. 48 (1983) 16–24;
(c) M.W. Rowbottom, N. Mathewsb, T. Gallagher, J. Chem. Soc. Perkin Trans. I 1
(1998) 3927–3930.
[5] (a) P.H. Jia, Q.L. Zhang, Q.M. Ou, Y. Huang, Org. Lett. 19 (2017) 4664–4667;
(b) P.H. Jia, Q.L. Zhang, H.X. Jin, Y. Huang, Org. Lett. 19 (2017) 412–415.
[6] Z.C. Chen, L. Tong, Z.B. Du, et al., Org. Biomol. Chem. 16 (2018) 2634–2638.
[7] Y.M. Li, C. Mgck-Lichtenfeld, A. Studer, Angew. Chem. Int. Ed. 55 (2016) 14435–
14438.
Appendix A. Supplementary data
Supplementary material related to this article can be
found, in the online version, at doi:https://doi.org/10.1016/j.
cclet.2018.08.021.
[8] T. Ishikawa, N. Kasai, Y. Yamada, T. Hanamoto, Tetrahedron Lett. 17 (2015) 1254–
1260.
[9] Y.Y. Liu, X.Y. Yu, J.R. Chen, et al., Angew. Chem. Int. Ed. 56 (2017) 9527–9531.
Please cite this article in press as: S. Guo, et al., Cyclopropanation of active methylene compounds with β-alkoxycarbonyl vinylsulfonium salts,
Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.08.021