Sc(OTf)3-catalyzed smooth tandem [3+2] cycloaddition/ring opening of donor-acceptor cyclopropane 1,1-diesters with enol silyl ethers

Article abstract of DOI:10.1016/j.tetlet.2008.09.028

Catalyzed by Lewis acids, donor-acceptor cyclopropane 1,1-diesters reacted with enol silyl ethers to afford 1,6-dicarbonyl compounds in moderate to excellent yields. This supplied a mild carbon-carbon bond-forming method from the ring opening of cyclopropanes. A smooth tandem [3+2] cycloaddition/ring opening process has been clearly proved by an independent experiment.

Full text of DOI:10.1016/j.tetlet.2008.09.028

Tetrahedron Letters 49 (2008) 6659–6662
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Tetrahedron Letters
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Sc(OTf)3-catalyzed smooth tandem [3+2] cycloaddition/ring opening
of donor–acceptor cyclopropane 1,1-diesters with enol silyl ethers
*
Jie Fang, Jun Ren, Zhongwen Wang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 30071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2008
Revised 2 September 2008
Accepted 9 September 2008
Available online 12 September 2008
Catalyzed by Lewis acids, donor–acceptor cyclopropane 1,1-diesters reacted with enol silyl ethers to
afford 1,6-dicarbonyl compounds in moderate to excellent yields. This supplied a mild carbon–carbon
bond-forming method from the ring opening of cyclopropanes. A smooth tandem [3+2] cycloaddition/
ring opening process has been clearly proved by an independent experiment.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Tandem
Cyclopropane
Cycloaddition
Enol silyl ether
Ring opening
Carbon–carbon bond formation and cleavage processes are very
important in organic synthesis. Combination of carbon–carbon
bond formation and cleavage in one reaction would supply syn-
thetic methodologies for efficient construction of complex carbon
skeletons.1 Because of the high efficiency in construction of com-
plex molecular framework, tandem reactions have attracted partic-
ular attention over the past few decades.2
Lewis acids, such D/A CP 1,1-diesters reacted with enol silyl ethers
to afford 1,6-dicarbonyl compounds under mild conditions in mod-
erate to excellent yields. Mechanism study clearly demonstrated a
smooth tandem process. To the best of our knowledge, this is the
first [3+2] cycloaddition examples of 1,1-di-EWG-activated cyclo-
propanes with enol silyl ethers, and the first tandem [3+2] cycload-
dition/ring opening process of EWG-activated cyclopropanes with
a clear tandem sequence. This reaction can also be thought as a for-
mal homologous Mukaiyama Michael addition. Comparing to the
reported nucleophilic ring opening of EWG-activated cyclopro-
panes,3,8 this supplied a mild and efficient carbon–carbon bond-
forming method with enol silyl ethers as the nucleophiles and
Sc(OTf)3 as a Lewis acid. We report herein our recent results.
Several groups have reported the reactions of D/A CP (alkoxyl or
siloxyl as the donor) and enol silyl ethers catalyzed by strong Lewis
acids or Bronsted acids.3c,d Two types of products were obtained in
these reactions: the ring ones (5-carbon ring skeleton) by the [3+2]
cycloadditions and/or the chain ones. An accepted tandem cyclo-
propane polarization/intermolecular Mukaiyama Aldol/intramo-
lecular Aldol mechanism was proposed (Scheme 1): under the
catalysis of Lewis acids, a separated 1,3-dipole was generated from
the polarization of cyclopropane ring and the carbocation could be
stabilized by the adjacent oxygen atom to form the oxonium. After
the nucleophilic addition of enol silyl ether to the oxonium (a
homo Mukaiyama Aldol), the chain product was produced and
the ring product was constructed by the subsequent intramole-
cular Aldol. We noticed that in the aforementioned D/A CP, there
was only one EWG as the acceptor and the donor(s) was (were)
Functionalized cyclopropanes have found broad applications in
modern organic synthesis owing to the unique reactivity of the
cyclopropane moiety.3 Cycloadditions of cyclopropanes are impor-
tant in this area. Most of the researches have been focused on the
[3+2] cycloadditions of electro-withdrawing group (EWG)-acti-
vated cyclopropanes, especially the donor–acceptor cyclopropanes
(D/A CPs, Scheme 1: A, B and C) with various dienophiles.3c,d,4
Among these examples, the donor–acceptor cyclopropane 1,1-
diesters (D/A CP diesters, Scheme 1: B), in which the donors were
aryls (at C2-position of cyclopropane moiety), have attracted more
attention in recent years, because they were easily available and
reactive to a large range of 1, n-dipoles including the aforemen-
tioned [3+2] cycloadditions, [3+3] cycloadditions with nitrones5
and azomethine imines,6 and [4+3] cycloadditions with iso-
benzofuran7 to efficiently construct 5 to 7-membered carbocycles
or heterocycles. During our study on tandem and cycloaddition
reactions of D/A CP 1,1-diesters (Scheme 1: B), we found a new
tandem [3+2] cycloaddition/ring opening reaction. Catalyzed by
* Corresponding author.
E-mail address: wzwrj@nankai.edu.cn (Z. Wang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.028

6660
J. Fang et al. / Tetrahedron Letters 49 (2008) 6659–6662
Me3SiO R3
LA
LA
O
O
O
R1
path a
R3
R4
O
OSiMe3
R3
O
R1
L A
OR2
R1
1
R1
R4
2
work-up
OR2
A
OR2
R4
OR2
O
O
1
path b
?
A
R1O
OR2
Ar
1
1
R1
2
LA
D
O
2
2
O
OSiMe3
R3
D
D
R1
B
A
C
OSiMe3
R3
acceptor (A) = ketone, ester, amide, etc.
donor (D) = alkoxyl or siloxyl group.
Ar = aryl group (donor).
R2O
R4
R4
OR2
Scheme 1. Some typical examples of D/A CP and the proposed mechanism for [3+2] cycloaddition of D/A CP (A) in references.
one or two alkoxyl (siloxyl) group(s) (Scheme 1: A and C). There
was no distinct evidence for the conversion of ring products to
chain products through ring opening process.
We selected the reaction of D/A CP 1,1-diester 1 (1.0 equiv) and
enol silyl ether 2a (1.5 equiv) in our initial investigation (Scheme
2). Sc(OTf)3 (20 mol %) was selected as the Lewis acid and the reac-
tion was run in dichloromethane (DCM). As expected from the
aforementioned mechanism, both of the ring product (3a) (by a
[3+2] cycloaddition) and the chain product 4a9 were observed.
However, it was noticed that when the reaction time was pro-
longed, the amount of 3a was gradually decreased and the amount
of 4a was gradually increased. At the end of the reaction, 4a was
obtained as almost the exclusive product. This phenomenon
strongly supported a smooth tandem [3+2] cycloaddition/ring
opening process (Scheme 3), which was quite different from the re-
ported one (Scheme 1). In order to confirm this, an independent
experiment was carried out and it was found that under the same
condition 3a could be smoothly transformed into 4a in a yield of
85%.
Several other Lewis acids (e.g., Yb(OTf)3, Cu(OTf)2, Zn(OTf)2,
Sn(OTf)2 and SnCl4) in different solvents (e.g., 1,2-dichloroethane,
DMF, toluene, THF and acetonitrile) have been screened (see Sup-
plementary data), and Sc(OTf)3 (20 mol %) in DCM was chosen as
the optimized conditon10 for further investigation.
O
O
OTMS
Scope of the substrates was studied next. Reactions of cyclopro-
pane 1 (1.0 equiv) and various enol silyl ethers 2 (1.5 equiv)11 were
carried out, and the results are summarized in Table 1. It was found
that except the ketene acetal 2e, most of the products were formed
in moderate to excellent yields. The result of 2j was complex. In or-
der to determine the stereochemistries of the [3+2] cycloaddition
products, reaction of 1 and 2a was stopped midway and 3a was
separated. NOESY experiment confirmed 3a as a sole cis-isomer
(Fig. 1). Compounds 4b, 4g, 4h, and 3i were mixtures of two stere-
omers which were unable to be separated.
BnO
(Ar =
OBn
Sc(OTf)3
DCM
+
Ph
Ar
p
-MeOC6H4)
2a
1
BnO2C
CO2Bn
Ar
O
BnO2C
BnO2C
Ph
OTMS
+
Ph
Ar
4a
85%
3a
Sc(OTf)3 (20 mol% ),
It was worth to note that reaction of 2i (R1 = H) and 1 afforded
the product 3i that was supposed to be obtained by the hydrolysis
Scheme 2.
LA
O
O
LA
OSiMe3
O
OR2
R3
O
O
LA
O
1
R1O
OR2
Ar
R4
R1O
OR2
Ar
R1O
2
Ar
LA
O
O
R4
O
O
Ar
R3
R1O
OR2
R1O
LA
O
O
SiMe3
OR2
SiMe3
R3
R4
R2O
O
Silyl transfer
- LA
O
R4
R4
Ar
R3
R3
R1O
R2O
R1O
Me3Si
Ar
O
O
O
O
OR2
Scheme 3. Proposed mechanism for the smooth tandem [3+2]/ring opening reaction.

J. Fang et al. / Tetrahedron Letters 49 (2008) 6659–6662
6661
Table 1
Sc(OTf)3-catalyzed tandem [3+2]/ring opening reactions of 1 and various enol silyl ethers 2
Ar
O
R1
H
H
BnO2C
BnO2C
BnO2C
Sc(OTf)3
20mol%
R1
O
O
CO2Bn
R1
OTMS
OTMS
R2
R3
+
R3 R2
4
BnO
OBn
R1
BnO2C
CH2Cl2
CO2Bn
Ar
R1
Ar
R3 R2
H
1
3
2
work-up
OH
Me Me
3i
Ar
(Ar =
p
-OMeC6H4)
Entry
Substrate
R1
R2
R3
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
C6H5
CH3
i-butyl
OEt
styryl
R1R3 C4H8
R1R3 C3H6
H
H
CH3
H
H
H
H
H
H
CH3
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
3i
94
99b
92
90
22
87
60b
95b
78
CH3
10
2j
CH3
CO2Et
H
4j
Complex
a
Yields of the isolated products.
A mixture of two stereomers.
b
Further investigations were expanded for reactions of substrate
Ph
Ha
O
O
2a and various EWG-activated cyclopropanes 512 (Table 2). When
the donors were substituted phenyl groups, reactions of the cyclo-
propane 1,1-diesters (1 and 5b–h) gave moderate to excellent
yields. In these examples, electron-donating-group-substituted
phenyls gave relatively higher yields, and electron-withdrawing-
group-substituted phenyls gave relatively lower yields. In case of
strong electron-withdrawing group (nitro group), 40 mol % of
Sc(OTf)3 and higher reaction temperature were needed to promote
the reaction. Reaction between 2a and vinyl cyclopropane diester
(5i) gave complex result and only 29% of the product was obtained.
When the donor was isopropyl or hydrogen, the desired products
were not observed. Different from the case of the D/A CP 1,1-dies-
ters, cyclopropane b-keto esters (5l and 5m) afforded only [3+2]
cycloaddition products in lower yields. It should also be noted that
the reaction of mono-EWG-activated D/A CP ketone (5n) with 2a
still proceeded successfully to afford the chain product (61%).
Ha'
He
CO2Bn
Ph
Hd
Hc
O
Hf
Hb
Si
Hc
CH3
CH3
H H
MeO
Figure 1. 2DNOESY correlation for compound 3a.
of the [3+2] cycloaddition product in the work-up process. This is
the only example of cyclopropane 1,1-diester 1 and enol silyl
ethers, in which the reaction stopped in the [3+2] stage.
Table 2
Sc(OTf)3-catalyzed ring opening reactions of 2a and substituted cyclopropanes 5
R1
R1
R2
OTMS
Sc(OTf)3
20mol%
R1 R3
O
R2
Ph
OTMS
+
Ph
R2
Ph
R3
CH2Cl2
R3
2a
5
8
7
Entry
Substrate
R1
R2
R3
Product
Yielda (%)
1
2
1
CO2Bn
CO2Bn
CO2Bn
CO2Bn
CO2Bn
CO2Bn
CO2Me
CO2Et
CO2Et
CO2Bn
CO2Bn
CO2Et
CO2Et
H
CO2Bn
4-MeOC6H4
4-MeC6H4
C6H5
4-NO2C6H4
3-MeOC6H4
2-ClC6H4
4-MeOC6H4
4-MeOC6H4
Vinyl
i-Propyl
H
C6H5
C6H5
4-MeOC6H4
4a
8b
8c
8d
8e
8f
8g
8h
8i
NR
NR
7l
7m
8n
94
92
87
73 (95)b
87
64
85
78
29
0
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
CO2Bn
CO2Bn
CO2Bn
CO2Bn
CO2Bn
CO2Me
CO2Et
CO2Et
CO2Bn
CO2Bn
COCH3
COC6H5
COC6H5
3
4c
5
6
7
8
9
10
11
12
13
14c
0
19
24
61
a
Yields of the isolated products.
Isolated yield based on the conversion of 5d.
40 mol % of Sc(OTf)3, 1,2-dichloroethane, 2.0 equiv of 2: 0 °C for 10 min, 40–45 °C for 4 h, room temperature overnight.
b
c

6662
J. Fang et al. / Tetrahedron Letters 49 (2008) 6659–6662
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. Engl. 2006, 45, 7134; (f) Pellissier, H.
Tetrahedron 2006, 62, 1619; (g) Pellissier, H. Tetrahedron 2006, 62, 2143.
3. For reviews, please see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66; (b)
Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. Rev. 1989, 89, 165; (c)
Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151; (d) Yu, M.; Pagenkopf, B.
L. Tetrahedron 2005, 61, 321; (e) Wenkert, E. Acc. Chem. Res. 1980, 13, 27; (f)
Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597; (g) Paquette, L. A. Chem. Rev.
1986, 86, 733; (h) Reissig, H. U. Top. Curr. Chem. 1988, 144, 73; (i) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117.
4. Some recent examples: (a) Venkatesh, C.; Singh, P. P.; Ila, H.; Junjappa, H.
Eur. J. Org. Chem. 2006, 5378; (b) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J.
Am. Chem. Soc. 2007, 129, 9631; (c) Takasu, K.; Nagao, S.; Ihara, M. Adv. Synth.
Catal. 2006, 348, 2376; (d) Shi, M.; Yang, Y.-H.; Xu, B. Tetrahedron 2005, 61,
1893; (e) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057; (f) Gupta,
A.; Yadav, V. K. Tetrahedron Lett. 2006, 47, 8043; (g) Sliwinska, A.; Czardybon,
W.; Warkentin, J. Org. Lett. 2007, 9, 695; (h) Carson, C. A.; Kerr, M. A. J. Org.
Chem. 2005, 70, 8242; (i) Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Bioorg. Chem.
2006, 299; (j) Christie, S. D. R.; Davoile, R. J.; Jones, R. C. F. Org. Bioorg. Chem.
2006, 2683; (k) Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang,
J.; Yu, M.; Pagenkopf, B. L. Adv. Synth. Catal. 2006, 348, 2385; (l) Korotkov, V. S.;
Larionov, O. V.; Hofmeister, A.; Magull, J.; de Meijere, A. J. Org. Chem. 2007, 72,
7504; (m) Korotkov, V. S.; Larionov, O. V.; de Meijere, A. Synthesis 2006, 21,
3542.
5. (a) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023; (b) Young, I. S.;
Kerr, M. A. Org. Lett. 2004, 6, 139; (c) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am.
Chem. Soc. 2005, 127, 5764; (d) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72,
8597; (e) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 3918.
6. Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10,
689.
7. Ivanova, O. A.; Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V.
Angew. Chem., Int. Ed. 2008, 47, 1107.
8. (a) Du, D.; Wang, Z. Tetrahedron Lett. 2008, 49, 956. and references cited
therein; (b) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8, 1709; (c) Shi, M.; Tang, X.-Y.;
Yang, Y.-H. J. Org. Chem. 2008, 73, 5311; (d) Shi, M.; Tang, X.-Y.; Yang, Y.-H. Org.
Lett. 2007, 9, 4017.
O
O
O
Ar
O
Sc(OTf)3
20mol%
O
O
O
Ph
O
O
8o (54%)
CH2Cl2
Ar
5o
-OMeC6H4)
(Ar =
Ph
p
+
OTMS
2f
Scheme 4. Preparation of compound 8o and its X-ray structure.
In order to identify the structure of the final chain products,
compound 8o was prepared by the reaction of 5o and diene 2f.
The structure of 8o was confirmed by single-crystal X-ray diffrac-
tion analysis13 (Scheme 4).
In conclusion, we have developed a smooth tandem [3+2]/ring
opening reaction between D/A CP 1,1-diesters and enol silyl ethers
to afford 1,6-dicarbonyl compounds under the catalysis of Sc(OTf)3.
This is the first [3+2] cycloaddition reaction of cyclopropane 1,1-
diesters with enol silyl ethers and supplied a mild carbon–carbon
bond-forming method by a formal homologous Mukaiyama Mi-
chael addition. Mechanism study has proved for the first time a
tandem cycloaddition sequence of EWG-activated cyclopropane.
9. Physical data for compound 4a: Colorless oil; 1H NMR (300 MHz, CDCl3): d 7.56
(d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.28–7.33 (m, 2H), 7.17–7.25 (m, 8H),
7.08–7.14 (m, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 5.07 (dd,
J = 12.3 Hz, J = 12.3 Hz, 2H), 4.89 (dd, J = 12.3 Hz, J = 12.3 Hz, 2H), 3.63 (S, 3H),
3.13–3.28 (m, 4H), 2.31–2.40 (m, 1H), 2.09–2.19 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 198.2, 169.2, 169.1, 158.6, 137.2, 135.6, 135.5, 134.6, 133.2, 128.9,
128.7, 128.5, 128.2, 114.2, 67.3, 67.2, 55.4, 50.4, 46.1, 38.5, 35.5; HRMS (ESI)
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 20572045 and 20421202), the ‘111 Project’ (B06005), Na-
tional Key Project of Scientific and Technical Supporting Programs
(No. 2006BAE01A01-5), and the Ministry of Education of China
(RFDF20070055022 and RSF[2005]383) for financial support.
calcd for C34H32O6 (M+Na)+: 559.2091, found 559.2100; IR (film):
m 3061, 3034,
2958, 2931, 2911, 2836, 1739, 1678, 1613, 1514, 1448, 1378, 1338, 1251, 1233,
1146, 1030, 984, 912, 822, 740, 731.
10. Typical procedure for the tandem [3+2] cycloaddition/ring opening process of
functionalized cyclopropanes and enol silyl ethers: A 25 mL three-necked flask
was charged with Sc(OTf)3 (20 mol %) and heated to 120 °C for 1 h under N2.
After the flask was cooled to 0 °C, a solution of cyclopropane (0.3 mmol) in
1 mL of dry CH2Cl2 was added. The mixture was stirred for 15 min at 0 °C. A
solution of enol silyl ether (0.45 mmol) in 1 mL of dry CH2Cl2 was added
dropwise to the flask over 2 min. After being stirred at 0 °C for 10 min, the
mixture was gently warmed to room temperature and stirred overnight.
Solvent was evaporated in vacuo and the residue was purified by flash
chromatography on silica gel to afford the product.
11. (a) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J. Tetrahedron
1987, 43, 2075; (b) Walshe, N. D. A.; Goodwin, G. B. T.; Smith, G. C.; Woodward,
F. E. Org. Synth. 1993, 8, 1; (c) Duhamel, P.; Hennequin, L.; Poirier, J. M.; Tavel,
G.; Vottero, C. Tetrahedron 1986, 42, 4777.
12. (a) Mapelli, C.; Turocy, G.; Switzer, F. L.; Stammer, C. H. J. Org. Chem. 1989, 54,
145; (b) Wolfe, S.; Ro, S.; Kim, C.-K.; Shi, Z. Can. J. Chem. 2001, 79, 1238.
13. The crystallographic data (excluding structure factors) of 8o have been
deposited with the Cambridge Crystallographic Data Center as
Supplementary Publication No. CCDC 686008. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.028.
References and notes
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