A novel ring-opening based tandem domino process of an activated vinyl cyclopropane

Article abstract of DOI:10.1016/j.tetlet.2007.12.027

An activated vinyl cyclopropane reacted with substituted benzaldehydes to afford α-methylene γ-butyrolactones in the presence of DABCO·6H₂O. This tandem domino process took place in aqueous media, and was presumably initiated with the ring open

Full text of DOI:10.1016/j.tetlet.2007.12.027

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 956–959
A novel ring-opening based tandem domino process
of an activated vinyl cyclopropane
Ding Du, Zhongwen Wang *
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
Received 18 September 2007; revised 4 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
An activated vinyl cyclopropane reacted with substituted benzaldehydes to afford a-methylene c-butyrolactones in the presence of
DABCOÁ6H2O. This tandem domino process took place in aqueous media, and was presumably initiated with the ring opening of cyclo-
propane by the nucleophilic addition of DABCOÁ6H2O.
Ó 2007 Elsevier Ltd. All rights reserved.
Tandem reactions have attracted particular attention
over the past few decades because of their high efficiency
in construction of complex molecular framework.1 As ver-
satile 3-carbon building blocks in modern organic synthe-
ses, activated cyclopropane derivatives have been widely
investigated in the field of nucleophilic ring-opening reac-
tions.2 Ring opening of activated cyclopropanes by nucleo-
philes gives carbanion (usually an enolate by the so-called
homologous Michael addition), which can be subsequently
trapped by electrophiles to form new carbon–carbon bonds
through a tandem domino process.3 This strategy is extre-
mely efficient to construct the carbon framework of organic
molecules. As a 5-carbon synthon, vinyl cyclopropanes
(VCPs) usually activated by not less than one electron-
withdrawing group (EWG), can also undergo nucleophilic
ring opening with either 1,3- or 1,5-mode (Fig. 1). The 1,5-
mode ring opening by nucleophilic addition,4 usually
promoted by metal, can provide potential utilities in
organic synthesis. However, to the best of our knowledge,
there are very limited reports taking advantage of the
aforementioned tandem strategy on activated VCPs.5
Herein, we report a novel metal-free tandem domino pro-
cess based on the 1,5-mode nucleophilic ring opening of
VCP affording the compounds with an a-methylene c-
butyrolactone core structure.
To further explore the chemistry of activated VCPs and
make use of them as 5-carbon synthons to construct com-
plex molecules by the tandem nucleophilic ring-opening
reactions, we synthesized a functionalized VCP (3).6 We
conceived that nucleophiles may attack 3 at C-1 position,
and the cleavage of 3-member ring would lead to an allylic
carbanion, which could subsequently be trapped by vari-
ous electrophiles (Scheme 1). Because of both the steric
and the electronic effects, the intermediate with anion at
C-5 position would be more stable than that with anion
at C-3 position and therefore preferred to undergo 1,5-
mode coupling rather than 1,3-mode coupling. We envi-
sioned that tertiary amines, such as DABCOÁ6H2O, may
promote the ring opening of 3.7 The preliminary results
showed a 1,5-mode, however, to our surprise, some more
complex transformations happened in aqueous media to
afford a 5-member ring lactone with moderate to good
stereoselectivity.
2
2
4
5
EWG
EWG
1
1
3
3
EWG
EWG
1
2
Fig. 1. Modes of ring opening of activated cyclopropanes and VCPs.
*
Corresponding author. Tel.: +86 022 23505942.
E-mail address: wzwrj@nankai.edu.cn (Z. Wang).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.027

D. Du, Z. Wang / Tetrahedron Letters 49 (2008) 956–959
957
CHO
NO2
4
O
O
5
3
EtO2C
CO2Et
Nu
EtO2C
CO2Et
DABCO·6H2O
+
OEt
EtO
Nu
dioxane/H2O(1:1)
70~80 °C
2
1
Ph
Ph
22 h
Ph
3
4a
1.0 equiv.
1.0 equiv.
EtO2C
CO2Et
O
O
EtO2C
CO2Et
EtO2C
E
Ar
O
E
Nu
Nu
Ph
Ar
+
O
EtO2C
Ph
Ph
Ph
6a
5a
Scheme 1. Designed nucleophilic addition-initiated tandem domino pro-
cess of 3.
Ar = 4-NO2C6H4
~40% combined yield
Scheme 2. DABCOÁ6H2O-mediating tandem domino ring-opening reac-
tion of 3 and 4a.
In our initial attempts, no reaction of 3 with 4-nitro-
benzaldehyde and anhydrous DABCO occurred in a vari-
ety of organic solvents, even with prolonged reaction
time or at elevated reaction temperature. Surprisingly,
when we chose 1,4-dioxane and water (v/v = 1:1) as a bin-
ary solvent system, two unexpected isomeric products (5a
and 6a, with a ratio of 3.8:1) were obtained.8 The combined
yield of 5a and 6a was 40%, together with 26% of recovered
4a (Scheme 2).
To drive the reaction to completion, a large excess of 4a
(up to 10.0 equiv) was employed, but resulting in no
improvement of the yield. The best ratio of 3 to 4a was
1.2:1.0 with a yield of 48% (based on 4a), still with 32%
of recovered 4a. Other Lewis bases (DBU, DMAP, Et3N,
N(CH2CH2OH)3 and PPh3) were also tested but gave no
positive results. Use of a stoichiometric amount of DAB-
COÁ6H2O (1.0 equiv to 3) was necessary. With a catalytic
amount of DABCOÁ6H2O, the reaction was very slow
and the yield was lower.
The solvent effect was also examined for the reaction of
3 with 4a in the presence of DABCOÁ6H2O.9 CH3CN/H2O
system was the best choice. It increased the reaction rate
and afforded moderate yield (50% based on 4a). The ratio
of the organic solvent to water was important under these
conditions. The mixed solvents with 1:1 (v/v) ratio were
optimized for both the reaction rate and the yield. The
ratio of the organic solvent to water did not significantly
affect the stereoselectivity (the ratio of the two isomers).
Some water-tolerant additives such as Yb(OTf)3 and
Cu(OTf)2 were also employed. Instead of activating the
carbonyl of 4a, these two Lewis acids accelerated the
decomposition of 3.
Under the optimized reaction conditions, we next car-
ried out the reactions of 3 with a number of substituted
benzaldehydes (Table 1). In most cases, when excess
amount of 3 was used, the conversions were over 90%,
while a moderate to large amount of substituted benzalde-
hydes were recovered. Substituents on the benzene ring
greatly affected the reaction rates, yields and stereoselec-
tivities. Strong electron-withdrawing groups (Table 1,
entries 1–5), which could increase the electrophilicity of
carbonyl, accelerated the reactions with relatively higher
yields; while the aldehydes bearing the electron-donating
groups (Table 1, entries 13 and 14) gave no desired prod-
ucts. These results indicated that carbanion intermediates
were generated by the nucleophilic addition of DAB-
COÁ6H2O. Most products were obtained with good stereo-
selectivities (Table 1, entries 2–5 and 7–11). Relative
stereochemistries were determined by X-ray crystallogra-
phy of 6a and 5h,10 as well as analysis of NOESY and
chemical shifts of two olefinic protons. When ethyl
glyoxylic acetate and cyclohexanecarboxaldehyde were
employed in the reactions, no desired products were
observed.
A plausible mechanism for the DABCOÁ6H2O-medi-
ated tandem domino reactions of 3 was proposed as
shown in Scheme 3. DABCOÁ6H2O could attack 3 either
at C-4 (path a) or C-1 (path b)7 position to initiate the cas-
cade process. In path a, Baylis–Hillman intermediate 7
could be generated. Intermediate 9 could be afforded by
the addition of another molecule of DABCOÁ6H2O
followed by elimination. In path b, the ring cleavage of
cyclopropane could lead to the formation of allylic carb-
anion intermediate 8, which should isomerize to the elec-
tronically and sterically more stable intermediate 9.
Intermediate 9 could react with the electrophilic aldehydes
to afford 10. After dehydration, 12 could be obtained.
Carbonyl at C-3 position could attack C-1 to form oxo-
nium 13, which should undergo the subsequent transfor-
mations to afford the final products.11 The substitutent
effects observed (Table 1) were consistent with the pro-
posed mechanism.
In conclusion, we have developed a novel tandem
domino process involving the nucleophilic ring-opening
of VCP (3) by DABCOÁ6H2O, the subsequent coupling
reactions with substituted benzaldehydes 4 and lactoniza-
tions. Although the reactions proceed in low to moderate
yields, and are limited to certain substituted aldehydes,
this work provides a potential synthetic strategy to use
the VCP as a 5-carbon synthon through a 1,5-mode

958
D. Du, Z. Wang / Tetrahedron Letters 49 (2008) 956–959
nucleophilic addition ring opening by a non-metal pro-
moter. Further studies on the scope of the reactions and
the synthetic applications are now being carried out in
this laboratory.
Table 1
DABCOÁ6H2O meditated ring-opening reactions of 3 and substituted benzenaldehydes 4
EtO2C
CHO
O
O
O
O
DABCO·6H2O
(1.2equiv.)
CH3CN/H2O(1:1)
EtO
OEt +
R
O
+
O
CO2Et
R
Ph
R
70~80 °C
Ph
Ph
4
3
5
6
1.0 equiv.
1.2 equiv.
Entry
Substrate
R
Conv. of 3 (%)
Conv. of 4 (%)
Time (h)
Product
Yielda (%)
Ratiog (5:6)
1
2
3
4a
4b
4c
4d
4e
4f
4-NO2
3-NO2
2-NO2
4-CN
3-CN
2-CN
3-CF3
3,5-2CF3
2,4-2CF3
4-Cl
>90
>90
>90
>90
>90
<10
77
67
65
66
63
65
100
42
>90
>90
23
18
22
23
53
64
1
63
56
44
72
48
30
28
46
5a, 6a
5b, 6b
5c, 6c
5d, 6d
5e, 6e
5f, 6f
5g,6g
5h, 6h
5i, 6i
50b
51b
53b
42b
41b
0
31b
28c
29c
20b
23b
Trace
0
2.5:1
>20:1
>20:1
>20:1
>20:1
4
5
6f
7
4g
4h
4i
>20:1
>20:1
>20:1
>20:1
>20:1
8d
9e
10
11
12
13
14
a
74
73
4j
>90
>90
>90
<10
>90
5j, 5j
5k, 6k
4k
4l
4-I
H
OH
OCH3
26
>90
<10
<10
4m
4n
0
Combined yield of 5 and 6.
Isolated yields based on 4.
Isolated yields based on 3.
b
c
d
e
f
With 1.0 equiv of 3, 1.2 equiv of 4 and 1.0 equiv of DABCOÁ6H2O.
With 1.0 equiv of 3, 3.0 equiv of 4 and 1.0 equiv of DABCOÁ6H2O.
4f reacted with DABCOÁ6H2O to give unknown products in 1 h.
g
Determined by chemical shifts of two different olefinic protons according to 1H NMR.
O
NR3
O
O
a
path a
path b
EtO
EtO
OEt
O
O
O
OEt
Ph
7
EtO
OEt
NR3
O
EtO
b
Ph
NR3
NR3
O
Ph
3
9
OEt
(NR3 = DABCO·6H2O)
NR3
Ph
8
O
O
O
O
O
O
EtO
OEt
Ar
EtO
OEt
EtO
OEt
Ar
ArCHO
H2O
-H2O
Ar
HO
NR3
O
NR3
OH
12
NR3
Ph
Ph
Ph
OH
11
10
Ο
Ο
OH
OH
OEt
EtO
OEt
-NR3
EtO
-EtOH
Products
Ar
Ar
Ο
Ο
Ph
Ph
14
13
Scheme 3. Proposed mechanism of the tandem domino reactions of 3 and aldehydes mediated by DABCOÁ6H2O.

D. Du, Z. Wang / Tetrahedron Letters 49 (2008) 956–959
959
M.; Yoon, S. K.; Hong, Y. T.; Kim, J. Chem. Commun. 2004, 1840; (c)
Tsuritani, T.; Shinokubo, H.; Oshima, K. Synlett 2002, 6, 978.
6. VCP 3 was prepared as a mixture of two diastereomers (anti/
syn = 8.3:1) and used in the reactions without further separation:
Davies, H. M. L.; Clark, T. J.; Church, L. A. Tetrahedron Lett. 1989,
30, 5057.
Acknowledgements
We thank the National Natural Science Foundation of
China (Nos. 20572045, 20542003 and 20421202), the ‘111
Project’ (B06005), the Ministry of Education of China
and Nankai University for financial support.
7. Budynina, E. M.; Ivanova, O. A.; Averina, E. B.; Kuznetsova, T. S.;
Zefirov, N. S. Tetrahedron Lett. 2006, 47, 647.
8. Physical data for compound 5a: 1H NMR: d 1.32 (t, J = 7.2 Hz, 3H);
3.04–3.12 (m, 1H); 3.54–3.60 (m, 1H); 4.31 (q, J = 7.2 Hz, 2H); 5.61
(t, 1H); 6.67 (s, 1H); 7.32–7.40 (m, 5H); 7.53 (d, 2H); 7.71 (s, 1H); 8.19
(t, 2H). 13C NMR: d 14.16, 37.65, 61.69, 78.22, 123.63, 125.39, 128.68,
128.85, 129.64, 130.48, 131.42, 137.96, 139.50, 141.13, 147.65, 165.74,
168.38. HRMS (ProMALDI) calcd for C22H19NO6Na (M+Na)+:
416.1105, found 416.1100. IR (film): m 3067, 3035, 2963, 2853, 1755,
1714, 1593, 1520, 1344, 1261, 1094, 1021, 800, 700 cmÀ1. Physical data
for compound 6a: 1H NMR: d 1.34 (t, J = 7.2 Hz, 3 H); 2.42–2.48 (m,
1 H); 3.02–3.08 (m, 1H); 4.32 (q, J = 7.2 Hz, 2H); 5.47 (t, 1H); 7.17–
References and notes
1. For some reviews of tandem domino reactions, please see: (a) Tietze,
L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131; (b)
Tieze, L. F. Chem. Rev. 1996, 96, 115; (c) Parsons, P. J.; Penkett, C.
S.; Shell, A. J. Chem. Rev. 1996, 96, 195; (d) Bunce, R. A. Tetrahedron
1995, 51, 13103; (e) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem., Int. Ed. 2006, 45, 7134; (f) Pellissier, H. Tetrahedron
2006, 62, 1619; (g) Pellissier, H. Tetrahedron 2006, 62, 2143.
7.33 (m, 5H); 7.44 (s, 1H); 7.54 (d, 2H); 7.80 (s, 1H); 8.18 (d, 2H). 13
C
2. 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)
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Rev. 2003, 103, 2597; (g) Paquette, L. A. Chem. Rev. 1986, 86, 733.
3. Tandem nucleophilic ring opening of cyclopropanes for new carbon–
carbon bond formation: (a) References cited in 2, and some selected
recent examples: (b) Shi, M.; Yang, Y. H.; Xu, B. Tetrahedron 2005,
61, 1893; (c) Timmons, C.; Chen, D.; Cannon, J. F.; Headley, A. D.;
Li, G. Org. Lett. 2004, 06, 2075; (d) Bertozzi, F.; Gundersen, B. V.;
Gustafsson, M.; Olsson, R. Org. Lett. 2003, 05, 1551; (e) Yang, Y. H.;
Shi, M. J. Org. Chem. 2005, 70, 10082; (f) Han, Z.; Uehira, S.;
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M. D.; Tirado, L.; Zhang, J.; Dike, N.; Herndon, J. W. J. Organomet.
Chem. 2005, 690, 5759; (c) Moreau, P.; Maffei, M. Tetrahedron Lett.
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1569; (e) Sebelius, S.; Olsson, V. J.; Szabo, K. J. J. Am. Chem. Soc.
2005, 127, 10478; (f) Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabo,
K. J. J. Am. Chem. Soc. 2006, 128, 8150.
NMR: d 14.19, 35.93, 62.03, 78.05, 123.96, 125.15, 128.62, 128.78,
129.63, 130.41, 130.67, 130.83, 139.58, 140.56, 147.93, 165.16, 170.22.
HRMS (MALDI) calcd for C22H19NO6Na (M+Na)+: 416.1105,
found 416.1105. IR (KBr): m 3061, 3039, 2986, 2964, 2900, 2854, 1753,
1713, 1669, 1625, 1598, 1523, 1346, 1255, 1203, 1023, 855 cmÀ1
.
9. Various solvents such as DME, DMF, THF, EtOH, dioxane and
CH3CN were employed. Yields were low to moderate and the
recovery of 4a was always observed. Stereoselectivity of the product
was not significantly affected by solvents.
10. The crystallographic data (excluding structure factors) of 6a and 5h
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 655766 and 655765,
respectively. 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).
11. When 3 and 4a reacted in the same solvent system at room
temperature for one week, both of the two reactants were consumed
and there was a fluorescent compound detected by TLC. After being
heated for 6–8 h, the fluorescent compound disappeared and the final
products were produced. This fluorescent compound was a high polar
solid and had a good solubility in water. A try to separate and
characterize this compound failed due to its unstability. We assumed
this as an intermediate—a tertiary ammonium salt (or base) formed
after the ring opening of cyclopropane by DABCOÁ6H2O.
5. Metal-promoted tandem nucleophilic ring opening of VCPs for new
carbon–carbon bond formation: (a) Chiusoli, G. P.; Costa, M.;
Pallini, L.; Terenghi, G. Trans. Met. Chem. 1982, 07, 304; (b) Yu, C.