Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives with diethyl 2-oxomalonate and ethyl 2-oxoacetate

Article abstract of DOI:10.1016/j.tet.2009.09.003

TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with diethyl 2-oxomalonate 2 afford a novel method for the synthesis of spiro-γ-lactone derivatives 3 in good to excellent yields via a sequential reaction involving a nucleophilic rin

Full text of DOI:10.1016/j.tet.2009.09.003

Tetrahedron 65 (2009) 9336–9343
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Tetrahedron
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Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives
with diethyl 2-oxomalonate and ethyl 2-oxoacetate
*
Xiang-Ying Tang, Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2009
Received in revised form 1 September 2009
Accepted 1 September 2009
Available online 4 September 2009
TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with diethyl 2-oxomalonate 2
afford a novel method for the synthesis of spiro-g-lactone derivatives 3 in good to excellent yields via
a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H2O, an
aldol-type reaction and a cyclic transesterification mediated by Lewis acid. On the other hand, we found
that TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones 1 with ethyl 2-oxoacetate 4 could also
provide the corresponding spiro-g-lactone derivatives 5 in moderate yields along with another spiro-g-
Keywords:
Lewis acid
1-Cyclopropyl-2-arylethanones
Diethyl 2-oxomalonate
Ethyl 2-oxoacetate
lactone derivatives 6 derived from the reaction of 1 with two molecules of ethyl 2-oxoacetate. The
plausible reaction mechanisms have also been provided on the basis of control experiments.
Ó 2009 Elsevier Ltd. All rights reserved.
1,6-Dioxa-spiro[4.4]non-3-en-2-ones
1. Introduction
explanations on the basis of previous literature and control
experiments.
Cyclopropane containing compounds, as versatile building
blocks in organic synthesis, have been well understood.1 The ring-
opening reactions of cyclopropyl ketones are synthetically useful
protocols in the construction of complex product structures that
have been studied extensively thus far.2 Previously, we reported
Lewis acids SnCl4 and TMSOTf-mediated reactions of cyclopropyl
2. Results and discussion
As shown in our previous communication,3a,d a plausible
mechanism for the formation of 1,6-dioxa-spiro[4.4]non-3-en-2-
one derivatives has been proposed on the basis of a ring-opening
reaction of 1-cyclopropyl alkyl ketone, intramolecular aldol-type
reaction as well as cyclic transesterification.3a,d However, this re-
action suffers from a drawback on the substrate scope, that is, the
substrates should contain a substitute on the cyclopropyl ring to
alkyl ketones with a-ketoesters and cyclopropyl aryl ketones with
allenic esters to afford novel methods for the synthesis of 1,6-dioxa-
spiro[4.4]non-3-en-2-ones with high stereoselectivities as well as
dihydrofuro[2,3-h]chromen-2-one and 2,3-dihydrobenzofuran-4-ol
derivatives in moderate to good yields under mild conditions
control the reaction pathway, affording the corresponding spiro-g-
(Scheme 1).3 It is well known that spiro-
g-lactones constitute an
lactone in highyield (Scheme 1). To extend the scope and limitations
of this reaction, we envisaged that if using diethyl 2-oxomalonate 2
(1.0 equiv), in which the carbonyl group is activated by two carboxyl
groups, as the substrate to react with 1-cyclopropyl-2-phenyl-
ethanone 1a (1.0 equiv) in the presence of TMSOTf (1.0 equiv), the
important class of oxygen-containing heterocyclic compounds and
such groups can be found in many biologically active natural
products (Fig. 1).4 Therefore, it is necessary to further explore such
synthetic method for the construction of biologically important
spiro-g-lactone derivatives from simple or commercially available
corresponding spiro-g-lactone derivative 3a could be also formed
starting materials. In this paper, we wish to report the full details on
the Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone
derivatives with diethyl 2-oxomalonate and ethyl 2-oxoacetate for
the construction of functionalized 1,6-dioxa-spiro[4.4]non-3-en-2-
one skeletons under mild conditions along with the mechanistic
under the standard conditions. To our delight, it was found that the
corresponding 1,6-dioxa-spiro[4.4]non-3-en-2-one derivative 3a
was obtained as a sole product in good yield (81%) within 12 h in 1,2-
dichloroethane (DCE) at 60 ꢀC (Table 1, entry 1). Inspirited by this
result, we next started to optimize the reaction conditions by
changing Lewis acids and the ratio of the substrates and employed
Lewis acid (1a/2a/Lewis acid). The results of these experiments are
summarized in Table 1. SnCl4 was first examined because it per-
formed very well in our previous work.3a However, we found that
* Corresponding author. Fax: þ86 21 64166128.
E-mail address: mshi@mail.sioc.ac.cn (M. Shi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.003

X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
9337
R1
R2
O
R3
O
O
OR4
SnCl4
R3
+
R1
DCE
O
O
O
R2
R1, R2 = aromatic, aliphatic group or H;
R3 = aromatic, aliphatic group or C(O)OEt
1,6-dioxa-spiro[4.4]non-3-en-2-ones
R
4 = methyl, ethyl or H.
O
OH
R
OEt
TMSOTf
DCE, 60 °C, 15 h
+
R
+
R
O
O
O
O
1.0 equiv
1.0 equiv
O
minor
major
dihydrofuro[2,3-h]chromen-2-one and 2,3-dihydrobenzofuran-4-ol derivatives
Scheme 1. SnCl4 and TMSOTf-mediated reactions of 1-cyclopropyl alkyl ketones with -ketoesters and cyclopropyl aryl ketones with allenic esters.
a
reaction very well, but affording 3a in 51% yield (Table 1, entry 9).
Thereby, TMSOTf was the best promoter among all these examined
Lewis and Brønsted acids. Further investigation by changing the
ratio of the starting materials and TMSOTf revealed that using
the ratio of 1a/2/TMSOTf as 1.5:1:1.5 afforded the corresponding 3a
in 97% yield under otherwise identical conditions (Table 1, entries
10–12).
O
H
O
O
O
O
O
H3C
CH3
O
OH
HO
H
Massarinoline A
(+)-Pyrenolide D
Next, we attempted to study the solvent effect in this reaction. In
the presence of TMSOTf, the reactions were conducted in various
solvents at 60 ꢀC for 12 h. The results of these investigations are
outlined in Table 2. Toluene and dichloromethane (DCM) benefited
this reaction quite well, producing 3a in 96% and 88% yields, re-
spectively (Table 2, entries 1 and 2). Using CH3CN and tetrahydro-
furan (THF) as the solvents produced 3a in 38% and 10% yields,
respectively, presumably due to that a nitrogen atom or an oxygen
atom could weakly coordinate with the Lewis acid to deactivate its
catalytic ability (Table 2, entries 3 and 4). However, other solvents
such as dimethyl sulfoxide (DMSO) and N,N-dimethylformamide
(DMF) gave complex product mixtures rather than the clean for-
mation of 3a (Table 2, entries 5 and 6).
Figure 1. Important compounds bearing a spiro- -lactone moiety.
g
Table 1
Reactions of 1-cyclopropyl-2-phenylethanone (1a) and diethy1 2-oxomalonate (2)
mediated by various Lewis acids
EtO2C
O
O
EtO
O
Lewis acid
O
O
Ph
Ph
+
60 °C, DCE
12 h
O
O
OEt
1a
3a
2
Entry
1a/2/Lewis acid
Lewis acid
Yielda (%)
3a
Table 2
1
2
3
4
5
6
7
8
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
TMSOTf
SnCl4
TiCl4
81
Solvent effects in the reaction of 1-cyclopropyl-2-phenylethanone (1a) with diethyl
2-oxomalonate (2) mediated by TMSOTf
db
Complexc
47
72
7
O
Bi(OTf)2Cl
InCl3$4H2O
BF3$Et2O
Nd(OTf)3
Sc(OTf)3
HOTf
TMSOTf
TMSOTf
TMSOTF
EtO
Ph
O
O
EtO
O
TMSOTf
60 °C, Solvent
12 h
+
O
Ph
O
35
39
51
O
O
OEt
9
1a
2
3a
10
11
12
1:1.5:1
1:3:1
1.5:1:1.5
81/(74)d
82
Entry
1a/2/TMSOTf
Solvent
Yielda (%)
97
3a
a
Isolated yields.
A product mixture was obtained.
The reaction became disordered and 3a was not formed.
TMSOTf (0.5 equiv) was used.
b
c
1
2
3
4
5
6
1.5:1:1.5
1.5:1:1.5
1.5:1:1.5
1.5:1:1.5
1.5:1:1.5
1.5:1:1.5
PhCH3
DCM
CH3CN
THF
DMSO
DMF
96
88
38
10
d
Complexb
Complexb
using SnCl4 (1a/2a/SnCl4¼1:1:1) as the Lewis acid in this reaction
afforded a complex product mixtures on the basis of 1H NMR
spectroscopic data (Table 1, entry 2). Using TiCl4 as the promoter
provided the similar result without the formation of 3a (Table 1,
entry 3). When other Lewis acids such as Bi(OTf)2Cl, InCl3$4H2O,
BF3$Et2O, Nd(OTf)3 and Sc(OTf)3 were used as the promoters under
the standard conditions, the reactions proceeded smoothly to give
3a in 7–72% yields (Table 1, entries 4–8). Brønsted acid tri-
fluoromethanesulfonic acid CF3SO3H (TfOH) could also promote this
a
Isolated yields.
b
The reaction became disordered and 3a was not formed.
With these optimized reaction conditions in hand, we next
turned our interest to examine the reaction generality by using
a variety of 1-cyclopropyl-2-arylethanones 1 under these optimal
conditions. The results are shown in Table 3. As for 1-cyclopropyl-

9338
X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
Table 3
Table 4
Reactions of Various cyclopropyl benzyl ketones (1) with diethyl 2-oxomalonate (2)
Reactions of 1-cyclopropyl-2-phenylethanone (1a) and diethyl 2-oxomalonate (4)
mediated by TMSOTf
mediated by various Lewis acids
O
O
O
H
H
EtO
O
O
O
O
O
H
Lewis acid
60 °C, DCE
12 h
EtO
O
TMSOTf (1.5 equiv)
60 C, Solvent
12 h
+
OEt
Ph
Ph
+
Ph
Ar
O
Ar
O
+
O
O
°
O
O
OEt
O
O
O
OEt
1a
6a
5a
4
1 (1.5 equiv)
2 (1.0 equiv)
3
Entry
1a/4/Lewis acid
Lewis acid
Yielda (%)
Entry
Ar
Yielda (%)
5a
6a
3
1
2
3
4
5
6
7
8
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:2:1
TMSOTf
HOTf
Bi(OTf)2Cl
SnCl4
63
48
11
16
13
1
2
3
4
5
6
7
8
1b, p-ClC6H4
3b, 97
3c, 99
3d, 96
3e, 97
3f, 82
3g, 99
3h, 96
3i, 66
1c, p-BrC6H4
1d, p-FC6H4
1e, m-FC6H4
1f, o-BrC6H4
1g, m-MeC6H4
1h, p-MeC6H4
1i, o-MeC6H4
38
db
TiCl4
Complexc
22
InCl3$4H2O
Ni(OAc)2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
TMSOTf
6
Complexc
Complexc
26
9
10
11
8
Complexc
68
a
Isolated yields.
14
a
Isolated yields.
A product mixture was obtained.
The reaction became disordered and 3a was not formed.
b
c
2-arylethanones 1b–e and 1g,h having electron-withdrawing or
electron-donating group on the benzene rings at the para- or
meta-position, the corresponding 1,6-dioxa-spiro[4.4]non-3-en-2-
one derivatives 3b–e and 3g,h were obtained in excellent yields
(Table 3, entries 1–4 and 6,7). For 1-cyclopropyl-2-arylethanones
1f and 1i bearing an electron-withdrawing Br atom or a moder-
ately electron-donating methyl group on the benzene rings at the
ortho-position, the corresponding 1,6-dioxa-spiro[4.4]non-3-en-2-
one derivatives 3f and 3i were obtained in 82% and 66% yields,
respectively (Table 3, entries 5 and 8). The yields of 3f and 3i are
slightly lower than those of 3b–e and 3g,h perhaps due to the
steric effect of the ortho-substituted groups of the starting mate-
rials 1f and 1i.
2-oxoacetate 4 and the results of these experiments are outlined in
Table 5. As can be seen from Table 5, for 1-cyclopropyl-2-aryle-
thanones 1b–d having substituents (Cl, Br and F atoms) on the
benzene rings at the para-position, the corresponding 1,6-dioxa-
spiro[4.4]non-3-en-2-one derivatives 5b–d were obtained as the
major products in moderate yields together with the minor prod-
ucts 6b–d in 20–28% yields (Table 5, entries 1–3). When the sub-
strates 1e and 1j bearing substituents (F atom or CF3 group) on the
benzene rings at the meta-position, the yields of the major spiro-
lactone products 5e and 5h were 59% and 50% along with 30% and
15% yields of the minor spiro- -lactone products 6e and 6h, re-
g-
g
Moreover, we also attempted to explore the Lewis acid-medi-
ated reactions of 1-cyclopropyl-2-arylethanones 1 with ethyl 2-
oxoacetate 4 since we envisioned that a similar reaction pathway
might be able to take place smoothly to give the corresponding
spectively (Table 5, entries 4 and 7). As for 1-cyclopropyl-2-aryle-
thanones 1f, 1i and 1k having ortho-substituted groups on the
benzene rings, the formation of spiro-
5i was significantly affected, leading to the spiro-
and 5i in 29–47% yields, while the spiro- -lactone products 6f, 6g
g-lactone products 5f, 5g and
g-lactones 5f, 5g
spiro-g-lactone derivative in good yield as well. Under the standard
g
reaction conditions established above, we investigated the reaction
of 1-cyclopropyl-2-phenylethanone 1a with ethyl 2-oxoacetate 4 in
DCE at 60 ꢀC in the presence of TMSOTf and found that the desired
and 6i were obtained in relatively higher yields (Table 5, entries 5, 6
and 8). Such reaction outcomes suggest that the sterically hindered
1-cyclopropyl-2-arylethanone can change the reaction pathway
and subsequently affect the product distribution.
spiro-g-lactone product 5a was indeed provided in 63% yield, but
interestingly along with another new product 6a in 11% yield,
which was assigned by the spectroscopic and analytic data (Table 4,
entry 1). Therefore, our next purpose was to optimize the reaction
conditions to produce both of the products 5a and 6a in higher
yields similarly by changing the Lewis or Brønsted acids as well as
the ratio of the starting materials and Lewis acid. The results of
these experiments are summarized in Table 4. Brønsted acid TfOH
could also promote this reaction smoothly as anticipated to give 5a
and 6a in 64% total yield (Table 4, entry 2). When Lewis acids
Bi(OTf)2Cl, InCl3$4H2O and Sc(OTf)3 were used in this reaction, the
corresponding products 5a and 6a were gained in 22–38% yields
and 6–13% yields, respectively (Table 4, entries 3, 6 and 9). Using
SnCl4 as the promoter afforded a complex product mixture on the
basis of the 1H NMR spectrum (Table 4, entry 4). Other Lewis acids
such as TiCl4, Ni(OAc)2 and Yb(OTf)3 were not suitable in this re-
action, leading to disordered reaction mixtures (Table 4, entries 5, 7,
8 and 10). Finally, we found that increasing the amount of ethyl 2-
oxoacetate 4 to 2 equiv afforded the corresponding products 5a and
6a in 68% and 14% yields, respectively (82% total yield) (Table 4,
entry 11).
In our previous work, a presumed reaction mechanism in the
reaction of cyclopropyl hexyl ketone with
a-ketoester has been
proposed.3a,d We considered that the reaction pathway is mainly
controlled by the steric effect. As shown in Scheme 2 using cyclo-
propyl hexyl ketone as the model (R1¼C5H11, path a), intermediate
A is first formed from the ring-opening reaction of cyclopropyl
hexyl ketone (R2¼H) with ambient H2O in the presence of Lewis
acid.3a,b Then, intermediate B3a is formed as a mixture of E- and
Z-isomers from the aldol condensation of intermediate A with
a
-ketoester at the C-3 position. Thus, product C3a can be formed
after an intramolecular transesterification process via intermediate
E-B.5 The highly conjugated product E-E3a can be formed by de-
hydration of intermediate D,3a which itself can be derived from
a Bradsher type cyclization reaction (or a Friedel–Crafts reaction) of
C.3a,5 On the other hand, product Z-E3a can be formed from Z-B3a via
dehydration of intermediate D0,3a which itself can be produced via
an intramolecular cyclization of intermediate C03a derived from
hydrolysis of Z-B.3a Alternatively, if the aldol-type reaction takes
place at the C-5 position in g-hydroxyketone A (path b), another
intermediate, F,3a would be formed along with regeneration of an
equivalent of H2O, which can react with 1 to initiate the next re-
action cycle. Intramolecular nucleophilic attack by the terminal
Under these optimal conditions, we next examined the re-
actions of many other 1-cyclopropyl-2-arylethanones 1 with ethyl

X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
9339
Table 5
Reactions of various cyclopropyl benzyl ketone (1) and diethyl 2-oxomalonate (2) mediated by TMSOTf
O
O
O
O
H
H
Ar
O
TMSOTf (1.0 equiv)
60 °C, DCE
12 h
H
OEt
Ar
+
Ar
+
O
O
O
O
1
OEt
O
6
4
5
Entry
Ar
Yielda (%)
5
6
1
2
3
4
5
6
7
8
1b, p-ClC6H4
1c, p-BrC6H4
1d, p-FC6H4
1e, m-FC6H4
1f, o-BrC6H4
1i, o-MeC6H4
1j, m-CF3C6H4
1k, o-ClC6H4
5b, 60
5c, 61
5d, 72
5e, 59
5f, 36
5g, 47
5h, 50
5i, 29
6b, 24
6c, 28
6d, 20
6e, 30
6f, 32
6g, 36
6h, 15
6i, 40
a
Isolated yields.
phenylethanone (R2 is not a hydrogen atom, R2sH), is treated with
diethyl 2-oxomalonate and ethyl 2-oxoacetate, the spiro- -lactone
O
OH
C5H11
C5H11
OH
g
O
HO
OH
product 3 or 5 can also be formed through the same reaction route
via intermediates A0, F0 and G0 shown in Scheme 3 (intermediates A,
F and G in Scheme 2). Besides the normal product 5, the reaction of
1a with ethyl 2-oxoacetate leads to a new product 6. The reaction
pathway has been shown in Scheme 3. The intermediate F00, derived
from an aldol reaction of F0 and another molecule of diethyl 2-
oxomalonate, is first formed. Intramolecular nucleophilic attack by
the terminal hydroxyl group at the ketone group affords the cor-
responding cyclic intermediate G00, which produces the product 6
via an intramolecular transesterification (Scheme 3).
C6H5
O
C'
O
C6H5
D'
R4OH
C5H11
-H2O
H2O
C5H11
O
O
OH
C6H5
O
O
OH
C6H5
MeO
R2 = H
O
Z-E
OMe
Z-B
C6H5
O
O
+
3
OH
C5H11
O
5
Path a
R2
C5H11
C6H5
E-B
OH
OMe
A
H2O
R2
LA
O
LA
O
O
R2
3
Path b
OH
C6H5
O
R2 = H
R1 = C6H5
R1
O
R2 = Ar or Me
R1
5
R1 = C5H11
H2O
A'
O
1a
OMe
Cyclopropyl Hexyl
Ketone
C6H5
MeOH
O
H2O
OR4
C5H11
HO
R3
H2O
C6H5
MeO
O
O
C5H11
C5H11
O
C6H5
O
O
O O
F
C6H5
HO
R3
R3
R4O
R3 = H
R4 = Et
C6H5
R2
HO
O
O
R4O
C
R2
H
O
O O
F'
O O
F"
O
OR4
R3
MeOH
C5H11
OR4
O
C6H5
MeO
C5H11
O
OH
C5H11
R3 = CO2Et or H
R4 = Et
HO
O
O
R2
-H2O
O
G
D
O
R3
R3
C6H5
O
C6H5
O
O
E
E-
R4O
R4O
HO
HO
Scheme 2. Proposed mechanism for the reaction of cyclopropyl hexyl ketone with
O
O
a
-ketoester.
G"
G'
OR4
O
hydroxyl group at the ketone group can take place, leading to the
corresponding cyclic intermediate G3a containing a hemiacetal
hydroxyl group. From intermediate G, the corresponding product H
can be formed via an intramolecular transesterification. If R2sH,
R4OH
R3
R4OH
R3
C6H5
O
C6H5
O
the aldol condensation of intermediate A with
a-ketoester at the C-
O
O
O
O
3 position is blocked out due to the steric effect and therefore, path
O
a is shut down and the corresponding spiro-
be obtained exclusively.
g-lactone product can
OR4
3 or 5
6
When 1-cyclopropyl-2-phenylethanone 1a (R2¼H), which is
Scheme 3. Proposed mechanism for the reaction of cyclopropyl keto 1a with diethyl 2-
oxomalonate and ethyl 2-oxoacetate.
a more common substrate than the substituted 1-cyclopropyl-2-

9340
X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
Now we can explain the steric and electronic effects of this
3. Experimental section
3.1. General remarks
reaction. When R1 is an alkyl group and R3 is an aryl or alkyl
group, the reaction pathway is not exclusive because the reaction
can take place at both of the C-3 and C-5 position in intermediate
A or A0 to give the corresponding product mixtures. Only if the C-3
position is blocked by an aryl or alkyl group (R2sH), the aldol
reaction can take place exclusively at the C-5 position and there-
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively. Mass and HRMS spectra
were recorded by EI methods. Organic solvents used were dried by
standard methods when necessary. Satisfactory CHN microanalyses
were obtained with an analyzer. Commercially obtained reagents
were used without further purification. All reactions were moni-
tored by TLC with silica gel coated plates. Flash column chroma-
tography was carried out using silica gel at increased pressure.
fore, the spiro-g
-lactone is the major product. When R1 is an aryl
group, the situation is quite complicated. Since in this case, the C-5
position is much more reactive to undergo the aldol reaction than
that of the C-3 position,3b,6 the condensation of 1-cyclopropyl-2-
arylethanone with diethyl 2-oxomalonate in which the carbonyl
group is activated by two carboxyl groups exclusively takes place
at the C-5 position to give the corresponding spiro-
g
-lactone
3.2. General procedure for the reaction of 1-cyclopropyl-2-
arylethanones with diethyl 2-oxomalonate
product in higher yield. Moreover, the steric effect cannot be
completely ignored in this case. If R3 is an aryl group, the aldol
reaction at the C-5 position becomes difficult and a product
mixtures can be obtained through path a and path b at the same
time.7 If R3 is a hydrogen atom, the aldol reaction of intermediate
F0 with another molecule of ethyl 2-oxoacetate can easily take
place to generate product 6.
1-Cyclopropyl-2-arylethanones 1 (0.3 mmol), ethyl buta-2,3-
dienoate (0.2 mmol), TMSOTf (0.3 mmol) and DCE (3.0 mL) were
added into a Schlenk tube. The reaction mixture was stirred at 60 ꢀC
for 12 h. The solvent was removed under reduced pressure and
then the residue was purified by a flash column chromatography.
Two control experiments were conducted by treatment of 2-
phenyl-1-(1-phenylcyclopropyl)ethanone 1l with diethyl 2-oxo-
malonate and ethyl 2-oxoacetate under the standard conditions,
3.3. General procedure for the reaction of 1-cyclopropyl-2-
arylethanones with ethyl 2-oxoacetate
the corresponding spiro-g-lactones 5j and 5k were obtained as the
sole products in 99% and 78% yields, respectively (Scheme 4). The
phenyl group at the C-3 position blocked out the aldol reaction of
intermediate F0 with another molecule of ethyl 2-oxoacetate,
1-Cyclopropyl-2-phenylethanones 1 (0.3 mmol), ethyl 2-oxoa-
cetate (0.6 mmol), TMSOTf (0.3 mmol) and DCE (3.0 mL) were
added into a Schlenk tube. The reaction mixture was stirred at 60 ꢀC
for 12 h. The solvent was removed under reduced pressure and
then the residue was purified by a flash column chromatography.
affording the spiro-
g-lactone 5k exclusively.
3.3.1. Compound 3a. A white solid. Mp 193–195 ꢀC. 1H NMR (CDCl3,
C6H5
O
C6H5
O
EtO2C
O
O
300 MHz, TMS)
d
1.21 (t, J¼7.2 Hz, 3H, CH3), 1.97–2.09 (m, 2H),
TMSOTf (1.0 equiv)
DCE, 60 °C
EtO
OEt
+
2.20–2.39 (m, 2H), 4.12–4.20 (m, 1H), 4.26 (q, J¼7.2 Hz, 2H, CH2),
4.33–4.38 (m, 1H), 7.42–7.52 (m, 3H, Ar), 7.57 (d, J¼7.5 Hz, 2H, Ar);
C6H5
1l
O
O
O
13C NMR (CDCl3, 75 MHz, TMS)
d 13.7, 24.3, 35.3, 61.7, 71.1, 113.7,
(1.5 equiv)
2 (1.0 equiv)
C6H5
5j, 99% yield
122.6, 128.1, 128.5, 129.1, 130.9, 161.4, 163.1, 165.5; IR (CH2Cl2):
n
3064, 2981, 2967, 2897, 1778, 1716, 1648, 1465, 1442, 1378,
1323 cmꢁ1; MS (EI) m/z (%): 288 [Mþ] (16.8), 202 (45.5), 174 (66.8),
171 (15.3), 130 (30.9), 129 (83.1), 103 (14.1), 102 (100). Anal. Calcd
for C16H16O5: C, 66.66%; H, 5.59%. Found: C, 66.60%; H, 5.73%.
C6H5
O
C6H5
O
H
O
TMSOTf (1.0 equiv)
DCE, 60 °C
OEt
+
H
C6H5
O
O
O
1l
(1.0 equiv)
C6H5
5k, 78% yield
4 (2.0 equiv)
3.3.2. Compound 3b. A yellow solid. Mp 76–78 ꢀC. 1H NMR (CDCl3,
300 MHz, TMS)
d
1.24 (t, J¼7.2 Hz, 3H, CH3), 1.92–2.08 (m, 2H),
Scheme 4. Two control experiments.
2.20–2.41 (m, 2H), 4.11–4.18 (m, 1H), 4.30 (q, J¼7.2 Hz, 2H, CH2),
4.33–4.39 (m, 1H), 7.43 (d, J¼8.7 Hz, 2H, Ar), 7.54 (d, J¼8.7 Hz, 2H,
Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.7, 24.2, 35.3, 61.8, 71.1,
In conclusion, we have further explored a reaction process in-
volving a sequential ring-opening reaction of cyclopropyl alkyl
ketones by H2O, followed by one intermolecular aldol-type re-
action and a cyclic transesterification in the reaction of 1-cyclo-
propyl-2-arylethanone derivatives with diethyl 2-oxomalonate
and ethyl 2-oxoacetate mediated by Lewis acid, which affords an
efficient synthetic protocol for the preparation of functionalized
1,6-dioxa-spiro[4.4]non-3-en-2-one skeletons in good yields.
113.4, 122.9, 127.5, 128.8, 129.6, 137.1, 161.1, 162.0, 165.1; IR (CH2Cl2):
n
3061, 2986, 2964, 2897, 1788, 1715, 1647, 1592, 1489, 1443, 1377,
1321 cmꢁ1; MS (EI) m/z (%): 322 [Mþ] (12.7), 236 (17.8), 210 (22.0),
208 (63.1), 163 (55.4), 138 (33.3), 136 (100.0), 99 (17.2). Anal. Calcd
for C16H15ClO5: C, 59.54%; H, 4.68%. Found: C, 59.62%; H, 4.62%.
3.3.3. Compound 3c. A white solid. Mp 79–81 ꢀC. 1H NMR (CDCl3,
300 MHz, TMS)
d
1.24 (t, J¼7.2 Hz, 3H, CH3), 1.93–2.09 (m, 2H),
Moreover, two kinds of spiro-g-lactone products were obtained at
2.20–2.37 (m, 2H), 4.11–4.18 (m, 1H), 4.28 (q, J¼7.2 Hz, 2H, CH2),
4.32–4.39 (m, 1H), 7.47 (d, J¼8.4 Hz, 2H, Ar), 7.60 (d, J¼8.4 Hz, 2H,
the same time in the TMSOTf-mediated reactions of 1-cyclopropyl-
2-arylethanone derivatives with ethyl 2-oxoacetate. A detailed
overview on the whole reaction mechanism has been provided.
The reaction scope is also extended to 1-cyclopropyl-2-aryletha-
nones, which do not have a substituent at the C3-position. Thus,
many new functionalized spiro-g-lactone derivatives can be syn-
thesized easily. Further work directed at elucidation of the detailed
mechanisms of this process and the application of it to the syn-
Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.7, 24.3, 35.3, 61.8, 71.1,
113.4, 122.9, 125.6, 128.0, 129.8, 131.7, 161.1, 162.1, 165.1; IR (CH2Cl2):
n
3050, 2972, 2904, 1769, 1722, 1641, 1585, 1490, 1453, 1369,
1326 cmꢁ1; MS (EI) m/z (%): 366 [Mþ] (13.0), 254 (72.1), 252 (68.1),
207 (57.9), 182 (97.6), 180 (100.0), 147 (52.3), 120 (82.8). Anal. Calcd
for C16H15BrO5: C, 52.34%; H, 4.12%. Found: C, 52.60%; H, 4.02%.
thesis of spiro-
in progress.
g-lactone containing natural products are currently
3.3.4. Compound 3d. A yellow solid. Mp 78–80 ꢀC. 1H NMR (CDCl3,
300 MHz, TMS)
d
1.24 (t, J¼7.2 Hz, 3H, CH3),1.94–2.14 (m, 2H), 2.20–

X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
9341
2.38 (m, 2H), 4.17 (q, J¼7.8 Hz, 1H), 4.28 (q, J¼7.2 Hz, 2H), 4.33–4.40
(m, 1H), 7.15 (dd, J¼8.1, 9.0 Hz, 2H, Ar), 7.62 (dd, J¼6.6, 9.0 Hz, 2H,
188 (52.2), 143 (39.8), 117 (12.9), 116 (100.0), 115 (20.9); HRMS (EI)
calcd for C17H18O5 (Mþ) requires 302.1154, found: 302.1155.
Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d 13.8, 24.3, 35.4, 61.9, 71.1,
113.5, 115.8 (d, JC–F¼21.7 Hz), 122.7, 125.2 (d, JC–F¼3.6 Hz), 130.7 (d,
3.3.10. Compound 5a. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
JC–F¼8.6 Hz), 161.4, 162.1, 164.1 (d, JC–F¼251.7 Hz), 165.3; IR
d
2.16–2.28 (m, 3H), 2.33–2.44 (m, 1H), 4.27–4.43 (m, 2H), 6.35 (s,
1H, CH), 7.42–7.49 (m, 3H, Ar), 7.62–7.65 (m, 2H, Ar); 13C NMR
(CDCl3, 75 MHz, TMS) 24.2, 35.8, 70.6, 114.8, 117.2, 127.7, 129.0,
129.5, 131.1, 162.1, 169.4; IR (CH2Cl2): 2981, 2900, 1765, 1718, 1621,
(CH2Cl2):
n 3110, 2983, 2961, 2895, 1775, 1715, 1650, 1598, 1509,
1468, 1377, 1229 cmꢁ1; MS (EI) m/z (%): 306 [Mþ] (9.4), 220 (22.8),
192 (43.6), 189 (10.4), 148 (18.0), 147 (66.2), 120 (100.0), 69 (12.6).
Anal. Calcd for C16H15FO5: C, 62.74%; H, 4.94%. Found: C, 62.85%; H,
4.90%.
d
n
1574, 1495, 1448, 1376, 1296, 1209, 1178 cmꢁ1; MS (EI) m/z (%): 216
[Mþ] (13.5), 171 (9.0), 160 (7.0), 130 (15.7), 129 (5.8), 103 (12.6), 102
(100.0), 76 (8.0); HRMS (EI) calcd for C13H12O3 (Mþ) requires
216.0786, found: 216.0793.
3.3.5. Compound 3e. A yellow solid. Mp 113–115 ꢀC. 1H NMR
(CDCl3, 300 MHz, TMS)
d
1.23 (t, J¼7.2 Hz, 3H, CH3), 1.99–2.15 (m,
2H), 2.22–2.38 (m, 2H), 4.12–4.20 (m, 1H), 4.28 (q, J¼7.2 Hz, 2H),
3.3.11. Compound 6a. A yellow solid. Mp 75–77 ꢀC. 1H NMR (CDCl3,
4.33–4.40 (m, 1H), 7.18–7.24 (m, 1H, Ar), 7.30–7.37 (m, 2H, Ar), 7.41–
300 MHz, TMS)
d
1.25 (t, J¼7.2 Hz, 3H, CH3), 3.26–3.39 (m, 1H),
7.48 (m, 1H, Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d
13.7, 24.3, 35.3,
3.46–3.54 (m, 1H), 4.06–4.24 (m, 2H), 4.34–4.43 (m, 1H), 4.53–4.59
61.9, 71.2, 113.5, 115.3 (d, JC–F¼23.4 Hz), 117.9 (d, JC–F¼21.3 Hz),
(m, 1H), 5.75 (t, J¼2.7 Hz, 1H, CH), 6.56 (s, 1H, CH), 7.39–7.47 (m, 3H,
123.5, 124.2 (d, JC–F¼2.8 Hz), 130.3 (d, JC–F¼8.4 Hz), 131.0 (d, JC–F
9.0 Hz), 161.1, 161.6, 162.3 (d, JC–F¼246.2 Hz), 165.1; IR (CH2Cl2):
¼
Ar), 7.50–7.53 (m, 2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.1,
n
30.7, 60.7, 69.2, 112.8, 115.9, 117.6, 128.0, 128.6, 129.0, 131.6, 156.1,
3070, 2989, 2905, 1782, 1717, 1610, 1582, 1487, 1442, 1378, 1348,
1269 cmꢁ1; MS (EI) m/z (%): 306 [Mþ] (16.8), 241 (23.7), 220 (32.6),
192 (43.7), 148 (29.9), 147 (89.7), 120 (100.0), 99 (17.4). Anal. Calcd
for C16H15FO5: C, 62.74%; H, 4.94%. Found: C, 62.73%; H, 4.73%.
160.4, 165.6, 168.7; IR (CH2Cl2): n 2982, 2906, 1769, 1716, 1677, 1622,
1575, 1495, 1449, 1375, 1331, 1290 cmꢁ1; MS (EI) m/z (%): 300 [Mþ]
(9.4), 176 (74.8), 148 (31.1), 147 (41.0), 131 (61.4), 102 (43.4), 91
(41.2), 69 (100.0); HRMS (EI) calcd for C17H16O5 (Mþ) requires
300.0998, found: 300.0996.
3.3.6. Compound 3f. A yellow solid. Mp 72–74 ꢀC. 1H NMR (CDCl3,
300 MHz, TMS)
d
1.07 (t, J¼7.2 Hz, 3H, CH3), 1.94–2.09 (m, 2H),
3.3.12. Compound 5b. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
2.23–2.37 (m, 2H), 3.86–3.93 (m, 1H), 4.09–4.26 (m, 2H), 4.30–4.33
(m, 1H), 7.30–7.34 (m, 1H, Ar), 7.40–7.42 (m, 2H, Ar), 7.67 (d,
d
2.16–2.32 (m, 3H), 2.35–2.45 (m,1H), 4.26–4.33 (m,1H), 4.36–4.43
(m, 1H), 6.34 (s, 1H, CH), 7.43 (d, J¼9.0 Hz, 2H, Ar), 7.57 (d, J¼9.0 Hz,
2H, Ar); 13C NMR (CDCl3, 75 MHz, TMS)
24.2, 35.8, 70.6, 114.6,
117.7, 128.0, 129.0, 129.3, 137.3, 160.8, 169.1; IR (CH2Cl2): 2982,
J¼8.1 Hz, 1H, Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d
13.5, 24.3, 34.7,
d
61.4, 71.3, 112.8, 121.6, 127.1, 128.8, 130.8, 131.2, 132.5, 159.6, 164.8,
n
166.1; IR (CH2Cl2):
n
3068, 2985, 2940, 2905, 1778, 1723, 1610, 1585,
2958, 1767, 1719, 1622, 1593, 1492, 1407, 1375, 1338, 1247,
1179 cmꢁ1; MS (EI) m/z (%): 250 [Mþ] (11.2), 138 (30.2), 137 (11.8),
136 (100.0),101 (12.3), 75 (9.6), 43 (14.3), 42 (16.0); HRMS (EI) calcd
for C13H11O3Cl (Mþ) requires 250.0397, found: 250.0402.
1473, 1435, 1378, 1345, 1263 cmꢁ1; MS (EI) m/z (%): 366 [MþꢁBr]
(40.1), 259 (33.7), 241 (100.0), 209 (31.6), 207 (32.0), 182 (38.7), 180
(40.7), 128 (21.4). Anal. Calcd for C16H15BrO5: C, 52.34%; H, 4.12%.
Found: C, 52.37%; H, 3.99%.
3.3.13. Compound 6b. A yellow solid. Mp166–168 ꢀC. 1H NMR
3.3.7. Compound 3g. A yellow solid. Mp 93–95 ꢀC. 1H NMR (CDCl3,
(CDCl3, 400 MHz, TMS)
d
1.25 (t, J¼7.2 Hz, 3H, CH3), 3.25–3.33 (m,
300 MHz, TMS)
d
1.21 (t, J¼7.2 Hz, 3H, CH3), 2.02–2.09 (m, 2H),
1H), 3.43–3.50 (m, 1H), 4.09–4.23 (m, 2H), 4.35–4.41 (m, 1H), 4.52–
4.57 (m, 1H), 5.71 (t, J¼2.8 Hz, 1H, CH), 6.54 (s, 1H, CH), 7.39 (dd,
J¼2.4, 6.8 Hz, 2H, Ar), 7.45 (dd, J¼2.4, 6.8 Hz, 2H, Ar); 13C NMR
2.19–2.33 (m, 2H), 2.39 (s, 3H, CH3), 4.11–4.19 (m,1H), 4.22–4.30 (m,
2H), 4.32–4.39 (m, 1H), 7.29–7.36 (m, 4H, Ar); 13C NMR (CDCl3,
75 MHz, TMS)
d
13.7, 21.3, 24.3, 35.4, 61.6, 71.1, 113.7, 122.5, 125.2,
(CDCl3, 75 MHz, TMS) d 14.1, 30.6, 60.8, 69.3,112.6,116.0,118.1,127.1,
128.4, 128.7, 129.1, 131.7, 138.2, 161.5, 163.2, 165.5; IR (CH2Cl2):
n
129.3, 129.4, 137.9, 155.8, 159.1, 165.5, 168.4; IR (CH2Cl2): n 3082,
3046, 2982, 2890, 1774, 1713, 1643, 1438, 1374, 1345, 1321,
1271 cmꢁ1; MS (EI) m/z (%): 302 [Mþ] (12.6), 216 (17.3), 188 (48.1),
144 (10.7), 143 (49.0), 117 (12.4), 116 (100.0), 115 (15.2). Anal. Calcd
for C17H18O5: C, 67.54%; H, 6.00%. Found: C, 67.67%; H, 6.04%.
3060, 3028, 1769, 1719, 1659, 1621, 1598, 1578, 1447, 1317, 1277,
1248 cmꢁ1; MS (EI) m/z (%): 334 [Mþ] (5.4),138 (32.3),137 (9.6),136
(100.0), 101 (10.3), 58 (11.1), 53 (9.7), 43 (33.8); HRMS (EI) calcd for
C17H15O5Cl (Mþ) requires 334.0608, found: 334.0609.
3.3.8. Compound 3h. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
3.3.14. Compound 5c. A yellow oil. 1H NMR (CDCl3, 400 MHz, TMS)
d
1.24 (t, J¼7.2 Hz, 3H, CH3), 1.97–2.14 (m, 2H), 2.19–2.36 (m, 2H),
d
2.17–2.35 (m, 3H), 2.39–2.43 (m, 1H), 4.25–4.31 (m, 1H), 4.36–4.41
(m, 3H), 6.34 (s, 1H, CH), 7.49 (d, J¼8.8 Hz, 2H, Ar), 7.59 (d, J¼8.8 Hz,
2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS)
24.2, 35.8, 70.7, 114.6,
117.8, 125.8, 128.5, 129.2, 132.3, 161.0, 169.0; IR (CH2Cl2): 3096,
2.40 (s, 3H, CH3), 4.09–4.16 (m,1H), 4.28 (q, J¼7.2 Hz, 2H), 4.32–4.39
(m, 1H), 7.25 (d, J¼8.4 Hz, 2H, Ar), 7.48 (d, J¼8.4 Hz, 2H, Ar); 13C
d
NMR (CDCl3, 75 MHz, TMS)
d
13.8, 21.4, 24.3, 35.6, 61.7, 71.1, 113.7,
n
122.0, 126.2, 128.3, 129.2, 141.7, 161.8, 162.9, 165.7; IR (CH2Cl2):
n
2981, 1765, 1717, 1621, 1587, 1487, 1403, 1339, 1310, 1247, 1179 cmꢁ1
;
2984, 2901, 1787, 1727, 1648, 1611, 1565, 1512, 1455, 1372, 1322,
1238 cmꢁ1; MS (EI) m/z (%): 302 [Mþ] (10.8), 216 (13.8), 189 (8.7),
188 (52.2), 143 (39.8), 117 (12.9), 116 (100.0), 115 (20.9); HRMS (EI)
calcd for C17H18O5 (Mþ) requires 302.1154, found: 302.1151.
MS (EI) m/z (%): 294 [Mþþ1] (12.9), 182 (94.6), 108 (100.0), 102
(23.6), 101 (41.5), 75 (26.1), 43 (20.4), 42 (28.4); HRMS (EI) calcd for
C13H11O3Br (Mþ) requires 293.9892, found: 293.9894.
3.3.15. Compound 6c. A yellow oil. 1H NMR (CDCl3, 400 MHz, TMS)
d
3.3.9. Compound 3i. A yellow solid. Mp 113–115 ꢀC. 1H NMR (CDCl3,
300 MHz, TMS)
1.25 (t, J¼7.2 Hz, 3H, CH3), 3.24–3.34 (m, 1H), 3.44–3.50 (m, 1H),
d
1.06 (t, J¼7.2 Hz, 3H, CH3),1.90–2.04 (m, 2H), 2.19–
4.08–4.23 (m, 2H), 4.35–4.41 (m, 1H), 4.51–4.57 (m, 1H), 5.71 (t,
2.32 (m, 2H), 2.25 (s, 3H, CH3), 3.84–3.91 (m, 1H), 4.08–4.18 (m, 2H),
J¼2.8 Hz, 1H, CH), 6.55 (s, 1H, CH), 7.37 (d, J¼8.8 Hz, 2H, Ar), 7.56 (d,
4.25–4.31 (m, 1H), 7.22–7.36 (m, 4H, Ar); 13C NMR (CDCl3, 75 MHz,
J¼8.8 Hz, 2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.1, 30.6, 60.8,
TMS)
d
13.6, 19.8, 24.2, 34.2, 61.4, 71.1, 113.4, 124.1, 125.3, 126.7,
2984,
69.3, 112.6, 116.0, 118.2, 126.3, 127.5, 129.4, 132.4, 155.7, 159.2, 165.5,
126.9, 129.4, 130.0, 135.7, 160.2, 165.2, 168.1; IR (CH2Cl2):
n
168.4; IR (CH2Cl2): n 3085, 3062, 2983, 2905, 1774, 1719, 1676, 1618,
2901, 1787, 1727, 1648, 1611, 1565, 1512, 1455, 1372, 1322,
1588, 1561, 1474, 1375, 1209, 1171 cmꢁ1; MS (EI) m/z (%): 378 [Mþ]
1238 cmꢁ1; MS (EI) m/z (%): 302 [Mþ] (10.8), 216 (13.8), 189 (8.7),
(10.0), 341 (35.2), 182 (100.0), 180 (92.9), 102 (38.5), 101 (26.9), 91

9342
X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
(34.0), 43 (43.6); HRMS (EI) calcd for C17H15O5Br (Mþ) requires
378.0103, found: 378.0106.
128.0, 129.1, 130.1, 131.5, 137.4, 156.1, 160.4, 165.5, 169.2; IR (CH2Cl2):
n
3106, 3063, 2982, 2904, 1774, 1719, 1677, 1637, 1568, 1484, 1460,
1375,1339,1210 cmꢁ1; MS (EI) m/z (%): 314 [Mþ] (1.5), 269 (4.1), 268
(5.1), 144 (6.5), 117 (10.3), 116 (100.0), 115 (30.9), 53 (4.9); HRMS (EI)
calcd for C18H18O5 (Mþ) requires 314.1154, found: 314.1152.
3.3.16. Compound 5d. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
d
2.18–2.27 (m, 3H), 2.35–2.45 (m, 1H), 4.25–4.43 (m, 2H), 6.30 (s,
1H, CH), 7.12–7.17 (m, 2H, Ar), 7.62–7.67 (m, 2H, Ar); 13C NMR
(CDCl3, 75 MHz, TMS) 24.2, 35.9, 70.6, 114.6, 116.2 (d, JC–F
21.8 Hz), 117.1, 125.8 (d, JC–F¼3.5 Hz), 129.9 (d, JC–F¼8.6 Hz), 160.9,
d
¼
3.3.22. Compound 5h. A white solid. Mp 79–81 ꢀC. 1H NMR (CDCl3,
400 MHz, TMS)
d 2.14–2.26 (m, 3H), 2.31–2.45 (m, 1H), 4.27–4.33
164.2 (d, JC–F¼251.7 Hz), 169.2; IR (CH2Cl2):
n
3104, 2963, 2898,
(m, 1H), 4.38–4.44 (m, 1H), 6.41 (s, 1H, CH), 7.61 (t, J¼8.0 Hz, 1H, Ar),
1764, 1624, 1605, 1509, 1458, 1414, 1340, 1309, 1231, 1179 cmꢁ1; MS
(EI) m/z (%): 234 [Mþ] (8.0), 178 (4.5), 149 (5.1), 148 (9.9), 121 (12.4),
120 (100.0), 70 (4.8), 42 (13.8); HRMS (EI) calcd for C13H11O3F (Mþ)
requires 234.0692, found: 234.0689.
7.73–7.75 (m, 1H, Ar), 7.81–7.83 (m, 1H, Ar), 7.88 (br s, 1H, Ar); 19F
NMR (CDCl3, 376 MHz, CFCl3):
d 15.3 (s, 1F); IR (CH2Cl2): n 3103,
2989, 2900, 1770, 1720, 1629, 1487, 1435, 1327, 1230, 1170, 1125,
1089 cmꢁ1; MS (EI) m/z (%): 284 [Mþ] (15.2), 199 (17.2), 198 (12.7),
171 (25.0), 170 (100.0), 169 (15.0), 151 (17.6), 42 (40.2); HRMS (EI)
calcd for C14H11O3F3 (Mþ) requires 284.0660, found: 284.0655.
3.3.17. Compound 6d. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
d
1.26 (t, J¼6.9 Hz,3H, CH3), 3.27–3.37 (m,1H), 3.42–3.53 (m,1H), 4.09–
4.22 (m, 2H), 4.34–4.43 (m, 1H), 4.52–4.59 (m, 1H), 5.72 (t, J¼2.7 Hz,
3.3.23. Compound 6h. A yellow oil. 1H NMR (CDCl3, 400 MHz, TMS)
1H, CH), 6.50 (s, 1H, CH), 7.09–7.27 (m, 2H, Ar), 7.50–7.55 (m, 2H, Ar);
d
1.25 (t, J¼7.2 Hz, 3H, CH3), 3.23–3.34 (m, 1H), 3.46–3.53 (m, 1H),
13C NMR (CDCl3, 75 MHz, TMS)
d
14.1, 30.6, 60.8, 69.2, 112.6, 116.0,
116.4 (d, JC–F¼21.9 Hz), 117.4, 124.9 (d, JC–F¼2.8 Hz), 130.3 (d, JC–F
8.9 Hz),155.9,159.2,164.4 (d, JC–F¼253.1 Hz),165.6,168.5; IR (CH2Cl2):
4.11–4.22 (m, 2H), 4.38–4.43 (m, 1H), 4.57 (td, J¼8.8, 2.8 Hz, 1H),
5.74 (t, J¼2.8 Hz, 1H, CH), 6.63 (s, 1H, CH), 7.57 (t, J¼7.2 Hz, 1H, Ar),
7.67–7.73 (m, 2H, Ar), 7.79 (br s, 1H, Ar); 19F NMR (CDCl3, 376 MHz,
¼
n
3104, 2983, 2905,1827,1769,1719,1677,1623,1605,1561,1510,1375,
CFCl3): d 62.4 (s, 1F); IR (CH2Cl2): n 3103, 2985, 2908, 1775, 1719,
1288,1237 cmꢁ1; MS (EI) m/z (%): 318 [Mþ] (5.4), 289 (8.4), 141 (10.3),
139 (30.7), 121 (10.0), 120 (100.0), 111 (11.0), 75 (9.5); HRMS (EI) calcd
for C17H15O5F (Mþ) requires 318.0904, found: 318.0911.
1677, 1648, 1628, 1487, 1436, 1376, 1334 cmꢁ1; MS (EI) m/z (%): 378
[Mþ] (6.5), 289 (13.0), 201 (9.3), 173 (9.3), 148 (7.6), 133 (7.7), 121
(11.3), 120 (100.0); HRMS (EI) calcd for C18H15O5F3 (Mþ) requires
368.0872, found: 368.0868.
3.3.18. Compound 5e. A yellow oil. 1H NMR (CDCl3, 400 MHz, TMS)
d
2.19–2.29 (m, 3H), 2.36–2.44 (m,1H), 4.28–4.34 (m,1H), 4.37–4.42
(m, 1H), 6.35 (s, 1H, CH), 7.16–7.21 (m, 1H, Ar), 7.31–7.35 (m, 1H, Ar),
7.41–7.47 (m, 2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS)
24.2, 35.8,
3.3.24. Compound 5i. A white solid. Mp 90–92 ꢀC. 1H NMR (CDCl3,
400 MHz, TMS)
d 1.95–2.07 (m, 2H), 2.24–2.35 (m, 2H), 4.02–4.08
d
(m, 1H), 4.30–4.35 (m, 1H), 6.39 (s, 1H, CH), 7.31–7.40 (m, 2H, Ar),
70.7, 114.5 (d, JC–F¼22.3 Hz), 114.6, 118.0 (d, JC–F¼20.5 Hz), 118.5,
123.6 (d, JC–F¼3.2 Hz), 130.7 (d, JC–F¼8.2 Hz), 131.5 (d, JC–F¼8.2 Hz),
160.8 (d, JC–F¼22.0 Hz), 162.7 (d, JC–F¼246.2 Hz), 168.9; IR (CH2Cl2):
7.50–7.52 (m, 1H, Ar), 7.63–7.65 (m, 1H, Ar); 13C NMR (CDCl3,
100 MHz, TMS)
130.3, 130.9, 133.2, 158.9, 169.3; IR (CH2Cl2):
d
24.2, 34.8, 70.8, 115.5, 123.3, 126.8, 129.1, 129.4,
3105, 3070, 2985,
n
n
3101, 2963, 2898, 1871, 1765, 1625, 1611, 1582, 1486, 1444, 1349,
2897, 1766, 1649, 1589, 1563, 1473, 1434, 1331, 1300, 1249, 1179,
1120 cmꢁ1; MS (EI) m/z (%): 250 [Mþ] (10.8), 171 (11.1), 164 (20.1),
138 (33.0), 137 (12.2), 136 (100.0), 101 (15.6), 42 (16.0); HRMS (EI)
calcd for C13H11O3Cl (Mþ) requires 250.0397, found: 250.0403.
1302, 1253 cmꢁ1; MS (EI) m/z (%): 234 [Mþ] (12.2), 189 (8.2), 178
(8.0), 149 (10.4), 148 (12.9), 121 (21.9), 120 (100), 42 (19.1); HRMS
(EI) calcd for C13H11O3F (Mþ) requires 234.0692, found: 234.0693.
3.3.19. Compound 6e. A yellow oil. 1H NMR (CDCl3, 400 MHz, TMS)
3.3.25. Compound 6i. A colourless oil. 1H NMR (CDCl3, 400 MHz,
d
1.26 (t, J¼7.2 Hz, 3H, CH3), 3.25–3.36 (m, 1H), 3.43–3.51 (m, 1H),
TMS)
d
1.26 (t, J¼7.2 Hz, 3H, CH3), 2.97–3.07 (m, 1H), 3.35–3.43 (m,
4.09–4.22 (m, 2H), 4.35–4.42 (m, 1H), 4.56 (td, J¼8.8, 2.8 Hz, 1H),
5.73 (t, J¼2.8 Hz, 1H, CH), 6.56 (s, 1H, CH), 7.15–7.22 (m, 2H, Ar),
7.30–7.33 (m, 1H, Ar), 7.38–7.44 (m, 1H, Ar); 19F NMR (CDCl3,
1H), 4.07–4.23 (m, 2H), 4.30–4.36 (m, 1H), 4.44–4.49 (m, 1H), 5.91
(t, J¼2.8 Hz, 1H, CH), 6.72 (s, 1H, CH), 7.27–7.38 (m, 2H, Ar), 7.49–
7.52 (m, 1H, Ar), 7.63 (dd, J¼2.0, 7.6 Hz, 1H, Ar); 13C NMR (CDCl3,
376 MHz, CFCl3):
d
32.6–32.6 (m, 1F); IR (CH2Cl2):
n
3103, 2983,
75 MHz, TMS) d 14.1, 30.9, 60.6, 69.3, 113.8, 116.2,124.3,126.8, 128.2,
2906, 1775, 1720, 1677, 1625, 1611, 1582, 1487, 1446, 1375,
1223 cmꢁ1; MS (EI) m/z (%): 378 [Mþ] (6.5), 289 (13.0), 201 (9.3),
173 (9.3), 148 (7.6), 133 (7.7), 121 (11.3), 120 (100.0); HRMS (EI) calcd
for C17H15O5F (Mþ) requires 318.0904, found: 318.0905.
129.4, 130.9, 131.2, 133.6, 155.2, 156.3, 165.5, 168.7; IR (CH2Cl2): n
3071, 2983, 2905, 1775, 1721, 1677, 1641, 1590, 1474, 1443, 1375,
1266 cmꢁ1; MS (EI) m/z (%): 334 [Mþ] (5.6), 164 (15.9), 138 (36.4),
137 (11.8), 136 (100.0), 121 (14.3), 101 (12.2), 91 (18.1); HRMS (EI)
calcd for C17H15O5Cl (Mþ) requires 334.0608, found: 334.0605.
3.3.20. Compound 5g. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
d
1.93–2.06 (m, 2H), 2.19–2.38 (m, 2H), 2.35 (s, 3H, CH3), 3.99–4.07
3.3.26. Compound 5j. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
(m, 1H), 4.28–4.33 (m, 1H), 6.10 (s, 1H, CH), 7.22–7.35 (m, 3H, Ar),
d
1.11 (t, J¼7.2 Hz, 3H, CH3), 2.33–2.42 (m, 1H), 2.69–2.77 (m, 1H),
7.48 (d, J¼7.8 Hz, 1H, Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d
20.7,
3.27–3.33 (m, 1H), 4.09–4.25 (m, 3H), 4.51 (t, J¼8.4 Hz, 1H), 7.10–
24.2, 34.7, 70.7, 115.8, 121.6, 125.8, 127.8, 129.6, 129.9, 130.9, 136.5,
7.13 (m, 2H, Ar), 7.25–7.31 (m, 3H, Ar), 7.48–7.58 (m, 3H, Ar), 7.62–
162.7, 169.7; IR (CH2Cl2):
n
3103, 3061, 2960, 2896, 1778, 1645, 1568,
7.64 (m, 2H, Ar); 13C NMR (CDCl3, 75 MHz, TMS)
d
13.6, 30.0, 52.2,
1485, 1455, 1382, 1330, 1300, 1253, 1179 cmꢁ1; MS (EI) m/z (%): 230
[Mþ] (4.5), 184 (5.1), 144 (11.0), 117 (11.1), 116 (100.0), 115 (53.4), 89
(5.8), 63 (4.9); HRMS (EI) calcd for C14H14O3 (Mþ) requires
230.0943, found: 230.0941.
69.4,112.9,123.4,128.0,128.4, 128.5, 128.6, 128.9, 129.5,131.0,133.2,
160.8, 163.0, 164.8; IR (CH2Cl2):
n 3063, 3030, 2983, 2903, 1779,
1730, 1650, 1602, 1573, 1496, 1446, 1373, 1346, 1315, 1259 cmꢁ1; MS
(EI) m/z (%): 364 [Mþ] (0.7), 129 (12.4), 119 (9.9), 118 (100.0), 117
(54.6), 115 (6.1), 103 (3.1), 102 (4.0); HRMS (EI) calcd for C22H20O5
(Mþ) requires 364.1311, found: 364.1306.
3.3.21. Compound 6g. A yellow oil. 1H NMR (CDCl3, 300 MHz, TMS)
d
1.27 (t, J¼7.2 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 2.90–3.04 (m, 1H),
3.38–3.49 (m, 1H), 4.08–4.20 (m, 2H), 4.25–4.33 (m, 1H), 4.39–4.45
(m, 1H), 5.83 (t, J¼3.0 Hz, 1H, CH), 6.32 (s, 1H, CH), 7.14–7.20 (m, 1H,
Ar), 7.27–7.32 (m, 2H, Ar), 7.42 (d, J¼3.0 Hz,1H, Ar); 13C NMR (CDCl3,
3.3.27. Compound 5k. A white solid. Mp 114–116 ꢀC. 1H NMR
(CDCl3, 400 MHz, TMS)
d 2.43–2.50 (m, 1H), 2.76–2.81 (m, 1H),
3.52–3.57 (m, 1H), 4.33–4.40 (m, 1H), 4.53–4.58 (m, 1H), 6.08 (s,
1H), 7.05–7.07 (m, 2H, Ar), 7.20–7.25 (m, 3H, Ar), 7.48–7.54 (m, 3H,
75 MHz, TMS)
d 14.1, 21.5, 31.2, 60.7, 69.3, 114.2, 116.1, 122.0, 126.0,

X.-Y. Tang, M. Shi / Tetrahedron 65 (2009) 9336–9343
9343
Ar), 7.67–7.70 (m, 2H, Ar); 13C NMR (CDCl3, 75 MHz, TMS)
52.5, 68.9, 114.2, 118.5, 127.7, 127.8, 128.2, 128.9, 129.2, 129.9, 131.2,
d 29.4,
(n) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66–72; (o) Rubin, M.; Rubina, M.;
Gevorgyan, V. Chem. Rev. 2007, 107, 3117–3179.
2. (a) Binger, P.; Bu¨ch, H. M. Cyclopropenes and Methylenecyclopropanes as Mul-
tifunctional Reagents in Transition Metal Catalyzed Reactions. In Topics in Current
Chemistry; de Meijere, A., Ed.; Springer: Berlin, 1987; Vol. 135, pp 109–131; (b)
Noyori, R.; Odagi, T.; Takaya, H. J. Am. Chem. Soc. 1970, 92, 5780–5781; (c) Lewis,
R. T.; Motherwell, W. B.; Shipman, M. J. Chem. Soc., Chem. Commun. 1988, 948–
950; (d) Lautens, M.; Ren, Y. J. Am. Chem. Soc. 1996, 118, 9597–9605 and refer-
ences therein; (e) Liu, L.; Montgomery, J. J. Am. Chem. Soc. 2006, 128, 5348–5349;
(f) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima, K. Tetrahedron 2001,
57, 987–995; (g) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M.
Angew. Chem., Int. Ed. 1999, 38, 3186–3189; (h) Smith, A. B., III; Scarborough, R. M.
Tetrahedron Lett. 1978, 19, 1649–1652; (i) Ogoshi, H.; Setsune, J.-I.; Yoshida, Z.-I. J.
Organomet. Chem. 1980, 185, 95–104; (j) Ogoshi, H.; Kikuchi, Y.; Yamaguchi, T.;
Toi, H.; Aoyama, Y. Organometallics 1987, 6, 2175–2178; (k) Hwu, R. J. J. Chem. Soc.,
Chem. Commun. 1985, 452–453; (l) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org.
Lett. 2002, 4, 3147–3150; (m) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett.
2002, 4, 4333–4336; (n) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124, 6312–
6316; (o) Lautens, M.; Han, W.; Liu, J. H.-C. J. Am. Chem. Soc. 2003, 125, 4028–
4029; (p) Scott, M. E.; Han, W.; Lautens, M. Org. Lett. 2004, 6, 3309–3312; (q)
Tsuritani, T.; Yamamoto, Y.; Kawasaki, M.; Mase, T. Org. Lett. 2009, 11, 1043–1045;
(r) Mauleo´n, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513–4520;
(s) Pagenkopf, B. L.; Morales, C. L. Org. Lett. 2008, 10, 157–159; (t) Korotkov, V. S.;
Larionov, A. H.; Hofmeister, A.; Magull, J.; de Meijere, A. J. Org. Chem. 2007, 72,
7504–7510; (u) Tanaka, M.; Ubukata, M.; Matsuo, T.; Yasue, K.; Matsuya, M.;
Kajimoto, Y.; Ogo, T.; Inaba, T. Org. Lett. 2007, 9, 3331–3334; (v) Sliwinska, A.;
Czardybon, W.; Warkentin, J. Org. Lett. 2007, 9, 695–698; (w) Zheng, X. M.; Kerr,
M. A. Org. Lett. 2006, 8, 3777–3779; (x) Ivanova, O. A.; Budynina, E. M.; Grishin,
Y. K.; Trushikov, I. V.; Verteletskii, P. V. Angew. Chem. 2008, 120, 1123–1126;
Angew. Chem., Int. Ed. 2008, 47, 1107–1110; (y) Avilov, D. V.; Malusare, M. G.;
Arslancan, E.; Dittmer, D. C. Org. Lett. 2004, 6, 2225–2228.
133.7, 161.1, 168.6; IR (CH2Cl2): n 3061, 3030, 2983, 2900, 1765, 1622,
1574, 1494, 1449, 1346, 1304, 1243, 1178, 1108, 1035 cmꢁ1; MS (EI)
m/z (%): 292 [Mþ] (0.4), 119 (10.2), 118 (100.0), 117 (68.9), 115 (8.2),
103 (5.8), 102 (14.4), 91 (8.2); HRMS (EI) calcd for C19H16O3 (Mþ)
requires 292.1099, found: 292.1103.
Acknowledgements
We thank the Shanghai Municipal Committee of Science and
Technology (08dj1400100-2), National Basic Research Program of
China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (20472096, 20872162,
20672127, 20821002 and 20732008).
Supplementary data
Spectroscopic data of all the new compounds and the detailed
descriptions of experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org. Supplemen-
tary data associated with this article can be found in online version,
at doi:10.1016/j.tet.2009.09.003.
3. (a) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8, 1709–1712; (b) Shi, M.; Tang, X.-Y.; Yang,
Y.-H. Org. Lett. 2007, 9, 4017–4021; (c) Shi, M.; Tang, X.-Y.; Yang, Y.-H. J. Org.
Chem. 2008, 73, 5311–5318; (d) Yang, Y.-H.; Shi, M. Eur. J. Org. Chem. 2006,
5394–5403.
4. (a) Nukina, M.; Hirota, H. Biosci. Biotechnol. Biochem. 1992, 56, 1158–1159; (b)
Ackland, M. J.; Hanson, J. R.; Hitchcock, P. B.; Ratcliffe, A. H. J. Chem. Soc., Perkin
Trans. 1 1985, 843–847; (c) Engstrom, K. M.; Mendoza, M. R.; Navarro-Villalobos,
M.; Gin, D. Y. Angew. Chem., Int. Ed. 2001, 40, 1128–1130.
References and notes
1. (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196; (b) Paquette, L. A.
Chem. Rev. 1986, 86, 733–750; (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165–198; (d) de Meijere, A.; Wessjo-
hann, L. Synlett 1990, 20–32; (e) Kulinkovich, O. G. Russ. Chem. Rev. 1993, 62, 839;
(f) Kulinkovich, O. G. Pol. J. Chem. 1997, 849; (g) Wenkert, E. Acc. Chem. Res. 1980,
13, 27–31; (h) Wenkert, E. Heterocycles 1980, 14, 1703–1708; (i) Seebach, D.
Angew. Chem. 1979, 91, 259–268; Angew. Chem., Int. Ed. Engl. 1979, 18, 239–258;
(j) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603–1624; (k) de Meijere, A.;
Kozhushkov, S. I. Eur. J. Org. Chem. 2000, 3809–3822; (l) de Meijere, A. Top. Curr.
Chem. 2000, 207, 89–147; (m) de Meijere, A. Top. Curr. Chem. 2000, 207, 149–227;
5. Yang, Y.-H.; Shi, M. J. Org. Chem. 2005, 70, 10082–10085.
6. The C-5 position is an activated methylene group because of the two sub-
stituents: phenyl and acyl groups.
7. When both the R1 and R3 were aryl groups, two products derived from path
a and path b were obtained.
C6H5
O
C6H5
O
C6H5
O
O
TMSOTf
DCE, 60 °C
OMe
Ph
+
C6H5
+
O
O
1a
O
O
spiro-γ-lactone, 14%
E-E, 20%