Lewis acid-catalyzed nucleophilic ring-opening/intramolecular Conia-ene reactions of methylenecyclopropane 1,1-diesters with propargyl alcohols

Article abstract of DOI:10.1016/j.tet.2010.11.048

We presented a Lewis acid-catalyzed nucleophilic ring opening of methylenecyclopropane (MCP) 1,1-diesters with propargyl alcohols. Unlike the proximal-bond cleavage mode observed in cases of unactivated MCPs, the intrinsic characteristic of MCP 1,1-dieste

Full text of DOI:10.1016/j.tet.2010.11.048

Tetrahedron 67 (2011) 763e768
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Tetrahedron
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Lewis acid-catalyzed nucleophilic ring-opening/intramolecular Conia-ene
reactions of methylenecyclopropane 1,1-diesters with propargyl alcohols
,
Bao Hu b, Jun Ren a, Zhongwen Wang a
*
a State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2010
Received in revised form 8 November 2010
Accepted 12 November 2010
Available online 24 November 2010
We presented a Lewis acid-catalyzed nucleophilic ring opening of methylenecyclopropane (MCP)
1,1-diesters with propargyl alcohols. Unlike the proximal-bond cleavage mode observed in cases of
unactivated MCPs, the intrinsic characteristic of MCP 1,1-diesters gave a regiospecific distal-bond
cleavage under attack of propargyl alcohols as nucleophiles. By combining a subsequent intramolecular
Conia-ene reaction, 3,5-dimethylenetetrahydropyrans could be obtained in either a stepwise or a one-
pot strategy.
Keywords:
Small ring systems
Ring opening
Ó 2010 Elsevier Ltd. All rights reserved.
Ring closing
Methylenecyclopropane
Propargyl alcohol
1. Introduction
FriedeleCrafts reaction5b under the catalysis of Yb(OTf)3 or
Sc(OTf)3. The introduction of the two geminal EWGs on the sp3
Methylenecyclopropanes (MCPs), a kind of highly strained
molecule, have been paid much attention due to their ready
availability1 and good reactivity.2 Recently, Lewis acid (LA)-
catalyzed nucleophilic ring-opening reactions of MCPs have been
extensively investigated. Typically, such nucleophilic ring-opening
reactions were carried out via either proximal3 or distal4 mode
(Scheme 1). Most of the LA-promoted nucleophilic ring-opening
processes were reported on unactivated MCPs, which were triggered
by an initial generation of a carbocation at one of the two sp2 car-
bons. For example, Shi and Xu found that the unactivated MCPs
reacted with alcoholic nucleophiles catalyzed by LAs to give the ring-
opening products through a proximal mode.3a For activated MCPs,
usually activated by an electron-withdrawing group (EWG) on sp3
carbon of the three-membered ring, only a few researches on LA-
catalyzed nucleophilic ring-opening were reported. Lautens et al.
reported a MgI2-mediated distal [3þ2] cycloaddition of MCPs
activated by a single EWG. This cycloaddition was proposed to be
initiated by a nucleophilic ring opening with an iodide anion.4c MCP
1,1-diesters have been recently developed in our lab for a novel
[3þ3] cycloaddition5a and a tandem ring-opening/intramolecular
carbon of the three-membered ring made the MCPa stable precursor
of an active 1,3-dipole and undergo the nucleophilic ring-opening
reaction with a regiospecifically distal-bond cleavage mode under
mild conditions.6 We hope to explore new LA-catalyzed nucleophilic
ring-opening reactions of MCP 1,1-diesters and to develop a new
strategy for the construction of cyclic skeletons by combining with a
subsequent cyclization of carbanionwith an electrophile (Scheme 2).
We now report an LA-catalyzed distally nucleophilic ring opening of
MCP 1,1-diesters with propargyl alcohols, and a combination of the
reaction with subsequent intramolecular Conia-ene cyclization7,8
via either a stepwise or a one-pot way (Scheme 3).
proximal
Nu
distal
Nu
δ-
δ+
Nu
dipolarization
dipolarization
Nu
δ-
δ+
Scheme 1. Two types of LA-catalyzed nucleophilic ring-opening modes.
R2
R2
R2
R2
Nu
E
CO2R1
CO2R1
CO2R1
CO2R1
LA
CO2R1
CO2R1
CO2R1
CO2R1
δ+
δ-
E
Nu
Nu
E
distal-bond
cleavage
* Corresponding author. Tel.: þ86 22 23498191; e-mail address: wzwrj@nankai.
edu.cn (Z. Wang).
Scheme 2. Combination of LA-catalyzed nucleophilic ring-opening and subsequent
URL: http://wzw.nankai.edu.cn/.
ring-closing of MCP 1,1-diesters.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.048

764
B. Hu et al. / Tetrahedron 67 (2011) 763e768
Table 1
R2
CO2R1
CO2R1
R2
Optimization of conditions for the ring-opening reaction of MCP 1,1-diester 1a with
propargyl alcohol 2aa
OH
One Pot
+
O
CO2R1
CO2R1
R3
2
1
R3
4
R1O2C
R2
CO2R1
Cat1
Cat2
Intramolecular
Entry
Ratio
Lewis acid
Temp (ꢀC)
Time (h)
Yieldb (%)
O
Ring opening
3
Conia-ene cyclization
1a/2a
3a
5a
R3
1
2
3
1:5
1:5
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Zn(OTf)2
In(OTf)3
Bi(OTf)3
InCl3
rt
24
18.5
22
26.5
22
43
4.5
7
Nrc
65
52
73
75
Scheme 3. Ring-opening/intramolecular Conia-ene reactions of MCP 1,1-diesters 1
with propargyl alcohols 2.
60
60
60
60
60
80
80
60
60
60
60
17
38
15
14
8
1:2.5
1:10
1:10
1:20
1:5
1:10
1:10
1:10
1:10
1:5
4
5d
6
77
2. Results and discussion
7d
8d
9d,e
10d
11d
12
54
44
Nrc
d
Initial experiments for optimal conditions were carried out
with MCP 1,1-diester 1a (1.0 equiv) and propargyl alcohol 2a
(5.0 equiv), and the results are summarized in Table 1. The
reaction in 1,2-dichloroethane (DCE) proceeded smoothly at 60 ꢀC
under catalysis of Yb(OTf)3 to afford 3a in 65% yield (Table 1,
entry 2). The main by-product observed in this reaction was the
FriedeleCrafts alkylation product 5a previously reported by us.5b
When the amount of 2a was decreased to 2.5 equiv, the yield
decreased from 65% to 52% (Table 1, entry 3). When the amount
of 2a was increased to 10.0 equiv, the yield was slightly improved
from 65% to 73% (Table 1, entry 4). The yield could be improved
to 77% when 20.0 equiv of 2a was used (Table 1, entry 6). Several
other LAs have also been tested (Table 1, entries 8e12) and it was
found that Eu(OTf)3 (Table 1, entry 12) also promoted the reaction
effectively. We chose the optimized conditions as in entry 4,
Table 1 for further investigation.
17
8
5
Trace
Trace
d
d
Trace
54
Eu(OTf)3
88
22
a
Reaction conditions: 0.5 mmol scale of 1a, 20 mol % of LA, 5.0 mL of DCE, Ar.
Isolated yields by silica gel chromatography.
No reaction occurred.
LA (50 mol %) was used.
Compound 1a was consumed.
b
c
d
e
(Table 2, entries 1e10). Reactions of aryl-substituted MCPs
containing either an electron-withdrawing group or an electron-
donating group on the benzene ring proceeded successfully
(Table 2, entries 2e6). The reaction of benzyl-substituted MCP
1,1-diester 1i with propargyl alcohol 2a afforded 3i in 21% yield
together with a FriedeleCrafts by-product 5i (24% yield, Table 2,
entry 9). The reaction of heptyl-substituted MCP 1,1-diester 1j
with propargyl alcohol 2a also proceeded successfully (Table 2,
entry 10). Under the similar conditions, reactions of 1a with
With the optimal reaction conditions established, the scope of
these ring-opening reactions was then studied. As revealed in
Table 2, various MCPs 1 were suitable for such transformation
Table 2
Ring-opening reactions of MCPs 1 with propargyl alcohols 2a
R1O2C
R2
CO2R1
O
R2
Yb(OTf)3
DCE, 60 o
OH
+
C
CO2R1
CO2R1
R3
3
R3
1
2
Entry
Substrate 1
R1
R2
E/Z ratio of 1b
Substrate 2
R3
Time (h)
Product 3
Yieldc,d (%)
E/Z ratio of 3b
1
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
Me
Me
Me
Me
Me
Et
C6H5
100:0
100:0
100:0
100:0
100:0
65:35
100:0
100:0
67:33
70:30
100:0
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
H
H
H
H
H
H
H
H
H
H
Me
26.5
75
64
16
41.5
22
15
44
15.5
23
46.5
3a
3b
3c
3d
3e
3f
3g
3h
3i
73
43
70
60
65
52
61
56
21
52
67
87:13
76:24
88:12
83:17
>20:1
90:10
92:8
86:14
88:12
30:70
84:16
4-FC6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
2-BrC6H4
4-MeOC6H4
C6H5
Bn
n-C7H15
C6H5
3
4e
5
6
7
8
9
10
11
Me
Me
Me
1j
1a
3j
3k
MeO2C
Ph
CO2Me
O
OH
12
1a
Me
C6H5
100:0
41.5
81:19
2c
3l
(66%)
H
Ph
Bn
N
H
N
13e
14
1a
1a
Me
Me
C6H5
C6H5
100:0
100:0
20
11
CO2Me
>20:1
Bn
2d
3m
(51%)
CO2Me
MeO2C
Ph
OH
CO2Me
OEt
75:25
2e
3n (62%)

B. Hu et al. / Tetrahedron 67 (2011) 763e768
765
Table 2 (continued)
Entry
Substrate 1
R1
R2
E/Z ratio of 1b
Substrate 2
R3
Time (h)
15.5
Product 3
Yieldc,d (%)
E/Z ratio of 3b
MeO2C
Ph
CO2Me
O
15
1a
1a
Me
C6H5
100:0
76:24
OH
3o (27%)
2f
MeO2C
Ph
CO2Me
O
OH
2g
16
Me
C6H5
100:0
8.5
d
3p (0%)
a
Reaction conditions: 0.5 mmol scale of 1, 10.0 equiv of 2, 20 mol % of Yb(OTf)3, 5.0 mL of DCE, 60 ꢀC, Ar.
Determined by 1H NMR after purification.
Isolated yields by silica gel chromatography.
The total yield is given for a mixture of the two diastereomers.
Reaction was carried out at 80 ꢀC.
b
c
d
e
nucleophiles 3-butyn-2-ol 2b, 3-butyn-1-ol 2c, and N-benzyl
propargyl amine 2d were also carried out successfully and the
ring-opening products 3kem were obtained in moderate yields
(Table 2, entries 11e13). In addition, several other aliphatic
alcohols were also investigated. Ethanol worked well and gave
ring-opening product 3n in 62% yield (Table 2, entry 14), iso-
propanol gave 3o in 27% yield (Table 2, entry 15). However,
probably due to the steric hindrance, no ring-opening product
was obtained for tert-butanol (Table 2, entry 16).
Table 3
Optimization of conditions for the ring-closing reaction of nucleophilic ring-opening
product 3aa
Ph
MeO2C
Ph
CO2Me
CO2Me
CO2Me
O
Lewis acid
solvent
O
4a
3a
Entry Lewis acid (equiv)
Solvent
Temp (ꢀC) Time (h) Yieldb (%)
For all of the MCPs 1,1-diesters except 1j, the ring-opening
products 3 were formed with good stereoselectivities (E/Z¼75:25
to >20:1). The different stereoselectivity in 3j (E/Z¼30:70) was
probably caused by the steric effect of the long aliphatic chain.
NOESY experiment confirmed E-3a as a major isomer (Fig. 1). By
comparing the change of the configuration of carbonecarbon
double bond in the MCPs and the ring-opening products, we can
see that no matter the E/Z ratios of MCPs are higher (e.g., Table 2,
entry 1: E/Z¼100:0) or lower (e.g., Table 2, entry 6: E/Z¼65:35), the
E/Z ratios of the ring-opening products are in the same level (for 3a:
E/Z¼87:13; for 3f: E/Z¼90:10). This strongly supported that a po-
larized TMM (trimethylenemethane) intermediate was involved in
the nucleophilic ring-opening process and thus an SN1 mechanism
might be implied (Scheme 4), which is different from that proposed
in the case of cyclopropane 1,1-diester.7
1
InCl3 (0.50)
InCl3 (0.30)
InCl3 (0.50)
Ph3PAuCl (0.10)
AuOTf (0.10)
Ni(ClO4)2$6H2O (0.50) DCE
InCl3 (0.50)
InCl3 (0.50)
DCE
DCE
DCE
DCE
DCE
60
60
65
80
10
80
66
21.5
12.5
15
7
16
15
10
38
47
16
2
3c
4
57
Nrd
d
5c,e
6c
7c
8c,f
Nrd
Nrd
16
THF
Toluene 65
a
Reaction conditions: 0.25 mmol scale of 3a, 7.0 mL of solvent, Ar.
Isolated yields by silica gel chromatography.
Et3N (0.10 equiv) was added.
No reaction occurred.
Compound 3a was slowly decomposed.
Compound 3a (20%) was recovered.
b
c
d
e
f
ineffective (Table 3, entries 4e6). In addition, several solvents were
tested and it was found that DCE is the best one for this trans-
formation. The structure of E-4a was established by 1H and 13C NMR
spectroscopy as well as single-crystal X-ray diffraction (Fig. 2).9
With the optimized reaction conditions in hand (Table 3, entry 3),
we next extended the ring-closing reactions to several other nucleo-
philic ring-opening products 3 (Table 4). Substrates with chlorine or
NOE
CO2Me
CO2Me
H
Ph
H
O
H
H
E-3a
NOE
Fig. 1. NOESY analysis of the ring-opening product E-3a.
R2
R2
R2
R2
CO2R1
CO2R1
substrate
CO2R1
CO2R1
CO2R1
CO2R1
CO2R1
CO2R1
product
configuration
configuration
Scheme 4. A proposed polarized TMM SN1 mechanism.
Following the successfully established nucleophilic ring-opening
process, an intramolecular Conia-ene cyclization was then consid-
ered to be carried out on the nucleophilic ring-opening product 3a.
Under the catalysis of 0.5 equiv of InCl3, the reaction proceeded
smoothly to afford 3,5-dimethylenetetrahydropyran 4a in 47% yield
(Table 3, entry 1). When 0.1 equiv of Et3N was added, the yield was
improved to 57% (Table 3, entry 3). Further investigation indicated
that other LAs, such as Ph3PAuCl, AuOTf, and Ni(ClO4)2$6H2O were
Fig. 2. X-ray crystal structure of E-4a.

766
B. Hu et al. / Tetrahedron 67 (2011) 763e768
Table 4
examples were also employed and the results are summarized in
Table 5. It should be noted that stereoselectivity in the one-pot
tandem process was higher, which is different from the stepwise
process.
Ring-closing reactions of several nucleophilic ring-opening products
3 in the
presence of InCl3/Et3Na
R2
R1O2C
R2
CO2R1
O
CO2R1
CO2R1
InCl3/Et3N
DCE, 65 o
O
C
3. Conclusions
R3
4
3
R3
In summary, an LA-catalyzed nucleophilic ring opening of MCP
1,1-diesters with propargyl alcohols has been achieved in a distal-
bond cleavage mode. This regiospecific reaction differs consider-
ably from the LA-promoted addition of alcohols to unactivated
MCPs. An LA-catalyzed intramolecular Conia-ene reaction of the
ring-opening products has also been disclosed. Finally, a highly
stereoselective one-pot tandem ring-opening/intramolecular
Conia-ene protocol has also been developed.
Entry Substrate 3 R1 R2
R3 Time Product 4 Yieldb,c E/Z
(h)
(%)
ratio
of 4d
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
3g
3h
3j
Me C6H5
H
H
H
H
H
H
H
H
H
15
9
25.5 4c
23 4d
16.5 4e
42.5 4f
15.5 4g
42
16
4a
4b
57
d
86:14
d
Me 4-FC6H4
Me 4-ClC6H4
Me 3-ClC6H4
Me 4-BrC6H4
Me 2-BrC6H4
Me 4-MeOC6H4
Et C6H5
39
38
<10
55
d
88:12
87:13
d
88:12
d
4. Experimental section
4.1. General method
8
4h
4j
4k
17
d
72:28
d
9e
10
Me n-C7H15
Me C6H5
3k
Me 24
10
78:22
a
Reaction conditions: 0.20e0.30 mmol scale of 3, 50 mol % of InCl3, 10 mol % of
All NMR spectra were recorded with a spectrometer at 400 MHz
(1H NMR) and 100 MHz (13C NMR) in CDCl3. The chemical shifts
were reported in parts per million referenced to CDCl3
Et3N, 7.0 mL of DCE, 65 ꢀC, Ar.
b
Isolated yields by silica gel chromatography.
c
The total yield is given for a mixture of two diastereomers.
d
Determined by 1H NMR after purification.
(
d
¼7.26 ppm) for 1H NMR and relative to the central CDCl3 reso-
e
Compound 3j was consumed.
nance (
d
¼77.0 ppm) for 13C NMR spectroscopy. Column chroma-
tography was performed on silica gel (100e200 or 200e300 mesh)
using petroleum ether and EtOAc as eluents. Thin layer chroma-
tography (TLC) was performed on Merck silica gel GF254 plates and
visualized by UV light (254 nm). Melting points were uncorrected.
All solvents were purified and dried using standard procedures.
Methylenecyclopropane 1,1-diesters 1 were prepared according to
literature methods.5,10
bromine on the phenyl group could also give the corresponding
products 3c, 3d, and 3f (Table 4, entries 3, 4, and 6), however we
cannot explain the negative results on 3e (Table 4, entry 5) and flu-
orophenyl-substituted substrate 3b (Table 4, entry 2). The reactions
of more sterically hindered substrates 3h and 3k resulted in de-
creased yields (Table 4, entries 1, 8, and 10). For substrate 3g with
methoxyl on the phenyl group or heptyl-substituted substrate 3j, the
reactions did not work (Table 4, entries 7 and 9).
Finally, we started to carry out the combination of nucleophilic
ring-opening reaction and intramolecular Conia-ene cyclization in
a one-pot process. It was found in the previous investigation that
a single LA was not enough effective for the one-pot operation,
challenge for this was a proper combination of selected catalysts,
especially the LAs. After many attempts devoted to the optimization
of conditions in the one-pot process of substrates 1a and 2a, Eu
(OTf)3/InCl3/Et3N system was proved to be the most suitable one,
although the yield was not good (Table 5, entry 1). Several other
4.2. General procedure for the ring-opening reactions of
MCPs 1 and propargyl alcohols 2
Yb(OTf)3 (62 mg, 0.10 mmol, 20 mol %), MCPs 1 (0.50 mmol,
1.0 equiv), propargyl alcohols 2 (5.00 mmol,10.0 equiv), and 5 mL of
dry DCE were introduced into an oven-dried three-necked flask.
The mixture was stirred at 60 ꢀC in an argon atmosphere. After
completion of the reaction (as monitored by TLC), the solvent was
evaporated in vacuo and the residue was purified on silica gel
chromatography (ethyl acetate/petroleum ether) to afford ring-
opening products 3. E- and Z-Isomers can be separated by silica gel
chromatography if desired.
Table 5
Tandem ring-opening/intramolecular Conia-ene reactions of MCPs 1 with propargyl
alcohols 2a
R2
4.2.1. Dimethyl 2-(1-phenyl-3-(prop-2-ynyloxy)prop-1-en-2-yl)-
R2
CO2R1
malonate (3a). Yellow oil; E/Z¼87:13; the E-isomer: 1H NMR (CDCl3,
Eu(OTf)3/InCl3/Et3N
OH
CO2R1
+
DCE, 80 o
C
400 MHz):
d
7.40e7.33 (m, 2H), 7.30 (d, J¼7.2 Hz,1H), 7.23 (d, J¼7.2 Hz,
O
CO2R1
CO2R1
R3
1H), 6.98 (s, 1H), 4.70 (s, 1H), 4.39 (s, 2H), 4.16 (d, J¼2.4 Hz, 2H), 3.73
1
2
R3
4
(s, 6H), 2.45 (t, J¼2.4 Hz,1H); 13C NMR (CDCl3, 75 MHz):
d 168.4,135.6,
134.4, 129.8, 128.5, 127.7, 79.6, 74.5, 71.4, 57.3, 52.7, 51.6; HRMS (ESI)
calcd for C17H18O5Na (MþNa)þ: 325.1046; found: 325.1052.
Entry Substrate R1 R2
Substrate R3 Time Product Yieldb,c E/Z
1
2
(h)
4
(%)
ratio
of 4d
4.2.2. Dimethyl 2-(1-(4-fluorophenyl)-3-(prop-2-ynyloxy)prop-1-en-
2-yl)malonate (3b). Slightly yellow oil; E/Z¼76:24; the E-isomer:
1
2
3
4
5
1a
1b
1h
1a
1k
Me C6H5
Me 4-FC6H4
Et C6H5
Me C6H5
Me 4-MeC6H4 2a
2a
2a
2a
2b
H
H
H
22
11
23
4a
4b
4h
39
26
17
37
32
>20:1
>20:1
>20:1
>20:1
92:8
1H NMR (CDCl3, 400 MHz):
d
7.25e7.19 (m, 2H), 7.05 (t, J¼8.4 Hz, 2H),
Me 10.5 4k
H 57.5 4n
6.92 (s, 1H), 4.63 (s, 1H), 4.37 (s, 2H), 4.16 (s, 2H), 3.73 (s, 6H), 2.45
(s, 1H); the Z-isomer: 1H NMR (CDCl3, 400 MHz):
7.32e7.28 (m,
2H), 7.03 (t, J¼8.4 Hz, 2H), 6.72 (s, 1H), 4.39 (s, 1H), 4.29 (s, 2H), 4.09
(s, 2H), 3.78 (s, 6H), 2.39 (s, 1H); 13C NMR (CDCl3, 75 MHz):
169.2,
d
a
Reaction conditions: 0.5 mmol scale of 1, 5.0 equiv of 2a or 2b, 20 mol % of
Eu(OTf)3, 50 mol % of InCl3, 10 mol % of Et3N, 7.0 mL of DCE, 80 ꢀC, Ar.
d
b
Isolated yields by silica gel chromatography.
c
168.6, 168.3, 163.5, 161.1, 134.1, 133.4, 131.6, 130.8, 130.8, 130.4, 130.4,
130.3,130.0, 79.5, 79.2, 74.7, 74.6, 71.4, 66.9, 57.8, 57.3, 56.3, 52.8, 51.5,
The total yield is given for a mixture of two diastereomers.
d
Determined by 1H NMR after purification.

B. Hu et al. / Tetrahedron 67 (2011) 763e768
767
31.2, 29.7; HRMS (ESI) calcd for C17H17FO5Na (MþNa)þ: 343.0952;
(t, J¼2.4 Hz, 1H), 2.17 (dd, J¼14.4, 7.2 Hz, 1.36H), 2.06 (dd, J¼14.4,
7.2 Hz, 0.64H), 1.42e1.35 (m, 2H), 1.35e1.18 (m, 8H), 0.87
found: 343.0952.
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 168.9, 168.5, 137.1,
4.2.3. Dimethyl 2-(1-(4-chlorophenyl)-3-(prop-2-ynyloxy)prop-1-en-
136.9, 127.8, 127.4, 79.7, 74.4, 74.3, 72.4, 65.8, 56.8, 56.6, 55.9, 52.6,
52.6, 51.0, 31.8, 29.3, 29.2, 29.1, 29.1, 29.0, 28.1, 27.9, 22.6, 14.1;
HRMS (ESI) calcd for C18H28O5Na (MþNa)þ: 347.1829; found:
347.1832.
2-yl)malonate (3c). Yellow oil; E/Z¼88:12; the E-isomer: 1H NMR
(CDCl3, 400 MHz):
d
7.32 (d, J¼8.4 Hz, 2H), 7.18 (d, J¼8.0 Hz, 2H), 6.90
(s, 1H), 4.61 (s, 1H), 4.36 (s, 2H), 4.16 (s, 1H), 4.15 (s, 1H), 3.71 (s, 6H),
2.45 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d
168.1, 134.0, 133.7, 133.0,
130.6, 130.4, 129.9, 128.7, 79.5, 74.7, 71.2, 57.4, 52.8, 51.5; HRMS (ESI)
4.2.11. Dimethyl 2-(3-(but-3-yn-2-yloxy)-1-phenylprop-1-en-2-yl)-
calcd for C17H17ClO5Na (MþNa)þ: 359.0657; found: 359.0654.
malonate (3k). Yellow oil; E/Z¼84:16; the E-isomer: 1H NMR
(CDCl3, 400 MHz):
d 7.37e7.33 (m, 2H), 7.31e7.24 (m, 3H), 6.98
4.2.4. Dimethyl 2-(1-(3-chlorophenyl)-3-(prop-2-ynyloxy)prop-1-en-
(s, 1H), 4.70 (s, 1H), 4.55 (d, J¼12.4 Hz, 1H), 4.32 (d, J¼12.4 Hz, 1H),
2-yl)malonate (3d). Slightly yellow oil; E/Z¼83:17; the E-isomer:
4.25 (dd, J¼6.8, 2.0 Hz, 1H), 3.72 (s, 6H), 2.45 (d, J¼2.0 Hz, 1H), 1.45
1H NMR (CDCl3, 400 MHz):
d
7.31e7.20 (m, 3H), 7.13 (d, J¼6.8 Hz,1H),
(d, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 168.5, 168.3, 135.7,
6.90 (s, 1H), 4.61 (s, 1H), 4.37 (s, 2H), 4.17 (s, 1H), 4.16 (s, 1H), 3.73
133.9, 130.1, 128.6, 128.5, 127.6, 83.5, 73.2, 70.5, 64.5, 52.7, 52.6, 51.6,
21.9; HRMS (ESI) calcd for C18H20O5Na (MþNa)þ: 339.1203; found:
339.1207.
(s, 6H), 2.45 (t, J¼2.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d 168.1,
137.4, 134.4, 132.7, 131.2, 129.8, 128.7, 127.8, 126.7, 79.4, 74.7, 71.1, 57.4,
52.8, 51.5; HRMS (ESI) calcd for C17H17ClO5Na (MþNa)þ: 359.0657;
found: 359.0652.
4.2.12. Dimethyl 2-(3-(but-3-ynyloxy)-1-phenylprop-1-en-2-yl)mal-
onate (3l). Yellow oil; E/Z¼81:19; the E-isomer: 1H NMR (CDCl3,
4.2.5. (E)-Dimethyl 2-(1-(4-bromophenyl)-3-(prop-2-ynyloxy)prop-
400 MHz): d 7.39e7.31 (m, 2H), 7.30e7.22 (m, 3H), 6.97 (s, 1H), 4.70
1-en-2-yl)malonate (3e). Yellow oil; the sole E-isomer: 1H NMR
(s, 1H), 4.33 (s, 2H), 3.71 (s, 6H), 3.61 (t, J¼6.8 Hz, 2H), 2.48
(CDCl3, 400 MHz):
6.89 (s, 1H), 4.60 (s, 1H), 4.36 (s, 2H), 4.16 (s, 1H), 4.15 (s, 1H), 3.72
(s, 6H), 2.45 (s, 1H); 13C NMR (CDCl3, 75 MHz):
168.1, 134.5, 133.0,
d
7.48 (d, J¼8.4 Hz, 2H), 7.12 (d, J¼8.0 Hz, 2H),
(t, J¼6.8 Hz, 2H), 1.98 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d 168.4,
135.8, 133.3, 130.2, 128.6, 128.5, 127.6, 81.3, 72.5, 69.4, 68.5, 52.7,
51.5, 19.8; HRMS (ESI) calcd for C18H20O5Na (MþNa)þ: 339.1203;
found: 339.1195.
d
131.7, 130.7, 130.2, 121.8, 79.4, 74.7, 71.2, 57.4, 52.8, 51.5; HRMS (ESI)
calcd for C17H17BrO5Na (MþNa)þ: 403.0152; found: 403.0153.
4.2.13. (E)-Dimethyl 2-(3-(benzyl(prop-2-ynyl)amino)-1-phenylprop-
4.2.6. Dimethyl 2-(1-(2-bromophenyl)-3-(prop-2-ynyloxy)prop-1-en-
1-en-2-yl)malonate (3m). Light golden oil; the sole E-isomer:
2-yl)malonate (3f). Yellow oil; E/Z¼90:10; the E-isomer: 1H NMR
1H NMR (CDCl3, 400 MHz):
d
7.38e7.21 (m, 10H), 6.77 (s, 1H), 4.67
(s, 1H), 3.73 (s, 6H), 3.54 (s, 2H), 3.43 (s, 2H), 3.16 (s, 2H), 2.03 (s, 1H);
13CNMR(CDCl3,75MHz):
169.0,138.3,136.2,133.6,132.3,129.2,129.1,
(CDCl3, 400 MHz):
d
7.59 (d, J¼8.0 Hz, 1H), 7.32e7.27 (m, 2H),
7.20e7.12 (m, 1H), 6.87 (s, 1H), 4.45 (s, 1H), 4.42 (s, 2H), 4.21 (s, 1H),
d
4.20 (s, 1H), 3.69 (s, 6H), 2.45 (s, 1H); 13C NMR (CDCl3, 75 MHz):
128.3, 128.1, 127.2, 127.1, 78.4, 73.2, 57.3, 55.4, 52.7, 52.6, 41.0; HRMS
d
168.0, 136.1, 133.8, 132.6, 130.9, 130.3, 129.4, 127.4, 124.0, 79.6, 74.6,
(ESI) calcd for C24H25NO4Na (MþNa)þ: 414.1676; found: 414.1676.
70.9, 57.0, 52.7, 51.7; HRMS (ESI) calcd for C17H17BrO5Na (MþNa)þ:
403.0152; found: 403.0152.
4.2.14. Dimethyl 2-(3-ethoxy-1-phenylprop-1-en-2-yl)malonate (3n).
Yellow oil; E/Z¼75:25; the E-isomer: 1H NMR (CDCl3, 400 MHz):
4.2.7. Dimethyl 2-(1-(4-methoxyphenyl)-3-(prop-2-ynyloxy)prop-1-
d
7.34 (dd, J¼14.0, 6.8 Hz, 3H), 7.26 (t, J¼6.8 Hz, 2H), 6.95 (s, 1H), 4.70
en-2-yl)malonate (3g). Slightly yellow oil; E/Z¼92:8; the E-isomer:
(s,1H), 4.29 (s, 2H), 3.72 (s, 6H), 3.53 (q, J¼7.2 Hz, 2H),1.22 (t, J¼7.2 Hz,
1H NMR (CDCl3, 400 MHz):
d
7.18 (d, J¼8.0 Hz, 2H), 6.89 (s, 2H), 6.87
3H); 13C NMR (CDCl3, 75 MHz):
d
168.5, 135.9, 133.1, 130.8, 129.0,
(s,1H), 4.71 (s,1H), 4.36 (s, 2H), 4.14 (s, 2H), 3.80 (s, 3H), 3.72 (s, 6H),
128.6, 128.5, 128.2, 127.5, 72.3, 66.0, 52.6, 51.5, 15.1; HRMS (ESI) calcd
2.44 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d
168.5, 159.1, 134.4, 129.9,
for C16H20O5Na (MþNa)þ: 315.1203; found: 315.1202.
128.5, 127.9, 114.0, 79.6, 74.5, 71.7, 57.1, 55.2, 52.7, 51.5; HRMS (ESI)
calcd for C18H20O6Na (MþNa)þ: 355.1152; found: 355.1155.
4.2.15. Dimethyl 2-(3-isopropoxy-1-phenylprop-1-en-2-yl)malonate
(3o). Colorless oil; E/Z¼76:24; the E-isomer: 1H NMR (CDCl3,
4.2.8. Diethyl 2-(1-phenyl-3-(prop-2-ynyloxy)prop-1-en-2-yl)malo-
400 MHz): d 7.38e7.31 (m, 3H), 7.29e7.27 (m, 2H), 6.97 (s, 1H), 4.72
nate (3h). Slightly yellow oil; E/Z¼86:14; the E-isomer: 1H NMR
(s, 1H), 4.29 (s, 2H), 3.72 (s, 6H), 3.68 (q, J¼6.0 Hz, 1H), 1.19
(CDCl3, 400 MHz):
d
7.37e7.31 (m, 2H), 7.28e7.21 (m, 3H), 6.96
(d, J¼6.0 Hz, 6H); 13C NMR (CDCl3, 75 MHz):
d 168.5, 132.6, 129.0,
128.6, 128.4, 128.1, 127.4, 71.7, 69.8, 52.6, 51.5, 22.0; HRMS (ESI)
(s, 1H), 4.64 (s, 1H), 4.39 (s, 2H), 4.21e4.13 (m, 6H), 2.44 (s, 1H), 1.25
(t, J¼7.2 Hz, 6H); 13C NMR (CDCl3, 75 MHz):
d
166.9, 134.8, 132.9,
calcd for C17H22O5Na (MþNa)þ: 329.1359; found: 329.1358.
128.9, 127.6, 127.4, 126.6, 78.6, 73.5, 70.2, 60.7, 56.1, 51.1, 12.9; HRMS
(ESI) calcd for C19H22O5Na (MþNa)þ: 353.1359; found: 353.1364.
4.3. General procedure for the ring-closing reactions of
nucleophilic ring-opening products 3
4.2.9. Dimethyl 2-(4-phenyl-1-(prop-2-ynyloxy)but-2-en-2-yl)malo-
nate (3i). Yellow oil; E/Z¼88:12; the E-isomer: 1H NMR (CDCl3,
Under a positive pressure of argon, to a stirred solution of
ring-opening products 3 (0.20e0.30 mmol, 1.0 equiv) in dry DCE
(7 mL) were added InCl3 (0.10e0.15 mmol, 50 mol %) and Et3N
(0.02e0.03 mmol, 10 mol %), followed by stirring at 65 ꢀC. After the
completion of the reaction (as monitored by TLC), the solution was
concentrated under reduced pressure to afford the crude products
4, which were purified by silica gel column chromatography using
petroleum ether and EtOAc as eluents. E- and Z-Isomers can be
separated by silica gel chromatography if desired.
400 MHz):
d 7.38e7.25 (m, 2H), 7.22e7.13 (m, 3H), 6.06e5.96
(m, 1H), 4.73 (s, 1H), 4.20 (s, 2H), 4.08 (s, 2H), 3.74 (s, 6H), 3.45
(d, J¼7.2 Hz, 2H), 2.39 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d 168.4,
139.1, 135.1, 134.7, 128.6, 128.5, 128.4, 126.3, 79.6, 74.4, 72.4, 56.8,
52.7, 51.2, 34.3; HRMS (ESI) calcd for C18H20O5Na (MþNa)þ:
339.1203; found: 339.1210.
4.2.10. Dimethyl 2-(1-(prop-2-ynyloxy)dec-2-en-2-yl)malonate (3j).
Slightly yellow oil; E/Z¼30:70: 1H NMR (CDCl3, 400 MHz):
d 5.82
(t, J¼7.2 Hz, 0.30H), 5.68 (t, J¼7.2 Hz, 0.70H), 4.22 (s, 1H), 4.19
4.3.1. Dimethyl 3-benzylidene-5-methylene-tetrahydropyran-4,4-di-
carboxylate (4a). Yellow solid, mp 122e124 ꢀC; E/Z¼86:14; the
(s, 1H), 4.16 (s, 1H), 4.06 (s, 1H), 4.05 (s, 1H), 3.73 (s, 6H), 2.40

768
B. Hu et al. / Tetrahedron 67 (2011) 763e768
E-isomer: 1H NMR (CDCl3, 400 MHz):
d
7.38e7.28 (m, 4H), 7.24e7.20
was evaporated in vacuo and the residue was purified by silica gel
chromatography to afford products 4.
(m,1H), 6.75 (s,1H), 5.21 (s,1H), 4.81 (s,1H), 4.29 (s, 2H), 4.28 (s, 2H),
3.40 (s, 6H); 13C NMR (CDCl3, 75 MHz):
d
168.5, 140.2, 135.9, 131.7,
129.6, 128.2,128.0,127.3,114.6, 72.9, 71.6, 52.7; HRMS (ESI) calcd for
4.4.1. (E)-Dimethyl 3-(4-fluorobenzylidene)-5-methylene-tetrahydro-
pyran-4,4-dicarboxylate (4b). White solid, mp 138e140 ꢀC; the sole
C17H18O5Na (MþNa)þ: 325.1046; found: 325.1053.
E-isomer: 1H NMR (CDCl3, 400 MHz):
d
7.33 (dd, J¼8.8, 6.0 Hz, 2H),
6.99 (t, J¼8.8 Hz, 2H), 6.68 (s,1H), 5.21 (s,1H), 4.82 (s,1H), 4.29 (s, 2H),
4.26 (s, 2H), 3.45 (s, 6H); 13C NMR (CDCl3, 75 MHz):
168.5, 140.1,
4.3.2. Dimethyl 3-(4-chlorobenzylidene)-5-methylene-tetrahydropyran-
4,4-dicarboxylate (4c). White solid, mp 145e147 ꢀC; E/Z¼88:12; the
d
E-isomer: 1H NMR (CDCl3, 400 MHz):
d
7.34e7.27 (m, 4H), 6.67
132.1, 130.1, 130.0, 128.5, 115.0, 114.8, 114.8, 72.7, 71.6, 52.8; HRMS
(s, 1H), 5.21 (s, 1H), 4.81 (s, 1H), 4.29 (s, 2H), 4.26 (s, 2H), 3.45
(ESI) calcd for C17H17FO5Na (MþNa)þ: 343.0952; found: 343.0952.
(s, 6H); 13C NMR (CDCl3, 75 MHz):
d
168.4, 140.0, 134.4, 133.3, 132.7,
129.7, 128.3, 128.2, 114.8, 72.7, 71.6, 52.8; HRMS (ESI) calcd for
4.4.2. Dimethyl 3-(4-methylbenzylidene)-5-methylene-tetrahydropyran-
C17H17ClO5Na (MþNa)þ: 359.0657; found: 359.0654.
4,4-dicarboxylate (4n). Yellow solid, mp 109e111 ꢀC; E/Z¼92:8; the
E-isomer: 1H NMR (CDCl3, 400 MHz):
d
7.22 (d, J¼8.0 Hz, 2H), 7.10 (d,
4.3.3. Dimethyl 3-(3-chlorobenzylidene)-5-methylene-tetrahydropyran-
J¼8.0 Hz, 2H), 6.71 (s, 1H), 5.19 (s, 1H), 4.81 (s, 1H), 4.28 (s, 2H), 4.26 (s,
4,4-dicarboxylate (4d). Pale yellow solid, mp 113e115 ꢀC; E/Z¼
2H), 3.41 (s, 6H), 2.31 (s, 3H); 13C NMR (CDCl3, 75 MHz):
d
168.6, 140.3,
87:13; the E-isomer: 1H NMR (CDCl3, 400 MHz):
d
7.35 (s, 1H),
137.0,133.0,131.2, 129.7, 128.7,128.2, 114.6, 72.9, 71.6, 52.7, 21.2; HRMS
7.27e7.21 (m, 3H), 6.65 (s, 1H), 5.21 (s, 1H), 4.83 (s, 1H), 4.30 (s, 2H),
(ESI) calcd for C18H20O5Na (MþNa)þ: 339.1203; found: 339.1197.
4.26 (s, 2H), 3.47 (s, 6H); 13C NMR (CDCl3, 75 MHz):
d
168.3, 140.0,
137.7, 133.8, 133.3, 129.4, 128.3, 127.9, 127.4, 126.4, 114.8, 72.5, 71.5,
52.8, 29.7; HRMS (ESI) calcd for C17H17ClO5Na (MþNa)þ: 359.0657;
found: 359.0654.
Acknowledgements
We thank the National Natural Science Foundation of China
(No. 20972069) and National Key Project of Scientific and Technical
Supporting Programs (973 Program) (No. 2010CB126106) for
financial support.
4.3.4. Dimethyl 3-(2-bromobenzylidene)-5-methylene-tetrahydropyran-
4,4-dicarboxylate (4f). Yellow solid, mp 128e131 ꢀC; E/Z¼88:12;
the E-isomer: 1H NMR (CDCl3, 400 MHz):
d
7.56 (t, J¼7.6 Hz, 2H),
7.24 (t, J¼7.6 Hz, 1H), 7.11 (t, J¼7.6 Hz, 1H), 6.56 (s, 1H), 5.20 (s, 1H),
Supplementary data
4.81 (s, 1H), 4.31 (s, 2H), 4.27 (s, 2H), 3.41 (s, 6H); 13C NMR (CDCl3,
75 MHz): d 168.5, 139.9, 136.1, 132.7, 132.0, 130.2, 129.1, 128.6, 127.0,
1H and 13C NMR spectra and NOESY of compound 3a. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2010.11.048. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
124.2, 114.7, 72.3, 71.4, 52.7; HRMS (ESI) calcd for C17H17BrO5Na
(MþNa)þ: 403.0152; found: 403.0157.
4.3.5. Diethyl 3-benzylidene-5-methylene-tetrahydropyran-4,4-di-
carboxylate (4h). Yellow oil; E/Z¼72:28; the E-isomer: 1H NMR
(CDCl3, 400 MHz):
d
7.38 (d, J¼7.2 Hz, 2H), 7.32e7.24 (m, 3H), 6.72
References and notes
(s, 1H), 5.19 (s, 1H), 4.86 (s, 1H), 4.30 (s, 2H), 4.27 (s, 2H), 3.99e3.89
(m, 2H), 3.73e3.62 (m, 2H), 1.14 (t, J¼7.2 Hz, 6H); 13C NMR (CDCl3,
75 MHz): 168.1, 140.4, 136.2, 131.8, 129.4, 128.3, 127.9, 127.3, 114.5,
73.0, 71.7, 62.0, 13.8; HRMS (ESI) calcd for C19H22O5Na (MþNa)þ:
353.1359; found: 353.1358.
1. (a) Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589e635; (b) Audran, G.; Pellissier, H.
Adv. Synth. Catal. 2010, 352, 575e608.
2. For selected reviews on reactions of MCPs, see: (a) Goti, A.; Cordero, F. M.;
Brandi, A. Top. Curr. Chem. 1996, 178, 1e97; (b) Brandi, A.; Cicchi, S.; Cordero, F. M.;
Goti, A. Chem. Rev. 2003, 103, 1213e1269; (c) Nakamura, I.; Yamamoto, Y. Adv.
Synth. Catal. 2002, 344, 111e129; (d) Binger, P.; Buch, H. M. Top. Curr. Chem.
1987, 135, 77e151; (e) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35,
867e877; (f) Pellissier, H. Tetrahedron 2010, 66, 8341e8375.
3. (a) Shi, M.; Xu, B. Org. Lett. 2002, 4, 2145e2148; (b) Shi, M.; Chen, Y.; Xu, B.;
Tang, J. Tetrahedron Lett. 2002, 43, 8019e8024; (c) Huang, X.; Yang, Y. Org. Lett.
2007, 9, 1667e1670.
4. (a) Miura, K.; Takasumi, M.; Hondo, T.; Saito, H.; Hosomi, A. Tetrahedron Lett.
1997, 38, 4587e4590; (b) Peron, G. L. N.; Kitteringham, J.; Kilburn, J. D.
Tetrahedron Lett. 1999, 40, 3045e3048; (c) Lautens, M.; Han, W. J. Am. Chem. Soc.
2002, 124, 6312e6316; (d) Huang, X.; Miao, M. J. Org. Chem. 2008, 73, 6884e6887.
5. (a) Hu, B.; Zhu, J.; Xing, S.; Fang, J.; Du, D.; Wang, Z. Chem.dEur. J. 2009, 15,
324e327; (b) Hu, B.; Xing, S.; Wang, Z. Org. Lett. 2008, 10, 5481e5484.
6. (a) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645e9660; (b) Lu, L.;
Chen, G.; Ma, S. Org. Lett. 2006, 8, 835e838.
4.3.6. Dimethyl
5-benzylidene-2-methyl-3-methylene-tetrahydropy-
ran-4,4-dicarboxylate (4k). Yellowish solid, mp 118e119 ꢀC; E/Z¼
78:22; the E-isomer: 1H NMR (CDCl3, 400 MHz):
d 7.37e7.27 (m, 4H),
7.25e7.17 (m, 1H), 6.71 (s, 1H), 5.21 (s, 1H), 4.85 (s, 1H), 4.46
(d, J¼14.0 Hz, 1H), 4.25 (d, J¼14.0 Hz, 1H), 4.19 (q, J¼6.4 Hz, 1H), 3.53
(s, 3H), 3.25 (s, 3H), 1.43 (d, J¼6.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d
169.0, 168.6, 144.8, 136.0, 132.4, 128.5, 128.2, 128.0, 127.2, 113.4, 74.5,
71.9, 53.0, 52.3, 19.6; HRMS (ESI) calcd for C18H20O5Na (MþNa)þ:
339.1203; found: 339.1204.
7. In the process of this research, Kerr et al. reported a similar example on
cyclopropane 1,1-diester: (a) Leduc, A. B.; Lebold, T. P.; Kerr, M. A. J. Org. Chem.
2009, 74, 8414e8416; (b) Lebold, T. P.; Leduc, A. B.; Kerr, M. A. Org. Lett. 2009, 11,
3770e3772.
4.4. General procedure for the one-pot tandem ring-opening/
intramolecular Conia-ene reactions
8. (a) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1e19; (b) Yamazaki, S. Chem.dEur.
J. 2008, 14, 6026e6036; (c) Clarke, M. L.; France, M. B. Tetrahedron 2008, 64,
9003e9031.
9. CCDC 779932 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Chem. 2010, 1358e1363.
An oven-dried 50 mL three-necked glassware was charged with
Eu(OTf)3 (60 mg, 0.10 mmol, 20 mol %), InCl3 (55 mg, 0.25 mmol,
50 mol %), and MCPs 1 (0.50 mmol, 1.0 equiv). Dry DCE (7 mL),
propargyl alcohols 2 (2.50 mmol, 5.0 equiv), and 7 mL (0.05 mmol,
10 mol %) of Et3N were then added sequentially under a positive
pressure of argon. The reaction mixture was heated to 80 ꢀC. After
the completion of the reaction (as monitored by TLC), the mixture