A catalytic method for the preparation of polysubstituted cyclopentanes: [3+2] cycloaddition of vinylidenecyclopropanes with activated olefins catalyzed by triflic imide

Article abstract of DOI:10.1021/jo802294s

[3+2] Cycloadditions of vinylidenecyclopropanes (VDCPs) with electron-deficient olefins, such as methyl vinyl ketone (MVK) and acrylaldehyde, proceed smoothly in the presence of a catalytic amount of triflic imide (Tf2NH) to give the corresponding functio

Full text of DOI:10.1021/jo802294s

A Catalytic Method for the Preparation of Polysubstituted
Cyclopentanes: [3+2] Cycloaddition of Vinylidenecyclopropanes
with Activated Olefins Catalyzed by Triflic Imide
Wei Li and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
ReceiVed October 13, 2008
[3+2] Cycloadditions of vinylidenecyclopropanes (VDCPs) with electron-deficient olefins, such as methyl
vinyl ketone (MVK) and acrylaldehyde, proceed smoothly in the presence of a catalytic amount of triflic
imide (Tf2NH) to give the corresponding functionalized cyclopentanes in good to high yields.
Introduction
convergent strategies for the formation of the cyclopentane
nucleus.8 In recent years, many efforts have been focused on
donor-acceptor (D-A) substituted cyclopropanes9,10 utilized
as equivalents of a three carbon 1,3-dipole unit for the formation
of five-membered carbocycles. In the presence of Lewis9b,c or
Brønsted acids,11 donor-acceptor cyclopropanes undergo ring-
opening to yield 1,3-zwitterions which react with electron-rich
olefins or alkynes to furnish multisubstituted five-membered
carbocyclic rings.
Vinylidenecyclopropanes (VDCPs) 1 are some of the most
remarkable organic compounds which have an allene moiety
connected by a cyclopropane ring and yet are thermally stable
and reactive substances in organic synthesis. Significant pio-
neering work has been done for this particular kind of organic
compounds;12 however, few reports on the cycloaddition of
VDCPs to form five-membered carbocyclic rings have been
Five-membered carbocyclic rings appear in the most classes
of organic materials including pharmaceutical agents, polymers,
natural products, and catalysts.1 Thus far, numerous methods
and strategies for the construction of five-membered carbocyclic
rings have been reported by traditional reactions such as Michael
addition,2 Aldol reaction,3 Wittig reaction,4 free radical cycliza-
tion,5 and rearrangement of some special compounds,6 as well
as by cyclizations in the presence of metal complexes.7
Moreover, some other synthetic strategies, such as [3+2], [4+1],
and [2+2+1] cycloadditions, are also available for the synthesis
of five-membered carbocyclic rings. Among these methodolo-
gies,[3+2]cycloadditionssbothconcertedandstepwisesrepresent
* Corresponding author. Fax: 86-21-64166128.
(1) For reviews, see: (a) Hudlicky, T.; Price, J. D. Chem. ReV 1989, 89, 1467–
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856 J. Org. Chem. 2009, 74, 856–860
10.1021/jo802294s CCC: $40.75 2009 American Chemical Society
Published on Web 12/02/2008

Preparation of Polysubstituted Cyclopentanes
reported so far.13 In contrast to cycloaddition reactions involving
the donor-acceptor cyclopropanes with electron-rich olefins,
we are pleased to disclose in this paper a novel strategy to
construct the cyclopentane nucleus from VDCPs and electron-
deficient olefins in the presence of Tf2NH.14
TABLE 1. Optimization of the [3+2] Cycloaddition Reaction
Conditions
Results and Discussion
entrya Bronsted acid
x
solvent
time
1 h
12 h
48 h
48 h
1 h
yield (%)b of 3a
At the outset of this study, the [3+2] cycloaddition of VDCP
1a with 1.5 equiv of methyl vinyl ketone (MVK) 2a was
examined by using several Brønsted acids in dichloromethane
and the results of these experiments are presented in Table 1.
Treatment of VDCP 1a with MVK 2a in the presence of triflic
imide (Tf2NH, 10 mol %) in CH2Cl2 at room temperature (25
°C) for 1 h afforded the polysubstituted cyclopentane 3a in 95%
yield (Table 1, entry 1). However, using other Brønsted acids,
such as trifluoromethanesulfonic acid (TfOH), p-methylbenze-
nesulfonic acid (p-TSA), and methanesulfonic acid (MeSO3H),
resulted in 3a in lower yields and most of 1a was recovered,
although TfOH is very effective in the [3+2] cycloaddition
reactions of diarylvinylidenecyclopropanes with nitriles12c (Table
1, entries 2-4). Since Tf2NH as the strong Brønsted acid is
very effective in some catalytic carbon-carbon bond-forming
reactions,15-18 the employed amount of Tf2NH was examined
in this cycloaddition. It was found that using 4.0 mol % of
1
Tf2NH
TfOH
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
10 CH2Cl2
4
4
4
4
4
4
4
4
95
16
8
11
97(95)f
68
_g
_g
3
2c
3d
4e
5
p-TSA
MeSO3H
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
CH2Cl2
toluene
acetonitrile 4 h
THF
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
6
7
8
9
4 h
4 h
4 h
10 min
10 min
1 h
10h
11i
12j
94
97
95
a Reaction conditions: VDCP (0.18 mmol) and MVK (1.5 equiv) were
dissolved in dry solvent (2.0 mL), Bronsted acid (x mol %) was added,
then the mixtures were stirred for different times at room temperature.
b Isolated yield. c 50% of 1a was recovered. d 62% of 1a was recovered.
e 58% of 1a was recovered. f The mixture was stirred for 10 min. g 3a
was not detected by TLC plates. h 2.0 equiv of MVK was added. i 1.2
equiv of MVK was added. j 1.0 equiv of MVK was added. MVK )
methyl vinyl ketone.
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FIGURE 1. ORTEP drawing of 3a.
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2719. (b) Yadav, V. K.; Sriramurthy, V. Angew. Chem., Int. Ed. 2004, 43, 2669–
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cited therein.
Tf2NH as the catalyst afforded 3a in 97% yield within 1 h and
95% yield within 10 min, respectively (Table 1, entry 5). The
examination of solvent effects revealed that the reaction was
much more sluggish in toluene, producing 3a in 68% yield
within 4 h (Table 1, entry 6). When the reaction was carried
out in polar solvents, such as acetonitrile, tetrahydrofuran (THF),
and ether, either no reaction occurred or 3a was obtained in
low yield (Table 1, entries 7-9). With use of 2.0, 1.2, and 1.0
equiv of MVK in CH2Cl2 at room temperature (25 °C), the
(14) Some recent examples for the construction of carbocycles catalyzed by
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4749–4753. (b) Takasu, K.; Miyakawa, Y.; Ihara, M.; Tokuyama, H. Chem.
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J. Org. Chem. Vol. 74, No. 2, 2009 857

Li and Shi
TABLE 2. The Cycloaddition Reactions of 1 with 2a under the Optimal Conditions
a Reaction conditions: 1 (0.18 mmol) and MVK (1.2 equiv) were dissolved in CH2Cl2 (2 mL) and Tf2NH (2 mg, 4 mol %) was added, then the
mixtures were stirred for different times at room temperature. b Isolated yield. c E- or Z-isomeric mixture ) 3:2. d E- or Z-isomeric mixture ) 3:1. e E-
or Z-isomeric mixture ) 3:2. f 4c:4c′ ) 2:1. g 4d:4d′ > 99:1.
reaction proceeded smoothly to give 3a in 94%, 97%, and 95%
yield within 10 min or 1 h, respectively (Table 1, entries 10-12).
The structure of 3a has been further confirmed by X-ray
diffraction and its CIF data have been presented in the
Supporting Information (Figure 1).19
the unsymmetrical VDCPs 1c and 1d, 4b and 4c were obtained
as the major regiochemical isomers of the side product mixtures
because the aromatic ring containing more electron-donating
methyl groups facilitates such intramolecular Friedel-Crafts
reaction (Table 2, entries 2 and 3). Using vinylidenecyclopro-
pane 1e bearing a strongly electron-donating methoxy group
on the benzene ring as the substrate afforded the expected
product 3e in 51% yield along with some other byproducts
(Table 2, entry 4). As for the substrate 1k, the corresponding
cycloadduct 3k was obtained in 31% yield, presumably due to
that the replacement of a phenyl group with a methyl group
would reduce the nucleophilicity of the allenic moiety and did
not facilitate such cycloaddition (Table 2, entry 10).21
With these optimal conditions in hand, we next examined
the scope and limitations of this interesting cycloaddition
reaction using a variety of vinylidenecyclopropanes 1 and the
results of these experiments are shown in Table 2. As for VDCPs
1f-j bearing electron-withdrawing groups on the benzene rings,
the cycloaddition reaction proceeded smoothly to provide the
corresponding five-membered carbocyclic products 3f-j in good
to excellent yields within 2 h (Table 2, entries 5-9). In the
case of the unsymmetrical VDCPs 1h-j, the cycloadducts 3h-j
were obtained as E- or Z-isomeric mixtures (Table 2, entries
7-9). However, as for vinylidenecyclopropanes 1b-d bearing
moderately electron-donating methyl groups on the benzene
rings, the cycloaddition reaction proceeded more rapidly to
afford the expected products 3b-d in moderate to good yields
(82%, 75%, and 52%, respectively) along with another byprod-
uct 4b,20 4c (4c′), and 4d (4d′) in low yields (13%, 25%, and
38%, respectively), indicating that electron-rich aromatic ring
facilitates such cycloaddition and the subsequent intramolecular
Friedel-Crafts reaction (Table 2, entries 1-3). In the case of
Next, on the basis of above results, we attempted to utilize
some other electron-deficient olefins 2 to react with 1a under
similar conditions and the results are summarized in Table 3.
The cycloaddition of 1a with acrylaldehyde 2b proceeded very
smoothly within 1 h, providing the corresponding cycloadduct
5a in 88% yield (Table 3, entry 1). In the reaction of 1a with
ethyl vinyl ketone 2c and phenyl vinyl ketone 2d, the expected
cycloadducts 5b and 5c were obtained in 92% and 85% yield
along with the byproduct 6b and 6c in 6% and 10% yield,
respectively, under identical conditions (Table 3, entries 2 and
3). Moreover, 1a could also react with 2-cyclohexen-1-one (2e;
10 equiv) smoothly to give cycloadduct 5d in 56% yield,
although a large excess amount of 2e was required (Table 3,
entry 4). However, as for the multisubstituted olefins, such as
pent-3-en-2-one (2f) and 3-methylbut-3-en-2-one (2g), complex
product mixtures were obtained under the standard reaction
(19) The crystal data of 3a have been deposited in CCDC with number
671319. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax +44-1223/336-033;
E-mail deposit@ccdc.cam.ac.uk).
(20) The stereochemistry of 4b has been further confirmed by X-ray
diffraction and its CIF data have been presented in the Supporting Information
(CCDC 691928). Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax +44-1223/336-033;
E-mail deposit@ccdc.cam.ac.uk).
(21) Li, W.; Shi, M. J. Org. Chem. 2008, 73, 6698–6705.
858 J. Org. Chem. Vol. 74, No. 2, 2009

Preparation of Polysubstituted Cyclopentanes
TABLE 3. The Cycloaddition Reactions of 1 with 2 under
Modified Conditions
SCHEME 2. A Proposed Mechanism of the Cycloaddition
Reaction
a Reaction conditions: 1a (0.18 mmol) and 2 (x equiv) were dissolved
in CH2Cl2 (2 mL) and Tf2NH (2 mg, 4 mol %) was added, then the
mixtures were stirred for different times at room temperature. b Isolated
yield.
generate intermediate A, which undergoes a 1,4-nucleophilic
addition reaction with the central carbon in the allene moiety of
1a to give intermediate B. Ring opening of cyclopropane in
intermediate B produces intermediate C. Product 3a is obtained
from intermediate C through an intramolecular nucleophilic attack.
The product 3a could be further transformed to the product 4a via
intermediate D, which was generated from 3a by protonation, and
a subsequent intramolecular Friedel-Crafts reaction. Alternatively,
intermediate D′ can also be given by protonation of 3a. However,
since intermediate D′ is less stable than the allylic cationic
intermediate D that is responsible for the formation of 4a, product
E is not formed in this reaction system. This is the reason why
product 4a can be exclusively produced in this reaction (Scheme
2).
SCHEME 1. The Transformation of 3 to 4 in the Presence
of Tf2NH
The generality of this cycloaddition reaction was also
examined by using a variety of vinylidenecyclopropanes 7
having two aromatic rings at the cyclopropane under the optimal
conditions and the results of these experiments are summarized
in Table 4. The corresponding cyclopentane derivatives 8a-f
were obtained in good to excellent yields (67-95%) whether
electron-donating or electron-withdrawing groups were intro-
duced on the benzene ring of 7 (Table 4, entries 1-6). The
structure of 8a has been further confirmed by X-ray diffraction
and its CIF data have been presented in the Supporting
Information.25
When vinylidenecyclopropane 9 was used to react with MVK,
we found that the corresponding five-membered carbocyclic
product 10 was formed in 23% yield along with a naphthalene
derivative 11 in 20% yield, suggesting that the substituted pattern
on the cyclopropane could also significantly affect the reaction
outcome. A plausible mechanism of this reaction was outlined
in Scheme 3. First, vinylidenecyclopropane 9 produces inter-
mediate F via a 1,4-nucleophilic addition to intermediate A
conditions, presumably due to the steric hindrance22,23 (Table
3, entries 5 and 6). It should be noted that some other electron-
deficient olefins, such as acrylic acid, methyl acrylate, and
acrylonitrile, could not react with vinylidenecyclopropanes under
the standard conditions.
To clarify the formation route of byproducts 4 and 6, a control
experiment was carried out by treatment of cycloadducts 3a
and 3b with Tf2NH in CH2Cl2. The corresponding products 4a
and 4b were provided in 85% and 83% yield, respectively,
suggesting that the byproducts 4 and 6 were derived from a
further intramolecular Friedel-Crafts reaction of 3 and 5 in the
presence of a strong Brønsted acid (Scheme 1).24
On the basis of the above results, a plausible reaction mechanism
for the cycloaddition of vinylidenecyclopropanes 1 (1a as the
example) with electron-deficient olefins 2 (MVK as the example)
is outlined in Scheme 2. First, MVK is protonated by Tf2NH to
(22) Please see the 1H and 13C NMR spectroscopic data of 3a in the SI and
Figure 1 above.
(23) As far as we know, there has been no report in the literature on any
skeleton analogy to 3a having all carbons substituted five-membered carbocycles.
(24) (a) Chavan, S. P.; Thakkar, M.; Kalkote, U. R. Tetrahedron Lett. 2007,
48, 643–646. (b) Janssen, C. G. M.; Godefroi, E. F. J. Org. Chem. 1984, 49,
3600–3603.
(25) The crystal data of 8a have been deposited in CCDC with number
678843. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax +44-1223/336-033;
E-mail deposit@ccdc.cam.ac.uk).
J. Org. Chem. Vol. 74, No. 2, 2009 859

Li and Shi
TABLE 4. The Cycloaddition Reaction of 7 with 2a under the
Optimal Conditions
electron-deficient olefins 2 to provide a variety of cyclopentane-
containing derivatives 3 and 8 in moderate to excellent yields
catalyzed by Tf2NH under mild conditions. Efforts are in
progress to elucidate further mechanistic details of these
reactions and to understand their scope and limitations.
Experimental Section
1
General Remarks. H NMR spectra were recorded on a 300
entrya
Ar1/Ar2
time (h)
yield (%)b of 8
MHz spectrometer in CDCl3 with tetramethylsilane as the internal
standard. Infrared spectra were measured on a spectrometer. Mass
spectra were recorded by the EI method, and HRMS was measured
on a Kratos Analytical Concept mass spectrometer (EI or MALDI).
Satisfactory CHN microanalyses were obtained with an analyzer.
Melting points are uncorrected. All reactions were monitored by
TLC with silica gel coated plates. Flash column chromatography
was carried out with use of 300-400 mesh silica gel at increased
pressure.
1
2
3
4
5
6
C6H5/C6H5, 7a
1
1
1
1
1
1
8a, 76
8b, 79
8c, 82
8d, 95
8e, 71
8f, 67
p-FC6H4/p-MeC6H4, 7b
C6H5/p-FC6H4, 7c
p-MeC6H4/C6H5, 7d
p-CIC6H4/C6H5, 7e
p-FC6H4/C6H5, 7f
a Reaction conditions: VDCP 7 (0.18 mmol) and MVK (1.2 equiv)
were dissolved in CH2Cl2 (2 mL) and Tf2NH (2 mg, 4 mol%) was
added, then the mixtures were stirred for 1 h at room temperature.
b Isolated yield.
General Procedure for the Cycloaddition of 1 with MVK.
Vinylidenecyclopropanes (VDCPs) 1 (0.18 mmol) and MVK (15
mg, 0.22 mmol, 1.2 equiv) were dissolved in CH2Cl2 (3 mL), then
Tf2NH (2 mg, 4 mol %) was added. The mixture was stirred for
0.5 to 2 h at room temperature (25 °C). The solvent was removed
in vacuo, and the residue was purified by flash column chroma-
tography on silica gel column with petroleum ether-EtOAc (40:
1) as an eluent.
SCHEME 3. The Reaction Mechanism of 9 with MVK 2a
Catalyzed by Tf2NH
1-(4-(Diphenylmethylene)-2,2-dimethyl-3-(propan-2-yli-
dene)cyclopentyl)ethanone, 3a: white solid, mp 150-152 °C; 1H
NMR (CDCl3, 300 MHz, TMS) δ 1.04 (s, 3H, CH3), 1.18 (s, 3H,
CH3), 1.64 (s, 3H, CH3), 1.67 (s, 3H, CH3), 2.16 (s, 3H, CH3),
2.30 (br s, 1H, CH), 2.67-2.72 (m, 2H, CH2), 7.13-7.16 (m, 5H,
Ar), 7.20-7.29 (m, 5H, Ar). 13C NMR (CDCl3, 75 MHz, TMS) δ
21.3, 23.0, 25.8, 28.9, 31.7, 34.5, 42.9, 63.5, 126.0, 126.7, 127.6,
127.9, 128.7, 130.4, 130.5, 137.2, 139.9, 140.1, 143.9, 144.1, 209.8.
IR (CH2Cl2) ν 3077, 3021, 2966, 2926, 2717, 1706, 1597, 1491,
1442, 1358, 1212, 1151, 1073, 1031, 770, 699, 586 cm-1. MS (%)
m/e 344 (M+, 13), 329 (9), 246 (11), 232 (19), 231 (100), 216 (12),
165 (5), 91 (3), 43 (4). Anal. Calcd. for C25H28O: C, 87.16; H,
8.19. Found: C, 87.18; H, 8.01.
Acknowledgments. We thank the Shanghai Municipal Com-
mittee of Science and Technology (06XD14005, 08dj1400100-
2), the National Basic Research Program of China (973)-
2009CB825300, and the National Natural Science Foundation
of China for financial support (20472096, 20872162, 20672127,
and 20732008).
similarly as shown in Scheme 2, which is then transformed to
intermediate G via a ring-opening process. Subsequent cycliza-
tion of G gives intermediate H, which undergoes isomerization
to furnish product 10. Alternatively, intermediate G′, which is
an equivalent of intermediate G, can afford intermediate I via
an intramolecular Friedel-Crafts reaction. Similarly, subsequent
aromatization of intermediate I furnishes product 11. The
structure of 11 was unambiguously determined by X-ray
diffraction and its CIF data have been summarized in the
Supporting Information.26
Supporting Information Available: Detailed description of
experimental procedures, full characterization of new com-
pounds 3, 4, 5, 6, 8, 10, and 11 shown in tables and schemes,
and X-ray crystal analysis data of 3a, 4b, 8a, and 11 (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802294S
Conclusion
(26) The crystal data of 11 have been deposited in CCDC with number
678269. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax +44-1223/336-033;
E-mail deposit@ccdc.cam.ac.uk).
We have developed an efficient method for the [3+2]
cycloaddition reactions of vinylidenecyclopropanes 1 and 7 with
860 J. Org. Chem. Vol. 74, No. 2, 2009