Acid-catalyzed domino Meinwald rearrangement of epoxides/intramolecular [3+2] cross-cycloaddition of cyclopropane-1,1-dicarboxylates

Article abstract of DOI:10.1002/ejoc.201402160

An acid-catalyzed domino Meinwald rearrangement of epoxides/intramolecular [3+2] cross-cycloaddition of cyclopropane 1,1-diesters was developed. This supplied a method for the construction of bridged oxa-[n.2.1] (n = 3, 4) skeletons. Copyright

Full text of DOI:10.1002/ejoc.201402160

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DOI: 10.1002/ejoc.201402160
Acid-Catalyzed Domino Meinwald Rearrangement of Epoxides/Intramolecular
[3+2] Cross-Cycloaddition of Cyclopropane-1,1-dicarboxylates
Wenju Zhu,[a] Jun Ren,[a] and Zhongwen Wang*[a]
Keywords: Rearrangement / Cycloaddition / Domino reactions / Small ring systems / Epoxides
An acid-catalyzed domino Meinwald rearrangement of epox-
ides/intramolecular [3+2] cross-cycloaddition of cycloprop-
ane 1,1-diesters was developed. This supplied a method for
the construction of bridged oxa-[n.2.1] (n = 3, 4) skeletons.
Introduction
Bridged oxa-[n.2.1] skeletons exist in many biologically
important natural products and are also useful building
blocks in organic synthesis.[1,2] We recently developed a ge-
neral and efficient strategy for the construction of bridged
skeletons through intramolecular cross-cycloaddition
(IMCC) of functionalized cyclopropanes with carbonyls,
imines, alkenes, and allenes (Scheme 1).[3] In our previous
study of the [3+2] IMCC of cyclopropane 1,1-diesters[4]
with carbonyls,[3e] we found that in comparison to the benz-
aldehyde [Scheme 2, Equation (1)] and phenylacetone sub-
strates [Scheme 2, Equation (2)], the phenylacetaldehyde
substrate was difficult to prepare to give the desired bridged
oxa-[3.2.1] skeleton owing to its instability during the isola-
tion process. In our recent research, we found that the phen-
ylacetaldehyde derivative could be in situ generated through
a Meinwald (Pinacol) rearrangement[5] of the epoxide and
that it took part in the subsequent [3+2] IMCC of cyclopro-
pane with the carbonyl group. This novel domino reaction
further expanded the scope of the IMCC strategy for the
construction of bridged skeletons [Scheme 2, Equation (3)].
Herein, we report these results.
Scheme 2.
Results and Discussion
Cyclopropane epoxide 1a was prepared as a mixture of
two diastereoisomers to start the investigation. Under catal-
ysis of scandium(III) trifluoromethanesulfonate [Sc(OTf)3,
0.03 equiv.] and upon performing this reaction at –10 °C for
0.5 h, a Meinwald rearrangement of the epoxide afforded
phenylacetaldehyde 3 in 65% yield (Table 1, entry 1). If the
reaction was run for an additional 2 h at 60 °C, cycload-
dition product 2a was obtained in 89% yield (Table 1, en-
try 2). The two diastereoisomers of 1a were then separated,
and the reaction of each under catalysis of Sc(OTf)3 at
60 °C for 2 h gave almost the same result (86 and 89% yield,
respectively).[6] A broad scope of Lewis and Brønsted acids
were then screened, and the results are listed in Table 1.
Most of the Lewis acids were quite effective for the domino
reaction. In most cases under Lewis acid catalysis
(0.03 equiv.), the reactions were finished within 2 h at 60 °C,
and the products were delivered in excellent yields. Several
Brønsted acids were also screened for this process. HCl, p-
toluenesulfonic acid (TsOH), and trifluoroacetic acid (TFA)
gave only Meinwald rearrangement product 3 (Table 1, en-
tries 27–29). However, to our surprise, we found that TfOH
Scheme 1. IMCC strategy of functionalized cyclopropanes for the
construction of bridged skeletons.
[a] State Key Laboratory and Institute of Elemento-Organic
Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Nankai University,
94# Weijin Road, Tianjin 300071, P. R. China
E-mail: wzwrj@nankai.edu.cn
http://wzw.nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402160.
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W. Zhu, J. Ren, Z. Wang
SHORT COMMUNICATION
was quite effective for the domino process. The reaction was 2eЈ, respectively (Table 2, entries 4 and 5). Substrate 1f also
completed within 12 h at room temperature and the product gave cycloaddition product 2f as a mixture of two diastereo-
was obtained in an excellent yield (96%; Table 1, entry 26). isomers (Table 2, entry 6). Substrate 1g with two methyl
This was important, because Brønsted acids have been ra- groups at the external carbon atom of the epoxy moiety
rely reported to be effective catalysts in cycloaddition reac- gave cycloaddition product 2g together with 2gЈ (Table 2,
tions of carbonyls with donor–acceptor cyclopropanes.
entry 7). Formation of 2dЈ, 2eЈ, and 2gЈ implied a stepwise
Table 1. Optimization for the intramolecular [3+2] domino cyclo-
addition of cyclopropane 1,1-diester 1a in the presence of acid cata-
lysts.[a]
Table 2. Acid-catalyzed domino Meinwald rearrangemement/[3+2]
IMCC.[a]
Entry
Cat.
T [°C]
t [h]
Yield[b] [%]
2
3
1
Sc(OTf)3
Sc(OTf)3
Er(OTf)3
Sn(OTf)2
Yb(OTf)3
Bi(OTf)3
Ga(OTf)3
Cu(OTf)
Cu(OTf)2
Cu(OTf)2·Ph
Em(OTf)3
In(OTf)3
Lu(OTf)3
Ha(OTf)4
Al(OTf)3
AgOTf
PPh3·AuCl/AgOTf
Ag(PF6)
Ag(SbF6)
TMSOTf
AuCl
PtCl2
SnCl4
–10
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
0.5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
65
2[c]
3
89
38
98
70
95
96
93
81
71
50
15
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26[c,d]
27[d]
28[d]
29[d]
67
91
65
85
92
82
69
10
Ͻ5
Ͻ5
Ͻ5
10
75
94
31
12
27
28
47
62
Ni(ClO4)2·6H2O
BF3·OEt2
TfOH
HCl
TsOH
31
96
–78 to 40 12
r.t.
60
60
60
12
2
2
88
91
90
TFA
2
[a] The reaction was conducted with 1a (0.1 mmol), Lewis or
Brønsted acid (0.03 equiv.), and 1,2-dichloroethane (DCE, 5 mL).
1
[b] Estimated by analysis of the crude product by H NMR spec-
troscopy. [c] Yield of isolated product. [d] Cat. (0.2 equiv.).
The scope of substrates 1 was then investigated (Table 2).
Substrates 1 with various substituents were investigated
(Table 2, entries 1–8). Substrates 1b and 1c with methyl and
ethyl groups at the external carbon atom of the epoxy moi-
ety gave corresponding cycloaddition products 2b and 2c,
respectively, in excellent yield (Table 2, entries 2 and 3).
However, instead of the cycloaddition products, substrates
[a] Reaction conditions: cyclopropane (0.1 mmol), TfOH
(0.2 equiv.), DCE (5 mL), 65 °C 4 h, Ar. [b] Yield of isolated prod-
uct. [c] T = 25 °C, 12 h. [d] TMSOTf (0.2 equiv.). [e] T = 32 °C,
1d and 1e with n-butyl and phenyl substituents gave 2dЈ and 12 h. [f] Sc(OTf)3 (0.2 equiv.), 80 °C, 8 h.
2
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Acid-Catalyzed Domino Rearrangement/Cross-Cycloaddition
Scheme 3. Proposed mechanism of the domino reaction.
solution of cyclopropane 1 (0.10 mmol) in DCE (5 mL). TLC was
used to monitor the reaction. After the mixture was cooled to room
temperature, the solvent was evaporated under reduced pressure,
and the residue was purified by flash column chromatography to
afford product 2.
mechanism of the [3+2] IMCC (Scheme 3). In these cases,
proton elimination was favored in the final cyclization step
owing to steric hindrance, which was also observed in our
previous study. This is important for understanding the
mechanism. If the methyl substituent was on the internal
carbon atom of the epoxy moiety, 2h was obtained as a
mixture (1:1) of two diastereoisomers in a total yield of
89% (Table 2, entry 8). Reaction of aliphatic substrate 1i
proceeded at 80 °C under catalysis of Sc(OTf)3 to afford the
product in 43% yield (Table 2, entry 9). Reactions of 1j and
1k were also successfully performed to afford 2j and 2k con-
taining a bridged oxa-[4.2.1] skeleton (Table 2, entries 10
and 11).
Dimethyl
8,9-Dihydro-5H-5,8-epoxybenzo[7]annulene-7,7(6H)-di-
carboxylate (2a): White solid, yield: 96%, m.p. 65–66 °C. Rf = 0.24
(EtOAc/petroleum ether, 1:6). 1H NMR (400 MHz, CDCl3): δ =
7.18–7.09 (m, 2 H), 6.98 (dd, J = 9.2, 3.8 Hz, 2 H), 5.40 (d, J =
6.1 Hz, 1 H), 5.10 (d, J = 7.1 Hz, 1 H), 3.77 (s, 3 H), 3.66 (s, 3 H),
3.38 (dd, J = 17.8, 6.1 Hz, 1 H), 2.94 (d, J = 13.1 Hz, 1 H), 2.58
(dd, J = 13.1, 7.2 Hz, 1 H), 2.53 (d, J = 17.8 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 171.45, 169.19, 139.51, 130.19,
128.25, 127.56, 126.13, 123.85, 78.71, 77.46, 64.88, 53.13, 52.80,
On the basis of the above results, a Meinwald (Pinacol)
rearrangement/[3+2] IMCC domino process is proposed
(Scheme 3). A Meinwald (Pinacol) rearrangement of the ep-
oxide affords phenylacetaldehyde, which gives either the
bridged skeleton through a [3+2] IMCC (a SN2-aldol dom-
ino process) or the enol ether through an elimination (inter-
rupted [3+2] IMCC).[7]
44.11, 31.05 ppm. IR (thin film): ν = 3024.1, 2954.0, 2846.2, 1739.2,
˜
1434.35, 1359.8, 1270.1, 1244.3, 1158.0, 1045.4, 758.9, 615.8 cm–1.
HRMS (ESI): calcd. for C15H16O5 [M + Na]+ 299.0890; found
299.0894.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H and 13C NMR spectra of all key intermediates and final prod-
ucts.
Conclusions
Acknowledgments
In summary, we developed an acid-catalyzed domino
Meinwald rearrangement/[3+2] intramolecular cross-cyclo-
addition (IMCC) of cyclopropane 1,1-diesters with epox-
ides. Besides Lewis acids, the Brønsted acid TfOH also ef-
fectively catalyzed the reactions. With the in situ generation
of acetaldehydes from epoxides, this further expands the
scope of the IMCC strategy for the construction of bridged
oxa-[3.2.1] and oxa-[4.2.1] skeletons.
The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 21172109, 21121002) and the Min-
istry of Science and Technology of the People’s Republic of China
(MOST) (grant numbers 2010CB126106, 2011BAE06B05).
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General Procedure: Under an argon atmosphere, the cat. (0.1 m in
DCE, 0.2 mL, 0.02 mmol) was added at room temperature to a
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W. Zhu, J. Ren, Z. Wang
SHORT COMMUNICATION
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Received: February 27, 2014
Published Online: ᭿
4
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Acid-Catalyzed Domino Rearrangement/Cross-Cycloaddition
Cycloaddition
W. Zhu, J. Ren, Z. Wang* ................ 1–5
Acid-Catalyzed Domino Meinwald Re-
arrangement of Epoxides/Intramolecular
[3+2] Cross-Cycloaddition of Cycloprop-
ane-1,1-dicarboxylates
An acid-catalyzed domino Meinwald re-
arrangement of epoxides/intramolecular
[3+2] cross-cycloaddition of cyclopropane
1,1-diesters is developed, which supplies a
method for the construction of bridged
oxa-[n.2.1] (n = 3, 4) skeletons.
Keywords: Rearrangement / Cycloaddition /
Domino reactions / Small ring systems /
Epoxides
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