Synthesis of the indene, THF, and pyrrolidine skeletons by lewis acid mediated cycloaddition of methylenecyclopropanes with aldehydes, N-tosyl aldimines, and acetals

Article abstract of DOI:10.1002/chem.200500447

Methylenecyclopropanes (MCPs 1) react with aldehydes, N-tosyl aldimines, and acetals to give the corresponding indene. THE and pyrrolidine cyclo-addition products in the presence of BF₂·'OEt₂ under mild reaction conditions. Some special transformations of MCPs 1 with aldehydes have been reported in this paper. A plausible reaction mechanism has been discussed, which is based on a deuterium-labeling experiment and the Prins-type reaction mechanism.

Full text of DOI:10.1002/chem.200500447

DOI: 10.1002/chem.200500447
Synthesis of the Indene, THF, and Pyrrolidine Skeletons by Lewis Acid
Mediated Cycloaddition of Methylenecyclopropanes with Aldehydes,
N-Tosyl Aldimines, and Acetals
Li-Xiong Shao,[a] Bo Xu,[a] Jin-Wen Huang,[a] and Min Shi*[b]
Abstract: Methylenecyclopropanes (MCPs 1) react with aldehydes, N-tosyl ald-
imines, and acetals to give the corresponding indene, THF, and pyrrolidine cyclo-
Keywords: cycloaddition · indene ·
addition products in the presence of BF3·OEt2 under mild reaction conditions.
methylenecyclopropanes · synthetic
Some special transformations of MCPs 1 with aldehydes have been reported in
methods · THF
this paper. A plausible reaction mechanism has been discussed, which is based on
a deuterium-labeling experiment and the Prins-type reaction mechanism.
Introduction
Recently, Yamamoto and co-workers reported the synthe-
sis of indenes by ytterbium(iii) triflate catalyzed carboalkox-
ylation/Friedel–Crafts reactions of arylidenecyclopropanes
with acetals. In this study, they reported that the reaction
was inert in solvents such as 1,2-dichloroethane (DCE) or
toluene and temperature sensitive, with 808C being a suita-
ble temperature for its completion.[9] However, in a prelimi-
nary communication, we described the Lewis acid BF3·OEt2-
mediated novel cycloaddition reactions of MCPs 1 with non-
activated aldehydes and N-tosyl aldimines under milder re-
action conditions (room temperature). By using this novel
[3+2] annulation or intramolecular Friedel–Crafts reaction,
the indene, THF, and pyrrolidine skeletons were generat-
ed.[10] In this paper, we report the full details of the
BF3·OEt2-mediated cycloaddition reactions of MCPs 1 with
aldehydes and N-tosyl aldimines, because of their potential
application for the synthesis of several biologically impor-
tant products. The BF3·OEt2-mediated cycloaddition reac-
tions of MCPs 1 with acetals at room temperature in 1,2-di-
chloroethane has also been discussed. In addition, we have
disclosed some special transformations of MCPs 1 with alde-
hydes in the presence of BF3·OEt2. A plausible reaction
mechanism for these transformations has been discussed,
based on both a deuterium-labeling experiment and the
Prins-type reaction mechanism.
Over the past few decades, there has been a mounting inter-
est in the application of methylenecyclopropanes (MCPs 1)
to synthetic transformations. An attractive feature of these
compounds is their surprising stability, despite a high level
of conformational strain.[1,2] In particular, increasing atten-
tion has been paid to the transition-metal-mediated reac-
tions of MCPs, which have been used in the construction of
interesting complex organic molecules.[3] Thus far, it has
been established that in the presence of transition metals,
such as Pd catalyst, MCPs 1 can react with aldehydes[4] or
imines[5] to give the corresponding [3+2] cycloaddition prod-
ucts.
In addition, we and others have reported both Lewis acid
mediated and thermo-induced cycloaddition reactions of
MCPs 1 with aldehydes or ketones to give other types of
cyclic products.[6–8] However, either activated aldehydes, ke-
tones, or MCPs 1 are required to render this type of cyclo-
addition possible.
[a] L.-X. Shao, B. Xu, Dr. J.-W. Huang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
[b] Prof. Dr. M. Shi
East China University of Science and Technology
130 Mei Long Lu, Shanghai 200237 (China)
Fax : (+86)21-6416-6128
Results and Discussion
Lewis acid mediated cycloaddition reactions of MCPs 1 with
aldehydes and N-tosyl aldimines: Initial attempts at cycload-
dition were made with MCP 1a (diphenylmethylenecyclo-
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
propane) and benzaldehyde 2a as the substrates. Of the
Lewis acids and solvents screened, the combination of
BF3·OEt2 and dichloromethane or 1,2-dichloroethane pro-
duced the best results for this transformation, and the corre-
sponding indene product 3a was obtained in a 55% yield,
along with 2,2,5-triphenyl-3,4-dihydro-2H-pyran (4a) in a
28% yield (dichloromethane, room temperature), rather
than the expected [3+2] cycloaddition product (Scheme
1).[6a]
mation of the cycloaddition products 6 and 7 at a higher
temperature than that described above.
Therefore, on the basis of the above investigations, it can
be concluded that a broad spectrum of MCPs 1, aldehydes
2, and N-tosyl aldimines 5 are able to undergo several types
of cycloaddition reaction to give the corresponding annula-
tion products in moderate to good yields under mild condi-
tions.
Lewis acid mediated cycloaddition reactions of MCPs 1 with
acetals: The reactions of MCPs 1 with selected acetals were
carried out in 1,2-dichloroethane under similar conditions to
those described previously (Table 1). The reactions proceed-
Table 1. BF3·OEt2-mediated (0.1 mmol) reactions of MCPs 1 (0.4 mmol)
with acetals (0.4 mmol) at room temperature.
Scheme 1. The cycloaddition reaction of MCP 1a with aldehyde 2a.
A series of MCPs 1 and aldehydes 2 or N-tosyl aldimines
5 were then subjected to the optimal reaction conditions de-
scribed above. For most cases, a wide range of indene deriv-
atives 3 were obtained as the major products in moderate to
high yields by using this methodology. For the reactions of
MCP 1a with N-tosyl aldimines (ArCH=NTs) 5, the corre-
sponding indenes 3 were formed as the sole products in
good yields (Scheme 2).[10]
Entry
MCPs 1[a]
Acetals [R3]
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1b
1c
1d
1d
1d
C6H5
8a, 78
8b, 70
8c, 61
8d, 50
8e, 50
8 f, 67
8g, 50
8h, 71
8i, 60
8j, 74
8k, 84
4-ClC6H4
4-NO2C6H4
4-CH3C6H4
C6H5
4-ClC6H4
4-NO2C6H4
C6H5
C6H5
4-ClC6H4
4-NO2C6H4
10
11
[a] For 1a R1 =R2 =C6H5, 1b R1 =R2 =4-MeOC6H4, 1c R1 =R2 =4-
MeC6H4, and 1d R1 =R2 =4-ClC6H4. [b] Isolated yields.
Scheme 2. BF3·OEt2-mediated (0.1 mmol) reactions of MCPs
(0.5 mmol) with aldehydes (1.0 mmol) or N-tosyl aldimines
(0.75 mmol) at room temperature.
1
5
ed smoothly to give the corresponding indene derivatives 8
in moderate to good yields at room temperature. The use of
either electron-donating or electron-withdrawing substitu-
ents on the benzene ring of the MCPs 1 had a slight affect
upon the yields of the indenes 8 produced. For example, de-
creased yields of the indenes 8 were obtained when using
MCPs 1 with electron-donating groups on the benzene ring
(in most cases these reactions were conducted under identi-
cal conditions, entries 4–8). The use of electron-donating or
electron-withdrawing groups on the phenyl ring of the ace-
tals also had a slight affect upon the yields of indenes 8 pro-
duced, depending on which MCP 1 was employed. Reac-
tions of MCP 1a (diphenylmethylenecyclopropane) with
acetals containing electron-withdrawing groups on the
phenyl ring produced the indenes 8 in lower yields relative
to those obtained when MCP 1d (di(4-chlorophenyl)methyl-
enecyclopropane) was reacted with these acetals (compare:
entries 1–3 with 9–11). For MCP 1b (di(4-methoxy-
phenyl)methylenecyclopropane, entries 4–7), the substitu-
ents on the phenyl ring of the acetals did not significantly
affect the yields of indenes 8 produced (entries 4, 5 and 7),
with the exception of the indene 8 f (entry 6), for which the
2
On the other hand, we found that when the reactions of
MCPs 1 with aliphatic aldehydes 2 or N-tosyl aldimines 5
were carried out at low temperatures (ꢀ258C), the corre-
sponding [3+2] cycloaddition products 6 (THF skeleton)
and 7 (pyrrolidine skeleton) were produced in moderate
yields, without the formation of indene products
(Scheme 3). This result suggests that the corresponding
indene products might be derived from the further transfor-
Scheme 3. BF3·OEt2-mediated (0.1 mmol) reactions of MCPs
1
(0.5 mmol) with aliphatic aldehydes 2 (1.0 mmol) and N-tosyl aldimines 5
(0.75 mmol) at ꢀ258C.
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M. Shi et al.
acetal employed contained a chlorine atom on the benzene
ring.
cases (entries 2 and 4–6), the corresponding 1,3-dioxepanes
11 were obtained as the major products. For the unsymmet-
rical MCP 1 f, the corresponding 1,3-dioxepane 11d was
formed as a mixture of the cis and trans isomers (entry 4,
see also the Supporting Information). The structure of 11b
was confirmed by single crystal X-ray diffraction analysis
(Figure 1).[11] For reactions involving nitrobenzaldehyde, it
Lewis acid mediated cycloaddition reactions of MCPs 1 with
triethylorthoformate: For the next step in our study, we
treated the MCPs 1 with triethylorthoformate (Table 2). The
Table 2. BF3·OEt2-mediated (0.1 mmol) reactions of MCPs 1 (0.8 mmol)
with triethylorthoformate (0.4 mmol) at room temperature.
Entry
MCPs 1[a]
Yield [%][b]
1
2
3
4
1a
1b
1d
1e
9a, 28
trace
9b, 9
9c, 19
10a, 10
10b, 13
10c, 20
10d, 59
[a] For 1a R1 =R2 =C6H5, 1b R1 =R2 =4-MeOC6H4, 1d R1 =R2 =4-
ClC6H4, and 1e R1 =R2 =4-FC6H4. [b] Isolated yields.
reactions proceeded smoothly at room temperature produc-
ing the corresponding indene derivatives 9 in trace-to-low
yields, along with the ring-opened products 10 and ethanol
for each case.[8a] This result can be explained as follows: in
the presence of the Lewis acid BF3·OEt2, triethylorthofor-
mate can easily release one molecule of ethanol, which can
then further react with the MCPs 1 to produce the ring-
opened products 10.[8a] For MCP 1b, which contains elec-
tron-donating groups on its phenyl rings, the corresponding
indene product was formed in trace amounts (entry 2).
Figure 1. The ORTEP drawing of 11b.
should be emphasized that the 1,3-dioxepane 11 can only be
isolated as a substrate at low temperatures (ꢀ208C) and iso-
lation of this product at room temperature is difficult.
For the reactions of MCPs 1 substituted with strongly
electron-donating groups, for example di(4-methoxyphenyl)-
methylenecyclopropane (1b), with various arylaldehydes,
the corresponding oxepanes 12 bearing a cyclopropyl group
at the 3,3’-position were obtained as the sole products
(Table 4). The formation of the oxepanes 12 is sensitive to
the reaction time. In the control experiments, we found that
by varying the reaction time from 1.5 h to 3 h, for the reac-
tion of MCP 1b with 4-nitrobenzaldehyde, the yield of 12a
was increased from 24% to 33%, with the conversion of
MCP 1b increasing dramatically from 50% to 77% (en-
tries 1 and 2). When the reaction time was prolonged to 5 h
the yield of 12a did not increase, but the conversion of
MCP 1b was increased by a further 5% (entries 2 and 3).
The slight increase in the isolated yield of 12a versus the
dramatic increase in the percentage conversion of MCP 1b
suggests that oxepane 12a is labile under the reaction condi-
tions. None of the desired products were obtained when re-
action time was prolonged to 24 h. Similar results were ob-
tained for the reaction of MCP 1b with the nitrobenzalde-
hydes 2b and 2d (entries 4–7). Therefore, for the remaining
arylaldehydes tested, the reactions of MCP 1b were carried
out within 2 h under otherwise identical conditions to the re-
actions described above (entries 8–13). As elucidated in
Table 4, the reactions proceeded smoothly to give the de-
Some interesting results based on the reactions of special
substrates: For the reactions of MCPs 1 with arylaldehydes,
bearing a strongly electron-withdrawing group such as NO2
on the benzene ring (nitrobenzaldehyde), we found that 1,3-
dioxepanes 11 and the corresponding indene products were
obtained at ꢀ208C for all cases (Table 3). In fact, for some
Table 3. BF3·OEt2-mediated (0.1 mmol) reactions of MCPs 1 (0.6 mmol)
with nitrobezadehydes (0.4 mmol).
Entry
MCPs 1[a]
Aldehydes 2[b]
Yield [%][c]
1
2
3
4
5
6
1a
1a
1a
1 f
1d
1e
2b
2c
2d
2c
2c
2c
3b, 39%
3c, 12%
3d, 22%
–
3e, 19%
3 f, 15%
11a, 21%
11b, 56%
11c, 12%
11d, 28% (3:4)[d]
11e, 43%
11 f, 17%
[a] For 1a R1 =R2 =C6H5, 1d R1 =R2 =4-ClC6H4, 1e R1 =R2 =4-FC6H4,
and 1 f R1 =C6H5 and R2 =2-ClC6H4. [b] For 2b R3 =3-NO2, 2c R3 =4-
NO2, and 2d R3 =2-NO2. [c] Isolated yields. [d] Ratio of the two isomers
see Supporting Information.
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Cycloaddition Reactions of Methylenecyclopropanes (MCPs)
FULL PAPER
Table 4. BF3·OEt2-mediated (0.06 mmol) reactions of MCP 1b
(0.8 mmol) with various aldehydes (0.4 mmol).
45% yield, although some unidentified products were also
formed (Scheme 5).
Entry
Aldehydes 2[a]
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
2c
2c
2c
2b
2b
2d
2d
2e
2 f
2g
2h
2i
1.5
3
5
2
5
2
5
2
2
2
2
2
2
12a, 24 (50)
12a, 33 (77)
12a, 33 (82)
12b, 31 (56)
12b, 34 (86)
12c, 34 (58)
12c, 34 (93)
12d, 38 (80)
12e, 47 (89)
12 f, 48 (74)
12g, 30 (72)
12h, 37 (55)
12i, 30 (52)
Scheme 5. BF3·OEt2-mediated reaction of MCP 1a with 4-nitrobenzalde-
hyde at room temperature.
To further clarify the reaction pathway, we also investigat-
ed the reaction of MCP 1a with 4-chlorobenzaldehyde by
using a short reaction time (1.5 h) and temperatures ranging
from ꢀ158C to room temperature. The THF products 6a
and 13a, the starting substrate 2e, the indene product 3g,
and the pyran product 4b were all isolated from this reac-
tion, with the indene product 3g and the pyran product 4b
requiring careful isolation procedures (Scheme 6). The struc-
2a
[a] For 2a R3 =C6H5, 2b R3 =3-NO2C6H4, 2c R3 =4-NO2C6H4, 2d R3 =2-
NO2C6H4, 2e R3 =4-ClC6H4, 2 f R3 =2,4-Cl2C6H3, 2g R3 =2,3-Cl2C6H3, 2h
R3 =3-FC6H4, and 2i R3 =2-ClC6H4. [b] Isolated yields (percentage con-
versions are shown in parentheses).
sired oxepane products 12 in moderate yields at >50% con-
version. Arylaldehydes with electron-withdrawing groups,
such as NO2, F, or Cl, on the phenyl ring are necessary for
this transformation to produce the corresponding oxepanes
12 in moderate yields (Table 4). The reaction of MCP 1b
with benzaldehyde also takes place, under identical condi-
tions, to produce oxepane 12i in 30% yield (entry 13). How-
ever, none of the desired products were obtained when aryl-
aldehydes bearing electron-donating groups on the benzene
ring such as 4-methoxybenzaldehyde and 4-methylbenzalde-
hyde were used for this reaction. Therefore, the choice of
substituent on the benzene ring of the MCPs 1 or arylalde-
hydes drastically affects the products produced from these
reactions.
Scheme 6. Reaction of MCP 1a with 4-chlorobenzaldehyde at ꢀ158C to
room temperature.
ture of 13a was confirmed by single-crystal X-ray diffraction
analysis (Figure 2).[12] We further, unambiguously, confirmed
that both 6a and 13a can be completely transformed into
Exploration of the reaction mechanism: In the following in-
vestigation, we found that the 1,3-dioxepane product 11b
was completely transformed to the indene product 3c (quan-
titative yield) within 1 h in the presence of BF3·Et2O at
room temperature. 4-Nitrobenzaldehyde was also formed
during this reaction (Scheme 4).
Scheme 4. BF3OEt2-mediated transformation of 11b to indene 3c at
room temperature.
Moreover, we also found that when the reaction of MCP
1a with 4-nitrobenzaldehyde was carried out at room tem-
perature for 16 h, the indene product 3c was obtained in
Figure 2. The ORTEP drawing of 13a.
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M. Shi et al.
indene 3g within 0.5 h, in the presence of BF3·Et2O at room
temperature (intramolecular Friedel–Crafts reaction).
Thus, based on the results described above, we can con-
clude that the indenes 3 can also be derived from the further
reaction of the THF products 6 and 13 or 1,3-dioxepane
products 11 in the presence of BF3·OEt2 at room tempera-
ture.
A deuterium-labeling experiment was also carried out,
under the same reaction conditions, by conducting the reac-
tion of MCP 1a with C6H5C(O)D (Scheme 7). The products
Scheme 7. Lewis acid promoted reaction of MCP 1a with C6H5C(O)D.
[D]3a and [D]4a were obtained in 46 and 30% yields, re-
spectively, with 99% D content at the C-1 position
(1H NMR and 13C NMR spectroscopic data is detailed in the
Supporting Information). Deuterium incorporation did not
occur at any other position in [D]3a and [D]4a.
On the basis of the deuterium-labeling experiment and
the fact that the indenes 3 can either be derived from the
THF products 6 and 13 or the 1,3-dioxepane products 11 in
the presence of BF3·OEt2, a plausible reaction mechanism
for the cycloaddition of MCPs 1 with aldehydes has been
proposed (Schemes 8 and 9). This reaction mechanism dif-
fers from that proposed in our preliminary communica-
tion.[10] Initially, reaction of BF3·OEt2 with trace amounts of
water in the reaction system generates the Brønsted acid
type catalyst A.[13] The reaction of catalyst A with MCPs 1
produces the zwitterionic intermediate B (the corresponding
counter ion of BF3·OEt2, that is OHꢀ, has been omitted in
all of the intermediates for convenience). Intermediate B
can probably form an oxonium type cationic intermediate C
with an aldehyde by a Prins-type reaction.[14] The intermedi-
ate C can then further react with another molecule of alde-
hyde to form the intermediate D, another oxonium-type cat-
ionic intermediate.[15] The intramolecular cyclization of D
(also a Prins-type reaction) affords the intermediate E, and
the release of a proton from this intermediate produces the
1,3-dioxepane product 11.[16] For nitrobenzaldehyde, which
contains a strongly electron-withdrawing group on its ben-
zene ring, the reaction of the intermediate C with an alde-
hyde and the intramolecular Prins-type reaction (Route 2)
can take place more easily than for other intermediates, as
the carbon atom of the carbonyl group is more positively
charged for this case. In the presence of Brønsted acid type
catalyst A, 1,3-dioxepane 11 liberates one molecule of the
corresponding aldehyde to give the corresponding THF
product 6.[16] Protonation at the oxygen atom of 6 by the
Brønsted acid type catalyst A affords the cationic intermedi-
ate H, which when followed by the intramolecular Friedel–
Crafts reaction, presumably via the intermediate I, furnishes
Scheme 8. Proposed reaction mechanism for the BF3·OEt2-mediated cy-
cloadditions of MCPs with aldehydes.
the indene product 3 (for arylaldehydes the intramolecular
Friedel–Crafts reaction occurs by the means of Route 1,
Scheme 8). In another route, protonation of the carbon–
carbon double bond of 6 affords the cationic intermediate J,
which when followed by the intramolecular Prins-type reac-
tion gives the cationic intermediate K. The subsequent re-
lease of a proton from K produces another THF product 13
(for aliphatic aldehydes by the means of Route 1 in
Scheme 8).
Alternatively, the intramolecular Prins-type reaction of in-
termediate C directly gives THF product 6 which can form
the indene 3 and THF product 13 in the similar way
(Route 2 in Scheme 8).
On the other hand, the Prins-type reaction of an arylalde-
hyde with MCP 1b (R1 =R2 =4-MeOC6H4) can give the cat-
ionic intermediate M, probably via intermediate L, in the
presence of the Brønsted acid type catalyst A.[13] This cat-
ionic intermediate M should be the most stable intermediate
in this reaction system as it is stabilized by the cyclopropyl
ring and the two phenyl groups, which both bear a strongly
electron-donating methoxy group.[17] This intermediate can
give the reactive cationic intermediate N by the means of a
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Cycloaddition Reactions of Methylenecyclopropanes (MCPs)
FULL PAPER
homoallylic rearrangement,[18] which can then react with an-
other molecule of MCP 1b to produce another stabilized
cationic intermediate O. The intramolecular Prins-type reac-
tion produces the product 12 and regenerates a proton
(Route 3 in Scheme 8).
Moreover, the intermediate B can also form the oxonium-
type cationic intermediate P with a molecule of the alde-
hyde by a Prins-type reaction, which when followed by a fur-
ther intramolecular Prins-type reaction furnishes the cation-
ic intermediate Q.[17] A 1,3-hydrogen shift[19] in intermediate
Q gives the cationic intermediate R. The subsequent 1,2-
aryl shift[20] and the liberation of a proton produces the cor-
responding pyran product 4 (Scheme 9).
Conclusion
In conclusion, we have developed some facile and effective
Lewis acid BF3·OEt2-mediated cycloaddition reactions of
MCPs 1 with nonactivated aldehydes, N-tosyl aldimines, and
acetals, which can be utilized for the synthesis of the indene,
THF, and pyrrolidine skeletons under mild conditions. For
the reactions of aryl-substituted MCPs 1 with aryl aldehydes,
acetals or N-tosyl aldimines at room temperature, the corre-
sponding indene products 3 and 8 are the major products
formed; however, for the reactions of MCPs 1 with aliphatic
aldehydes or N-tosyl aldimines at lower temperatures and
with relatively shorter reaction times, the corresponding
THF products 6 or the pyrrolidine products 7 are the major
products formed.
Several special transformations have also been reported
in this paper. For example: 1) For the low-temperature reac-
tions of aryl-substituted MCPs 1 with aryl aldehydes, which
contain strongly electron-withdrawing groups, the corre-
sponding 1,3-dioxepanes 11 and the indenes 3 are formed
(1,3-dioxepanes 11 can be transformed into the indenes 3 at
room temperature in the presence of BF3·OEt2). 2) For the
low-temperature reactions of aryl-substituted MCPs 1,
which contain strongly electron-donating groups on their
benzene rings, with aryl aldehydes, the corresponding oxe-
panes 12 are obtained at >50% conversion of the employed
MCP 1.
The reaction mechanism has been discussed on the basis
of deuterium-labeling and control experiments outlined in
this paper. The Prins-type reaction is a key reaction pathway
in this mechanism. At low reaction temperatures and with
short reaction times, indenes 3, pyranes 4, and the THF
products 6 and 13 can be isolated. The THF products 6 and
13 can be completely transformed into indenes 3 at room
temperature or during a prolonged reaction time at low
temperature, in the presence of BF3·OEt2. Therefore, the in-
denes 3 are the most stable products produced in these reac-
tions. As a result of the ready availability of the starting ma-
terials and the ease of operation of these novel reactions,
they have the potential to be applied to the construction of
several biologically important products. Efforts to determine
the scope and limitations of these reactions are currently un-
derway in this laboratory.
Scheme 9. Proposed reaction mechanism for the BF3·OEt2-mediated for-
mation of product 4.
In the above mentioned mechanism, the Prins-type reac-
tion is a key reaction pathway, and the deuterium-labeled
proton did not migrate during the reaction. To verify this
Prins-type reaction mechanism, we carried out the same re-
action in the presence of a Brønsted acid, under otherwise
identical conditions. In fact, we found that the correspond-
ing indene derivatives were obtained when trifluorometh-
anesulfonic acid (CF3SO3H, TfOH, 0.1 equiv) was used as
the catalyst in dichloromethane at room temperature, al-
though in somewhat lower yields. The results from these ex-
periments suggest that the above mentioned transformations
were involved in the Brønsted acid catalyzed reaction of an
olefin with an aldehyde, a Prins-type reaction (Scheme 10).
Experimental Section
1
General methods: Melting points are uncorrected. H and 13C NMR spec-
tra were recorded at 300 and 75 MHz, respectively. Mass spectra were re-
corded by using EI, ESI or Maldi methods, and HRMS was conducted
on a Finnegan MA+ mass spectrometer. The organic solvents used were
dried by standard methods when necessary. Satisfactory CHN microanal-
yses were obtained by using a Carlo–Erba 1106 analyzer. For purification
purposes, the commercially obtained aldehydes were recrystallized or dis-
solved in dichloromethane, washed with NaHCO3 aqueous solution, and
redistilled in vacuo. All reactions were monitored by TLC analysis with
Huanghai GF254 silica-gel-coated plates. Flash column chromatography
was carried out using 300–400 mesh silica gel under increased pressure.
Deuterated benzaldehyde (C6H5C(O)D) was purchased from Aldrich.
Scheme 10. Reaction of MCPs 1 (0.5 mmol) with aldehydes (1.0 mmol) in
the presence of CF3SO3H (0.1 mmol) at room temperature.
Chem. Eur. J. 2006, 12, 510 – 517
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M. Shi et al.
General procedure for the reaction of MCPs 1 with aldehydes to produce
indene systems (Method A): BF3·Et2O (0.1 mmol) was added to a solu-
tion of the MCP 1 (0.5 mmol) and aldehyde (1.0 mmol) in dichloro-
methane (1.5 mL), under an argon atmosphere. The resulting reaction
mixture was then stirred for 24 h at room temperature. After this time,
the mixture was quenched by the addition of aqueous NaHCO3 solution,
and the product was extracted with dichloromethane (3”10 mL). The or-
ganic layers produced were then dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. Purification of the crude
product was achieved by silica-gel column chromatography.
Org. Chem. 2004, 69, 3202–3204; l) B. H. Oh, I. Nakamura, S. Saito,
Y. Yamamoto, Heterocycles 2003, 61, 247–257.
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1989, 111, 7285–7286; c) R. Noyori, N. Hayashi, M. Kato, J. Am.
Chem. Soc. 1971, 93, 4948–4950.
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113, 1338–1340. Angew. Chem. Int. Ed. 2001, 40, 1298–1300.
[5] B. H. Oh, I. Nakamura, S. Saito, Y. Yamamoto, Tetrahedron Lett.
2001, 42, 6203–6205.
[6] For the Lewis acid mediated cycloaddition of MCPs with activated
ketones or aldehydes see: a) M. Shi, B. Xu, Tetrahedron Lett. 2003,
44, 3839–3842; for the MgI2-mediated ring expansions of methyl-
enecyclopropyl amides and imides see: b) M. Lautens, W. Han, J.
Am. Chem. Soc. 2002, 124, 6312–6316; c) M. Lautens, W. Han,
J. H.-C. Liu, J. Am. Chem. Soc. 2003, 125, 4028–4029; for the cyclo-
addition of MCPs, activated by a carbonyl group, with allyltrime-
thylsilane in the presence of TiCl4 see: d) H. Monti, D. Rizzotto, G.
Leandri, Tetrahedron 1998, 54, 6725–6738; for the cycloaddition of
gem-dialkoxysubstituted MCPs with aldehydes and imines upon
heating see: e) S. Yamago, E. Nakamura, J. Org. Chem. 1990, 55,
5553–5555; f) S. Yamago, M. Yanagawa, E. Nakamura, Chem. Lett.
1999, 879–880.
[7] For some related Lewis acid or Brønsted acid mediated reactions of
MCPs see: a) G. L. N. Peron, J. Kitteringham, J. D. Kilburn, Tetrahe-
dron Lett. 1999, 40, 3045–3048; b) K. Miura, M. Takasumi, T.
Hondo, H. Saito, A. Hosomi, Tetrahedron Lett. 1997, 38, 4587–
4590; c) G. L. N. Peron, J. Kitteringham, J. D. Kilburn, Tetrahedron
Lett. 2000, 41, 1615–1618; d) L. Patient, M. B. Berry, J. D. Kilburn,
Tetrahedron Lett. 2003, 44, 1015–1017; e) G. Peron, D. Norton, J.
Kitteringham, J. D. Kilburn, Tetrahedron Lett. 2001, 42, 347–349;
f) L. Patient, M. B. Berry, S. J. Coles, M. B. Hursthouse, J. D. Kil-
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Rajamaki, J. D. Kilburn, Chem. Commun. 2005, 1637–1639.
[8] For some of the Lewis acid or Brønsted acid mediated transforma-
tions of MCPs conducted in this laboratory see: a) M. Shi, B. Xu,
Org. Lett. 2002, 4, 2145–2148; b) J.-W. Huang, M. Shi, Tetrahedron
2004, 60, 2057–2062; c) L.-X. Shao, M. Shi, Eur. J. Org. Chem. 2004,
426–430; d) Y. Chen, M. Shi, J. Org. Chem. 2004, 69, 426–431; e) L-
X. Shao, M. Shi, Adv. Synth. Catal. 2003, 345, 963–966; f) M. Shi, Y.
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General procedure for the reaction of MCPs 1 with acetals to produce
indene systems (Method B): BF3·Et2O (0.1 mmol) was added to a solu-
tion of the MCP 1 (0.4 mmol) and acetal (0.4 mmol) in 1,2-dichloro-
ethane (1.0 mL), under an argon atmosphere. The resulting reaction mix-
ture was then stirred for 24 h at room temperature. After this time, the
mixture was quenched by the addition of aqueous NaHCO3 solution, and
the product was extracted with dichloromethane (3”10 mL). The organic
layers produced were then dried over anhydrous Na2SO4, and the solvent
was removed under reduced pressure. Purification of the crude product
was achieved by silica-gel column chromatography.
Compound 3a: A yellow liquid; 1H NMR (300 MHz, CDCl3, TMS): d=
2.26–2.35 (m, 1H), 2.73–2.83 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 4.61 (s,
1H), 7.08–7.48 ppm (m, 14H, Ar); 13C NMR (75 MHz, CDCl3): d=30.6,
57.4, 62.2, 119.8, 123.8, 125.1, 126.7, 126.9, 127.4, 128.2, 128.5, 128.8,
129.1, 134.8, 139.6, 141.5, 144.6, 144.9, 148.1 ppm; IR (Nujol): n˜ =3564,
3388, 3061, 3024, 2952, 2882, 2237, 1734, 1598, 1493, 1452, 1443, 1247,
1073, 1044, 909, 774, 750, 737, 701 cmꢀ1; MS (EI): m/z (%): 312 (100)
[M]+, 294 (56), 281 (62), 203 (84); HRMS: m/z calcd for C23H20O:
312.1514; found: 312.1505 [M]+.
Compound 4a: A white solid; m.p. 142–1448C; 1H NMR (300 MHz,
CDCl3, TMS): d=2.31 (t, J=6.6 Hz, 2H), 2.67 (t, J=6.6 Hz, 2H), 7.10–
7.34 (m, 12H, Ar, CH=), 7.43–7.46 ppm (m, 4H, Ar); 13C NMR (75 MHz,
CDCl3): d=20.9, 31.8, 81.1, 113.0, 123.9, 125.8, 125.9, 127.1, 128.27,
128.33, 139.0, 140.7, 144.5 ppm; IR (Nujol): n˜ =3081, 3058, 3021, 2966,
2919, 2844, 1941, 1648, 1596, 1494, 1447, 1376, 1165, 1058, 1007, 892, 757,
746, 694 cmꢀ1; MS (EI): m/z (%): 312 (13) [M]+, 180 (100), 179 (34), 165
(39); HRMS: calcd for C23H20O: 312.1514; found: 312.1526 [M]+.
Acknowledgements
We thank the State Key Project of Basic Research (Project 973, No.
G2000048007), the Shanghai Municipal Committee of Science and Tech-
nology, the Chinese Academy of Sciences (KGCX2-210-01), and the Na-
tional Natural Science Foundation of China for financial support
(20025206, 203900502, and 20272069).
[10] M. Shi, B. Xu, J.-W. Huang, Org. Lett. 2004, 6, 1175–1178.
[11] Crystal data of 11b: formula: C30H24N2O6·CH2Cl2; Mr: 593.44; color,
habit: colorless, prismatic; crystal system: triclinic; lattice type:
primitive; lattice parameters: a=8.8296(7), b=9.0971(8), c=
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19.3280(16) Š, a=86.203(2)8, b=80.525(2)8, g=73.713(2)8, V=
[2] For recent reviews see: a) I. Nakamura, Y. Yamamoto, Adv. Synth.
Catal. 2002, 344, 111–129; b) A. Brandi, S. Cicchi, F. M. Cordero, A.
Goti, Chem. Rev. 2003, 103, 1213–1269; for some more recent relat-
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meyer, M. T. Bes, Eur. J. Org. Chem. 2003, 472–478; d) V. N. Belov,
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3
1469.5(2) Š ; space group: P1; Z=2; 1calcd =1.341 gcmꢀ3; F000 =616;
¯
diffractometer: Rigaku AFC7R; residuals: R/wR: 0.0882/0.2680.
CCDC-210597 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[12] Crystal data of 13a: formula: C23H19OCl; Mr: 346.83; color, habit:
colorless, prismatic; crystal system: monoclinic; lattice type: primi-
tive; lattice parameters: a=10.0390(7), b=19.8339(14), c=
9.2205(7) Š, a=908, b=104.7300(10)8, g=908, V=1775.6(2) Š3;
space group: P21/c; Z=4; 1calcd =1.297 gcmꢀ3; F000 =728; diffractom-
eter: Rigaku AFC7R; residuals: R/wR: 0.0545/0.1228. CCDC-
210599 contains the supplementary crystallographic data for this
516
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Chem. Eur. J. 2006, 12, 510 – 517

Cycloaddition Reactions of Methylenecyclopropanes (MCPs)
FULL PAPER
paper. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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[13] For related papers, which report that trace amounts of water are re-
quired to trigger the first formation of cation B with the Lewis acid
BF3 (BF3 +H2O+Me2CH=CH2!Me3CH+BF3OHꢀ) see: a) A. G.
Evans, D. Holden, P. Plesch, M. Polanyi, H. A. Skinner, M. A. Wein-
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G. Rasul, G. A. Olah, J. Am. Chem. Soc. 2004, 126, 15770–15776;
the reaction of MCP 1a with benzaldehyde 2a in anhydrous di-
chloromethane was also studied by bubbling boron trifluoride from
a cylinder into the reaction solution by the means of a Schlenk tube,
under an argon atmosphere. The reaction proceeded slowly under
these reaction conditions; however, when the reaction solution was
exposed to the ambient atmosphere the reaction proceeded smooth-
ly to give the cycloaddition products in good yields.
[14] For a review of the Prins-type reaction see: a) D. R. Adams, S. P.
Bhatnagar, Synthesis 1977, 661–672; for some recent related papers
see: b) C.-M. Yu, S.-K. Yoon, Y.-T. Hong, J.-M. Kim, Chem.
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Received: April 20, 2005
Published online: September 15, 2005
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