Lewis acid-mediated cycloaddition of methylenecyclopropanes with aldehydes and imines: A facile access to indene, THF, and pyrrolidine Skeletons via Homoallylic Rearrangement Protocol

Article abstract of DOI:10.1021/ol0498242

Methylenecyclopropanes (MCPs) 1 can react with aldehydes and aldimines to give the corresponding indene, THF, and pyrrolidine cycloaddition products in the presence of BF₃·OEt₂ under mild reaction conditions.

Full text of DOI:10.1021/ol0498242

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1175-1178
Lewis Acid-Mediated Cycloaddition of
Methylenecyclopropanes with Aldehydes
and Imines: A Facile Access to Indene,
THF, and Pyrrolidine Skeletons via
Homoallylic Rearrangement Protocol
Min Shi,* Bo Xu, and Jin-Wen Huang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@pub.sioc.ac.cn
Received January 30, 2004
ABSTRACT
Methylenecyclopropanes (MCPs) 1 can react with aldehydes and aldimines to give the corresponding indene, THF, and pyrrolidine cycloaddition
products in the presence of BF3‚OEt2 under mild reaction conditions.
Methylenecyclopropanes (MCPs) 1 are highly strained but
readily accessible molecules that have served as useful
building blocks in organic synthesis.1,2 So far, it has been
Scheme 1. Pd-Catalyzed and Lewis Acid-Mediated Reaction
Patterns of MCPs 1
determined that in the presence of transition metals such as
Pd catalysts, MCPs 1 can react with aldehydes3 or imines4
to produce the corresponding [3+2] cycloaddition products.
In addition, they also can react with polar nucleophiles such
as ROH5 and R2NH6 to furnish ring-opened products
(Scheme 1, pattern I).
Recently, we found that Lewis acid-mediated ring-opening
reactions of MCPs 1 with nucleophiles, such as alcohols7
(1) For synthesis of MCPs: Brandi, A.; Goti, A. Chem. ReV. 1998, 98,
598.
(2) For recent reviews, see: (a) Nakamura, I.; Yamamoto, Y. AdV. Synth.
Catal. 2002, 344, 111. (b) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A.
Chem. ReV. 2003, 103, 1213.
(3) Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2001, 40, 1298.
and aromatic amines,8 took place via a novel pathway
(homoallylic rearrangement) to give the corresponding ring-
opened products under mild conditions (Scheme 1, pattern
II). In addition, we and others also reported Lewis acid-
(4) Oh, B. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 6203.
(5) (a) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 1999, 38, 3365. (b) Camacho, D. H.; Nakamura, I.; Saito,
S.; Yamamoto, Y. J. Org. Chem. 2001, 66, 270.
(6) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem. 1998, 63,
6458.
(8) (a) Shi, M.; Chen, Y.; Xu, B.; Tang, J. Tetrahedron Lett. 2002, 43,
8019. (b) Xu, B.; Shi, M. Org. Lett. 2003, 5, 1415.
(7) Shi, M.; Xu, B. Org. Lett. 2002, 4, 2145.
10.1021/ol0498242 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/04/2004

mediated or thermo-induced cycloadditions of MCPs 1 with
aldehydes or ketones to give other types of cyclic products
(Scheme 1, pattern II).9 However, either activated aldehydes
and ketones or activated MCPs 1 are required to render this
type of cycloaddition possible. In fact, MCPs 1 are generally
13.6 kcal/mol more strained than cyclopropanes.10 Strain in
an organic molecule often correlates with its increased
reactivity because the relief of ring strain provides a potent
thermodynamic driving force. Therefore, MCPs 1 are also
expected to react with the unactivated normal aldehydes in
the presence of Lewis acid. In this paper, we wish to disclose
this transformation in the presence of Lewis acid BF3‚Et2O
(Scheme 1, pattern II).
formed in 15% yield (Scheme 2). BF3‚Et2O is the best Lewis
acid for this transformation. This reaction proceeded smoothly
in 1,2-dichloroethane (DCE) as well, but became sluggish
in other solvents such as tetrahydrofuran (THF), ethylene
glycol dimethyl ether (DMF), 1,4-dioxane, and acetonitrile
(CH3CN).
Table 1 summarizes of the results in the reaction of various
MCPs 1 with aldehydes and aldimines under the optimized
Table 1. The Reaction of MCPs 1 with Aldehydes and
Aldimines
We first examined the Lewis acid BF3‚Et2O-mediated
reaction of diphenylmethylenecyclopropane 1a with alde-
hydes and aldimines (ArCHdNTs) at room temperature (20
°C) in dichloromethane (DCM) (Scheme 2). We found that
yield,b %
entrya
MCP 1 (R1/R2)
1a (H/C6H5)
1a
1a
1a
1a
1b (MeO-/p-MeC6H4) 4-BrC6H4
1b 4-ClC6H4
1a (Me-/p-MeC6H4) 4-BrC6H4
R′
X
2
3
Scheme 2. The Cycloaddition of MCP 1a with Aldehydes and
Aldimines
1
2
3
4
5
6
7
8
9
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2,4-Cl2C6H3
O
2a , 65 3a , 10
2b, 78 3b, 8
2c, 34 3c, 30
2d , 5 3d , 45
2e, 75 3e, trace
2f, 91
2g, 95
2h , 68
2i, 66
O
O
O
O
O
O
O
O
1a
iPr
10 1a
11 1a
12 1a
13 1a
14 1a
C6H5
4-ClC6H4
4-CF3C6H4 NTs 2l, 73
2,4-Cl2C6H3 NTs 2m , 71
3-FC6H4
NTs 2j, 75
NTs 2k , 71
NTs 2n , 75
a All reactions were carried out with MCPs 1a-c (0.5 mmol), aldehydes
(1.0 mmol), or aldimines (0.75 mmol) in the presence of BF3‚Et2O (20
mol %) at room temperature for 24 h. b Isolated yields.
the major reaction products were the indene derivatives 2
along with dihydro-2H-pyran derivatives 3 (in some cases)
rather than the expected [3+2] cycloaddition products.11 But
no reaction occurred in the presence of weak Lewis acids
such as Yb(OTf)3, Sn(OTf)2, Cu(OTf)2, and AlF3. By means
of the stronger Lewis acid AlCl3 in the reaction of 1a with
benzaldehyde, the corresponding chlorinated product 2′ was
conditions. The product 3 was only isolated in the reaction
of 1a with arylaldehydes (Table 1, entries 1-5). For MCP
1b having a strongly electron-donating methoxy group on
the benzene ring, the corresponding indene derivatives 2f
and 2g were obtained in higher yields as a sole product in
each reaction (Table 1, entries 6 and 7). In the reaction of
1a with aliphatic aldehyde, the indene product 2i was formed
in moderate yield (Table 1, entry 9). By using aldimines as
the substrates, similar results were obtained under the same
conditions (Table 1, entries 10-14). However, with other
imines such as ArCHdNR (R ) alkyl or aryl group) as the
substrate, no reaction occurred.
(9) For the Lewis acid-mediated cycloaddition of MCPs with activated
ketone or aldehyde, see: (a) Shi, M.; Xu, B. Tetrahedron. Lett. 2003, 44,
3839. For the MgI2-mediated ring expansions of methylenecyclopropyl
amides and imides, see: (b) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002,
124, 6312. (c) Lautens, M.; Han, W.; Liu, J. H.-C. J. Am. Chem. Soc. 2003,
125, 4028. For the cycloaddition of silylated MCPs with aldehydes in the
presence of TiCl4, see: (d) Patient, L.; Berry, M. B.; Killburn, D.
Tetrahedron Lett. 2003, 44, 1015. For the cycloaddition of MCPs activated
by a carbonyl group with allyltrimethylsilane in the presence of TiCl4 see:
Monti, H.; Rizzotto, D.; Leandri, G. Tetrahedron 1998, 54, 6725. For the
cycloaddition of gem-dialkoxy-substituted MCPs with aldehydes and imines
upon heating, see: (e) Yamago, S.; Nakamura, E. J. Org. Chem. 1990, 55,
5553. (f) Yamago, S.; Yanagawa, M.; Nakamura, E. Chem. Lett. 1999, 879.
For Ni(0)-catalyzed reactions of MCPs that occur by the proximal bond
cleavage (pattern II), see: (g) Binger, P.; Schafer, B. Tetrahedron Lett.
1988, 29, 4539. (h) Binger, P.; Wedemann, P. Tetrahedron Lett. 1985, 26,
1045. (i) Noyori, R.; Odagi, T. J. Am. Chem. Soc. 1970, 92, 5780. (j)
Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35, 867.
On the other hand, we found that if the reaction was carried
out at -25 °C, the corresponding [3+2] cycloaddition
products 411 (THF or pyrrolidine skeleton) were produced
in moderate yields in the reaction of MCPs 1 (including
aliphatic MCP 1e) with aliphatic aldehydes and aldimines
for 12 h. The results are summarized in Table 2. Meanwhile,
with arylaldehydes as the substrates at -25 °C for 12 h, the
reaction produces the same products as shown in Table 1.
(10) de Meijere, A.; Kozhushkov, S. I.; Khlebnikov, A. F. Top. Curr.
Chem. 2000, 207, 89.
(11) The structures of 3d, 4b, and 5a were further determined by X-ray
diffraction (Supporting Information).
1176
Org. Lett., Vol. 6, No. 7, 2004

Scheme 4. The Reaction of MCP 1a with C6H5C(O)D
Table 2. The Reaction of MCPs 1 with Aldehydes and
Aldimines at -25 °C
Promoted by Lewis Acid
yield,b %
entrya
R(MCPs)
C6H5 1a
R′
X
4
1
2
3
4
5
6
7
8
9
10
11
12
13
nBu
iPr
O
O
O
O
O
O
NTs
NTs
NTs
NTs
NTs
NTs
NTs
4a , 45
4b, 58
4c, 54
4d , 50
4e, 41
4f, 45
4g, 41
4h , 40
4i, 43
4j, 45
4k , 48
4l, 54
4m , 55
and 13C NMR charts in the Supporting Information).
Deuterium incorporation did not occur at other carbons of 2
and 3.
The mechanism of this novel annulation is proposed in
Scheme 5 on the basis of the obtained results. The addition
1a
4-MeC6H4 1c
4-ClC6H4 1d
Bu 1e
1e
1a
1a
1a
1a
1a
iPr
iPr
iPr
iBu
C6H5
4-ClC6H4
4-BrC6H4
4-CF3C6H4
2,4-Cl2C6H3
4-BrC6H4
iPr
Scheme 5. The Proposed Mechanism of Cycloaddition of
MCPs with Aldehyde Promoted by Lewis Acid
1a
1a
a All reactions were carried out with MCPs 1 (0.5 mmol), aldehydes
(1.0 mmol), or aldimines (0.75 mmol) in the presence of BF3‚Et2O (20
mol %) at -25 °C, using DCM as a solvent. b Isolated yields.
To probe the reaction pathway for the formation of 2 and/
or 3, we investigated the reaction of MCP 1a with p-
chlorobenzaldehyde at -25 °C within shorter reaction time
(0.5 h). The desired [3+2] cycloaddition products 4n and
5a11 were isolated besides 2a and 3a by careful isolation
(Scheme 3). We further confirmed that 4n and 5a can be
Scheme 3. The Reaction of MCP 1a with
p-Chlorobenzylaldehyde at -25 °C within 0.5 h
of MCP 1 to the Lewis acid-activated aldehyde gives the
cyclopropylcarbinyl cation A and its resonance-stabilized
zwitterionic intermediate B and C, respectively. The ho-
moallylic rearrangement of cations A and C produces 4 and
512 which can further produce the exchangeable intermediates
D and E, respectively, in the presence of Lewis acid.13 The
tandem intramolecular Friedel-Crafts reaction from D
produces the indene derivative 2 (for arylaldehydes). The
intramolecular cyclization of cation C furnishes cation F,
which can be viewed as a nonclassical carbenium cation.14
The aryl migration in cation F (for arylaldehydes), which
has been clearly indicated by the deuterium-labeling experi-
ment, takes place in the presence of Lewis acid to produce
another cation G, which gives intermediates H and I. The
proton migration of I finally affords product 3.15 On the basis
of this proposed mechanism, the results shown in Tables 1
completely transformed to 2a in the presence of BF3‚Et2O
at room temperature within 0.5 h (intramolecular Friedel-
Crafts reaction). Thus, we believe that indene 2 is derived
from the further reaction of the [3+2] annulation product
catalyzed by BF3‚Et2O.
To clarify the mechanism of this reaction, the deuterium-
labeling experiment was carried out by conducting the
reaction of 1a with C6H5C(O)D under the same conditions
(Scheme 4). 2-d and 3-d are obtained in 46% and 30% with
99% D content at the C-1 position, respectively (1H NMR
(12) Carey, F. A.; Tremper, H. S. J. Am. Chem. Soc. 1969, 91, 2967.
(13) Kulkarni, S. U.; Patil, V. D. Heterocycles 1982, 18, 163.
(14) Olah, G. A.; Schleyer, P. v. R. Carbonium Ions; Wiley: New York,
1968; Vol. 1, pp 45-47.
Org. Lett., Vol. 6, No. 7, 2004
1177

and 2 can be rationalized as follows. For MCPs 1 having a
strongly electron-donating group on the benzene ring (electron-
rich aromatic ring), the intramolecular Friedel-Crafts reac-
tion preferably takes place to give indene 2 as a sole product
(Table 1, entries 6-8). For aliphatic aldehydes, the formation
of intermediates C and D is a disfavored process because
the alkyl group cannot stabilize these cationic intermediates
and the formal [3+2] cycloaddition product 4 is exclusively
formed at low temperature (Table 2, entries 1-6). On the
other hand, for aldimine, it is impossible to produce the
intermediate B due to the steric hindrance of NTs group.
Therefore, the formation of 4 or 2 is a favorable process. At
any rate, in this novel transformation of MCPs 1 mediated
by BF3‚Et2O, the thermodynamically stable cyclized product
is exclusively formed in each case during a long reaction
time.
be potentially useful for the construction of several biologi-
cally important products such as pyrrolizidine alkaloids.16
Efforts are underway to elucidate the mechanistic details of
this reaction and to disclose the scope and limitations of this
reaction.17
Acknowledgment. We thank the State Key Project of
Basic Research (Project 973) (No. G2000048007), Shanghai
Municipal Committee of Science and Technology, Chinese
Academy of Sciences (KGCX2-210-01), and the National
Natural Science Foundation of China for financial support
(20025206, 203900502, and 20272069).
1
Supporting Information Available: 13C and H NMR
spectral and analytic data and X-ray diffraction data for
compounds in Tables 1 and 2 and Schemes 1-4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In this letter, we described a Lewis acid BF3‚Et2O-
mediated novel cycloaddition reaction of MCPs 1 with
normal aldehydes and aldimines. The indene, THF, and
pyrrolidine skeletons generated in this novel [3+2] annula-
tion or tandem intramolecular Friedel-Crafts reaction may
OL0498242
(16) For example, 4m, which shows strong anti-acetylcholine, anti-
histamine, and anti-barium activities, has been synthesized by a much longer
procedure. Ohki, S.; Hamaguchi, F.; Yanagi, T.; Yoshino, M. Chem. Pharm.
Bull. 1966, 14, 187.
(17) For other special transformations of MCPs 1 with aldehydes, see
the Supporting Information.
(15) This type of phenyl migration has been reported. See: (a) Kirmse,
W.; Gunther, B. R. J. Am. Chem. Soc. 1978, 100, 3619. (b) Wiberg, K. B.;
Ashe, A. J. J. Am. Chem. Soc. 1968, 90, 63. (c) Schleyer, P. R.; Majerski,
Z. J. Am. Chem. Soc. 1970, 93, 665. (d) Majerski, Z.; Schleyer, P. R. J.
Am. Chem. Soc. 1971, 93, 665.
1178
Org. Lett., Vol. 6, No. 7, 2004