presence of CF3SO3H, but this led to low yields and mixtures
of products.11 This structure could also be obtained by a
palladium-catalyzed cyclization of 2-(2-bromobenzyl)-me-
thylenecyclohexanes, but this reaction has a limitation, the
requirement for a stoichiometric quantity of palladium.10 We
previously reported a new approach to functionalized 1,3-
bis exocyclic dienes 1 that was particularly efficient for
forming six-membered rings (Scheme 1) and explored their
conditions (Table 1). We found the reaction to be highly
sensitive to the amount that was used (entries 1-4). Indeed,
to achieve a good conversion, the reaction has to be
conducted in the presence of 6 equimolecular amounts of
BF3‚Et2O. Complexation of the Lewis acid by the ester
groups certainly explains the necessity to use a large excess
of Lewis acid in that case.
Table 1. Lewis Acid Screening for Friedel-Crafts Cyclization
of 1a
Scheme 1. Palladium-Catalyzed Synthesis of
1,3-Bis-exocyclic Dienes
entry Lewis acid
equiv
conditions
yield (%)
1
2
3
4
5
6
7
8
9
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
TiCl4
SnCl4
ZnBr2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
1.5
3
4
6
6
6
6
1
0.2
0.1
CHCl3, 40°C, 30 h
CHCl3, 40°C, 6 h
CHCl3, 40°C, 4 h
CHCl3, 40°C, 7 h
CHCl3, 40°C, 30 h
CHCl3, 40°C, 6 h
Et2O, reflux, 30 h
toluene, reflux, 6.5 h
toluene, reflux, 4 h
toluene, reflux, 24 h
a
b
b
93
b
92
a
85
96
85
synthetic potential.12 In line with this, these exodienes were
recently engaged in Diels-Alder reactions with very reactive
dienophiles to reach synthetically useful carbocycles.13
However, with relatively unreactive dienophiles such as
N-phenylmaleimide (NPM), these 1,3-bis exocyclic dienes
failed to undergo the thermal Diels-Alder reaction. As many
Diels-Alder reactions are known to be accelerated by Lewis
acid catalysts,14 compound 1a was reacted with NPM in
CHCl3 at 40 °C using an excess of BF3‚Et2O (6 equiv).
Surprisingly, instead of the desired product, the tricyclic
compound 2a having the 4a-methyltetrahydrofluorene skel-
eton was obtained in 93% yield. This compound would result
from an internal Friedel-Crafts alkylation (Scheme 2).15
10
a Starting material was recovered. b Intense degradation of the reaction
mixture.
A series of Lewis acidic metal reagents were also screened
(entries 5-7). SnCl4 showed the best activity leading to 2a
in high isolated yield. The mild Lewis acid ZnBr2 was
ineffective to promote the reaction, and TiCl4 led to the
formation of a complex mixture of products. Recently, the
beneficial effect of rare earth metal Lewis acids such as
scandium triflate in Friedel-Crafts reaction, in particular for
acylation or alkylation reactions, has been reported.16 A 96%
yield of 2a was obtained when 20% of this acid was used
(entry 9). Lowering the quantity to 10% gave also good
results, but a prolonged heating time was necessary (entry
10).
Scheme 2. Lewis Acid-Catalyzed Cyclization of 1a
For the mechanism of this Sc(OTf)3-catalyzed Friedel-
Crafts alkylation, the reaction should proceed via an in-
tramolecular attack of the arene onto the exomethylene
double bond of 1 electrophilically activated by the metal
triflate to furnish intermediate 4 (Scheme 3, path a).
Another possible pathway should be the formation of alkyl
cation 3 by the reaction of 1 with the metal triflate followed
by attack of the arene (Scheme 3, path b). A subsequent loss
of a proton leads to aromatization and regenerates the
catalyst.
The reaction of 1a was then examined with various
amounts of BF3‚Et2O in order to determine the optimal
(5) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.;
Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911-1921.
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Chakravarty, J.; Dasgupta, R.; Ray, J. K.; Ghatak, U. R. Proc. Indian Acad.
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688-693.
(12) Lomberget, T.; Bouyssi, D.; Balme, G. Synlett 2002, 1439-1442.
(13) Lomberget, T.; Bouyssi, D.; Balme, G. To be published.
(14) Carruthers, W. In Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990; Vol. 8.
(7) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5937-5947.
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(15) For a related internal cyclization, see: Akita, H.; Naito, T.; Oishi,
T. Chem. Lett. 1979, 1365.
(16) (a) Kawada, A.; Mitamura, S.; Matsuo, J.-I.; Tsuchiya, T.; Koba-
yashi, S. Bull. Chem. Soc. Jpn. 2000, 73, 2325-2333. (b) Song, C. E.;
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