Reversal of chemoselectivity in diels-alder reaction with α,β-unsaturated aldehydes and ketones catalyzed by bronsted acid or Lewis Acid

Article abstract of DOI:10.1021/ol047341s

(Chemical Equation Presented) High chemoselectivity was observed in the Diels-Alder reaction of α,β-unsaturated aldehyde and α,β-unsaturated ketone with cyclopentadiene. Using Tf₂NH as catalyst, the reaction gave Diels-Alder adduct derived from α,β-unsaturated ketone as a major product. On the other hand, bulky Lewis acid, B(C₆F₅)₃, gave mainly the cycloadduct of α,β-unsaturated aldehyde and cyclopentadiene.

Full text of DOI:10.1021/ol047341s

ORGANIC
LETTERS
2
005
Vol. 7, No. 7
251-1253
Reversal of Chemoselectivity in
Diels Alder Reaction with
-Unsaturated Aldehydes and Ketones
Catalyzed by Brønsted Acid or Lewis
Acid
1
−
r,â
Daisuke Nakashima and Hisashi Yamamoto*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
yamamoto@uchicago.edu
Received December 24, 2004
ABSTRACT
High chemoselectivity was observed in the Diels
Using Tf NH as catalyst, the reaction gave Diels
bulky Lewis acid, B(C , gave mainly the cycloadduct of r,â
−
−
Alder reaction of
Alder adduct derived from
-unsaturated aldehyde and cyclopentadiene.
r
,
â
-unsaturated aldehyde and
r,â-unsaturated ketone with cyclopentadiene.
2
r,â
-unsaturated ketone as a major product. On the other hand,
6
F
)
5 3
The Brønsted acid catalyzed Diels-Alder reaction was
reported by Wassermann in 1942. This was almost two
catalyzed Diels-Alder reaction has not been reported.
Control of the chemoselectivity in the Diels-Alder reaction
is still of great synthetic interest. Herein we describe a highly
chemoselective Diels-Alder reaction catalyzed by Brønsted
acid and the unprecedented reversal of the chemoselectivity
by the choice of acid catalyst.
Our studies began with the chemoselective Diels-Alder
reaction using numerous Brønsted acids. In the presence of
various Brønsted acid catalysts, the Diels-Alder reaction
of cyclopentadiene with acrolein and ethyl vinyl ketone (1
equiv of each), was carried out at -78 °C for 1 h. After the
reaction, the ratio of Diels-Alder adducts of R,â-unsaturated
aldehyde 1 and of R,â-unsaturated ketone 2 was determined
1
decades earlier than the discovery of the Lewis acid
2
accelerated Diels-Alder reaction. The Lewis acid-catalyzed
Diels-Alder reaction is one of the most investigated areas
in organic synthesis. Many regio-, chemo-, diastereo-, and
enantioselective Diels-Alder reactions catalyzed by various
3
Lewis acids have been developed to date. In contrast, the
Brønsted acid-catalyzed Diels-Alder reaction has not re-
ceived much attention for a long time. Only a few reports
describe the diastereo- and enantioselective Diels-Alder
4
reactions catalyzed by Brønsted acid. To the best of our
knowledge, research on the chemoselective Brønsted acid
(
4) (a) Sammakia, T.; Berliner, M. A. J. Org. Chem. 1995, 60, 6652.
(
1) (a) Wassermann, A. J. Chem. Soc. 1942, 618. (b) Wassermann, A.
(b) Schuster, T.; Bauch, M.; D u¨ rner, G.; G o¨ bel, M. W. Org. Lett. 2000, 2,
179. (c) Palmo, C.; Oiarbide, M.; Garcia, J. M.; Gonz a´ lez, A.; Lecumberri,
A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288. (d) Schreiner, P. R.;
Wittkopp, A. Org. Lett. 2002, 4, 217. (e) Huang, Y.; Unni, A. K.; Thadani,
A. N.; Rawal, V. H. Nature. 2003, 424, 146. (f) Thadani, A. N.; Stankovic,
A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846. (g)
Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 1336.
J. Chem. Soc. 1942, 623.
(2) Yate, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436.
(
3) For recent reviews, see: (a) Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S., Jøgensen, K. A., Ed.; Wiley-VCH: Weinheim,
002. (b) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: Weinhelm, 2000; Vols. 1 and 2. (c) Lewis Acid Reagent: A Practical
Approach; Yamamoto, H., Ed.; Oxford University Press: Oxford, 1999.
2
1
0.1021/ol047341s CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/02/2005

of SnCl
Thus, Tf NH showed high ketone selectivity and SnCl
6 5 3
B(C F ) revealed high aldehyde selectivity.
4 6 5 3
or B(C F ) , the reaction gave 1 as a major product.
2
4
and
Table 1. Chemoselective Diels-Alder Reaction with Brønsted
Acids
To explore the generality of such a chemoselective Diels-
Alder reaction catalyzed by super Brønsted acids or Lewis
acids, we studied other R,â-unsaturated aldehydes and
ketones. The reactivity of methacrolein and ethyl vinyl ketone
with cyclopentadiene was compared, and the results are
4
summarized in Table 3. In the presence of SnCl the reaction
a
entry
1
catalyst, mol %
yield (%)
ratio of 1/2
Tf2NH, 5
Tf2NH, 5
C6F5CHTf2, 5
C6F5CHTf2, 5
TfOH, 5
86
93
86
84
79
45
8
12:88
5:95
8:92
1:99
9:91
Table 3. Scope and Limitation of Dienophile
b
2
3
4
b
5
6
7
MsOH, 5
p-TsOH‚H2O, 5
29:71
38:63
a
Isolated yield. b The reaction was carried out at -96 °C.
a
entry
1
2
3
4
catalyst, mol %
yield (%)
ratio of 3/2
1
Tf2NH, 5
Tf2NH, 5
SnCl4, 5
93
94
94
87
20:80
11:89
40:60
75:25
by H NMR. The results are summarized in Table 1.
b
Surprisingly, most Brønsted acids gave 2 almost exclusively.
Although the reaction with super Brønsted acids, which are
B(C6F5)3, 20
triflylimide (Tf
rophenylbistriflylmethane (C
and gave desired the cycloadducts quantitatively (entries 1,
, and 4), the reactivity of methanesulfonic acid and
p-toluenesulfonic acid were relatively poor (entries 5 and
). Thus, super Brønsted acids seem to be a suitable catalyst
for the Diels-Alder reaction. It was noted that the ratio of
/2 was improved from 12:88 to 5:95 when the reaction with
Tf NH was carried out at -96 °C (entry 2).
Typical Lewis acids, BF ‚OEt , TiCl , EtAlCl
B(C , were also examined for the same reaction, and the
results are summarized in Table 2. When BF ‚OEt , TiCl
2
NH), triflic acid (TfOH), and pentafluo-
a
Isolated yield. b The reaction was carried out at -96 °C.
5
6 5 2
F CHTf ), proceeded smoothly
3
unexpectedly proceeded ketone selectively (entry 3 in Table
). This would be due to the lower reactivity of methacrolein
than acrolein. However, Tf NH and B(C still revealed
ketone selectivity (11:89) and aldehyde selectivity (75:25),
respectively (entries 2 and 4 in Table 3).
3
6
2
6 5 3
F )
1
2
Unfortunately, the ketone selectivity was completely lost
for methacrolein and 3-methyl-3-buten-2-one (Scheme 1).
3
2
4
2 4
, SnCl , and
6 5 3
F )
3
2
4
,
Scheme 1. Chemoselective Diels-Alder Reaction with
Methacrolein and 3-Methyl-3-butene-2-one
Table 2. Chemoselective Diels-Alder Reaction with Various
Lewis Acids
a
entry
catalyst, mol %
yield (%)
ratio of 1/2
1
2
3
4
5
BF3‚OEt2, 5
TiCl4, 5
EtAlCl2, 5
SnCl4, 5
25
92
89
73
88
26:74
25:75
28:72
97:3
This would be due to the significantly decreased reactivity
of R,â-unsaturated ketone by the substituent on the R-posi-
tion. A substituent on the â-position also decreases the
reactivity of both R,â-unsaturated aldehyde and ketone. The
reaction was conducted at a higher temperature. Nevertheless,
B(C6F5)3, 50
85:15
a
Isolated yield.
(5) (a) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem., Int.
Ed. 2001, 40, 4077. (b) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Synlett.
2
or EtAlCl was used as a catalyst, the reaction gave mainly
2
002, 1296. (c) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Synlett. 2002,
299. (d) Hasegawa, A.; Ishihara, K.; Yamamoto, H. Angew. Chem., Int.
2. However, the ratios of 1/2 were lower than those of super
1
Brønsted acids (entries 1-3). Furthermore, in the presence
Ed. 2003, 42, 5731.
1252
Org. Lett., Vol. 7, No. 7, 2005

Tf
2
NH and B(C
6
F
5
)
3
showed high ketone and aldehyde
the smallest Lewis acid, which would be insensitive to the
steric effect. Therefore, Brønsted acid selectively coordinates
a more basic carbonyl group such as R,â-unsaturated ketone.7
selectivity, respectively (Scheme 2).
6 5 3
On the other hand, bulky Lewis acid, B(C F ) , preferentially
coordinates to R,â-unsaturated aldehyde due to the severe
steric repulsion present in R,â-unsaturated ketone (Figure
Scheme 2. Chemoselective Diels-Alder Reaction with
Crotonaldehyde and 2-Hexen-4-one
1
).
These chemoselectivities were observed for other dienes;
thus, 1,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene, and
isoprene with Tf NH and B(C F ) expectedly gave the
2 6 5 3
corresponding Diels-Alder adduct with high chemoselec-
tivity (Table 4).
Table 4. Scope and Limitation of Diene
Figure 1. Coordination of acid catalysis for the high chemose-
lectivity.
In conclusion, we have described the utility of Brønsted
acid as an effective catalyst for the Diels-Alder reaction of
R,â-unsaturated ketone. Brønsted acid and bulky Lewis acid
catalyst showed high chemoselectivity in the Diels-Alder
reaction, and we propose that this high chemoselectivity
arises from a combination of steric as well as electronic
effects of the dienophile.
Acknowledgment. Financial support for this project has
been provided by SORST, Japan Science and Technology
(JST).
Supporting Information Available: Experimental pro-
cedure and full characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Previously, we reported high chemoselective Diels-Alder
reactions using exceptionally bulky Lewis acids. Bulky
Lewis acid can recognize the two different carbonyl groups
by the steric effect. The present chemoselectivity can be
explained as follows: Brønsted acid could be regarded as
6
OL047341S
(7) The importance of the Lewis basisity of the carbonyl compounds on
chemoselectivity between aldehyde and ketone in Lewis acid catalysis have
been reported. (a) Mikami, K.; Terada, M.; Nakai, T. J. Org. Chem. 1991,
56, 6, 5456. (b) Chen, J.-x.; Sakamoto, K.; Orita, A.; Otera, J. J. Org. Chem.
1998, 63, 9739. (c) Asao, N.; Asano, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2001, 40, 3206.
(
6) (a) Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 1992,
1
1
4
14, 1089. (b) Maruoka, K.; Imoto, H.; Yamamoto, H. J. Am. Chem. Soc.
994, 116, 12115. (c) Maruoka, K.; Saito, S.; Yamamoto, H. Synlett 1994,
39. (d) Saito, S.; Maruoka, K.; Yamamoto, H. Kagaku 1995, 50, 190.
Org. Lett., Vol. 7, No. 7, 2005
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