Lewis acid-catalyzed tandem Diels-Alder reaction/retro-Claisen rearrangement as an equivalent of the inverse electron demand hetero Diels-Alder reaction

Article abstract of DOI:10.1021/jo050821s

A highly stereoselective formal inverse electron demand hetero Diels-Alder reaction (HDA) occurs on reaction of 2-aryl-α,β-unsaturated aldehydes with cyclopentadiene. The major pathway for this transformation is shown to be a Lewis acid-catalyzed tandem Diels-Alder reaction/retro-Claisen rearrangement.

Full text of DOI:10.1021/jo050821s

Lewis Acid-Catalyzed Tandem Diels-Alder Reaction/Retro-Claisen
Rearrangement as an Equivalent of the Inverse Electron Demand
Hetero Diels-Alder Reaction
Huw M. L. Davies* and Xing Dai
Department of Chemistry, University at Buffalo, The State University of New York,
Buffalo, New York, 14260-3000
hdavies@acsu.buffalo.edu
Received April 22, 2005
A highly stereoselective formal inverse electron demand hetero Diels-Alder reaction (HDA) occurs
on reaction of 2-aryl-R,â-unsaturated aldehydes with cyclopentadiene. The major pathway for this
transformation is shown to be a Lewis acid-catalyzed tandem Diels-Alder reaction/retro-Claisen
rearrangement.
Introduction
ing electron-withdrawing groups such as ester,3a,e-f
phosphonate,3b or sulfone groups.3g,h The reaction usually
occurs by a direct HDA reaction. In the reaction with
cyclopentadiene, however, some examples are known of
HDA products that are derived from a Diels-Alder
reaction followed by a retro-Claisen rearrangement.4
HDA reactions involving simple R,â-unsaturated alde-
hyde as substrates are less common.3i Herein, we describe
that 2-aryl-R,â-unsaturated aldehydes are effective sub-
strates for stereoselective HDA cycloadditions with cy-
clopentadiene. Furthermore, the mechanism of the cy-
cloaddition is shown to be a Lewis acid-catalyzed tandem
Diels-Alder cycloaddition/retro-Claisen rearrangement.4,5
The inverse electron demand hetero Diels-Alder (HDA)
reaction of enones with electron-rich olefins is a simple
approach for the formation of dihydro- and tetrahydro-
pyran derivatives,1 which are prevalent structural sub-
units in a variety of biologically important natural
compounds, including carbohydrates, pheromones, iri-
doids, and polyether antibiotics.2 Although several suc-
cessful examples of enantioselective inverse electron
demand HDA reactions have been achieved,3 most of the
reported methods are limited to enone derivatives bear-
(1) (a) Tietze, L. F.; Kettschau, G.; Gewart, J. A.; Schuffenhauer,
A. Curr. Org. Chem. 1998, 2, 19. (b) Tietze, L.; Kettschau, G. Top. Curr.
Chem. 1997, 189, 1. (c) Boger, D. L. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon:
Oxford, 1991; Vol. 5, pp 451-512. (d) Boger, D. L.; Weinreb, S. M.
Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: San Diego, CA, 1987.
(2) Representative examples: (a) Chavez, D. E.; Jacobsen, E. N. Org.
Lett. 2003, 5, 2563. (b) Phorboxazole: Searle, P. A.; Molinski, T. F. J.
Am. Chem. Soc. 1995, 117, 8126. (c) Altohyrtin: Kobayashi, M.; Aoki,
S.; Kitigawa, I. Tetrahedron Lett. 1994, 35, 1243. (d) Miyakolide: Higa,
T.; Tanaka, J.; Komesu, M.; Gravalos, D. C.; Puentes, J. L. F.;
Bernardinelli, G.; Jefford, C. W. J. Am. Chem. Soc. 1992, 114, 7587.
(e) Zincophorin: Brooks, H. A.; Gardner, D.; Poyser, J. P.; King, T. K.
J. Antibiot. 1984, 37, 1501. (f) Bryostatin 1: Pettit, G. R.; Herald, C.
L.; Doubek, D. L.; Herald, D. L. J. Am. Chem. Soc. 1982, 104, 6846.
(g) Palytoxin: Cha, J. K.; Christ, W. J.; Finan, J. M.; Fujioka, H.; Kishi,
Y.; Klein, L. L.; Ko, S. S.; Leder, J.; McWhorter, W. W.; Pfaff, K.-P.;
Yonaga, M.; Uemura, D.; Hirata, Y. J. Am. Chem. Soc. 1982, 104, 7369.
(h) X-537A (Lasalocid A): Westley, J. W.; Evans, R. H.; Williams, T.;
Stempel, A. Chem. Commun. 1970, 71. (i) Monensin: Agtarap, A.;
Chamberlin, J. W.; Pinkerton, M.; Steinrauf, L. J. Am. Chem. Soc.
1967, 89, 5737.
Results and Discussions
Recently, we reported a formal [4 + 3] cycloaddition
between cyclopentadiene and R,â-unsaturated aldehydes
(3) (a) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M.
Angew. Chem., Int. Ed. 1998, 37, 3372. (b) Evans, D. A.; Johnson, J.
S. J. Am. Chem. Soc. 1998, 120, 4895. (c) Evans, D. A.; Johnson, J. S.;
Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635. (d) Thorhauge, J.;
Johannsen, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37, 2404.
(e) Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2000, 65, 4487. (f) Juhl, K.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2003, 42, 1498. (g) Wada, E.; Yasuoka, H.; Kanemasa, S. Chem.
Lett. 1994, 9, 1637. (h) Wada, E.; Pei, W.; Yasuoka, H.; Chin, U.;
Kanemasa, S. Tetrahedron 1996, 52, 1205. (i) Gademann, K.; Chavez,
D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 3059.
(4) (a) Hanessian, S.; Compain, P. Tetrahedron 2002, 58, 6521. (b)
Arimori, S.; Kouno, R.; Okauchi, T.; Minami, T. J. Org. Chem. 2002,
67, 7303. (c) Boeckman, R. K., Jr.; Flann, C. J.; Poss, K. M. J. Am.
Chem. Soc. 1985, 107, 4359. (d) Weichert, A.; Hoffmann, H. M. R. J.
Org. Chem. 1991, 56, 4098.
10.1021/jo050821s CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/16/2005
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J. Org. Chem. 2005, 70, 6680-6684

Diels-Alder Reaction/Retro-Claisen Rearrangement
TABLE 1. [4 + 2] Reactions between 1,2-Phenyl-2-butenal (1b) and Cyclopentadiene
reaction condition
product ratioa
entry
Me2AlCl (equiv)
T/°C
t/h
2a
3a
4a
5a
6
7
conv (%)
yield (%)b
1
2
3
4
5
6
7
8
1.1
-20
-20
-20
-20
0
6
19
39
59
68
53
0
4
42
39
29
19
24
0
7
15
5
13
7
86
93
100
91
100
86
100
100
-
0.5
6
3
7
2a(26) 4a (27)
2a (46) 4a+5a (26)
-
0.1
6
2
7
1
2
0.02
0.1
6
4
5
4
6
43
0
0
0
5
57
0
0
6
4
8
-
1.0
25
0.7
6
0
0
6 (26) 7 (31)
2a (55) 4a+5a (30)
2a (71) 4a+5a (4)
0.1
-40
-40
60
89
1.5
2
35
7
3.5
2
0.05
20
a The ratio was determined from a 500 MHz 1H NMR spectrum of the crude reaction mixture. b Yield after chromatographic purification.
(eq 1).6 The reaction was shown to proceed by a [4 + 2]
cycloaddition followed by a Lewis acid-catalyzed ring
expansion. A requirement for this transformation was the
presence of an electron-donating substituent on the R,â-
unsaturated aldehyde.
under forcing conditions is a reasonable expectation. On
lowering the reaction temperature to -40 °C, the dihy-
dropyrans and Diels-Alder cycloadducts are cleanly
formed (entries 7 and 8), and the optimum conditions for
the formation of 2a is 0.05 equiv of Lewis acid and
extended reaction time of 20 h. Under these conditions,
2a was obtained in 71% isolated yield (entry 8). Reducing
the reaction temperature to -78 °C resulted in very low
conversion.
With optimized reaction conditions in hand, the scope
of this reaction was then determined. The hetero [4 + 2]
cycloaddition is effective for various 2-aryl-R,â-unsatur-
ated aldehydes with excellent diastereoselectivity and
moderate to good yields of 2 (Table 2). The major
competing reaction is the formation of the Diels-Alder
cycloadducts 4 and 5. Specifically, both 2-substituted
acroleins (1b to 1d)8 and 2,3-disubstituted acroleins (1a,
1e-j)9 afford the desired products. The most interesting
substrate for this reaction was cyclic substrate 1j.10 The
steroid-type product 2j was generated in one step,
although the yield is relatively low. The indole derivative
1k did not form the hetero [4 + 2] adduct, and the
reaction was not complete even after 20 h. Ketone 1l only
generated the Diels-Alder cycloadduct 4l, which indi-
cates that an aldehyde functionality is necessary for the
retro-Claisen rearrangement.11
During the preliminary experimental studies it became
clear that this reaction is greatly influenced by the nature
of the Lewis acid. For example, if AlCl3 or AlMe3 was used
as the Lewis acid, very low conversions were observed
and the starting aldehyde was recovered. Furthermore,
the reaction is also influenced by the temperature and
the amount of Lewis acid (Table 1). Even though catalytic
amounts of the Lewis acid and long reaction time at low
temperature favor the formation of dihydropyran 2,
complete conversion of the Diels-Alder cycloadduct 4 did
To expand the range of this reaction, various other
substrates were examined. When 2-phenyl-2-butenal (1a)
was used, the reaction gave a complex mixture of five
products in addition to the expected [4 + 3] cycloadduct
6 (Table 1). Two diastereomeric dihydropyrans 2a and
3a, two diastereomeric Diels-Alder cycloadducts 4a and
5a, the [4 + 3] cycloadduct 6, and the tricyclic product 7
were formed. Because the dihydropyrans are the products
of a formal HDA reaction where the cyclopentadiene
behaves as the dienophile,3b,c,4,7 further studies were
conducted to optimize the reaction toward the formation
of 2a. Decreasing the amount of Lewis acid in reactions
conducted at -20 °C resulted in a steady improvement
in the yield of the dihydropyran 2a (entries 1-4). In
contrast, when the reaction temperature was increased,
the amount of the [4 + 3] cycloadduct 6 and the tricycle
7 increased (entries 5 and 6). Indeed, when a full
equivalent of Lewis acid is used at 25 °C, 6 and 7 become
the major products (26 and 31% isolated yields, respec-
tively). Because 6 and 7 are presumably derived from
Lewis acid-catalyzed rearrangements of the Diels-Alder
cycloadducts (1,2-shift from 4a or 5a for 6, Cope re-
arrangement from 5a for 7), their preferential formation
(5) For reviews of the Claisen rearrangement and tandem cycload-
ditions, see: (a) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (b)
Hiersemann, M.; Abraham, L. Eur. J. Org. Chem. 2002, 1461. (c)
Neuschutz, K.; Velker, J.; Neier, R. Synthesis 1998, 227.
(6) (a) Davies, H. M. L.; Dai, X. J. Am. Chem. Soc. 2004, 126, 2692.
(b) Niess, B.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2005, 44,
26.
(7) Examples of cyclopentadiene behaving as dienophile: (a) Corey,
E. J.; Munroe, J. E. J. Am. Chem. Soc. 1982, 104, 6129. (b) Ismail, Z.
M.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1982, 21, 859.
(c) Dvora´k, D.; Arnold, Z. Tetrahedron Lett. 1982, 23, 4401. (d)
Nenajdenko, V. G.; Statsuk, A. V.; Balenkova, E. S. Tetrahedron 2000,
56, 6549.
(8) 1b, 1c, 1d, and 1l were synthesized according to literature
procedures: (a) Laitalainen, T.; Kuronen, P.; Hesso, A. Org. Prep.
Proced. Int. 1993, 25, 597. (b) Takano, S.; Inomata, K.; Samizu, K.;
Tomita, S.; Yanase, M.; Suzuki, M.; Iwabuchi, Y.; Takumichi, S.;
Ogasawara, K. Chem. Lett. 1989, 1283. 1d must be reacted im-
mediately because it is very prone to dimerize.
(9) 1f, 1h, and 1i were synthesized according to a literature
procedure: Kim, J.-K.; Kulawiec, R. J. J. Org. Chem. 1996, 61, 7656.
(10) Song, Z.; Beak, P. J. Am. Chem. Soc. 1990, 112, 8126.
(11) The product 4l was refluxed in toluene for 24 h. There was no
retro-Claisen rearrangement, and the starting material was recovered.
J. Org. Chem, Vol. 70, No. 17, 2005 6681

Davies and Dai
TABLE 2. Me2AlCl-Catalyzed Reaction of Cyclopentadiene with r,â-Unsaturated Aldehydesa
a Reaction was conducted at -20 to -40 °C for 20 h using 5-20 mol % Me2AlCl and 5 equiv of diene. NOE studies support the relative
configurations of all the products. See Supporting Information for specific details for each substrate. b Yield after chromatographic
purification. c de was determined from a 500 MHz 1H NMR spectrum of the crude reaction mixture. d Isolated yield of the mixture of
endo and exo diastereomers.
not occur. Further complications with the chemistry is
the possibility of generating other rearrangement prod-
ucts such as 6 and 7 and the retro-Diels-Alder reaction
under the Lewis acid-catalyzed reaction conditions.
To understand the equilibrium chemistry further,
control experiments were conducted with clean sub-
strates (Scheme 1). Treatment of the [4 + 2] cycloadduct
4a with Me2AlCl resulted in a rearrangement product,
but the ratio was dependent on the amount of Lewis acid
used. When 4a was treated with a catalytic amount of
Me2AlCl (5 mol %) at -40 °C, the dihydropyran 2a was
the major product, although some retro-Diels-Alder
reaction to form the unsaturated aldehyde 1a also
occurred. When a stoichiometric amount of Me2AlCl was
used in the reaction of 4a at -40 °C, the ratio of 2a and
4a was closer to 1:1 and the amount of the retro-Diels-
Alder reaction was much greater. These results indicate
that Me2AlCl is not only acting as a Lewis acid catalyst
but also influences the product distribution, presumably
coordinating more favorably to 4a than to 2a. The
equilibrium between 4a and 2a can also be reached
starting from 2a, and again the retro-Diels-Alder reac-
6682 J. Org. Chem., Vol. 70, No. 17, 2005

Diels-Alder Reaction/Retro-Claisen Rearrangement
SCHEME 1
tion is a significant side reaction. As indicated in Table
1, entry 6, the formal [4 + 3] cycloadduct 6 and the
tricyclic product 7 are preferentially formed under more
vigorous Lewis acid-catalyzed conditions. Indeed, the
formation of 6 appears to be an irreversible process
because 6 did not revert back to the other products, even
under forcing Lewis acid-catalyzed conditions, while 7
was unstable under such forcing conditions.
The above experiments demonstrate that the equili-
bration between 2a and 4a can be induced by Lewis acids
but do not distinguish whether the interconversion is a
direct Claisen rearrangement or involves a retro-cycload-
dition to 1a and cyclopentadiene followed by a subsequent
cycloaddition. To distinguish between these two possibili-
ties, enantioenriched 2a and 4a were prepared and
studied in the rearrangement. The enantioenriched
material was prepared according to eqs 2 and 3. The
reaction of 1a with cyclopentadiene catalyzed by R-
BINOL-modified aluminum Lewis acid 8 (10 mol %) at
-40 °C in dichloromethane generated dihydropyran 2a
and normal [4 + 2] adduct 4a both in 44% ee (eq 2). When
the toluene was used as solvent, the hetero [4 + 2]
product 2a (25% ee) and normal [4 + 2] adduct 4a (56%
ee) were obtained with different enantiomeric excess (eq
3). These results indicate that 2a in eq 2 could have been
derived from a tandem Diels-Alder reaction/retro-
Claisen rearrangement because 2a and 4a have the same
enantiomeric excess but 2a from eq 3 must have been
generated, at least partially, from a different reaction
pathway.
With the enantioenriched material in hand, control
experiments were conducted under thermal and the Me2-
AlCl-catalyzed reaction conditions. Heating endo [4 + 2]
adduct 4a (44% ee) under reflux in toluene for 3 h
resulted in 43% conversion to 2a while retaining the
enantiomeric excess (44% ee, eq 4). In contrast, 2a
remained unchanged under these reaction conditions (eq
5). These indicate the thermal rearrangement of 4a to
2a is a direct retro-Claisen rearrangement.
The Lewis acid-catalyzed rearrangement between 4a
and 2a was more complex than the thermal reaction.
Treatment of 2a (44% ee) with 10 mol % Me2AlCl at -40
°C in DCM for 4 h resulted in a mixture of 4a (40% ee)
and 2a (40% ee) as well as small quantities of the exo
isomer 5a (eq 6). Under the same conditions, 4a (56%
ee) was converted to a mixture of 2a (40% ee) and 4a
(37% ee) and small quantities of the exo isomer 5a. (eq
7). The drop in enantioselectivity indicates that under
the Lewis acid conditions the retro-cycloadditions are
occurring in competition with the Claisen rearrangement.
Furthermore, these results confirm that under the Lewis
acid conditions the retro-Claisen rearrangement is re-
versible. It is still not clear whether the drop in enantio-
selectivity in the conversion of 4a to 2a in eq 7 is simply
due to the reversible nature of the Diels-Alder reaction
or whether some of 2a was formed from a hetro-Diels-
Alder reaction. The fact that some of the enantiomeric
excess is retained in the conversion of 4a to 2a (eq 7)
indicates that the retro-Claisen rearrangement between
4a and 2a is a viable process.
A general overview of the reaction of 2-phenylacrolein
1a with cyclopentadiene is given in Scheme 2. All the
steps are Lewis acid-catalyzed, including the retro-Diels-
J. Org. Chem, Vol. 70, No. 17, 2005 6683

Davies and Dai
In conclusion, we have discovered and developed a
novel formal inverse electron demand hetero Diels-Alder
reaction between 2-aryl-R,â-unsaturated aldehydes and
cyclopentadiene. This reaction is highly stereoselective
and provides access to a variety of dihydropyran deriva-
tives. Detailed mechanism studies demonstrated that the
major pathway for the transformation is a Lewis acid-
catalyzed tandem Diels-Alder reaction/retro-Claisen
rearrangement.
Experimental Section
Representative Procedure for the Me2AlCl-Catalyzed
Reaction of Cyclopentadiene with r,â-Unsaturated Al-
dehydes. Dimethylaluminum chloride (0.14 mL, 0.14 mmol,
1.0 M in hexanes) was added dropwise to a stirred solution of
2-phenyl-2-butenal 1a (0.42 g, 2.78 mmol) and CH2Cl2 (5 mL)
followed by cooling for 10 min at -40 °C. After 15 min, an
aliquot of freshly distilled precooled cyclopentadiene (0.92 g,
13.95 mmol) was added by syringe to the reaction mixture,
giving a clear yellow solution. The resulting mixture was kept
stirring at -40 °C for 20 h. The reaction was quenched by
addition of 3 mL of saturated NaHCO3 solution, extracted with
ether (2×), and the combined extracts were washed with water
and brine, dried over MgSO4, and concentrated. The crude
product was purified by column chromatography on silica gel
using 1-2% diethyl ether/pentane as eluent to give 2a as a
colorless oil: 418 mg (71% yield); and a mixture of 4a and 5a
as colorless oil: 23 mg (4% yield, 3.5:1 mixture).
(4S*,4aR*,7aR*)-4,4a,5,7a-Tetrahydro-4-methyl-3-phen-
ylcyclopenta[b]pyran (2a): 1H NMR (500 MHz, CDCl3) δ
7.30-7.16 (m, 5H), 6.63 (s, 1H), 6.16 (m, 1H), 6.00 (m, 1H),
4.84 (br d, J ) 6.0 Hz, 1H), 3.16 (m, 1H), 2.68 (m, 1H), 2.42-
2.32 (m, 2H), 1.00 (d, J ) 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 143.1, 139.0, 137.1, 131.5, 128.1, 126.9, 125.8, 118.2,
80.6, 43.4, 33.1, 27.8, 16.6; IR (neat) 2931, 1639, 1176, 761,
701 cm-1; HRMS (EI) calcd for C15H16O [M]+, required m/z:
212.1196, found m/z: 212.1198.
Alder reaction, but a delicate balance exists between the
Diels-Alder reaction products 4a and 5a and the dihy-
dropyran 2a. The control experiments to date are not
conclusive regarding the possibility of 2a being partially
formed by direct hetero Diels-Alder reaction between
cyclopentadiene and 1a. The optimum conditions for the
formation of 2a are low temperatures and catalytic
amounts of Lewis acid. An additional amount of Lewis
acid drives the equilibrum more toward the Diels-Alder
cycloadducts 4a and 5a, while high temperatures favor
other irreversible rearrangements to 6 and 7.
SCHEME 2
(1S*,2S*,3R*,4R*)-3-Methyl-2-phenylbicyclo[2.2.1]hept-
5-ene-2-carbaldehyde (4a): 1H NMR (500 MHz, CDCl3) δ
9.33 (s, CHO, 1H), 7.38-7.18 (m, 5H), 6.39 (dd, J ) 5.5, 3.0
Hz, 1H), 6.17 (dd, J ) 5.5, 3.0 Hz, 1H), 3.47 (br s, 1H), 2.63
(br s, 1H), 2.60 (m, 1H), 2.00 (d, J ) 8.5 Hz, 1H), 1.65 (d, J )
8.5 Hz, 1H), 0.64 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 198.9, 141.6, 136.7, 133.1, 129.4, 128.4, 126.9, 67.0,
51.1, 47.2, 44.8, 37.9, 20.2; IR (neat) 2968, 1712 (CdO), 1463,
704 cm-1; HRMS (EI) calcd for C15H16O [M]+, required m/z:
212.1196, found m/z: 212.1196.
Acknowledgment. Financial support of this work
by the National Science Foundation (CHE-0350536) is
gratefully acknowledged.
Supporting Information Available: Full experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050821S
6684 J. Org. Chem., Vol. 70, No. 17, 2005