Lewis Acid Induced Tandem Diels-Alder Reaction/Ring Expansion as an Equivalent of a [4 + 3] Cycloaddition

Article abstract of DOI:10.1021/ja039908q

Aluminum chloride induced reaction between cyclopentadiene and α,β-unsaturated aldehydes results in the stereoselective formation of the products of a formal [4 + 3] cycloaddition. The reaction proceeds by a tandem Diels?Alder reaction/ring expansion. Cop

Full text of DOI:10.1021/ja039908q

Published on Web 02/14/2004
Lewis Acid Induced Tandem Diels-Alder Reaction/Ring Expansion as an
Equivalent of a [4 + 3] Cycloaddition
Huw M. L. Davies* and Xing Dai
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York, Buffalo, New York 14260-3000
Received December 2, 2003; E-mail: hdavies@acsu.buffalo.edu
Table 1. [4 + 3] Cycloaddition of 1,3-Cyclopentadiene with
R,â-Unsaturated Aldehydesa
The Lewis acid-catalyzed Diels-Alder reaction between cyclo-
pentadiene and R,â-unsaturated aldehydes is one of the most widely
studied reactions in organic synthesis.1 Not only does the reaction
have broad utility in total synthesis,1 but also it has become a classic
reaction for the evaluation of new chiral Lewis acids.2 In this paper,
we describe that, under appropriate conditions, the stereoselective
formation of formal [4 + 3] cycloadducts 3 (eq 1) occurs instead
of the usual Diels-Alder reaction. This transformation is shown
to be a Lewis acid induced tandem Diels-Alder cycloaddition/
ring expansion, and this interpretation has ramifications regarding
the mechanism of other reported “[4 + 3] cycloadditions”.3
The novel transformation was discovered during studies to
explore the synthetic utility of the highly functionalized cyclopen-
tenecarboxaldehyde 4 (eq 2).4 Under forcing conditions, the reaction
of 4 with excess diethylaluminum chloride (5 equiv), followed by
quenching of the reaction at -78 °C, formed the Diels-Alder
products 5a and 5b in 40% yield. On quenching the reaction at 0
°C, however, the major product was the formal [4 + 3] cycloadduct
6 (45% yield), containing four new stereocenters.
a Reaction conditions: 1.1 equiv of AlCl3, 2.5 equiv of diene, -78 to 0
°C, CH2Cl2, 2 h. b Isolated yield after chromatographic purification. c The
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.
kinetic products, but for 3a-c, epimerization to the 3â products is
readily achieved as illustrated for the equilibration of 3 to 8 (eq 3).
Treatment of 3a with 1.0 equiv of HCl generated a 9:91 mixture
of 3a and 8a from which the 3â isomer 8a was readily isolated in
83% yield.
Having discovered this unexpected transformation, efforts were
made to determine its generality (Table 1). A range of Lewis acids
were explored, and the optimized conditions were 1.1 equiv of
aluminum chloride with warming of the reaction mixture from -78
to 0 °C over the course of 2 h. The [4 + 3] cycloaddition is very
effective between cyclopentadiene and 2-substituted (2a,b) and 2,3-
disubstituted (2c-e) acrolein derivatives. In each case, the 3-endo
diastereomer is formed with excellent diastereocontrol.5 The
presence of a 2-substituent in 2 is a requirement for this chemistry
because the reaction with crotonaldehyde (2f) formed the Diels-
Alder product 7, which showed no tendency toward ring expansion.
Ring strain also appears to be a factor as the reaction of 2a with
cyclohexadiene gave only the Diels-Alder product.
The observation of the exclusive formation of Diels-Alder
products 5a and 5b in the reaction of 4 at -78 °C suggests that the
[4 + 3] cycloadducts are formed by a tandem Diels-Alder reaction/
ring expansion. This was verified by preparing the Diels-Alder
products, followed by treatment of the cycloadducts with a slight
A particularly attractive feature of these [4 + 3] cycloadditions
is that either the 3R or the 3â diastereomer of the cycloadduct can
in many cases be selectively obtained. The 3R products 3 are the
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C O M M U N I C A T I O N S
excess of aluminum chloride. In the case of the Diels-Alder
products derived from 2a and 2b, very effective ring expansion to
the [4 + 3] cycloadducts was observed. The reaction of aluminum
chloride with the exo and endo isomers 9a and 9b derived from 2d
was especially interesting as the major exo isomer 9a underwent
an essentially quantitative rearrangement to the [4 + 3] cycloadduct
3d (eq 4), while the minor endo isomer 9b preferentially underwent
a retro-Diels-Alder reaction (eq 5).6 The retro-Diels-Alder reaction
was a major side reaction for the Diels-Alder cycloadducts derived
from 2c and 2e, which may explain why the yields for the formation
of 3c and 3e (Table 1) are relatively low.
Due to the fact that a stoichiometric amount of Lewis acid is
required to efficiently induce the formation of the formal [4 + 3]
cycloadducts, the use of chiral Lewis acids for the direct transfor-
mation would not be practical. The asymmetric synthesis of the
formal [4 + 3] cycloadducts, however, can be readily achieved in
a two-step process beginning with a chiral Lewis acid-catalyzed
asymmetric Diels-Alder reaction followed by aluminum chloride
induced rearrangement (eq 8). For example, using Faller’s ruthenium-
based chiral Lewis acid,2c the Diels-Alder product 13 was obtained
in 85% ee. Aluminum chloride induced rearrangement of 13
generated 14 in 74% yield with retention of the enantioselectivity.
This is consistent with the formation of 14 from the direct
rearrangement of 13 rather than a retro-Diels-Alder followed by
a [4 + 3] cycloaddition, where loss of enantioselectivity would be
expected.
On the basis of these observations, it became of interest to
reevaluate the recently published studies by Harmata on the
scandium triflate-catalyzed reaction of the 2-siloxyacrolein 10 with
cyclopentadiene, which results in the formation of [4 + 3]
cycloadducts 11a,b (eq 6).3a Although the mechanism of this
reaction has not been fully elucidated, the working hypothesis has
been a stepwise mechanism involving a zwitterionic intermediate,
which preferentially forms the [4 + 3] cycloadduct rather than the
[4 + 2] cycloadduct. A recent computational study on the reaction
of 2-siloxyacrolein with furan supported a stepwise mechanism.7
An alternative mechanistic possibility would be the tandem Diels-
Alder reaction/ring expansion.
In conclusion, we have discovered a remarkably simple method
to achieve a formal [4 + 3] cycloaddition between cyclopentadiene
and R,â-unsaturated aldehydes, which proceeds by a tandem Diels-
Alder reaction/ring expansion. Further studies are in progress to
determine the full scope of this chemistry.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0350536). We thank Oksana O. Gerlits
for the X-ray crystallographic analysis and Dr. Jaemoon Yang for
helpful discussions.
Supporting Information Available: Full experimental data for the
compounds described in this paper (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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