Cascade olefin isomerization/intramolecular diels-alder reaction catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1002/anie.201402067

The addition of an N-heterocyclic carbene to the carbonyl group of an α,β,γ,δ-unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels-Alder reaction, for which mechanistic studies implicate Lewis base catalysis. Preliminary studies into the utility of the products have been undertaken with reductive and oxidative cleavage, giving materials for potential use in complex-target synthesis. NHC-catalyzed cascade: The addition of an N-heterocyclic carbene (NHC) to the carbonyl group of an α,β,γ, δ-unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels-Alder reaction. Preliminary studies into the utility of the products using reductive and oxidative cleavage gave substrates for potential use in the synthesis of complex targets.

Full text of DOI:10.1002/anie.201402067

Angewandte
Chemie
DOI: 10.1002/anie.201402067
NHC Catalysis
Cascade Olefin Isomerization/Intramolecular Diels–Alder Reaction
Catalyzed by N-Heterocyclic Carbenes**
Marcin Kowalczyk and David W. Lupton*
Abstract: The addition of an N-heterocyclic carbene to the
carbonyl group of an a,b,g,d-unsaturated enol ester affords
a hemiacetal azolium intermediate that enables a cascade olefin
isomerization/Diels–Alder reaction, for which mechanistic
studies implicate Lewis base catalysis. Preliminary studies
into the utility of the products have been undertaken with
reductive and oxidative cleavage, giving materials for potential
use in complex-target synthesis.
T
he capacity of N-heterocyclic carbenes (NHCs)[1] to engage
with non-aldehyde-containing substrates introduces exciting
opportunities in reaction discovery.[1h] In 2009, we reported an
early example of nucleophilic NHC catalysis with ester
substrates.[2,3] Since then, NHC-catalysis with esters, and
starting materials in the ester oxidation state, has received
increased attention.[4] In most instances, these substrates (i.e.
1) provide acyl azolium intermediates (i.e. 2),[5] which then
engage in a remarkable array of reaction cascades.[6,7] How-
ever, in certain cases hemiacetal azolium species 3,[8] a direct
precursor to the acyl azolium intermediate, can be applied in
reaction discovery. For example hemiacetal azolium species
3a undergoes sigmatropic rearrangement in the transforma-
tion of enol ester 4 to dihydropyranone 5 [Eq. (1)].[2,6c] This
mechanism is supported by the work of Bode and co-workers,
who exploited hemiacetal azolium intermediates derived
from kojic acid in a related reaction.[9a] Despite these
observations and the intense research activity on NHC
catalysis, the hemiacetal azolium intermediate is yet to be
exploited in any other NHC-catalyzed transformations.
Recently we became intrigued by the potential of the
hemiacetal azolium intermediate to enable olefin isomer-
ization reactions (Figure 1). Olefin-containing materials are
ubiquitous and their isomerization, particularly to unstable
isomers, can be challenging.[10,11] We postulated that the
NHC-mediated formation of hemiacetal azolium species 3b
would eliminate the intrinsic stabilizing effect of conjugation
within dienyl ester 6, thereby lowering the barrier for olefin
isomerization, and enabling reaction discovery [Eq. (2)].
Herein, we describe the realization of this strategy with the
Figure 1. NHC-mediated reactions via hemiacetal azolium intermedi-
ates.
NHC-catalyzed cascade olefin isomerization/Diels–Alder
reaction. In addition to demonstrating a novel application
of the hemiacetal azolium intermediate, this study defines
a concise entry to functionalized bicyclo[2.2.2]octanes (i.e. 8),
motifs found in a range of natural products.
Our investigation commenced with dienyl ester 6a.[12]
Previous studies with a,b-unsaturated enol esters annulated
across the a- and b-positions (see 4) have shown that they are
resistant to Coates–Claisen rearrangement [Eq. (1)],[6b] hence
6a should not undergo this undesired reaction. In addition,
the activation energy for olefin isomerization of 1,3-hexa-
diene through [1,5] shift is 41 kcalmolÀ1,[13] with conjugation
to the ester moiety likely to increase this value, thus
uncatalyzed olefin isomerization is unlikely. To confirm this
hypothesis, diene 6a was heated at reflux in a range of
solvents, including the high-boiling ortho-dichlorobenzene. In
all cases, bicyclooctane 8a was not observed (Table 1,
entry 1). In contrast, 10 mol% of IMes (A1) in 1,4-dioxane
at 1018C (Table 1, entry 2) rearranged dienyl ester 6a to the
bicyclo[2.2.2]octane 8a, albeit after an extended reaction time
[*] M. Kowalczyk, Dr. D. W. Lupton
School of Chemistry, Monash University
Clayton 3800, Victoria (Australia)
E-mail: david.lupton@monash.edu
[**] The authors thank Dr. Andreas Stasch (Monash University) for
crystallography, and the Australian Research Council through the
Discovery (DP120101315) and Future Fellowship (FT110100319)
programs for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402067.
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Table 1: Selected optimizations.
Table 2: Scope of the cascade olefin isomerization/intramolecular
Diels–Alder reaction.[a]
Entry
Catalyst[a]
Solvent
T [8C]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
–
o-Cl2C6H4
1,4-dioxane
THF
xylene
toluene
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
181
6
48
48
72
72
6
6
6
6
6
–
A1
A1
A1
A1
A1
A2
A1[d]
A1[e]
A1
B[g]
101
trace
3
100[c]
138
22
20
64
57
32
51
41
–
150[c]
181
181
181
9
10
11
181
181[f]
181
6
[a] NHCs were generated using equimolar tBuOK except as noted.
[b] Yields of isolated products following flash column chromatography
on silica gel. [c] Sealed tube. [d] A1 generated and isolated from salt by-
products. [e] A1 generated with LiHMDS (10 mol%). [f] Heated using
microwave irradiation. [g] B generated with KHMDS (10 mol%). Entry in
bold marks optimized reaction conditions. Bn=benzyl, Dip=2,6-
diisopropylphenyl, Mes=2,4,6-trimethylphenyl.
[a] Yields of isolated products following flash column chromatography
on silica gel. [b] Diastereoselectivity determined by 1H NMR analysis.
and in low yield. Similar results were obtained in THF heated
within a sealed tube (Table 1, entry 3), while xylene at reflux
or toluene in a sealed tube provided 8a in 22 and 20% yield
respectively (Table 1, entries 4 and 5). When the reaction was
heated at reflux in ortho-dichlorobenzene, bicyclooctane 8a
was isolated in an acceptable yield of 64% after 6 hours
(Table 1, entry 6). Changing the catalyst to the more hindered
IPr (A2; Table 1, entry 7) decreased the yield, as did the use
of IMes (A1) in the absence of salt by-products,[14] or
generated using LiHMDS, or with microwave heating
(Table 1, entries 8–10). Finally, using the electron-rich triazol-
ylidene B, designed for substrates in the ester oxidation
state,[6i] only decomposition of the starting materials was
observed (Table 1, entry 11).
The generality of the reaction was examined with a,b,g,d-
unsaturated enol esters 6a–q (Table 2). Using para-substi-
tuted acetophenone derivatives, the sensitivity of the reaction
to electronic effects was investigated. When either electron-
rich (6b and d) or electron-poor substrates (6c) were
subjected to the standard reaction conditions, bicyclo-
[2.2.2]octanes 8b–d were isolated in comparable yields.
Bicyclic aromatic moieties could be incorporated (i.e. 8e),
while the furan-containing product 8 f could only be accessed
in modest yield. Unfortunately, the use of alkyl-substituted
enol esters failed to provide the expected product (i.e. 8g).
Regarding the modest yield of furan 8 f, we postulated that
olefin isomerization should be favored by non-hydrogen
substituents at C5 (R2 = CH3), and hence the modest yield of
bicyclo[2.2.2]octanes should improve. This proved to be the
case with product 8h, which was prepared in 44% yield
(compare with 8 f, 34% yield). Similarly, naphthyl-containing
substrate 6i and acetophenone derivatives 6j–m provided the
expected bicyclo[2.2.2]octanes 8i–m with yields that were
increased by around 10%. Changing R2 to ethyl (i.e. 6n)
unfortunately hampered the reaction, with 8n isolated in
11% yield. Next, aldehyde-derived enols were examined
using phenylacetaldehyde-derived substrate 6o, which was
converted to 8o in a low yield. Unfortunately, the introduc-
tion of a methyl substituent at C5 with this type of enol
decreased the yield (8o versus 8p), presumably as a conse-
quence of steric crowding effects. Finally, the diastereoselec-
tivity of the reaction was examined with 6q, a substrate that
bears a stereogenic methyl group at C6 (R2 = CH3). While this
reaction was successful, bicyclo[2.2.2]octane 8q was formed
with little diastereoselectivity.
While nucleophilic catalysis of the olefin isomerization
provides a reasonable mechanistic explanation for this trans-
formation (Figure 1), an alternate mechanism might involve
the deprotonation of 6a by the NHC to generate enolate 9,
which is protonated to give an unconjugated diene en route to
8a (Scheme 1). To test this scenario, the reaction was
attempted using a range of non-nucleophilic Brønsted bases.
In all cases, unreacted starting materials were isolated
[Eq. (5)].[15] While this result is consistent with a process
mediated by a Lewis base, more compelling support was
obtained using DMAP as the catalyst. While DMAP is a good
Lewis base, it has low Brønsted basicity, and would be unable
to generate enolate 9.[16] In the event, the use of DMAP
provided the expected lactone 8a in 23% yield of isolated
product, presumably via hemiacetal pyridinium intermediate
10 [Eq. (6)].
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dismissed. Attempts to prepare the desmethyl variant (11b,
R = H) by allylic oxidation and elimination strategies have
not been successful because of a rapid olefin isomerization
during substrate synthesis.[19] Further mechanistic studies are
currently being conducted to clarify the impact of the NHC on
the Diels–Alder step, and other aspects of the reaction
mechanism.
Finally, derivatization of the bicyclo[2.2.2]octanes was
examined through oxidative and reductive ring-openings.
When lactone 8a was exposed to one equivalent of LiAlH4,
conversion to diol 14 was achieved in 99% yield of isolated
product, with X-ray analysis of a single crystal confirming the
structure (Scheme 3).[20] Next, the oxidative cleavage of the
double bond within 8d was examined. In this case, ozonolysis
provided access to diastereomerically pure and heavily
functionalized bicyclo[3.2.1]heptane 15.
Scheme 1. Comparison between Brønsted base mediated and nucleo-
philic catalysis. DMAP=4-dimethylaminopyridine, HMDS=hexame-
thyldisilazane, LDA=lithium diisopropylamide.
Reversible fragmentation of the hemiacetal azolium
intermediate to form the acyl azolium species could occur
under the reaction conditions. To establish whether this
occurs, cross-over studies using 6d and j were performed
[Eq. (7)]. In this case, none of the crossed products (i.e. 8a or
8m) were observed, thus indicating that the formation of the
acyl azolium intermediate is unlikely. Finally, the involvement
of the NHC in the Diels–Alder process was examined. Enol
ester 11a was prepared by Birch reduction of benzoic acid
12[17] followed by standard conversions (Scheme 2).[12] This
substrate proved to be viable in a thermal Diels–Alder
reaction, providing lactone 13 in good yield after 6 hours.[18]
When this reaction was repeated with 10 mol% A1, and taken
to partial conversion, the yield of bicycle 13 was comparable
to that without the catalyst. These results indicate that the
NHC is unlikely to be accelerating the cycloaddition, however
the impact of the quaternary methyl group cannot be
Scheme 3. Derivatization studies.
In conclusion, ester-containing materials served as novel
substrates for reaction discovery using NHCs. In this study, we
were able to achieve a cascade olefin isomerization/Diels–
Alder reaction. This sequence defines a novel entry to
bicyclo[2.2.2]octanes materials bearing an array of substitu-
ents. These can be elaborated oxidatively or reductively to
provide heavily functionalized products.
Received: February 4, 2014
Revised: February 27, 2014
Published online: && &&, &&&&
Keywords: Diels–Alder reaction ·
.
hemiacetal azolium intermediates · N-heterocyclic carbenes ·
olefin isomerization · organocatalysis
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[15] These controls have also been performed with tBuOK in both
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[20] CCDC 983932 contains the supplementary crystallographic data
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4
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Communications
NHC Catalysis
M. Kowalczyk,
D. W. Lupton*
&&&& — &&&&
Cascade Olefin Isomerization/
Intramolecular Diels–Alder Reaction
Catalyzed by N-Heterocyclic Carbenes
NHC-catalyzed cascade: The addition of
an N-heterocyclic carbene (NHC) to the
carbonyl group of an a,b,g,d-unsaturated
enol ester affords a hemiacetal azolium
intermediate that enables a cascade
olefin isomerization/Diels–Alder reac-
tion. Preliminary studies into the utility of
the products using reductive and oxida-
tive cleavage gave substrates for potential
use in the synthesis of complex targets.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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These are not the final page numbers!