High Reactivity of Strained Seven-Membered-Ring trans-Alkenes

Article abstract of DOI:10.1002/anie.201510056

trans-Oxasilacycloheptenes are highly reactive strained alkenes. Competition reactions showed that these seven-membered ring trans-alkenes underwent [4+2] cycloaddition reactions faster than a trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10⁹. trans-Oxasilacycloheptenes are strained seven-membered-ring trans-alkenes that underwent [4+2] cycloaddition reactions faster than a bicyclic trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10⁹.

Full text of DOI:10.1002/anie.201510056

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International Edition: DOI: 10.1002/anie.201510056
German Edition: DOI: 10.1002/ange.201510056
Strained Molecules
High Reactivity of Strained Seven-Membered-Ring trans-Alkenes
Jillian R. Sanzone and K. A. Woerpel*
Abstract: trans-Oxasilacycloheptenes are highly reactive
strained alkenes. Competition reactions showed that these
seven-membered ring trans-alkenes underwent [4+2] cyclo-
addition reactions faster than a trans-cyclooctene. They also
reacted with quinones and dimethyl acetylenedicarboxylate to
form adducts with high diastereoselectivity. Kinetic studies
showed that ring strain increases nucleophilicity by approx-
imately 109.
S
train-promoted reactions have emerged as important
transformations in organic synthesis[1] and chemical biology.[2]
Among the strained systems investigated, the eight-mem-
bered-ring trans-alkenes have found numerous applica-
tions.[3–8] In contrast, studies of the reactivity of seven-
membered-ring trans-alkenes are much less common because
these compounds are particularly difficult to prepare.[9–11]
Limited studies of the chemistry of trans-cycloheptenes
demonstrate that they undergo transformations typical of
reactions of alkenes, such as dihydroxylations[11,12] and
reactions with acids.[12–14] They also participate in reactions
observed for trans-cyclooctenes, such as [4+2] cycloaddi-
tions,[3,10] but those reactions were generally low-yielding.
Herein, we demonstrate that highly strained trans-oxasi-
lacycloheptenes undergo fast, high-yielding, and, in most
cases, stereoselective reactions. These strained alkenes are
more reactive in a [4+2] cycloaddition than the most reactive
trans-cyclooctene.[15,16] The tunable synthesis of these seven-
membered-ring trans-alkenes allows access to new strain-
promoted reactions, including stereoselective reactions with
substrates containing electron-deficient p-bonds.
Scheme 1. Reaction of trans-oxasilacycloheptene 1 with diene 2.
alkene 4 was used.[21] Initial experiments were performed to
characterize and isolate cycloadducts 5 and 7 (ꢀ 97% isolated
yield). The relative reactivities of the different strained
alkenes were established by a competition experiment
(Scheme 2). This experiment revealed that trans-alkene 4
reacted seven-times faster with diene 2 than trans-cyclooctene
6 did. The enhanced reactivity of alkene 4 is likely due to the
higher distortion of the trans double bond[12] compared to
trans-cyclooctene 6, which is itself conformationally dis-
torted.[16]
Seven-membered-ring trans-alkenes are so reactive that
they undergo cycloaddition reactions with the highly sub-
Initial studies revealed that trans-alkene 1 was highly
reactive in a [4+2] cycloaddition reaction. This seven-
membered-ring trans-alkene, which was synthesized from
1,3-pentadiene, benzaldehyde, and a di-tert-butyl silylene
source,[14] reacted with diene
2 within five minutes
(Scheme 1). Purification of the product afforded cycloadduct
3 in 98% yield. Although the cycloaddition occurred with
retention of the geometry of the trans-alkene,[17] poor facial
selectivity on the diene occurred.[18]
A competition experiment established the high reactivity
of trans-oxasilacycloheptenes. Rates of cycloaddition reac-
tions of the seven-membered-ring system were compared to
trans-cyclooctene 6,[19] a protected variant of a trans-cyclo-
octene reported to react faster than other strained alkenes in
cycloadditions.[2,16] To control for steric effects,[20] the trans-
[*] J. R. Sanzone, Prof. K. A. Woerpel
Department of Chemistry, New York University
100 Washington Square East, New York, NY 10003 (USA)
E-mail: kwoerpel@nyu.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510056.
Scheme 2. Competition reactions of diene 2 with trans-alkenes 4 and 6.
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stituted diene 2, even when the alkene is sterically hindered.
Cycloaddition of diene 2 with trisubstituted alkene 8 required
only 20 minutes to form cycloadduct 9 as a single diastereo-
mer in 96% yield [Eq. (1)]. This stereoisomer is likely favored
because it minimizes developing steric interactions between
a phenyl group of the diene and the fused six-membered ring
of the alkene.
Scheme 4. Formation of enones 11a and 11b.
Control experiments suggest that strain is responsible for
the high reactivity of seven-membered-ring trans-alkenes.
The less-strained cis-alkene isomer of 8 (cis-8) was prepared
by photochemical isomerization of trans-8 (Scheme 3). This
alkene was unreactive in cycloaddition reactions even after
100 days.
days compared to one hour. At least six products were
1
formed, as determined by H NMR spectroscopy, but none
were formed in sufficient quantities to assign structures.
The reaction with quinone 10a permits the estimation of
how much ring strain increases the nucleophilicity of trans-
alkene 8. Kinetic studies of the reaction between alkene 8 and
quinone 10a showed that the rate constant was comparable to
that of the reaction between a silyl ketene acetal and quinone
10a.[24] Considering how much more nucleophilic silyl ketene
acetals[25] are than trisubstituted alkenes,[26] the strain of
alkene 8 accounts for a rate acceleration of approximately 109.
The modular assembly of seven-membered-ring trans-
alkenes from dienes and aldehydes by silylene transfer[14]
enables the synthesis of other electron-rich trans-cycloal-
kenes. Strained silyl enol ether 12, the first example of a silyl
enol ether incorporated into a trans-cycloalkene, was even
more reactive with quinones.[27] Upon exposure to quinone
10a or 10b, phenols 13a and 13b, respectively, were formed as
single stereoisomers [Eq. (3)]. These reactions, which likely
involve addition of silyl enol ether 12 to the quinone followed
by cyclization onto the resulting oxocarbenium ion inter-
mediate,[24] preserved the geometry of the alkene in the
product. The observation that unstrained cyclic silyl enol
Scheme 3. Synthesis of cis-8 and attempted reaction with diene 2.
The high reactivity of these compounds permitted the
development of new strain-promoted reactions. Trisubstituted
alkene 8 reacted with benzoquinone 10a to form enone 11a as
a single diastereomer (Scheme 4).[22,23] There was even
a reaction with the quinone 10b, which is over 1000-times
less electrophilic than quinone 10a.[24] Although the enones
11a and 11b could arise from concerted ene reactions
between the alkene and the quinone, these reactions likely
proceed by stepwise mechanisms involving zwitterionic
intermediates (intermediate A, Scheme 4).[24] As with cyclo-
addition reactions, the alkene must be strained: the less
strained alkene cis-8 did not react with 10a even after several
days.
In comparison to trans-alkene 8, trans-cyclooctene 6 was
much less reactive. Even with the more reactive quinone 10a
[Eq. (2)], reactions were considerably slower, requiring eight
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ether 14 did not react with quinone 10a after one week
[Eq. (4)] indicates that the reactions of alkene 12 are strain-
promoted.[28]
Seven-membered-ring trans-alkenes were also highly
reactive with an electron-deficient alkyne (Scheme 5). trans-
Enol ether 12 reacted with two equivalents of dimethyl
The products of reactions of trans-oxasilacycloheptenes
can be functionalized to afford products without silicon
atoms. Treatment of 13b with a Lewis acid eliminated
Me3SiOH [Eq. (6)], and desilylation in the presence of D2O
provided the deuterium-labeled benzofuran 19. The benzo-
furan moiety is found in compounds displaying anti-inflam-
matory and anti-tumor activities.[33]
In conclusion, seven-membered-ring trans-alkenes are
highly reactive species in a number of reactions. They are
more reactive in Diels–Alder cycloadditions than trans-cyclo-
octenes. Substituted trans-alkenes undergo rapid and stereo-
selective reactions with quinones and DMAD.
Scheme 5. Reactions of trans-cycloalkenes 12 and 8 with DMAD.
Acknowledgements
acetylenedicarboxylate (DMAD)[29] in less than ten minutes
to form acetal 16 as a single diastereomer.[30] An enol ether
was not required for this reaction: bicyclic alkene 8 reacted
with DMAD in 15 minutes to form acetal 17 as a single
stereoisomer (Scheme 5). These reactions likely proceed by
conjugate addition to DMAD and ring-closure to form an
oxocarbenium ion intermediate. Addition of a second equiv-
alent of DMAD and subsequent cyclization forms the acetal
product.[31]
This research was supported by the National Science Foun-
dation (CHE-1362709). We thank Dr. Chin Lin (NYU) for
assistance with NMR spectrometry and mass spectrometry.
We thank Dr. Chunhua Hu (NYU) for X-ray analysis and the
NYU Molecular Design Institute for purchasing a single-
crystal diffractometer.
Keywords: alkenes · cycloaddition · cycloheptenes · silicon ·
strained molecules
The high reactivity of the trans-oxasilacycloheptenes with
DMAD contrasts with the reactivity of this alkyne with other
alkenes. In comparison to the seven-membered-ring system,
trans-cyclooctene 6 reacted slowly (four days compared to
ꢁ 15 minutes) and unselectively with DMAD, resulting in
a mixture of at least four products [Eq. (5)]. Only lactone 18
could be identified from that mixture. The slow and unse-
lective reaction of trans-alkene 6 with DMAD is consistent
with earlier studies of reactions of strained alkenes with this
alkyne.[30,32] Unstrained silyl enol ether 14 and alkene cis-8
also did not react with DMAD even after 45 days.
How to cite: Angew. Chem. Int. Ed. 2016, 55, 790–793
Angew. Chem. 2016, 128, 800–803
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Published online: November 27, 2015
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