Dearomative Intramolecular (4+3) Cycloadditions of Arenes with Epoxy and Aziridinyl Enolsilanes

Article abstract of DOI:10.1002/anie.201704155

An intramolecular (4+3) cycloaddition of epoxy and aziridinyl enolsilanes with benzene, naphthalene, and anthracene derivatives is reported. Highly functionalized polycyclic alcohols and amines are generated under relatively mild reaction conditions with yields up to 89 %. Optically enriched cycloadducts are obtained from cycloadditions of enantiomerically pure epoxides and aziridines.

Full text of DOI:10.1002/anie.201704155

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Title: Dearomative Intramolecular (4+3) Cycloadditions of Arenes with
Epoxy and Aziridinyl Enolsilanes
Authors: Jesse Ling, Sarah Lam, Kam-Hung Low, and Pauline Chiu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704155
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Dearomative Intramolecular (4+3) Cycloadditions of Arenes with
Epoxy and Aziridinyl Enolsilanes
Jesse Ling,[a] Sarah Lam,[a] Kam-Hung Low‡[b] and Pauline Chiu*[a]
Furthermore, there have been no reports of any intramolecular
(4+3) cycloadditions with arenes.
Dedicated to Prof. Albert Padwa on his 80th birthday
We have been studying the applications of epoxy and
aziridinyl enolsilanes in inter- and intramolecular (4+3)
cycloadditions with conventional dienes such as cyclopentadiene
and furan.[10] In some cycloadditions with furan derivatives,
Friedel–Crafts (FC) alkylation products were also observed as
minor products. Experiments and computational studies are
consistent with an activated epoxide or aziridine as the dienophile
that undergoes cycloaddition to effectively transfer chirality to the
cycloadduct.[11]
Abstract: An intramolecular (4+3) cycloaddition of epoxy and
aziridinyl enolsilanes with benzene, naphthalene and anthracene
derivatives is reported. Highly functionalized polycyclic alcohols and
amines are generated under relatively mild conditions with yields up
to 89%. Optically enriched cycloadducts are obtained from
cycloadditions of enantiomerically pure epoxides and aziridines.
Arenes are readily available from the petrochemical industry,
and widely used as starting materials for synthesis. Alongside the
classical aromatic substitution chemistry, a rapidly growing library
of dearomatization reactions that convert arenes to more reactive
compounds, expand the synthetic potential of these readily
available feedstock chemicals. Many of these dearomative
reactions exploit the reactivity of the more electron-rich aromatics,
such as indoles and phenols.[1]
When these enolsilanes were subjected to intermolecular
reactions with arenes, Friedel–Crafts alkylation products were
produced, as expected.[12] However, we were intrigued to find that
in the triethylsilyl triflate (TESOTf)-catalyzed reaction of benzene-
tethered epoxy enolsilane 1a, along with the FC product 3a, a
dearomatized (4+3) cycloadduct 2a resulting from ipso-attack was
observed under these mild reaction conditions (Scheme 1). This
cycloaddition is unusual as it is a rather facile (4+3) cycloaddition
engaging a simple benzene derivative. We envisaged that, should
this dearomative (4+3) cycloaddition become the predominant
reaction pathway, given the ubiquity of functionalized seven-
membered rings in natural products and the commercial
availability of arenes, it would be an attractive synthetic protocol.
In particular, dearomative cycloadditions, such as Diels–Alder
reactions that employ arenes as dienes, allow the efficient
construction of polycyclic alkenes with high atom economy.
However, because of the substantial resonance stability of
aromatic compounds, this cycloaddition is typically unfavorable.
Benzene derivatives are especially notorious for their inertness as
dienes, even in the intramolecular mode. They have been
reported to undergo cycloaddition only with the most reactive of
dienophiles, such as electron-deficient allenes[2], benzynes[3] and
photoactivated azo derivatives,[4] and often requiring vigorous
reaction conditions.
1. cat. TESOTf
CH2Cl2,
OH
O
H
-78 °C, 1 h
OH
+
O
2. Et3N-3HF
r.t., 1 h
OTES
O
The (4+3) cycloaddition between oxyallyl cations and dienes
is a well-established strategy to seven-membered rings, and its
utility is amply demonstrated through the synthesis of natural
products.[5] However, examples of the dearomative (4+3)
cycloaddition with arenes have been sparse. Although several
oxyallyl cation precursors have been examined,[6-9] only
anthracene derivatives underwent reaction to any synthetically
significant degree. The analogous cycloadditions with benzene
and naphthalene derivatives proceeded with very low yields.
1a
2a
22%
3a
62%
Scheme 1. Dearomative (4+3) Cycloaddition and Friedel–Crafts alkylation of 1a.
We synthesized and examined the reactions of a series of
benzene derivatives under TESOTf catalysis (Table 1). Substrate
1b bearing meta substituents hindering competitive FC cyclization
compared with 1a, reacted to provide an increased yield of the
(4+3) cycloadduct 2b (Table 1, Entry 2). Dimethylbenzene 1c,
having both ortho-positions blocked by substitution, was expected
to further disadvantage FC cyclization, but it was uncertain
whether the escalated hindrance would obstruct all reactions,
including cycloaddition. Gratifyingly, the reaction of 1c afforded
an 89% yield of (4+3) cycloadduct 2c as the sole product (Table
1, Entry 3). These results demonstrate that when the competitive
FC reaction was suppressed, even the most aromatic arene,
benzene, reacted as a diene and was readily dearomatized
through (4+3) cycloaddition.
[a]
Dr. J. Ling, Dr. S. Lam, Prof. P. Chiu
Department of Chemistry and State Key Laboratory of Synthetic
Chemistry
The Univeristy of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
E-mail: pchiu@hku.hk
[b]
‡
Dr. K.-H. Low
Department of Chemistry, The University of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
E-mail: khlow@hku.hk
X-ray crystallographer
Increasing the length of tether between the benzene
nucleus and the dienophile also disfavored the competitive FC
Supporting information for this article is given via a link at the end of
the document.
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reaction because cyclization would form a seven-membered ring.
Indeed, (4+3) cycloadducts were obtained in the reactions of 1d
and 1e in moderate to good yields (Table 1, Entries 4, 5). The
aziridinyl enolsilane 1f underwent cycloaddition under protic acid
activation to generate tricyclic amine 2f in good yield (Table 1,
Entry 6).[13]
membered rings (1k–1n) reacted satisfactorily. gem-Dimethyl
substituents increased the efficiency of intramolecular bond
formation,[14] and improved the cycloaddition yield (Table 2, Entry
6). Heteroatoms on the tether are well-tolerated (Table 2, Entries
7, 8).
Table 2. Dearomative (4+3) cycloadditions of naphthalene derivatives[a]
Table 1. Dearomative (4+3) cycloadditions of benzene derivatives[a]
Entry
1[c]
Substrate
Cycloadduct[b]
Entry
1
Substrate
Cycloadduct[b]
2[c]
2[c,d]
3
4[d]
3[c]
5
4[c]
6[e]
5[e]
[a] Typical conditions: TESOTf (5–10 mol%), CH2Cl2, 78 °C, with/without
2,6-lutidine; then Et3N-3HF, r.t. [b] Isolated yields. [c] 44% of FC cyclization
product was isolated; see SI for details. [d] 1.1 equiv TESOTf was used. [e]
TFA (5 equiv.), EtNO2, -78 °C.
We further expanded the substrate scope to examine the
cycloaddition with polycyclic arenes (Table 2). Although
naphthalene derivatives are more reactive than benzene, still
there are few literature examples of their (4+3) cycloadditions.[9]
However, naphthalene 1g successfully underwent cycloaddition
under the typical reaction conditions to generate 2g in good yields
(Table 2, Entry 1). Similarly, the (4+3) cycloadditions of 1h and 1i
also proceeded smoothly with yields up to 89% (Table 2, Entries
2, 3). Substitution on the enolsilane had a detrimental effect on
the cycloaddition (Table 2, Entry 4). Substrates that undergo
intramolecular (4+3) cycloadditions to produce intervening 6-
6
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44% of the unreacted starting material was recovered in its
desilylated form. We surmise that the cycloaddition of 1p is
unfavorable because the transition state experiences both 1,2-
torsional and 1,3-diaxial strains (Figure 1).
7
8[f]
H
OTES
10 mol% TESOTf
1 mol% 2,6-lutidine
HO
O
O
CH2Cl2, -78 °C, 5 min
then Et3N-3HF
1o
2o
84%
H
10 mol% TESOTf
1 mol% 2,6-lutidine
O
HO
OTES
O
CH2Cl2
[a] General conditions: 1. TESOTf (10 mol%), CH2Cl2, -78 °C, with or without
2,6-lutidine; 2. Et3N-3HF, r.t. [b] Isolated yield. [c] ≤10% FC cyclization
product was isolated; see SI for details. [d] TFA (5 equiv.), EtNO2, -78 °C.
[e] TESOTf (1.1 equiv.) was used. [f] TESOTf (50 mol%) was used.
-78 to -40 °C, 1.5 h
then Et3N-3HF
1p
2p 21%
Scheme 2. Dearomative (4+3) cycloadditions of anthracene derivatives.
The diastereoselectivities of these cycloadditions with
naphthalenes could be rationalized by considering the major
interactions between the arene and the tether.[15] As shown in
Figure 1, 1,2-torsional strain disfavors the formation of the -
diastereomeric cycloadduct. In the cycloaddition of 1l, the gem-
dimethyl groups (R = Me) severely increased the torsional strain,
resulting in an overwhelming preference for 2l-(Table 2, Entry
6). Cycloadditions resulting in intervening five-membered rings do
not experience this strain as much, which explains the preferential
formation of -diastereomers (Table 2, Entries 1–3). On the other
hand, 1,3-diaxial strain generally disfavors the formation of the -
diastereomeric cycloadduct, but when this steric interaction is
relieved by oxygen substitution in 1m,[16] then the selectivity for
the diastereomer is high (Table 2, Entry 7).
The proposed mechanism of the dearomative (4+3)
cycloaddition is illustrated using substrate 1l (Scheme 3).
TESOTf-activated epoxide 1l* is the intermediate that undergoes
cycloaddition, on the basis of our previous computational
studies.[18] Ipso attack from the backside produces spiro arenium
(σ-complex) 4. Enolsilane addition following pathway a achieves
overall cycloaddition in a stepwise manner. The resultant silylated
oxonium 5 propagates the catalytic cycle by silylating another
molecule of 1l. In this reaction, cyclic ether 7 was also isolated in
~10% yield, which could be explained when 4 follows an
alternative fragmentation pathway b towards tertiary carbocation
6.[19] The intermediacy of 4 supports this cycloaddition as
proceeding in a stepwise manner.
Dearomative (4+3) cycloaddition
Optically active cycloadducts are generated when
enantiomerically enriched starting materials are employed. To
illustrate, the reaction of epoxy enolsilane ()-1g of 91% ee
produced (+)-2g as the major (4+3) cycloadduct with retained
ee. Similarly, the reaction of aziridinyl enolsilane (+)-1h of 95% ee
generated (+)-2h, whose absolute stereochemistry has been
established by X-ray crystallographic analysis (Figure 2).[20]
These optically enriched cycloadducts could be useful for the
asymmetric synthesis of natural products or bioactive molecules.
TESO
TES
O
TESO
O
TES
H
H
3
3
R
2
H
2
R
H
R = H or Me
1,2-torsional strain
in the (4+3) cycloaddition
disfavours diastereomer
1,3-diaxial strain
in the (4+3) cycloaddition
disfavours diastereomer
OH
NHTs
O
O
H
H
Figure 1. Destabilizing steric effects in dearomative (4+3) cycloadditions.
(+)-2g- 
ee = 91%
(+)-2h-
ee = 92%
Since anthracene is well-known to be reactive as a diene,[17]
as expected, 1o underwent cycloaddition to generate polycyclic
ketone 2o in a very high yield (Scheme 2). However, the
cycloaddition of its homologue, 1p, was very inefficient, and up to
Figure 2.
cycloadditions.
Optically enriched cycloadducts from dearomative (4+3)
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TES
OTES
1l
O
OTES
b
O
Desilylative
workup
H
H
TESOTf
a
OTES
OTES
1l
2l
1l*
O
TES
a
4
1l*
b
5
O
O
Desilylative
workup
O
OTES
OTES
TES
OTES
7
6
Scheme 3. Mechanism of dearomative (4+3) cycloaddition with epoxy enolsilanes.
To show the potential of this (4+3) cycloaddition to address
synthetic targets beyond bridged polycycles, we exploited the
reactivity afforded by the olefinic bond that directly resulted from
cycloaddition: the reductive ozonolysis of cycloadduct 2h-β
produced triol 8, having a 6,7,5-fused carbotricyclic framework
and five stereocenters, as a single diastereomer (Scheme 4).
Keywords: dearomatization •cycloaddition • arenes • enolsilane
• synthetic methods
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In conclusion, we report the first dearomative (4+3)
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obtained when enantiomerically enriched epoxides or aziridines
are used. We have demonstrated a representative cleavage of
the cycloadduct to reveal a stereochemically defined, fused
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dearomative cycloaddition should make it a useful addition to the
arsenal of dearomatization reactions.
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We thank the University of Hong Kong, The State Key Laboratory
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and the Seed Funding for Basic Research for financial support.
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Entry for the Table of Contents
COMMUNICATION
Jesse Ling, Sarah Lam, Kam-Hung Low
and Pauline Chiu*
Page No. – Page No.
Dearomative Intramolecular (4+3)
Cycloadditions of Arenes with Epoxy
and Aziridinyl Enolsilanes
Dearomative cycloaddition: Arenes react as dienes to undergo intramolecular
(4+3) cycloadditions with epoxy/aziridinyl enolsilanes. This stepwise cycloaddition is
facile at low temperatures, even for dearomatizing benzenes.
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