Br?nsted Acid-Promoted Cyclodimerization of Indolyl Ketones: Construction of Indole Fused-Oxabicyclo[3.3.1]nonane and -Cyclooctatetraene Ring Systems

Article abstract of DOI:10.1021/acs.orglett.0c03895

A Br?nsted acid-promoted cyclodimerization of C(3)-, C(2)-, or N(1)-substituted indole ketone derivatives is described. A wide range of structurally diverse bisindole fused-9-oxabicyclo[3.3.1]nonane and bisindole fused-cyclooctatetraene (COT) derivatives can be prepared in good to high yields with high efficiency.

Full text of DOI:10.1021/acs.orglett.0c03895

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Letter
Brønsted Acid-Promoted Cyclodimerization of Indolyl Ketones:
Construction of Indole Fused-Oxabicyclo[3.3.1]nonane and
-Cyclooctatetraene Ring Systems
Lang Zhao, Zhi-Hua Yan, Shuai Tang, Zhong-Lin Wei, and Wei-Wei Liao*
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ABSTRACT: A Brønsted acid-promoted cyclodimerization of C(3)-, C(2)-, or N(1)-substituted indole ketone derivatives is
described. A wide range of structurally diverse bisindole fused-9-oxabicyclo[3.3.1]nonane and bisindole fused-cyclooctatetraene
(COT) derivatives can be prepared in good to high yields with high efficiency.
reactions7e,f to construct such oxacyclic bridged-ring structures
s a privileged structural motif, the indole core is
in recent decades.7 For examples, Yao et al. reported a
1
Aubiquitously present in a range of biological compounds.
Brønsted acid-promoted dimerization of o-alkynylbenzalde-
hydes to provide a convenient one-step synthesis of sym-
metrical 2,3,6,7-dibenzo-9-oxabicyclo[3.3.1]nona-2,6-dienes in
the presence of 45% aqueous HBF4 in acetic acid.7c The Liu
group has developed elegant TM-catalyzed cyclizations to
prepare 9-oxabicyclo[3.3.1]nonadienes from 2-alkynyl-1-car-
bonylbenzenes via oxonium ion intermediates.7e,f However, the
synthetic route for the construction of fused-9-
oxabicyclo[3.3.1]nonane frameworks with the substituents at
the bridgehead carbon is still limited. Furthermore, the
development of bisindole fused-9-oxabicyclo[3.3.1]nonane
derivatives is still unexploited considering the fact that
structural elaboration of the indole core with additional ring
fusion represents an efficient and useful approach for exploiting
the indole scaffolds for new biological activities.8
Among various indole ring-containing compounds, bisindole
deriviatives have attracted considerable interest due to their
broad range of biological properties and frequent occurrence in
natural products,1a,b,2 in which two indole units can be
incorporated into fused or open systems. Therefore, various
methods have been developed to construct these structurally
diverse scaffolds,3,4 in which the dimerization of two identical
indole derivatives provides a direct and efficient strategy for
accessing various bisindole derivatives.3a,b,d−f Among them,
dehydrodimerization around the indole core is a common
approach that affords various bisindole frameworks with an
open system.3a,b,d,e In addition, a number of synthetic methods
for the construction of bisindoles incorporating an extra cyclic
ring between two indole rings via a cyclodimerization of two
identical indole derivatives have also been demonstrated. For
example, the cyclodimerizations of vinylindoles or indole-
derived donor−acceptor cyclopropane molecules have proven
to be quite efficient in assembling six- or five-membered ring
systems fused with two indole moieties.4
With the goal of developing a practical and efficient
synthetic approach for the construction of various polycyclic
frameworks from readily accessible starting materials,9 we
Received: November 25, 2020
9-Oxabicyclo[3.3.1]nonane skeletons frequently occur in
bioactive molecules and natural products, and compounds
comprised of this oxatricyclic framework have shown potency
toward HIV-1 inhibition and central nervous system
diseases.5,6 There are several established methods such as
Brønsted acid-7a−d and transition metal (TM)-catalyzed
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© XXXX American Chemical Society
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A

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Letter
envisioned that the cyclodimerization of two identical indoles
bearing a ketone moiety may provide an efficient approach for
accessing indole fused-9-oxabicyclo[3.3.1]nonane derivatives
via a facile electrophilic addition/cyclization sequence. Herein,
we report a Brønsted acid-catalyzed cyclodimerization of
C(3)-, C(2)-, or N(1)-substituted indole ketone substrates to
prepare structurally diverse bisindole fused-9-
oxabicyclo[3.3.1]nonane derivatives, coupled with the for-
mation of bisindole fused-cyclooctatetraene (COT) from 2-
substituted indole ketone substrates (Scheme 1).
smoothly in n-Bu2O and furnished the desired product 2a in
high yield with a short reaction time, while other solvents can
afford 2a with low to medium levels of production. However, a
polar solvent failed to give any desired product (entry 10).
Further investigation indicated that the addition of several
additives such as Na2SO4 and 5 Å molecular sieves can
facilitate this cyclodimerization with the smaller amount of
TfOH, and a better result can be obtained in 97% yield in the
presence of TfOH (0.75 equiv) and Na2SO4 within 1.5 h
(entries 11 and 12). Although any attempts to further reduce
the amount of TfOH failed to provide 2a with reasonable yield
by surveying other reaction parameters such as the reaction
temperature and the reaction concentration, we were pleased
to find that 15 mol % HNTf2 enabled this cyclodimerization to
procced well and afforded 2a with comparable yield in toluene,
albeit with a prolonged reaction time (for details, see the
Supporting Information).
Scheme 1. Working Plan
With the optimized reaction conditions in hand, the
investigation of the substrate scope of the cyclodimerization
of 3-substituted indole ketones was carried out first. As shown
in Scheme 2, this cyclodimerization was amenable to a wide
a
Scheme 2. Substrate Scope for Cyclodimerization of 1
We initially examined the cyclodimerization of 3-substituted
indole ketone 1a in the presence of several Brønsted acids in
toluene at 30 °C (Table 1, entries 1−5). The results indicated
a
Table 1. Optimal Reaction Conditions
b
entry
catalyst (equiv)
solvent
t (h)
yield of 2a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
HOAc (3.0)
TFA (3.0)
MsOH (3.0)
TfOH (3.0)
PPA (3.0)
BF3·Et2O (1.5)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (0.75)
TfOH (0.3)
HNTf2 (0.15)
toluene
toluene
toluene
toluene
toluene
toluene
hexane
DCM
n-Bu2O
DMF
n-Bu2O
n-Bu2O
toluene
24
24
24
24
24
24
24
24
4
24
1.5
11
24
nd
nd
17
69
14
38
65
19
94
nd
97
34
94
c
d
d
e
a
Reactions were performed with 1a (0.4 mmol), catalyst, and solvent
b
c
(0.2 M) at 30 °C under a nitrogen atmosphere. Isolated yields. A
49% yield of 3a was obtained. Na2SO4 (0.8 mmol, 2 equiv) was
added. At a concentration of 0.4 M.
d
a
For condition A, reactions were performed with 1a (0.4 mmol),
e
TfOH (0.75 equiv), Na2SO4 (2 equiv), and n-Bu2O (0.2 M) at 30 °C
under a nitrogen atmosphere. For condition B, reactions were
performed with 1a (0.4 mmol), HNTf2 (0.15 equiv), and toluene (0.4
M) at 30 °C under a nitrogen atmosphere. Yields of isolated products.
that HOAc and TFA did not afford any desired product, while
the desired bisindole fused-9-oxabicyclo[3.3.1]nonane 2a
could be obtained when organic sulfonic acids or PPA was
employed. Lewis acids such BF3·Et2O and TiCl4 gave inferior
results (entry 6 and Table S1). Notably, carbazole 3a could be
observed when MsOH was employed. Though TfOH-
catalyzed reaction gave a promising 69% yield, 300 mol %
TfOH and the sluggish process made this transformation far
from efficient. Next, in the presence of TfOH as a catalyst,
different types of solvents were evaluated (entries 7−10). It
turned out that the desired cyclodimerization of 1a proceeded
b
c
The X-ray structure of 2a is shown. 1a (2 mmol). TfOH (3.0
d
equiv). HNTf2 (0.5 equiv).
range of C(3)-substituted indole ketones 1 bearing different
R1−R3 groups, providing the bisindole fused-9-
oxabicyclo[3.3.1]nonane products 2 in high yields in the
presence of TfOH (Con. A) or HNTf2 (Con. B). At first,
different N-alkyl substituents (R1) of 3-substituted indole
substrates were evaluated and N-ethyl-substituted indole 1b
B
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a
provided a result similar to that of substrate 1a, while a
prolonged reaction time was required when N-benzyl indole 1c
was employed (2c). However, N-acylated indole and free
(NH) indole analogues (1d and 1e, respectively) failed to give
any desired products. Substrates bearing alkyl groups such as
ethyl, benzyl, n-butyl, and isopentyl groups can be employed in
this cyclization to give the desired products (2f−2i,
respectively) in good yields; the cyclodimerization reactions
could not be applied to isopropyl and phenyl (R2) ketone
analogues (1j and 1k, respectively), and no desired reactions
occurred under the optimized reaction conditions, presumably
due to the steric hindrance effects. In addition, various N-
methylindoles with both electron-rich [OMe (1l) and Me
(1p)] and electron-poor [Cl and Br (1m−1o)] groups (R3) at
the phenyl ring worked well and gave rise to the corresponding
products (2l−2p) in good yields in the presence of 15 mol %
HNTf2, regardless of the substitution patterns. However,
current BA-catalyzed cyclodimerization seemed to be sensitive
to R4 and R5 groups, and no desired products were observed
when either R4 or R5 was introduced (2q and 2r). Additionally,
treatment of a 3-substituted indole aldehyde with either TfOH
or HNTf2 led to a complex mixture (2s).
Scheme 3. Substrate Scope for Cyclodimerization of 4
Next, we turned our attention to the feasibility of the
cyclodimerization of C(2)-substituted indole ketones 4 by
moving the ketone unit from C(3) to C(2) (Scheme 3).
Although 2-substituted indole ketone 4a contained a more
nucleophilic C(3) site, initially performing the reactions of 4a
under the aforementioned reaction conditions did not give the
desired product 5a in reasonable yield. After modifying the
reaction conditions (Table S2), we were pleased to find that
isosteric bisindole fused-9-oxabicyclo[3.3.1]nonane isomer 5a
can be obtained in high yield in the presence of D-CSA (0.15
equiv) in toluene at 60 °C. It should be noted that the less
acidic D-CSA was more efficient than strong BAs such as TfOH
and HNTf2, and no corresponding carbazole analogue was
observed in the cyclodimerization of 2-substituted indole
ketone 4a. Subsequently, a range of C(2)-substituted indole
ketones bearing different substituents (R2 = alkyl, and R3 =
MeO, Me, or Cl) were examined, and the cyclodimerization
reactions displayed good functional group compatibility and
proceeded in high yields with a variety of different products
formed (Scheme 3, 5b and 5d−5j).
When we directed our attention to the synthesis of bisindole
fused-9-oxabicyclo[3.3.1]nonanes by using C(2)-substituted
indolyl aryl ketones 6, we found that this BA-catalyzed
cyclodimerization gave bisindole fused cyclooctatetraenes 7,
instead of bisindole fused 9-oxabicyclo[3.3.1]nonanes 5. Under
the slightly modified reaction conditions (0.3 equiv of D-CSA),
the cyclization of 6a can procced smoothly to afford bisindole
fused cyclooctatetraene 7a in 75% yield. The 2-substituted
indolyl aryl ketones bearing either electron-withdrawing or
electron-donating groups (R3 or R2) with different substituent
patterns are amenable to the reaction conditions and afforded
the desired products (7b−7i) with good to high yields.
Notably, the bisindole fused-cyclooctatetraene framework is
the core structure of indole alkaloid caulerpin, which displayed
antinociceptive and anti-inflammatory activities,10 as well as
indole-based optoelectronic materials that showed unique
optoelectronic characteristics with wide optical band gaps and
redox-active properties.11 The structures of fused 9-
oxabicyclo[3.3.1]nonanes and fused cyclooctatetraenes were
unambiguously confirmed by the exemplification of X-ray
a
Reactions were performed with 4 (0.2 mmol) and D-CSA (0.15 or
0.3 equiv) in toluene (0.2 M) under a nitrogen atmosphere. Yields of
isolated products.
7a are shown.
bD-CSA (0.3 equiv). The X-ray structures of 5a and
crystal structural analysis of products 2a, 5a, and 7a (Schemes
2 and 3).
Encouraged by these results, we examined N(1)-substituted
indolyl ketones 8 for the construction of bisindole aza-
analogues 9 consequently (Scheme 4). To our delight, the
desired cyclodimerization of N(1)-substituted indolyl ketone
8a proceeded smoothly in the presence of 30 mol % TfOH and
n-Bu2O at 50 °C and delivered bisindole aza-analogue 9a in
86% yield. C(3) ethyl-substituted indole 8b was also examined,
which gave the desired product 9b in 60% yield under the
slightly modified reaction conditions. However, substrate 8c
C
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a
nonane derivatives, several cross cyclodimerization experi-
ments were conducted (Scheme 6). Treatment of 3-substituted
Scheme 4. Substrate Scope for Cyclodimerization of 8
Scheme 6. Cross Cyclodimerization Experiments
a
Reactions were performed with 8 (0.2 mmol) and TfOH (0.3 equiv)
in n-Bu2O (0.2 M) under a nitrogen atmosphere. Yields of isolated
b
products. TfOH (0.75 equiv), 30 °C.
with the unshielded reactive C(3) site did not give the
corresponding bisindole analogue 9c. N(1)-substituted indolyl
ketones bearing various R1 substituents such as ethyl, isopentyl,
and benzyl groups were well tolerated and gave the desired
products in good yields (9d−9f), while aryl-substituted N(1)-
substituted indole 8g did not afford any desired product. In
addition, N(1)-substituted indoles with both electron-rich
[OMe (8i)] and electron-poor [Cl (8h)] groups (R3) can
furnish the desired products (9h and 9i) in good yields (for
details about the initial investigation of catalytic enantiose-
lective cyclodimerization, see Schemes S3−S35).
indole ketone 1a and 2-substituted indole ketone 4a with BA
did not give cross cyclodimerized product 5aa under either
condition A or condition B and afforded the corresponding
cyclodimerized product 2a or 5a instead. The cross cyclo-
dimerization experiment between 1a and 8a also failed to give
cross cyclization product 9aa. Notably, the cyclodimerization
between 1a and 1b or 4a and 8a delivered the corresponding
cross cyclization product 5ab (30% yield) or 9ab (60% yield)
along with a homogeneous cyclodimerization product (2a, 2b,
or 5a), which indicated that the cyclodimerization may be
prone to occur between indole substrates with similar
reactivities.
Further extension of the application of this cyclodimeriza-
tion to access other bisheteroarene fused 9-oxabicyclo[3.3.1]-
nonanes was examined (Scheme 5). Other than indole
Scheme 5. Preparation of Bisheteroarene Fused 9-
Oxabicyclo[3.3.1]nonanes
On the basis of our results and the preceding reports,7 a
possible mechanism was proposed (for details, see Scheme
S2).
In summary, we have developed a novel Brønsted acid-
catalyzed cyclodimerization of C(3)-, C(2)-, or N(1)-
substituted indole ketone derivatives, which provided a
practical and efficient protocol for the preparation of
structurally diverse bisindole fused 9-oxabicyclo[3.3.1]nonanes
and bisindole fused cyclooctatetraenes (COT). Under the
optimized reaction conditions, various bisindole fused 9-
oxabicyclo[3.3.1]nonanes with the substituents at the bridge-
head carbon can be prepared from readily available starting
materials in good to high yields with efficiency.
substrates, 5-substituted thiophenes 10 tethered ketone
moieties at the C(3) position can readily deliver the desired
fused polycyclic heterocyclic products (11a and 11b) in good
yields under the optimized reaction conditions. However, 5-
unsubstituted analogue 10c and thiophene 10d tethered
ketone moieties at the C(2) position gave the corresponding
benzo-fused thiophenes (12c and 12d). Additionally, BA-
catalyzed cyclodimerizations of other electron-rich heteroarene
analogues such as benzo-fused thiophene, pyrrole, and furan
with the tethered ketone moieties did not give bisheteroarene
fused-9-oxabicyclo[3.3.1]nonane derivatives (for details, see
Scheme S1).
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03895.
Experimental procedures and analytical data for all new
compounds (PDF)
In addition, to explore the diversity of this transformation to
access other asymmetric bisindole fused-9-oxabicyclo[3.3.1]-
D
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Org. Lett. XXXX, XXX, XXX−XXX

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Accession Codes
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CCDC 2036366−2036368 and 2036603 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Wei-Wei Liao − Department of Organic Chemistry, College of
Chemistry, Jilin University, Changchun 130012, China;
orcid.org/0000-0001-6225-4258; Email: wliao@
jlu.edu.cn
Authors
Lang Zhao − Department of Organic Chemistry, College of
Chemistry, Jilin University, Changchun 130012, China
Zhi-Hua Yan − Department of Organic Chemistry, College of
Chemistry, Jilin University, Changchun 130012, China
Shuai Tang − Department of Organic Chemistry, College of
Chemistry, Jilin University, Changchun 130012, China
Zhong-Lin Wei − Department of Organic Chemistry, College
of Chemistry, Jilin University, Changchun 130012, China
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Mouscadet, J. F.; Cotelle, P. Synthesis and HIV-1 Integrase Inhibitory
Activities of Catechol and Bis-Catechol Derivatives. Bioorg. Med.
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NSFC (21772063) and the Open
Project of the State Key Laboratory for Supramolecular
Structure and Materials (sklssm202017) for financial support.
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