One-Pot Synthesis of Cycloocta[b]indole Through Formal [5+3] Cycloaddition Using Donor–Acceptor Cyclopropanes

Article abstract of DOI:10.1002/ejoc.201900610

A new approach to cycloocta[b]indole through formal [5+3] cycloaddition was developed. This methodology was realized by using an indole derivative as a C5 unit and a cyclopropane derivative as a C3 unit. These two units have both donor and acceptor proper

Full text of DOI:10.1002/ejoc.201900610

A Journal of
Accepted Article
Title: One-Pot Synthesis of Cycloocta[b]indole through Formal [5+3]
Cycloaddition Using Donor-Acceptor Cyclopropanes
Authors: Akito Okabe, Shinji Harada, Takuya Takeda, and Atsushi
Nishida
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900610
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10.1002/ejoc.201900610
European Journal of Organic Chemistry
COMMUNICATION
One-Pot Synthesis of Cycloocta[b]indole through Formal [5+3]
Cycloaddition Using Donor-Acceptor Cyclopropanes
Akito Okabe,[a] Shinji Harada,*[a],[b] Takuya Takeda,[a] and Atsushi Nishida*[a],[b]
Abstract: A new approach to cycloocta[b]indole through formal [5+3]
cycloaddition was developed. This methodology was realized by using
an indole derivative as a C5 unit and a cyclopropane derivative as a
C3 unit. These two units have both donor and acceptor properties.
Two carbon-carbon bonds were formed stepwise by the successive
addition of a Lewis acidic catalyst and a Brønsted base. The reaction
Recently, we designed a novel donor-acceptor (D-A) indole
derivative 1 as a C5 unit and developed intermolecular [5+2]
cycloheptannulation using alkyne as a C2 unit (Scheme 1, route
A).[8] This C5 indole 1 contains both nucleophilic carbon (Ca) and
electrophilic carbon (Cb). We then envisioned that the
combination of this D-A indole with an appropriate C3 unit would
afford 8-membered ring compounds. Among C3 units, we chose
D-A cyclopropane.[9] D-A cyclopropane contains both nucleophilic
carbon (Cc) and electrophilic carbon (Cd), and has been widely
used for intermolecular cycloaddition.[10] It is typically activated by
Lewis acid to form 1,3-dipolar species, where the negative charge
at Cc is stabilized by the acceptor substituent (e.g., electron-
withdrawing group) while the positive charge at Cd is stabilized by
the donor substituent (e.g., electron-donating group and/or
conjugated system). Although there are several reports on the use
of a combination of indole derivatives and D-A cyclopropane to
construct indole-fused 5- and 6-membered ring systems,[11] to the
best of our knowledge there have been no reports on the
construction of an 8-membered ring through an intermolecular
could be performed as
a one-pot process. Optically active
cycloocta[b]indole was also synthesized by using this methodology
with a chiral cyclopropane as a C3 substrate.
Introduction
Cycloocta[b]indole is a tricyclic heterocycle, and its cyclooctane
ring shares two carbons of indole at the C2 and C3 positions. The
cycloocta[b]indole skeleton is seen in many natural and
biologically active compounds.[1] For example, iprindole (Figure 1)
has been used for the treatment of depression,[2] and talcarpine[3]
is a macroline alkaloid,[4] which is a family of more than 150
compounds with potent hypotensive and antibiotic activities.
While cycloocta[b]indoles have been shown to have attractive
biological activities, there are few examples of the synthesis of the
skeleton.[5] This is due to the general difficulty of constructing 8-
membered carbocycles.[1d],[6],[7]
reaction. Herein, we report
a
one-pot synthesis of
cycloocta[b]indole skeleton through formal [5+3] cycloaddition by
a stepwise alkylation/Michael addition process between D-A
indole and D-A cyclopropane (Scheme 1, route B).
b
a
EWG
N
C5 unit
PG
1
N
H
Cycloocta[b]indole
MeO2C CO2Me
O
c
H
R2
7
CO2Me
CO2Me
Me
d
R1
R2
R1
R
R
Me
C2 unit
C3 unit
N
CHO
H
8
EWG
EWG
N
route A
route B
N
N
NMe2
N
Me
Talcarpine
antimalarial activity
Our
PG
PG
Iprindole
antidepressant
Previous Work
This Work
Scheme 1. Construction of Indole-Fused Carbocycles Using a Common C5 Unit.
Figure 1. Biologically Active Alkaloids with a Cycloocta[b]indole Skeleton
Results and Discussion
[a]
[b]
Mr. A. Okabe, Dr. S. Harada, Dr. T. Takeda, Prof. Dr. A. Nishida
Graduate School of Pharmaceutical Sciences
Chiba University
1-8-1 Inohana, Chuo-ku, Chiba 260-8675 (Japan)
E-mail: s.harada@faculty.chiba-u.jp, anishida@faculty.chiba-u.jp
Homepage: http://www.p.chiba-u.jp/lab/gousei/en/index.html
Dr. S. Harada, Prof. Dr. A. Nishida
Molecular Chirality Research Center
Chiba University
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
We screened Lewis acids using indole 1a and cyclopropane 2a
as substrates (Table 1). When metal triflates were used as Lewis
acids at 80 ºC in 1,2-dichloroethane (DCE), only ring-opening and
subsequent alkylation took place to afford alkylated product 3aa
in good yields (entries 1-4). No cycloadduct was observed for
every entry, therefore we first examined the optimal catalyst for
the alkylation. Yb(OTf)3 promoted the alkylation in the highest
yield, and other lanthanide triflates were examined. However,
both lanthanum and europium triflates required a longer reaction
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900610
European Journal of Organic Chemistry
COMMUNICATION
time to consume indole 1a (entries 5 and 6). Although InI3 was the
optimal catalyst in our previous report,[8] it gave 3aa in 78% yield
(entry 7). TiCl4 was not a suitable catalyst, and most of 1a was
recovered (entry 8). BF3•OEt2 required a longer reaction time to
consume 1a, and the yield of 3aa was 74% (entry 9). The desired
cyclization was not realized under these conditions, however,
Yb(OTf)3 was selected as a suitable catalyst for alkylation. When
the amount of Yb(OTf)3 was decreased to 5 mol% (entry 10), the
yield of 3aa was comparable to the result in entry 4.
drastically with the choice of base. This might be due to a change
in the conformation of the intermediate, but further investigation is
still necessary. Amine bases were not appropriate for this reaction
(entries 9 and 10). Therefore, we chose NaH, which gave the best
yield and diastereoselectivity, for cyclization.
Table 2. Cyclization under Basic Conditions
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
Ph
Ph
base (2.0 equiv.)
CO2Me
Table 1. Screening of Lewis Acids for the Activation of D-A Cyclopropane
solvent (0.1 M)
rt, time
N
N
MeO2C CO2Me
Me
Me
3aa
4aa
Ph
2a
MeO2C
Ph
(1.1 equiv.)
CO2Me
CO2Me
Entry Base
Solvent
DCE
Time (h)
Yield (%) cis : trans[a]
Lewis acid
(20 mol%)
CO2Me
1
NaH
24
24
24
24
6
92
86
67
78
69
80
0
7.1 : 1.0
1.0 : 1.1
3.5 : 1.0
1.5 : 1.0
1.4 : 1.0
1.0 : 1.0
—
DCE (0.1 M)
80 ºC
N
Me
1a
N
2
KHMDS
NaOH
CsOH
KOH
DCE
THF
THF
THF
THF
THF
Me
3aa
MeO2C
3
CO2Me
Ph
4
CO2Me
N
5
Me
4aa
6[b]
7
KOH
6
Not obtained
K2CO3
24
Entry
Lewis Acid
Time (h)
Yield (%)
Recov. of
1a (%)
8[b]
9
K2CO3
NEt3
THF
DCE
DCE
24
24
18
79
0
2.9 : 1.0
—
1
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
La(OTf)3
Eu(OTf)3
InI3
0.5
4
78
87
79
92
92
92
78
5
0
2
trace
10[c]
DBU
0
—
3
0.5
0.5
8
0
[a] Determined by 1H NMR of the Crude Material. These isomers can be
separated by multiple elution with preparative TLC. [b] 18-Crown-6 (2.0
equiv.) was added. [c] Carried out at 80 ºC.
4
0
5
0
6
1
0
7
1
0
We realized the stepwise synthesis of cycloocta[b]indole from C5
indole 1 and C3 cyclopropane 2 by using a catalytic amount of
ytterbium triflate and then a stoichiometric amount of Brønsted
base. We then tried a one-pot process. After we confirmed that
1a was consumed by TLC and cooled the reaction mixture, we
added NaH to the mixture. The one-pot synthesis of
cycloocta[b]indole was successfully achieved to give 4aa in 84%
yield (Scheme 2).
8
TiCl4
4
<92
0
9
BF3•OEt2
Yb(OTf)3
9
74
94
10[a]
4
0
[a] 5 mol% of Lewis acid was used.
MeO2C
Yb(OTf)3 (5 mol%)
DCE (0.1 M), 80 °C, 4 h
Ph
CO2Me
CO2Me
We then tried to construct an 8-membered ring using 3aa as a
cyclization precursor (Table 2). The desired reaction proceeded
under basic conditions. With the addition of two equivalents of
NaH, cycloocta[b]indole 4aa was obtained in 92% yield with 7.2:1
(cis-4aa:trans-4aa) diastereoselectivity after stirring for 24 hours
at room temperature (entry 1).[12] KHMDS also afforded cyclized
product 4aa in comparable yield, however the selectivity was
decreased to only 1:1.1 (entry 2). In entries 3-8, milder inorganic
bases were examined, but the yields of 4aa were less than the
yield in entry 1. Notably, the diastereoselectivity changed
1a
+
2a
then NaH (2 equiv.)
rt, 24 h
(1.1 equiv.)
N
Me
4aa
84%, cis : trans = 3.9:1[a]
Scheme 2. One-Pot Synthesis of Cycloocta[b]indole. [a] Determined by 1H NMR
of the Crude Material.
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10.1002/ejoc.201900610
European Journal of Organic Chemistry
COMMUNICATION
2a (1.1 equiv.)
Yb(OTf)3 (5 mol%)
DCE (0.1 M)
The scope of the substrates was examined following the one-pot
process in Scheme 2. D-A cyclopropanes 2 with various types of
donor substituents are summarized in Table 3. When electron-
donating and -withdrawing groups were installed on the benzene
ring as a donor substituent, cyclized products 4 were obtained in
high yields (4ab-4ad). Cyclopropanes with a methyl group on the
benzene ring afforded 4ae-4ag in good to high yields, though the
reaction time of alkylation (1st step) varied according to the
position of the methyl group. A heteroaromatic ring and styryl
group were applicable, and desired cyclized products 4ah and 4ai
were obtained in moderate yields. When vinylcyclopropane
derivative 2j was used, thermal activation was necessary for the
completion of cyclization. The cyclized product 4aj was obtained
in 52% yield.
MeO2C
CO2Me
Ph
R2
EWG
R2
80 ºC, time
EWG
N
R1
then NaH (2 equiv.)
rt, 24 h
N
R1
1
4
MeO2C
MeO2C
CO2Me
CO2Me
Ph
CO2Me
CO2Me
Ph
MeO
N
N
Me
Bn
4ca
1 h, 58%
cis:trans = 3.7:1.0
MeO2C
4ba
6 h, 82%
cis:trans = 3.6:1.0
CO2Me
Ph
COMe
N
4da
Me
4 h, 77%
cis:trans = 3.2:1.0
Table 3. Scope of Substituents on Cyclopropane[a]
[a] Diastereomeric ratio was determined by 1H NMR of the crude material.
Yb(OTf)3 (5 mol%)
DCE (0.1 M)
MeO2C
MeO2C CO2Me
CO2Me
CO2Me
R
80 ºC, time
1a
+
R
then NaH (2 equiv.)
rt, 24 h
2
N
(1.1 equiv.)
Me
4
To elucidate the reaction mechanism, optically active
cyclopropane (S)-(–)-2a[11e],[14] was applied to the stepwise
synthesis of cycloocta[b]indole (Scheme 3). First, the chiral
alkylated product (R)-(–)-3aa was obtained in 85% yield without a
significant loss of enantiopurity. After cyclization under basic
conditions, the enantiopurity of (–)-4aa was comparable to that of
(–)-3aa. The enantiomeric excess of (–)-4aa could be enriched by
a single recrystallization operation, and the relative and absolute
configuration of the enantiomerically-pure (–)-4aa was
unambiguously confirmed by X-ray crystallographic analysis.[15]
From the structural information of the X-ray analysis, the
stereochemistry of the chiral carbon of (S)-(–)-2a was revealed to
be inversed. This result strongly supported that the alkylation step
proceeded in an SN2 fashion. It has been reported that the
nucleophilic ring-opening of D-A cyclopropane took place via an
SN2-like reaction pattern,[9] thus our result agreed with those in
previous reports.
Yield
R’
cis:trans
Time (%)
(4aa) 4 h 84
4-MeO (4ab) 10 min 84
MeO2C
R’
H
3.9:1.0
3.3:1.0
8.3:1.0
1.6:1.0
2.4:1.0
3.6:1.0
1.7:1.0
CO2Me
4-Cl (4ac) 5 h
4-CF3 (4ad) 15 h
4-Me (4ae) 45 min 61
85
87
CO2Me
N
3-Me (4af) 1.5 h
2-Me (4ag) 6.5 h
91
88
Me
4aa-4ag
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
Ph
S
CO2Me
CO2Me
N
N
N
Me
Me
Me
4aj
4ah
1 h, 51%
cis:trans = 2.0:1.0
4ai
23 h, 52%[b]
cis:trans = 1.4:1.0
30 min, 59%
cis:trans = 5.2:1.0
[a] Diastereomeric ratio was determined by 1H NMR of the crude material.
[b] The second cyclization step was carried out at 80 ºC.
Yb(OTf)3
(5 mol%)
MeO2C CO2Me
CO2Me
DCE (0.1 M)
80 °C, 2 h
N
Ph
(S)-(–)-2a
(98% ee, 1.1 equiv.)
Me
1a
Next, we surveyed the scope of C5 indole derivatives 1 (Table 4).
A benzyl group instead of methyl on indole nitrogen gave 4ba in
comparable yield. When non-protected substrate (R1=H) was
used, the alkylation step proceeded in 62% yield (4 h), although
the second cyclization step gave a complex mixture and we could
not identify the corresponding cyclized product. A methoxy group
at the C5 position on the indole ring accelerated the alkylation
step, but 4ca was obtained in moderate yield. An indole substrate
with ketone as an electron-withdrawing group was also applicable,
and cyclized product 4da was obtained in 77% yield.[13]
MeO2C
Ph
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
Ph
NaH (2 equiv.)
DCE (0.1 M)
rt, 24 h
N
Me
N
(–)-4aa
81%, 96% ee
cis:trans = 6.8:1.0
Me (R)-(–)-3aa
85%, 96% ee
Scheme 3. Stepwise Synthesis of Optically Active Cycloocta[b]indole.
Table 4. Scope of C5-indole Substrates[a]
The proposed mechanism of this process is shown in Scheme 4.
Ytterbium salt was coordinated by a dicarbonyl moiety of the
cyclopropane substrate to form an activated species A.
Subsequent Friedel-Crafts alkylation between A and D-A indole
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10.1002/ejoc.201900610
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COMMUNICATION
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MeO2C CO2Me
MeO2C
CO2Me
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R
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CO2Me
Yb(OTf)3
N
then NaH
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Me
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donor carbon
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acceptor carbon
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OMe
O
CO2Me
N
Me
D
N
Na
Me 1a
Intramolecular
Michael Addition
Friedel-Crafts
Alkylation
Na
CO2Me
MeO2C
R
MeO2C
R
CO2Me
CO2Me
NaH
CO2Me
N
N
Me
Me
C
B
Scheme 4. Plausible Reaction Mechanism.
Conclusions
We developed
a
novel synthetic approach toward
a
cycloocta[b]indole skeleton. The combination of a pair of D-A
substrates enabled the construction of an 8-membered ring
through formal [5+3] cycloaddition in a one-pot process. Various
substituents could be installed on the substrate. Optically active
cycloocta[b]indole was also synthesized. With C5 D-A indole 1 as
a common substrate, a synthetic approach to indole-fused both 7-
and 8-membered rings can be realized. Work on the development
of asymmetric reaction and the construction of 8-membered
heterocycles is ongoing.
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Acknowledgments
[8]
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T. Takeda, S. Harada, A. Okabe, A. Nishida, J. Org. Chem. 2018, 83,
11541-11551.
This work was supported by the Japan Society for the Promotion
of Science (JSPS) KAKENHI [Grant Numbers 16K08154 (SH),
19K06991 (SH), 17J03524 (TT), and 17H03969 (AN)], and the
Tokyo Biochemical Research Foundation [Grant Number 16-B1-
5 (SH)]. We acknowledge the Institute for Global Prominent
Research, Chiba University, for providing financial support.
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Keywords: Medium-ring compounds • Synthetic methods •
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Supporting Information.
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10.1002/ejoc.201900610
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
A new approach to cycloocta[b]indole
through formal [5+3] cycloaddition
was developed. This methodology
was realized by using an indole
derivative as a C5 unit and a
cyclopropane derivative as a C3 unit.
Two carbon-carbon bonds were
formed stepwise by the addition of a
Lewis acidic catalyst and a Brønsted
base. The reaction could be
Eight-membered Ring
Akito Okabe, Shinji Harada,* Takuya
Takeda, and Atsushi Nishida*
Page No. – Page No.
One-Pot Synthesis of
Cycloocta[b]indole through Formal
[5+3] Cycloaddition Using Donor-
Acceptor Cyclopropanes
performed as a one-pot process.
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