A straightforward approach to tetrahydroindolo[3,2-b]carbazoles and 1-indolyltetrahydrocarbazoles through [3+3] cyclodimerization of indole-derived cyclopropanes

Article abstract of DOI:10.1002/chem.201502287

A rapid new approach to produce biologically relevant bisindoles, namely indolyltetrahydrocarbazoles and indolo[3,2-b]carbazoles, has been developed, based on the Ga(OTf)₃-catalyzed [3+3] cyclodimerization of indole-derived donor-acceptor cyclopropanes. Chemoselectivity of the process depends on the location of the three-membered ring at the indole core. Gemination for creation: A new method for bisindole assembly was proposed through [3+3] cyclodimerization of indole-derived cyclopropanes. Variations in the cyclopropane position at the indole core fine-tune the process towards the selective formation of indolyltetrahydrocarbazoles or indolo[3,2-b]carbazoles.

Full text of DOI:10.1002/chem.201502287

DOI: 10.1002/chem.201502287
Communication
&
Dimerization |Hot Paper|
A Straightforward Approach to Tetrahydroindolo[3,2-b]carbazoles
and 1-Indolyltetrahydrocarbazoles through [3+3]
Cyclodimerization of Indole-Derived Cyclopropanes
Olga A. Ivanova,[a] Ekaterina M. Budynina,*[a, b] Victor N. Khrustalev,[c, d] Dmitriy A. Skvortsov,[a]
Igor V. Trushkov,[a, b] and Mikhail Ya. Melnikov[a]
Abstract: A rapid new approach to produce biologically
relevant bisindoles, namely indolyltetrahydrocarbazoles
and indolo[3,2-b]carbazoles, has been developed, based
on the Ga(OTf)3-catalyzed [3+3] cyclodimerization of
indole-derived donor–acceptor cyclopropanes. Chemose-
lectivity of the process depends on the location of the
three-membered ring at the indole core.
Due to their versatile bioactivity, bisindoles[1] are among the
most privileged natural and synthetic compounds of pharma-
ceutical relevance. Members of the bisindole family have signif-
icant differences in their structures, with representatives rang-
ing from the molecules formed by two identical or similar
indole units to those assembled from conceptually different
indole-derived fragments. The former case can be exemplified
by alkaloids malasseziazoles—indolocarbazoles produced by
skin fungi Malassezia sp., which are responsible for many skin
diseases,[2] as well as asterriquinones, bis(indolyl)cyclohexane-
derived alkaloids isolated from Aspergillus terreus and exhibited
anticancer and anti-HIV properties[3] (Figure 1A). Meanwhile,
the complex molecular architecture of widely known antican-
cer Vinca alkaloids, vincristine and vinblastine, can exemplify
bisindoles comprising two different indole subunits.
Though wide structural variety within the bisindole family
disallows a general synthetic approach to these compounds,
[a] Dr. O. A. Ivanova, Dr. E. M. Budynina, Dr. D. A. Skvortsov, Dr. I. V. Trushkov,
Prof. M. Ya. Melnikov
Figure 1. General strategy of this work.
Department of Chemistry, M. V. Lomonosov Moscow State University
Leninskie Gory 1-3, Moscow 119991 (Russian Federation)
E-mail: ekatbud@kinet.chem.msu.ru
the coupling of two indole-containing species can be consid-
ered as a basic concept in their assembly. In this work, we
report a new convenient method for bisindole construction
based on the strategy of donor–acceptor (D-A) cyclopropane[4]
cyclodimerization (Figure 1B). In the context of our recent re-
search revealing three different ways of [3+3] cyclodimeriza-
tion[5] of arylcyclopropane-1,1-diesters[6] to 9,10-dihydroanthra-
cenes, 1-aryltetralins and 1,4-diarylcyclohexanes (Figure 1C), an
ability to assemble analogous bisindole skeletons can be pre-
dicted for the indole-derived D-A cyclopropanes. These com-
pounds, combining a fragment of an activated cyclopropane
and the indole core, possess several reactive sites that can
[b] Dr. E. M. Budynina, Dr. I. V. Trushkov
Laboratory of Chemical Synthesis
Federal Research Center of Pediatric Hematology
Oncology and Immunology named after Dmitry Rogachev
Samory Mashela 1, Moscow 117997 (Russian Federation)
[c] Prof. V. N. Khrustalev
A. N. Nesmeyanov Institute of Organoelement Compounds
Russian Academy of Sciences
Vavilova 28, Moscow 119991 (Russian Federation)
[d] Prof. V. N. Khrustalev
Peoples’ Friendship University of Russia
Miklukho-Maklaya 6, Moscow 117198 (Russian Federation)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502287.
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endow such cyclopropanes with numerous types of reactivity
and open rapid approaches to diverse ring systems. However,
despite the apparent attractiveness of indole-derived D-A cy-
clopropanes (particularly as promising precursors of biological-
ly active compounds), their chemistry is currently poorly stud-
ied.[7] This can be caused by the high and diverse reactivity of
these cyclopropanes, which makes their study a challenging
problem.
Table 1. Optimization of reaction conditions for the dimerization of 1a
into carbazole 3a.
Our previous study revealed that the application of the con-
ditions that are appropriate for [3+3] cyclodimerization of ar-
ylcyclopropane-1,1-diesters to N-alkyl-indolyl-cyclopropanes in-
duces an unusual domino process, affording pentaleno[1,6a-
b]indoles,[8a] whereas the simple replacement of the N-alkyl
group by tosyl tunes [3+2] dimerization towards cyclopenta-
[b]indoles.[8b] Further efforts were directed to design new
routes to bisindoles, that is, fine-tuning the reaction towards
novel chemoselective [3+3] cyclodimerization of indole-de-
rived cyclopropanes.
Entry
Lewis acid
([mol%])
Solvent
(c [m])
T
[8C]
t
[h]
Yield [%][a]
(cis/trans)[b]
1
2
3
4
5
6
7
8
9
10
Sn(OTf)2 (17)
Sn(OTf)2 (20)
Sn(OTf)2 (10)
Sn(OTf)2 (15)
Sn(OTf)2 (9)
Sn(OTf)2 (20)
Yb(OTf)3 (20)
Ga(OTf)3 (20)
TiCl4 (120)
CH3NO2 (0.1)
CH3NO2 (0.06)
CH3NO2 (0.1)
CH3NO2 (0.1)
CH3NO2 (0.1)
CH3NO2 (0.1)
CH3NO2 (0.06)
CH3NO2 (0.06)
CH3NO2 (0.1)
CH2Cl2 (0.06)
RT
RT
RT
0
50
50
RT
RT
RT
RT
3
45 (66:34)
45 (66:34)
27 (65:35)
<10[c]
20[c]
15[c]
1.2
17
1
0.5
0.5
2
0.5
2
0.5
–
Herein, we report straightforward approaches to 1-indolyl-
tetrahydrocarbazoles and indolo[3,2-b]carbazoles through [3+
3] cyclodimerization of 2-(3-indolyl)- (1) and 2-(2-indolyl)cyclo-
propane-1,1-diesters (2). Parent cyclopropanes 1 and 2 are
readily available from the corresponding 3- and 2-indolecarb-
aldehydes through the standard synthetic sequence of Knoe-
venagel/Corey–Chaykovsky reactions.[9]
65 (90:10)
<10[c]
55 (72:28)
BF3·Et2O (120)
[a] Yields were determined by 1H NMR. [b] Diastereomeric ratio (cis/trans)
was determined by means of NMR analysis of crude products. [c] Com-
plex mixture of products. Diastereomeric ratio was not determined.
We started our research by optimizing the reaction condi-
tions for the cyclodimerization of 3-indolyl-derived cyclopro-
panes and examined N-benzyl-protected cyclopropane 1a as
a model compound. Most experiments were carried out in
polar CH3NO2 while varying Lewis acids and reaction tempera-
ture as well as the concentration of 1a and its ratio versus an
initiator. Selected representative results are summarized in
Table 1. These experiments revealed that catalytic amounts of
Sn(OTf)2 (Table 1, entries 1–6) or Ga(OTf)3 (entry 8) induce [3+
3] cyclodimerization to 1-indolyltetrahydrocarbazole 3a. The
same product is formed when the reaction is carried out in the
presence of stoichiometric amounts of BF3·Et2O in nonpolar
CH2Cl2 (entry 10). The most efficient and highly cis-diastereose-
lective cyclodimerization was found to proceed in 0.5 h, cata-
lyzed by 20 mol% of Ga(OTf)3 at room temperature (entry 8).
With the optimized conditions in hand, we extended the
scope of this [3+3] cyclodimerization to a series of 2-(3-indo-
lyl)cyclopropane-1,1-diesters 1b–e (Table 2). Desired carbazoles
3b–e were obtained in 57–71% yields, predominantly as cis-
isomers.[10] A brief survey of substituents in the indole core of
1 revealed that electronic factors have no noticeable influence
on the reaction efficiency, while diastereoselectivity depends
on the steric effect of the N-protecting group dramatically. The
bulky benzyl group provides very high cis-diastereoselectivity
(Table 2, entries 1, 4, and 5), whereas its replacement with the
more compact methyl (entries 2 and 3) leads to a decrease in
diastereoselectivity that can result in only slight predominance
of the cis-isomer.
Table 2. [3+3] Cyclodimerization of cyclopropanes
1,2,3,4-tetrahydrocarbazoles 3.[a]
1
into 1-indolyl-
Entry
1,3
X
R
d.r.
(cis/trans)[b]
Yield
[%][c]
1
2
3
4
5
a
b
c
d
e
H
H
Br
F
Bn
Me
Me
Bn
Bn
90:10
58:42
71:29
95:5
65
70
66
71
57
Cl
95:5
[a] Conditions: 0.06m solution of 1 in CH3NO2, Ga(OTf)3 (20 mol%), room
temperature, 0.5 h. [b] Diastereomeric ratio was determined by means of
NMR analysis of crude products. [c] Isolated yields.
A simple translation of the same reaction conditions to 2-in-
dolyl-derived cyclopropanes 2 allowed us to discover an alter-
native type of [3+3] cyclodimerization leading to tetrahydroin-
dolo[3,2-b]carbazoles 4. Compounds 2a–e,g, containing N-
alkyl-2-indolyl substituents with halogen or alkyl groups, easily
gave cyclodimers 4a–e,g with good yields and diastereoselec-
tivity (Table 3, entries 1–4,7). An exception was revealed for N-
(methoxymethyl)cyclopropane 1 f, which gives only traces of
the dimeric product under the studied conditions (entry 6).
Structural assignments for the products 3 were made by
means of 1D and 2D NMR experiments; structures of cyclodi-
mers cis- and trans-3a as well as cis-3b were unambiguously
confirmed by single-crystal X-ray analysis.[11]
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generated species are sufficiently activated towards a nucleo-
philic attack of the indole in the second cyclopropane mole-
cule, resulting in dimeric intermediates I-2 and I-5. The forma-
tion of I-2 was strongly supported by the isolation of the acy-
clic dimer 5 in a five-minute experiment with cyclopropane 2a.
Subsequent Ga(OTf)3-initiated cyclopropane ring opening leads
to intermediates I-3 and I-6, whose further reactivities are sig-
nificantly different. This is apparently caused by a noticeable
difference in the stability of benzyl cationic centers in 2- (I-3)
and 3-indolyl-substituted (I-6) species as well as in the nucleo-
philicity of the C-3 and C-2 sites of the indole core. The inter-
mediate I-3, containing a more reactive benzyl cationic center
as well as a more nucleophilic unoccupied C-3 indole posi-
tion,[12] undergoes intramolecular electrophilic aromatic substi-
tution (SEAr), yielding symmetric tetrahydroindolo[3,2-b]-
carbazole 4. For the intermediate I-6, wherein the benzyl
cation is less reactive and the C-3 position of the second
indole is occupied, the attack of a malonyl anion on a benzyl
site is more preferable, yielding 1-indolyltetrahydrocarbazoles
3.
Table 3. [3+3] Cyclodimerization of cyclopropanes 2 to tetrahydroindo-
lo[3,2-b]carbazoles 4.[a]
Entry
2,4
R
R1
R2
d.r.
(trans/cis)[b]
Yield
[%][c]
1
2
3
4
5
6
7
a
b
c
d
e
f
Me
Me
Me
Bn
H
F
Cl
F
H
H
H
H
H
H
H
H
H
Et
90:10
80:20
69:31
85:15
>95:5
–
76
79
75
75
70
trace
72
4-MeOC6H4CH2
MeOCH2
Me
g
95:5
[a] Conditions: 0.06m solution of 2 in CH3NO2, Ga(OTf)3 (20 mol%), room
temperature, 0.5 h. [b] Diastereomeric ratio was determined by means of
NMR analysis of crude products. [c] Isolated yields.
The change in diastereomeric ratios of dimers 5 (trans/cis
50:50) and 4a (trans7cis 90:10) provides compelling evidence
for the formation of 4 via the ring-opened intermediate I-3
rather than the polarized cyclopropane. This can occur through
the cyclopropane ring opening in I-2 furnishing I-3 with a pro-
chiral benzyl cation; subsequent cyclization predominantly
leads to the thermodynamically more stable trans-4a.[10]
An alternative mechanism for the dimerization of 1 can also
be proposed. It involves a reverse order in the formation of
two CÀC bonds, where malonyl anion–benzyl cation coupling
is ahead of the intramolecular electrophilic aromatic substitu-
tion. Recently, we reported a similar mechanism for the dimer-
ization of 2-aryl-substituted cyclopropane-1,1-diesters.[5a] How-
ever, that reaction was initiated by stoichiometric amounts of
a strongly activated Lewis acid, which induced complete cyclo-
propane ring opening to a zwitterion. This fact points to
higher probability of the malonyl anion–benzyl cation coupling
occurring at the first step of the dimerization. Meanwhile, after
being treated with a strongly activated Lewis acid, 3-indolyl-
derived cyclopropanes of type 1 were recently found to under-
go different cyclodimerizations, affording pentaleno[1,6a-
b]indole derivatives.[8a]
Strongly activated Lewis acids intensify oligo- and polymeri-
zation, leading to complex mixtures of nonidentified products.
Indolocarbazoles 4a–e, g were formed predominantly as
trans-isomers (Table 3, entries 1–5,7), with the highest trans-
diastereoselectivity (>95:5) achieved for N-PMB derivative 4e
(entry 5). The relative cis-configurations of the minor isomers
of 4b,c were confirmed by single-crystal X-ray analysis.
NMR monitoring of 2a dimerization revealed its complete
conversion in 5 min after the addition of the catalyst. However,
acyclic dimer 5 was the only product of the five-minute experi-
ment, obtained in 78% isolated yield and with 50:50 d.r.
(Scheme 1). The desired cyclodimer 4a was completely formed
in 76% yield and with 90:10 d.r. in approximately 30 min after
the treatment of intermediate product 5 with the catalyst.
We subsequently applied the developed methodology to-
wards 2-benzofuran- and 2-benzothiophene-derived cyclopro-
panes 6 and 7. Acidophobic benzofuryl derivative 6, activated
with Sn(OTf)2, cyclodimerized into dibenzofuran 8 in only 20%
yield (Scheme 3). Benzothienyl derivative 7 underwent cyclodi-
merization under harsher conditions, affording benzobis[b]ben-
zothiophene 9. Different chemoselectivity for cyclodimerization
of 6 and 7 can be explained by the higher tendency of 2-sub-
stituted benzothiophene ring to undergo C-3 electrophilic sub-
stitution in comparison with 2-substituted benzofuran.[13]
The importance of the developed synthetic approaches to
bisindoles of types 3 and 4 is primarily defined by the pharma-
ceutical and industrial value of these compounds. Thus, 4-indo-
lyltetrahydrocarbazoles of type 3 are known to exhibit cytotox-
ic and antiangiogenic activity,[14] whereas indolo[3,2-b]carb-
Scheme 1. “Time-resolved” dimerization of cyclopropane 2a.
These results allowed us to elucidate some mechanistic aspects
of the studied cyclodimerization.
According to the proposed mechanism for [3+3] cyclodi-
merizations of cyclopropanes 2 and 1 (A and B in Scheme 2),
the initial steps of these two domino processes are apparently
identical. Ga(OTf)3 is coordinated at ester group(s) of cyclopro-
pane molecules, inducing the cyclopropane polarization or
their ring opening to zwitterions I-1 and I-4. In any case, the
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Scheme 2. Proposed mechanism of cyclodimerization. SEAr=Electrophilic aromatic substitution.
sters. The process is characterized by synthetic simplicity and
provides ample opportunities to achieve significant increases
in structural complexity within one reaction in a highly chemo-
and stereoselective manner. Chemoselectivity depends on the
position of three-membered ring at the indole core while dia-
stereoselectivity is mostly regulated by the steric effect of the
N-protecting group in the indole. Extension of this methodolo-
gy to the assembly of bisindolylcyclohexanes and the develop-
ment of an asymmetric variant of the process is currently un-
derway.
Acknowledgements
We thank the Russian Scientific Foundation (project 14-13-
01178) for supporting this work.
Scheme 3. Cyclodimerization of 2-benzofuryl- and 2-benzothienyl-derived
cyclopropanes 6 and 7.
Keywords: cyclopropanes · dimerization · domino reactions ·
indoles · Lewis acids
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Received: June 11, 2015
Published online on August 6, 2015
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