A simple and efficient method for constructing azepino[4,5-b]indole derivatives via acid catalysis

Article abstract of DOI:10.1039/c6ob02722a

A new synthetic methodology has been developed to prepare the biologically important azepino[4,5-b]indole derivatives under Br?nsted acid catalysis. The notable features of this protocol include its operational simplicity, high reaction yields and environmentally benign and mild reaction conditions.

Full text of DOI:10.1039/c6ob02722a

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DOI: 10.1039/C6OB02722A
Journal Name
ARTICLE
A Simple and Efficient Method for Constructing Azepino[4,5-
b]indole Derivatives via Acid Catalysis
a
a
a
a
Siva Senthil Kumar Boominathan, Mutra Mohana Reddy, Ruei-Jhih Hou, Hui-Fen Chen, Jeh-Jeng
Wang*
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
DOI: 10.1039/x0xx00000x
A new synthetic methodology has been developed to prepare the biologically important azepino[4,5-b]indole derivatives
under Bronsted acid catalysis. The notable features of this protocol include its operational simplicity, mild conditions, high
reaction yields and environmentally benign reaction conditions.
www.rsc.org/
Indole-fused polycycles represent the most common structural
Currently, we are interested in developing new synthetic
motifs found in numerous naturally occurring alkaloids, methods from
bioactive molecules, and pharmaceuticals. Among them, the heterocyclic scaffolds. Continuing our research interest in this

-keto sulfonamide/ether precursors to valuable
1
8
azepino[4,5-b]indole structures have received increasing area, we conceptualize that indole-linked
-keto sulfonamides
attention due to their prevalence in several natural products Scheme 1 eq 3) could be converted into azepino[4,5-b]indoles
(
;
such as ngouniensine, paullones, arboflorine, andraginine, with the aid of suitable catalysts. Compared to intermolecular
subincanadine-F, ibogamine alkaloids, tronocarpine, and addition reactions between indoles with carbonyl compounds,
2
malassezindoles (Figure 1). These structures also have proven intramolecular reactions are less prevalent in the literature.
pharmacological effects as anti-tumour agents, cyclin Herein, we report a concise route to achieving azepino[4,5-
dependent kinase (CDK)-inhibitors, and glycogen synthase b]indoles via Bronsted acid catalysis with elusive substitution
3
kinase (GSK)-inhibitors. As a consequence, simple and patterns.
improved synthetic methods for these frameworks are highly
desirable.
Due to their biological importance, various synthetic
strategies have been developed for the synthesis of
azepino[4,5-b]indole derivatives from conventional to modern
methods. The conventional approaches to these compounds
include Fischer-indole synthesis, Friedel-Crafts type acylation,
4
and electrocyclic ring closure reactions. Despite the great
efforts, these reactions suffer from poor reaction yields, harsh
reaction conditions, and
a restricted substrate scope.
Considering modern approaches, Lewis acid-catalysed
cyclization of alkynes, metal-catalysed cascade reactions, and
5
radical oxidative aromatic substitution reactions are notable.
In 2007, Echavareen et al. reported a gold-catalysed
intramolecular cyclization of indole-linked alkynes to indole
6
annulated compounds (Scheme 1
;
eq 1). In 2009, a palladium-
catalysed domino Tsuji/Trost-Heck reaction from N-allylated
tryptamines was developed by Stewart and co-workers
7
(
Scheme 1; eq 2).
Figure 1. Representative Natural Products
a.
b.
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
00 Shihquan Road, Kaohsiung 80708, Taiwan. Fax: (+886)-7-312-5339; phone:
+886)-7-312-1101; e-mail: jjwang@kmu.edu.tw
Department of Medical Research, Kaohsiung Medical University Hospital, No.100,
Tzyou 1st Rd, Kaohsiung 807, Taiwan.
1
(
†
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
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J. Name., 2013, 00, 1-3 | 1
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1. Optimization studies
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DOI: 10.1039/C6OB02722A
S.No
Reagent
Solvent
Time (hr)
Yield (%)
1
2
TfOH
TFA
DCE
DCE
1
8
95
70
3
4
5
p-TsOH
DCE
DCE
DCE
24
24
24
24
24
8
55
43
15
CH
FeCl
Sc(OTf)
In(OTf)
BF .Et
3 3
SO H
3
Scheme 1. Previous reports to azepino[4,5-b]indoles
6
7
3
DCE
DCE
28
Traces
85
3
8
3
2
O
DCE
Results and Discussion
The desired starting materials were synthesized from the
commercially available substrates as shown in Scheme 2
Initially, the tryptamine/tryptophan derivatives (A) were
tosylated in the presence of triethyl amine to afford the
corresponding tosylated derivatives (B), followed by base-
9
10
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
nitromethane
DCM
acetonitrile
toluene
DMF
1
3
24
24
24
1
92
89
40
11
12
13
.
Traces
Traces
80
1
4 a
5b
DCE
1
DCE
1
85
mediated alkylation with
-bromoketones resulting in the
formation of compound in quantitative reaction yields.
1
General reaction conditions: 1a (0.5 mmol), catalyst (20 mol%), solvent (0.15 M) at
the mentioned reaction time at room temperature; [a] 10 mol% of catalyst was
o
used; [b] Reaction performed at 50 C.
Having the optimized set of reaction conditions in hand, the
scope of the transformation was then explored with various
substituted tryptamine and tryptophan derivatives as shown in
Scheme 2. Synthetic scheme for the starting materials
Table 2. The reaction tolerates a wide range of substituents at
1
To validate our hypothesis, we initiated optimization studies the R position, such as phenyl (2a), p-anisyl (2b), o-anisyl (2c),
using compound 1a as a model substrate, and the observed p-tolyl (2d), p-Cl-Ph (2e), 3,4-di-Cl-ph (2f), p-F-Ph (2g), and
results are summarized in Table 1. To our delight, a catalytic naphthyl (2h) with good to excellent yields. However, some of
amount of trifluoromethanesulfonic acid (TfOH) in 1,2- the substituents require more reaction time to complete the
1
dichloroethane (DCE) provided the expected compound 2a in an reaction. Unfortunately, the R substituted with alkyl groups like
excellent yield within a short span of time (Table 1; entry 1). X- t-butyl (2i) and ethyl (2j) group were failed to proceed. At this
ray analysis unambiguously confirmed the molecular structure stage, we don’t have any rationalization for the failure of these
9
2
of compound 2a (Figure 2). Encouraged by this outcome, the reactions. Replacing the R substituent with methyl (2k) and
reaction was screened with different Bronsted acids such as phenyl (2l) produced the corresponding products and moderate
trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TsOH), and reaction yields presumably due to steric hindrance.
methanesulfonic acid (MeSO H), (Table 1, entries 2-4), but none Additionally, the conversion rates of these two reactions at
3
of them were as efficient as TfOH. Alternatively, the feasibility room temperature were slow and required elevated
of the reaction was investigated with Lewis acid catalysts (Table temperature (60 °C) to complete. Switching the simple indoles
3 2
1, entries 5-8), and BF . Et O was noticeable in terms of the to an N-substituted indole did not interfere with the cyclization,
reaction yield. Subsequent solvent studies revealed that and the respective product (2m) was obtained in a 45% yield.
4
dichloroethane was the suitable choice (Entries 9-13). Moreover, replacing the tosyl group at R with other sulfonyl
Decreasing the equivalents of TfOH and increasing the reaction groups such as phenyl sulfonyl (2n) and nosyl (2o) gave the
temperature were detrimental to the reaction yield (Entries 14 desired products. In addition to sulfonyl groups on nitrogen,
4
and 15). Finally, we determined that 20 mol% of TfOH in DCE when the R substituent was replaced with a benzyl group (2p),
(entry 1) presented the optimized reaction conditions for this the expected product observed with low yield and compound
conversion.
started decomposing over a period of time. It should be noted
that attempts to prepare the starting materials with other N-
substituents such as phenyl, Boc and acetyl failed. As an
alternative to the tryptamine-derived precursors, the methyl
esters of L-tryptophan scaffolds were also synthesized and
scrutinized under standard reaction conditions. As expected,
2
| J. Name., 2012, 00, 1-3
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
the substrates were suitable for this transformation, delivering
the respective products (2q-t). Finally, substitution at the R
View Article Online
DOI: 10.1039/C6OB02722A
6
position with phenyl (2u) and tolyl (2v) groups led to conversion
into the corresponding compounds in high yields.
Table 2. Substrate Scope
Scheme 3: Plausible reaction mechanism
Based on the observed results, we presume that the
reaction may proceed through electrophilic substitution via the
10
most probable indole C-3 attack (Scheme 3). Initially, the
Bronsted acid assisted the electrophilic activation of the
carbonyl group of compound
1, thus triggering the nucleophilic
attack at the indole C-3 position leading to the formation of
1
1
spiro intermediate
rearrangement followed by the loss of a proton to give hydroxyl
intermediate . Finally, the intermediate proceeds through
E1-type elimination via carbocation intermediate , furnishing
B
.
Then, it rapidly undergoes
D
D
E
the desired product 2.
Conclusions
In summary, we have developed a mild and efficient
approach to azepino[4,5-b]indole derivatives via a catalytic
amount of TfOH. Given its simple and straightforward nature to
prepare the indole-fused heterocycle, this synthetic method is
expected to find broad applications in organic synthesis and
medicinal chemistry. The biological screening of the synthesized
molecules is underway in our laboratory.
Reaction conditions: 1a-v (0.5 mmol), TfOH (20 mol%) in DCE (0.15 M) and stirred
at RT for the given time; [a] Reaction performed at 60 C; [b] Product slowly
o
decomposed.
Acknowledgements
We gratefully acknowledge the financial support from the
Ministry of Science and Technology (MOST), Taiwan, and the
Centre for Research Resources and Development of Kaohsiung
Medical University for NMR analyses.
Notes and references
‡
Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the matter
under discussion, limited experimental and spectral data, and
crystallographic data.
Figure 2. X-ray crystal structure of Compound 2a
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