N-Bromo-succinimide promoted synthesis of β-carbolines and 3,4-dihydro-β-carbolines from tetrahydro-β-carbolines

Article abstract of DOI:10.1016/j.tetlet.2016.01.081

Herein, we report a facile synthesis of 3,4-dihydro-β-carbolines and aromatic β-carbolines from tetrahydro-β-carbolines, mediated by N-bromosuccinimide in toluene at 0°C to room temperature (rt), in good to moderate yields.

Full text of DOI:10.1016/j.tetlet.2016.01.081

Accepted Manuscript
N-bromo-succinimide promoted synthesis of β-carbolines and 3, 4-dihydro-β-
carbolines from tetrahydro-β-carbolines
Santanu Hati, Subhabrata Sen
PII:
S0040-4039(16)30081-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.081
TETL 47245
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 November 2015
21 January 2016
22 January 2016
Please cite this article as: Hati, S., Sen, S., N-bromo-succinimide promoted synthesis of β-carbolines and 3, 4-
dihydro-β-carbolines from tetrahydro-β-carbolines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.01.081
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Graphical Abstract
N-bromo-succinimide promoted synthesis of
-carbolines and 3, 4-dihydro--carbolines
from tetrahydro--carbolines
Leave this area blank for abstract info.
Santanu Hati and Subhabrata Sen*

1
Tetrahedron Letters
N-bromo-succinimide promoted synthesis of -carbolines and 3, 4-dihydro--
carbolines from tetrahydro--carbolines
Santanu Hati and Subhabrata Sen
Department of Chemistry, School of Natural Science, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar, Uttar Pradesh 201314, India
Email: subhabrata.sen@snu.edu.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Here in, we report a facile synthesis of 3, 4-dihydro--carbolines and aromatic -carbolines
from tetrahydro--carbolines, mediated by N-bromosuccinimide in toluene at 0 °C to room
temperature (rt), in good to moderate yield.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
-carboline
Tetrahydro--carboline
N-bromosuccinimide
3, 4-dihydro--carboline
Harmine
1. Introduction
bifunctional quinone catalyst to generate 3,4-dihydro--
carbolines.7a Few alternative strategies to access aromatic -
Aromatic-carboline moieties are present in a variety of
biologically active alkaloidal natural products as well as
pharmaceutically relevant compounds.1a-c Diverse -carboline
drivatives have exhibited various biological activities such as
antitumor, antimalarial, antileishmanial, antibacterial and etc.1a-c
For example Harmine (a fluorescent alkaloid with known
telepathine properties), Harmaline (a reversible MAO-A inhibitor
[RIMA]), Harmalol, Isoeudistomin U (DNA binding agents), 3,
4-dihydro-5(S)-5-carboxystrictosidine, Eudistomin are few of the
aromatic -carboline derivatives showing pronounced biological
activity. Additionally compounds possessing these ring systems
have also been used as building blocks in the generation of
pharmaceutically relevant molecules. 2-6
carbolines involved elimination of N-tosyltetrahydro--
carbolines by sodium hydroxide and ring closure of -aryl
amides with phosphorus oxychloride (POCl3).11 and 13
Drawing inspiration from these reports and in continuation to
our endeavor to develop practical synthetic strategies for
pharmaceutically relevant compounds, a trial reaction of 1a with
catalytic NBS in THF resulted in the formation of 3, 4-dihydro--
carboline 2a and unreacted 1a in the ratio of 20:80 (Scheme 1b).
This result indicated that NBS is capable to promote the
oxidative dehydrogenation of the tetrahydro--carboline 1a. We
optimized this protocol and here in we report a facile synthesis of
-carbolines and 3, 4-dihydro--carbolines starting from
tetrahydro--carbolines with NBS in appropriate solvent at 0 °C
to rt (Scheme 1c).
By virtue of wide range of biological applications, aromatic -
carbolines have become an important target of synthesis. In
general, these molecules are synthesized via a Pictet-Spengler
2. Results and discussion
reaction
dehydrogenation.
followed by oxidative decarboxylation
or
7-13
Initially for the optimization of the synthesis of 3, 4-dihydro-
-carbolines 1a was used as the model substrate (Table 1). The
reactions were conducted in various solvents such as toluene,
tetrahydrofuran (THF), acetonitrile (ACN) and methanol with the
reaction temperature maintained between 0 °C to rt (to inhibit
any ring bromination by NBS). The average time taken for
complete consumption of 1a ranged from 3-6 h. The product
conversion was monitored by LCMS. With 0.5 equivalents of
NBS, the dihydro--carboline derivative 2a was immediately
Oxidative decarboxylation strategies are
tedious and required high temperature with reagents like
potassium dichromate (K2Cr2O7) in acetic acid (AcOH) and
persulphates with catalytic silver or copper salts, until recently
when Kamal et al. reported a mild diacetoxyiodobenzene (DIB)
mediated decarboxylative oxidation of terahydro--carbolines.8c,
9-12
Additionally dehydrogenation strategies typically involved
large quantities of oxidants such as DDQ, SeO2, and IBX/TBAB
(Scheme 1a).8
Interestingly, Stahl. et al. reported a
and 12
bioinspired aerobic oxidation of tetrahydro--carbolines with
———
 Subhabrata Sen. Tel.: +91-120-381-9100; e-mail: subhabrata.sen@snu.edu.in

2
Tetrahedron Letters
obtained in all the solvents, though in methanol the yield was
lowest
(entry
4,
Scheme 1. Synthesis of aromatic -carbolines and 3, 4-dihydro--carbolines
Table 1). Equimolar amount of NBS led to a considerable
improvement of yield of 2a. The toluene and acetonitrile
provided the best results with 84 and 82% yield respectively.
Finally a slight increase of NBS to 1.1 equivalent in toluene
further improved the yield to ~95%. Based on these observations
it was concluded that 1.1 equivalent of NBS in toluene at 0 °C→
room temperature (rt), is the optimal condition for the synthesis
of 3, 4-dihydro--carbolines.
Table 1
Optimization of 3, 4-dihydro--carbolines
Conversion (%)a
Time (h)
Entry
N-bromosuccinimide (mmols)
Solvents
2a
35
45
38
12
70
84
82
65
95
1a (unreacted)
1
2
3
4
5
6
7
8
9
0.5
ʺ
Tetrahydrofuran
Toluene
4
6
4
6
45
45
43
43
5
ʺ
Acetonitrile
Methanol
ʺ
1.0
ʺ
Tetrahydrofuran
Toluene
-
ʺ
Acetonitrile
Methanol
3
ʺ
21
-
1.1
Toluene
a
The
reactions
were
monitored
by
LCMS,
that
provided
the
%ge
conversion

3
Hence with the optimized protocol in hand, the generic nature
of the process was explored. Accordingly tetrahydro--carbolines
(1b-n) with a variety of functionality on the aromatic and
aliphatic moiety were converted to the corresponding 3, 4-
dihydro--carbolines (2b-n) (Scheme 2). The reactions were
conducted in 100mg scale and simple purification by column
chromatography afforded the desired products 2b-2n.
Irrespective of the nature of the substituents on the aromatic
ring, the yields were good to moderate and ranged from 60-88%
(Scheme 2). The aliphatic variant 2f with octanal was generated
in 72% yield (Scheme 2). To propose a mechanistic explanation
of this transformation we postulate that the Br+ from NBS
brominates the piperidine N- (A) followed by elimination of HBr
to afford 2 (Scheme 2).
Scheme 2. NBS mediated synthesis of 3, 4-dihydro--carbolines
substrate. To our pleasant surprise the reaction with two
equivalent of NBS in toluene at 0 °C→rt showed ~85%
conversion to aromatic -carboline ester 4a (Scheme 3). LCMS
monitoring of the reaction indicated the formation of the 3, 4-
dihydro--carboline intermediate 2o which was then further
oxidized to 4a. To further confirm the formation of 2o, it was
isolated, purified and characterized by 1H and 13C-NMR.
Additionally, 1o was further reacted with 1.1 equivalent of NBS
to generate 2o. This methodology afforded a bevy of aromatic -
carboline esters (4b-4g) from their appropriate precursors in
moderate to excellent yields (Scheme 3).
Next, we examined the scope of our protocol towards the
synthesis of aromatic -carboline derivatives (Scheme 3) from
tetrahydro--carboline esters (derived from the condensation of
L-tryptophan methyl ester and appropriate aldehydes).
Transformation of this type has been previously conducted under
mild condition by using IBX (2 equiv.) and tetrabutyl ammonium
bromide (0.5 equiv.) in acetonitrile at room temperature for 2h.8f
Hence we were hopeful that we would be able to repeat similar
results with NBS, especially after obtaining the 3, 4-dihydro--
carbolines (2a-n). Accordingly 1p was chosen as the model
Scheme 3. Synthesis of aromatic -carboline esters

4
Tetrahedron
3. Conclusion
In conclusion, we have devised an efficient strategy for the
synthesis of aromatic--carbolines and its 3, 4-dihydro analogs
through an efficient oxidative dehydrogenation of the
corresponding tetrahydro--carbolines under mild condition. This
strategy used NBS for the first time in such oxidative
dehydrogenation reactions thereby providing the desired
compounds in decent yields. Additionally this further provides a
practical approach to access these classes of heterocycles that can
be applied effectively in generating combinatorial libraries and
will expedite compound generation during projected structure
activity relationship studies.
4. Acknowledgements
The authors thank Shiv Nadar University for the support. SH
acknowledges SNU for the graduate scholarship.
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