Iodine-catalyzed chemoselective dehydrogenation and aromatization of tetrahydro-β-carbolines: A short synthesis of Kumujian-C, Eudistomin-U, Norharmane, Harmane Harmalan and Isoeudistomine-M

Article abstract of DOI:10.1016/j.tetlet.2018.04.043

Temperature controlled chemoselective dehydrogenation and aromatization of tetrahydro-β-carbolines, using molecular I₂ and H₂O₂, in DMSO solvent affords a practical access to a series of corresponding 3,4-dihydro-β-carbolines and β-carbolines respectively. This method has been successfully employed in the short synthesis of Kumujian-C, Eudistomin-U, Norharmane Harmane Harmalan and Isoeudistomin-M.

Full text of DOI:10.1016/j.tetlet.2018.04.043

Accepted Manuscript
Iodine-catalyzed chemoselective dehydrogenation and aromatization of Tetra-
hydro-β-carbolines: a short synthesis of Kumujian-C, Eudistomin-U, Norhar-
mane, Harmane Harmalan and Isoeudistomine-M
Sunil Gaikwad, Dayanand Kamble, Pradeep Lokhande
PII:
S0040-4039(18)30513-6
https://doi.org/10.1016/j.tetlet.2018.04.043
TETL 49906
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 March 2018
16 April 2018
18 April 2018
Please cite this article as: Gaikwad, S., Kamble, D., Lokhande, P., Iodine-catalyzed chemoselective dehydrogenation
and aromatization of Tetrahydro-β-carbolines: a short synthesis of Kumujian-C, Eudistomin-U, Norharmane,
Harmane Harmalan and Isoeudistomine-M, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.04.043
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Tetrahedron Letters
Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Iodine-catalyzed chemoselective dehydrogenation and aromatization of Tetrahydro-β-
carbolines: a short synthesis of Kumujian-C, Eudistomin-U, Norharmane, Harmane
Harmalan and Isoeudistomine-M
Sunil Gaikwad, Dayanand Kamble and Pradeep Lokhande*
Center for Advance Studies, Department of Chemistry, Savitribai Phule Pune University,
Pune 411007, India, Email: pdlokhande@chem.unipune.ac.in, sunilunipune2012@gmail.com
ARTICLE INFO
ABSTRACT
Temperature controlled chemoselective dehydrogenation and aromatization of tetrahydro-β-
carbolines, using molecular I2 and H2O2, in DMSO solvent affords a practical access to a series
of corresponding 3, 4-dihydro-β-carbolines and β-carbolines respectively. This method has been
successfully employed in the short synthesis of Kumujian-C, Eudistomin-U, Norharmane
Harmane Harmalan and Isoeudistomin-M.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Dehydrogenation
Aromatization
Iodine
Carbolines
Kumujian-C
Eudistomin-U
1. Introduction.
combination of IBX-CeCl3 for the partial dehydrogenation of
Aromatic β-carboline alkaloid scaffolds are observed in diverse
natural sources1 and show a broad range of biological activities
such as neuroprotection,2 antiviral,3 antitumor,4 anti-HIV,5
antimalarial,6 antiplasmodial,7 anti-leishmanial,8 anti-allergic9 etc.
Diverse β-carbolines derivatives exhibit tyrosine-phosphorylation
regulated kinase (DYRK) activity10 acetylcholinesterase
inhibition.11The β-carboline moiety is a very important synthetic
intermediate for a variety of pharmaceutically important natural
products and drug molecules (fig. 1). The Significant biological
properties of β-carboline makes it synthetically important unit.
Enormous efforts have been devoted for inventing efficient and
cost-effective catalysts for the dehydro-aromatization of
heterocyclic compounds under mild conditions.12Several methods
have been developed to synthesize β-carbolines. Pictet–Spengler
reaction is one of the methods used to obtain tetrahydro-β-
carbolines, which upon dehydrogenation offers β-carbolines. The
reagents such as K2Cr2O7,13 KMnO4,14 copper salts,15 Palladium
tetrahydro-β-carbolines to 3,4-dihydro-β-carbolines.
Fig. 1. Carboline alkaloids and drugs.
Recently Water et al., have reported Dess-Martin periodinane
(DMP) and 2-iodoxybenzoic acid (IBX) mediated oxidative
aromatization, partial dehydrogenation of tetrahydro-β-carbolines
at room temperature.25a Kamal et al., have reported PhI(OAc)2
(diacetoxyiodobenzene) mediated oxidative decarboxylation of
on carbon,16,35g sulphur,17 SeO2,18 MnO2,19 NCS,20 DDQ21and
22
NBS
have been used for the oxidative aromatization and
dehydrogenation. Whereas K. C. Nicolaou etal.,l23 have reported
IBX-mediated oxidative dehydrogenation of a secondary amine,
Shannon S. Stahl et al.,23c reported oxidation of secondary amines
and nitrogen heterocycles using 1,10-phenanthroline-5,6-
dione/ZnI2, recently Subhabrata Sen et al.,24 have used the
tetrahydro-β-carbolines to the corresponding β-carbolines25b
.
However, most of the reported methods for the aromatization of
tetrahydro-β-carbolines generally involve the following
drawbacks. Pd mediated reactions need a higher temp. (up to 150
°C), long reaction hours, low yields, along with the possibility of
C-N bond cleavage.26 Selenium mediated reactions need huge

2
Tetrahedron Letters
quantity of SeO2 (10 equiv) offering very less yield (65 %).27
of I2. Changing the peroxide from H2O2 to tert- butylhyd-
peroxide (TBHP) with 10 and 25 mol% of I2 at room temperature
could lead to 54 and 56% of 2a. Therefore we decided to
continue with H2O2. Further, to check the effect of enhanced
temperature. The reaction was carried out at 80 oC with 25 mol%
I2 surprisingly, resulted in 87% of 2a and a trace quantity of
aromatized product β-carboline 3a.However at 20 oC increases in
temperature offered exclusively the β-carboline 3a in 88% yield
over 10 hours. Increasing the iodine quantity to 50, 75 and 100
mol% could lead to 89-90% yield at the most (entry 13, 14, and
15, table 1). Therefore we preferred to continue with 25 mol% of
I2. Notably, an increase in the reaction temperature minimizes
the use of molecular iodine and offers the aromatized product
(Entry 12, Table 1). Here the controlled dehydrogenation and the
aromatization of tetrahydro-β-carboline is temperature
dependent.
Sulphur mediated reactions need 2 days to deliver aromatized
product in low yields.28 DDQ and chloranil were found useful in
some cases but yields obtained were not satisfactory always.21
While hypervalent iodine reagent IBX is usually required in
super stoichiometric amounts and/or often requires ester
functionality for successful β-carboline formation.
We have been always interested in iodine mediated, significant
organo-synthetic transformations. Some of the recent molecular
I2 mediated methods especially oxidative dehydrogenation
reactions reported by our research group are, I2/DMSO mediated
facile
dehydrogenation
of
dihydropyridazin-3(2H)one,29
oxidative cyclizations of 2′-hydroxy and 2’- allyloxy chalcones
directly to the corresponding flavones and iodoflavones30 instead
of flavanones. Regioselective oxidative dehydrogenation in
anilinodihydrochalcones.30Aaromatization and halogenation of
3,3a,4,5-tetrahydro-3-aryl-2-phenyl-2H-benzo[g]indazoles.31
Aromatization and in-situ iodination of tetrahydrocarbazoles.32
In pursuance of our efforts to develop new synthetic methods for
the compounds of medicinal importance, we attempted the
synthesis of 3,4-dihydro-β-carboline, and aromatic-β-carbolines
using molecular iodine under easy reaction conditions.
Additionally, this method has been employed for the synthesis of
bioactive alkaloids such as Kumujian-C, Eudistomin-U
Isoeudistomin-U, Norharmane, Harmane, Harmalan, and
Isoeudistomin-M.
Table 2. Chemoselective dehydrogenation of tetrahydro-β-
carboline
1. Result and Discussion
Accordingly, when tetrahydro-β-carboline 1a was stirred with 10
mol% molecular iodine at r.t. in DMSO, we got 3,4-dihydro-β-
carboline 2a with 50% yield (entry 1, Table1). Increasing amount
of molecular iodine to 25 mol% could not improve the yield
significantly (55%) (Entry2, Table1). It is reported in the
literature that peroxide promotes the dehydrogenation reaction.33
Therefore, we employed TBHP and H2O2 (100 mol% each) along
with 10 mol% I2 in separate reactions, resulting in 60% yield of
the selectively oxidized product 2a (3, 4-dihydro-β-carboline)
(Entry 3, Table1). Increasing the I2 to 25 mol% could not lead to
better yield.
Table 1. Optimization of oxidative dehydrogenation and
aromatization reaction
a Yields: 35% 3,4-dihydro-β-carboline; 50% β-carboline
b Yields: 25% 3,4-dihydro-β-carboline; 55% β-carboline
Entry
I2
Oxidant
(100
mol%)
-
Temp
(°C)
Time
(h)
Yielda
% (2a)
Yieldb
% (3a)
(mol%)
Having the selective oxidation and aromatization condition in
hand, we planned to explore the selective oxidation condition
first. Accordingly, a range of tetrahydro-β-carbolines was
subjected under the selective oxidation condition (entry 7, Table
1), substrates bearing electron-donating substituents offered
excellent yields (up to 92%) (Entry 2m, Table 2). In case of
ortho-amino substitution, dihydro-β-carboline was obtained in
80% yield (entry 2p, table 2). However, in case of electron-
withdrawing substituents like ortho-NO2 and ortho-chloro the
obtained yields of the dihydro-β-carbolines were 25% and 35%
respectively, along with 55% and 50% corresponding β-
carbolines. Slight low yields were observed in case of
heterocyclic aryl rings (entry 2n, and 2o, Table 2).
A range of tetrahydro-β-carbolines was next examined to probe
the substrate scope of I2-H2O2 mediated aromatization process.
Tetrahydro-β-carbolines with the substitutions such as Me, OMe
and halogens on the phenyl ring offered β-carbolines in very
good yields (table 3). Interestingly, tetrahydro-β-carbolines
bearing an o-chlorophenyl, o-nitrophenyl got converted into the
corresponding β-carboline in quite better yields, (Entry 3e and
3q, Table 3) contrary to the chemoselective dehydrogenation of
the same substrates (Entry 2e and 2q, Table 2)
1
2
3
10
25
10
25
10
25
50
100
10
25
25
25
50
75
100
RT
RT
RT
RT
60
4
4
3
50
55
60
60
65
72
90
90
54
56
87
-
-
-
-
-
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
TBHP
TBHP
H2O2
H2O2
H2O2
H2O2
H2O2
4
5
6
3
4
4
-
-
-
60
7
8
60
60
2
2
-
-
9
RT
RT
80
100
100
100
100
4
-
10
11
12
13
14
15
4
2
10
8
-
Trace
88
89
90
90
-
8
8
-
-
a,b.Clear TLC observed in long rage wavelength.
Therefore we thought to increase the temperature, accordingly,
when the reaction was carried out at 60 C a slight increase in
yield of the 2a (65%) was observed. Use of 25 mol% of I2,
resulted in 72% yield at 60 oC. To our delight, we got 90 % yield
of 2a with 50 mol% I2 in just 2 hours. However no further
improvement was observed in terms of the yield with 100 mol%
o
.

Tetrahedron Letters
Scheme 2. Synthesis of norharmane.
Table 3. Synthesis of β-carbolines.
Subsequently, Pictet-Spengler condensation of tryptamine &
acetaldehyde provides 1-methyl-1,2,3,4-tetrahydro-β-carboline 10
90% yield. Dehydrogenation of 10 under the optimized conditions
proceeded smoothly, affording Harmane22,25b11 in (78% yield
Scheme3).
Scheme 3. Synthesis of harmane.
Finally, we also carried out the total synthesis of Kumujian-C 14,
which consists of formyl group at the C-1 position of ring C. We
planned to apply aromatization reaction for the synthesis of
Kumujian-C.
The various tetrahydro-β-carbolines underwent the oxidative
dehydrogenation prompted us to investigate the applicability of
this method toward the synthesis of some important marine
alkaloids such as Kumujian-C, Eudistomin-U, Norharmane,
Harmane. Kumujian-C isolated from root wood of Picrasma
quassioides34a. Eudistomin-U was isolated from the marine
ascidian lissoclinum fragile and was reported to possess
anticancer activities with strong DNA binding potential,
antimicrobial activity as well as exhibit antiviral activities against
herpes simplex virus-1 and polio vaccine type-1 virus.34b There
are seven reports available for the synthesis of Eudistomin-
U22,25,35.Eudistomin-U was first reported by Molina et al.,using an
iminophosphorane intermediate.35a Queguiner et al.,prepared the
natural product via sequential metalations35b. While Yamaguchi
& Itami reported a novel oxidative C–H/C–H coupling in their
total synthesis.35c Witulski Bernhard and Co-worker used a novel
Ru or Rh-catalyzed [2+2+2] cyclization to generate the natural
product35d. More recently Stephen Water and co-worker reported
aromatization of Pictet-Spengler intermediate to generate
eudistomin-U25.Later Kamal and co-worker used NCS &
Scheme 4: Synthesis of Kumujian-C
Accordingly, the required tetrahydro-β-carboline 12 was
achieved from the tryptamine 7 and dimethoxy glyoxal. The I2
mediated aromatization of ring C under the optimized reaction
condition (Entry 12, Table 1) offered intermediate 13 which upon
o
stirring in AcOH at 60 C delivered Kumujian-C36 14 in 40%
overall yield.
PhI(OAc)2 reagent for the total synthesis of alkaloid22,25
.
However, most of these syntheses need expensive metal
catalysts,35 critical reaction conditions prolonged reaction hours,
multistep reaction sequence, resulting in low overall yield. We
describe an efficient, three-step synthesis of Eudistomin-U.
Synthesis of Eudistomin-U commenced with Pictet-Spengler
reaction of tryptamine and N-acetyl-Indole-3-carbaldehyde to
obtain the tetrahydro-β-carboline core 4. Followed by oxidation
of the obtained core 4 using I2-DMSO under optimized
conditions produced aromatized intermediates 5 (77% yields)
subsequence deprotection gives eudistomin-U (60% yields,
Scheme1).
Scheme 5: a Plausible mechanism for the I2/DMSO/H2O2
mediated aromatization of tetrahydro-β-carbolines.
N-iodination of tetrahydro-β-carboline 15 takes place in the first
step to give intermediate 16. The dehydroiodination of N-
iodotetrahydrocarboline results in the imine intermediate 17. This
imine intermediate gives ammonium intermediate 18 on further
N-iodination. Subsequent deprotonation and dehydro-iodination
offer the β-carboline. The generated HI further reacts with
DMSO to regenerate the molecular iodine, along with dimethyl
sulfide (DMS).37b The regeneration of molecular I2 helps to
continue the cycle. The formed dimethylsulfide is oxidized to
DMSO in presence of H2O2 to speed up the reaction time.37a
Conclusion
Scheme 1. Synthesis of eudistomin-U.
Synthesis of Norharman22,25b 9 has been carried out by Pictet
Spengler cyclization reaction of tryptamine & formaldehyde (37-
41% W/V) to obtain 1,2,3,4-tetrahydro-β-carboline 87% 8. The
oxidation of tetrahydro-β-carboline 8 under the optimized
reaction condition gives 9 in (82% yield Scheme2).
In summary, we have developed a simple, efficient and metal
free iodine mediated method, for the chemoselective
dehydrogenation and aromatization of tetrahydro-β-carbolines to
3,4-dihydro-β-carbolines and β-carbolines. This protocol has
been utilized for the synthesis of a library 3,4-dihydro-β-
carboline derivatives as well as bioactive alkaloids Kumujian-C
14, Eudistomin-U 5, Isoeudistomin-M 2o, Norharmane 8,
Harmane 10 and Harmalan 2t analogs.

4
Tetrahedron Letters
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SVG is thankful to UGC-BSR.( UGC file No F.4-3/2006(BSR)
dated Dec 2011], UGC‐ New Delhi, EUPHRATES, an Erasmus
Mundus Lot 13 project 2013-2540/001-001 (Europe, India) led
by the University of Santiago de Compostela (Spain) & UPE II,
SPPU for Ph.D. fellowship & support of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at………………
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Tetrahedron Letters
Highlights
 30 Examples.
 I2 catalysed chemoselective dehydrogenation
of tetrahydro-β-carboline to 3,4-dihydro-β-
carboline.
 I2 catalysed a new synthesis of synthesis
Kumujian-C, Eudistomin-U, Harmalan and
Isoeudistomine-M.
 Products synthesized in good to excellent yields.

6
Tetrahedron Letters
Graphical Abstract
Iodine-catalyzed chemoselective dehydrogenation
Leave this area blank for abstract info.
and aromatization of Tetrahydro-β-carbolines:
A short synthesis of Kumujian-C, Eudistomin-U, Norharmane, Harmane, Harmalan and
Isoeudistomin-M
Sunil Gaikwad, Dayanand Kamble and Pradeep D. Lokhande*