A one-pot direct regioselective iodination of Fischer-Borsche product using periodic acid in PEG-400

Article abstract of DOI:10.1016/j.tetlet.2019.03.022

A metal-free and greener approach for the one-pot direct iodination and dehydrogenation of dihydrobenzo[a]carbazoles has been developed using periodic acid in polyethylene glycol-400 (PEG-400) under mild condition. This method has been proven to be tolerate to a broad range of functional groups, with good to excellent yields include metal-free inexpensive catalyst, easy work-up, benign reaction condition and high regioselectivity. The solvent has been successfully recycled up to 5 times without any loss of activity in an aqueous medium.

Full text of DOI:10.1016/j.tetlet.2019.03.022

Accepted Manuscript
A one-pot direct regioselective iodination of Fischer-Borsche product using pe-
riodic acid in PEG-400
Monica H. Ghom, Mahavir S. Naykode, Vivek T. Humne, P.D. Lokhande
PII:
S0040-4039(19)30230-8
https://doi.org/10.1016/j.tetlet.2019.03.022
TETL 50663
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 November 2018
2 March 2019
8 March 2019
Please cite this article as: Ghom, M.H., Naykode, M.S., Humne, V.T., Lokhande, P.D., A one-pot direct
regioselective iodination of Fischer-Borsche product using periodic acid in PEG-400, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.03.022
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A one-pot direct regioselective iodination of Fischer-Borsche product using
periodic acid in PEG-400
Monica H. Ghom, Mahavir S. Naykode, Vivek T. Humne* and P. D. Lokhande*
Centre for Advance Studies, Department of Chemistry, Savitribai Phule Pune University,
Pune-411007, India
Abstract
A metal-free and greener approach for the one-pot direct iodination and dehydrogenation of
dihydrobenzo[a]carbazoles has been developed using periodic acid in polyethylene glycol-
4
00 (PEG-400) under mild condition. This method has been proven to be tolerate to a broad
range of functional groups, with good to excellent yields include metal-free inexpensive
catalyst, easy work-up, benign reaction condition and high regioselectivity. The solvent has
been successfully recycled up to 5 times without any loss of activity in an aqueous medium.
Keywords: Regiocontrolled iodination, benzocarbazole, PEG-400, periodic acid.
Halogenation is a ubiquitous process found in the synthesis of natural and bioactive
1
substances. Halogenated carbazoles have been seen to be a significant intermediate in the
total synthesis of various carbazole natural products, including in organic materials such as
2
thermal, electrical, optical, and visible-light emitting applications. During the last few
1

decades, the development of novel protocol for the synthesis of benzo[a],[b],and[c]-
3
carbazoles has considerable attention. Various synthetic approaches have been cited in
4
a
4b
literature; Pd-catalyzed hetero- and carboannulations, Cu-catalyzed α-C-arylation, Au-
4
c
4d
catalyzed direct aryl annulation, Rh-catalyzed aryl annulation
followed by an
4
e
4f
intramolecular C(sp2)–H bond functionalization, domino annulation of indoles, tandem
4
g
cyclization/C−H functionalization of two different alkynes, cascade process involving of
4h
isocyanide insertion and benzylic C(sp3)-H activation, metalation-Suzuki-Miyaura cross-
4
i
coupling strategy. However, Fischer-Borsche synthesis is the most common practical
method used for the preparation of benzocarbazoles. In general, this involves the
condensation of phenylhydrazine and α or β-tetralone, followed by aromatization. The final
step, aromatization of dihydrobenzo[a]carbazole, is the most challenging task. To the best of
our knowledge, very few reagents are documented in the literature to afforded aromatization
process (scheme 1). Following limitations have been observed in the aromatic process; (a)
5
a
Pd/C is often used with high boiling point solvent, (b) DDQ, an organic-derived reagent is
5
b
used, and (c) transition metal-based transformations are used for the preparation of
5
c
benzocarbazoles.
Scheme 1. One-pot iodination of dihydrobenzocarbazole
Polyethylene glycol (PEG) is a well-known interesting green solvent system. The PEG used
as an environmental benign solvent has proved to have many applications, particularly, in
6
coupling, oxidation and reduction reactions. Several reviews covered PEG chemistry and its
7
applications in biotechnology and medicinal chemistry. To the best of our knowledge, direct
2

iodination and aromatization of dihydrobenzocarbazoles is not reported till date. Therefore, in
this report, we developed a direct regioselective iodination of dihydrobenzocarbazole using
periodic acid in PEG-400 under mild condition.
Table 1. Optimization of reaction condition
Product
Product
(3)
Entry Reagents
Solvent/Tempt/Time
DMSO/RT/24 h
a
(
2)
b
a
I
2
(5-100 mol%)
ND
ND
b
c
d
I
I
I
I
(
I
(
2
2
2
2
(50 mol%)
(100 mol%)
(150 mol%)
/TBHP
20 mol%/2 equiv)
/TBHP
20 mol%/2 equiv)
DMSO/100 ºC /12 h
DMSO/100 ºC /12 h
DMSO/100 ºC /12 h
81
52
ND
ND
36
67
e
f
DMSO/80ºC /12 h
ND
74
2
c
PEG-400 /RT-100 ºC /24 h
ND
ND
g
h
i
PIDA
IBX
Dess-Martin
PEG-400/ RT /12 h
PEG-400/ RT /12 h
PEG-400/ RT /2 h
ND
ND
ND
20
35
18
d
j
H
5
IO
6
(100 mol%) PEG-400/ RT /4 h
61
ND
k
H
5
IO
6
(200 mol%) PEG-400/RT /4 h
ND
80
a
b
c
d
Isolated yield
Not determined
PEG-1000 and 4000 and ethylene glycol were studied
Isolated yield with recovery of starting substance
Our experiment was started with the condensation of commercially available phenylhydrazine
and α-tetralone under acidic condition, which was ready converted to
dihydrobenzo[a]cabazole by the Fischer-Borsche synthesis. We wish to study the efficacy of
a one-pot iodination of dihydrobenzo[a]carbazole using periodic acid in PEG-400 under mild
condition. Inspired from our previous report, we studied the different proportional of iodine
8
for one-pot iodination process. A catalytic to equal-proportional of iodine in dimethyl
3

sulphoxide was employed, did not afforded the desired product at room temperature (Table 1,
entry a). To increase the temperature and molar proportional of iodine, dehydrogenated-
product was noticed (Table 1, entry b). At equal proportional of iodine, the mixture of
dehydrogenated and iodinated-products were noticed (Table 1, entry c). While, sole product
of iodination was isolated using iodine at 100 ºC (Table 1, entry d). Addition of oxidant lead
to gradual increase of yield of 3 (Table 1, entry e). Literature survey shows that there is no
report found for one-pot direct iodination and aromatization of dihydrobenzo[a]carbazole
through greener approach. Previous, we reported the regioselective deallylation protocol
9
using molecular iodine in PEG-400. To make the greener synthetic protocol, the same
condition was used for one-pot direct iodination of dihydrobenzo[a]carbazole, the desired
product was not observed. (Table 1, entry f). The reason was might be iodine in PEG was
unable to afford strong oxidised reagent. Based on these results, we encouraged to study the
different oxidising-reagents for one-pot iodination of dihydrobenzo[a]carbazole. Therefore,
we studied the various type of commercially available oxidising reagents having iodine-
source (Table 1, entry g-i). Unsatisfactory yields were obtained with these reagents. However,
when equal proportional of periodic acid was applied in PEG-400 afforded the
dehydrogenated product in 61% yield (Table 1, entry j). To our delight, two-fold of periodic
acid in PEG-400 give the iodinated product in good yield at room temperature (Table 1, entry
k). Therefore, the most befitting reagent was found to be periodic acid in PEG-400.
To understand the role of polyethylene glycol (PEG) as a reaction medium, we also
performed the one-pot iodination of same substrate in ethylene glycol, triethylene glycol and
other glycols such as PEG-600, PEG-4000, PEG-6000 and PEG-8000. In ethylene glycol and
triethylne glycol, the product was observed in low yield (28 and 24%). However, as the
molecular weight of PEGs increases, the viscosity increases. Because of this reason, we
raised the temperature up to 70ºC to liquefy the PEG. However, the increase of temperature
4

did not affect the yield of the one-pot iodinated product 3. Thus, polyethylene glycol-400
established as a best reaction solvent for this condition.
a
Scheme 2. Reaction scope of one-pot iodination of dihydrobenzocarbazole
a
Reaction condition: Substrate 4 (0.9 mmol), periodic acid (1.8 mmol) in PEG-400, RT
To test the substrate scope, we examined the transformation with a variety
dihydrobenzo[a]carbazole 4a–n under the optimized reaction condition (Scheme 2). All N-
alkyl dihydrobenzo[a]carbazoles furnished the corresponding iodo-products 5a-d in good to
5

excellent yield. While N-allyl dihydrobenzo[a]carbazole 5e did not work under optimal
condition, this might be due the interactive nature of allyl group with iodine. Thereafter, we
investigated the eff ect of substituents at the 3- and 8-position of dihydrobenzo[a]carbazoles.
The 3-methoxy derivative gave their corresponding regioselective iodo-product 5f in good
yield. Similarly, regioselective iodination was occurred at the 5-position of
dihydrobenzo[a]carbazole when the 3 and 8-position was secured by other functionalities. All
the regioselective iodo-products 5g-n obtained in good to excellent yield. This concluded that
there is no effect of substituent on regioselective iodination process.
The plausible mechanism is shown in scheme 3. The dihydrobenzo[a]carbazole has
susceptible to reduce the oxidation state of periodic acid, converted to iodic acid through the
dehydrogenation process. The excess of periodic acid might be help for protonation. The
resulting iodic acid could strongly be chelated with PEG-400 to afforded the iodinated
10
product.
5 6
Scheme 3. Proposed mechanism for one-pot iodination using H IO in PEG-400
To investigate the scalability of one-pot iodination process, 4a was studied on 3 g scale.
Gratifyingly, the reaction proceeded to generate 5a in 90% yield after 6 hours. To determine
the reusability of the solvent, the reaction mixture was extracted with ethylacetate. The
combined organic layer was dried over anhydrous sodium sulphate and solvent was
6

evaporated. The remaining mother liquor was subjected to vacuum distillation to remove
water leaving PEG behind in the container. The recovered PEG was subjected to charge same
substrate 4a under optimal condition to achieved 86-90% yield of 5a up to five times without
loss of its activity.
In conclusion, we report for the first time the synthesis of one-pot direct regioselective
iodination and dehydrogenation of dihydrobenzo[a]carbazoles using periodic acid in PEG-
4
00 at room temperature. The present method proven to be convenient and greener over the
conventional method. Other features of the present process are; the usage of recyclable and
reusable solvent; a good substrate scope with good to high yields and ease of scale-up. In
addition, the reaction opens up a new avenue for cheap, convenient, and green synthesis of
iodo-derived benzocarbazoles.
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Highlights of the work





Iodination is a well-known process used for the various organic transformations.
Direct regioselective iodination and dehydrogenation was achieved in one-pot.
The present method is metal-free and greener.
Various novel iodo-substituted benzo[a]carbazoles have been synthesized.
Resulting 5-iodo-benzo[a]carbazoles could have valuable significant in organic
chemistry and material chemistry.
1
0