Total synthesis of diverse oxygenated carbazoles by modified aromatization using molecular iodine

Article abstract of DOI:10.1016/j.tetlet.2016.01.002

A convenient route has been developed for mono and dioxygenated carbazole alkaloids from 1-oxotetrahydrocarbazoles. The key step of the synthetic route is the aromatic process of 1-oxotetrahydrocarbazoles using molecular iodine. To our knowledge, this is

Full text of DOI:10.1016/j.tetlet.2016.01.002

Accepted Manuscript
Total synthesis of diverse oxygenated carbazoles by modified aromatization
using molecular iodine
Vivek T. Humne, Mahavir S. Naykode, Monica H. Ghom, Pradeep D. Lokhande
PII:
S0040-4039(16)30002-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.002
TETL 47166
Reference:
Tetrahedron Letters
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6 October 2015
31 December 2015
2 January 2016
Please cite this article as: Humne, V.T., Naykode, M.S., Ghom, M.H., Lokhande, P.D., Total synthesis of diverse
oxygenated carbazoles by modified aromatization using molecular iodine, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.01.002
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Graphical Abstract
Total synthesis of diverse oxygenated
carbazoles by modified aromatization using
molecular Iodine
Leave this area blank for abstract info.
Vivek T. Humne, Mahavir S. Naykode, Monica H. Ghom, Pradeep D. Lokhande
Iodine mediated aromatic process
Fuctional group transformation
R2
R1O
Oxo-formation
N
OR3
H
Fischer-Borsche synthesis
1- and 1,6-Dioxygenated carbazole alkaloids

1
Tetrahedron Letters
Total synthesis of diverse oxygenated carbazoles by modified aromatization using
molecular iodine
Vivek T. Humne,* Mahavir S. Naykode, Monica H. Ghom, Pradeep D. Lokhande*
Center for Advance Studies, Department of Chemistry, Savitribai Phule Pune University (Formerly University of Pune),
Pune-411007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient route has been developed for mono and dioxygenated carbazole alkaloids from 1-
oxotetrahydrocarbazoles. The key step of the synthetic route is the aromatic process of 1-
oxotetrahydrocarbazoles using molecular iodine. To our knowledge, this is the first report to
manifest a direct synthesis of clausine E, mukonine, mukoeic acid and mukoline, from readily
available ester-containing building blocks by using Fischer-Borsche method.
Available online
Keywords:
Molecular iodine
2009 Elsevier Ltd. All rights reserved.
Aromatization
1-oxygenated carbazoles
1,6-dioxygenated carbazoles
Carbazole alkaloids are the important class of nitrogen
containing heterocycles present in many natural products and
pharmaceutical ingredients.1 Fischer-Borsche is the widely use
practical method of its metal-free protocol, good regiospecificity,
high yield and easy purification.2 This process involves the
condensation of phenylhydrazine with cyclohexanone, followed
by aromatization. Moreover, applications of the Fischer -Borsche
synthesis has been abound in various total synthesis of complex
natural products.3
The oxygenated carbazoles are attracted a great interest due to
their diverse and significant biological activities.4 Many synthetic
approaches has been carried out for oxygenated carbazoles by
using transition metals5 but very few routes has been known from
Fischer-Borsche method in the literature. However, following
drawbacks are noticed in the conventional process of Fischer-
Borsche process; (a) difficult to introduce oxygen functionality at
the appropriate position of carbazole scaffold, (b) longer reaction
time and high temperature are required in the final step of
aromatization, (c) protection and deprotection steps are required,
and (d) low overall yield. Therefore, most of the research groups
divert their synthesis from Fischer-Borsche protocol. We
reasoned that the readily available precursor would constitute
diversity oriented new approach to this important class of
compound. Therefore, development of aromatic process of 1-
oxotetrahydrocarbazole and their utility to construct the diverse
1- and 1, 6-dioxygemated carbazole alkaloid is exceedingly
desirable.
Figure 1. Natural occurring 1- and 1, 6-dioxygenated carbazoles
A cytotoxic carbazole alkaloid; koenoline7 and their easily
oxidizable murrayanine derivative were obtained from the Indian
M. koenigii.8 Mukoline and Mukolidine were isolated from
Murraya koenigii Spreng, and their extract exhibited antibacterial
activity (Figure 1).9 Recently, mukoline and mukolidine has been
synthesized from aryl amine with the combine treatment of
palladium (II) acetate and copper (II) acetate in pivalic acid.10
Including, Nozaki and his co-workers investigated the double N-
arylation of primary amines with 2,2’-biphenylylene ditriflates
for mukonine.11a Mal and his co-workers11b,c introduced [4+2]
annulation process starting from furoindolones and dimethyl
maleate. Traditionally, Saha et al11c,d attempted 1-oxygenated
carbazoles using Japp-Klingemann method.
Of particular interest are 1,6-dioxygenated carbazoles,
Chakraborty et al isolated clausenol and clausenine from the dried
stem bark of Clausena anisata (Figure 1).12 Both alkaloids show
antibiotic activities, among these clausenol was found to be more
active, and their inhibition against other bacteria can be compared
Mukoeic acid, the first carboxylic acid derivative of 1-
oxygenated carbazole was isolated from the bark of Murraya
koenigii and their ester derivatives such as mukonine and
clausine E were isolated from the plants of the Rutaceae family.6

2
Tetrahedron Letters
to streptomycin. Despite these intensive investigations, there are
only four synthetic reports are documented: (a) condensation of
substituted cyclohexanone with 4-methoxybenzene diazonium
chloride under Japp-Klingemann condition,12 (b) Lin and Zhang
derived biscarbazoles via the formation of clausenol by Suzuki
cross-coupling,13 (c) Knölker et al attempted Buchwald–Hartwig
amination followed by palladium(II)-catalyzed oxidative
cyclization,14 (d) Fagnou and his co-workers described the
palladium based coupling protocol for clausenine.15
good yield.16 Initially, 2a was our model substrate to study the
efficacy of the aromatic process. In continuous of our work based
on iodine-mediated transformations,17a,b recently, we reported the
aromatization of tetrahydrocarbazoles using a catalytic amount of
molecular iodine.17c,d When similar condition was employed, no
remarkable change was observed. Previously, it was found that
Oliveria et al. aromatized the similar kind of motif in two steps;
(a) introduction of bromo group at α-position of 1-
oxotetrahydrocarbazole and, (b) followed by aromatization using
LiBr/Li2CO3 in DMF.18 To accompany Oliveria protocol, we
synthesized α-bromo requisite (3a) was aromatized by using
LiBr/Li2CO3 in DMF to lead clausine E (4a) with 76% yield. On
Table 1. Aromatization of 1- oxotetrahydrocarbazole under
different reaction conditions
Scheme 1. Retrosynthetic analysis
Entry
Condition
Time (h)
2
Yield (%)a
3a/4a
A concise retrosynthetic analysis of oxygenated carbazole
alkaloids is represented in scheme 1. We designed the diverse 1-
and 1, 6-dioxygenated carbazoles from 1-oxotetrahydrocarbazole,
a18 LiBr, Li2CO3, DMF, 120 ºC
NDc/69
as
a
key intermediate. The aromatic process of 1-
LiHMDS, THF:HMPA, -78
b19
oxotetrahydrocarbazole could furnish the respective target
molecules followed by functional group transformations. The
appropriate tetrahydrocarbazoles could conceive from the
commercial available starting materials by Fischer-Borsche
method. The elegant of our synthesis is to introduced hydroxyl
and ester-functionality at the appropriate position of carbazole
scaffold.
1
8
ND/48
ºC then PhNTf2 in THF
c
I2, KBr, DMSO, 100 ºC
ND/ND
d
e
I2, NaBr, DMSO, 100 ºC
I2, LiBr, DMSO, 80 ºC b
6
1
47/ND
ND/87
a Isolated yield
b Different proportion of I2 and LiBr were screened
c ND = Not determine
careful search of a literature, Sissouma et al19 proposed the total
synthesis of Calothrixin B without protection of indole nitrogen
by using enolate formation, followed by dehydrogenation.
Enolate of substrate 2a was trapped by triflate and
dehydrogenated in situ (Table 1, entry b). In this case, the
aromatic product 4a was isolated with moderate yield after
deprotection process.
Scheme 2. Synthesis of 1-oxotetrahydrocarbazole
We started our experiment from commercially available
phenylhydrazine and cylcohexanone, which readily converted to
appropriate tetrahydrocarbazoles by Fischer-indolization. The 1-
oxo-tetrahydrocarbazole-6-methylcarboxylate
(2a-b)
was
obtained from 1a-b by treating with periodic acid in methanol in

3
The enolation of substrate 2a followed by oxidative
dehydrogenation by molecular iodine could reduce the total steps
and increase the overall yield. We screened the different set of
reaction conditions to aromatize the substrate 2a (Table 1). To
avoid the expensive catalyst and harsh condition, we tried
different types of readily available salts, but these salts did not
afford the desired product 4a. However product 3a was isolated
with 47% by the combined treatment of NaBr and iodine in
DMSO at 100 ºC (Table 1, entry d). The combination of LiBr (1
equiv.) and molecular iodine (25 mol%) in DMSO at 80 ºC lead
to increase the yield of clausine E 4a (Table 1, entry e, 87%).
Further increase the amount of molecular iodine did not
significantly affect the reaction yield. In the next step, o-
methlyation was carried out by diazomethane in methanol to
afford mukonine (5a) in 98% yield.20 Treatment of 5a with 10%
NaOH in methanol accomplished the mukoeic acid (6) with
excellent yield. However, under similar optimal condition, we
have successfully achieved isomer 5b from 2b.
In conclusion, we have demonstrated a convenient, general
and flexible synthesis for the diverse structure of carbazole
alkaloids with good to excellent overall yields. In the present
approach, construction of a suitably substituted basic carbazole
framework in just 4-5 steps by modifying the aromatization
process is remarkable. The present method is expedient and
elegant furnishes an alternative method to aromatic process.
Syntheses of these alkaloids have been accomplished without
involving any discrete protection-deprotection steps. Further
studies on the synthesis of other carbazole alkaloids and their
analogues with additional biological studies are currently in
progress and will be reported in due course.
Acknowledgments
VTH is thankful to CSIR, New Delhi, India, for the award of a
senior research fellowship and MSN is thankful to UGC, New
Delhi, India, for the award of a senior research fellowship. We
thanks Dr, Santosh Misal, Indiana University Bloomington,
Indiana, USA for helpful discussion.
To our delight, 5a-b on our hand, we turn our synthesis to
diverse structure of carbazoles from a single precursor. The
substrates 5a-b were reduced to their corresponding alcohols 7a-
b
by lithium aluminium hydride in THF under reflux
References and notes
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