Tert -Butylhydroperoxide-Mediated Oxidation of Carbazole-3-carboxyaldehydes

Article abstract of DOI:10.1055/s-0036-1591897

Oxidation of carbazole-3-carboxyaldehydes promoted by a 70% aqueous solution of tert -butylhydroperoxide leads to the corresponding carbazole-3-carboxylic acids in good yields. This transition-metal-free oxidation protocol is attractive for the synthesis of pharmaceutically important carbazole analogues.

Full text of DOI:10.1055/s-0036-1591897

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
A
en
Synlett
R. Meesala et al.
Letter
tert-Butylhydroperoxide-Mediated Oxidation of Carbazole-3-
carboxyaldehydes
Ramu Meesala*a
Ahmad Saifuddin Mohamad Arshadb
Mallikarjuna Rao Pichikaa
Mohd Nizam Mordib
Sharif Mahsufi Mansorb
O
O
R'
R'
H
OH
TBHP (6.0 equiv)
DMSO, 100 °C, 12 h
N
R
N
R
61–72%
R = Et, CH2Ph
R' = H, Me, Br, OEt, NO2
a
Department of Pharmaceutical Chemistry, International Medical
University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala
Lumpur, Malaysia
b
Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden,
Penang, Malaysia
meesalaramu@gmail.com
6
Received: 07.11.2017
Accepted after revision: 26.12.2017
Published online: 29.01.2017
reagent (CrO /H SO /acetone) or manganese salts. Howev-
3
2
4
7
er, these methods produce toxic Mn and Cr by-products.
Methods involving metal-free reagents such as oxone,
biomimetic-flavin,
been reported to perform this transformation. Various al-
ternative metal-mediated oxidations employing Ca, Ni,
Se, Mg, W, Co, Pd, V, Mo, and Au have also been
reported. Mixtures of an oxidant, tert-butylhydroperoxide
or H O , and a metal catalyst such as CuCl, AgNO3,
8
DOI: 10.1055/s-0036-1591897; Art ID: st-2017-d0822-l
porphyrin sensitizer,9 NHC,
10
11
have
Abstract Oxidation of carbazole-3-carboxyaldehydes promoted by a
70% aqueous solution of tert-butylhydroperoxide leads to the corre-
12
13
sponding carbazole-3-carboxylic acids in good yields. This transition-
metal-free oxidation protocol is attractive for the synthesis of pharma-
ceutically important carbazole analogues.
14
15
16
17
18
19
20
21
22
23
2
2
Key words oxidation, carbazole-3-carboxyaldehyde, carbazole-3-
carboxylic acid, tert-butylhydroperoxide, dimethyl sulfoxide (DMSO)
24
Bi O , have also been reported to perform this transfor-
2
3
mation. With regard to oxidation of carbazole-3-aldehydes
to the corresponding carbazole-3-carboxylic acids, only
Carbazole alkaloids have been isolated from animal,
plant, microbial, and marine sources. They exhibit antitu-
KMnO425 and MnO /KCN in MeOH followed by subsequent
2
1
26
basic hydrolysis have been reported. However, the Mn
mor, anti-inflammatory, antimalarial, antiviral, antibiotic,
anti-HIV, psychotropic, antihistaminic, antioxidative, and
antituberculosis activities. Carbazole derivatives have also
side products formed in these methods are potentially envi-
ronmentally polluting. Hence, the development of a simple
and economical method for the oxidation of carbazole-3-
aldehydes remains a goal.
7
been applied for the treatment of ischemic heart disease,
congestive heart failure and hypertension.[
1−3]
Naturally
Aqueous tert-butylhydroperoxide (TBHP) is a powerful
oxidant and this, combined with its stability and low toxici-
ty, mean that it is an appropriate reagent for manufacturing
occurring carbazole-3-carboxylic acid alkaloids, for example
mukoeic acid, isomukonidine, clausine K, and pityriazole
Figure 1), also exhibit promising biological activities.4
processes. Herein, we describe an efficient transition-
27
(
metal-free method for the direct oxidation of carbazole-3-
carboxyaldehydes to the corresponding carbazole-3-
carboxylic acids by employing aq 70% TBHP (6.0 equiv) in
DMSO at 100 °C.
O
O
O
OH
OH
OH
OH
OMe
R
N
N
H
We commenced our studies by examining the reaction
of 9-ethyl-carbazole-3-carboxyaldehyde (1a) in the pres-
ence of 1.0 and 3.0 equivalents of aq 70% TBHP in DMSO at
room temperature for 12 hours, but there was no reaction
N
H
OMe
H
Mukoeic acid
Isomukonidine (R = H)
Clausine K (R = OMe)
Pityriazole
N
H
Figure 1 Naturally occurring carbazole-3-carboxylic acid alkaloids
(Table 1, entries 1and 2). However, when the reaction was
carried at 50 °C, product formation was observed (entry 3).
The best outcome was obtained by employing 6.0 equiva-
lents of TBHP in DMSO at 100 °C for 12 hours (entry 5). Fur-
ther increasing the number of equivalents of TBHP led to no
improvement in yield (entry 6).
Synthesis of carboxylic acids by oxidation of various
substrates is one of the fundamental transformations in
5
organic synthesis. Generally, carboxylic acids can be pre-
pared by the oxidation of aldehydes employing Jones’
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

B
Synlett
R. Meesala et al.
Letter
Table 1 Screening of the Reaction Conditions
In summary, we have demonstrated a transition-metal-
free, simple, and inexpensive method for oxidation of
carbazole aldehydes to furnish the corresponding acids in
good yields. The economical and environmental friendly
nature of the TBHP oxidant and compatibility with a variety
of substrates make this protocol useful for the synthesis of
carbazole analogues, particularly in the pharmaceutical
arena.
CHO
COOH
TBHP
DMSO, 100 °C, 12 h
N
N
Et
Et
1a
2a
Entry
TBHP (equiv)
Temp (°C)
Yield (%)a
1
2
3
4
5
1
3
3
3
6
8
RT
RT
nrb
nr
Funding Information
This work was supported by a Ministry of Science, Technology and
Innovation grant (06-02-09-SF0041), the International Medical Uni-
versity, Malaysia and Research University (RUI) Grant Scheme
50
25
53
65
66
100
100
100
(1001/CDADAH/811257), Universiti Sains Malaysia.
)(
6
a
Supporting Information
Isolated yield.
nr = no reaction.
b
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591897.
S
u
p
p
o
nrtogI
i
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
Using the optimized reaction conditions, we examined
the oxidation of a variety of carbazole-3-carboxyaldehyde
28
derivatives to explore the scope and generality of the
reaction (Scheme 1). Carbazole-3-carboxylic acids were
furnished in good yields and substituents such as methyl,
ethoxy, bromine, nitro at C-6 and ethyl, benzyl at C-9 were
tolerated well. The products were fully characterized by IR,
References and Notes
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Scheme 1 Synthesis of carbazole-3-carboxylic acids
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–1
IR (KBr): 3458, 2925, 1678, 1597, 1469, 1382, 1230, 724 cm
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2
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C