One-pot access to tetrahydrobenzo[c] carbazoles from simple ketones by using O2 as an oxidant

Article abstract of DOI:10.1039/c9ob02751c

An effective and operationally simple one-pot Br?nsted acid catalyzed cascade method is demonstrated for the synthesis of diversely functionalized carbazole frameworks starting from protecting group free 2-alkenyl indoles. The employment of easily availab

Full text of DOI:10.1039/c9ob02751c

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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/C9OB02751C
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PAPER
One-pot access to tetrahydro benzo[c]carbazole from simple
ketones by using O2 as oxidant
Shuvendu Saha and Modhu Sudan Maji*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An effective and operationally simple one-pot Brønsted acid Owing to the ever-increasing potential applications of aza-
catalyzed cascade method is demonstrated for the synthesis of heterocycles, the facile and efficient methods are still required
diversely functionalized carbazole frameworks starting from for acquiring polyfunctionalized carbazoles which will be the
protecting group free 2-alkenyl indoles. The employment of easily immediate precursors of benzo[c]carbazoles4-5 in one-pot
available unactivated ketones as annulating partners, mostly pathway.6
A plethora of synthetic approaches for the
unexplored for the synthesis of carbazoles, is the major highlight of construction of carbazoles can be categorized into two primary
this protocol. This protocol is step- and atom-economic, molecular modes, first, construction of the internal pyrrole ring from
oxygen was used as the green oxidant, water was the only by- arene frameworks through C–C7 or C–N8 bond formation. A
product and amenable to different functional groups. Moreover, second strategy, namely benzannulation,9 has gained increasing
gram-scale synthesis and downstream modification of the obtained importance in the recent years due to ready access to the
products demonstrate the synthetic applicability of this protocol.
diverse indole derivatives. However, these protocols often
entail multistep endeavours, harsh reaction conditions,
restricted to specific starting materials, use of precious metal
catalysts and required either stoichiometric amount of
expensive oxidant or dehydrogenating agent like DDQ or Pd/C,
thus revealing their limitations.
Carbazoles and benzocarbazoles are privileged class of aza-
heterocycles embedded in many naturally occurring alkaloids
and synthetic compounds that exhibit a wide range of attractive
biological activities (Figure 1).1-2
Fig. 1. A few significant carbazole derivatives.
Scheme 1 Previous Reports and this Strategy.
In addition, these aza-heterocycles serve as key building blocks
for the design of OLED materials, electroluminescent and hole
transport materials, and photoconductors due to their wide
band gap and promising optoelectronic properties.3
Therefore, devising elegant approach is highly desirable to
access diversely functionalized carbazoles by employing readily
available starting materials as well as catalysts in order to curtail
the aforementioned limitations. Inspired by the synthetic
challenges, and as a part of our continuing research program on
Brønsted acid catalysis,10 we anticipated that carbazole can be
prepared by one-pot Brønsted acid catalyzed benzannulation
pathway using simple and ubiquitous ketones, specifically cyclic
Department of Chemistry, Indian Institute of Technology Kharagpur,
Kharagpur 721302, India. E-mail: msm@chem.iitkgp.ac.in.
†Electronic Supplementary Information (ESI) available: For ESI and NMR spectra See
DOI: 10.1039/x0xx00000x
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ketones. But comparatively lesser reactivity of ketones due to reaction using air as a source of the molecular oxygen, yield of
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DOI: 10.1039/C9OB02751C
the lack of electrophilic nature and steric influence make the the reactions diminished significantly (entry 9). On conducting
nucleophilic attack more challenging. In 2018,10b our group have the reaction under N2 instead of oxygen, yield of the reaction
reported a benzannulation strategy using active methylene decreased drastically (entry 10). The (E)-2a was more effective
group to get versatile substituted carbazoles, however under as the corresponding (Z)-isomer provided 3aa in 75% yield
the similar reaction conditions ketones failed to provide (entry 11). On decreasing the reaction temperature, the yield of
carbazoles (Scheme 1). These challenges prompted us to the reaction decreases drastically due to incomplete
develop a fresh route to handle the problem and, herein, we consumption of different intermediates (entry 12).
reveal our result on Brønsted acid catalyzed one-pot cascade
benzannulation strategy using simple ketones as annulating
partner to access wide varieties of NH-free carbazoles. To our
delight, advancement of this method has been achieved via
curtailing multistep sequential method to one pot cascade
annulation strategy using oxygen11 as sole oxidant.12 This
method showed an excellent route for the rapid generation of
benzo[c]carbazoles precursors from 2-alkenyl indoles in one
pot. Worthy to mention, this method does not require first
generation of 3-alkenyl indole via sulfone formation strategy.10a
Table 1. Optimization of the Reaction Conditionsa
aReaction conditions: 2a (0.20 mmol), 1a-1l (0.40 mmol), A (15 mol%), EtOAc-decalin,
180 oC; isolated yield. b3ae was isolated along with its second regioisomer.
Scheme 2 Scope of Electrophilesa.
entry acid cat.
(mol%)
solvent
Temp (oC)
180
yield (3aa%)b
1
25
EtOAc-decalin
75
2
3
25
25
25
25
15
10
15
15
15
15
15
EtOAc-decalin
EtOAc-xylene
EtOAc-DMSO
decalin
130
180
180
180
180
180
180
180
180
180
130
53
51
4
ND
<10
81
5
6
EtOAc-decalin
EtOAc-decalin
EtOAc-decalin
EtOAc-decalin
EtOAc-decalin
EtOAc-decalin
EtOAc-decalin
7
61
8c
9d
10e
11f
12
43
55
<10
75
37
c
aReaction conditions: 1a (0.30 mmol), 2a (0.15 mmol). bIsolated yield. PTSA·H2O
was used as catalyst. dAir as oxidant. eN2 in place of O2. f(Z)-2a was used in place of
(E)-2a.
Keeping this strategy in mind, the optimization of the
reaction conditions was initiated by choosing (E)-2-styryl-1H-
indole 2a and commercially available cyclohexanone 1a as
model substrates under molecular oxygen as sole oxidant. By
conducting the reaction using readily available diphenyl
phosphate as catalyst (25 mol%) in EtOAc-decalin mixed solvent
aReaction conditions: 2b-2o (0.20 mmol), 1a (0.40 mmol), A (15 mol %), EtOAc-decalin,
180 oC; isolated yield.
Scheme 3 Scope of 2-alkenylindolesa.
o
at 180 C furnish carbazole 3aa in 75% yield (Table 1, entry 1).
On decreasing the reaction temperature, the yield decreased to
53% (entry 2) and other mixed solvents did not give better
outcome (entries 3-5). Upon varying the catalyst loading,
highest yield of 3aa was recorded when 15 mol% catalyst was
employed (81%, entries 6-7). Yield of the reaction decreased to
43% upon employing a stronger Brønsted acid catalyst (entry 8).
It has been found that concentration of oxygen plays a crucial
role for the oxidative aromatization reaction as on executing the
To study the generality of this tandem benzannulation, at first
several cyclic or acyclic ketones bearing no active methylene
group were reacted with 2a
.
Cyclopentanone and
cycloheptanone provided carbazoles 3ab and 3ac in modest
yields (Scheme 2). 4-tert-Butylcyclohexanone also reacted
smoothly to furnish carbazole 3ad in 57% yield. When
unsymmetrical cyclohexanone was utilized, a mixture of
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regioisomers 3ae and 3ae' were isolated in 67% overall yield (in In conclusion, we have demonstrated an efficient, Brønsted acid
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DOI: 10.1039/C9OB02751C
4.4:1 ratio). To our delight, acetone was found to be an elegant catalyzed one-pot benzannulation strategy to access a rich
annulating partner furnishing carbazole 3af in 65% yield. assortment of diversified carbazoles from a variety of 2-
Pleasingly, even less reactive aryl ketones, namely alkenylindoles and appropriate ketones. Molecular oxygen as
acetophenone and acetylpyridines delivered carbazoles 3ag-3ai the green oxidant and water as sole by-product render this
in moderate yields. 1,4- and 1,2-Cyclohexanediones also method economically as well as environmentally benign. In
reacted well to afford carbazoles 3aj and 3ak bearing a ketone addition, efficacy of this new protocol has been reinforced
functional group and hence providing opportunity for further through gram scale synthesis and easy aromatization to furnish
downstream modifications. Butanedione and acetyl benzoyl are benzocarbazole compounds.
also suitable annulating partners to provide carbazoles 3al and M.S.M. gratefully acknowledge Council of Scientific & Industrial
3am bearing a ketone moiety at the 4-position. The sterically Research, India (Sanction No. 02(0322)/17/EMR-II) for funding.
hindered cyclopropyl methyl ketone and pinacolone failed to SSH sincerely thanks UGC India for fellowships.
provide desired carbazoles.
Subsequently, a variety of substituted 2-alkenylindoles 2b-2o
were screened using cyclohexanone as an annulating partner.
The 2-alkenylindoles bearing methyl, methoxy and chloride
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