Br?nsted acidic ionic liquid catalyzed synthesis of benzo[a]carbazole from renewable acetol and 2-phenylindoles in a biphasic system

Article abstract of DOI:10.1016/S1872-2067(19)63370-X

An efficient metal-free strategy for the synthesis of pharmaceutically relevant benzo[a]carbazoles from the derivatives of readily available 2-phenylindole and bio-renewable acetol in an aqueous biphasic system was developed. This protocol employed a sulfone-containing Br?nsted acidic ionic liquid as the catalyst, which could be used for five times without a noticeable decrease in its activity and selectivity. Various substituted 2-phenylindoles and α-hydroxyketones participated in the reaction smoothly, with water as the sole byproduct. Mechanistically, the reaction involved the conventional carbon-nucleophile-induced Heyns-type rearrangement and downstream intramolecular olefination.

Full text of DOI:10.1016/S1872-2067(19)63370-X

Chinese Journal of Catalysis 40 (2019) 1135–1140
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Communication
Brönsted acidic ionic liquid catalyzed synthesis of
benzo[a]carbazole from renewable acetol and
2-phenylindoles in a biphasic system
Minghao Li a, Fengtian Wu a, Yanlong Gu a,b,
*
a Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key Laboratory of Material Chemistry and
Service Failure, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000,
Gansu, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient metal-free strategy for the synthesis of pharmaceutically relevant benzo[a]carbazoles
from the derivatives of readily available 2-phenylindole and bio-renewable acetol in an aqueous
biphasic system was developed. This protocol employed a sulfone-containing Brönsted acidic ionic
liquid as the catalyst, which could be used for five times without a noticeable decrease in its activity
and selectivity. Various substituted 2-phenylindoles and α-hydroxyketones participated in the reac-
tion smoothly, with water as the sole byproduct. Mechanistically, the reaction involved the conven-
tional carbon-nucleophile-induced Heyns-type rearrangement and downstream intramolecular
olefination.
Received 13 March 2019
Accepted 3 April 2019
Published 5 August 2019
Keywords:
Benzo[a]carbazole
Brönsted acid ionic liquid
Bio-renewable acetol
2-Phenylindole
© 2019, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
The realization of simple and green synthetic procedures is
an important goal in organic synthesis [1,2]. In this context,
tandem reactions have been widely adopted to combat the
tedious operational procedure associated with multistep syn-
thesis [3–8]. While many acid-catalyzed tandem reactions have
been developed [9,10], the ever-increasing demand for novel
molecules with biological and material uses and the laborious
process of the conventional stepwise synthesis have resulted in
the continuous search for developing simple and efficient tan-
dem reactions.
Acetol can be readily produced through the staged pyrolysis of
biomass at low temperatures of 200−300 °C [15]. Although
some acetol-derived heterocycles including pyrazine [16], oxa-
zoline [17], furan [18], and quinoxaline [19] have been report-
ed, incorporating acetol into novel heterocycles is still desired.
The synthesis of benzo[a]carbazoles has garnered much at-
tention due to their wide application in medicinal chemistry
(compounds A and B in Scheme 1) and photographic materials
(compound C in Scheme 1) [20–24]. Numerous synthetic
methodologies have been developed to construct this privi-
leged core material in the past few decades [25–38]. Among
those, protocols with 2-phenylindole as the starting material
have recently emerged as one of the most appealing methods
Incorporation of renewable chemicals into heterocycles
constitute one of the important ways to valorize biomass,
which also follow the principles of green chemistry [11–14].
* Corresponding author. Tel: +86-27-87543032; Fax: +86-27-87543632; E-mail: klgyl@hust.edu.cn
This work was supported by the National Natural Science Foundation of China (21761132014, 21872060), the Fundamental Research Funds for the
Central Universities of China (2016YXZD033), the Fundamental Research Funds for the Central Universities (2019kfyXJJS072), and Opening fund of
Hubei Key Laboratory of Material Chemistry and Service Failure (2017MCF01K).
DOI: S1872-2067(19)63370-X | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 40, No. 8, August 2019

1136
Minghao Li et al. / Chinese Journal of Catalysis 40 (2019) 1135–1140
Table 1
AcO
Ph
Ph
Reaction of 1a and 2a under homogeneous conditions.
O
N
N
N
OAc
H
H
B: antiestrogenic property
A: antitumor activity
C: photochromic material
R
Tsuchimoto and Shirakawa's work
OMe
ln(Nf)3
(1)
+
N
H
R
N
H
R1
R2
Jiao's work
[Pd] / O2
R1
R2
Entry
1
2
3
4
5
6
7
8
Catalyst
LiBr
H3BO3
ZnCl2
BiCl3
Al(OTf)3
Sc(OTf)3
Cu(OTf)2
PTSA
TfOH
TfOH
Solvent
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
MeNO2
MeCN
1,4-Dioxane
DCE
Toluene
EtOH
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2-H2O
EtNO2-H2O
EtNO2-H2O
EtNO2-H2O
Yield of 3a (%)
+
(2)
(3)
N
H
ND
ND
ND
15
32
35
33
34
37
28
19
ND
8
ND
ND
35
32
45
92
90
77
62
68
N
H
R1
R2
Zhang and Fan's work
O
[Rh] / [Cu]
R2
R1
+
N
H
N
H
N2
Our previous work
O
O
BiCl3
(4)
+
9
Br
N
H
N
H
10
11
12
13
14
15
16 a
17 a
18 a
19 b
20 b,c
21 b,c
22 b,c,d
23 b,c,e
TfOH
TfOH
TfOH
TfOH
This work
O
Acidic IL
OH
+
(5)
N
H
N
TfOH
Scheme 1. Benzo[a]carbazole analogues and the approaches for their
TfOH-4a
TfOH-4b
TfOH-4c
TfOH-4c
TfOH-4c
TfOH-4d
TfOH-4c
TfOH-4c
synthesis from 2-phenylindole.
since elaborate design and multistep synthesis of the starting
material is avoided. However, until now there have been only
four approaches to implement this transformation as shown in
Scheme 1: (1) In(ONf)3-catalyzed [4+2] benzannulation with
propargyl ethers (Eq. (1)) [39,40], (2) palladium-catalyzed
aerobic-oxidative cycloaromatization with internal alkynes (Eq.
(2)) [41], (3) Rh(III)-catalyzed cascade reactions with α-diazo
carbonyl compounds (Eq. (3)) [42,43], and (4) BiCl3-catalyzed
benzannulation with α-bromoacetaldehyde (Eq. (4)) [44]. Con-
sidering the versatility of benzo[a]carbazoles, the development
of novel methods, such as metal-free methods, to synthesize
this structural motif from readily available starting materials
are in demand. Herein, we report for the first time, the
Brönsted acidic ionic liquid (BAIL)-catalyzed synthesis of ben-
zo[a]carbazole from 2-phenylindole (Eq. (5), Scheme 1) in a
biphasic system with the following features: (1) renewable
counter-reagent, (2) recyclable catalyst, (3) high atom economy
(with water as the sole byproduct), and (4) high chemoselec-
tivity.
We commenced our study with acetol and 2-phenylindole in
nitroethane at 95 °C. As shown in Table 1, no reaction occurred
by employing weak acid catalysts such as LiBr and H3BO3 (Ta-
ble 1, entries 1 and 2). ZnCl2 did not catalyze the reaction either
(Table 1, entry 3). However, the product (3a) was formed, al-
beit in a very low yield, when BiCl3 catalyst wasused (Table 1,
entry 4). Strong acids such as Al(OTf)3, Sc(OTf)3, Cu(OTf)2,
PTSA and TfOH were also examined for their catalytic activity
(Table 1, entries 5–9). However, the maximum yield reached
only 37% with TfOH (Table 1, entry 9). We then attempted to
examine the change in the yield using organic solvents such as
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), TfOH (10 mol%),
solvent (1.0 mL), zwitterion (0.25 g, if mentioned) at 95 °C for 1 h, iso-
lated yield. 1.0 equivalent of zwitterion based on TfOH. b 20.0 equiva-
a
lents (250.0 mg) of zwitterion based on TfOH. c 8.0 equivalents of water
based on zwitterion. d 60 °C. e 30 min.
nitromethane,
acetonitrile,
1,4-dioxane,
and
1,2-dichloroethane, but there was no increase in the yield (Ta-
ble 1, entries 10–13). The non-polar solvent, toluene, and the
protic solvent, ethanol, also failed to improve the yield (Table 1,
entries 14 and 15). The reaction also gave two byproducts,
3a-a and 3a-b. Thus, in order to improve reaction selectivity,
we performed the reaction under biphasic conditions. Unfor-
tunately, neither the aqueous biphasic systems (Table S1) nor
the non-aqueous biphasic systems (Table S2) proved successful
in enhancing the yield of 3a. BAILs have been widely used in
organic catalysis [45–48]. Thus, some triflic acid-derived BAILs
were examined in this study. Considering the hygroscopic
property of BAILs, they were prepared in situ by mixing the
corresponding zwitterions with TfOH. The imidazolium- (4a)
and pyridinium-type (4b) BAILs showed similar catalytic activ-
ity as TfOH (Table 1, entries 16 and 17). However, in the pres-
ence of the ammonium-type (4c) BAIL, 3a was obtained in 45%
yield (Table 1, entry 18). In addition, the yield of 3a increased
with an excess amount of 4c, based on triflic acid (Table S3).
When 20 equivalents of 4c were used, 3a was obtained in 92%

Minghao Li et al. / Chinese Journal of Catalysis 40 (2019) 1135–1140
1137
yield (Table 1, entry 19). Since 3a was formed through a dehy-
dration process, 8 equivalents of water, based on 4c, was added
to check whether the excess amount of zwitterion played the
role of a reservoir. However, the reaction yield did not change
significantly (Table 1, entry 20). With 8 equivalents of water, 4c
was completely dissolved in the aqueous phase and a biphasic
system was formed in conjunction with nitroethane (Fig. S1).
After the reaction, the TfOH remained in the aqueous phase and
both the acid and 4c could be reused for five times (Fig. 1). Ni-
troethane was necessary for this reaction and replacement of
nitroethane with other organic solvents resulted in reduced
yields (Table S4). The ability of the amphiphilic zwitterion (4c
vs 4d), reaction temperature, and time also affected the yield
(Table 1, entries 21–23). Thus, the optimized conditions for the
reaction was obtained with TfOH (10 mol%), 4c (200 mol%),
and H2O (1600 mol%) in EtNO2 (1.0 mL) at 95 °C for 1 h.
The scope of the substrates was then probed under the op-
timized conditions (Fig. 2). An apparent electronic effect could
be observed by varying the substituents on the indole ring of
2-phenylindole. 2-phenylindoles with an electron-donating
substituent at the C5-position produced the corresponding
benzo[a]carbazoles in excellent yields (3b and 3c). The conge-
ners with weak electron-withdrawing substituents such as
5-fluoro-2-phenylindole and 5-chloro-2-phenylindole, only
gave a moderate yield. However, by increasing the reaction
time, the corresponding benzo[a]carbazoles, 3d and 3e, were
obtained in 72% and 75% yields, respectively. A similar ten-
dency was also observed by varying the substituents at the
benzene ring of 2-phenylindole (3g, 3h, and 3i vs 3j). The
N-substituted 2-phenylindole reacted readily with acetol to
produce 3k in 86% yield, which reportedly exhibits pro-
nounced antitumor activity against leukemia, renal cancer,
colon cancer, and malignant melanoma cell lines [23]. Two
Fig. 2. Substrate scope for 2-phenylindole.
ate yield. 2,2-Diethoxyethanol as a masked glycolaldehyde [49],
which is a biomass-derived chemical compound synthesized
from cellulose or glucose, formed 5b in 80% yield. However,
substitutions at the alpha position of the hydroxyl group
seemed to be unfavorable since no expected products were
obtained with 3-hydroxy-2-butanone and benzoin (5c and 5d).
However, α-methoxyacetone gave the same product as acetol in
89% yield.
A proposed mechanism for this reaction is depicted in Fig. 3.
The reaction was triggered by the Brönsted acid mediated nu-
cleophilic addition of indole to ketone [50,51], followed by de-
hydrogenation to generate intermediate I. The carbocation
intermediate I resonates with the iminium intermediate II and
the oxonium intermediate III. Michael addition of intermediate
II to 1a gave the byproduct 3a-b while the isomerization of
intermediate III via 2-phenylindole migration [52–54] followed
by deprotonation furnished the byproduct 3a-a. We believed
that the main product 3a was formed through the intermediate
V, which was generated from intermediate I either by dehydra-
tion followed by protonation or hydride migration. Mechanis-
tically, however, the formation of 3a directly from intermediate
IV via 6π-electrocyclization followed by dehydration could not
be ruled out. The existence of many electrophiles (intermedi-
ates I–IV, 3a-a, and 1a) and nucleophiles (1a and 2a) simulta-
2-heteroarylindoles,
2-(furan-2-yl)-1H-indole,
and
2-(thiophen-2-yl)-1H-indole, were also used in this reaction,
with which the target products, 3l and 3m, were isolated in
76% and 75% yields, respectively.
To understand the limitation of this protocol we also exam-
ined
the
-hydroxyketones
reacted
(Scheme
smoothly
2).
with
-Hydroxyacetophenone
2-phenylindole to generate the desired product (5a) in moder-
100
90
88
85
85
82
80
60
40
20
0
1
2
3
4
5
Number of recycles
Scheme 2. Substrate scope for α-hydroxyacetones.
Fig. 1. Recyclability of the catalyst present in the aqueous phase.

1138
Minghao Li et al. / Chinese Journal of Catalysis 40 (2019) 1135–1140
great potential for the synthesis of pharmaceutically relevant
benzo[a]carbazole derivatives.
Notes
The authors declare no competing financial interest.
Acknowledgment
The Cooperative Innovation Center of Hubei province and
the testing center of HUST are acknowledged.
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Graphical Abstract
Chin. J. Catal., 2019, 40: 1135–1140 doi: S1872-2067(19)63370-X
Brönsted acidic ionic liquid catalyzed synthesis of benzo[a]carbazole
from renewable acetol and 2-phenylindoles in a biphasic system
Minghao Li, Fengtian Wu, Yanlong Gu *
Huazhong University of Science and Technology; Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences
An expeditious synthesis of benzo[a]carbazole from readily available
2-phenylindoles and bio-renewable acetol catalyzed by
Brönsted acidic ionic liquid is reported.
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Brönsted酸性离子液体催化α-羟基丙酮和2-苯基吲哚反应合成苯并[a]咔唑
李明浩a, 吴丰田a, 顾彦龙a,b,*
a华中科技大学化学与化工学院, 能量转换与存储材料化学教育部重点实验室,
材料化学与服役失效湖北省重点实验室, 湖北武汉430074
b中国科学院兰州化学与物理研究所羰基合成与选择氧化国家重点实验室, 甘肃兰州730000
摘要: 以生物质基平台化合物为原料合成含氧/氮杂环是实现生物质高值转化的重要途径. α-羟基丙酮可通过生物质分段
热解获得, 是一种重要的生物质平台化合物. 尽管吡嗪, 恶唑啉, 呋喃, 和喹喔啉等α-羟基丙酮衍生化杂环化合物已有报道,
但将α-羟基丙酮转化为其它类型杂环仍具有很大的吸引力.
苯并[a]咔唑化合物因其在医药和光学材料有广泛的应用而备受关注. 在过去二十年里, 开发出了许多合成苯并[a]咔
唑的方法, 其中从简单易得的2-苯基吲哚出发, 构建苯并[a]咔唑的方法最具吸引力, 但目前基于2-苯基吲哚合成苯并[a]咔
唑的报道只有4例: (1) ln(OTf)3催化2-苯基吲哚和炔丙基醚的[4+2]反应; (2) Pd催化2-苯基吲哚与端炔氧化环化; (3) Rh(III)
催化2-苯基吲哚与α-重氮羰基化合物串联环化; (4) BiCl3催化2-苯基吲哚与α-溴乙缩醛苯环化反应. 考虑到苯并[a]咔唑化

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Minghao Li et al. / Chinese Journal of Catalysis 40 (2019) 1135–1140
合物广泛的应用性, 从简单易得的原料出发, 发展新型的(例如非过渡金属催化)构建该类杂环的方法十分有必要.
本文报道了Brönsted酸性离子液体催化2-苯基吲哚和生物质基α-羟基丙酮的串联反应, 构建了一系列苯并[a]咔唑化合
物. 首先通过对催化剂、溶剂和温度等参数的筛选, 确定了最佳反应条件为1a (0.3 mmol), 2a (0.45 mmol), TfOH (10 mol%),
4c (2.0 equiv.), H2O (16.0 equiv.), 硝基乙烷 (1.0 mL), 95 °C, 1 h. 在标准条件下, 给电子和拉电子基团取代的2-苯基吲哚都
可以很好地参与反应, 反应收率在70%–92%之间, 相对富电子2-苯基吲哚, 较贫的2-苯基吲哚反应活性更高, 2-呋喃或噻吩
吲哚也可以顺利参与反应. 在考察α-羟基丙酮同系物的反应活性时发现, α-羟基苯乙酮和α-羟基乙缩醛可以很好地参与反
应, 但在α-羟基苯丙酮的α位引入取代基时, 目标产物不能有效生成. 值得说明的是, 在合成的苯并[a]咔唑化合物中, 3k具
有抗白血病和抗肿瘤活性, 另外反应中离子液体催化体系可以重复使用5次.
关键词: 苯并[a]咔唑; Brönsted酸性离子液体; α-羟基丙酮; 2-苯基吲哚; 串联反应
收稿日期: 2019-03-13. 接受日期: 2019-04-03. 出版日期: 2019-08-05.
*通讯联系人. 电话: (027)87543032; 传真: (027)87543632; 电子信箱: klgyl@hust.edu.cn
基金来源: 国家自然科学基金(21761132014, 21872060); 中央高校基本科研业务费专项资金(2016YXZD033, 2019kfyXJJS072); 材
料化学与服役失效湖北省重点实验室开放基金(2017MCF01K).
本文的电子版全文由Elsevier出版社在ScienceDirect上出版(http://www.sciencedirect.com/science/journal/18722067).