Unexpected activated carbon-catalyzed pyrrolo[1,2-a]quinoxalines synthesis in water

Article abstract of DOI:10.1016/j.cclet.2019.04.007

An interesting and recyclable activated carbon/water catalytic system for efficient synthesis of pyrrolo[1,2-a]quinoxaline derivatives was developed. The intramolecular C–N and C–C bond can be easily constructed in water under mild condition. This reaction features a broad substrate scope, a good tolerance to water and air, metal-free, additive-free and redox reagent-free.

Full text of DOI:10.1016/j.cclet.2019.04.007

Accepted Manuscript
Title: Unexpected activated carbon-catalyzed
pyrrolo[1,2-a]quinoxalines synthesis in water
Authors: Qi Sun, Liyan Liu, Yu Yang, Zhenggen Zha,
Zhiyong Wang
PII:
DOI:
Reference:
S1001-8417(19)30159-7
https://doi.org/10.1016/j.cclet.2019.04.007
CCLET 4900
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Chinese Chemical Letters
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Revised date:
Accepted date:
28 January 2019
6 March 2019
3 April 2019
Please cite this article as: Sun Q, Liu L, Yang Y, Zha Z, Wang Z, Unexpected activated
carbon-catalyzed pyrrolo[1,2-a]quinoxalines synthesis in water, Chinese Chemical
Letters (2019), https://doi.org/10.1016/j.cclet.2019.04.007
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Communication
Unexpected activated carbon-catalyzed pyrrolo[1,2-a]quinoxalines synthesis in
water
Qi Sun, Liyan Liu, Yu Yang, Zhenggen Zha, Zhiyong Wang
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Center for Excellence in
Molecular Synthesis of Chinese Academy of Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of
Chemistry and Materials Science in University of Science and Technology of China, Hefei 230026, China
ARTICLE INFO
Article history:
Received 28 January 2019
Received in revised form 7 March 2019
Accepted 12 March 2019
Available online
 Corresponding author.
E-mail address: zwang3@ustc.edu.cn
Graphical Abstract
In this manuscript, an efficient method for the synthesis of pyrrolo[1,2-a]quinoxaline derivatives was developed. By virtue of the
activated carbon/ water system, a facile protocol was established to construct the intramolecular C-N and C-C bond at the same
time. Meanwhile, this reaction has a wide substrate scope and good functional group tolerance. All these transformations can be
performed smoothly under mild conditions without any transition metal, additive, oxidant and reductant.
ABSTRACT
An interesting and recyclable activated carbon/water catalytic system for efficient synthesis of pyrrolo[1,2-a]quinoxaline derivatives was developed. The
intramolecular C-N and C-C bond can be easily constructed in water under mild condition. This reaction features a broad substrate scope, a good tolerance to
water and air, metal-free, additive-free and redox reagent-free.
Keywords:
Pyrrolo[1,2-a]quinoxalines Activated carbon
C-C C-N bond-forming
Metal free
Water solvent
Pyrrolo[1,2-a]quinoxalines as one of the most important nitrogen-containing heterocycles display special physiological properties
and biological activities [1]. Accordingly, many methods for syntheses of pyrrolo[1,2-a]quinoxalines and the derivatives have been
developed over the past decades. The traditional approaches generally can be classified into two categories. One is the copper-
catalyzed Ullmann-type coupling reaction of pyrrole analogues via an intramolecular or intermolecular cyclization [2a,b,c]. The other
is utilizing the amines as the starting materials with aldehydes, alkyl- or aryl-acid chlorides to obtain the corresponding structural
motifs [2d,e,f]. In 2012, a new method to construct these N-heterocycles involved an aryl nitro reduction and an aerobic oxidation of
the alcohols was developed [3]. The inactive substrates benzyl alcohols were employed in this transformation. Very recently, a new
———

strategy to synthesize indolo- and pyrrolo[1,2-a]quinoxalines from benzylamines promoted by molecular iodine was developed by
Jayaprakash et al. [4]. Despite these tremendous developments, a green and practical methodology is in highly urgent demand due to
the harsh conditions involved in the previous work, including toxic solvents, large excess of metals and high reaction temperature.
As continued interest in the development of simple and general synthetic methods to access this structural moiety, on the other hand,
heterogeneous catalysts have been witnessed explosive developments due to their excellent catalytic efficiency and easy recycling
advantage [5]. In the past decade, chemists prefer to choose various kinds of modified carbon materials or metal supported on different
templates (including activated carbon) as catalysts to construct C-N or C-C bonds directly, which was recognized as the fundamental in
the synthesis of numerous natural products and pharmaceutical intermediates [6]. With great efforts focused on the heterogeneous
catalysis [7], people usually use activated carbon (AC) as a heterogeneous catalyst template for its cheap and the stability in both acidic
and basic media [8]. However, activated carbon as a catalyst has long been neglected in the organic reactions [9]. Additionally, water,
as a cost-effective and environmentally benign solvent in synthetic chemistry, has been widely studied in our group [10] and the other
groups [11]. Herein, we wish to unveil a novel method to synthesize pyrrolo[1,2-a]quinoxalines from amines and 1-(2-
nitrophenyl)pyrrole derivatives. The reaction can be catalyzed by activated carbon in water without any other additive.
Mechanistically, two hydrogen-transfer processes are proposed as the key steps in the catalytic cycle.
At the outset of this investigation, we selected the reaction of benzylamine (1a) with 1-(2-nitrophenyl)pyrrole (2a) as the model
reaction (Table 1). In our initial studies, the reaction was carried out in water and several nano-catalysts, such as Pd/C, Pd/diatomite,
Pt/C, Pt/TiO2, Pt/ZrO2 and Au/TiO2, were examined in the reaction (entries 1-6). The details were deposited in Supporting information.
Interestingly, the cyclization product 3aa was produced in good yield only in the presence of activated carbon (AC). Subsequently,
different carbon materials were screened and only AC could obtain 3aa in 11% yield when the dosage of AC was 0.6% of 2a by the
weight (entry 7). Gratifyingly, 3aa was obtained in 99 % yield when the amount of catalyst was increased to 15% of 2a by the weight
(entries 11-13). Further screening the solvent showed that the yield largely decreased when several types of organic solvents were
employed instead of water, affording few or a trace amount of the desired product, except for toluene with 72% yield (entries 14-16).
These results indicated that the combination of activated carbon and water established a highly efficient system for 3aa synthesis. It is
worth mentioning that the reaction could also perform well under air atmosphere to furnish the final product with 71% yield (entry 17).
Table 1 Optimizatiion of reaction conditions for the one-pot synthesis of 3aa.a
Entry
1
2
3
4
Catalyst (mol%)
Pd/C (2)
Pd/diatomite (2)
Pt/C (2)
Pt/TiO2 (2)
Pt/ZrO2 (2)
Au/TiO2 (2)
AC
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Yield (%)b
75
45
90
n.d
n.d
n.d
11
5
6
7c
8
9
C60 (10)
C70 (10)
Graphene (10)
AC
AC
AC
AC
AC
AC
AC
H2O
H2O
H2O
H2O
H2O
H2O
Tol
1,4-Dioxane
DM
n.d
n.d
Trace
65
80
99
72
n.d
Trace
71
10
11d
12e
13f
14f
15f
16f
17g
H2O
Tol = Toluene; DMF = N,N-dimethylformamide.
a Recation conditions: 1a (0.75 mmol), 2a (0.25 mmol) and solvent (1.0 mL) in a sealed tube at 140 oC under a N2 atmosphere for 20 h.
b Yield of the isolated product based on 2a.
c AC, 0.6% by the weight of 2a.
d AC, 5% by the weight of 2a.
e AC, 10% by the weight of 2a.
f AC, 15% by the weight of 2a.
h The reaction being carried out under air.
With the most efficient catalyst in hand, a broad range of amines 1a-u were prepared and employed in the reaction under the
optimized conditions to explore the scope of this transformation (Scheme 1). The electronic effect of substituents on the aryl ring of the
benzylamines was first examined. The results showed that the electronic properties of benzylamines have little influence on this
reaction. A series of amines, bearing either electron-donating groups (p-Me and p-MeO) or electron-withdrawing group (p-F, p-Cl, p-
Br, p-CF3) on the aryl ring, could be converted to the desired products (3ba-3ia) in excellent yields. The yield of 3ja could be at a good
level under the catalysis of AC. In contrast, the low yield of 51% for 3ja was observed when the AC was replaced by Pt/C. Even the
reaction hardly occurred under catalysis of Pd/C instead of AC. This meant that AC could efficiently restrain 4-bromobenzylamine

from being reduced to benzylamine by its liberating hydrogen. As expected, the benzylamines with ortho-substituent ring could be
efficiently converted into the corresponding products (3ka-3la) with high yields. 1-Naphthalenemethanamine, piperonyl-amine and 2-
chloro-4-fluorobenzylamine could also perform well with excellent yields (3ma-3oa). Gratifyingly, the aromatic heterocycles such as
pyridine, furan and thiophene, were well tolerated in the reaction, affording the corresponding products with good yields (3pa-3ra). To
our delight, aliphatic amines could also be employed as the substrates to give the corresponding products with moderate yields (3sa-
3ta).
Scheme 1. Reaction of 1-(2-nitrophenyl)pyrrole derivatives with various amines, the isolated products’ yields are based on 2. a 2 mol % Pt/C, b2 mol% Pd/C,
was used instead of AC. c 2.0 mmol amine was used. d1.0 mmol benzlyamine was used.
Next, we turned our attention to assess the scope of the nitro compounds. The 1-(2-nitrophenyl)pyrroles with various functional
groups such as -Me, -MeO and halogen (F and Cl), even with different substitution patterns, could still react smoothly with
benzylamine to furnish the desired products in good yields (3ab-3ag). To further investigate the scope of this reaction, 3-nitro-2-
pyrrolopyridine was employed, obtaining 3ah with a good yield of 89%. The yield of the product 6-phenylindolo[1,2-a]quinoxaline
(3ai) was decreased to 56% perhaps due to the low nucleophilicity of the indole substituted nitrobenzene [4].
Table 2 Recycling of activated carbon for the synthesis of pyrrolo[1,2-a]quinoxaline. a
Run
Yield (%)b
1
2
3
4
5
6 c
98
99
98
91
86
81
a The reactions were carried out with 1a (0.75 mmol), 2a (0.25 mmol), a solvent (1.0 mL) and an initial catalyst (activated carbon, 15% by the weight of 2a) for
20 h under a N2 atmosphere.
b Yield of the isolated product is based on 2a.
c Catalyst (activated carbon, 15% of 2a by the weight).

To probe the reusability of the catalyst AC, the model reaction was performed in the presence of activated carbon. The recycle of the
catalyst could be realized by a simple manipulation of filtration. A little loss of the catalytic activity was observed after the fifth round,
as shown in Table 2. When the additional catalyst was added to maintain the amount of AC (run 6), an excellent yield of 98% was
obtained again. These results showed that the catalyst could be reused at least 6 times without the erosion of its activity.
Scheme 2. Control experiments. Standard condition: 1a or 1a" (0.75 mmol), 2a or 2a' (0.25 mmol), activated carbon (15% by the weight of 2a or 2a') and H2O
(1 mL) in a sealed tube at 140 oC under a N2 atmosphere for 20 h.
To figure out the reaction mechanism, some control experiments were conducted (Scheme 2). When the reaction was carried out in
the absence of activated carbon, the product 3aa cannot be obtained (Scheme 2a), indicating that activated carbon was necessary for
this reaction. Furthermore, when compound 1a'' and 2a' were employed as the substrates instead of 1a and 2a under the activate
carbon/water catalytic system, 89% of 3aa was obtained (Scheme 2b), but no product was observed in the absence of activated carbon
(Scheme 2c). In Scheme 2d, compound 2a was employed in the reaction under H2 atmosphere, 2a' can not be generated. And when 1a
was used separately under the standard condition, compound 1a' was detected with 41% yield by GC-MS. Finally, we replaced 2a with
2a' to react with 1a under the optimized condition, affording the product 3aa with 72% yield, which revealed that 2a' might be a key
intermediate for this transformation.
According to the control experiment results and previous reports [9a,b,c], we proposed a plausible mechanism (Scheme 3). At the
very beginning of hydrogen-transfer process, the dehydrogenative oxidation of the benzylamine (1a) produces its corresponding
carbonyl compound (1a'') and 1-(2-nitrophenyl)pyrrole (2a) is reduced to 1-(2-aminophenyl)-1H-pyrrole (2a’) by in situ generated b.
Then 2a' can react rapidly with 1a'' to afford the intermediate 4-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (c) under the catalysis of
AC. Subsequently, c can be readily oxidized to the product 3aa in the presence of AC. Afterwards, the second hydrogen-transfer
process takes place with the reduction of 2a to 2a'. In the whole catalytic cycle, the amine and the intermediate 4-phenyl-4,5-
dihydropyrrolo[1,2-a]quinoxaline are used as reductants (hydrogen donor) once respectively and 1-(2-nitrophenyl)pyrrole is used as
the oxidant (hydrogen acceptor) twice.
In conclusion, by using AC as the catalyst and water as solvent, a novel catalytic system was developed for the synthesis of
pyrrolo[1,2-a]quinoxalines. The reaction can be carried out smoothly under mild condition and the scope of amines and nitro
compounds was extended widely. A variety of quinoxalines can be obtained with good to excellent yield. It is noteworthy that no
transition metal, additive, oxidant and reductant were involved in this reaction. Only water was used as the solvent and the reactions
can tolerate air. The reuse of AC catalyst could be achieved by a simple phase separation process without obvious loss of its catalytic
activity. Studies on the application of this method and the detailed mechanism are in progress.

Scheme 3. Proposed mechanism for the reaction.
Acknowledgments
We are grateful for the financial support from the Natural Science Foundation of China (Nos. 21432009, 21672200, 21472177,
21772185 and 21801233) and for the assistance of the product characterization from the Chemistry Experiment Teaching Center of
University of Science and Technology of China. This work was supported by the Strategic Priority Research Program of the Chinese
Academy of Sciences (No. XDB20000000).

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