Graphene oxide as an active carbocatalyst for cyanation of quinoline and isoquinoline N-Oxides

Article abstract of DOI:10.1016/j.tet.2021.131964

Graphene oxide was found to be a highly efficient and cost-effective heterogeneous catalyst for the direct metal-free transformation of quinoline and isoquinoline N-oxides into the corresponding nitriles under mild conditions. This method is simple, econo

Full text of DOI:10.1016/j.tet.2021.131964

Tetrahedron 83 (2021) 131964
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Graphene oxide as an active carbocatalyst for cyanation of quinoline
and isoquinoline N-Oxides
,
, **,
Panpan Huang a 1, Xiangjun Peng b 1, Genhong Qiu b, Keyang Yu b, Hong Li a,
Lingting Kong a, Jiaming Hu a, Zhengwang Chen a, Qing Huang a ***, Liangxian Liu a
,
, *
a Department of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi, 341000, PR China
b School of Pharmaceutical Science, Gannan Medical University, Ganzhou, Jiangxi, 341000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Graphene oxide was found to be a highly efficient and cost-effective heterogeneous catalyst for the direct
metal-free transformation of quinoline and isoquinoline N-oxides into the corresponding nitriles under
mild conditions. This method is simple, economic and environmentally benign, representing a useful
Received 20 October 2020
Received in revised form
15 January 2021
Accepted 22 January 2021
Available online 29 January 2021
strategy for the convenient synthesis of
a-cyano N-oxides that are difficult to prepare by transition-
metal-free catalyzed methods. In vitro, compound 2s exhibited good activities against T-24 cell lines
with IC50 values in 10.23 1.05 mM. Further studies investigated the mechanism of the effective inhi-
bition of cell growth, including apoptosis ratio dection, cell cycle analysis, measurement of Ca2þ gen-
eration, ROS, and mitochondrial dysfunction.
Keywords:
Graphene oxide
Heterocyclic N-Oxides
(Iso)quinoline
Nitrile
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
only a few examples have been reported for the cyanation of het-
erocyclic N-oxides, especially the transition-metal-free catalyzed
Heterocyclic N-oxides, especially heterocyclic aromatic N-ox-
ides, often exhibit potent biological activities and are used as drugs
[1,2] (Fig. 1). For example, isoquinoline alkaloid (A) was isolated
from the leaves of Neolitsea sericea var. aurata Hayata, a plant native
to Orchid Island, Taiwan [3a]. compound (B) was isolated from
Stigmatella aurantiaca and utilized as a potent antibiotic [3b],
cyanation reactions [10] (Scheme 1).
Recognizing the importance of heterocyclic N-oxides and CeH
cyanation, we questioned whether carbon-based materials can be
employed as benign catalysts to promote CeH cyanation of (iso)
quinoline N-oxides as initial raw materials. We recognized that if
such a process could be developed, it would represent a powerful
method for the synthesis of (iso)quinoline via a direct and atomic
economical strategy as well as it would open the door for numerous
related transformations using the carbocatalysis platform. And the
method avoided using the transition-metal, phosphorus reagent
and base additives.
Oxadiazole 2-oxide (C), identified from
a quantitative high-
throughput screen, was shown to inhibit a parasite enzyme, thio-
redoxin glutathione reductase (TGR), with activities in the low
micromolar to low nanomolar range [3c], while compound (D) was
designed, synthesized, and tested for their ability to inhibit p38
a
MAP kinase [2a]. On the other hand, the presence of a NeO bond
also serves as an important handle to activate the heterocycle, thus
allowing diverse functionalization of heterocycles, such as alkeny-
lation [4], alkynylation [5], arylation [6], amidation [7], acetox-
ylation [8], and sulfonylation [9]. However, despite these advances,
In recent years, graphene oxide (GO), which is usually prepared
by oxidizing graphite and consists of hydrophilic oxygenated gra-
phene sheets bearing oxygen functional groups on their basal
planes and edges, have attracted much attention due to potential
applications in plastic electronics, solar cells, optical materials and
biosensors [11]. We recently reported a GO-promoted alkylation
strategy to access 3,30-bisindolylmethane derivatives and a GO/air
oxidative strategy for the synthesis of N-acylisoindolin-1-one de-
rivatives [12]. However, a high weight loading of GO relative to the
substrate is usually required when GO was used as a substitute for
metal catalysts [11c,13]. Thus, its potential as a catalyst in organic
transformation remains relatively unexplored [14].
* Corresponding author.
** Corresponding author.
*** Corresponding author.
E-mail address: liuliangxian1962@163.com (L. Liu).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tet.2021.131964
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

P. Huang, X. Peng, G. Qiu et al.
Tetrahedron 83 (2021) 131964
Fig. 1. Selected examples of bioactive natural products and compounds containing the NeO scaffold.
Scheme 1. Strategies for C2-cyanation of quinoline and other N-oxides.
Recently, Sun’s group reported a regioselective synthesis of 2-
cyanoquinoline derivatives by the PhI(OAc)2 mediated NeO bond
disruption and direct cyanation of quinoline N-oxide substrates
[10d]. The reaction system featured an accelerator of NeO bond
cleavage. In view of the potent biological activities from N-oxides,
we want to preserve the NeO bond after N-oxides were function-
alized. Based on the great versatility of aryl and heteroaryl nitriles
in chemical transformations and their frequent appearance in
natural products, biologically active products, pharmaceuticals, and
specialty materials [15], as well as an inspirement from oxadiazole
2-oxide c as a TGR inhibitor, we herein report a green GO-catalyzed
procedure for the cyanation of quinoline and isoquinoline N-oxides
with benzoyl cyanide under metal-free and base-free reaction
conditions, where the functionalization occurred at the 2-position
of quinoline N-oxides and 1-position of isoquinoline N-oxides.
Generally, the transition-metal-free catalyzed cyanation of N-ox-
ides is accompanied by the NeO bond cleavage. To the best of our
knowledge, this is the first example that GO as a carbocatalyst has
been applied in the chemical transformations of heterocyclic N-
oxides.
2. Results and discussion
The GO material used in this investigation was prepared by
Hummers oxidation of graphite and subsequent exfoliation, as re-
ported [16]. The obtained GO material was characterized by X-ray
powder diffraction (XRD), transmission electron microscopy (TEM),
visible Raman spectroscopy, atomic force microscopy (AFM), and
infrared spectrum (IR) (see the Supporting Information).
Initially, we commenced our investigation by the reaction of
2

P. Huang, X. Peng, G. Qiu et al.
Tetrahedron 83 (2021) 131964
quinoline N-oxide (1a) with TMSCN as a model reaction. After
extensive experimentation, the desired product 2a was obtained in
25% yield when 50 wt % of GO was selected as a catalyst in dioxane
at 100 ꢀC for 8 h (Table 1, entry 1). It is important that the NeO bond
cleavage is not occurring. To avoid producing hazardous HCN gas,
replacing TMSCN with NH4SCN, CH3CN, 2-phenylacetonitrile, 2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), azobisisobutyr-
benzoyl cyanide. As shown in Table 2, a wide range of quinoline N-
oxides, including chloro, bromo, methyl, methoxy and nitro, can be
employed as effective coupling partners. Generally, the introduc-
tion of electron-donating or electron-withdrawing groups at the C-
5, -6, -7, or -8 position of the quinoline N-oxides all proceeded with
the smooth coupling with benzoyl cyanide, affording the corre-
sponding products in moderate to excellent yields and with good
regioselectivity. Particularly compelling is the cyanation of 5-
(phenylethynyl)quinolone N-oxide (2o), which proceeded in good
yield despite the presence of an alkyne group. The structure of 2b
was confirmed by X-ray analysis (see the Supporting Information
for more details).
This methodology also proved applicable to isoquinoline N-ox-
ides (2p-2s), which could proceed efficiently and afford the corre-
sponding products in moderate to excellent yields and with good
regioselectivity. Unfortunately, 1t and 1u were not converted into
their target products.
onitrile
(AIBN)
or
N-cyano-N-phenyl-p-methyl-
benzenesulfonamide (NCTS) resulted in no reaction (Table 1, entries
2e6). However, the cyanation product 2a was isolated in 56% yield
by using benzoyl cyanide as a “CN” source (Table 1, entry 7). With
the encouraging preliminary result, different solvents such as
toluene, H2O, EtOH, DMF, and DMSO, were investigated (Table 1,
entries 8e12), and DMSO gave the best result with 89% yield
(Table 1, entry 12). We also tried this reaction using graphite or
graphene instead of GO. The results showed that graphite and
graphene were inefficient (Table 1, entries 13 and 14).
As expected, the control experiments clearly showed that GO is
essential for this reaction, as no cyanation product was observed in
the absence of the GO catalyst (Table 1, entry 15). Subsequent ef-
forts were directed toward optimizing the GO loadings (Table 1,
entries 16 and 17). By lowering the catalyst loading to 40 wt %, it
was observed that product could be isolated in 71% yield. However,
further lowering catalyst loading to 30 wt % made the reaction
become sluggish, which resulted in product 2a in 33% yield along
with 60% recovered starting material. The investigation on the ef-
fect of the reaction temperature proved that 100 ꢀC was appropriate
for this reaction (Table 1, entries 18 and 19). Finally, the best result
was obtained by using GO (50 wt %) in DMSO at 100 ꢀC for 8 h under
air atmosphere.
In addition, the cyanations of other heteroarene N-oxides, such
as 2,2-dimethyl-3,4-dihydro-2H-pyrrole 1-oxide 4, with benzoyl
cyanide was presented in Scheme 2.
GO as a carbocatalytic material could be easily scaled up because
of its low-cost and abundantly available. In order to demonstrate
the effectiveness of this new strategy, a gram scale reaction was
performed under the standard conditions. 10 mmol 1a and
15 mmol benzoyl cyanide were subjected to the reaction in the
presence of GO (726 mg, 50 wt %) in 20 mL DMSO 100 ꢀC under air
atmosphere. After 8 h, the desired product 2a was obtained in 85%
yield, which demonstrated the practical application of this protocol
to prepare 2-cyanoquinoline 1-oxides on a gram-scale (Scheme 3).
As we all know, one-pot synthesis can simplify a lot of pro-
cessing procedure and reduce the loss of material compared to
multi-step reactions. We envisaged that the cyanation of quinoline
N-oxide could be realized in “one-pot” by starting with quinoline as
substrate. We initiated our studies with quinoline as substrate and
After establishment of the optimal reaction conditions, we
evaluated the generality of the GO- catalyzed cyanation, and the
results are summarized in Table 2. We first examined the scope of
differentially substituted quinoline N-oxides in the cyanation with
Table 1
Screening of the reaction conditionsa.
Entry
Catalyst (wt%)b
yano source
Solvent
T (oC)
Time (h)
Yieldc
1
2
3
4
5
6
7
8
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
GO (50)
Graphite (50)
Graphene (50)
e
TMSCN (3 equiv)
CH3CN(3 equiv)
PhCH2CN(3 equiv)
DDQ (3 equiv)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
H2O
EtOH
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
8
25
0
0
0
0
24
24
24
24
24
8
8
8
8
8
AIBN (3 equiv)
NCTS (3 equiv)
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
benzoyl cyanide
0
56
28
N.R.
N.R.
N.R.
89
N.R.
N.R.
N.R.
71
33
80
83
9
10
11
12
13
14
15
16
17
18
19
8
24
24
24
8
24
8
GO (40)
GO (30)
GO (50)
GO (50)
110
8
a
Reaction conditions: A mixture of 1a (0.3 mmol) and benzoyl cyanide (1.5 equiv) in solvent (1 mL) was placed in an oil bath under air atmosphere.
With respect to the substrate 1a.
Isolated yield after purification by column chromatography.
b
c
3

P. Huang, X. Peng, G. Qiu et al.
Tetrahedron 83 (2021) 131964
Table 2
Substrate scope of quinoline N-oxides with benzoyl cyanidea,b
.
a Reaction conditions: A mixture of N-oxides (0.3 mmol), GO (50 wt %) and benzoyl cyanide (1.5 equiv) in DMSO (1 mL) was placed in an oil bath at 100 ꢀC under air atmosphere
for 8 h b Isolated yield after purification by column chromatography.
Scheme 2. The cyanation of pyrrole oxide with benzoyl cyanide.
Scheme 4. One-pot synthesis of 2a using quinolone as substrate.
When the reaction of quinolone 6 instead of 1a with benzoyl
cyanide was performed under standard conditions, the product 2a
was not detected (Scheme 5b), which indicates that the oxidation of
quinoline is the prerequisite condition. Furthermore, we used the
substrate 7 to perform the reactions. Under the standard condi-
tions, 2a was not detected and 7 was basically recovered (Scheme
Scheme 3. Scale-up reaction between 1a and benzoyl cyanide.
5c). These results indicated that 7 was not likely the key interme-
diate in this protocol and the NeO bond has been cut off during the
reaction. These experimental results suggested that the reaction
MCPBA as oxidant in CH2Cl2 at 0 ꢀC for overnight. After completion
follows a different route [10d]. When the graphene instead of GO as
of oxidation for the synthesis of the intermediate quinoline N-oxid
the catalyst was also added under the standard conditions, no
1a and concentration, GO, benzoyl cyanide and DMSO were added,
desired product was detected (Table 1, entry 14), confirming that
and the resultant mixture was stirred at 100 ꢀC for 8 h. To our
the presence of abundant epoxide groups and carboxylic acid
delight, 2a was isolated in 83% yield after a lot of research (Scheme
groups on GO was indispensable.
4).
Because the GO-catalyzed cyanation of N-oxides was performed
In order to gain some insight into the mechanism of this reac-
under open air, the role of molecular dioxygen in this reaction was
tion, a series of control experiments were conducted as shown in
explored. Notably, the reaction yield was not increased under an
Scheme 5. Initially, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
oxygen atmosphere, but a more rapid conversion of the starting
or butylated hydroxytoluene (BHT) as a radical inhibitor was added
material to the reaction product was observed. However, the
under the standard conditions. As expected, 2a was isolated in good
product 2a was obtained only in 30% yield under an argon atmo-
yields (80% and 78%, respectively) (Scheme 5a), suggesting that the
sphere (Scheme 5d). These results indicated that O2 and GO are
reaction did not follow a free-radical pathway.
essential for the cyanation.
4

P. Huang, X. Peng, G. Qiu et al.
Tetrahedron 83 (2021) 131964
recovered-GO displays certain activity after 6 cycles (see the Sup-
porting Information). The result indicates that the loss of epoxide
groups and carbonyl functional groups results in a great decrease of
recovered-GO catalytic activity, which suggests that GO with high-
oxygen content is critical to this reaction.
On the basis of these experimental results and the relevant re-
ports [10d,18], a plausible reaction pathway for this metal-free
catalytic cyanation of quinoline N-oxide is shown in Scheme 6.
Initially, the quinoline N-oxide is first activated by the hydroxyl
groups and carbonyl functional groups on GO to generate a highly
active electrophilic species [19]. Next, the highly active electrophilic
species can be transformed into dearomatized intermediate 8
through regioselective nucleophilic attacks of cyanide ion (come
from the hydrolysis of benzoyl cyanide) at a-carbon of quinoline.
Finally, intermediate 8 underwent oxidation in the presence of GO
and air to give intermediate 9, followed by the dehydration of 9 to
provide the 2-cyano product 2a.
The in vitro antiproliferative activities of all prepared products
was evaluated against T-24 (human bladder cancer), NCIeH460
(human lung cancer cell), HepG2 (human hepatocellular cancer),
MGC-803 (human gastric cancer), Hela (human cervical cancer
cells) and HL-7702 (human normal liver) cells, by MTT colorimetric
assay to explore the potential pharmacological activity of synthe-
sized compounds. Camptothecin (CPT) was used as a positive
control (Table 3). The table showed that two products demon-
strated moderate to favorable inhibition activity against these tu-
mor cell lines. Among these compounds, 2s showed the strongest
activity with IC50 values of 10.23 1.05, 13.67 1.16, 15.69 1.74,
Scheme 5. Control experiments.
GO with high-oxygen content is usually labile at higher tem-
perature. X-ray photoelectron spectroscopy (XPS) and Fourier
transform infrared (FT-IR) analysis showed that a large of epoxide
groups and carbonyl functional groups are lost when GO partici-
pates the reaction (Fig. 2). For example, the results show a signifi-
cant decrease in the intensity of CeO and C]O peaks in the high-
resolution XPS spectra of the recycled (one time) catalyst samples
(GO-r1) (Fig. 2a).
Furthermore, energy dispersive X-ray spectroscopy (EDXS) and
X-ray photoelectron spectroscopy (XPS) were utilized to determine
the carbon/oxygen content of the GO and recovered-GO. Table S1.
(ESIy) shows the percentage of C was increased to 88.1% from 59.7%,
while the O content was decreased to 10.5% from 39.7% (see the
Supporting Information). The removal of oxygen functionalities is
attributed to the effective removal of oxidative fragments and to a
dehydration reaction driven by the high reaction temperature [17].
The catalyst reusability was examined using a GO catalyst, and
the model substrates of 1a and benzoyl cyanide. The sample was
separated by filtration after the first reaction run and used for the
second one under the same conditions. The desired product 2a was
obtained only in 48% yield when the recovered-GO was used again
as catalyst in the CeH cyanation of quinoline N-oxide, but the
14.53 0.94 and 14.86 1.63 mM against T-24, NCIeH460, HepG2,
MGC-803, Hela cells, respectively (Table 3). The inhibiting effect of
compound 2s was more evident on tumor cells than that on normal
human cells HL-7702.
The apoptosis effects of compound 2s on T-24 cells were further
studied on MTT assay results. T-24 cells were tested with com-
pound 2s at different concentrations (control, 5, 10 and 15
24 h in Fig. 3. Treatment of 15 M compound 2s evidently increased
the percentage of apoptotic T-24 cells to 15%. Cell viability signifi-
mM) for
m
cantly decreased at > 20 mM, and almost all of the T-24 cells died in
48 h.
The cell cycle distribution of compound 2s-treated T-24 cells
was examined by flow cytometry to investigate the inhibition effect
of compound 2s on cell proliferation through cell cycle arrest
(Fig. 4). The percentage of T-24 cells at G1 phase was markedly
decreased from 48.83% (control group) to 2.43% (15
mM) after in-
cubation with compound 2s. Meanwhile, cells in S phase decreased
Fig. 2. a. XPS C1s spectra of GO and GO-r1(Recovered-GO); b. FT-IR spectrum of GO and Recovered-GO.
5

P. Huang, X. Peng, G. Qiu et al.
Tetrahedron 83 (2021) 131964
Scheme 6. Proposed reaction mechanism.
Table 3
The IC50
(m
M)a,b values of antiproliferative activities.
Comp.
T-24
NCIeH460
HepG2
MGC-803
Hela
HL-7702
2ꢀ
2s
CPT
20.85 1.06
10.23 1.05
3.15 0.84
22.17 1.10
13.67 1.16
5.63 0.94
22.96 1.54
15.69 1.74
4.12 0.26
20.98 1.25
14.53 0.94
5.67 1.21
24.37 1.47
14.86 1.63
3.46 0.73
60.87 2.33
41.53 1.64
6.46 0.83
a
Data are expressed as means SD of three independent experiments.
b
Compounds with IC50
(
m
M) values > 50
m
M are considered inactive.
Fig. 3. Induction of apoptosis by compound 2s in T-24 cells.
Fig. 4. Effects of 2s on cell cycle distribution in T-24 cells for 24 h.
from 44.87% to 12.96% (15
indicates that compound 2s caused a remarkable G1 phase arrest.
m
M) in the control group. This finding
oxides with benzoyl cyanide was first developed, which provides
an approach to prepare a variety of -cyano quinoline and iso-
a
quinoline N-oxides under mild and neutral conditions without
using any acid or base. This protocol is highly green and practical
due to the use of inexpensive GO as the catalyst. Metal-free con-
ditions, broad substrate scope with diverse substitution patterns,
3. Conclusions
A new GO-catalyzed cyanation of quinoline and isoquinoline N-
6

P. Huang, X. Peng, G. Qiu et al.
Tetrahedron 83 (2021) 131964
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Generally, the transition-metal-free catalyzed cyanation of N-ox-
ides is accompanied by the NeO bond cleavage. Furthermore,
compound 2s induced T-24 apoptosis, decreased mitochondrial
membrane potential, arrested cell cycle at the G1 phase, elevated
intracellular reactive oxygen species level and intracellular free
Ca2þ level in human bladder cancer cells.
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Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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The authors are grateful to the National Natural Science Foun-
dation of China (21462002), Jiangxi Province Office of Education
Support Program (GJJ190755, GJJ190757, GJJ190788), Practice and
Innovation Training Program for College Students in Jiangxi Prov-
ince (201910413013, 202010413013) and Scientific Research Project
of Gannan Medical University (ZD201819) for financial support.
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