Metal-Free, Initiator-Free Graphene Oxide-Catalyzed Trifluoromethylation of Arenes

Article abstract of DOI:10.1002/asia.201700939

The direct C?H trifluoromethylation of arenes catalyzed by graphene oxide (GO) under safe conditions is described. This strategy is metal-free, initiator-free, safe, and scalable. It employs a readily available CF₃ source and the reaction can b

Full text of DOI:10.1002/asia.201700939

CHEMISTRY
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Accepted Article
Title: Metal-free, Initiator-free Graphene Oxide Catalyzed
Trifluoromethylation of Arenes
Authors: Jingyu Zhang, Yun Yang, Jingxian Fang, Guo-Jun Deng, and
Hang Gong
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10.1002/asia.201700939
Chemistry - An Asian Journal
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Metal-free,
Initiator-free
Graphene
Oxide
Catalyzed
Trifluoromethylation of Arenes
Jingyu Zhang, Yun Yang, Jingxian Fang, Guo-Jun Deng and Hang Gong*
Abstract: The direct C–H trifluoromethylation of arenes catalyzed by
graphene oxide (GO) under safe conditions is described. This
strategy is metal free, initiator free, safe, and scalable. It employs a
readily available CF3 source and could easily control the reaction to
obtain a mono-trifluorinated product. This method opened a new
field for GO-catalyzed chemistry.
Arene trifluoromethylation is attractive because of the special
effects of trifluoromethyl (CF3) on parent molecules. These
effects include improvements in stability, solubility, polarity,
dipole moment, lipophilicity, and catabolic stability.[1] Although
rare in nature, synthetic trifluorinated aromatics have been
widely applied in various fields, especially in pesticides and
pharmaceuticals (Fig. 1).[2] Thus, developing synthetic strategies
Scheme 1. Examples of the application of arene trifluoromethylation.
for the selective trifluoromethylation of arenes is of great interest
among scientists. Many functionalized molecules, such as aryl
halides or pseudohalides, aryl boronic derivatives, and aromatic
acids, were used as substrates for the trifluoromethylation of
arenes (Scheme 1, A and B).[3] These methods often use
poisonous fluorinating reagents, pre-synthesized functional
substrates, as well as stoichiometric metal salts. With the
development of transition metal-catalyzed chemistry, the metal-
catalyzed direct C–H bond trifluoromethylation of arene was also
developed thoroughly (Scheme 1, C).[3,4] These methods
reduced the number of reaction steps and improved the atomic
economic efficiency and synthesis efficiency. However, the
metal residue remains a continuous concern in pharmaceuticals
and materials fields.[5]
Given our recent research on trifluoromethylation[6] and
graphene oxide (GO)-catalyzed reactions,[8] the current work
describes the GO-catalyzed trifluoromethylation of arenes in the
absence of metal and initiator under safe conditions. Despite the
extensive use of this strategy in catalytic reactions,[9] to the best
of our knowledge, GO-catalyzed trifluoromethylation has not
been reported.
The trifluoromethylation reaction was commenced by using
sym-trimethoxybenzene as template substrate (0.1 mmol), GO
(10 mg) as catalyst, and NaSO2CF3 (Langlois’ reagent, 3.0
equiv.)[10] as CF3 source in various solvents (1.0 mL) at 100 °C
under air (Table 1, Entries 1–6; Table S1, Entries 1–13). When
ethyl chloroacetate was used as solvent, a moderate yield (60%)
of the desired product was achieved (Table 1, Entry 5).
Increasing or reducing the reaction temperature is not beneficial
to this reaction (Table 1, Entries 7–8; Table S1, Entries 14–19).
This reaction could be finished within 12 h. Prolonging the
reaction time does not also aid the transformation (Table 1,
Entries 9–10; Table S1, Entries 20–24). To augment the yield of
this reaction, we examined several additives (Table 1, Entries
11–15; Table S1, Entries 25–33). When 10 mol% NH4NO3 was
used, an improved yield of 65% was achieved (Table 1, Entry
15). When the amount of NH4NO3 was increased to 20 mol%, a
good yield of 73% was achieved (Table 1, Entry 17). Particularly,
this transformation showed good selectivity; almost no di-
trifluoromethylated product was detected when NH4NO3 was
employed as additive (Table 1, Entries 15–18). Moreover,
increasing the amount of GO catalyst did not increase the yield
(Table 1, Entries 19–20). Further experiments indicated that
increasing the CF3SO2Na amount did not benefit the reaction
(Table 1, Entries 21–22; Table S1, Entries 39–41). Finally, we
checked the reaction atmosphere and observed that the
transformation could be conducted more effectively under air
than in other conditions (Table 1, Entries 17, 23–24).
Furthermore, the influence of metal impurities in GO was
investigated (please see Scheme S1 in Supporting
Recently,
a
metal-free procedure for direct aromatic
trifluoromethylation was developed by our group[6] and other
researchers[3,7] (Scheme 1, D). Nevertheless, the preparation
and use of concentrated peroxides or persulfides leads to
exposure to certain dangerous chemicals. Thus, developing
metal-free and initiator-free direct C–H trifluoromethylation of
arenes under safe conditions is desirable.
Figure 1. Examples of the application of arene trifluoromethylation.
[a]
Mr. J. Zhang, Mr. Y. Yang, Mr. J. Fang, Dr. G.-J. Deng, Dr. H. Gong
The Key Laboratory of Environmentally Friendly Chemistry and
Application of the Ministry of Education, College of Chemistry,
Xiangtan University, Xiangtan 411105, China.
E-mail: hgong@xtu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Table 1. Selected optimization results.a
Table 2. GO-catalyzed trifluoromethylation of arenes.a
Entry
Solvent
H2O
Additive
Yield/% (2a:3a)
1
2
—
—
0
THF
7 (7:0)
3
4
5
CH3CN
EtOAc
—
—
—
35 (35:0)
35 (35:0)
60 (60:0)
ClCH2CO2Et
6
BrCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
—
—
—
36 (35:1)
55 (55:0)
39 (39:0)
7b
8c
9d
10e
11
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
—
—
I2
25 (25:0)
56 (53:3)
0
12
13
14
15
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
iPr2NEt
H3PO4
43 (43:0)
38 (38:0)
42 (42:0)
65 (65:0)
KHCO3
NH4NO3
16f
17g
18g,h
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
NH4NO3
NH4NO3
NH4NO3
58 (58:0)
73 (73:0)
74 (74:0)
19g,i
20g,j
21g,k
22g,l
23g,m
24g,n
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
ClCH2CO2Et
NH4NO3
NH4NO3
NH4NO3
NH4NO3
NH4NO3
NH4NO3
65 (65:0)
74 (74:0)
43 (43:0)
69 (69:0)
51 (51:0)
69 (69:0)
a Unless otherwise noted, all reactions were conducted at 0.1 mmol scale with
CF3SO2Na (3 equiv), GO (10 mg), and additive (10 mol%) in a sealed tube in 1
mL solvent under air atmosphere for 12 h. Yields are detected by GC-MS
using naphthalene as internal standard. All other optimization reaction results
please see Table S1 in Supporting Informations; b Reaction temperature is
110 oC; c reaction temperature is 90 oC; d Reaction time is 6 h; e Reaction time
a Unless otherwise noted, all reactions were conducted at 0.2 mmol scale with
CF3SO2Na (3 equiv), GO (20 mg), and NH4NO3 (20 mol%) in a sealed tube in
1 mL ClCH2CO2Et under air atmosphere for 12 h. Yields are detected by GC-
MS using naphthalene as internal standard. The isolated yields were
presented.
f
g
h
is 18 h; 5 mol% NH4NO3 was added; 20 mol% NH4NO3 was added; 30
mol% NH4NO3 was added; i 5 mg GO was added; j 15 mg GO was added; k
2
This transformation can be easily scaled up to the gram level
by using GO (100 mg, 20 wt%) as catalyst, 1b (0.5 gram, 2.38
mmol) as the substrate, CF3SO2Na (1.1 g, 3.0 equiv.) as CF3
source, and NH4NO3 (38 mg, 20 mol%) as additive in
ClCH2CO2Et (5 mL). The mixture was stirred in a sealed tube
under air at 100 °C for 72 h. A good yield of 73% was achieved;
this yield is comparable to that of the template reaction (Scheme
2).
l
m
equiv of CF3SO2Na was used; 4 equiv of CF3SO2Na was used;
Under
argon atmosphere; n Under oxygen atmosphere.
Information), and the catalytic activity of GO was found to be
unrelated to metal impurities.
The scope of the substrate was examined using the reliable
trifluoromethylation protocol (Table 2). Generally, this
transformation depends highly on the electronic degree of the
substrate. Nearly all of the arenes substituted with three
electron-rich groups were converted into the desired
trifluoromethylation product at good yields (Table 2, 2a–e).
However, when the electronic effect of the substituents are
inconsistent, or less electron-donating groups are observed in
the arene, trifluoromethylation yield diminishes. In this case, only
a moderate yield could be achieved (Table 2, 2f–h). This
reaction is also compatible with ester, ketone, and halogen.
However, only moderate yields could be achieved because of
the negative inductive effect of these groups (Table 2, 2i–l).
Alkoxy-substituted thiophene also improved this transformation,
as shown by the obtained moderate to good yield (Table 2, 2m–
n). Unfortunately, almost none of the desired product or only
poor yield was attained when less electron-rich or electron-poor
arenes were used as substrates (Table 2, 2o–v).
The radical inhibition experiment was conducted using
TEMPO as blocker (Scheme 3). Only a trace amount of the
desired product was detected and thus indicated that the
transformation is probably achieved through a radical process.
Loh’s work demonstrated that the unpaired electrons of
porous GO plays a critical role in the aerobic oxidative
reaction of amine. In this reaction, tandem single-electron
transfer (SET) of amine to the GO shell and further to
oxygen could occur and gather the superoxide radical.[11]
Given the current investigation and our previous work,6 a
reasonable mechanism was proposed (Scheme 4). The
trifluoromethyl radical and superoxide radical were formed
through a tandem SET process. Subsequently, a radical
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purified by preparative thin-layer chromatography on silica gel with
petroleum ether and ethyl acetate to yield the pure product.
Acknowledgements
Scheme 2. Gram-scale reaction.
We are grateful to the National Natural Science Foundation of
China (No. 21402168), Scientific Research Foundation of Hunan
Provincial Education Department (No. 15B232) and Hunan 2011
Collaborative Innovation Center of Chemical Engineering &
Technology with Environmental Benignity and Effective
Resource Utilization for their support of our research.
Scheme 3. Radical inhibition experiment.
Keywords: trifluoromethylation • graphene oxide • metal-free •
initiator-free
addition of trifluoromethyl radical to arene occurred and
accessed the intermediate phenyl radical (I). The hydrogen
atom of phenyl radical was abstracted by the superoxide radical
to accomplish the aromatization reaction, and the target
molecule (T.M.) was achieved. Additionally, we thought that the
alkoxy group also benefits this transformation because of the
stabilization of radical intermediate (I).
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direct C–H trifluoromethylation of arenes under safe conditions
is
described.
The
initial-free
process
of
radical
trifluoromethylation is promising. This strategy possesses
several advantages, such as being metal free, initiator free, safe,
and scalable. The other benefits include the use of readily
available CF3 source and the easy control of the reaction to
obtain the mono-trifluorinated product. Therefore, the proposed
method introduced a new field for GO-catalyzed chemistry.
Experimental Section
[8] J. Zhang, S. Chen, F. Chen, W. Xu, G. Deng, H. Gong, Adv. Synth. Catal.
2017, DOI: 10.1002/adsc.201700178.
A typical experimental procedure: A solution of arene (0.2 mmol), GO (20
mg), CF3SO2Na (3.0 equiv), and NH4NO3 (20 mol%) in ClCH2CO2Et (1
mL) was stirred in a sealed tube under air atmosphere at 100 °C for 12 h.
The reaction mixture was then filtered and washed with ethyl acetate.
Afterwards, the solvent was evaporated in vacuo. The residue was
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Entry for the Table of Contents (Please choose one layout)
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Jingyu Zhang, Yun Yang, Jingxian Fang,
Guo-Jun Deng and Hang Gong*
Page No. – Page No.
Metal-free, Initiator-free Graphene
Oxide Catalyzed Trifluoromethylation
of Arenes
The direct C–H trifluoromethylation of arenes catalyzed by graphene oxide (GO)
under safe conditions is described. This strategy is metal free, initiator free, safe,
and scalable.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.