A metal-free picolinamide assisted electrochemical ortho-trifluoromethylation of arylamines

Article abstract of DOI:10.1016/j.tetlet.2020.152623

An eco-friendly and effective electrochemical process was developed for the ortho-trifluoromethylation of arylamines using CF₃SO₂Na as the trifluoromethyl source, affording the desired products in moderate to good yields with high regioselectivity under mild reaction conditions. Importantly, the requirement for both transition metals and oxidants utilized in previous methods were avoided. A radical mechanism was proposed on the basis of various control experiments.

Full text of DOI:10.1016/j.tetlet.2020.152623

Journal Pre-proofs
A metal-free picolinamide assisted electrochemical ortho-trifluoromethylation
of arylamines
Kai Wang, Jiahao Hou, Tingting Wei, Changjun Zhang, Renren Bai,
Yuanyuan Xie
PII:
DOI:
Reference:
S0040-4039(20)31128-X
https://doi.org/10.1016/j.tetlet.2020.152623
TETL 152623
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 August 2020
23 October 2020
29 October 2020
Please cite this article as: Wang, K., Hou, J., Wei, T., Zhang, C., Bai, R., Xie, Y., A metal-free picolinamide
assisted electrochemical ortho-trifluoromethylation of arylamines, Tetrahedron Letters (2020), doi: https://
doi.org/10.1016/j.tetlet.2020.152623
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Tetrahedron Letters
journal homepage: www.elsevier.com
A metal-free picolinamide assisted electrochemical ortho-
trifluoromethylation of arylamines
Kai Wang,a Jiahao Hou,b Tingting Wei,b Changjun Zhang,a Renren Bai,b and Yuanyuan Xiea,b*
a Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou,
310014, China.
b College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China.
E-mail: xyycz@zjut.edu.cn (Y. Xie).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An eco-friendly and effective electrochemical process was developed for the ortho-
trifluoromethylation of arylamines using CF3SO2Na as the trifluoromethyl source, affording the
desired products in moderate to good yields with high regioselectivity under mild reaction
conditions. Importantly, the requirement for both transition metals and oxidants as utilized in
previous methods were avoided. A radical mechanism was proposed on the basis of various
control experiments.
Available online
Keywords:
ortho-Trifluoromethylation
Arylamines
Electrochemical C-H functionalization
Metal- and oxidant-free

electrons instead of traditional oxidants [13]. In 2018, Lei and
co-workers [14d] developed direct electrochemical
oxytrifluoromethylation and aminotrifluoromethylation of
alkenes. In the same year, Zeng and co-workers [14e] described
Introduction
Fluorine-containing organic compounds have attracted
increasing attention in materials, [1] pharmaceutical [2] and
agrochemical chemistry. [3] Especially, the incorporation of
trifluoromethyl groups into organic compounds [4] has gained
attention due to their special chemical characteristics and
metabolic stabilities.
a
an
electrochemical
trifluoromethylarylation
of
N-
arylacrylamides catalyzed by bromide. Both of these reactions
use CF3SO2Na as the trifluoromethyl source, which proves that
the trifluoromethylation reaction can be realized under metal-
free and oxidant-free conditions via electrochemistry. Inspired
by these studies and in combination with our previous efforts in
trifluoromethylation, [12e] we have developed a metal-free,
electrochemical process for the ortho-trifluoromethylation of
Traditional methods for trifluoromethylation have been
implemented with aryl halides [5] or boronic acids, requiring
dangerous fluoridation reagents and harsh reaction conditions.
[6] Presently, with the development of transition-metal-
catalyzed C-H activation, numerous direct functionalization
reactions have been reported. [7] Among these reactions, direct
trifluoromethylations [8] have gained significant attention,
especially using arylamine derivatives. In 2010 and 2012, the
ortho-trifluoromethylation of 2-phenylpyridines was developed
by Yu and co-workers [7a] with Pd(OAc)2 as the catalyst. Later,
in 2013, and also with the participation of Pd(OAc)2, Shi and
co-workers reported the direct ortho-trifluoromethylation of
acetamide [7b], and a similar reaction was demonstrated by Xi
and co-workers with CuCl [7c]. However, the use of precious
metals, large amounts of oxidants, and expensive
trifluoromethylating reagents such as Umemoto's reagent [9],
Togni's reagent [10] and TMSCF3 [11] were required in these
works.
arylamine
derivatives
using
CF3SO2Na
as
the
trifluoromethylating reagent.
Results and Discussion
Initially, we commenced our investigation using the model
reaction of N-phenylpicolinamide 1a as the starting material and
CF3SO2Na 2a as the trifluoromethylated reagent. The
electrochemical reaction was carried out in an undivided cell
which was equipped with a C anode and a Pt cathode, and stirred
o
at 50 C under an air atmosphere for 2 h in the presence of n-
Bu4BF4 using MeCN as the solvent. Gratifyingly, product 3a
was formed in 58% yield (Table 1, Entry 1). Encouraged by this
result, we then screened several other anodes including
reticulated vitreous carbon (RVC), Pt, Ni, and Cu; however, the
yields decreased to 47%, 38%, 55%, and 17%, respectively
(Table 1, Entries 2-5). At the same time, when the cathode was
changed from Pt to C, no product was detected (Table 1, Entry
6). Solvents such as CH3OH and 1,4-dioxane were inferior to
MeCN (Table 1, Entries 7-8). Meanwhile increasing or
decreasing the current density and replacement of the electrolyte
did not improve the yield (Table 1, Entries 9-13). The
transformation also did not take place without an electric current
(Table 1, Entry 14).
In recent years, CF3SO2Na (a low-cost, hypotoxic and stable
trifluoromethylated reagent) has proven to be effective in direct
trifluoromethylation [12]. In 2017, Zhang and co-workers [12a]
established a nickel(II)-catalyzed ortho-trifluoromethylation of
arylamines. Next, in 2018, the photoinduced ortho-
trifluoromethylation of arylamines was described by Xia and co-
workers, employing ferrocene as the catalyst [12d]. In 2019,
another visible-light mediated ortho-trifluoromethylation was
reported by An, Li and co-workers [12f] (Fig. 1).
Table 1.
Reaction optimization.a,b
Zhang's work [12a]
O
C(+)-Pt(-), I = 15 mA
O
NiSO4•6H2O (10 mol%)
K2S2O8 (2.0 eq.)
O
O
n-Bu4NBF4 (0.3 eq.)
N
H
N
H
+
CF
3SO2Na
N
+
CF
3SO2Na
N
H
H
CF3
N
N
MeCN, 50 °C, 2 h, Air
undivided cell
H2O, 50 °C, 12 h, Air
CF3
N
N
N
1a
2a
3a
Xia's work [12d]
O
O
Entry
Variation from the standard conditions
Yield 3a [%]b
Iron-catalyzed (15 mol%)
UV,acetone, 36 h, rt
N
H
+
CF
3SO2Na
N
CF3
H
N
1
2
3
4
5
6
7
8
9
None
58
47
38
55
17
Trace
26
31
50
53
RVC anode instead of C anode
Pt anode instead of C anode
Ni anode instead of C anode
Cu anode instead of C anode
C cathode instead of Pt cathode
CH3OH instead of CH3CN
1,4-dioxane instead of CH3CN
10 mA instead of 15 mA
An's and Li's work [12f]
O
Eosin Y (5 mol%)
CuCl2 (10 mol%)
(NH4)2S2O8 (2.0 eq.)
O
O
+
CF
3SO2Na
R
N
R
N
H
H
Blue LED
MeCN, 20 h, Air
CF3
Our work
C(+)-Pt(-), I=15 mA
n-Bu4NBr (0.3 eq.)
O
R2
R2
10
11
12
13
14
20 mA instead of 15 mA
R1
N
R1
N
H
CF
3SO2Na
2a
+
MeCN, 50 °C, Air, 2 h
undivided cell
n-Bu4NCl instead of n-Bu4NBF4
n-Bu4NBr instead of n-Bu4NBF4
n-Bu4NI instead of n-Bu4NBF4
No electricity
27
51
46
N.R.
H
H
CF3
3
1
Figure 1. Representative examples of the direct ortho-trifluoromethylation
of arylamines.
a Reagents and conditions: C anode, Pt cathode, constant current = 15 mA,
1a (0.3 mmol), 2a (1.5 eq.), n-Bu4NBF4 (0.3 eq.), CH3CN (3 mL), C anode
(d = 6 mm), Pt plate cathode (5 mm × 5 mm × 0.3 mm ), 50 oC, 2 h, air.
b Isolated yield.
Recently, electrochemistry has received widespread
attention as an effective method to realize radical reactions using

CF
3SO2Na (1.5 eq.)
c N.R. = No reaction.
O
C(+)-Pt(-), I = 15 mA
O
H2N
n-Bu4NBF4 (0.3 eq.)
HCl. EtOH
N
H
N
N
H
MeCN, 50 °C, 22 h, Air
undivided cell
CF3
N
F3C
With the optimum electrolysis trifluoromethylation protocol
in hand, we next examined the scope and limitations of the
reaction using various arylamines. As shown in Table 2,
electron-donating and electron-withdrawing arylamines were
tolerated, and gave the desired products in 17-63% yield (Table
2, 3a-3l), although electron-donating ones performed better.
Specifically, taking para-substituted arylamines as an example
(Table 2, 3b-3f), the 4-CH3 arylamine was isolated in 53% yield
while the yield of 4-Cl, 4-Br, 4-CN, and 4-NO2 arylamines were
less than 45%. Furthermore, both para-substituted (Table 2, 3b-
3f) and meta-substituted arylamines (Table 2, 3i-3l) gave higher
yields than ortho-substituted arylamines (Table 2, 3g-3h),
which indicated that steric hindrance has a significant influence
on this transformation. Finally, naphthyl derived picolinamides
and other nitrogen heterocyclic amides also afforded the desired
products in good yields (Table 2, 3m-3q).
3a
7
, 85%, 0.64g
, 47%, 1.25g
1a
, 10 mmol
Scheme 1. Gram scale reaction.
To gain further insight into the mechanism of this
transformation, several control experiments were implemented
(Scheme 3). Firstly, we conducted the trifluoromethylation
reaction under the standard conditions with the addition of 3.0
equivalents of TEMPO. Unsurprisingly, none of the desired
product was obtained, which revealed that a radical pathway
could explain the process. Next, different amides were used
instead of 1a; however, none of the desired product was
detected, which indicated that the pyridine ring was necessary
for the reaction. Further research was carried out with an On/Off
experiment, which showed that a continuous electric current
was required (Scheme 2).
O
TEMPO (3.0 eq.),
standard conditions
O
(1)
+
N
CF
3SO2Na
N
H
H
CF3
3a
, N.R.
N
N
Table 2.
1a
2a
Substrate scope for the trifluoromethylation reaction.a,b
O
O
O
N
H
(2)
N
C(+)-Pt(-), I=15 mA
n-Bu4NBF4 (0.3 eq.)
N
O
O
R2
R2
H
X
4a,
4b,
N.R.
N.R.
R1
N
R1
N
CF
3SO2Na
4c, X=O, N.R.
4d,
+
MeCN, 50 °C, Air, 2 h
undivided cell
H
H
X=S, N.R.
H
CF3
3
2a
1
current density On or Off
O
O
Cl
n-Bu4NBF4 (0.3 eq.)
O
O
N
N
H
O
+
CF3SO2Na
(3)
N
H
MeCN, 50 °C, 4 h, Air
undivided cell
CF3
N
N
N
H
2a
N
1a
3a
H
H
CF3
N
CF3
N
N
N
3a,
3a,
3a,
0-1 h, current density On,
1-3 h, current density On,
3-4 h, current density On,
31%,
31%,
58%.
CF3
N
3b,
53%
3c,
42%
3a,
58%
NO2
Scheme 2. Investigation of the mechanism.
CN
Br
O
O
O
N
N
N
H
H
We then carried out cyclic voltammetry (CV) experiments.
It could be clearly observed that the oxidation potential (EP/2
of CF3SO2Na was 1.43 V, which was oxidized to the
trifluoromethyl radical. Meanwhile, the oxidation potential of
1a was not detected. It was then found that the oxidation
potential (EP/2) changed to 1.56 V when CF3SO2Na was added,
which presumably generated complex C (see Scheme 3).
H
CF3
N
CF3
CF3
N
)
3f,
3d,
27%
45%
3e,
31%
CH3
F
O
O
O
N
H
N
N
H
H
CF3
CF3
N
CF3
N
3g,
17%
3h,
25%
3i,
51%
F
Cl
Br
O
O
O
N
H
N
H
N
H
CF3
41%
N
N
CF3
N
CF3
3j,
3k,
49%
3l,
53%
O
O
O
N
H
N
N
H
N
CF3
N
CF3
H
N
CF3
N
3o,
51%
3m,
3n,
43%
O
49%
O
N
N
H
N
H
CF3
CF3
N
3q,
61%
3p,
63%
a Reagents and conditions: C anode, Pt cathode, constant current = 15 mA,
1a (0.3 mmol), 2a (1.5 eq.), n-Bu4NBF4 (0.3 eq.), CH3CN (3 mL), C anode
(d = 6 mm), Pt plate cathode (5 mm × 5 mm × 0.3 mm ), 50 oC, 2 h, air.
b Isolated yield.
Figure 2. Cyclic voltammograms. a: blank; b: 1a (10 mM, red); c: 2a (15
mM, blue); d: 1a (10 mM) + 2a (15 mM, pink).
Considering that the initial substrates were readily obtained
and the method was easy to operate, a gram scale reaction was
performed (Scheme 1); the desired product 3a was obtained in
47% yield and subsequently 7 was obtained in 85% using our
previously described method. [12e]
On the basis of above findings and previous reports [12a,
14i] we proposed the following plausible mechanism via a
radical coupling pathway (Scheme 3).

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O
2 e
-
N
H
2 e
N
-
1a
2 H
Na
CF3SO2
- e-, -H
O
+
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7238.
2 e
-
N
H2
CF3
N
A
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O
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O
O
PT
N
N
N
H
CF3
H
N
N
N
CF3
B
3a
C
Scheme 3. Plausible mechanism of trifluoromethylation
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through oxidation at the anode. Next, 1a was oxidized into
intermediate A through deprotonation at the anode. After
which, B was formed via resonance from A. Then, species C
was obtained by radical coupling between the CF3 radical and
B. Finally, the desired product 3a was generated through a
proton-transfer (PT) process.
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Conclusion
In summary, we have developed an efficient and practical
protocol for the electrochemical ortho-trifluoromethylation of
anilines under transition metal-free and oxidant-free conditions.
This electrochemical method tolerated a broad substrate scope
and the expected products were obtained in moderate to good
yields. Primary investigation demonstrated that a radical
mechanism was involved.
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Acknowledgements
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This work was supported by the National Natural Science
Foundation of China, NSFC (No. 21978273 and 21576239)
and National Key R&D Program of China (No.
2018YFC0214100).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://
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(g) Zhao, H. B.; Hou, Z. W.; Liu, Z. J.; Zhou, Z. F.; Song, J. S.; Xu, H.
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An electrochemical method for the synthesis of ortho-trifluoromethylation of arylamines was developed.
The addition of transition metals and oxidants was not required.
The desired products were obtained in moderate to good yields.
The study of the reaction mechanism revealed that a radical step was involved in this transformation.
Declaration of interests
☒ 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.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
A metal-free picolinamide assisted
electrochemical ortho-
trifluoromethylation of arylamines
C(+)-Pt(-), I=15 mA
n-Bu4NBF4 (0.3 eq.)
O
O
R2
R2
R1
N
R1
N
CF
3SO2Na
+
MeCN, 50 °C, Air, 2 h
undivided cell
H
H
H
CF3
3
2a
1
 Metal and Oxidant free
 Mild condition and broad substrate scope
 17 examples, up to 63% yield
Kai Wang, Jiahao Hou, Tingting Wei, Changjun
Zhang, Renren Bai and Yuanyuan Xie *