Nickel-Catalyzed Direct C-H Trifluoromethylation of Free Anilines with Togni's Reagent

Article abstract of DOI:10.1021/acs.orglett.8b01216

An efficient nickel-catalyzed C-H trifluoromethylation for the synthesis of trifluoromethylated free anilines using Togni's reagent has been developed. This approach exhibits a good functional group tolerance, good regioselectivity, and chemoselectivity under mild conditions. The newly developed economical one-step method is a better alternative to synthesize trifluoromethylated free anilines.

Full text of DOI:10.1021/acs.orglett.8b01216

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Direct C−H Trifluoromethylation of Free Anilines
with Togni’s Reagent
Xianying Gao,† Yang Geng,† Shuaijun Han,† Apeng Liang,† Jingya Li,‡ Dapeng Zou,*,†
Yusheng Wu,*,†,‡,§ and Yangjie Wu*,†
†The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Zhengzhou University, Zhengzhou 450052, People’s Republic of China
‡Tetranov Biopharm, LLC. and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052,
People’s Republic of China
§Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New Brunswick, New Jersey 08901, United States
S
* Supporting Information
ABSTRACT: An efficient nickel-catalyzed C−H trifluoromethylation
for the synthesis of trifluoromethylated free anilines using Togni’s
reagent has been developed. This approach exhibits a good functional
group tolerance, good regioselectivity, and chemoselectivity under
mild conditions. The newly developed economical one-step method is
a better alternative to synthesize trifluoromethylated free anilines.
romatic amines are important intermediates in organic
chemistry and fundamental building blocks of bioactive
Scheme 1. Methods for Preparation of Trifluoromethyl-
Substituted Free Anilines
a
A
compounds.1 Notably, the aromatic amino group can be
converted to different functional groups such as halogen,
hydrogen, hydroxyl, cyano, azido, boronate, and trifluoro-
methyl groups. CF3-containing molecules have additional
unique properties, such as remarkable biological activity, high
lipophilicity, and significant metabolic stability.2 Because of the
central position of aromatic amino and trifluoromethyl groups
containing molecules (Figure 1), introduction of trifluoro-
a
DG = directing group.
Figure 1. Drug molecules containing the CF3 group.
and Shi’s group, respectively.6 Although these methods usually
result in a high regioselectivity, the removal of the protecting
groups significantly decrease the functional group compatibility
(Scheme 1, reaction 3). More recently, two elegant works of
photoredox-catalyzed trifluoromethylation of free anilines were
also presented using different trifluoromethyl sources by Zhu’s
and Zhang’s groups (Scheme 1, reaction 4).7
Although the above works represent very promising
advances, the exploration of novel methodologies as an
alternative option remains highly desirable. To the best of
our knowledge, the direct C−H bond trifluoromethylation of
free anilines catalyzed by nickel still remains undeveloped. As
part of our particular interest in transition-metal-catalyzed
methyl substituents into aromatic amine has attracted
continuous interest in organic synthesis.3 However, only a
few examples for the direct installation of a CF3 group into free
anilines have been reported4−7 (as shown in Scheme 1). The
reason is that the N atom of free anilines is more active.7a In
1987, Wakselman and co-workers first reported trifluorome-
thylation of free anilines using trifluoromethyl bromide in the
presence of zinc and sulfur dioxide under pressure (Scheme 1,
reaction 1).4 Subsequently, some electrophilic trifluoromethy-
lation strategies were used to access trifluoromethyl-substituted
free anilines. However, there were relatively few aniline
substrates involved (Scheme 1, reaction 2).5 Recently, the N-
protected anilines were used to generate the trifluoromethy-
lated free amines by introducing a CF3 group and subsequently
removing the protecting groups in the same year by Xi’s group
Received: April 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
direct C−H functionalization and fluorine chemistry,8 herein,
we report a direct nickel-catalyzed C−H trifluoromethylation
of the readily available aromatic free amines with Togni’s
reagent under mild conditions.
At first, we examined the reaction of aniline 1a with Togni’s
reagent (2) under various conditions, and the results are
summarized in Table 1. When the reaction of 1a with 2 was
nickel catalysts (Table 1, entry 8). Increasing or decreasing the
amount of the catalyst loading led to a decrease in the yield
(Table 1, entries 9 and 10). A range of bases were also
screened (Table 1, entries 11−15), but none of them were
found to be effective for the reaction. Among the solvents
tested, DMSO was found to be the best choice (Table 1,
entries 16−20), and the trifluoromethylated product was
obtained in 66% total yield (Table 1, entry 20). The yield was
improved to 71% when the reaction was conducted at 35 °C
(Table 1, entries 20−22). Increasing the amount of 1a led to
an improvement in the yield (Table 1, entries 23−25). When
3.0 equiv of 1a was used, the yield was increased to 88%
(Table 1, entry 25). Carefully monitoring of the reaction
showed that the reaction was completed within 2 h at 35 °C in
DMSO (1 mL) (89%) (Table 1, entry 26). Finally, two control
experiments to probe the role of nickel catalyst were carried
out under the optimized conditions (Table 1, entries 27 and
28). When 5 mol % Ni(OH)2 was used, the product yield
decreased to 70% (Table 1, entry 27), while only 52% yield
was obtained in the absence of Ni(OH)2 (Table 1, entry 28).
This result revealed that the nickel catalyst is necessary for our
reaction.
Under the optimized reaction conditions, diverse free
anilines 1a−1v were reacted with Togni’s reagent 2 to give
the desired products in good to excellent yields (see Scheme
2). Various functional groups, including alkyl, alkoxy, cyano,
trifluoromethyl, ester, acyl, phenyl, halide, and amide were
compatible under the standard conditions. In addition, the
molecular structure of product 3i was further confirmed
through single-crystal X-ray diffraction (XRD) analysis. Much
to our satisfaction, trifluoromethylation of halogen-substituted
and boronate-containing anilines proceeded smoothly to give
the desired products, which provides a convenient platform for
further elaboration (3m−3u). Among them, the trifluorome-
thylation reaction of 1s was also scaled up in gram scale, and
the product 3s was afforded in 77% yield. Furthermore,
anilines bearing methoxy groups and bromo atom at different
positions were well-tolerated, and the corresponding products
were obtained in good yields (3d−3f and 3q−3s). For the o-
substituted anilines, a mixture of ortho- and para-trifluor-
omethyl substituted anilines were obtained (3d and 3q).
Whereas, in case of m-substituted anilines, there are usually
three reactive positions (3e and 3r). Meanwhile, the
trifluoromethylation reaction proceeded at the para position
when using di-ortho-substituted aniline as a substrate (3g). In
contrast to previous directing-group strategy, the para-CF3
products were the major products for the substrates 1d and 1e.
To further demonstrate the potential utility of this method-
ology for medicinal chemistry, the trifluoromethylation of an
antibacterial drug dapsone 1v was investigated, and the target
product was obtained in good yield (90%).
a
Table 1. Optimization of the Reaction Conditions
b
temperature
yield
(%)
entry
Ni source
base
solvent
(°C)
1
2
3
4
NiCl2·6H2O
Ni(OTf)2
Ni(PPh3)2Cl2
Ni(OAc)2·
4H2O
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
80
80
80
80
38
49
38
30
5
6
Ni(OH)2
Ni(NO3)2·
6H2O
K2CO3
K2CO3
dioxane
dioxane
80
80
53
35
7
8
NiBr2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
DMAP
t-BuOK
DIPEA
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
toluene
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
35
35
35
35
35
35
35
38
35
48
50
49
c
9
10
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
Ni(OH)2
d
11
12
13
14
15
16
17
18
19
20
21
22
42
trace
trace
35
trace
n.d.
65
39
66
60
71
58
80
88
89 (81)
70
e
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
f
23
g
24
h
25
26
i
ci
,
27
28
i
52
a
Reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2 (0.3 mmol, 1.2
equiv), Ni source (10 mol %), K2CO3 (3.0 equiv), dioxane (2.0 mL),
b
80 °C, under Ar, 12 h. Total yields of product 3a and 3a′ are
determined by GC analysis using dipentyl phthalate as an internal
standard. The total isolated yields of product 3a and 3a′ are given in
c
d
To gain insight into the reaction mechanism, two control
experiments were performed under the optimized conditions
(see Scheme 3). When the radical scavengers TEMPO and 1,1-
diphenylethylene were added separately to the trifluoromethy-
lation reaction mixture, only a small amount of product was
formed and GC-MS analysis showed that compounds 4 and 5
were produced (see Scheme 3, eqs 1 and 2). These results
suggested that the reaction might involve a radical process.
According to the previous literature,6b,7a,9 and the above
experiment results, a plausible mechanism is proposed (see
Scheme 4). First, the CF3 radical A and Ni(III) species B was
generated from the Togni’s reagent in the presence of Ni(II).
parentheses. Run with 5 mol % Ni(OH)2. Run with 20 mol %
e
f
Ni(OH)2. Not detected. A substrate ratio of 1a/2 = 1:2 was used.
g
h
A substrate ratio of 1a/2 = 2:1 was used. A substrate ratio of 1a/2 =
i
3:1 was used. The reaction was conducted for 2 h in DMSO (1 mL).
carried out in dioxane using NiCl2·6H2O as a catalyst, and in
the presence of K2CO3 (3.0 equiv) at 80 °C under argon for 12
h, two isomers 3a and 3a′ were obtained in 38% total yield
(Table 1, entry 1). Next, a survey of the different nickel
catalysts was investigated (Table 1, entries 1−7) and Ni(OH)2
was found to be the best catalyst (Table 1, entry 5). The
product could be obtained in 35% yield in the absence of
B
DOI: 10.1021/acs.orglett.8b01216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Nickel-Catalyzed C−H
Scheme 4. Proposed Mechanism
Trifluoromethylation of Free Anilines with Togni’s
a b
,
Reagent
obtained in good to excellent yields under mild conditions.
The present work provides a more concise and efficient
alternative protocol to synthesize trifluoromethylated free
anilines, compared to most trifluoromethylation protocols.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01216.
Experimental details, characterizations, NMR spectra
analysis of the products (PDF)
Accession Codes
CCDC 1835608 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
a
Standard reaction conditions: 1 (1.5 mmol, 3.0 equiv), 2 (0.5 mmol,
1.0 equiv), Ni(OH)2 (10 mol %), K2CO3 (3.0 equiv), DMSO (2.0
b
c
mL), 35 °C, under Ar, 2 h. Isolated yield. The isomer ratio of C2/
C4. dThe isomer ratio of C2/C4/C6. eThe reaction was conducted for
12 h. fThe isolated yield of product 3s is given within parentheses on
gram scale.
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 3. Mechanistic Studies
*E-mail: zdp@zzu.edu.cn
*E-mail: yusheng.wu@tetranovglobal.com
*E-mail: wyj@zzu.edu.cn
ORCID
Yusheng Wu: 0000-0001-7023-9541
Yangjie Wu: 0000-0002-0134-0870
Notes
The authors declare no competing financial interest.
Addition of the CF3 radical to the ortho position (or para
position) of aniline formed the intermediate radical C. The
oxidation of C by Ni(III) species B then afforded the
carbocation D, and returned Ni(II) species to the catalytic
cycle. Finally, the deprotonation of D gave the desired product
3 under the action of base.
In summary, we have developed a direct nickel-catalyzed C−
H trifluoromethylation of free anilines using Togni’s reagent.
This one-step method exhibits a good functional group
tolerance. A variety of trifluoromethylated free anilines were
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (Nos. 21172200 and 21702191) for financial support.
■
REFERENCES
■
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DOI: 10.1021/acs.orglett.8b01216
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b01216
Org. Lett. XXXX, XXX, XXX−XXX