Regioselective Ortho Amination of an Aromatic C-H Bond by Trifluoroacetic Acid via Electrochemistry

Article abstract of DOI:10.1021/acs.orglett.9b01910

A trifluoroacetic acid-facilitated ortho amination of alkoxyl arene has been established via anodic oxidation in an undivided cell. In the absence of any additional metal or oxidant reagents, a series of aromatic and heteroaromatic amine derivatives have

Full text of DOI:10.1021/acs.orglett.9b01910

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Ortho Amination of an Aromatic C−H Bond by
Trifluoroacetic Acid via Electrochemistry
Jing-Hao Wang,†,‡ Tao Lei,†,‡ Xiao-Lei Nan,†,‡ Hao-Lin Wu,†,‡ Xu-Bing Li,†,‡ Bin Chen,†,‡
Chen-Ho Tung,†,‡ and Li-Zhu Wu*,†,‡
†Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Beijing 100190, P. R. China
‡School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: A trifluoroacetic acid-facilitated ortho amination of alkoxyl arene has been established via anodic oxidation in an
undivided cell. In the absence of any additional metal or oxidant reagents, a series of aromatic and heteroaromatic amine
derivatives have been synthesized in good to excellent yields. Our findings reveal the possibility of achieving complete ortho-
selective amination of a simple arene, which emerges as an efficient route for facile and large-scale organic synthesis.
Scheme 1. Amination of Arene
n aromatic amine derivative is a significant structural
Amotif that widely exists in natural products, agro-
chemicals, pharmaceuticals, and medical compounds,1 which
leads to the hot topic of its construction in organic chemistry.
Traditional methods using metal-catalyzed (e.g., Pd and Cu)2,3
cross coupling of aromatic halide (or psudohalide) and
nitrogen species has been regarded as the most significant
way to realize selective C−N bond formation, but starting
material prefunctionalization and ligand elaboration are needed
(Scheme 1a). A more straightforward and atom-economical
way would be direct C−N bond formation from C−H/N−H
cross coupling. In this context, directing group-assisted
selective C−H activation/amination processes by either
transition metal (such as Pd,4 Rh,5 Ru,6 Cu,7 etc.) catalysis
or electrocatalysis in which Co participates8−10 achieved highly
ortho-selective C−H amination. Other seminal methods like
photocatalysis11 or metalla-photocatalysis12 also realized the
amination, but they showed poor selectivity for the substituted
substrate due to the weak control of the reaction site (Scheme
1b). To date, the site-selective amination of arene remains
challenging to achieve with high selectivity for a simple arene
without a strong directing group.
This work discloses that trifluoroacetic acid (TFA) can
control the electrocatalytic amination of alkoxy arenes with
unprecedented high ortho selectivity. As is known, electro-
catalysis and photoelectrocatalysis are promising for the
construction of C−C and C−N bonds in a series of cross-
coupling reactions.13−19 Herein, direct oxidative C−H/N−H
cross coupling of arenes by employing pyrazole as the
amination reagent has been realized with 2 equiv. of TFA.
Ortho-selective aromatic amine derivatives have been synthe-
sized in good to excellent yields (Scheme 1c). More
significantly, the strong effect of TFA to control nearly the
regiospecificity for the ortho isomer is uncovered for the first
time, which shows great potential in practical organic synthesis.
Initially, anisole 1 and pyrazole 2 were used as model
substrates. The electrochemical reactions were carried out in
an undivided cell equipped with a reticulated vitreous carbon
(RVC) anode and a platinum plate cathode. When the solution
Received: June 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01910
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
n
of 1, 2, and 0.1 M Bu4NOAc in 1,1,1-trifluoroethanol (TFE)
was electrolyzed, an 83% yield of the amino product was
observed with a moderate ortho/para ratio (64:19 3b:3a)
(Table 1, entry 2). To our surprise, with the addition of TFA,
With the optimized reaction conditions in hand, we tried to
explore the substrate generality of this electrochemical
transformation (Scheme 2). Initially, a series of monosub-
a
Scheme 2. Substrate Scope of Anisole
a
Table 1. Optimization of Conditions
yield (%)
conversion of
entry
1
electrolysis conditions
1 (%)
3a
3b
3
C(+)/Pt(−), 5 mA/4 h, TFE,
85
trace
75
75
TFA, rt, Ar
2
3
4
5
6
7
8
9
no TFA
92
93
64
81
73
90
73
62
78
79
92
79
89
88
0
19
trace
64
56
trace
29
25
72
83
56
HFIP as the solvent
DCE as the solvent
CH3COOH as the additive
PivOH as the additive
TfOH as the additive
NaHCO3 as the additive
nBu4NBF4 as the electrolyte
nBu4NClO4 as the electrolyte
RVC as the cathode
nickel foam as the cathode
Pt plate as the anode
under 10 mA and 2 h
under air
14
17
trace
16
trace
43
42
72
47
16
31
16
10
11
12
13
14
15
16
trace
50
63
26
59
18
21
5
trace
trace
68
84
31
59
37
37
no electric current
not detected
a
Conditions: RVC anode (500 PPI, 1.0 cm × 1.0 cm × 0.5 cm), Pt
plate as the cathode (0.5 cm × 1 cm), 1 (0.2 mmol), 2 (0.4 mmol),
nBu4NOAc (0.1 M), 2 equiv. of TFA, TFE (4.0 mL), rt, Ar.
Conversion and yield determined by GC analysis with tetradecane as
the internal standard. The yield was based on 1 (0.2 mmol).
a
Standard conditions: RVC anode (500 PPI, 1.0 cm × 1.0 cm × 0.5
cm), Pt plate as the cathode (0.5 cm × 1 cm), 1 (0.2 mmol), 2 (0.4
mmol), Bu4NOAc (0.1 M), 2 equiv. of TFA, TFE (4.0 mL), rt, Ar.
Isolated yields were provided. Reaction ran without TFA.
n
b
almost a single ortho isomer was formed with a yield of 75%
(Table 1, entry 1). Further solvent screening demonstrated
that 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as a solvent
could also give the regioselectivity with a decreased 56% yield
(Table 1, entry 3), and no desired product was obtained when
TFE was replaced by 1,2-dichloroethane (DCE), methanol
(MeOH), ethanol (EtOH), or acetonitrile (CH3CN) (Table
S1). Then, other different additives instead of TFA, including
acetic acid (CH3COOH), pivalic acid (PivOH), trifluorome-
thanesulfonic acid (TfOH), and NaHCO3, were tested. The
results showed that acetic acid, pivalic acid, and NaHCO3
yielded product 3 in 43%, 42%, and 47% yields, respectively,
with poor selectivities. Notably, TfOH exhibited similar
activity with TFA, and a yield of 72% for the ortho product
was obtained (Table 1, entries 5−8). In addition, the
parameters of this electrolytic system were further optimized.
Replacement of the electrolyte, cathode, or anode gave lower
yields and poorer regioselectivity (Table 1, entries 9−13).
Increasing the current density or reaction in the air atmosphere
preserved the selectivity but decreased the yields (Table 1,
entries 14 and 15). Finally, no product could be observed
when the reaction was carried out in the absence of electricity,
demonstrating the nature of electrocatalysis (Table 1, entry
16).
stituted anisole derivatives were examined. For methyl, ethyl, i-
Pr, and n-Bu substitutions, the absence of TFA delivered good
yields but poor selectivities, providing mixtures of ortho and
para amination products (3−6, <3.2:1 o:p). When the acid was
added, almost pure ortho isomers were formed (≥40:1 o:p).
These results further demonstrated the excellent regiocontrol
by strong Bronsted acid TFA. Likewise, other monosubstituted
anisole derivatives, such as tert-butyl phenyl ether and (prop-2-
ynyloxy)benzene, selectively furnished the ortho amination in
52% (>50:1 o:p) and 60% (>50:1 o:p) yields, respectively, in
the presence of TFA (7 and 8). Unfortunately, no
corresponding products were formed for ortho-disubstituted
arene (9), and meta-disubstituted arenes gave high para
isomers (10 and 11). With respect to 1,4-disubstituted arenes,
corresponding amination products with a single ortho isomer
were afforded (12 and 13). Interestingly, 2,4-dichloroanisole,
which has three substitutions, gave a single ortho product in a
moderate yield (14). In addition, other aromatic compounds
like naphthalene and 2-methoxynaphthalene were also
investigated to selectively furnish C1 amination products (15
and 16). Even 6-methoxyquinoline could be converted into a
single isomer (17) in 68% yield.
B
DOI: 10.1021/acs.orglett.9b01910
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Subsequently, a series of heterocyclic amines as amination
reagents were studied to expand the synthetic utility of this
method (Scheme 3). In the presence of TFA, pyrazole with
Scheme 4. Scale-Up Reaction and Control Experiment
a
Scheme 3. Substrate Scope of Amines
of anisole 1 and pyrazole 2 could give a 71% isolated yield of
the ortho isomer (>50:1 o:p) (Scheme 4b). However, when 2
equiv. of TEMPO or BHT was added for radical capture, no
corresponding C−N coupling products were formed, demon-
strating a possible radical pathway in this system (Scheme 4c).
In addition, cyclic voltammetry of two substrates showed that
the oxidation potentials of anisole 1 and pyrazole 2 were 1.67
and 2.10 V versus SCE, respectively (Figure S2). Clearly,
anisole was oxidized first under electrolytic conditions.
On the basis of the aforementioned results, a possible
mechanism for the electro-oxidative amination reaction is
outlined in Scheme 5. Initially, anisole was oxidized to
a
Standard conditions: RVC anode (500 PPI, 1.0 cm × 1.0 cm × 0.5
cm), Pt plate as the cathode (0.5 cm × 1 cm), 1 (0.2 mmol), 2 (0.4
mmol), Bu4NOAc (0.1 M), 2 equiv. of TFA, TFE (4.0 mL), rt, Ar.
Isolated yields were provided. Reaction ran without TFA.
n
Scheme 5. Proposed Mechanism
b
different groups worked smoothly and could be selectively
transferred into its corresponding ortho products. For example,
the pyrazole derivatives bearing a methyl, tert-butyl, or halogen
group at 4-position showed good activities to form the ortho
isomer with 55−74% yields and a >50:1 o:p ratio (18−22). 3-
Methyl-1H-pyrazole mainly produced the N-1 product in 33%
yield (>50:1 o:p), along with 14% N-2 product (1:15 o:p)
(23). Moreover, disubstituted 3,5-dimethyl-1H-pyrazole and
3,5-diisopropyl-1H-pyrazole were well tolerated with good
yields and ortho selectivity (24 and 25, >50:1 o:p). It should be
noted that benzotriazole instead of pyrazole as the amination
agent could give a 57% yield of the ortho product (>50:1 o:p)
under the optimized condition, while a 83% yield of the
mixture with a 1:1.7 o:p ratio was detected without TFA,
further highlighting the importance of TFA for selective
amination. Similarly, the method could also be applied to two
other derivatives such as benzimidazole, 1,2,4-triazoles, which
gave the corresponding C−N coupling products in good yields
but low selectivities. Apparently, the TFA enabled us to adjust
the regioselectivity for ortho priority (27 and 28). Finally, a
scaled-up reaction of template in 5 mmol was carred out. After
the reaction system was electrolyzed at 50 mA for 10 h, 3 was
obtained in 64% yield and the selectivity remained >50:1 o:p
(Scheme 4a), indicating the robustness of this strategy and its
great potential for practical organic synthesis and industral
application.
corresponding radical cation intermediate I on the anode
surface through a single-electron transfer. The fluorinated
solvent had the function of stabilizing radical cations.20
Subsequently, pyrazole as a nucleophile attacked the radical
cation to form intermediate II probably via TFA-assisted
hydrogen bond interaction.21 Then, intermediate III was
afforded with the loss of one proton. Followed by the
rearomatization, final product 3b was formed.
In summary, we have developed an electrochemical oxidative
C−H/N−H cross coupling, which realized the almost
completely ortho-selective amination of arene. TFA plays an
essential role in the control of regioselectivity. This protocol
To understand this reaction, several control experiments
were carried out. Under the optimized condition, the reaction
C
DOI: 10.1021/acs.orglett.9b01910
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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.9b01910.
Materials and methods, condition optimization and
general experimental procedures, scale-up reaction,
control experiments, cyclic voltammetry experiments,
characterization data for all products, references, and 1H
and 13C spectra of products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lzwu@mail.ipc.ac.cn.
ORCID
Bin Chen: 0000-0003-0437-1442
Chen-Ho Tung: 0000-0001-9999-9755
Li-Zhu Wu: 0000-0002-5561-9922
Notes
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Amination by Cobalt Catalysis in a Renewable Solvent. Angew. Chem.,
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Ackermann, L. Electrochemical Cobalt-Catalyzed C-H Activation.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science and
Technology of China (2017YFA0206903), the National
Natural Science Foundation of China (21861132004 and
21603248), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB17000000), the Key
Research Program of Frontier Sciences of the Chinese
Academy of Sciences (QYZDY-SSW-JSC029), the Youth
Innovation Promotion Association of the Chinese Academy
of Sciences (2018031), and the K. C. Wong Education
Foundation.
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