Direct Synthesis of Primary Anilines via Nickel-mediated C(sp2)-H Aminations

Article abstract of DOI:10.1002/adsc.201701371

An efficient and mild protocol for the direct conversion of arene C?H bonds to C?NH₂ without the need for extra deprotection step has been established, and to the best of our knowledge, this is the first time that the synthesis of primary anilines via nickel-mediated C(sp²)-H activations has been reported. This approach utilizes 8-aminoquinoline as the directing group and sodium azide, a cheap and commercially available material, as the nitrogen source. In addition, the reaction is highly selective, affording the mono-ortho-aminated benzamides only. The reaction tolerates a broad range of substrates with diverse functional groups and the corresponding ortho-aminated benzamides were efficiently synthesized in 41–82% yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201701371

Title: Direct Synthesis of Primary Anilines via Nickel-mediated
C(sp²)-H Aminations
Authors: Lin Yu, Xiang Cheng, Da Liu, Liang Hu, Yongqi Yu, Hang
Huang, Ze Tan, and Qingwen Gui
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701371
Link to VoR: http://dx.doi.org/10.1002/adsc.201701371

Advanced Synthesis & Catalysis
10.1002/adsc.201701371
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Synthesis of Primary Anilines via Nickel-mediated
2
C(sp )-H Aminations
a
a
a
a
a
a
a,
Lin Yu, Xiang Chen, Da Liu, Liang Hu, Yongqi Yu , Hang Huang, Ze Tan *and
b,
Qingwen Gui *
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering,
Hunan University, Changsha 410082, P. R. China.
e-mail: ztanze@gmail.com
College of Science, Hunan Agricultural University, Changsha 410128, P. R. China.
b
e-mail: gqw1216@163.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient and mild protocol for the direct new ways to construct C-N bonds via C-H activation
conversion of arene C–H bonds to C–NH
without the need mode since a direct C-H bond amination approach
2
for extra deprotection step has been established, and to the would be much more concise and atom economical.
best of our knowledge, this is the first time that the
synthesis of primary anilines via nickel-mediated C(sp )-H
activations has been reported. This approach utilizes 8-
aminoquinoline as the directing group and sodium azide, a
cheap and commercially available material, as the nitrogen
source. In addition, the reaction is highly selective,
affording the mono- ortho-aminated benzamides only. The using cheap transition metals as the promoter.
Indeed, C-N bond formation via C-H activation
2
catalyzed or mediated by noble transition metals has
[7]
long been known. However, due to cost issues
associated with expensive catalysts, recently chemists
are beginning to develop C-H amination reactions
[8-11]
reaction tolerates a broad range of substrates with diverse With suitable bidentate directing groups, considerable
functional groups and the corresponding ortho-aminated
benzamides were efficiently synthesized in 41-82% yields.
advances have been made in the area of arene C-H
bond aminations and a variety of cheap metal
[
8]
[9]
[10]
[11]
promoters including Cu, Ni, Co or Fe salts
have been shown to be competent catalysts or
Keywords: C-H activation; primary aniline; nickel salt;
sodium azide; anthranilic acid
2
promoters for the C(sp )-H bond amination. For
example, Daugulis group in 2013 was the first to
report a copper-catalyzed selective ortho-amination
of N-(quinolin-8-yl)benzamide with alkylamines
The development of new ways for the synthesis of C-
N bonds has always been a central topic in organic
synthesis because C-N bonds are ubiquitous in
organic compounds.[ Among the various C-N bond
containing compounds, anilines hold a special place
due to their wide presence in natural products,
[8a]
under the assistance of 8-aminoquinoline. Shortly
after that, Nakamura and Ilies reported that a similar
ortho-amination reaction can take place with N-
(quinolin-8-yl)benzamide using N-chloroamines as
1]
[11]
the amine source under Fe-catalysis.
Later on,
pharmaceuticals,
dyes,
pigments
and
Zhang and Liu disclosed a nickel-catalyzed version
agrochemicals.[ Traditionally, the synthesis of
anilines has largely relied on the reduction of
nitroarenes which themselves are produced through
the classical electrophilic aromatic nitration
2]
[9]
using silver salt as the oxidant. In 2016, Zhang
further demonstrated that cobalt catalyst can also be
[
10b]
used to catalyze the same amination process.
[12]
[3]
Besides 8-aminoquinoline, other directing groups
reaction. However, this method tends to suffer from
problems such as producing large amount of toxic
waste, harsh reaction conditions as well as selectivity
issues. Alternatively, anilines can be efficiently
constructed through transition metal catalyzed
[8b]
such
as
2-aminophenyl
oxazoline,
2-
[
10a]
aminopyridine-1-oxide
as well as 2-aminophenyl
pyrazole have been shown to be viable auxiliaries
for cheap transition metal promoted C(sp )-H
[8j]
2
[
4]
couplings such as Buchwald-Hartwig amination,
aminations. Although numerous elegant works were
reported in this field, most achievements of
aromatic C−H bond aminations can only furnish a
Ullmann-Goldberg coupling[
5]
and Chan-Lam
need to use
reaction.[
6]
However,
the
prefunctionalized starting materials and expensive
catalysts and ligands make them less desirable. In
light of above problems, chemists are searching for
[8-
limited scope of aryl secondary or tertiary amines.
11]
The direct conversion of aromatic C–H bonds to
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701371
C–NH
2
promoted by cheap transition metal is
phase transfer catalysts such as tetrabutylammonium
acetate (TBAA), tetrabutylammonium iodide (TBAI),
or tetrabutyla-mmonium bromide (TBAB) was added
into the reaction mixture, and the best yield of 59%
was achieved with the addition of 2 equiv of TBAA
actually rare.[ Coincidentally, primary anilines are
extremely useful because they can serve as precursors
for many other functional groups, such as aryl
diazonium salts, azoaryls, haloaryls as well as a broad
13]
(
Table 1, entries 10-12). The yield of 3a could be
[14]
scope of aryl secondary or tertiary amines. Taking
this into consideration and also in continuation of our
efforts on the development of new reactions based on
C−H activations,[ we launched a study toward the
synthesis of primary anilines. Herein, we disclose a
novel route for the direct conversion of aromatic C–H
further elevated to 72% with appropriate amount of
water was added into the reaction mixture (Table 1,
entries 13-15). It is worthwhile to point out that the
reaction is highly mono-selective and no diamination
product is observed. After establishing TBAA and
water as the optimal additives, we focused on
15]
investigating other nickel salts such as NiBr
Ni(OTf) as promoter. Unfortunately, we did not see
any improvement with all the other nickel salts tested
Table 1, entries 14, 16-18). It should be noted that in
2
, NiI
2
,
bonds to C–NH
2
through nickel-mediated C−H
2
activation using sodium azide, a cheap and
commercially available material, as the nitrogen
source under mild conditions. The reaction exhibits
high chemo- and mono-selectivity in forming various
primary anilines products, which can be easily
converted into anthranilic acids, a critical scaffold in
(
the absence of nickel salt, the reaction failed to
deliver the desired products and all the starting
materials were recovered from the reaction system
(
Table 1, entry 19). This indicated that nickel catalyst
perfumes, agrochemicals and medicinal chemistry
played an indispensable role in this reaction.
Moreover, we found that the reaction did not proceed
at all using a catalytic amount of nickel salt (5 mol%)
Figure 1). [
16]
(
using O
1).
2
or Ag
2
CO as oxidant (Table 1, entry 20 and
3
2
Table 1. Screening of the reaction conditions for the
a
amination of 1a
Figure 1. Biologically active anthranilic acid derivatives
Entry
Ni salt
NiCl
NiCl2
NiCl
NiCl2
Base
PO
TEA
Solvent
Additive
Yield(%)b
Our original plan was to install an azide
functionality on the aromatic ring through metal
1
2
3
4c
5
6
7
8
9
2
K
3
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMAc
DMF
-
21
0
2
-
catalyzed 8-aminoquinoline assisted C(sp )-H
2
KOAc
tBuOK
-
18
0
activations since azides are very useful intermediates
[17]
-
for transformations such as “Click chemistry”.
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
2
2
2
2
2
2
2
2
2
2
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
-
47
46
44
0
However, much to our surprise, preliminary
experimental results showed that actually a primary
aniline derivative 3a was obtained instead of the
expected azide 4 when N-(quinolin-8-yl)benzamide
-
-
DCE
-
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
-
0
1
a was treated with 4 equiv of NaN
3
(2a), 2 equiv of
PO in DMSO
at 100 C under a nitrogen atmosphere (Table 1, entry
). In order to optimize the reaction conditions,
1
0
TBAI
TBAB
TBAA
TBAA
TBAA
TBAA
TBAA
TBAA
TBAA
TBAA
TBAA
TBAA
53
52
59
67
72
70
64
62
65
0
NiCl in the presence of 1 equiv of K
2
3
4
o
11
1
1
1
1
1
1
1
1
2
1
3c
4d
5e
6d
7d
8d
9d
various bases, solvents, additives, nickel salts and
oxidants were screened (Table 1). Tests revealed that
K
2
CO was the optimal base while bases such as TEA,
3
NiBr
NiI
2
KOAc, and t-BuOK either gave inferior yields or
failed completely (Table 1, entries 2-5). Surprisingly,
better yields of 3a were achieved with only 0.5 equiv
of base. The use of more or less amount of base
actually was detrimental to the reaction (not shown in
Table 1). On the other hand, replacing solvent DMSO
with DMAc, DMF, DCE or MeCN did not benefit the
reaction (Table 1, entries 6-9). Subsequently, we
further examined the possibility of using water and
2
Ni(OTf)
-
2
2 f
1g
0
NiCl
NiCl
0
2
2
2
0
aReaction conditions: amide 1a (0.2 mmol), 2 (0.8 mmol), Ni salt
0.4 mmol), Base (0.1 mmol), Additive (0.4 mmol), Solvent (4.0
(
o
b
c
2
mL), 100 C under N for 24 h. Isolated yield. Add 0.05 mL
water as additive. Add 0.10 mL water as additive. Add 0.15 mL
d
e
[
15g]
phase transfer catalyst as additives.
Gratifyingly,
f
g
water as additive. Ni salt (0.05 mmol) and under O
0.05 mmol), Ag CO (0.4 mmol).
2
. Ni salt
we found that the yield of 3a can be increased if a
(
2
3
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701371
Experiments also showed that 2 equiv of NiCl
2
was
groups. Gratifyingly, a benzamide bearing a vinyl
group on the para-position underwent the desired
coupling to give the corresponding product 3e in 62%
yield, indicating that the vinyl group was not
sensitive toward the reaction conditions. In contrast,
the reaction of a nitro-substituted benzamide failed to
deliver the desired product when it was subjected to
the optimum reaction conditions, as decomposition of
the starting material was observed (Table 2, entry
necessary for the reaction to reach completion and
further increasing the amount of NiCl did not
2
improve the yield. Based on the above results, we
decided to set reacting 1a with 4 equiv of 2a, 2 equiv
of NiCl
2
, 2 equiv of TBAA and H
2
O (0.50 mL/mmol)
CO in DMSO at
in the presence of 0.5 equiv of K
2
3
o
1
00 C as our standard conditions.
In order to explore the scope and limitation of this
direct conversion of aromatic C–H bond to C–NH
3m). This suggested that the electron density on the
2
phenyl ring is a critical factor for the reaction. It
should be noted that a pyridine derived amide was
also found to be a viable coupling partner, furnishing
reaction, various benzamides with diverse functional
groups were tested under the established reaction
conditions. We found that the reaction worked very
well for a variety of substituted benzamides,
affording the corresponding primary anilines in yields
ranging from 41-82% and the results were
summarized in Table 2. As illustrated in Table 2, this
protocol was compatible with a wide range of
functional groups such as alkyl, alkoxy, vinyl, fluoro,
chloro, bromo, ester, aryl as well as trifluoromethyl
3t in 41% yield. In addition, even though 2-fluoro or
2-chloro substituted benzamide reacted normally to
generate 3q in 65% yield or 3r in 43% yield
respectively, what was obtained from the reaction of
2-bromobenzamides with sodium azide was actually
3a (Scheme 1, Eq 1). We suspected that a
nucleophilic aromatic substitution of the bromide
took place before the C-H activation. We were
Table 2. Scope of the benzamidesa,b
disappointed to find that
a
1-cyclohexene-1-
carboxylic acid derived amide failed to react when it
was subjected to the optimized conditions (not shown
in Table 2).
Scheme 1. Nickel-mediated reaction of 2-bromo-
benzamide with sodium azide.
The synthetic utility of this method was
demonstrated by converting our products into several
representative scaffolds. 1,2,3-benzotriazine-4-(3H)-
one derivative 5 can be efficiently constructed with
tert-butyl nitrite and 3a in 85% yield (Scheme 2, Eq
[18]
2
). Meanwhile, quinazolin-4(3H)-one 6 can be
Scheme 2. Removal of the directing group and
derivatization of the obtained products.
aReaction conditions: amide 1a (0.2 mmol), 2 (0.8 mmol), NiCl
0.4 mmol), K CO (0.1 mmol), TBAA (0.4 mmol), H O (0.1
mL), Solvent (4.0 mL), 100 C under N for 24 h. Isolated yield.
2
(
2
3
2
o
b
2
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701371
obtained in 81% yield by treating 3a with
complexation of benzamide 1a with nickel salt to
afford Ni(II)-complex I, which subsequently
undergoes chelation-directed C-H activation to form
benzaldehyde under an oxygen atmosphere. (Scheme
19]
2
, Eq. 3).[ Moreover, we were able to remove the
directing group by simple hydrolysis in methanol and
subsequent careful pH-adjustment. The resultant
anthranilic acid was transformed into a biologically
active compound glycosminine according to literature
procedure in excellent yield (Scheme 2, Eq. 4 and
intermediate II. Intermediate II next reacts with HN
generated in situ to form a Ni-nitrenoid intermediate
3
[22f-h]
III.
Finally, intermediate III is transformed to 3a
after nitrene inserts into the C-Ni bond followed by
protonolysis. Since not much is known about the
reaction, other mechanisms could also operate here.
For example, although the transformation of azide 4
to 3a did not occur under the standard conditions, the
formation of azide 4 as an intermediate couldn’t be
fully ruled out.
[20,21]
5
).
To gain insight into the mechanism of our reaction,
a series of mechanistic experiments were performed
Scheme 3). First, radical inhibition experiments were
(
implemented. We found that radical scavengers such
as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
and 1,1-diphenylethylene (DPE) did not affect the
reaction efficiency under optimized conditions
Scheme 4. Possible reaction mechanism
(
Scheme 3, Eq. 6 and 7). These results suggested that
the reaction may not involve radical process. A
possible intermediate was synthesized and
4
subjected to the optimum conditions. However, no
desired 3a was formed and yet azide 4 was
completely consumed. Kinetic isotopic effect (KIE)
studies of this amination with sodium azide showed
that intermolecular K
when a 1:1 mixture of 1a and 1a-d
the optimized conditions in the same flask (Scheme 3,
Eq. 9). On the other hand, K /K was determined to
be around 2.6 if the reactions of 1a and 1a-d were
run parallelly. The competitive and parallel K /K
H
/K
D
of 1a to 1a-d
5
was 1.9
In conclusion, we have developed an efficient and
mild protocol for the direct conversion of aromatic C-
5
was subjected to
H bonds to C–NH via 8-aminoquinoline assisted
2
H
D
2
nickel-mediated C(sp )-H activations. Highly mono-
selective ortho-amination of benzamides was
achieved by treating various benzamides with sodium
azide in the presence of simple Ni-salt. Compared
with other known methods, our approach gives the
primary anilines directly and utilizes cheap sodium
azide as the nitrogen source. Notable features of the
protocol include mild reaction conditions, excellent
mono-selectivity and ortho-selectivity as well as good
functional group compatibility. Preliminary study
indicated that the reactions may go through a C-H
activation process. Current efforts are directed
towards making this reaction catalytic and the results
will be reported in due course.
5
H
D
values suggested that the cleavage of the ortho C-H
bond may be involved in the rate-determining step.
Scheme 3. Mechanistic Studies
Experimental Section
Benzamide 1 (0.2 mmol), NaN
3
(52 mg, 0.8 mmol), NiCl
(14 mg, 0.1 mmol), TBAA
O (0.1 mL) and DMSO (4.0 mL)
2
(
(
52 mg, 0.4 mmol), K
120 mg, 0.4 mmol), H
2 3
CO
2
were added to a 35 mL Schlenk flask equipped with a
high-vacuum PTFE valve-to-glass seal. Then the flask was
sealed under N and stirred at 100 °C for 24 h. After the
2
reaction was quenched by addition of water, the mixture
was extracted with dichloromethane, and the combined
organic layer was dried over sodium sulfate. Concentration
in vacuo followed by silica gel column purification with
petroleum ether /ethyl acetate eluent gave the desired
product 3.
Although the exact mechanism is still not clear at
present, based on the preliminary mechanistic
[22]
experiments and literature precedents, a plausible
2
mechanism for the nickel-mediated C(sp )-H
amination of benzamides is proposed and depicted in
Scheme 4. The reaction is initiated by the
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701371
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COMMUNICATION
Direct Synthesis of Primary Anilines via Nickel-
2
mediated C(sp )-H Aminations
Adv. Synth. Catal. Year, Volume, Page – Page
Lin Yu, Xiang Chen, Da Liu, Liang Hu, Yongqi
Yu, Hang Huang, Ze Tan* and Qingwen Gui*
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