Chemoselective aerobic oxidation of 2-amino-N-benzylanilines into N-(2-aminophenyl)imines via a nitroxide-free copper catalysis

Article abstract of DOI:10.1016/j.tetlet.2019.03.039

Chemoselective oxidative synthesis of N-(2-aminophenyl)imines from 2-amino-N-benzylanilines was accomplished through combined use of O₂(air) and copper salt. This transformation was performed at room temperature, and the mild oxidation was efficient and chemoselective without using nitroxyl radicals and ligands.

Full text of DOI:10.1016/j.tetlet.2019.03.039

Accepted Manuscript
Chemoselective aerobic oxidation of 2-amino-N-benzylanilines into N-(2-ami-
nophenyl)imines via a nitroxide-free copper catalysis
Yadong Zhai, Jing Rong, Zhicheng Zhang, Xiang Cao, Zhenni Su, Qingfa Zhou,
Chuanzhou Tao
PII:
S0040-4039(19)30256-4
https://doi.org/10.1016/j.tetlet.2019.03.039
TETL 50680
DOI:
Reference:
Tetrahedron Letters
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13 March 2019
15 March 2019
Please cite this article as: Zhai, Y., Rong, J., Zhang, Z., Cao, X., Su, Z., Zhou, Q., Tao, C., Chemoselective aerobic
oxidation of 2-amino-N-benzylanilines into N-(2-aminophenyl)imines via a nitroxide-free copper catalysis,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.039
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Yadong Zhaia, Jing Ronga, Zhicheng Zhanga, Xiang Caoa, Zhenni Sua, Qingfa Zhoub, Chuanzhou Taoa,c,

1
Tetrahedron Letters
Chemoselective aerobic oxidation of 2-amino-N-benzylanilines into N-(2-
aminophenyl)imines via a nitroxide-free copper catalysis
Yadong Zhaia, Jing Ronga, Zhicheng Zhanga, Xiang Caoa, Zhenni Sua, Qingfa Zhoub*, Chuanzhou Taoa,c
a School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, P. R. of China
b State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China
c.Marine Resources Development Institute of Jiangsu, Lianyungang 222005, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Chemoselective oxidative synthesis of N-(2-aminophenyl)imines from 2-amino-N-
benzylanilines was accomplished through combined use of O2(air) and copper salt. This
transformation was performed at room temperature, and the mild oxidation was efficient and
chemoselective without using nitroxyl radicals and ligands.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
Aerobic oxidation
N-(2-aminophenyl)imine
2-Amino-N-benzylaniline
N-(2-aminophenyl)imines are not only valuable structural
motifs in a variety of chemosensors [1] and bioactive molecules
[2], but also serve as building blocks to produce multidentate
ligands which were extensively studied in the transition metal
catalysis (Scheme 1) [3]. Development of new methods for the
synthesis of N-(2-aminophenyl)imines is of significant interest.
Recently, great progress has been made in oxidative
dehydrogenation of amines to synthesize imines [4]. Nevertheless,
oxidative synthesis of the N-(2-aminophenyl)imines from
corresponding amines is more challenging since oxidation of the
amino is generally more facile than oxidation of the carbon atom,
and amines tend to deactivate metal catalysis.
nitriles. Our group [7a] and others [7b, 7c] have developed
copper catalyst systems to directly convert benzylic amines into
aryl nitriles or imines (Scheme 2). When referred to secondary
amines, homogeneous catalysts for aerobic oxidative synthesis of
imines have been studied using Pd [8], Ru [9], Co [10] and Cu
[11]. These reactions represented major advances in the imine
synthesis, but usually were carried out at 80–100oC. Recently,
Oisaki and Kanai reported an efficient copper catalyst system for
aerobic oxidation of secondary amines to imines at room
temperature. Nitroxyl radical compound ketoABNO (9-
azabicyclo[3.3.1]nonan-3-one-N-oxyl) and ligand tBu2bpy were
critical for the transformation (Scheme 2) [12].
Scheme 1. Selected important compounds containing the N-(2-
aminophenyl)imine core.
Oxidation of organic compounds with O2 as a sole oxidant has
remarkable advantages, including its abundance, low cost, and
benign by-products (usually H2O). For this reason, considerable
efforts have been devoted in recent years to develop transition-
metal-catalyzed aerobic oxidation reactions [5, 6]. One such
e—xa—mp—le is aerobic oxidation of amines to afford imines or
Scheme 2. Homogeneous transition-metal-catalyzed aerobic oxidation of
amines.
 Corresponding author. School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, PR China; E-mail address: taocz@hhit.edu.cn
(C. Tao), zhouqingfa@cpu.edu.cn (Q. Zhou)

2
Tetrahedron
Table 2. Optimizing the reaction conditions for copper-catalyzed aerobic
oxidation of secondary amines to imines a
As part of our ongoing efforts to develop aerobic oxidation
of amines [7a], herein, we disclose a homogeneous copper
catalysis to accomplish efficient conversion secondary amines
into the corresponding aldimines and ketimines at room
temperature (Scheme 2). Without the need of nitroxyl radical and
ligands, the reaction occurred effectively at room temperature.
This new approach is versatile for various 2-amino group,
including –NH2, –NHCOR and –NHCONHPh, to yield the
important framework of N-(2-aminophenyl)imines. Moreover,
the catalytic system expands the toolbox for synthesis of imines
through aerobic oxidation of amines at room temperature.
Initially, we attempted to perform the reaction by treating
secondary amine (1a) with O2(air) as the oxidant at room
temperature. As shown in Table 1, with CuBr as the catalyst,
aerobic oxidation of amine (1a) was unsuccessful (entry 1), and
no imine product was detected. Then, we systematically
evaluated different amino groups at 2-position of N-benzylaniline.
Successfully, dramatic improvement was observed when 2-
amino-N-benzylaniline (1b) was chosen as substrate, and 87%
yield of N-(2-aminophenyl)imines (2b) was isolated (entry 2).
The reaction exhibited high chemoselectivity between the amino
and carbon atom. Changing the amino into (4-
Entry
1
2
3
4
5
6
7
8
1
Change from optimal conditions
none
CuCl instead of CuBr
Cu(OAc)2 instead of CuBr
none
CuCl instead of CuBr
CuBr2 instead of CuBr
CuCl2 instead of CuBr
Cu(OAc)2 instead of CuBr
Cu(NO3)2 instead of CuBr
MeOH instead of DMF
CH2Cl2 instead of DMF
THF instead of DMF
Toluene instead of DMF
Py instead of Et3N
2
Yieldb/%
87
75
80
94
84
82
82
1b
1b
1b
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
2b
2b
2b
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
77
67
9
10
11
12
13
14
15
71
77
50
48
28
82
Amount of Et3N is 2 eq.
methylphenyl)sulfonamido failed to oxidize the amine (entry 3).
After screening other amino group, we found benzamido and
(tert-butoxycarbonyl)amino groups gave moderate yields (entries
4–5). Delightfully, when 2-(3-phenylureido)-N-benzylaniline (1f)
was selected as starting material, the yield of oxidation product
(2f) was up to 94% (entry 6).
a Reaction conditions: 0.2 mmol amine 1, 10 mol% catalyst loading, 0.8
mmol additive, 0.5 mL solvent, room temperature (22-25 oC), air, 5h. b The
yields are isolated yields.
The above results show that CuBr/Et3N/DMF is an efficient
combination for the aerobic synthesis of N-(2-
aminophenyl)benzaldimines from amines. Using the optimized
conditions, we next explored the scope and generality of the
process (Table 3). The reaction was proven to be effective for 2-
amino-N-benzylaniline carrying electron-donating and electron-
withdrawing groups on benzyl scaffold. The good to excellent
isolated yields of aldimines were obtained (68–87%, 2b, 2g–2i),
and the group –NH2 was well tolerated in the oxidation reactions.
It was found that benzyl scaffolds of 2-(3-phenylureido)-N-
benzylicanilines carrying electron-donating and electron-
withdrawing groups could be smoothly converted into the imines
with good to excellent isolated yields (up to 94%, 2f, 2j–2l). The
substrates carrying an ortho-substituent on the benzyl group were
also found to readily participate in the reaction (82–86%, 2m,
2n). When 2-(3-phenylureido)-N-cinnamylaniline was used as
substrate, the reaction gave 82% yield of the corresponding imine
(2o). The catalysis was also tolerant of heteroaryl group, and
pyridyl-containing aniline reacted smoothly to afford the
corresponding aldimine in moderate yield (58%, 2p). In addition,
N-benzhydrylaniline also could be converted into ketimine under
the standard conditions, and excellent yield was obtained (84%,
2q).
Table 1. Screening the amino groups for copper-catalyzed aerobic oxidation
of secondary amines to imines a
Entry
Amine 1
-FG
Imine 2
2a
Yield b/%
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
NH2
NHTs
NHCOPh
NHBoc
NHCONHPh
0
2b
87
0
2c
2d
57
54
94
2e
2f
a Reaction conditions: 0.2 mmol amine 1, 10 mol% CuBr, 0.8 mmol Et3N, 0.5
mL DMF, room temperature (22-25 oC), air, 5 h. b The yields are isolated
yields.
Next, we evaluated the reaction parameters in the copper-
catalyzed aerobic oxidation of secondary amines to imines (Table
2). Initially, we assessed the reaction conditions for 2-amino-N-
benzylaniline (1b). Cuprous and cupric salts gave high yields in
the aerobic oxidation of secondary amines to imines (entries 1–3).
For 2-(3-phenylureido)-N-benzylaniline (1f), various copper salts
were evaluated in the atmosphere at room temperature. It was
found that the copper sources with different valences all gave
excellent yields (entries 4–9) and the yield was up to 94% with
CuBr (entry 4). Using CuBr as a catalyst at room temperature,
the solvents were screened (entries 10–13). It was found that
good yields of the desired products were obtained in MeOH
(entry 10) and DCM (entry 11), and moderate yields were
obtained in THF (entry 12) and Toluene (entry 13). When we
replaced the additive triethylamine with pyridine, the yield of
imine decreased, which may be related to the decrease of
alkalinity (entry 14). We tried to reduce the amount of the
trimethylamine, however, the yield of imine was decreased (entry
15).

3
Table 3. The scope and generality of copper-catalyzed aerobic oxidation of
some literature support, since Solomon et al. reported in 2018 a
very interesting finding that intramolecular hydrogen bonding
enhanced stability and reactivity of mononuclear cupric
superoxide complexes (II) [13].
secondary amines to imines a,b
Scheme 5. The postulated mechanism for the copper-catalyzed aerobic
oxidation of 2-amino-N-benzylanilines.
In summary, we have developed an aerobic oxidative
synthesis of imines from secondary amines. With copper as
catalyst, the conversion of 2-amino-N-benzylanilines into
aldimines and ketimines were realized with O2(air) as the
oxidant. This new protocol combined copper in a single reaction
system and showed great substrate tolerance providing efficient
access to a variety of imines in a highly concise fashion. Further
studies on the mechanism of this process is underway. Given the
fact that N-(2-aminophenyl)imines play an important role in
chemosensors and bioactive molecules, we anticipate this method
will find practical applications in various synthesis of relevant
imines.
a Reaction conditions: 0.4 mmol amine 1, 10 mol% CuBr, 1.6 mmol
triethylamine, 0.5 mL DMF, room temperature (22-25 oC), air, 5 h. b The
yields are isolated yields.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21402062), the Six Talent Peaks Project of Jiangsu
Province (2016-YY-004), and the Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, Haiyan Project of Lianyungang (2018-QD-004), 521
Project of Lianyungang and Postgraduate Research & Practice
Innovation Program of Jiangsu Province (KYCX17_2076,
KYCX18_2600).
To showcase the scalability of this process, a gram-scale
reaction was performed with 2-(3-phenylureido)-N-benzylaniline
(1f). Gratifyingly, secondary amine (1f) underwent efficient
oxidation on gram-scale (4 mmol/1.27 g) resulting in an 87%
isolated yield of the imine (2f, 1.1g) without modification of the
optimized conditions (Scheme 3).
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5
Highlights



Copper as catalyst, without nitroxyl radicals
and ligands
Molecular oxygen as the sole oxidant at room
temperature.
Gram-scale synthesis