Copper-catalyzed synthesis of oxime ethers from iminoxy radical (C[dbnd]N–O[rad]) and maleimides via radical addition

Article abstract of DOI:10.1016/j.tetlet.2019.151188

An efficient Cu(II)-catalyzed radical addition of maleimides has been achieved. The identified copper catalyst enables the formation of oxime radicals (N–O[rad]) by cleaving the O–H bond in ketoximes, followed by the radical addition to N-substituted male

Full text of DOI:10.1016/j.tetlet.2019.151188

Journal Pre-proofs
Copper-catalyzed synthesis of oxime ethers from iminoxy radical (C=N-O•) and
maleimides via radical addition
Ziwei Han, Subo Shen, Feng Zheng, Han Hu, Jianmin Zhang, Shizheng Zhu
PII:
S0040-4039(19)30963-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151188
TETL 151188
Reference:
Tetrahedron Letters
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Accepted Date:
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19 September 2019
20 September 2019
Please cite this article as: Han, Z., Shen, S., Zheng, F., Hu, H., Zhang, J., Zhu, S., Copper-catalyzed synthesis of
oxime ethers from iminoxy radical (C=N-O•) and maleimides via radical addition, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.151188
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Graphical Abstract
Copper-catalyzed synthesis of oxime ethers from
iminoxy radical (C=N-O•) and maleimides via
radical addition
Leave this area blank for abstract info.
Ziwei Han a, Subo Shen a, Feng Zheng b, Han Hu a, Jianmin Zhang a,c,*, Shizheng Zhu c,*
a Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, PR China
b Shanghai Aerospace Chemical Application Research Institute, Shanghai 201109, PR China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, PR China
O
R
O
N
N R
O
OH
R2
O
.
N
N
Cu(OAc)2 H2O
O
O
N
75 oC
R1
R1
R2
o-DCB, N2, 8 h
R1
R2
confirmed by
EPR spectroscopy

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper-catalyzed synthesis of oxime ethers from iminoxy radical (C=N-O•) and
maleimides via radical addition
Ziwei Hana, Subo Shen a, Feng Zhengb, Han Hua, Jianmin Zhanga, c, and Shizheng Zhuc, 
a Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, PR China
b Shanghai Aerospace Chemical Application Research Institute, Shanghai 201109, PR China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
PR China
———
ARTICLE INFO
ABSTRACT
 Jianmin Zhang. E-mail: jmzhang@shu.edu.cn
 Shizheng Zhu. E-mail: zhusz@mail.sioc.ac.cn
Article history:
An efficient Cu(II)-catalyzed radical addition of maleimides has been achieved. The identified
copper catalyst enables the formation of oxime radicals (N-O•) by cleaving the O-H bond in
ketoximes, followed by the radical addition to N-substituted maleimides. The oxime radicals (N-
O•) were detected and confirmed by EPR spectroscopy and variable-temperature 1H-NMR. The
simple one-pot reaction realizes the facile preparation of a variety of oxime ether adduct
products in moderate to good yields.
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
radical addition
oxime radical
maleimides
1. Introduction
As one of the prominent medicinal moieties, the oxime ether
group offers very attractive options for drug design in a variety of
Ketoximes are readily available and important building blocks
for organic synthesis with broad applications in pharmaceutical
and biological chemistry [1]. As depicted in Figure 1, there are
mainly three types of oximes (Figure 1): hydroxyl oxime I (-OH),
oxime ether II (-OR3), oxime ester III (-OCOR4). In radical
chemistry, imine radical (C=N•) appears frequently formed by
oxime esters and oxime ethers [2,3], while iminoxy radical
(C=N-O•) is less pronounced from hydroxyl oxime by the
homolysis of O-H bond [4-9]. Common radical addition reactions
of ketoximes mostly involved intramolecular cycloadditions,
while the intermolecular radical additions were rarely reported
[6,10]. Based on previous reports, we found that ketoximes could
readily generate oxime radicals in the presence of Cu(II) catalysts
[11], and we also provided evidence in our previous work [12].
An electron transfer process occurs between the Cu(II) and
oximes, forming iminoxy radicals with the generation of Cu(I).
In the presence of strong bases, traditional Michael addition
reactions could easily occur between ketoximes and various
olefins, such as α,β-unsaturated nitriles, α,β-unsaturated esters,
α,β-unsaturated phosphates [13]. However, the radical addition
reactions of ketoximes with unsaturated compounds were lack of
attention to this point of view.
pharmaceutical preparation and pesticides [14,15], which exhibit
excellent anticancer activities and larvicidal activities against pest
(Figure 2) [16,17].
Figure 2 Medicine and pesticide containing oxime ether functional group
In the screening of unsaturated compounds to react with
iminoxy radical, we surprisingly found that N-ethylmaleimide
could easily react with ketoximes in the presence of
Cu(OAc)2·H2O catalyst. The corresponding oxime ether products
could be smoothly prepared from a variety of ketoximes (Scheme
1). Maleimides are important building blocks in chemical
synthesis for biological and material sciences with stiff toroidal
structure,
providing
various
functionalized
fused-
pyrrolidinedione skeletons, and as radical acceptor in radical
reaction [18].
O
O
OH
N
Cu(OAc)2.H2O
N
N
N
+
O
HO
O
R3O
R4
O
O
N
N
N
1a
2
3a
O
R1 R2
R1 R2
R1 R2
Scheme 1 Cu(II)-catalyzed the radical addition of ketoximes and N-
ethylmaleimide
I
II
III
Figure 1 The three types of oxime

2
Tetrahedron
20
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Ph3P
o-DCB
o-DCB
o-DCB
75
75
75
N2
N2
N2
39
71
73
2. Organisation of the template
21
K2S2O8
NaHSO3
We chose the simple and readily available acetophenone oxime
1a and N-ethylmaleimide 2 as our starting materials for our
initial studies. In the presence of 20 mol% Cu(OAc)2·H2O, O-(N-
ethyl-2,5-dicarbonyl pyrrolidine)-oxime ether 3a was already
realized in 54% yield (Table 1, entry 1). The structure of 3a was
unambiguously confirmed by single crystal X-ray diffraction
analysis [19]. Continuous optimization of reaction conditions was
carried to improve the conversion yield, including temperatures,
catalysts and additives (see in supplementary material). The
reaction temperature was found to be important for the reaction
22
23
24
Cu(OAc)2·H2O
Cu(OAc)2·H2O
M.S.
o-DCB
o-DCB
75
75
N2
N2
74
66
1,10-
Phenanthr
oline
a
Condation: 1a (0.15 mmol), 2 (0.1 mmol), Cu(OAc)2·H2O (0.02 mmol), o-DCB
b
(0.3 mL), 8 h in the atmosphere of N2. Condation: 1a (0.175 mmol), 2 (0.1
mmol), catalyst (0.02 mmol), solvent (0.3 mL), additive (1.5 mmol), 8 h in the
o
(Table 1, entries 1-4). At 75 C, the reaction yield was further
c
d
atmosphere of N2. Condation: in the atmosphere of Air. Condation: in the
atmosphere of O2.
improved to 82% by employing excesses of acetophenone oxime
(Table 1, entry 5). However, the radical reactions were
dramatically inhibited in the aerobic atmospheres (Table 1,
entries 6-7). Among the common copper catalysts,
Cu(OAc)2·H2O showed higher catalytic effect than others (Table
1, entries 8-11). Control reaction indicated that copper catalyst is
crucial for the process (Table 1, entry 12). It is not surprised that
the same product could be obtained in the presence of a base via
Michael addition, but in a relative lower yield compared to the
copper-catalyzed radical addition (Table 1, entries 13-14).
Screening on other bases and additives could not realize higher
yields (Table 1, entries 15-24). Thus the optimized reaction
conditions were achieved as below: in the presence of 20 mol%
of Cu(OAc)2·H2O, a mixture of acetophenone oxime 1a and N-
ethylmaleimide 2 (1.75:1) was refluxed in anhydrous o-DCB at
75 oC for 8h under N2, giving O-(N-ethyl-2,5-dicarbonyl
pyrrolidine)-oxime ether 3a in 82% yield.
Then the investigation on the substrate scope of this reaction
was carried out. Different substituted ketoximes 1 were used to
react with N-ethylmaleimide 2. As shown in Table 2, a series of
O-(N-ethyl-2,5-dicarbonyl pyrrolidine)-oxime ethers were readily
accessed in moderate to good yields. By applying the optimal
reaction conditions, substrates with electron-donating groups,
such as methoxyl, methyl, hydroxy, could give the corresponding
products in good yields, up to 86% (3b-3f). Electron-
withdrawing groups, including fluorine, chlorine, bromine,
trifluoromethyl, phenyl and even strong electron-deficient nitro
group were tolerated with the catalytical radical addition process
(3g-3x). Ketoximes with more sterically hindered groups were
also successfully converted into the desired products in moderate
to good yields (3y, 3z, 3za, 3zb, 3zd). Even the heterocyclic
substrate with thiophene moiety could also generate the product
in 71% yield (3zc). After the replacement of ethly of maleimides
with phenyl, benzyl and cyclohexyl, the reactions still
successfully took place to gain the desired oxime ethers (5a-5zc,
7a-7zc, 9a-9x). However, aliphatic ketone oximes had too weak
responses to gain the target products because of its low activity.
In addition, the radical reactions could not occur between
ketoximes and other electron-deficient olefins such as α,β-
unsaturated nitriles, α,β-unsaturated esters and so on (Scheme 2)
[18d]. The failures in such traditional α,β-unsaturated Michael
acceptors were probably due to their inferior tolerances with
oxime radicals.
Table 1 The optimization of reaction conditions
O
O
OH
N
Catalyst, Additive
Solvent, T, 8 h
N
N
N
+
O
O
O
3a
1a
2
Entry
Cat.
Additive
Solvent
T
Atm.
Yieldb
(%)
(oC)
1
2
Cu(OAc)2·H2O
/
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
90
N2
N2
N2
N2
N2
Air
O2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
54 a
49 a
69 a
40 a
82
21 c
12 d
69
45
2
Cu(OAc)2·H2O
/
60
75
120
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
Table 2 Cu(OAc)2·H2O catalyzed one-pot synthesis of O-(N-
3
Cu(OAc)2·H2O
/
substituted-2,5-dicarbonyl pyrrolidine)-oxime ethers
4
Cu(OAc)2·H2O
/
O
OH
R2
O
N
5
Cu(OAc)2·H2O
/
Cu(OAc)2.H2O
N2, o-DCB, 75 oC, 8 h
N
R1
N
R
R1
N
R
+
O
R2
6
Cu(OAc)2·H2O
/
O
O
1
2
4
6
8
3
5
7
9
R = Et
R = Ph
R = Bn
R = Cy
R = Et
7
Cu(OAc)2·H2O
/
R = Ph
R = Bn
R = Cy
8
Cu(OAc)2
/
/
O
O
O
O
O
O
O
N
O
O
O
O
O
O
N
N
O
N
O
N
9
Cu
O
O
O
O
O
O
O
O
O
O
N
O
N
O
N
N
CH3
N
10
11
12
13
14
15
16
17
18
19
CuI
/
H3CO
H3
C
H3CO
CuCl
/
21
5
3d
84%
3a
82%
3b
85%
3e
86%
3c
86%
/
/
O
N
N
N
O
N
N
O
O
Cu(OAc)2·H2O
K2CO3
K2CO3
Cs2CO3
Cs2CO3
DIPEA
Et3N
DBU
85
51
0
O
N
O
O
N
O
O
N
F
N
F
N
F
F
/
HO
F
3i
3j
3f
53%
3g
15%
3h
74%
78%
71%
Cu(OAc)2·H2O
O
N
N
/
/
/
/
0
N
N
N
O
O
O
O
N
O
N
O
N
O
O
N
F
F
F
50
40
47
N
F
F
F
F
F
F
3k
74%
3l
42%
3o
76%
3m
70%
3n
F
F
81%

3
O
O
O
O
O
cleaved and providing evidence for the transformation from
N
N
N
N
N
O
O
O
O
O
ketoxime 1z to radical A. These facts were consistent with our
assumption about the proposed radical mechanism as follows
(Scheme 4): under the catalysis of Cu(OAc)2·H2O, the homolytic
cleavage of O-H bonds of ketoxime releases oxime radicals A,
and CuIH via single electron transfer from CuII. Then the oxime
radical A attacks the double bond of N-ethyl maleimide 2 to
generate the free radical intermediate B, which captures the
hydrogen radical released by single electron transfer from the
previously generated CuIH. The desired product 3z is eventually
afforded together with regeneration of the Cu(II) catalyst.
O
O
O
N
O
O
N
N
N
Cl
N
Br
Cl
F3C
Cl
3p
3q
74%
3r
53%
3s
79%
3t
82%
78%
O
O
O
O
O
N
N
N
N
N
O
O
O
O
O
O
O
N
O
O
O
N
N
N
N
O2N
O2N
Br
Ph
3u
3v
3w
3y
3x
70%
66%
61%
89%
56%
O
O
O
O
O
N
N
N
N
N
O
O
O
O
O
O
N
O
N
O
N
O
N
O
N
O
S
OH
O
N
Cu(OAc)2.H2O, TEMPO (5 equiv)
N
3zb
3z
3za
59%
3zd
3zc
N
N
+
64%
71%
71%
43%
O
N2, o-DCB, 75 oC, 8 h
Ph
O
Ph
N
O
Ph
Ph
O
O
Ph
N
O
O
N
N
N
O
2
O
O
O
O
O
1z
3z
O
O
O
N
O
O
N
N
N
N
S
Scheme 3 The reaction of ketoxime and N-ethylmaleimide with TEMPO
H3CO
O2N
F
5a
5c
5i
5x
5zc
81%
79%
74%
63%
70%
Bn
O
Bn
O
Bn
O
Bn
N
O
Bn
N
O
N
N
N
O
O
O
O
O
O
O
O
N
O
O
N
N
N
N
S
F
O2N
H3CO
7a
80%
7zc
65%
7c
75%
7i
70%
7x
60%
Cy
O
Cy
O
Cy
O
N
N
N
O
O
O
O
O
O
N
N
N
F
O2N
9x
30%
9a
50%
9i
50%
a
Condition: ketoximes 1 (1.05 mmol), N-substituted maleimides (0.6 mmol),
Cu(OAc)2·H2O (0.12 mmol) in o-DCB (1.8 mL) at 75 oC for 8 h in N2.
Figure 3 EPR spectrum of individual components
OH
R2
O
Cu2+
Cu2+
Cu2+
N
N
N
N
CN
(1)
CN
o-1
+
R1
R1
R1
R1
R2
1
OH
R2
O
N
COOMe
(2)
(3)
COOMe
o-2
+
R1
R2
1
OH
R2
O
N
COOMe
MeOOC
COOMe
+
COOMe
R1
R2
1
o-3
Scheme 2 Cu(II)-catalyzed the radical addition of ketoximes and other
electron-withdrawing olefins
Control experiments were performed to gain some insight into
the reaction mechanism. When a strong radical scavenger
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to the
reaction, the reaction was totally blocked (Scheme 3).
Furthermore, the oxime radical was also confirmed by EPR
spectroscopy. Each individual component of the used raw
materials could not give any radical signals in the EPR test
(Figure 3). When the ketoxime 1z was treated by catalyst
Figure 4 EPR spectrum of oxime radical generated by 1z with Cu(II)-catalyst
in toluene
o
Cu(OAc)2·H2O under elevated temperature 90 C, strong radical
signal was observed in the EPR spectroscopy (Figure 4). As
shown in Figure 5, the signals of radical A generated from 1z (g
= 2.01746, g = 1.99899, g = 1.97980, ḡ = 1.99875, aN= 30.84 G)
appeared, and they are quite coincident with the reported
literatures
[20].
Variable-temperature
1H-NMR
was
Figure 5 EPR detection of radical A
simultaneously carried out to monitor possible intermediates A.
At room temperature, the two peaks at 11-10 ppm shift indicate a
pair of cis-trans isomers [21] of the ketoxime structure (Figure 6).
However, these signals became faint during raising temperatures,
and disappeared completely at 90 oC. Over the temperature range
from room temperature to 90 oC, the H (-OH) intensities
decreased continuously, indicating that the O-H bond was

4
Tetrahedron
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Figure 6 Monitoring of radical A by variable-temperature 1H-NMR
O
OH
N
N
H
+
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(2017) 7830;
1z
A
Radical
O
(b) Krylov, I. B.; Paveliev, S. A.; Shumakova, N. S.; Syroeshkin, M. A.;
Shelimov, B. N.; Nikishin, G. I.; Terent'ev, A.O. RSC Adv. 8 (2018)
5670;
N
CuII
CuIH
O
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2
O
O
N
N
O
O
H
O
O
N
N
3z
B
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Scheme 4 Plausible mechanism for the radical addition reaction
Conclusions
In summary, we have developed an efficient Cu(II)-catalyzed
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radical addition reaction of ketoximes with N-substituted
maleimides. In the presence of Cu(OAc)2·H2O catalyst , the
reaction of readily available ketoximes and N-substituted
maleimides could easily access to a series of O-(N-substituted-
2,5-dicarbonyl pyrrolidine)-oxime ether products in moderate to
good yields. The oxime radical has been confirmed by EPR
spectroscopy. Furthermore, variable-temperature 1H-NMR
indicates the radical addition reaction mechanism. Further
evaluations on other radical reactions using ketoximes as well as
the studies of the insight into the reaction mechanism are ongoing
in our laboratory.
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Acknowledgments
We gratefully acknowledge the National Nature Science
Foundation of China (No. 21272151) for financial support.
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[19] CCDC 1868576 contains the supplementary crystallographic data for
3a. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
See also the Supporting Information.
[20] (a) Thomas, J. R. J. Am. Chem. Soc. 86 (1964) 1446;
(b) Lagercrantz, C. Acta Chem. Scand. B. 42 (1988) 414.
[21] (a) Trost, B. M.; Richardson, J.; Yong, K. J. Am. Chem. Soc. 128 (2006)
2540;
References and notes
[1] (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. (2005) 4505;
(b) Kassa, J.; Kuca, K.; Bartosova, L.; Kunesova, G. Curr. Org. Chem.
11 (2007) 267.
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1155.
[3] (a) Blake, J. A.; Pratt,D. A.; Lin, S.; Walton, J. C.; Mulder, P.; Ingold,
K. U. J. Org. Chem. 69 (2004) 3112;
(b) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127 (2005) 11240.
(b) Vaillant, F. L.; Garreau, M.; Nicolai, S.; Gryn'ova, G.; Corminboeuf,
C.; Waser, J. Chem. Sci. 9 (2018) 5883.
[4] Peter de Lijser, H.J.; Kim, J. S.; McGrorty, S. M.; Ulloa, E. M. Can. J.
Chem. 81 (2003) 575.

5
Supplementary Material
Highlights
1) An efficient Cu(II)-catalyzed radical addition reaction of
ketoximes with N-substituted maleimides.
2)
Synthesis
of
O-(N-substituted-2,5-dicarbonyl
pyrrolidine)-oxime ether products in moderate to good
yields.
3) The evidence of oxime radical confirmed by EPR
spectroscopy.
4) The radical addition reaction mechanism indicated by
variable-temperature 1H-NMR.