Cu/Ag-Cocatalyzed Aerobic Oxidative Amination and CuCl2-Mediated Aerobic Oxidative Chloroamination of Maleimides

Article abstract of DOI:10.1002/ejoc.201600923

An efficient Cu(OAc)₂/Ag₂CO₃-cocatalyzed approach for the synthesis of 3-aminomaleimides and 3-amino-4-indolylmaleimides has been developed with satisfactory yields. A series of primary and secondary amines are compatible with this reaction. In addition, treatment of maleimides with primary amines using 1 equiv. of CuCl₂leads to the formation of chloroamination products such as 3-amino-4-chloromaleimides by a radical-type mechanism.

Full text of DOI:10.1002/ejoc.201600923

A Journal of
Accepted Article
Title: Cu/Ag cocatalyzed aerobic oxidative amination and CuCl2 mediated aerobic
oxidative chloroamination of maleimides
Authors: Yu-Long An; He-Hui Zhang; Zhen-Hua Yang; Long Lin; Sheng-Yin Zhao
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600923
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600923
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
Cu/Ag cocatalyzed aerobic oxidative amination and CuCl2
mediated aerobic oxidative chloroamination of maleimides
Yu-Long an,[a] He-Hui Zhang,[a] Zhen-Hua Yang,[a] Long Lin,[a] and Sheng-Yin Zhao*[a,b]
Oxidative amination and chloroamination
Abstract: An efficient Cu(OAc)2/Ag2CO3 cocatalyzed approach for
the synthesis of 3-aminomaleimides and
Procedure A is limited to the synthesis of the secondary enamine
products; the tertiary enamine products cannot be prepared via
this method.[4] Although procedure B is an efficient way to
synthesize a wide range of 3-aminomaleimides, continuing
exploration is of great significance considering that the starting
materials should be halogenated and hydroxylated from
maleimides. Therefore, the development of efficient synthetic
methods to access these 3-aminomaleimides are attractive for
organic chemists.
3-amino-4-indolylmaleimides has been developed with satisfied
yields. A series of primary and secondary amines are compatible with
this reaction. In addition, the treatment of maleimides with primary
amines using one equivalent of CuCl2 leads to the formation of
chloroamination products such as 3-amino-4-chloromaleimides by a
radical-type mechanism.
In recent years, transition metal-catalyzed oxidative amination
of arenes[6] and alkenes[7] has attracted considerable attention
because it provides an efficient synthesis for various
nitrogen-containing products. Several transition metals have
been studied as catalysts and oxidants such as Pd, Ru, Rh, Co
and so on.[8] However, these reactions suffer from the limitations
such as pre-functionalization, high catalyst loadings, long
reaction times, expensive and hazardous reagents.[7d-7e]
Furthermore, most of the reaction substrates were focused on
styrene and α,β-unsaturated carbonyl compounds such as
acrylic esters. Nevertheless, to the best of our knowledge, an
efficient directly synthesis of 3-aminomaleimides and
3-amino-4-chloromaleimides has not yet been explored. The
maleimides are unstable in the presence of strong acids and
bases, and are apt to polymerize and decompose. Thus, an
efficient, economical and environmentally benign Lewis acid
catalyst is highly desirable for this process. Recently, our group
has been interested in the synthesis of indolylmaleimides and
related derivatives.[9] Herein, we report an efficient synthetic
Introduction
3-Aminomaleimides and their derivatives have a wide range of
applications in the fields of natural products,[1] pharmaceuticals,[2]
and material sciences.[3] Therefore, a certain attention has been
paid to their synthesis. To date, several synthetic methods have
been established, and could be summarized as the following
procedures: 1) Reactions of N-benzyldiphenylsulfilimines, which
were prepared by treating diphenylsulfilimine with alkyl halides in
refluxing chloroform, with maleimides (Scheme 1, Procedure A).[4]
2) Dehydrohalogenation or dehydration coupling of 3-substituted
maleimides with amines in the presence of triethylamine or acetic
acid, respectively (Scheme 1, Procedure B).[5]
strategy
toward
3-aminomaleimides
and
3-amino-4-indoylmaleimides through Cu/Ag cocatalyzed aerobic
oxidative amination of maleimides. In addition, the treatment of
maleimides with primary amines using one equivalent of CuCl2
leads to the formation of 3-amino-4-chloromaleimides (Scheme 1,
Procedure C).
Results and Discussion
Scheme 1. Synthesis of 3-aminomaleimides
Initially, N-phenylmaleimide 1a and piperidine 2a were chosen as
model substrates to optimize the reaction conditions. Ag2CO3 or
Cu(OAc)2 were chosen as catalysts. The reactions were
performed at 120℃ for 12 hours (monitoring by TLC) opening to
the air. The results were shown in Table 1. Fortunately, with
solely 0.2 equivalent of Ag2CO3 or Cu(OAc)2 in the system, both
of oxidative amination and Michael addition reactions could
proceed. 1-Phenyl-3-(piperidin-1-yl)-1H-pyrrole-2,5-dione 3a and
1-phenyl-3-(piperidin-1-yl)pyrrolidine-2,5-dione 4a were obtained
in moderate yields (entries 1, 3). None of Cu(OAc)2.H2O, CuI,
CuCl2, FeCl3, I2, FeCl2.4H2O, CoCl2.6H2O or NiCl2.6H2O could
give much better selectivity for the synthesis of 3a (entries 5-12).
Several parameters were altered in an attempt to improve the
[a]
[b]
Y. L. An, H. H. Zhang, Z. H. Yang, L. Lin, Prof. Dr. S. Y. Zhao
Department of chemistry, Donghua University,
No.2999 North Renmin Road, Shanghai 201620, P.R. China
E-mail: syzhao8@dhu.edu.cn
Prof. Dr. S.Y. Zhao
State Key Laboratory of Bioorganic & Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P.R. China
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
yield of desired product. We found that increasing the dosage of
Ag2CO3 or Cu(OAc)2 to 1 equivalent, the oxidative amination
product 3a yielded 83% and 85%, respectively. Michael addition
product 4a could hardly be isolated (entries 2, 4). When the
reaction was performed under a N2 atmosphere in the presence
of 0.2 equivalent of Cu(OAc)2, the yield of product 4a could be
improved, while the oxidative amination product 3a was obtained
with 18% yield (entry 13). It could be indicated that oxygen
played an important role in the oxidative amination reactions
(entries 13, 14). Interestingly, when 0.2 equivalent of Cu(OAc)2
worked with 0.2 equivalent of Ag2CO3, only the oxidative
amination product 3a could be obtained with 92% yield and the
reaction could be completed within 2 hours (entry 15). Taking the
place of Ag2CO3 with 0.4 equivalent of AgNO3, the yield of 3a
reduced to 78% (entry 16). Reducing the temperature to 80℃
leads to long reaction time and decreased the yield of product 3a
(entry 17). The reactions proceeded in DMF, DMSO and
1,4-dioxane lead to lower yields (entries 18-20). The above result
demonstrated that Cu(OAc)2/Ag2CO3 are more effective catalysts.
It should be noted that, without any catalyst or oxidant, only
Michael addition product 4a could be obtained in about 80%
(entry 21).
isolated and characterized (see the Supporting Information). The
yields and reaction time were summarized in Scheme 2.
As shown in Scheme 2, various amines, such as secondary
amines, primary alkylamines and arylamines, were examined
under the optimized reaction conditions. Satisfied yields were
obtained from the secondary amines (71%-95%; 3a, 3e-3n). For
the primary alkylamines, this reaction gave moderate yields
(55%-74%; 3b, 3c, 3o). But poor yields were obtained using
arylamines as substrates (38%-46%; 3d, 3p). What’s more,
these reactions took shorter time using the secondary amines
(1.5-5 h) than primary alkyl amines (8-10 h) and arylamines (10
h). And the better yields were obtained using N-substituted
maleimides as substrates compared to maleimide (NH)
(71%-84%; 3k-3l).
Table 1. Optimization of reaction conditions [a]
Entry
Catalyst
[equiv.]
Time
[h]
Solvent
Yield[b][%]
3a
35
83
72
85
65
28
42
50
32
0
4a
46
trace
15
trace
20
55
50
10
trace
72
1
2
3
4
5
6
7
8
Ag2CO3(0.2)
Ag2CO3(1)
Cu(OAc)2(0.2)
Cu(OAc)2(1)
Cu(OAc)2.H2O(0.2)
CuI(0.2)
CuCl2(0.2)
FeCl3 (0.2)
I2 (0.2)
FeCl2.4H2O (0.2)
CoCl2.6H2O (0.2)
NiCl2.6H2O (0.2)
Cu(OAc)2(0.2)
Cu(OAc)2(0.2)/O2(ball)
Cu(OAc)2(0.2)/Ag2CO3(0.2)
Cu(OAc)2(0.2)/AgNO3(0.4)
Cu(OAc)2(0.2)/Ag2CO3(0.2)
Cu(OAc)2(0.2)/Ag2CO3(0.2)
Cu(OAc)2(0.2)/Ag2CO3(0.2)
Cu(OAc)2(0.2)/Ag2CO3(0.2)
12
12
12
12
12
12
12
12
12
12
12
12
12
8
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DMF
DMSO
Dioxane
PhCl
9
10
11
12
13[c]
14
15
16
17[d]
18
19
20
21
0
75
10
18
88
92
78
80
83
81
66
0
65
68
trace
0
trace
trace
trace
trace
trace
80
2
5
12
8
8
Scheme 2. Scope of Cu/Ag-cocatalyzed oxidative amination of maleimides.
Optimal reaction condition: maleimide (1.5 mmol), amine (1.6 mmol), Cu(OAc)2
(0.3 mmol), Ag2CO3 (0.3 mmol), PhCl (3 mL), air, 120℃ (isolated yields are
given).
12
2
[a] Reaction conditions: N-phenylmaleimide 1a (1.0 mmol), piperidine 2a (1.1
mmol). [b] Isolated Yield. [c] Under a N2 atmosphere. [d] 90℃, 12 h.
Since
the
3-amino-4-indolylmaleimides[1,2c-d]
and
3-amino-4-phenylmaleimides[2a-b] exist widely in both natural
products and pharmaceuticals, we next explored the scope of
this reaction for 3-arylmaleimides 5, which were synthesized
according to our previous work[9] (see the Supporting Information
for detail). The corresponding products were also obtained with
With the optimized conditions in hand, we set out to investigate
the scope of the present Cu/Ag cocatalyzed aerobic oxidative
amination of maleimides. A series of 3-aminomaleimides were
synthesized from maleimides and amines. All products had been
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
moderate yields (21%-70%; 6a-6g, Scheme 3). In addition, the
product 3a could not react with piperidine to yield the
corresponding product 3aa in the protocol (Scheme 3).
be also isolated with Ag2CO3 (0.2 equiv) or Cu(OAc)2 (0.2 equiv)
as catalyst (Table 1, entry 1, 3). However, this reaction
completed within 2 h under Cu/Ag cocatalyzed protocol (Table 1,
entry 15). These results indicate (i) a directly aerobic oxidative
amination of maleimides possibly proceeds through the
sequential reactions; (ii) Michael addition and dehydrogenation
oxidative process exist in this reaction.
Based on above evidence, the plausible pathway is proposed
in Scheme 5. Initially, Ag(I) coordinated to activate the double
bond of maleimides (1) followed by the rapid nucleophilic
1,4-addition.[11] The azo-Michael addition of amines (2) with
malimeids under Ag(I) catalysis would generate intermediates 4,
which are oxidized to the aimed products 3 quickly in the
presence of Cu(OAc)2. Cu(I) species in this reaction could be
converted into Cu(II) system by O2 oxidation in the air[12,7f]
.
Scheme 5. Proposed reaction mechanism for oxidative amination.
Interestingly, when treatment of maleimide 1 with primary
amines 2 in the presence of CuCl2 (1 equiv.) in PhCl at 120℃ for
3 h, chloroamination products 7 were obtained in good yields
(Scheme 6). The structure of 7a was further clearly confirmed by
single-crystal X-ray diffraction.
Scheme 3. Scope of Cu/Ag-cocatalyzed oxidative amination of
3-arylmaleimides. Optimal reaction condition: maleimide (1.5 mmol), amine
(1.6 mmol), Cu(OAc)2 (0.3 mmol), Ag2CO3 (0.3 mmol), PhCl (3 mL), air, 120℃
(isolated yields are given).
To understand the reaction mechanism, additional
experiments were carried out (Scheme 4). Michael addition
reactions of amines to maleimides could occur without any
catalyst.[10] Michael addition product 4a was obtained with 80%
yields when N-phenylmaleimides was treated with piperidine
without any catalyst in the reaction (Table 1, entry 21). Next, we
investigated the reactions of cyclopentylamine, benzylamine and
4-methylaniline with N-phenylmaleimide at 120 ℃ in PhCl.
Products 4a-4d were isolated in moderate yields after 2-12 h
(Scheme 4). They could be further oxidized to products 3a-3d for
1-2 h in good yields (86%-94%) with the optimized protocol.
Scheme 6. CuCl2 mediated oxidative chloroamination of maleimides. Optimal
reaction conditions: maleimide (1.5 mmol), amine (1.6 mmol), CuCl2 (1.5 mmol),
PhCl (3 mL), air, 120℃ (isolated yields are given). [a] In the presence of CuCl2
(0.3 mmol) / Ag2CO3 (0.3 mmol) yield 7a and 3b 15% and 68%, respectively.
CuCl2 could work as Lewis acid, oxidant and chloride source.[13]
However, both oxidative amination and chloroamination products
could be isolated in the presence of CuCl2 and Ag2CO3 (Scheme
6, Note: a, 7a, 3b, 15% and 68%, respectively). Using the
secondary amine as substrate in the CuCl2 catalyzed protocol,
Scheme 4. Control experiments.
The results suggested Michael addition products 4 could be
the intermediates in the aerobic amination reaction. They could
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
only oxidative amination and Michael addition products could be
obtained (Table 1, entry 7, 3a, 4a, 42% and 50%, respectively). It
seems that the nucleophilicity of the amines has an important
influence in the CuCl2 mediated chloroamination. And strong
nucleophilic agents are apt to the Michael addition in the protocol
for oxidative amination products. Only the oxidative amination
product 3b could be isolated from both the azo-Michael addition
product 4b in the CuCl2 mediated protocol and maleimide 1a and
amine 2b in the CuCl2 mediated protocol in the presence of
TEMPO (Scheme 7). It suggested that a general CuCl2 promoted
radical procedure occurred in the oxidative chloroamination. [13c-e,
3-amino-4-arylmaleimides as natural products, biologically active
compounds, and pharmaceutical agents.
Experimental Section
General
Unless otherwise noted, all the materials were purchased from
commercial suppliers and used without further purification. Petroleum
ether (PE) refers to a hydrocarbon mixture with a boiling range of 60-90℃.
TLC was performed on silica gel polygram SILG/UV 254 plates and
visualized by quenching of UV fluorescence (λmax = 254 nm). Silica gel
(100-200 microns) was used for all chromatographic separations. Melting
points were determined with RY-1 apparatus and uncorrected. IR spectra
14a]
What is more, arylamines mainly provided the aromatic azo
products in the presence of CuCl2 and had awful reactivity in the
chloroamination protocol.[14]
were recorded as KBr pellets on
a
Shimadzu model 470
spectrophotometer. NMR (1H and 13C) spectra were recorded using a
Bruker AV 400 MHz spectrometer in DMSO-d6 and CDCl3 with TMS as
internal standard. Chemical shifts (δ) were recorded in ppm. Mass spectra
were acquired on Waters micromass GCT premier, Agilent technologies
5973N and thermo Fisher scientific LTQ FT Ultra. The X-ray
crystal-structure determination of 7a was obtained on a Bruker SMART
APEX II CCD system. All of the products were known compounds, and
1
the data of m.p. and H NMR were in accord with those reported in the
literature.
General procedure for oxidative amination of maleimides and
amines (synthesis of compound 3a-p and 6a-g).
Scheme 7. Control experiments.
A mixture of maleimides 1 or 5 (1.5 mmol), amines 2 (1.6 mmol),
Cu(OAc)2 (0.3 mmol) and Ag2CO3 (0.3 mmol) in 3 mL of PhCl was stirred
at 120 ℃ under air. After the reaction completed (monitoring by TLC),
the solvent was removed. The residue was fully dissolved in ethyl acetate
(30 mL). Filtering out the insoluble substances, the organic phases were
washed with H2O (20 mL×3), dried over Na2SO4, concentrated and
purified by silica gel column chromatography to yield the pure products 3
or 6.
A
plausible mechanism for oxidative chloroamination is
proposed in Scheme 8. First, the proton-coupled electron
transfer from amine 2 to CuCl2 generates radical I. [13c-e, 14a] Then,
Michael addition occurs to form the intermediate II, followed by
the oxidative reaction by CuCl2 to provide the final product 7.
Cu(I) species could be converted into Cu(II) system by O2 in the
air[12,7f]
.
1-phenyl-3-(piperidin-1-yl)-1H-pyrrole-2,5-dione (3a).[15] Yellow solid;
yield: 0.38 g, 92%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 12:1); m.p.
100-102 ℃; IR(KBr): 3100, 2929, 2847, 1701, 1611, 1494, 1445, 1379,
1202, 1113, 741, 697cm-1; 1H NMR (400 MHz, CDCl3): δ 1.71 (s, 6H),
3.71 (brs, 4H), 5.04 (brs, 1H), 7.32 (t, J = 7.6 Hz, 3H), 7.43 (t, J = 7.3 Hz,
2H); 13C NMR (101 MHz, CDCl3): δ 24.03(2C), 25.72(2C), 48.79, 88.30,
126.47(2C), 127.31, 128.86(2C), 131.96, 150.00, 166.12, 169.83; MS
(ESI): m/z = 257.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd C15H17N2O2 for
257.1285, found 257.1284.
Scheme 8. Proposed reaction mechanism for oxidative choroamination.
3-(cyclopentylamino)-1-phenyl-1H-pyrrole-2,5-dione (3b). Yellow solid;
yield: 0.28 g, 74%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 20:1); m.p.
108-110 ℃; IR(KBr): 3326, 3122, 3040, 2953, 2868, 1708, 1644, 1502,
1448, 1392, 1200, 902, 765, 688 cm-1; 1H NMR (400 MHz, CDCl3): δ
1.63–1.85 (m, 6H), 2.06 (dd, J = 14.4, 7.4 Hz, 2H), 3.82 (m, 1H), 5.00 (s,
1H),5.52 (s, 1H), 7.36 (dd, J = 18.9, 7.7 Hz, 3H), 7.47 (t, J = 7.4 Hz, 2H);
13C NMR (101 MHz, CDCl3): δ 23.87(2C), 32.54(2C), 55.81, 84.70,
125.94(2C), 127.31, 128.95(2C), 131.91, 148.36, 166.48, 171.14; MS
(ESI): m/z = 257.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd C15H17N2O2 for
257.1285, found 257.1284.
Conclusions
In summary, we have successfully developed a novel aerobic
oxidative amination of maleimides catalyzed by Cu/Ag
cocatalysts.
A
series
of
3-aminomaleimides
and
3-amino-4-arylmaleimides could be synthesized in moderate to
good yields. However, using one equivalent of CuCl2 in the
reaction leads to the formation of 3-amino-4-chloromaleimides by
a radical-type mechanism. This method offers the important
motifs for the synthesis of 3-aminemaleimides and
3-(benzylamino)-1-phenyl-1H-pyrrole-2,5-dione (3c).[4] Yellow solid;
yield: 0.23 g, 55%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 15:1); m.p.
110-112 ℃; IR(KBr): 3340, 3116, 3055, 2933, 2866, 1705, 1639, 1497,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
1444, 1392, 1203, 1117, 1027, 973, 874, 784, 742, 691 cm-1; 1H NMR
(400 MHz, CDCl3): δ 4.39 (d, J = 5.0 Hz, 2H), 5.01 (s, 1H), 5.90 (s, 1H),
7.38-7.45 (m, 10H); 13C NMR (101 MHz, CDCl3): δ 48.52, 85.71,
125.90(2C), 127.38, 127.79(2C), 128.39, 128.97(2C), 129.08(2C), 131.82,
135.56, 148.74, 166.35, 171.01; MS (ES): m/z = 278 [M]+, 249, 216, 187,
173, 157, 146, 129, 91, 68.
1239, 1132, 943, 861, 768, 681cm-1; 1H NMR (400 MHz, CDCl3): δ 2.00 (s,
4H), 2.97 (s, 3H), 3.28 (s, 2H), 3.89 (s, 2H), 4.72 (s, 1H); 13C NMR (101
MHz, CDCl3): δ 23.28, 24.08, 26.30, 48.93, 50.21, 85.55, 148.64, 166.92,
171.92; MS (ESI): m/z = 181.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd
C9H13N2O2 for 181.0927, found 181.0927.
3-(benzyl(methyl)amino)-1-methyl-1H-pyrrole-2,5-dione (3j). Yellow
solid; yield: 0.31 g, 91%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 15:1);
m.p. 36-38 ℃; IR(KBr): 2930, 1751, 1699, 1614, 1439, 1384, 1245, 1030,
1-phenyl-3-(p-tolylamino)-1H-pyrrole-2,5-dione (3d). Yellow solid; yield:
0.16 g, 38%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 20:1); m.p.
220-222 ℃; IR(KBr): 3314, 3252, 3062, 2930, 1759, 1698, 1619, 1533,
1444, 1404, 1200, 1105, 1029, 910, 811, 777, 737, 686 cm-1; 1H NMR
(400 MHz, CDCl3): δ 2.37 (s, 3H), 5.61 (s, 1H), 7.10 (d, J = 7.6 Hz, 2H),
7.23 (d, J = 7.7 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H),
7.47 (t, J = 7.4 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 20.92, 88.46,
119.06(2C), 125.89(2C), 127.57, 129.06(2C), 130.35(2C), 131.68, 134.76,
135.66, 142.67, 167.10, 171.38; MS (ESI): m/z = 279.1 [M+H]+. HRMS
(ESI): m/z [M+H]+ calcd C17H15N2O2 for 279.1128, found 279.1126.
1
937, 760, 696 cm-1; H NMR (400 MHz, CDCl3): δ 2.98 (s, 3H), 3.20 (s,
3H), 4.90 (s, 2H), 7.21 (d, J = 7.1 Hz, 2H), 7.33 (dt, J = 21.9, 7.2 Hz, 4H);
13C NMR (101 MHz, CDCl3): δ 23.42, 29.71, 38.84, 88.23, 127.41(2C),
127.86, 128.87(3C), 150.72, 167.18, 171.03; MS (ESI): m/z = 231.1
[M+H]+. HRMS (ESI): m/z [M+H]+ calcd C13H15N2O2 for 231.1128, found
231.1128.
3-(pyrrolidin-1-yl)-1H-pyrrole-2,5-dione (3k). Yellow solid; yield: 0.21 g,
84%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 8:1); m.p. 212-214 ℃;
IR(KBr): 3167, 3100, 3019, 2955, 2920, 2866, 1744, 1686, 1617, 1453,
1403, 1331, 1223, 1109, 964, 911, 780, 739, 662 cm-1; 1H NMR (400 MHz,
CDCl3): δ 2.01 (s, 4H), 3.30 (s, 2H), 3.89 (s, 2H), 4.73 (s, 1H), 7.29 (s, 1H);
13C NMR (101 MHz, CDCl3): δ 24.09, 26.28, 48.93, 50.31, 86.95, 148.77,
166.99, 171.42; MS (ESI): m/z = 167.1 [M+H]+. HRMS (ESI): m/z [M+H]+
calcd C8H11N2O2 for 167.0815, found 167.0815.
3-(di-n-butylamino)-1-phenyl-1H-pyrrole-2,5-dione (3e). Yellow solid;
yield: 0.35 g, 79%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 30:1); m.p.
42-44 ℃; IR(KBr): 3114, 3032, 2957, 2868, 1750, 1705, 1613, 1498,
1457, 1381, 1200, 1160, 1115, 926, 767, 694 cm-1; 1H NMR (400 MHz,
CDCl3): δ 0.96 (t, J = 6.8 Hz, 6H), 1.36 (dd, J = 13.9, 6.8 Hz, 4H), 1.64 (s,
4H), 3.23 (s, 2H), 3.82 (s, 2H), 4.95 (s, 1H), 7.32 (dd, J = 15.2, 7.6 Hz, 3H),
7.44 (t, J = 7.6 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 13.85(2C),
20.13(2C), 27.88, 31.48, 50.16, 53.09, 86.83, 126.44(2C), 127.25,
128.87(2C), 132.03, 149.38, 165.70, 169.96; MS (ESI): m/z = 301.2
[M+H]+. HRMS (ESI): m/z [M+H]+ calcd C18H25N2O2 for 301.1911, found
301.1910.
Ethyl-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)piperidine-4-carboxylat
e (3l). Yellow solid; yield: 0.27 g, 71%; Rf = 0.15 (Petrumlem ether/Ethyl
acetate 3:1); m.p. 110-112 ℃; IR(KBr): 3154, 3106, 3039, 2975, 2869,
2747, 1724, 1622, 1456, 1350, 1312, 1199, 1122, 1039, 975, 889, 775
cm-1; 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J = 7.1 Hz, 3H), 1.82 (td, J =
14.2, 3.7 Hz, 2H),2.02 (dd, J = 13.5, 2.9 Hz, 2H), 2.58 (td, J = 10.2, 5.0 Hz,
1H), 3.18 (t, J = 11.7 Hz, 2H), 4.17 (q, J = 7.1 Hz, 4H), 4.93 (s, 1H),7.37 (s,
1H); 13C NMR (101 MHz, CDCl3): δ 14.23, 27.63, 40.24(2C), 46.59,
60.86(2C), 90.32, 150.33, 167.41, 170.41, 173.84; MS (ESI): m/z = 253.1
[M+H]+. HRMS (ESI): m/z [M+H]+ calcd C12H17N2O4 for 253.1183, found
253.1183.
1-phenyl-3-(pyrrolidin-1-yl)-1H-pyrrole-2,5-dione (3f).[15] Yellow solid;
yield: 0.34 g, 95%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 10:1); m.p.
98-100 ℃; IR(KBr): 3100, 3058, 2981, 2875, 1700, 1625, 1501, 1450,
1380, 1344, 1203, 1113, 1034, 947, 774, 689 cm-1; 1H NMR (400 MHz,
CDCl3): δ 2.02 (s, 4H), 3.35 (s, 2H), 3.94 (s, 2H), 4.89 (s, 1H), 7.32 (dd, J
= 18.4, 7.7 Hz, 3H), 7.43 (t, J = 7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3):
δ 24.08, 26.35, 49.11, 50.45, 86.04, 126.30(2C), 127.18, 128.86(2C),
132.12, 148.18, 165.60, 170.42; MS (EI): m/z = 242 [M]+, 213, 186, 170,
158, 145, 119, 95, 77, 69.
1-(4-bromophenyl)-3-(pyrrolidin-1-yl)-1H-pyrrole-2,5-dione
(3m).
Yellow solid; yield: 0.43 g, 90%; Rf = 0.15 (Petrumlem ether/Ethyl acetate
10:1); m.p. 150-152 ℃; IR(KBr): 3116, 2971, 2875, 1703, 1622, 1486,
1455, 1375, 1278, 1206, 1107, 1037, 943, 820, 754, 699 cm-1; 1H NMR
(400 MHz, CDCl3): δ 2.03 (s, 4H), 3.35 (s, 2H),3.95 (s, 2H), 4.89 (s,
1H),7.28 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H); 13C NMR (101 MHz,
CDCl3): δ 24.09, 26.33, 49.17, 50.54, 86.06, 120.62, 127.59(2C), 131.24,
131.93(2C), 148.16, 165.22, 169.87; MS (ESI): m/z = 321.0 [M+H]+,
323.0[M+2+H]+. HRMS (ESI): m/z [M+H]+ calcd C14H14N2O2Br for
321.0233, found 321.0233.
3-(4-methylpiperazin-1-yl)-1-phenyl-1H-pyrrole-2,5-dione (3g). Yellow
solid; yield: 0.36 g, 88%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 1:5);
m.p. 120-122 ℃; IR(KBr): 3124, 3045, 2966, 2853, 2793, 1703, 1617,
1498, 1449, 1387, 1293, 1255, 1205, 1129, 1001, 918, 768, 696 cm-1; 1H
NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 2.55 (brs, 4H), 3.78 (brs, 4H),
5.09 (s, 1H),7.32 (d, J = 7.3 Hz, 3H), 7.44 (t, J = 7.0 Hz, 2H); 13C NMR
(101 MHz, CDCl3): δ 46.05, 47.10(2C), 54.40(2C), 89.65, 126.45(2C),
127.46, 128.92(2C), 131.77, 149.75, 166.06, 169.60; MS (ESI): m/z =
272.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd C15H18N3O2 for 272.1394,
found 272.1393.
1-benzyl-3-(4-morpholinyl)-1H-pyrrole-2,5-dione (3n).[5a] Yellow solid;
yield: 0.35 g, 86%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 6:1); m.p.
120-122 ℃; IR(KBr): 3173, 3098, 3016, 2975, 2862, 1743, 1685, 1613,
1449, 1400, 1329, 1216, 1108, 964, 910, 781, 660 cm-1; 1H NMR (400
MHz, CDCl3): δ 3.70 (s, 4H), 3.79 (s, 4H),4.64 (s, 2H), 4.98 (s, 1H),7.30
(d, J = 12.6 Hz, 2H),7.37 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 40.99(2C), 47.14(2C), 66.28, 89.76, 127.59, 128.36(2C), 128.59(2C),
136.83, 150.06, 166.90, 170.34; MS (EI): m/z = 272 [M]+, 254, 241, 229,
215, 201, 181, 163, 151, 140, 123, 106, 91, 77.
3-(dimethylamino)-1-phenyl-1H-pyrrole-2,5-dione (3h).[15] Yellow solid;
yield: 0.27 g, 85%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 10:1); m.p.
132-134 ℃; IR(KBr): 3100, 3051, 2930, 2805, 1745, 1689, 1624, 1494,
1384, 1303, 1216, 1165, 1110, 934, 781, 693 cm-1; 1H NMR (400 MHz,
CDCl3): δ 3.25 (brs, 6H), 4.97 (s, 1H), 7.33 (d, J = 7.5 Hz, 3H), 7.44 (t, J =
7.2 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 39.69(2C), 87.71, 126.43(2C),
127.33, 128.88(2C), 131.96, 150.47, 165.74, 169.68; MS (EI): m/z = 216
[M]+, 201, 187, 173, 159, 144, 117, 106, 91, 82, 69.
3-(n-butylamino)-1-phenyl-1H-pyrrole-2,5-dione (3o).[3] Yellow solid;
yield: 0.26 g, 72%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 25:1); m.p.
128-130 ℃; IR(KBr): 3260, 3112, 3032, 2959, 2859, 1700, 1616, 1521,
1453, 1399, 1293, 1207, 1062, 890, 777, 694, 656 cm-1; 1H NMR (400
MHz, CDCl3): δ 0.97 (t, J = 7.3 Hz, 3H), 1.48–1.38 (m, 2H), 1.70–1.62 (m,
1-methyl-3-(pyrrolidin-1-yl)-1H-pyrrole-2,5-dione (3i). Yellow solid;
yield: 0.24 g, 88%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 15:1); m.p.
90-92 ℃; IR(KBr): 3102, 2961, 2914, 2874, 1719, 1601, 1444, 1384,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
2H), 3.24 (q, J = 6.7 Hz, 2H), 4.97 (s, 1H), 5.55 (s, 1H), 7.41–7.29 (m, 3H),
7.44 (t, J = 7.6 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 13.72, 20.06,
30.57, 44.13, 84.11, 125.92(2C), 127.34, 128.97(2C), 131.85, 149.12,
166.36, 171.19; MS (EI): m/z = 244 [M]+, 215, 201, 187, 173, 160, 146,
124, 106, 97, 77, 68.
MHz, CDCl3): δ 13.49, 19.58, 23.92, 32.20, 33.02, 43.40, 93.61, 103.35,
109.38, 119.69, 120.15, 121.89, 129.02, 129.40, 136.57, 142.82, 168.62,
173.08; MS (ESI): m/z = 312.2 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd
C18H22N3O2 for 312.1707, found 312.1705.
Ethyl-1-(4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)
piperidine-4-carboxylate (6e). Orange solid; yield: 0.19 g, 36%; Rf =
0.15 (Petrumlem ether/Ethyl acetate 1:3); m.p. 164-166 ℃; IR(KBr): 3320,
3052, 2969, 2857, 1700, 1623, 1533, 1444, 1343, 1184, 1097, 1039, 938,
895, 746, 659 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.24 (t, J = 7.0 Hz, 3H),
1.86–1.70 (m, 4H), 2.44 (d, J = 8.5 Hz, 1H), 3.07 (t, J = 12.0 Hz, 2H),
4.23–4.08 (m, 4H), 7.28–7.09 (m, 3H), 7.36 (d, J = 7.8 Hz, 1H), 7.50 (d, J
= 7.5 Hz, 1H) , 7.58 (s, 1H), 8.69 (s, 1H); 13C NMR (101 MHz, CDCl3): δ
14.18, 28.36(2C), 40.52, 47.58(2C), 60.63, 101.32, 105.60, 111.53,
120.07, 120.29, 122.42, 125.40, 127.82, 135.81, 143.48, 168.52, 171.49,
174.28; MS (EI): m/z = 367 [M]+, 338, 322, 294, 266, 252, 238, 227, 212,
195, 184, 168, 155, 140, 128. HRMS (EI): m/z [M]+ calcd C20H21N3O4 for
367.1532, found 367.1530.
3-((4-methoxyphenyl)amino)-1-phenyl-1H-pyrrole-2,5-dione
(3p).
Yellow solid; yield: 0.20 g, 46%; Rf = 0.15 (Petrumlem ether/Ethyl acetate
15:1); m.p. 184-186 ℃; IR(KBr): 3305, 3257, 3066, 2914, 2839, 1755,
1699, 1618, 1549, 1508, 1450, 1404, 1247, 1112, 1031, 823, 767, 739,
687 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.84 (s, 3H), 5.55 (s, 1H), 6.96 (d,
J = 8.5 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.36 (t, J = 7.3 Hz,
1H), 7.41 (d, J = 7.8 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H); 13C NMR (101 MHz,
CDCl3): δ 55.62, 87.46, 115.02(2C), 120.83(2C), 125.91(2C), 127.59,
129.09(2C), 131.17, 131.64, 143.14, 156.90, 167.03, 171.46; MS (ESI):
m/z = 295.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd C17H15N2O3 for
295.1077, found 295.1077.
3-(1H-indol-3-yl)-1-phenyl-4-(pyrrolidin-1-yl)-1H-pyrrole-2,5-dione
(6a). Orange solid; yield: 0.35 g, 65%; Rf = 0.15 (Petrumlem ether/Ethyl
acetate 8:1); m.p. 208-210 ℃; IR(KBr): 3315, 3054, 2965, 2874, 1749,
1694, 1627, 1538, 1495, 1440, 1387, 1244, 1198, 1100, 938, 742, 690
Ethyl-1-(4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)piperi
dine-3-carboxylate (6f). Orange solid; yield: 0.20 g, 38%; Rf = 0.15
(Petrumlem ether/Ethyl acetate 1:2); m.p. 182-184 ℃; IR(KBr): 3312,
3051, 2939, 2856, 1700, 1624, 1533, 1442, 1343, 1267, 1232, 1183,
1106, 1018, 915, 861, 745, 659 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.20 (t,
J = 6.9 Hz, 3H), 1.50 (dd, J = 22.4, 10.8 Hz, 1H), 1.70–1.59 (m, 2H), 2.00
(d, J = 11.4 Hz, 1H), 2.59 (s, 1H), 3.08 (t, J = 11.6 Hz, 1H), 3.30 (t, J =
11.4 Hz, 1H), 3.84 (d, J = 12.7 Hz, 1H), 4.09 (q, J = 6.7 Hz, 2H), 4.28 (d, J
= 13.1 Hz, 1H), 7.24–7.12 (m, 3H), 7.34 (d, J = 7.7 Hz, 1H) , 7.49 (d, J =
7.5 Hz, 1H),7.66 (s, 1H), 8.77 (s, 1H); 13C NMR (101 MHz, CDCl3): δ
14.09, 24.67, 26.82, 41.68, 48.68, 49.88, 60.64, 101.79, 105.44, 111.55,
120.01, 120.24, 122.36, 125.48, 127.74, 135.86, 143.57, 168.52, 171.62,
173.10; MS (EI): m/z = 367 [M]+, 338, 322, 294, 266, 252, 238, 227, 212,
195, 184, 168, 155, 140, 128. HRMS (EI): m/z [M]+ calcd C20H21N3O4 for
367.1532, found 367.1535.
1
cm-1; H NMR (400 MHz, CDCl3): δ 1.78 (s, 4H), 3.61 (s, 4H), 7.20–7.08
(m, 3H), 7.32 (d, J = 7.9 Hz, 2H),7.45 (d, J = 4.1 Hz, 4H), 7.53 (d, J = 7.5
Hz, 1H), 8.47 (s, 1H); 13C NMR (101 MHz, CDCl3): δ 25.26(2C),
50.65(2C), 94.01, 105.98, 111.29, 119.95, 120.08, 122.12, 125.73,
126.25(2C), 127.03, 128.82(2C), 129.87, 132.41, 135.45, 143.42, 166.45,
171.16; MS (ESI): m/z = 358.2 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd
C22H20N3O2 for 358.1550, found 358.1548.
3-(1H-indol-3-yl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione
(6b). Orange solid; yield: 0.39 g, 70%; Rf = 0.15 (Petrumlem ether/Ethyl
acetate 4:1); m.p. 124-126 ℃; IR(KBr): 3356, 3056, 2965, 2917, 2855,
1754, 1700, 1628, 1532, 1497, 1386, 1268, 1235, 1111, 1020, 927, 851,
744, 694 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.67 (s, 8H), 7.20 (dd, J =
16.9, 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.43 (dt, J = 14.8, 7.1 Hz, 5H),
7.59 (d, J = 7.6 Hz, 1H), 8.54 (s, 1H); 13C NMR (101 MHz, CDCl3): δ
48.53(2C), 67.06(2C), 101.44, 105.43, 111.55, 120.30, 120.51, 122.65,
125.68, 126.31(2C), 127.35, 127.70, 128.92(2C), 132.02, 135.72, 142.08,
167.30, 170.28; MS (ESI): m/z = 374.1 [M+H]+. HRMS (ESI): m/z [M+H]+
calcd C22H20N3O3 for 374.1499, found 374.1497.
3-(4-chlorophenyl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione
(6g). Orange solid; yield: 0.37 g, 68%; Rf = 0.15 (Petrumlem ether/Ethyl
acetate 12:1); m.p. 134-136 ℃; IR(KBr): 3056, 2965, 2901, 2855, 1751,
1702, 1623, 1495, 1430, 1388, 1276, 1162, 1109, 1021, 950, 915, 851,
1
787, 749, 695 cm-1; H NMR (400 MHz, CDCl3): δ 3.60 (s, 4H), 3.74 (s,
4H), 7.35 (dd, J = 20.3, 7.0 Hz, 6H), 7.45 (d, J = 6.8 Hz, 3H); 13C NMR
(101 MHz, CDCl3): δ 49.37(2C), 66.79(2C), 104.41, 126.29(2C), 127.57,
128.45(2C), 128.95(3C), 131.49(2C), 131.68, 133.91, 143.09, 166.50,
169.39; MS (ESI): m/z = 369.1 [M+H]+, 371.1 [M+2+H]+. HRMS (ESI): m/z
[M+H]+ calcd C20H18N2O3Cl for 369.1000, found 369.1000.
Ethyl-1-(4-(2-methyl-1H-indol-3-yl)-2,5-dioxo-1-phenyl-2,5-dihydro-1
H-pyrrol-3-yl)piperidine-4-carboxylate (6c). Orange solid; yield: 0.40 g,
58%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 5:1); m.p. 88-90 ℃;
IR(KBr): 3353, 3054, 2975, 2933, 2950, 1697, 1625, 1551, 1496, 1455,
1387, 1318, 1185, 1105, 1040, 920, 861, 744, 691 cm-1; 1H NMR (400
MHz, CDCl3) : δ 1.24 (t, J = 6.9 Hz, 3H), 1.92–1.62 (m, 5H), 2.39 (s, 3H),
3.17–2.99 (m, 2H), 4.02 (d, J = 11.2 Hz, 1H), 4.12 (dd, J = 13.8, 6.8 Hz,
2H), 4.45 (d, J = 10.3 Hz, 1H), 7.12 (dd, J = 13.7, 6.7 Hz, 2H), 7.27 (s, 1H),
7.41–7.33 (m, 2H), 7.46 (s, 4H), 8.23 (s, 1H); 13C NMR (101 MHz, CDCl3):
δ 13.18, 14.18, 28.52, 40.53, 47.36, 60.60, 99.49, 102.90, 110.55, 119.02,
120.12, 121.56, 126.24, 127.15, 128.84, 129.30, 132.20, 135.13, 135.39,
144.44, 167.06, 169.94, 174.21; MS (ESI): m/z = 458.2 [M+H]+. HRMS
(ESI): m/z [M+H]+ calcd C27H28N3O4 for 458.2074, found 458.2072.
General procedure for Michael addition of malmeimides with amines
(synthesis of compounds 4a-d).
A mixture of N-phenylmaleimide 1a (0.34 g, 2.0 mmol) and amines 2 (2.1
mmol) in 3 mL of PhCl was stirred at 120 ℃ under air condition. After the
reaction completed (monitoring by TLC), the solvent was removed. The
residue was fully dissolved in ethyl acetate (30 mL). Filtering out the
insoluble substances, the organic phases were washed with H2O (20
mL×3), dried (Na2SO4), concentrated and purified by silica gel column
chromatography (eluent: ethyl acetate–PE, 1: 3) to yield the pure product
4.
3-(n-butylamino)-1-methyl-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-
dione (6d). Orange solid; yield: 0.10 g, 21%; Rf = 0.15 (Petrumlem
ether/Ethyl acetate 10:1); m.p. 134-136 ℃; IR(KBr): 3330, 3100, 3052,
2952, 2869, 1753, 1700, 1655, 1546, 1449, 1384, 1337, 1294, 1241,
1104, 1055, 995, 819, 746, 686 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.72 (t,
J = 7.2 Hz, 3H), 1.20–1.07 (m, 2H), 1.42–1.32 (m, 2H), 3.09 (s, 3H), 3.16
(t, J = 6.7 Hz, 2H), 3.85 (s, 3H), 5.19 (s, 1H), 7.21–7.10 (m, 2H),7.28–7.23
(m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H); 13C NMR (101
1-phenyl-3-(piperidin-1-yl)-2,5-pyrrolidinedione (4a).[10] White solid;
yield: 0.41 g, 80%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 1:1); m.p.
116-118 ℃; IR(KBr): 3059, 2926, 2846, 2804, 1777, 1696, 1597, 1494,
1448, 1377, 1273, 1202, 1159, 1107, 897, 847, 746, 692 cm-1; 1H NMR
(400 MHz, CDCl3): δ 1.51 (d, J = 3.9 Hz, 2H), 1.66 (d, J = 4.7 Hz, 4H),
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
2.68–2.53 (m, 2H), 2.85 (dd, J = 17.6, 3.9 Hz, 3H), 3.05 (dd, J = 18.6, 9.1
Hz, 1H), 3.96 (dd, J = 8.7, 4.3 Hz, 1H), 7.29 (d, J = 7.0 Hz, 2H), 7.42 (t, J =
7.3 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 24.02,
26.03, 32.04, 50.25, 63.15, 126.51, 128.72, 129.20, 131.56, 174.50,
175.39; MS (ESI): m/z = 259.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd
C15H19N2O2 for 259.1441, found 259.1441.
131.48, 139.72, 164.68, 166.63; MS (ESI): m/z = 293.1[M+2+H]+, 291.1
[M+H]+. HRMS (ESI): m/z [M+H]+ calcd C15H16N2O2Cl for 291.0895, found
291.0895.
3-chloro-4-(benzylamino)-1-phenyl-1H-pyrrole-2,5-dione (7b). Yellow
solid; yield: 0.41 g, 88%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 20:1);
m.p. 106-108 ℃; IR(KBr): 3333, 3034, 2933, 1772, 1720, 1665, 1591,
1
3-(cyclopentylamino)-phenyl-2,5-pyrrolidinedione (4b). White solid;
yield: 0.35 g, 68%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 3:1); m.p.
114-116 ℃; IR(KBr): 3283, 3060, 2950, 2901, 2861, 1702, 1543, 1500,
1457, 1392, 1178, 883, 746, 695, 626 cm-1; 1H NMR (400 MHz, CDCl3): δ
1.39 (d, J = 4.8 Hz, 2H), 1.59 (s, 2H), 1.74 (s, 2H), 1.93 (s, 2H), 2.03 (s,
1H), 2.76 (dd, J = 17.6, 2.4 Hz, 1H), 3.11 (dd, J = 17.8, 8.1 Hz, 1H),
3.30–3.18 (m, 1H), 3.97 (s, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 6.7
Hz, 1H), 7.47 (t, J = 6.6 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 23.61,
23.88, 32.79, 33.65, 37.55, 55.80, 59.08, 126.36(2C), 128.73, 129.22(2C),
131.63, 174.40, 177.20; MS (ESI): m/z = 259.1 [M+H]+. HRMS (ESI): m/z
[M+H]+ calcd C15H19N2O2 for 259.1441, found 259.1440.
1503, 1448, 1394, 1264, 1214, 1101, 1038, 929, 786, 741, 693 cm-1; H
NMR (400 MHz, CDCl3): δ 4.87 (d, J = 6.3 Hz, 2H), 5.71 (s, 1H),
7.38–7.32 (m, 5H), 7.76–7.39 (m, 5H); 13C NMR (101 MHz, CDCl3): δ
47.14, 90.59, 125.74(2C), 127.70(2C), 127.76, 128.36, 129.10(2C),
129.13(2C), 131.37, 136.90, 139.79, 164.55, 166.45; MS (ESI): m/z =
315.1[M+2+H]+, 313.1 [M+H]+. HRMS (ESI): m/z [M+H]+ calcd
C17H14N2O2Cl for 313.0738, found 313.0738.
3-(butylamino)-4-chloro-1-phenyl-1H-pyrrole-2,5-dione (7c). Yellow
solid; yield: 0.37 g, 90%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 35:1);
m.p.: 82-84 ℃; IR(KBr): 3326, 3055, 2957, 2866, 1715, 1668, 1517, 1460,
1402, 1271, 1219, 1099, 984, 915, 783, 740, 687, 628 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.98 (t, J = 7.1 Hz, 3H), 1.50–1.39 (m, 2H), 1.72–1.63 (m,
2H), 3.67 (q, J = 6.5 Hz, 2H), 5.50 (s, 1H), 7.41–7.29 (m, 3H), 7.44 (t, J =
7.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 13.71, 19.70, 32.86, 43.03,
89.39, 125.72(2C), 127.66, 129.05(2C), 131.47, 140.24, 164.62, 166.58;
MS (EI): m/z = 280[M+2]+, 278[M]+, 251, 249, 237, 235, 222, 207, 194,
180, 164, 146, 131, 119, 104, 88, 77, 57; HRMS (EI): m/z [M]+ calcd
C14H15N2O2Cl for 278.0822, found 278.0827.
3-(benzylamino)-1-phenyl-2,5-pyrrolidinedione (4c).[16] White solid;
yield: 0.28 g, 50%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 4:1); m.p.
92-94 ℃; IR(KBr): 3320, 3071, 3026, 2930, 2849, 1783, 1712, 1596,
1495, 1455, 1383, 1325, 1185, 1030, 747, 696 cm-1; 1H NMR (400 MHz,
CDCl3): δ 2.44 (s, 1H), 2.72 (d, J = 17.9 Hz, 1H), 3.04 (dd, J = 17.9, 8.3 Hz,
1H), 4.02–3.88 (m, 3H), 7.28 (d, J = 7.3 Hz, 3H), 7.43–7.34 (m, 5H), 7.47
(t, J = 6.7 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 36.63, 51.97, 55.60,
126.34(2C), 127.67, 128,37(2C), 128.76(3C), 129.23(2C), 131.57, 138.60,
174.20, 176.92; MS (ESI): m/z = 281.1 [M+H]+. HRMS (ESI): m/z [M+H]+
calcd C17H17N2O2 for 281.1285, found 281.1282.
3-chloro-4-(cyclopentylamino)-1H-pyrrole-2,5-dione (7d). Yellow solid;
yield: 0.27 g, 83%,; Rf = 0.15 (Petrumlem ether/Ethyl acetate 10:1); m.p.:
140-142 ℃; IR(KBr): 3319, 3171, 3055, 2962, 2866, 1766, 1709, 1650,
1508, 1350, 1163, 1034, 966, 912, 741, 710, 646 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.63–1.52 (m, 2H), 1.81–1.64 (m, 4H), 2.08 (d, J = 6.0 Hz, 2H),
4.43 (d, J = 5.8 Hz, 1H), 5.29 (s, 1H), 7.48 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 23.86(2C), 34.81(2C), 54.49, 89.79, 140.39, 165.36, 167.36; MS
(EI): m/z = 216[M+2]+, 214[M]+, 187, 185, 172, 146, 108, 87, 68; HRMS
(EI): m/z [M]+ calcd C9H11N2O2Cl for 214.0509, found 214.0507.
3-[(4-methylphenyl)amino]-1-phenyl-2,5-pyrrolidinedione (4d). White
solid; yield: 0.14 g, 25%; Rf = 0.15 (Petrumlem ether/Ethyl acetate 8:1);
m.p. 188-190 ℃; IR(KBr): 3369, 3335, 2920, 1770, 1699, 1620, 1510,
1450, 1398, 1289, 1194, 1117, 1005, 944, 866, 806, 739, 692 cm-1; 1H
NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 2.87 (dd, J = 17.9, 5.2 Hz, 1H),
3.44 (dd, J = 17.9, 8.2 Hz, 1H), 4.55 – 4.44 (m, 1H), 6.63 (d, J = 7.5 Hz,
2H), 7.10 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 8.2 Hz,
1H), 7.53 (t, J = 7.3 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 20.48, 38.39,
53.39, 114.19(2C), 126.32(2C), 128.94(2C), 129.15, 129.32(2C),
130.08(2C), 131.49, 143.67, 173.64, 176.09; MS (ESI): m/z = 281.1
[M+H]+. HRMS (ESI): m/z [M+H]+ calcd C17H17N2O2 for 281.1285, found
281.1283.
1-benzyl-3-chloro-4-(cyclopentylamino)-1H-pyrrole-2,5-dione
(7e).
Yellow solid; yield: 0.40 g, 89%; Rf = 0.15 (Petrumlem ether/Ethyl acetate
50:1); m.p.: 84-86 ℃; IR(KBr): 3324, 3026, 2957, 2870, 1766, 1713, 1656,
1
1507, 1438, 1403, 1350, 1258, 1171, 1077, 895, 738, 698, 623 cm-1; H
NMR (400 MHz, CDCl3) δ 1.54 (dd, J = 12.1, 5.8 Hz, 2H), 1.68 (dt, J =
24.3, 11.8 Hz, 4H), 2.05 (dd, J = 11.9, 5.6 Hz, 2H), 4.39 (dd, J = 13.0, 6.5
Hz, 1H), 4.64 (s, 2H), 5.25 (s, 1H), 7.38–7.26 (m, 5H); 13C NMR (101 MHz,
CDCl3) δ 23.85(2C), 34.80(2C), 41.90, 54.55, 88.83, 127.85, 128.49(2C),
General procedure for chloroamination of malmeimides with primary
amines (synthesis of compounds 7a-f).
128.66(2C), 136.22, 139.92, 165.45, 167.54; MS (EI): m/z
=
306[M+2]+,304[M]+, 275, 236, 213, 197, 173, 159, 106, 91, 69, 51; HRMS
(EI): m/z [M]+ calcd C16H17N2O2Cl for 304.0979, found 304.0978.
A mixture of maleimide 1 (1.5 mmol), primary amines 2 (1.6 mmol), and
CuCl2 (0.20 g, 1.5 mmol) in 3 mL of PhCl was stirred at 120 ℃ under air
condition. After the reaction completed (monitoring by TLC), the solvent
was removed. The residue was fully dissolved in ethyl acetate (30 mL).
Filtering out the insoluble substances, the organic phases were washed
with H2O (20 mL× 3), dried over Na2SO4, concentrated and purified by
silica gel column chromatography (eluent: ethyl acetate–PE, 1: 30) to
yield the pure product 7.
3-(benzylamino)-4-chloro-1-methyl-1H-pyrrole-2,5-dione
(7f).[17]
Yellow solid; yield: 0.29 g, 78%; Rf = 0.15 (Petrumlem ether/Ethyl acetate
30:1); m.p.: 122-124 ℃; IR(KBr): 3318, 2937, 1713, 1656, 1512, 1447,
1383, 1261, 1167, 1088, 985, 908, 860, 739, 695 cm-1; 1H NMR (400 MHz,
CDCl3) δ 3.02 (s, 3H), 4.80 (d, J = 6.2 Hz, 2H), 5.54 (s, 1H), 7.31 (d, J =
7.2 Hz, 2H), 7.37 (dt, J = 13.0, 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
24.28, 47.06, 127.61(2C), 90.03, 128.27, 129.08(2C), 137.02, 140.08,
165.73, 167.81; MS (EI): m/z = 252 [M+2]+, 250[M]+, 215, 183, 156, 125,
103, 91, 77, 65, 51.
3-chloro-4-(cyclopentylamino)-1-phenyl-1H-pyrrole-2,5-dione
(7a).
Yellow solid; yield: 0.40 g, 92%; Rf = 0.15 (Petrumlem ether/Ethyl acetate
25:1); m.p. 130-132 ℃; IR(KBr): 3322, 2961, 2870, 1768, 1717, 1664,
1
1594, 1500, 1451, 1402, 1266, 1211, 1098, 992, 788, 739, 691 cm-1; H
NMR (400 MHz, CDCl3): δ 1.72 (ddd, J = 33.6, 16.2, 6.7 Hz, 6H),
2.18–2.09 (m, 2H), 4.51 (dd, J = 12.8, 6.3 Hz, 1H), 5.46 (d, J = 6.3 Hz, 1H),
7.43–7.32 (m, 3H), 7.47 (t, J = 7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ
23.90(2C), 34.86(2C), 54.68, 89.36, 125.76(2C), 127.67, 129.06(2C),
Acknowledgements
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
[10]
[11]
[12]
[13]
a) A. Mustafa, W. Asker, S. Khattab, S. M. A. D. Zayed, J. Org. Chem.
1961, 26, 787-789; b) J. Bergman, T. Brimert, Acta. Chem. Scand. 1999,
53, 48-56.
The authors acknowledge financial support from Shanghai
Municipality Natural Science Foundation (No. 15ZR1401400),
the Open Funds from the State Key Laboratory of Bioorganic &
Natural products Chemistry in Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences(2013) and the
Fundamental Research Funds for the Central Universities from
the Ministry of Education of China (CUSF-DH-D-2016028 and
BCZD2016004).
a) F. Hu, R. Lalancette, M. Szostak, Angew. Chem. Int. Ed. 2016, 55,
5062-5066; b) S. Eckhardt, P. S. Brunetto, J. Gagnon, M. Priebe, B.
Giese, K. M. Fromm, Chem. Rev. 2013, 113, 4708-4754,
a) K. Monir, A. K. Bagdi, S. Mishra, A. Majee, A. Hajra, Adv. Synth.
Catal. 2014, 356, 1105-1112; b) Y. Yang, F. Ni, W. M. Shu, S. B. Yu, M.
Gao, A. X. Wu, J. Org. Chem. 2013, 78, 5418-5426.
a) J. B. Xia, S. L. You, Org. Lett. 2009, 11, 1187-1190; b) G. Cheng, Y.
Hu, Chem. Commun. 2007, 3285-3287; c) S. Q. Li, P. Xiong, L. Zhu, X.
Y. Qian, H. C. Xu, Eur. J. Org. Chem. 2016, 2016, 3449-3455; d) P.
Xiong, F. Xu, X. Y. Qian, Y. Yohannes, J. Song, X. Lu, H. C. Xu, Chem.
Eur. J. 2016, 22, 4379-4383; e) Y. F. Wang, H. Chen, X. Zhu, S. Chiba,
J. Am. Chem. Soc. 2012, 134, 11980-11983.
Keywords: maleimides • aerobic • amination • chloroamination
[1]
[2]
a) B. Hugon, F. Anizon, C. Bailly, R. M. Golsteyn, A. Pierre, S. Leonce, J.
Hickman, B. Pfeiffer, M. Prudhomme, Bioorg. Med. Chem. 2007, 15,
5965-5980; b) S. Deslandes, S. Chassaing, E. Delfourne, Mar. Drugs.
2009, 7, 754-786; c) T. Kimura, S. Kanagaki, Y. Matsui, M. Imoto, T.
Watanabe, M. Shibasaki, Org. Lett. 2012, 14, 4418-4421.
[14]
a) C. Zhang, N. Jiao, Angew. Chem. Int. Ed. 2010, 49, 6174-6177; b) M.
Zhang, R. Zhang, A. Q. Zhang, X. Li, H. Liang, Synthetic. Commun.,
2009, 39, 3428-3435.
a) N. S. Patil, G. B. Deshmukh, S. V. Patil, A. D. Bholay, N. D. Gaikwad,
Eur. J. Med. Chem. 2014, 83, 490-497; b) J. Fang, D. Huang, W. Zhao,
H. Ge, H. B. Luo, J. J. Xu, Chem. Inf. Model. 2011, 51, 1431-1438; c) S.
Y. Zhao, Y. W. Yang, H. Q. Zhang, Y. Yue, M. Fan, Arch. Pharm. Res.
2011, 34, 519-526; d) A. C. Schmole, A. Brennfuhrer, G. Karapetyan, R.
Jaster, A. Pews-Davtyan, R. Hubner, S. Ortinau, M. Beller, A. Rolfs, M.
J. Frech, Bioorg. Med. Chem. 2010, 18, 6785-6795.
[15]
[16]
[17]
N. S. Patil, G. B. Deshmukh, K. A. Mahale, K. S. Gosavi, S. V. Patil,
Indian. J. Chem. B. 2015, 54B, 272-278.
Y. Bi, L. Bailly, F. Marsais, V. Levacher, C. Papamicael, G. Dupas,
Tetrahedron. Asymmetry, 2004, 15, 3703-3706.
A. Perjessy, M. Augustin, M. Kohler, Collect. Czech. Chem. Commum.
1985, 50, 1305-1311.
[3]
A. B. Mabire, M. P. Robin, W. D. Quan, H. Willcock, V. G. Stavros, R. K.
O’Reilly, Chem. Commun. 2015, 51, 9733-9736.
[4]
[5]
Y. Tamura, H. Matsushima, M. Ikeda, Tetrahedron. 1976, 32, 431-435.
a) A. Tourteau, E. Merlet, A. Bontemps, M. Leland, P. Helissey, S.
Giorgi-Renault, S. Desbene-Fink, Eur. J. Org. Chem. 2015, 2015,
7028-7035; b) B. Budke, J.H. Kalin, M. Pawlowski, A. S. Zelivianskaia,
M. Wu, A. P. Kozikowski, P. P. Connell, J. Med. Chem. 2013, 56,
254-263; c) E. Awuah, A. Capretta, J. Org. Chem. 2011, 76, 3122-3130;
d) A. Brennfuhrer, H. Neumann, A. Pews-Davtyan, M. Beller, Eur. J. Org.
Chem. 2009, 2009, 38-42; e) M. Tanaka, S. Sagawa, J. Hoshi, F.
Shimoma, I. Matsuda, K. Sakoda, T. Sasase, M. Shindo, T. Inaba,
Bioorg. Med. Chem. Lett. 2004, 14, 5171-5174.
[6]
[7]
a) N. A. Romero, K. A. Margrey, N. E. Tay, D. A. Nicewicz, Science.
2015, 349, 1326-1330; b) J. Roane, O. Dougulis, J. Am. Chem. Soc.
2016, 138, 4601-4607; c) G. Li, C. Jia, K. Sun, Org. Lett. 2013, 15,
5198-5201; d) L. B. Zhang, S. K. Zhang, D. H. Wei, X. J. Zhu, X. Q. Hao,
J. J. H. Su, L. Niu, M. P. Song, Org. Lett. 2016, 18, 1318-1321; e) S.
Manna, P. O. Serebrennikova, I. A. Utepova, A. P. Antonchick, O. N.
Chupakhin, Org. Lett. 2015, 17, 4588-4591.
a) Y. Mizuta, K. Yasuda, Y. Obora, J. Org. Chem. 2013, 78, 6332-6337;
b) M. V. Jimenez, M. I. Bartolome, J. J. Perez-Torrente, D. Gomez, F. J.
Modrego, L. A. Oro, ChemCatChem. 2013, 5, 263-267; c) X. Jin, K.
Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed. 2014, 53, 455-458; d) L.
L. Chng, J. Zhang, J. Yang, M. Amoura, J. Y. Ying, Adv. Synth. Catal.
2011, 353, 2988-2998; e) X. Ji, H. Huang, W. Wu, X. Li, H. Jiang, J. Org.
Chem. 2013, 78, 11155-11162; f) Y. Yang, W. M. Shu, S. B. Yu, F. Ni,
M. Gao, A. X. Wu, Chem. Commun. 2013, 49, 1729-1731.
[8]
[9]
a) J. Jiao, K. Murakami, K. Itami, ACS Catal. 2016, 6, 610-633; b) Y. G.
Zhu, R. G. Cornwall, H. F. Du, B. G. Zhao, Y. A. Shi, Acc. Chem. Res.
2014, 47, 3665-3678; c) M. R. Yadav, R. K. Rit, M. Shankar, A. K.
Sahoo, Asian J. Org. Chem. 2015, 4, 846-864; d) M. D. Mihovilovic, M.
Schneurch, ChemCatChem. 2014, 6, 2194-2196; e) T. B. Nguyen, M.
Corbin, P. Retailleau, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2015, 17,
4956-4959.
a) Y. L. An, Z. H. Yang, H. H. Zhang, S. Y. Zhao, Org. Lett. 2016, 18,
152-155; b) Z. H. Yang, Z. H. Chen, Y. L. An, S. Y. Zhao, RSC. Adv.
2016, 6, 23438-23447; c) Y. L. An, Y. X. Deng, W. Zhang, S. Y. Zhao,
Synthesis. 2015, 47, 1581-1592; d) Y. L. An, Z. Y. Shao, J. Cheng, S. Y.
Zhao, Synthesis. 2013, 45, 2719-2726.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600923
FULL PAPER
FULL PAPER
Yu-Long an, He-Hui Zhang, Zhen-Hua
Yang, Long Lin, and Sheng-Yin Zhao*
Page No. – Page No.
Cu/Ag cocatalyzed aerobic oxidative
amination and CuCl2 mediated
aerobic oxidative chloroamination of
maleimides
A novel aerobic oxidative amination of maleimides catalyzed by Cu/Ag cocatalysts
and aerobic oxidative chloroamination of maleimides mediated by CuCl2 have been
developed.
A
series of 3-aminomaleimides, 3-amino-4-indolylmaleimides and
3-amino-4-chloromaleimides have been synthesized with satisfied yields.
*Oxidative amination and chloroamination
This article is protected by copyright. All rights reserved