Selective and tunable synthesis of 3-arylsuccinimides and 3-arylmaleimides from arenediazonium tetrafluoroborates and maleimides

Article abstract of DOI:10.1039/c6ra00136j

A highly efficient synthetic strategy for synthesizing 3-arylsuccinimides has been developed from arenediazonium tetrafluoroborates and maleimides in the presence of TiCl₃. The reactions generated 3-arylsuccinimides in satisfactory yields under mild reaction conditions. In addition, 3-arylmaleimides were obtained by the coupling of arenediazonium tetrafluoroborate and maleimides catalyzed by CuCl. This methodology provided the selective and tunable synthesis of two classes of products by simply switching different metal reagents. The methods are simple, efficient and practical.

Full text of DOI:10.1039/c6ra00136j

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Selective and tunable synthesis of 3-arylsuccinimides and
3-arylmaleimides from arenediazonium tetrafluoroborates and
maleimides
ZhenꢀHua Yanga,1, ZhongꢀHui Chena,1, YuꢀLong Ana and ShengꢀYin Zhao*a,b
,
aDepartment of Chemistry, Donghua University, No.2999 North Renmin Road, Shanghai 201620,
P. R. of China;
bState Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China.
*Corresponding author. Tel: +86 21 67792436; Fax: +86 21 67792608ꢀ805; Eꢀmail:
syzhao8@dhu.edu.cn
Received:
DOI:
Accepted after reversion:
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Abstract: A highly efficient synthetic strategy for 3ꢀarylsuccinimides has been developed from
arenediazonium tetrafluoroborates and maleimides in the presence of TiCl3. The reactions
generated 3ꢀarylsuccinimides in satisfactory yields under mild reaction conditions. In addition,
3ꢀarylmaleimides were obtained by the coupling of arenediazonium tetrafluoroborate and
maleimides catalyzed by CuCl. This methodology provided the selective and tunable synthesis of
two classes of products by simply switching different metal reagents. The methods are simple,
efficient and practical.
Keywords: Maleimide, Arenediazonium tetrafluoroborate, 3ꢀArylsuccinimide, 3ꢀArylmaleimide,
Titanium (III) chloride, Cuprous chloride
1

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Succinimides and related maleimides are an important class of heterocyclic compounds,
especially due to the wide range of biological activity that is demonstrated by representative
examples of these molecules (Scheme 1).2 3ꢀSubstituted maleimide and succinimide compounds
are also versatile building blocks in organic synthesis. They serve as key precursors in the
synthesis of a variety of natural products3, pharmaceuticals4 and functional materials.5 Therefore,
the development of efficient synthetic methods to access these succinimides and maleimides are
attractive for organic chemists.
CH3
N
Cl
O
O
O
N
N
N
O
phensuximide
Cl
anticonvulsant agents
H
N
H
O
O
N
O
O
Br
N
O
H
anti-inflammatory agents
antibacterial agents
Scheme 1 Examples of 3ꢀsubstituted succinimides and maleimides as biological targets
In view of the synthetic expediency of 3ꢀsubstitued succinimides and maleimides, many
methods have been developed for their synthesis (Scheme 2). Generally, 3ꢀarylsuccinimides can
be prepared by the reaction of 3ꢀarylsuccinic acid with urea6 or ammonia2b under 180~200℃.
Ironꢀcatalyzed synthesis of succinimides by carbonylation of different terminal and internal
alkynes with ammonia or amines was reported by Driller in 2009. Fe3(CO)12 catalyzed the
carbonylation of 3ꢀhexyne with 20 bar CO in presence of NH3 to give 3,4ꢀdiethylsuccinimide with
84% yield.7 Microwaveꢀenhanced rhodiumꢀcatalyzed conjugatedꢀaddition of arylboronic acids to
maleimides provided 3ꢀarylsuccimides with 34~80% yields.8 AlCl3 or AlBr3ꢀmediated addition of
benzene with maleimides was developed by Olah with 34~83% yield using a large excess amount
of AlCl3 or AlBr3.9 However, the above methods have many disadvantages such as low or
moderate yield, poor selectivity, complex manipulation and unwanted side products. Most of the
2

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reactions usually demand high catalyst loadings, long reaction times, expensive and hazardous
reagents, and special reaction conditions to enhance reactivity such as high temperature and
microwave irradiation.8 Thus, an efficient, economical and environmentally synthetic
methodology is highly desirable for this process.
Arenediazonium salts have been increasingly used by organic chemists in crossꢀcoupling
reactions due to both their wide availability and high reactivity as arylation reagents.10 Notably,
the superelectrophile properties of arenediazonium salts allows the reaction to proceed under mild
conditions (T<60℃), without the need of the ligands, and occasionally base. The simple and
efficient experimental procedure these reagents enable features many advantages including lower
energy, cost, waste, all of which are of interest for the development of sustainable processes. For
the synthesis of 3ꢀarylmaleimides, the classical method for the direct C3ꢀH arylation of maleimide
is the Meerwein arylation, but this copperꢀmediated method of maleimide arylation suffers from
low or moderate yields.11 Hence, 3ꢀarylmaleimide derivatives were usually prepared from
3ꢀarylsuccinimide using DDQ and MnO2 as oxidation agents.12 In our continuing research
program directed toward the synthesis of succinimide and related maleimide derivatives,13 we
became intrigued by the idea of using inexpensive Lewis acids to obtain 3ꢀsubstituted
succinimides and maleimides from maleimides and diazonium salts. As an example, TiCl3 is
currently widely used as both a free radical initiator and reductive in organic syntheses.14 In light
of the important pharmaceutical implications of the unique structural motif of 3ꢀarylsuccinimides
and 3ꢀarylmaleimides, herein we report an efficient synthetic strategy toward 3ꢀarylsuccinimides
from arenediazonium tetrafluoroborates and maleimides in the presence of TiCl3. In addition,
3ꢀarylmaleimides were obtained by the coupling of arenediazonium tetrafluoroborates and
maleimides catalyzed by CuCl (Scheme 2).
3

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Previous work
urea
COOH
COOH
O
NH OH
4
N
R
O
R
H
52~89% yield (Lit. 6)
R
3
CO, H NR
2
3
N
R
R
2
O
O
1
Fe (CO)
3
12
R
R
2
1
44~88% yield (Lit. 7)
O
H
N
O
H
[RhCl(cod)]
2
B(OH)
N
O
2
O
+
R
KOH, Dioxane/H O
2
R
34~80% yield (Lit. 8)
H
N
O
O
H
AlCl
N
3
O
O
+
or AlBr
3
R
R
R=H, 66%; R=CH , 83%;
3
R=3-Cl,4-Cl, 34% (Lit. 9)
only threeexamples
This work
NH2
R1
1. HBF4
R2
2. NaNO2
R2
N
O
O
N
O
O
R2
N
N2BF4
TiCl3
acetone
CuCl
O
O
+
R1
DMF
R1
R1
Scheme 2 Synthesis of 3ꢀarylmaleimides and 3ꢀarylsuccinimides ramifications
We initiated our studies by examining catalyst usefulness and reaction conditions using
maleimide(1) and benzenediazonium tetrafluoroborate(2) as a model system because the product
4

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is easy to detect and isolate. First, benzenediazonium tetrafluoroborate was prepared from aniline,
fluoroboric acid and sodium nitrite by the classic procedure, because it is more stable than the
corresponding chlorides and avoids side reactions induced by halogens. Since, titanium(III) salts
served as monoelectronic reducing metal cations in the hemolytic reductive arylation of
olefins,14,15. we used commercial available titanium(III) chloride, which is 15% in 2N HCl
solution. The maleimides are unstable in the presence of strong acids and bases, and are apt to
polymerize and decompose. To avoid this, sodium acetate was used to adjust pH in reaction
solutions. The reactions were run at weak acidic conditions (pH 4~5) at 0~5℃, thereby preventing
the polymerization of maleimides. In addition, arenediazonium tetrafluoroborates were used
instead of arenediazonium chlorides in order to avoid the formation of chlorosuccinimides.
Fortunately, 3ꢀphenylsuccinimide was obtained with 78% yield(Table 1, entry 2). Under TiCl3ꢀfree
conditions, no reaction took place and only the starting material 3 was recovered(Table 1, entry 1).
A survey of the literature revealed that such addition of benzenediazonium tetrafluoroborate and
maleimide was, to the best of our knowledge, novel and heretofore unexplored. Several
parameters were altered in an attempt to improve the yield of desired product. We found that
prolonging the reaction time actually decreased yield; additionally, using other radical agents, such
as SnCl2, FeSO4, Sm(CF3SO3)2, and TiCl4 did not allow the synthesis of 3ꢀphenylsuccinimide
(Table 1, entries 3ꢀ8). Notably, higher temperatures or a longer reaction time led to decreased
yields due to polymerization and partial decomposion of maleimide. Using DMF, DMSO, THF or
CH3CN as the reaction solvent, gave unacceptably poor yields of product (Table 1, entries 14ꢀ18).
The above results demonstrated that TiCl3 is a more effective reductive arylation reagent in
comparison to other metallic reagents. It should be noted that without any catalyst, the reaction did
not generate the desired product at all. In addition, 3ꢀarylmaleimide was obtained by the coupling
of arenediazonium tetrafluoroborate and maleimide catalyzed by CuCl in DMF with 86% yield.
H
N
O
O
H
H
N
N
O
O
N2BF4
O
O
NH2
1. HBF4
3
2. NaNO2
+
Lewis acid
2
1
5a
4a
5

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Table 1 Optimization of the Reaction Conditionsa
Entry
Catalyst
—
Solvent
Acetone
Time (h)
12
6
Yieldb(4a)%
Yieldb (5a)%
1
2
3
4
5
6
7
8
9
0
78
0
0
0
C
C
TiCl3
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
DMSO
DMSO
H2O
SnCl2
6
0
C
FeSO4
12
12
12
12
12
6
0
0
C
Fe2(SO4)3
0
0
C
Sm(CF3SO3)3
0
0
C
ZnCl2
0
0
C
TiCl4
0
0
CuCl
CuCl
12
15
14
0
54
49
46
33
25
0
10
11
12
13
14
15
16
17
18
19
20
21
12
12
12
12
12
6
CuCl2
Pd(AcO)2
PdCl2
0
C
TiCl3
0
C
TiCl3
48
38
55
20
0
0
C
TiCl3
THF
12
12
12
6
0
C
TiCl3
CH3CN
DMF
0
C
TiCl3
0
CuCl
CuCl
CuCl
CH3CN
DMF
0
6
0
86
43
DMSO
6
0
aReaction conditions: Benzenediazonium tetrafluoroborate(2.0 mmol), maleimide(2.4 mmol) and catalyst (0.4
mmol) in solvent (15 mL), reaction temperature is around 0 to 25℃. bIsolated yield. ccatalyst (4.4 mmol)
Subsequently, the influence of the amount of TiCl3 on the reaction was also evaluated under
identical reaction conditions. Increasing the loading of TiCl3 initially led to a sharp increase in the
yield and further to a steady state. The yield approached 78% by using 200 mol% of TiCl3 as
reaction agent. This result demonstrated titanium (III) chloride reacted with benzenediazonium
6

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tetrafluoroborate and maleimide as a reaction agent, and was not serving as a catalyst.
To further illustrate the utility of this method, a series of substrates including aromatic amines
and maleimides was applied to this protocol. The results are summarized in Table 2. In some cases,
isolated yields were good and ranged from 60 to 83%. The aryl rings with electronꢀwithdrawing
and donating moieties gave a satisfactory yield. The former led to slightly lower yields than the
latter, because of the difference of nucleophilicity. The yields of compounds 4b, 4i and 4j are
lower because of the negative inductive effect of nitro and CF3 groups (table 2, entry 2,9) and the
yield of compound 4f is low due to the steric hindrance of substitution in the phenyl group. The
reaction provided a convenient route to prepare 3ꢀarysuccinimide.
Table 2 TiCl3ꢀinducedreductive arylation of arenediazonium tetrafluoroborates with maleimidesa
ArN2BF4
Entry
1
Maleimide
Product
Time (h) Yield%
H
N
H
O
O
N2BF4
N
O
O
6
8
78%
67%
4a
H
H
2
3
4
N
O
O
O2N
N2BF4
N2BF4
N2BF4
N
O
O
O
O
O2N
4b
H
H
N
N
O
O
Cl
O
O
6
6
76%
72%
Cl
4c
H
N
H
N
O
O
Br
Br
4d
7

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H
H
N
5
6
N
O
O
H3CO
N2BF4
O
O
O
O
6
6
80%
H CO
3
4e
H
Cl
H
N
N
O
O
N2BF4
Cl
60%
CH3
CH
3
4f
H
N2BF4
H
N
7
8
9
N
O
O
O
O
O
O
6
6
8
79%
83%
65%
4
g
CH3
N
CH3
N
O
O
N2BF4
4h
Ph
N
Ph
O2N
N2BF4
O
O
N
O
O
O2N
4i
Ph
Ph
N
F3C
Cl
10
11
N
O
O
O
O
N2BF4
6
6
62%
82%
Cl
CF3
O
4j
Ph
N
H3CO
N2BF4
O
Ph
N
O
O
H3CO
4k
8

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Ph
Ph
12
N
O
O
N
O
O
6
73%
H3CO
N2BF4
H3CO
4l
aReaction conditions:arenediazonium tetrafluoroborate(2.0 mmol), maleimide(2.4 mmol) and TiCl3 (4.4 mmol),
reaction temperature 0ꢀ25℃. bIsolated yield.
According to our results, we believed that Ti3+ has played two functions in our reaction of
aryldiazonium tetrafluoroborate with maleimide. A plausible mechanism is proposed for
TiCl3ꢀinduced reductive arylation in Scheme 3. First, homolytic cleavage of diazonium salts to
produce aryl radicals 6 by titanium(III) salts may occur, which is also effective in reducing the
αꢀcarbonylalkyl radical adduct to maleimide for compound 7. Compound 7 was reduced by
titanium(III) to generate target compound 4. So, the amount of titanium(III) chloride required for
optimal reactivity is at least twice the amount of maleimides (Scheme 3).
N2 BF4
.
Ti(III)
Ti(IV)
O
N2
R1
R1
2
6
R2
N
R2
N
R2
N
Ti(III)
H+
O
O
.
O
O
O
R1
.
6
2
R1
R1
7
4
Scheme 3 Proposed mechanism of the reaction for preparation 3ꢀarylsuccinimides
The 3ꢀarylmaleimide derivatives were traditionally prepared from 3ꢀarylsuccinimide using
DDQ and MnO2 as oxidation agents.12 In 2001, a new synthesis method of αꢀarylmaleimide was
reported by Yasuhiro through the reaction of 1,1ꢀdis(methylthio)ꢀ2ꢀnitroethylene with aryl cyanide
followed by intramolecular interconversion, and hydrolysis, this scheme allowed
αꢀarylmaleimides derivatives to be obtained with high yield.16 In 2008, Roshchin and Zhou
9

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reported that the Heck reaction of maleimides with aryl iodides in the presence of PdCl2(MeCN)2,
Bu4NCl and HCOOK afforded the corresponding 3ꢀarylmaleimides in moderate yields.17 Classic
Meerwein arylation was adopted to prepare 3ꢀarylmaleimide using arenediazonium chloride with a
low to moderate yield. Chlorosuccinimides were generated as byproducts. In 2009, Petzer
provided a modified Meerwein reaction of diazonium salts and maleimide to yield
chlorosuccinimides. The target Nꢀmethylꢀ2ꢀphenylmaleimides were obtained following thermal
dehydrohalogenation of the intermediate chlorosuccinimides in the presence of 2,6ꢀlutidine.18 The
strategy was used for the synthesis of 3ꢀarylmaleimides.19 However, this approach is cumbersome
and gave a low yields. An improved procedure was clearly necessary for their synthesis.
We investigated the Meerweinꢀtype arylation of maleimides with arenediazonium
tetrafluoroborate under neutral conditions at room temperature. After extensive experimentation
and evaluation of key parameters including temperature, solvent system, concentration and
reaction time, an efficient synthesis of 3ꢀarylmaleimide was developed by the coupling of
arenediazonium tetrafluoroborate and maleimide catalyzed by CuCl. Fortunately, we found this
reaction worked well using DMF as the solution. The optimal reaction conditions are shown in
Table 1, and the results are summarized in Table 3. In some cases, isolated yields were good and
ranged from 78 to 91%. This method provided selective and tunable synthesis of 3ꢀarylmaleimides.
We can obtain the desired product (5a) in the presence of Pd(OAc)2 and PdCl2 at around 30%
yield (Table 1, entry 12ꢀ13). The above results demonstrated that CuCl is a more effective catalyst
in comparison to Pd(OAc)2 and PdCl2. DMF is a more suitable solvent for this reaction.
Diarylation and sandmeyerꢀtype sideꢀproducts were not obtained.
Table 3 CuClꢀinduced reaction of arenediazonium tetrafluoroborates with maleimidesa
Entry
1
Maleimide
ArN2BF4
Product
Time (h) Yield%b
H
H
N
N2BF4
N
O
O
O
O
6
85%
5a
10

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H
N
F3C
Cl
H
N
2
3
4
5
6
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N2BF4
6
6
6
6
6
6
78%
83%
84%
91%
87%
81%
Cl
CF3
5b
5c
5d
H
N
H
N
Br
N2BF4
N2BF4
N2BF4
Br
H
N
H
N
Cl
Cl
H
H
N
N
O
O
H3CO
CH3O
5e
Ph
N
Ph
N
Br
N2BF4
O
O
O
O
O
O
Br
5f
H
N
H
N
O
O
7
O2N
N2BF4
O2N
5g
aReaction conditions: arenediazonium tetrafluoroborate(2.0 mmol), maleimide(2.4 mmol) and CuCl(0.4 mmol),
reaction temperature 0ꢀ25℃. bIsolated yield.
According to the reported literature,20 a possible mechanism for Meerwein arylation is
proposed in Scheme 4, in which arenediazonium tetrafluoroborate was decomposed to aryl radical
11

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6 and nitrogen by copper (I). At the same time, Cu(I) converts to Cu(II). The aryl radical coupling
with maleimide generates intermediate 7. The reaction may procced via deprotonation of 7
followed by one electron oxidation to give products 5.
R
2
O
N
N BF
2 4
O
R
1
R
1
2
Cu(I)
5
Cu(II)
Cu(II)
R
2
O
.
N
R
1
O
.
R
1
6
7
R
2
N
O
O
3
Scheme 4 Proposed catalytic cycle for the reaction of arenediazonium tetrafluoroborate and
maleimide catalyzed by CuCl.
In summary, we report a selective and tunable method for the arylation and reductive
arylation of challenging maleimides, which are prone to undergo facile hydrolysis and
polymerization. The reactions were optimized to generate the desired products in moderate to
excellent yields. Apart from broad substrate scope and good functionalꢀgroup compatibility, this
methodology provided the selective synthesis of two classes of products by simply switching
different metal reagents. This method offers one of the important motifs for the synthesis of
3ꢀsubstituted succinimides and maleimides as natural products, biologically active compounds,
and pharmaceutical agents. Further application of this method for the preparation of new potent
bioactive molecules is ongoing in our group.
Melting points were uncorrected and were determined with RYꢀ1 apparatus.Infrared (IR) spectra
12

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1
were determined as KBr pellets on a Shimadzu model 470 spectrophotometer. H NMR and 13C
NMR spectra were recorded using a Bruker AV 400 MHz spectrometer in CDCl3and DMSOꢀd6
with tetraꢀmethylsilane as internal standard. Chemical shifts (δ) are expressed in ppm. EI mass
spectra were recorded on Shimadzu QPꢀ2010 GCꢀMS system and Waters Micromass GCT system.
Silica gel (100ꢀ200 microns) was used for all chromatographic separations. All materials were
obtained from commercial suppliers and were used as received. The purity of substrates and the
monitoring of reactions were performed by TLC on silica gel polygram SILG/UV 254 plates.
General procedure for the synthesis of aryldiazonium tetrafluoroborates
Aniline (50 mmol) was dissolved in the 40% (V/V) fluoroboric acid (200 mmol). After cooling to
0 ℃, an aqueous solution of sodium nitrite (3.6 g, 51 mmol) in 15 mL H2O was added dropwise
for 20 min. The mixture was stirred for 3 h and the thick precipitate was collected and washed
with diethyl ether (2×10 mL). The arenediazonium tetrafluoroborate was dried in vacuo (10ꢀ3 mbar)
for 10 minutes and was then directly used without further purification.
General procedure for the synthesis of 3-arylsuccinimides 4a-4l
Sodium acetate (3 mmol) was added with stirring to a solution of 15% titanium(III) chloride(4.4
mmol) in 10 mL acetone at 10℃. A solution of maleimide derivatives (2.4 mmol) in 5 mL acetone
is added dropwise to the reaction mixture at 0 ℃ and then the solid arzenediazoium
tetrafluoroborate (2 mmol) was added over the course of 1 hour. The nitrogen evolution stopped
after 30~40 min. The cooling bath was removed. The solution was warmed to room temperature
with continuous stirring and maintained for 3 hours or overnight. The solution was concentrated
under vacuum to remove acetone, and extracted with ether acetate (3×20 mL). The combined
extracts were washed with saturated sodium chloride solution, dried, evaporated to dryness, and
chromatographed on silica gel (eluting with ether acetate and petroleum ether) to yield specified
1
products 4a~4l. All of the products were known compounds, and the data of mp and H NMR
were in accord with those reported in the literature.
3-phenylpyrrolidine-2,5-dione (4a) 8b
Yield: 0.27g(78%); a white crystalline solid; mp 85ꢀ87℃. IR (KBr): 3220, 3073, 1777, 1711, 1348,
1180, 756, 703, 641cmꢀ1; 1H NMR (400 MHz, CDCl3) δ: 2.82 (dd, J = 4.0, 4.0 Hz, 1H), 3.22 (dd, J
= 12.0, 8.0 Hz, 1H), 4.05 (d, J = 8.0 Hz, 1H), 7.22 – 7.39 (m, 5H), 9.34 (s, 1H).; 13C NMR (101
13

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MHz, CDCl3) δ: 38.27, 47.33, 127.44, 128.08, 129.25, 136.69, 176.66, 178.41.; MS (EI): m/z
175[M]+, 104, 78, 51.
3-(4-nitrophenyl)-pyrrolidine-2,5-dione (4b)6
Yield: 0.29g(67%); a yellow crystalline solid; mp 145ꢀ147℃. IR (KBr): 3215, 1779, 1711, 1598,
1518, 1345, 1270, 1179, 855, 753cmꢀ1.; 1H NMR (400 MHz, CDCl3) δ: 2.92 (dd, J = 4.0, 8.0 Hz,
1H), 3.33 (dd, J = 8.0, 12.0 Hz, 1H), 4.25 (d, J = 12.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 8.26 (d, J
= 8.0 Hz, 2H), 8.40 (s, 1H).; 13C NMR (101 MHz, CDCl3) δ: 37.59, 46.86, 124.43, 128.57, 143.31,
147.72, 174.70, 176.06.; MS (EI): m/z 220[M]+, 177, 149, 119, 103, 91,77.
3-(4-chlorophenyl)-pyrrolidine-2,5-dione (4c)21
Yield: 0.32g(76%); a yellow crystalline solid; mp 128ꢀ130℃. IR (KBr): 3204, 1780, 1711, 1491,
1
1384, 1180, 1092, 825, 741, 671cmꢀ1.; H NMR (400 MHz, CDCl3)δ: 2.86 (dd, J = 4.0, 8.0 Hz,
1H), 3.27 (dd, J = 8.0, 12.0 Hz, 1H), 4.09 (d, J = 12.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.38 (d, J
= 8.0 Hz, 2H), 8.74 (s, 1H).; 13C NMR (101 MHz, CDCl3) δ: 38.00, 46.64, 128.81, 129.43, 134.15,
134.90, 175.90, 177.60.; MS (EI): m/z 209[M]+, 138, 103, 77, 51.
3-(4-bromophenyl)-pyrrolidine-2,5-dione (4d)22
Yield: 0.36g(72%); a yellow crystalline solid; mp 130ꢀ132℃. IR (KBr): 3198, 1701, 1482, 1346,
1181, 820, 730, 629cmꢀ1.; 1H NMR (400 MHz, CDCl3)δ: 2.87 (dd, J = 4.0, 8.0 Hz, 1H), 3.28 (dd, J
= 8.0, 12.0 Hz, 1H), 4.09 (d, J = 12.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H),
8.52 (s, 1H).; 13C NMR (101 MHz, CDCl3)δ: 37.93, 46.71, 122.23, 129.13, 132.40, 135.41,
175.65, 177.29.; MS (EI): m/z 255[M]+, 182, 103, 77, 51.
3-(4-methoxyphenyl)-pyrrolidine-2,5-dione (4e)8b
Yield: 0.33g(80%); a yellow crystalline solid; mp 135ꢀ137℃. IR (KBr): 3220, 1778, 1708, 1513,
1
1347, 1249, 1177, 1029, 828, 698cmꢀ1.; H NMR (400 MHz, CDCl3)δ: 2.83 (dd, J = 4.0, 8.0 Hz,
1H), 3.21 (dd, J = 8.0, 12.0 Hz, 1H), 3.80 (s, 3H), 4.02 (d, J = 12.0 Hz, 1H), 6.90 (d, J = 8.0 Hz,
2H), 7.16 (d, J = 8.0 Hz, 2H), 8.79 (s, 1H).; 13C NMR (101 MHz, CDCl3)δ: 38.32, 46.59, 55.36,
114.66, 128.52, 128.62, 159.34, 176.51, 178.54.; MS (EI): m/z 205[M]+, 134, 119, 91, 65.
3-(2-chloro-6-methylphenyl)-pyrrolidine-2,-5-dione (4f)
Yield: 0.26g(60%); a yellow crystalline solid; mp 152ꢀ155℃. IR (KBr): 3214, 3076, 1779, 1711,
1
1459, 1348, 1273, 1178, 859, 778, 731cmꢀ1.; H NMR (400 MHz, CDCl3) δ: 2.25,2.43 (s, 3H),
2.74,3.02 (dd, J = 4.0, 8.0 Hz, 1H), 3.14,3.25 (dd, J = 8.0, 12.0 Hz, 1H), 4.42,5.01 (d, J = 8.0 Hz,
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1H), 7.16ꢀ7.18 (m, 3H), 8.60 (s, 1H).; 13C NMR (101 MHz, CDCl3)δ: 21.09, 36.09, 43.16, 128.67,
129.14, 129.37, 132.48, 133.82, 139.62, 175.93, 177.67.; HRMS (EI): m/z [M]+calcd
forC11H10NO2Cl, 223.0400; found, 223.0402.
3-(Naphthalen-1-yl)-pyrrolidine-2,5-dione (4g)8b
Yield: 0.35g(79%); a yellow crystalline solid; mp 150ꢀ152℃. IR (KBr):3222, 3066, 1775, 1709,
1349, 1268, 1183, 781, 734, 694, 630cmꢀ1.; 1H NMR (400 MHz, DMSOꢀd6) δ : 2.72 (dd, J = 4.0,
8.0 Hz, 1H), 3.23(dd,J = 8.0, 12.0 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H),
7.51 (t, J = 8.0 Hz, 1H), 7.55 – 7.63 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H),
11.54 (s, 1H).; 13C NMR (101 MHz, DMSOꢀd6) δ: 38.92, 44.22, 123.89, 125.65, 126.09, 126.42,
127.02, 128.30, 129.28, 131.73, 134.06, 135.10, 178.11, 180.23.; MS (EI): m/z 225[M]+, 154, 126,
102, 76, 51.
1-methyl-3-phenylpyrrolidine-2,5-dione (4h)23
Yield: 0.31g(83%); a white crystalline solid; mp 70ꢀ72℃. IR (KBr): 2944, 1773, 1702, 1437, 1381,
1282, 1119, 952, 806, 474cmꢀ1; 1H NMR (400 MHz, CDCl3)δ: 2.86 (dd, J = 4.0, 8.0 Hz, 1H), 3.10
(s, 3H), 3.24 (dd, J = 8.0, 12.0Hz), 4.05 (d, J = 8.0 Hz), 7.24ꢀ7.26 (m, 2H), 7.31ꢀ7.37 (m, 3H).; 13
C
NMR (101 MHz, CDCl3)δ: 25.22, 37.13, 45.97, 127.38, 127.97, 129.20, 137.08, 176.22, 177.79.;
MS (EI): m/z 189[M]+, 104, 78.
3-(4-nitrophenyl)-1-phenylpyrrolidine-2,5-dione (4i)24
Yield: 0.38g(65%); a white crystalline solid; mp 118ꢀ120℃. IR (KBr): 3070, 1779, 1712, 1599,
1511, 1385, 1347, 1183, 857, 750,cmꢀ1.; 1H NMR (400 MHz, CDCl3) δ : 3.04 (dd, J = 4.0, 8.0 Hz,
1H), 3.46 (dd, J = 9.8, 18.5 Hz, 1H), 4.35 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.45 (d, J =
8.0 Hz, 1H), 7.51ꢀ7.55 (m, 4H), 8.29 (d, J = 8.0 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ: 36.60,
45.62, 124.48, 126.34, 128.63, 129.04, 129.36, 131.52, 143.83, 147.70, 174.06, 175.28.; MS (EI):
m/z 296[M]+, 175, 149, 119, 103, 91, 77.
3-(3-chloro-4-trifluoromethylphenyl)-1-phenylpyrrolidine-2,5-dione (4j)
Yield: 0.43g(62%); a white crystalline solid; mp 155ꢀ157℃. IR (KBr): 1711, 1488, 1395, 1321,
1
1269, 1193, 1140, 1033, 749cmꢀ1.; H NMR (400 MHz, CDCl3)δ: 3.01 (dd, J = 4.0, 8.0 Hz, 1H),
3.45 (dd, J = 8.0, 12.0 Hz, 1H), 4.28 (d, J = 8.0 Hz, 1H), 7.34ꢀ7.47 (m, 2H), 7.44 ꢀ7.60(m, 5H),
7.69 (s, 1H).; 13C NMR (101 MHz, CDCl3)δ: 36.59, 45.09, 121.13, 123.85, 126.35, 126.90,
129.00, 129.34, 131.54, 131.81, 132.33, 132.39, 135.77, 174.07, 175.49.; HRMS (EI): m/z
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[M]+calcd forC17H11NO2F3Cl, 353.0430; found, 253.0426.
3-(4-methoxyphenyl)-1-phenylpyrrolidine-2,5-dione (4k)25
Yield: 0.46g(82%); a white crystalline solid; mp 170ꢀ172℃. IR (KBr): 1709, 1606, 1504, 1456,
1241, 1194, 1030, 737, 694cmꢀ1.; 1H NMR (400 MHz, DMSOꢀd6) δ: 2.89 (dd, J = 4.0, 8.0 Hz, 1H),
3.25(dd, J = 8.0, 12.0 Hz,1H), 3.73 (s, 3H), 4.26 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H),
7.31ꢀ7.33 (m, 4H), 7.39ꢀ7.41 (m, 1H), 7.47ꢀ7.51 (m, 2H).; 13C NMR (101 MHz, DMSOꢀd6) δ:
37.67, 45.51, 55.60, 114.61, 127.69, 128.78, 129.33, 129.73, 130.31, 133.14, 159.03, 175.93,
177.96.; MS (EI): m/z 281[M]+, 134,119,91,65.
3-(4-methoxyphenyl)-1-benzylpyrrolidine-2,5-dione (4l)23
Yield: 0.43g(73%); a white crystalline solid; mp 108ꢀ110℃. IR (KBr): 1702, 1511, 1394, 1344,
1250, 1165, 1032, 833, 702 cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6) δ: 2.81 (dd, J = 4.0, 8.0 Hz, 1H),
3.23 (dd, J = 8.0, 12.0 Hz, 1H), 3.73 (s, 3H), 4.19 (d, 8.0 Hz, 1H), 4.61 (s, 2H), 6.90 (d, J = 8.0 Hz,
2H), 7.18ꢀ7.20 (d, J = 8.0 Hz, 2H), 7.26ꢀ7.32 (m, 3H), 7.33 (t, J = 8.0 Hz, 2H).; 13C NMR (101
MHz, DMSOꢀd6) δ: 37.22, 42.11, 45.16, 55.59, 114.59, 127.88, 128.97, 129.48, 130.18, 136.71,
158.98, 176.66, 178.56.; MS (EI): m/z 295[M]+, 187, 162,134,119,91,65.
General procedure for the synthesis of 3-arylmaleimide 5aꢀ5g
Arzenediazoium tetrafluoroborateis (2 mmol) was added to an iceꢀcold suspension of maleimide
derivative (2.4 mmol) and cuprous chloride (0.4 mmol) in 5 mL DMF. Evolution of nitrogen
began almost immediately in most cases. After 0.5 hour at 0~5℃, the mixture was warmed to
room temperature with continuous stirring and there maintained for 6 hours or overnight. The
mixture was added to 10 mL H2O and extracted with ether acetate (3×20 mL). The combined
extracts were washed with saturated sodium chloride solution, dried, evaporated to dryness, and
chromatographed on silica gel (eluting with ether acetate and petroleum ether ) to yield specified
products 5a~5g.All of the products wereknown compounds, and the data of mp and 1H NMR were
in accord with those reported in the literature.
3-phenyl-1H-pyrrole-2,5-dione (5a)16b
Yield: 0.29 g(85%); a yellow crystalline solid (85% yield); mp 167ꢀ168℃. IR(KBr): 3351, 3199,
1
1727, 1339, 1186, 1125, 1012, 819, 736cmꢀ1.; H NMR (400 MHz, DMSOꢀ
d
6) δ: 7.18 (s, 1H),
7.50 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 11.03 (s, 1H).; 13C NMR (101 MHz,
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DMSOꢀd6)δ: 126.33, 129.06, 129.23, 129.44, 131.16, 143.53, 172.15, 172.63.; MS (EI): m/z
173[M]+, 102, 76, 51.
3-(4-chloro-3-trifluoromethylphenyl)-1H--pyrrole-2,5-dione (5b)
Yield: 0.42 g(78%); a yellow crystalline solid; mp 218ꢀ220℃. IR (KBr): 3351, 3183, 1721, 1602,
1395, 1333, 1253, 1128, 1020, 937, 880, 829, 704cmꢀ1.; 1H NMR (400 MHz, DMSOꢀd6) δ: 7.42 (s,
1H), 7.88 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 11.18 (s, 1H).; 13C NMR (101
MHz, DMSOꢀd6) δ: 121.70, 124.41, 128.08, 128.53, 129.08, 132.67, 133.20, 134.39, 140.92,
171.71, 172.24.; HRMS (EI): m/z [M]+calcd forC11H5NO2F3Cl, 274.9960; found, 274.9961.
3-(4-bromophenyl)-1H-pyrrole-2,5-dione (5c)11b
Yield: 0.41 g(83%); a yellow crystalline solid; mp 206ꢀ209℃. IR (KBr): 3350, 3196, 1726, 1484,
1
1392, 1341, 1185, 1123, 1009, 821, 743cmꢀ1.; H NMR (400 MHz, DMSOꢀd6) δ: 7.24 (s, 1H),
7.72 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.0 Hz, 2H), 11.07 (s, 1H).; 13C NMR (101 MHz, DMSOꢀd6)
δ: 124.95, 126.92, 128.66, 130.98, 132.31, 142.37, 171.98, 172.43.; MS (EI): m/z 251[M]+, 180,
101, 75, 50.
3-(4-chlorophenyl)-1H-pyrrole-2,5-dione (5d)16b
Yield: 0.34 g(84%); a yellow crystalline solid; mp 178ꢀ180℃. IR (KBr): 3204, 1723, 1644, 1345,
1
1188, 1015, 875, 822, 749cmꢀ1.; H NMR (400 MHz, DMSOꢀd6) δ: 7.23 (s, 1H), 7.58 (d, J = 8.0
Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 11.06 (s, 1H).; 13C NMR (101 MHz, DMSOꢀd6) δ: 126.88,
128.33, 129.38, 130.81, 136.00, 142.26, 171.98, 172.48.; MS (EI): m/z 207[M]+, 136, 101, 75, 50.
3-(4-methoxyphenyl)-1H-pyrrole-2,5-dione (5e)16b
Yield: 0.37 g(91%); a yellow crystalline solid; mp 176ꢀ178℃. IR (KBr): 3351, 3193, 1725, 1595,
1
1501, 1335, 1253, 1179, 1126, 1016, 828, 734cmꢀ1.; H NMR (400 MHz, CDCl3)δ: 3.90 (s,
3H),6.62 (s, 1H,CH), 7.00 (d, J = 8.0 Hz, 2H), 7.41 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H).; 13C NMR
(101 MHz, CDCl3)δ: 55.46, 114.54, 121.17, 121.72, 130.54, 135.13, 144.22, 162.19, 170.10,
170.82.; MS (EI): m/z 203[M]+, 132, 117, 89, 63, 51.
3-(4-bromophenyl)-1-phenyl-1H-pyrrole-2,5-dione (5f)
Yield: 0. 0.56g(87%);a yellow crystalline solid; mp 150ꢀ152℃. IR(KBr): 3029, 1704, 1597, 1493,
1
1395, 1208, 1132, 1073, 1008, 824cmꢀ1; H NMR (400 MHz, DMSOꢀd6) δ: 7.39–7.44 (m, 3H),
7.50–7.54 (m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H).; 13C NMR (101 MHz,
DMSOꢀd6) δ: 125.30, 126.26, 127.50, 128.30, 128.54, 129.33, 131.06, 132.15, 132.45, 142.02,
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169.55, 169.74.; MS (EI): m/z 327[M]+, 248, 182, 101, 75, 63, 51.; HRMS (ESI): m/z
[M+H]+calcd forC16H11NO2Br, 327.9968; found, 327.9964.
3-(4-nitrophenyl)-1H-pyrrole-2,5-dione (5g)26
Yield: 0.35 g(81%); a yellow crystalline solid; mp 195ꢀ197℃. IR (KBr):3233, 3087, 1697, 1591,
1508, 1345, 1127, 917, 863, 747, 675 cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6) δ: 7.44 (s, 1H), 8.23
(d, J = 8.7 Hz, 2H),8.34 (d, J = 8.7 Hz, 2H),11.22 (s, 1H).; 13C NMR (101 MHz, DMSOꢀd6)
δ:124.23, 129.89, 130.31, 135.60, 141.39, 148.63, 171.63, 172.10.; MS (EI): m/z 218[M]+, 175,
147, 117, 89, 51.
Acknowledgements
The authors acknowledge financial support from Shanghai Manucipical Natural Science
Foundation (No. 15ZR1401400) and 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 (CUSFꢀDHꢀDꢀ2015048 and CUSFꢀDHꢀDꢀ2016028) for financial
support. We are grateful to Mr. William Alborn for reviewing and editing this article.
Supplementary data
Electronic supplementary information (ESI) available: NMR spectra of all the final compounds.
See DOI:
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Graphic Abstract
Selective and tunable synthesis of 3-arylsuccinimides and
3-arylmaleimides from arenediazonium tetrafluoroborates and
maleimides.
Zhen-Hua Yanga,, Zhong-Hui Chena,, Yu-Long Ana and Sheng-Yin Zhao*a,b
,
aDepartment of Chemistry, Donghua University, No.2999 North Renmin Road, Shanghai 201620,
P. R. of China;
bState Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China.
Abstract: A highly efficient and tunable synthetic strategy for 3-arylsuccinimides or
3-arylmaleimides has been developed from arenediazonium tetrafluoroborates and maleimides
with satisfactory yields in the presence of TiCl3 or CuCl. This methodology provided the selective
and tunable synthesis of two classes of products by simply switching different metal reagents. The
methods are simple, efficient and practical.
R2
R2
N
O
O
N
O
O
R2
N2BF4
TiCl3
N
CuCl
DMF
O
O
+
acetone
R1
R1
R1