Copper-catalyzed intermolecular thioamination of maleimides with thiols and formamides: A one-step construction of 3-Amino-4-Thiomaleimides using formamides as nitrogen sources

Article abstract of DOI:10.1055/s-0037-1610536

A highly efficient copper-catalyzed intermolecular C(sp₂)-H thioamination of maleimides with thiols and formamides in the presence of fluoroboric acid is reported using various readily available formamides as nitrogen sources and solvents. A diverse range of 3-Amino-4-Thiomaleimides is obtained with good yields under mild conditions, involving C-N and C-S bond formation. This methodology enriches current C-N and C-S bond formation chemistry and features operational simplicity and excellent functional-group tolerance.

Full text of DOI:10.1055/s-0037-1610536

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
A
en
Z.-H. Yang et al.
Paper
Synthesis
Copper-Catalyzed Intermolecular Thioamination of Maleimides
with Thiols and Formamides: A One-Step Construction of 3-Ami-
no-4-thiomaleimides Using Formamides as Nitrogen Sources
Zhen-Hua Yanga
Jia-Nan Zhua
Ze-Hui Jina
Jian Zhenga
R2
R2
O
N
O
CuI (0.2 equiv)
O
N
R3
O
O
R1S
H
+
H
N
R4
+
R3
N
HBF4, O2, 120 °C
R1S
H
H
R4
Sheng-Yin Zhao*a,b
R1 = aryl, alkyl
R2, R3, R4 = H, aryl, alkyl
23 examples, 27–87% yields
Unperturbed double bond
High functional-group tolerance
a Department of Chemistry, College of Chemistry,
Chemical Engineering and Biotechnology, Donghua
University, No. 2999 North Renmin Road, Shanghai
201620, P. R. of China
High efficiency and atom economy
Formamides as the nitrogen sources
C–S and C–N bond formation in one step
Direct C(sp2)–H bond difunctionalizations
syzhao8@dhu.edu.cn
b State Key Laboratory of Bioorganic & Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032,
P. R. of China
Received: 21.04.2018
Accepted after revision: 29.06.2018
Published online: 07.08.2018
Metal-catalyzed direct functionalization of C–H bonds
has gained enormous attention over the past few decades
as a powerful and straightforward method to construct new
C–X bonds (X = heteroatom).5 In particular, copper-cata-
lyzed aerobic oxidative reactions have become increasingly
attractive.6 In addition, N,N-dimethylformamide (DMF) is a
polar solvent that has been used as a precursor for –NMe2,
–CONMe2, –CHNMe2 and –CN groups.7 Among these trans-
formations, the decarbonylation of DMF as a source of –NMe2
has elicited the attention of chemists.8 Replacement of pun-
gent and toxic dimethylamine by DMF is highly desirable
from the standpoint of green chemistry. In consideration of
our previous studies on maleimides9 and the importance of
the introduction of nitrogen and sulfur functional groups,10
we herein present an extremely practical and highly effi-
cient method for preparing 3-amino-4-thiomaleimides via
copper-catalyzed intermolecular thioamination of maleim-
ides using formamides as nitrogen sources and solvents.
Initially, p-thiocresol (1a), maleimide (2a) and DMF (3a)
were used as the model substrates to optimize the reaction
conditions. The reaction was performed at 120 °C in the
presence of CuCl as the catalyst and acetic acid as an addi-
tive under air for 8 hours. The desired product 4a was iso-
lated in 18% yield (Table 1, entry 1). The yield of 4a dramat-
ically increased to 43% when the reaction was conducted
under an atmosphere of pure oxygen (Table 1, entry 2).
Clearly, O2 was beneficial to the efficient formation of 4a.
We next altered several parameters to improve the yield of
the desired product. First, several copper salts were exam-
ined, among which CuI showed the best activity (Table 1,
entries 2–5). In addition, no reaction occurred in the ab-
sence of a catalyst (Table 1, entry 6), and none of the de-
sired product was obtained when the copper catalyst was
replaced with other metal catalysts such as AgNO3 or FeCl3
(Table 1, entries 7 and 8). The use of Mn(OAc)3 as the cata-
DOI: 10.1055/s-0037-1610536; Art ID: ss-2018-h0276-op
Abstract A highly efficient copper-catalyzed intermolecular C(sp2)–H
thioamination of maleimides with thiols and formamides in the pres-
ence of fluoroboric acid is reported using various readily available for-
mamides as nitrogen sources and solvents. A diverse range of 3-amino-
4-thiomaleimides is obtained with good yields under mild conditions,
involving C–N and C–S bond formation. This methodology enriches
current C–N and C–S bond formation chemistry and features opera-
tional simplicity and excellent functional-group tolerance.
Key words copper catalysis, thioamination, maleimides, thiols, for-
mamides
Maleimides constitute the core structure of numerous
natural products and pharmaceuticals with diverse biologi-
cal activities.1 They can also be converted into diverse, im-
portant heterocyclic frameworks such as succinimides, pyr-
rolidines, lactims, and γ-lactams.2 Thus, a great deal of at-
tention has been focused on the development of new
synthetic routes to access functionalized maleimides.3 In
particular, as a result of their antibacterial and antitumor
activities, the development of more concise and efficient
methods to construct 3-amino-4-thiomaleimides has par-
ticular significance in organic synthesis and the pharma-
ceutical industry.4 However, to the best of our knowledge,
an intermolecular thioamination of maleimides using for-
mamides as nitrogen sources has not yet been reported. The
most likely reason is that dimethylamine is a poisonous,
flammable gas with a strong pungent odor. It is extremely
dangerous and is difficult to manipulate at high tempera-
tures. Thus, the further development of novel and practical
nitrogen sources for the one-step construction of 3-amino-
4-thiomaleimides still remains a considerable challenge.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
Z.-H. Yang et al.
Paper
Synthesis
lyst resulted in only a 18% yield of product 4a (Table 1, entry
9). This implies that Cu plays an important role in this reac-
tion. Subsequently, a series of additives was examined (Ta-
ble 1, entries 10–14). HBF4 afforded the best result for this
transformation. Moreover, when different amounts of HBF4
were used (Table 1, entries 14–16), one equivalent of HBF4
was found to provide the highest yield. None of the desired
product was obtained in the absence of an additive (Table 1,
entry 17), suggesting the importance of acid in the reaction.
Subsequent experiments varying the amount of CuI showed
that 20 mol% of CuI was optimal (Table 1, entries 18–20). Fi-
nally, examination of the effect of the reaction temperature
indicated that 120 °C was ideal for successful product for-
mation (Table 1, entries 19, 21 and 22).
With optimized reaction conditions in hand, we next in-
vestigated the substrate scope with regard to the thiol com-
ponent. As shown in Scheme 1, the reactions proceeded
smoothly in moderate to good yields with substrates con-
taining electron-donating groups and electron-withdraw-
ing groups. In general, thiophenols bearing electron-with-
drawing groups produced lower yields. For example, when
3-methoxythiophenol was treated with maleimide and
DMF under the optimized conditions, the isolated yield of
4b was 87%, whereas a thiophenol with a strong electron-
withdrawing 4-NO2 group furnished a lower yield (65%) of
4f. Halogens were all well tolerated, and the corresponding
products (4d, 4e, 4l, and 4o) could be applied in further re-
actions. Product 4e was crystallized and X-ray crystal struc-
Table 1 Optimization of the Reaction Conditionsa
H
N
O
O
O
H
N
SH
+
catalyst
O2
O
O
+
CH3
S
N
CH3
H
N
R2
H3C
CH3
CH3
R2
N
O
O
O
1a
2a
3a
4a
CuI (20 mol%)
N
CH3
O
O
R1S
H
H
N
+
+
R1S
N CH3
HBF4 (1 equiv)
O2, 120 °C, 8 h
CH3
CH3
3a
CH3
O
1
2
4
Entry
Catalyst (equiv)
Additive
Temp (°C)
Yield (%)b
H
H
H
H
N
N
N
N
O
1c
2
CuCl (1.0)
CuCl (1.0)
CuBr (1.0)
CuI (1.0)
CuCl2 (1.0)
–
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
HCl
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
140
18
43
51
66
27
0
O
O
O
O
O
O
S
N
CH3
S
N
CH3
N
CH3
S
N
CH3
S
CH3
CH3
CH3
CH3
3
4
O
CH3
Br
CH3
5
4a, 82%
4b, 87%
4c, 76%
4d, 71%
H
6
H
N
H
N
H
N
N
O
O
O
O
O
O
O
O
7
AgNO3
0
S
N
CH3
N
CH3
S
N
CH3
S
N CH3
CH3
S
8
FeCl3
0
CH3
CH3
CH2
CH3
F
H3C
9
Mn(OAc)3
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (0.5)
CuI (0.2)
CuI (0.1)
CuI (0.2)
CuI (0.2)
18
25
39
65
47
76
36
71
0
10
11
12
13
14
15d
16e
17
18
19
20
21
22
NO2
4e, 73%
4f, 65%
4g, 57%
4h, 79%
L-proline
benzoic acid
HI
CH3
N
H
N
H
H
N
N
O
O
O
O
O
O
O
O
S
N
CH3
S
N CH3
CH3
S
N
CH3
S
N CH3
HBF4
CH3
CH2
CH3
(CH2)11 CH3
H2C
OH
H3C
HBF4
HBF4
Cl
4i, 73%
4j, 65%
4k, 78%
4l, 75%
–
HBF4
79
82
54
69
75
N
O
O
HBF4
N
N
N
O
O
O
O
O
O
HBF4
S
N
CH3
S
N
CH3
S
N
CH3
S
N
CH3
CH3
HBF4
CH3
CH3
CH3
HBF4
Cl
4o, 67%
O
CH3
CF3
4m, 58%
a Reaction conditions: 1a (2.1 mmol), 2a (2.0 mmol), 3a (6.0 mL), catalyst,
additive (2.0 mmol), O2 balloon, 8 h.
b Yield of isolated product.
4n, 83%
4p, 71%
Scheme 1 Cu-catalyzed C–H difunctionalization of maleimides with
thiols and dimethyl formamide. Reagents and conditions: 1 (2.1 mmol),
2 (2.0 mmol), 3 (6 mL), CuI (20 mol%), HBF4 (1 equiv), O2 balloon, 8 h.
c Air atmosphere.
d HBF4 (1.0 mmol).
e HBF4 (3.0 mmol).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

C
Z.-H. Yang et al.
Paper
Synthesis
R2
N
ture analysis unambiguously confirmed the structure of the
thioamination product (Figure 1).11 Steric effects had mini-
mal influence on the transformation, as shown by the com-
parable yields of the products 4e (73%) and 4o (67%) ob-
tained from the 2-F and 3-Cl substrates, respectively. More-
over, aliphatic thiols also underwent smooth conversion to
give products 4h–k in yields of 65–79%. Importantly, N-
substituted maleimides (methyl, phenyl, and benzyl)
showed no significant impact on the reaction yields, afford-
ing compounds 4l–p in 58–83% yield. We also tested the
functional group tolerance in the reaction of thioglycol, ma-
leimide, and DMF, observing that a hydroxy substituent had
no marked effect on the reaction, with product 4j being ob-
tained in 65% yield. However, no reaction occurred when
the maleimide was replaced with other alkenes such as ma-
leic anhydride, benzoquinone, styrene or norbornene.
R2
N
O
O
O
CuI (20 mol%)
R3
O
O
+
R1S
H
+
H
O
N
R4
HBF4 (1 equiv)
O2, 120 °C, 8 h
R3
R1S
N
R4
1
2
3
5
H
N
H
H
N
N
O
O
O
O
O
S
NH
N
S
N
S
CH3
CH3
CH3
CH3
CH3
Cl
5b, 42% (53%),a (45%),b (0%),c 5c, 27% (34%)a
5a, 56%
CH3
N
O
O
N
N
N
O
O
O
O
O
O
S
NH
S
NH
S
N
S
N
F
CH3
CH3
OCH3
CH3
5e, 78%
Br
5g, 65%
5d, 69%
5f, 71%
Scheme 2 Cu-catalyzed C–H difunctionalization of maleimides with
thiols and various formamides. Reagents and conditions: 1 (2.1 mmol), 2
(2.0 mmol), 3 (6 mL), CuI (20 mol%), HBF4 (1 equiv), O2 balloon, 8 h,
unless otherwise indicated. a Reagents and conditions: 1 (2.1 mmol), 2
(2.0 mmol), dibutylamine or aniline (2.1 mmol), DMA (6 mL), CuI (20
mol%), HBF4 (1 equiv), O2 balloon, 8 h. b Reagents and conditions: 1 (2.1
mmol), 2 (2.0 mmol), dibutylamine (2.1 mmol), DMSO (6 mL), CuI (20
mol%), HBF4 (1 equiv), O2 balloon, 8 h. c Reagents and conditions: 1 (2.1
mmol), 2 (2.0 mmol), dibutylamine (2.1 mmol), toluene (6 mL), CuI (20
mol%), HBF4 (1 equiv), O2 balloon, 8 h.
Figure 1 ORTEP representation of the X-ray crystal structure of 4e
A series of formamides was also examined to expand
the synthetic utility of this protocol (Scheme 2). With N,N-
disubstituted formamides, lower yields of products (4a vs
5a and 5b) were obtained when longer alkyl chains were
present. These results could be attributed to increased ste-
ric hindrance surrounding the formamide nitrogen. Mean-
while, the formamides derived from cyclic amines pro-
duced higher yields (5e and 5f) compared with those de-
rived from linear amines. Again, substituents (methyl,
phenyl, and benzyl) on the maleimide nitrogen had no ob-
vious impact on the reaction yield. Finally, we used dibutyl-
amine instead of N,N-dibutylformamide in several typical
solvents (DMA, DMSO and toluene). DMA was slightly su-
perior to the others and proved to be the best solvent for
this transformation. However, the yields of the desired
products 5b and 5c were not improved to any great extent
when formamides were replaced with amines. The results
can be attributed to the larger steric hindrance of dibutyl-
amine and weaker nucleophilicity of aniline.
acid was performed. The reaction proceeded smoothly, de-
livering the 3-amino-4-thiomaleimide 4a in 76% yield un-
der the optimized reaction conditions (Scheme 3).
H
N
O
O
O
H
N
SH
CuI (20 mol%)
CH3
O
O
H
N
S
N
CH3
+
+
H3C
CH3
CH3
HBF4 (1 equiv)
O2, 120 °C, 8 h
1a
2a
3a
4a
CH3
2.604 g
21 mmol
1.94 g
20 mmol
3.98 g
76%
60 mL
Scheme 3 Gram-scale synthesis 3-amino-4-thiomaleimide 4a
To acquire insight into the mechanism, various control
experiments were conducted. First, a small amount of
bis(4-methylphenyl)disulfide (6a) was obtained in the re-
action between p-thiocresol (1a) and N-phenylmaleimide
(2b) under standard conditions in DMA (6 mL), in addition
to the thio-Michael addition oxidative dehydrogenation
product 7a (65%) (Scheme 4, eq a). Second, N-phenylma-
leimide (2b) was reacted with 1-formylpyrrolidine (3b) to
produce 1-phenyl-3-(pyrrolidin-1-yl)-1H-pyrrole-2,5-di-
one (8a) in 78% yield (Scheme 4, eq b). We also found that
the aza-Michael addition product 9a could be easily oxi-
dized to 8a in good yield in ten minutes (Scheme 4, eq c). At
To further demonstrate the value of this synthetic
method, a gram-scale copper-catalyzed intermolecular
C(sp2)–H thioamination of maleimide (2a) with p-thiocre-
sol (1a) and formamide 3a in the presence of fluoroboric
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
Z.-H. Yang et al.
Paper
Synthesis
Ph
N
the same time, the product 7a could further react with 1-
formylpyrrolidine (3b) by nucleophilic substitution to pro-
duce 8a in 64% yield (Scheme 4, eq d). Subsequent treat-
ment of 8a with bis(4-methylphenyl)disulfide (6a) proved
that product 5e could be obtained in good yield (Scheme 4,
eq e). However, these Michael addition reactions failed un-
der standard conditions, excluding the possibility of double
Michael addition and oxidative dehydrogenation processes
in the reaction (Scheme 4, eqs f–h). None of target product
5e was detected under a N2 atmosphere (Scheme 4, eq i),
suggesting that oxygen plays an important role in the for-
mation of the product. Moreover, when the radical scaven-
gers TEMPO (2.0 equiv) and BHT (2.0 equiv) were added to
the reaction mixture, respectively, the thioamination of N-
phenylmaleimide (2b) proceeded smoothly to afford the
desired product 5e in 73% or 65% yield. These results there-
fore ruled out the possibility of a radical pathway (Scheme
4, eqs j and k). In addition, 5e was obtained in 86% yield
when 1-formylpyrrolidine (3b) was replaced with pyrroli-
dine (12a) (Scheme 4, eq l). These results show that the
compounds 6a, 7a, 8a, 9a and 14a are all intermediates in
the reaction, and that 12a is another intermediate obtained
via decarbonylation of 1-formylpyrrolidine (3b).
Ph
N
CuI (20 mol%)
O
O
R5S SR5
O
O
(a)
+
R5S
H
+
HBF4 (1 equiv)
DMA (6 mL), O2
120 °C, 8 h
R5S
1a
2.1 mmol
2b
2.0 mmol
6a
12%
7a
65%
R5 = 4-MeC6H4
Ph
Ph
N
O
CuI (20 mol%)
HBF4 (1 equiv)
O
O
N
O
O
H
N
(b)
+
N
O2, 120 °C, 8 h
2b
3b
8a
78%
2.0 mmol
6.0 mL
Ph
N
Ph
N
Ph
N
O
CuI (20 mol%)
O
HBF4 (1 equiv)
O
O
O
HBF4 (1 equiv)
O2, 120 °C, 8 h
O
O
H
N
+
(c)
DMA (6 mL), O2
120 °C, 10 min
N
N
2b
2.0 mmol
3b
9a
71%
8a
81%
6.0 mL
Ph
Ph
N
O
N
O
O
HBF4 (1 equiv)
O2, 120 °C, 8 h
O
O
+
H
N
(d)
N
R5S
7a
3b
8a
1.0 mmol
3.0 mL
64%
Ph
Ph
N
CuI (20 mol%)
HBF4 (1 equiv)
N
O
O
O
O
R5S SR5
(e)
+
DMA (6 mL), O2
120 °C, 8 h
R5S
N
O
N
O
6a
8a
1.0 mmol
5e
85%
1.05 mmol
Ph
Ph
N
N
HBF4 (1 equiv)
O
O
R5S
H
+
(f)
DMA (6 mL), O2
120 °C, 8 h
Based on the above experimental data and precedents, a
putative mechanism is depicted in Scheme 5. Formamide 3
is decarbonylated by HBF4 to form amine 12.10 Next, the
amine 12 undergoes an aza-Michael addition with maleim-
ide 2 to form 3-aminosuccinimide 9, which could afford 3-
aminomaleimide 8 via a copper-catalyzed aerobic oxidative
dehydrogenation.12 Because the reaction is conducted un-
der O2, the Cu(I) species in this reaction is easily oxidized to
Cu(II), showing that the reaction can be catalyzed by a cop-
per species with O2 as the terminal oxidant.13 Alternatively,
compound 8 could also be easily obtained via the nucleop-
hilic substitution between amine 12 and 3-thiomaleimide
7,14 which have also been synthesized by thio-Michael ad-
dition and oxidative dehydrogenation processes.9b Next, the
Cu(I) catalyst interacts with disulfide 6 to generate inter-
mediate I.15 Subsequently, the regioselective electrophilic
attack of I on 3-aminomaleimide 8 at the 4-position (via its
isomer 15) results in the formation of the intermediate II,
which undergoes deprotonation to furnish the maleimide
product and regenerate the copper catalyst.16 At the same
time, the oxidation of the in situ generated R1SH species by
O2 reproduces disulfide 6.17 Oxygen plays an important role
in the regeneration of the catalytically active species and
the oxidative dimerization of the thiols.
R5S
N
N
1a
1.05 mmol
8a
1.0 mmol
10a
0%
Ph
CuI (20 mol %)
HBF4 (1 equiv)
Ph
N
N
O
R5S
O
O
O
R5S
H
+
(g)
DMA (6 mL), O2
120 °C, 8 h
SR5
R5S
1a
7a
11a
1.05 mmol
HN
1.0 mmol
0%
Ph
Ph
N
CuI (20 mol%)
HBF4 (1 equiv)
N
O
O
O
O
(h)
+
DMA (6 mL), O2
120 °C, 8 h
N
N
N
12a
1.05 mmol
8a
1.0 mmol
13a
0%
Ph
Ph
N
Ph
O
N
N
O
O
O
O
O
O
+
CuI (20 mol%)
R5S
H
+
(i)
H
N
+
HBF4 (1 equiv)
N2, 120 °C, 8 h
R5S
N
1a
2.1 mmol
2b
3b
14a
55%
9a
2.0 mmol
6.0 mL
26%
Ph
Ph
N
O
H
CuI (20 mol%)
TEMPO (2 equiv)
N
O
O
O
O
+
R5S
H
+
(j)
N
HBF4 (1 equiv)
N2, 120 °C, 8 h
R5S
N
1a
2.1 mmol
2b
3b
5e
2.0 mmol
6.0 mL
73%
Ph
N
Ph
N
O
CuI (20 mol%)
BHT (1 equiv)
O
O
O
O
(k)
R5S
H
+
H
N
+
HBF4 (1 equiv)
N2, 120 °C, 8 h
R5S
N
1a
2.1 mmol
2b
3b
5e
In summary, we have reported an efficient strategy for
the thioamination of maleimides with thiols and forma-
mides in the presence of fluoroboric acid, using various for-
mamides as the nitrogen sources and solvents. Using an in-
expensive Cu(I) catalyst, maleimides have been successfully
coupled with two different heteroatom-based nucleophiles
under mild conditions, offering 3-amino-4-thiomaleimides
in good yields. The operational simplicity, inexpensive na-
2.0 mmol
6.0 mL
65%
Ph
N
CuI (20 mol%)
HBF4 (1 equiv)
Ph
N
O
O
O
O
(l)
R5S
H
HN
+
+
DMA (6 mL), O2
120 °C, 8 h
R5S
N
1a
2.1 mmol
2b
12a
5e
2.0 mmol
2.1 mmol
86%
Scheme 4 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

E
Z.-H. Yang et al.
Paper
Synthesis
ture of the reaction components, excellent functional group
tolerance and the importance of the heteroatom-function-
alized maleimides bode well for the rapid adaptation of this
reaction in chemical synthesis and clinical medicine.
3-(Dimethylamino)-4-[(4-methylphenyl)thio]-1H-pyrrole-2,5-di-
one (4a)
Yield: 0.43 g (82%); yellow crystalline solid; mp 187–189 °C.
IR (KBr): 3180, 1758, 1687, 1605, 1478, 1425, 1338, 1288, 1239, 1117,
1041, 933, 847, 757, 647 cm–1
.
R2
1H NMR (400 MHz, DMSO-d6): δ = 2.24 (s, 3 H), 3.38 (s, 6 H), 7.05 (d,
J = 6.6 Hz, 2 H), 7.10 (d, J = 6.7 Hz, 2 H), 10.75 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 20.89, 42.04, 86.15, 125.74,
R2
H
N
Michael
addition
O
O
N
R3
O
O
R3
H
HBF4
O
N
N
R4
+
R3
R4
N
R4
130.22, 134.77, 136.41, 152.33, 167.19, 171.00.
3
12
2
9
MS (EI): m/z = 262 [M]+, 229, 190, 135, 105, 91, 65.
HRMS (EI): m/z [M]+ calcd for C13H14O2N2S: 262.0776; found:
R2
N
O2, H+
H2O
O
O
262.0777.
[CuI]
[CuII]
R3
N
R4
8
3-(Dimethylamino)-4-[(3-methoxyphenyl)thio]-1H-pyrrole-2,5-
dione (4b)
O2, H+
[CuI]
H2O
R2
R2
N
Michael
O
addition
N
Yield: 0.48 g (87%); yellow crystalline solid; mp 150–152 °C.
O
O
O
R1S
H
+
[CuII]
IR (KBr): 3177, 1684, 1603, 1484, 1424, 1337, 1241, 1040, 933, 840,
R1S
795, 752, 649 cm–1
.
1
2
14
1H NMR (400 MHz, DMSO-d6): δ = 3.39 (s, 6 H), 3.72 (s, 3 H), 6.68 (d,
J = 4.0 Hz, 1 H), 6.71 (d, J = 4.3 Hz, 2 H), 7.20 (t, J = 7.8 Hz, 1 H), 10.78
(s, 1 H).
R3
R2
N
R2
N
H
N
R4
O
O
O
O
12
13C NMR (101 MHz, DMSO-d6): δ = 42.09, 55.57, 85.30, 99.99, 111.01,
117.64, 130.54, 141.48, 152.59, 160.25, 167.08, 170.92.
R3
N
R4
R1S
8
7
MS (EI): m/z = 278 [M]+, 245, 233, 206, 192, 151, 121, 96, 64.
HRMS (EI): m/z [M]+ calcd for C13H14O3N2S: 278.0725; found:
R1S SR1
Cu(I)
H2O
6
278.0731.
R2
N
O2
O
O
3-(Dimethylamino)-4-(phenylthio)-1H-pyrrole-2,5-dione (4c)
Yield: 0.38 g (76%); yellow crystalline solid; mp 188–190 °C.
IR (KBr): 3164, 2375, 1749, 1692, 1605, 1466, 1418, 1336, 1111, 1028,
+
R1SH
R1S SR1
R3
N
R4
8
1
Cu(I)
I
R2
N
R2
N
R2
N
O
O
935, 843, 737, 650 cm–1
.
O
O
Cu(I)
R3
+
O
O
R1S
N
1H NMR (400 MHz, DMSO-d6): δ = 3.39 (s, 6 H), 7.11 (d, J = 7.3 Hz, 1
H), 7.16 (d, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.7 Hz, 2 H), 10.78 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.07, 85.45, 125.41, 125.45,
R3
N
15
R4
R4
4 or 5
R3
N
R1S
R1SCu(I)
R1SCu(I)
R4
II
Scheme 5 Proposed reaction mechanism
129.58, 139.99, 152.59, 167.12, 170.94.
MS (EI): m/z = 248 [M]+, 215, 177, 121, 96, 65.
HRMS (EI): m/z [M]+ calcd for C12H12O2N2S: 248.0619; found:
248.0622.
All experiments were carried out under O2 or N2 atmospheres. All
chemicals and solvents were obtained from commercial suppliers and
used without further purification. Melting points were determined
with a RY-1 melting point apparatus and are uncorrected. IR spectra
were recorded as KBr pellets on a Shimadzu 470 spectrophotometer.
NMR (1H and 13C) spectra were recorded using Bruker AV 400 or 600
MHz spectrometers in DMSO-d6 or CDCl3 with TMS as the internal
standard. Chemical shifts (δ) are recorded in ppm. Mass spectra were
acquired on Waters Micromass GCT Premier, Agilent Technologies
5973N and Thermo Fisher Scientific LTQ FT Ultra spectrometers.
3-[(4-Bromophenyl)thio]-4-(dimethylamino)-1H-pyrrole-2,5-di-
one (4d)
Yield: 0.46 g (71%); yellow crystalline solid; mp 192–194 °C.
IR (KBr): 3213, 1753, 1705, 1605, 1424, 1329, 1242, 1004, 935, 840,
797, 720, 641 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.39 (s, 6 H), 7.13 (d, J = 8.0 Hz, 2
H), 7.46 (d, J = 8.0 Hz, 2 H), 10.83 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.12, 84.55, 118.13, 127.49,
132.28, 139.79, 152.72, 166.99, 170.81.
3-Amino-4-thiomaleimides 4 and 5; Typical Procedure
A solution of CuI (0.4 mmol), thiol 1 (2.1 mmol), maleimide 2 (2.0
mmol), formamide 3 (2.0 mmol) and 40% HBF4 (6 mL) was stirred at
120 °C for 8 h under O2. After cooling to room temperature, H2O (10
mL) was added and the resulting mixture was extracted with EtOAc
(3 × 10 mL). The combined organic phase was dried over anhydrous
Na2SO4, concentrated and purified by silica gel column chromatogra-
phy (eluent: EtOAc/PE, 1:5~20) to yield the pure product 4 or 5.
MS (EI): m/z = 326 [M]+, 255, 214, 199, 171, 139, 96, 81.
HRMS (EI): m/z [M]+ calcd for C12H11O2N2SBr: 325.9725; found:
325.9727.
3-(Dimethylamino)-4-[(2-fluorophenyl)thio]-1H-pyrrole-2,5-di-
one (4e)
Yield: 0.39 g (73%); yellow crystalline solid; mp 210–212 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

F
Z.-H. Yang et al.
Paper
Synthesis
IR (KBr): 3161, 2376, 1748, 1691, 1607, 1468, 1414, 1337, 1249, 1120,
1112, 1029, 933, 810, 751, 646 cm–1
IR (KBr): 3252, 2914, 2851, 1765, 1695, 1592, 1463, 1426, 1332, 1247,
.
1023, 935, 718, 642 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.39 (s, 6 H), 7.13–7.21 (m, 4 H),
10.84 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.14, 82.22, 115.66 (d, J = 20.6
Hz), 125.77 (d, J = 3.1 Hz), 127.02 (d, J = 3.1 Hz), 127.11, 127.90 (d, J =
2.5 Hz), 153.28, 158.24 (d, J = 241.0 Hz), 166.89, 170.74.
MS (EI): m/z = 266 [M]+, 233, 195, 139, 109, 96.
HRMS (EI): m/z [M]+ calcd for C12H11O2N2FS: 266.0525; found:
1H NMR (400 MHz, DMSO-d6): δ = 0.85 (t, J = 6.8 Hz, 3 H), 1.23–1.31
(m, 18 H), 1.43–1.50 (m, 2 H), 2.56 (t, J = 7.2 Hz, 2 H), 3.39 (s, 6 H),
10.54 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.44, 22.57, 28.46, 29.03, 29.17,
29.22, 29.40, 29.43, 29.47, 29.49, 31.76, 36.23, 42.10, 91.06, 150.26,
167.70, 171.21.
MS (EI): m/z = 340 [M]+, 172, 157, 139, 115, 100, 85, 69, 55, 40.
HRMS (EI): m/z [M]+ calcd for C18H32O2N2S: 340.2185; found:
266.0529.
340.2187.
3-(Dimethylamino)-4-[(4-nitrophenyl)thio]-1H-pyrrole-2,5-dione
(4f)
3-(Dimethylamino)-4-[(2-hydroxyethyl)thio]-1H-pyrrole-2,5-di-
one (4j)
Yield: 0.38 g (65%); yellow crystalline solid; mp 203–205 °C.
Yield: 0.28 g (65%); yellow crystalline solid; mp 143–145 °C.
IR (KBr): 3212, 1755, 1704, 1611, 1511, 1424, 1336, 1078, 1042, 935,
844, 740, 647 cm–1
.
IR (KBr): 3546, 3266, 2921, 1746, 1700, 1605, 1344, 1005, 939, 750,
646 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.39 (s, 6 H), 7.43 (d, J = 8.9 Hz, 2
H), 8.11 (d, J = 8.9 Hz, 2 H), 10.91 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.23, 82.80, 124.55, 125.64,
1H NMR (400 MHz, DMSO-d6): δ = 2.64 (d, J = 6.0 Hz, 2 H), 3.40 (s, 6
H), 3.49 (d, J = 5.6 Hz, 2 H), 4.71 (s, 1 H), 10.57 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 38.83, 42.21, 60.29, 90.30, 150.52,
145.09, 150.34, 153.13, 166.77, 170.50.
167.64, 171.51.
MS (EI): m/z = 293 [M]+, 260, 222, 166, 139, 120, 96, 82, 69, 55, 42.
MS (EI): m/z = 216 [M]+, 198, 183, 172, 153, 139, 127, 115, 100, 85, 70,
57, 42.
HRMS (EI): m/z [M]+ calcd for C8H12O3N2S: 216.0569; found:
HRMS (EI): m/z [M]+ calcd for C12H11O4N3S: 293.0470; found:
293.0474.
216.0574.
3-(Dimethylamino)-4-(2-naphthalenylthio)-1H-pyrrole-2,5-dione
(4g)
3-(Cyclohexylthio)-4-(dimethylamino)-1H-pyrrole-2,5-dione (4k)
Yield: 0.40 g (78%); yellow crystalline solid; mp 160–162 °C.
IR (KBr): 3161, 3038, 2930, 2849, 1755, 1687, 1596, 1427, 1337, 1256,
Yield: 0.34 g (57%); yellow crystalline solid; mp 178–180 °C.
IR (KBr): 3213, 3051, 1757, 1702, 1606, 1500, 1426, 1341, 1250, 1199,
1123, 1043, 939, 849, 812, 746, 648 cm–1
.
1198, 1110, 1038, 934, 854, 749, 650 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.41 (s, 6 H), 7.34 (d, J = 8.5 Hz, 1
H), 7.41–7.50 (m, 2 H), 7.63 (s, 1 H), 7.84 (d, J = 6.9 Hz, 3 H), 10.83 (s, 1
1H NMR (400 MHz, DMSO-d6): δ = 1.21 (s, 5 H), 1.55 (s, 1 H), 1.68 (s, 2
H).
H), 1.83 (s, 2 H), 2.81 (s, 1 H), 3.40 (s, 6 H), 10.54 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.13, 85.31, 122.85, 124.38,
125.77, 127.14, 127.34, 128.13, 129.03, 131.41, 134.09, 137.82,
152.86, 167.23, 171.04.
MS (EI): m/z = 298 [M]+, 265, 253, 226, 184, 171, 141, 127, 115, 96, 81,
69, 55, 42.
13C NMR (101 MHz, DMSO-d6): δ = 25.79, 25.92, 33.05, 42.31, 47.58,
89.93, 150.67, 167.74, 171.50.
MS (EI): m/z = 254 [M]+, 172, 157, 139, 115, 100, 85, 70, 55, 41.
HRMS (EI): m/z [M]+ calcd for C12H18O2N2S: 254.1089; found:
254.1090.
HRMS (EI): m/z [M]+ calcd for C16H14O2N2S: 298.0776; found:
298.0775.
3-[(4-Chlorophenyl)thio]-4-(dimethylamino)-1-methyl-1H-pyr-
role-2,5-dione (4l)
3-(Dimethylamino)-4-(ethylthio)-1H-pyrrole-2,5-dione (4h)
Yield: 0.32 g (79%); yellow crystalline solid; mp 120–122 °C.
IR (KBr): 3161, 3033, 2969, 2927, 1753, 1683, 1604, 1421, 1343, 1251,
Yield: 0.44 g (75%); yellow crystalline solid; mp 106–108 °C.
IR (KBr): 2937, 1751, 1699, 1609, 1434, 1382, 1254, 1191, 1137, 1092,
1049, 977, 816, 750 cm–1
.
1199, 1117, 1046, 931, 844, 763, 635, 592 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.90 (s, 3 H), 3.43 (s, 6 H), 7.22 (d,
J = 7.5 Hz, 2 H), 7.34 (d, J = 7.6 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6): δ = 1.13 (t, J = 7.4 Hz, 3 H), 2.57 (q, J =
7.4 Hz, 2 H), 3.39 (s, 6 H), 10.55 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.79, 30.16, 42.22, 90.47, 150.56,
13C NMR (101 MHz, DMSO-d6): δ = 24.50, 42.31, 83.45, 127.21,
129.41, 130.02, 139.20, 152.69, 165.72, 170.12.
167.70, 171.30.
MS (EI): m/z = 296 [M]+, 263, 228, 211, 155, 125, 100, 96, 85, 68.
HRMS (EI): m/z [M]+ calcd for C13H13O2N2SCl: 296.0386; found:
MS (EI): m/z = 200 [M]+, 185, 172, 157, 139, 125, 115, 100, 85, 70, 57,
42.
HRMS (EI): m/z [M]+ calcd for C8H12O2N2S: 200.0619; found:
296.0379.
200.0621.
3-(Dimethylamino)-1-phenyl-4-{[4-(trifluoromethyl)phe-
nyl]thio}-1H-pyrrole-2,5-dione (4m)
3-(Dimethylamino)-4-(dodecylthio)-1H-pyrrole-2,5-dione (4i)
Yield: 0.45 g (58%); yellow crystalline solid; mp 174–175 °C.
Yield: 0.50 g (73%); yellow crystalline solid; mp 83–85 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
Z.-H. Yang et al.
Paper
Synthesis
IR (KBr): 3082, 2960, 1754, 1704, 1608, 1498, 1388, 1324, 1205, 1164,
1115, 1007, 961, 828, 745, 694, 624 cm–1
3-[(4-Chlorophenyl)thio]-4-(diethylamino)-1H-pyrrole-2,5-dione
(5a)
.
1H NMR (400 MHz, DMSO-d6): δ = 3.48 (s, 6 H), 7.36 (s, 3 H), 7.50 (s, 4
Yield: 0.35 g (56%); yellow crystalline solid; mp 150–151 °C.
H), 7.63 (s, 2 H).
IR (KBr): 3225, 2978, 1760, 1701, 1590, 1474, 1380, 1339, 1281, 1203,
1128, 1088, 1009, 898, 813, 781, 755, 650 cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 42.60, 82.91, 99.98, 125.81,
126.05, 126.27, 127.20 (q, J = 290.0 Hz), 127.50, 129.16, 132.57,
145.82, 152.82, 164.48, 168.88.
1H NMR (400 MHz, DMSO-d6): δ = 1.14 (t, J = 6.9 Hz, 6 H), 3.78 (q, J =
6.8 Hz, 4 H), 7.16 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2 H), 10.85 (s, 1
H).
MS (EI): m/z = 392 [M]+, 359, 245, 215, 189, 145, 100, 96, 82.
13C NMR (101 MHz, DMSO-d6): δ = 13.94, 45.80, 83.36, 126.44,
HRMS (EI): m/z [M]+ calcd for C19H15O2N2SF3: 392.0806; found:
128.95, 129.39, 138.27, 150.35, 166.29, 170.28.
392.0810.
MS (ESI): m/z = 311 [M + H]+.
3-(Dimethylamino)-4-[(3-methoxyphenyl)thio]-1-phenyl-1H-pyr-
role-2,5-dione (4n)
HRMS (ESI): m/z [M + H]+ calcd for C14H16O2N2ClS: 311.0616; found:
311.0615.
Yield: 0.59 g (83%); yellow crystalline solid; mp 106–108 °C.
IR (KBr): 2936, 1756, 1706, 1608, 1489, 1425, 1384, 1284, 1239, 1124,
3-(Cyclohexylthio)-4-(dibutylamino)-1H-pyrrole-2,5-dione (5b)
Yield: 0.28 g (42%); yellow crystalline solid; mp 114–116 °C.
IR (KBr): 3242, 2926, 2864, 1751, 1767, 1573, 1446, 1322, 1119, 1034,
1038, 961, 851, 748, 687, 623, 553 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.47 (s, 6 H), 3.74 (s, 3 H), 6.73 (dd,
J = 8.2, 2.4 Hz, 1 H), 6.79 (t, J = 2.0 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H),
7.23 (t, J = 8.0 Hz, 1 H), 7.33–7.39 (m, 3 H), 7.47 (t, J = 7.6 Hz, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.53, 55.60, 84.72, 111.14,
111.21, 117.83, 127.49, 128.00, 129.15, 130.58, 132.64, 141.18,
152.44, 160.31, 164.64, 169.10.
920, 732, 654 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 0.90 (t, J = 7.3 Hz, 6 H), 1.20 (s, 5 H),
1.23–1.33 (m, 4 H), 1.52–1.55 (m, 5 H), 1.68 (s, 2 H), 1.83 (s, 2 H), 2.90
(s, 1 H), 3.76–3.80 (m, 4 H), 10.55 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.07, 19.50, 25.66, 25.78, 30.58,
33.00, 47.29, 50.99, 89.56, 148.84, 167.53, 171.15.
MS (EI): m/z = 338 [M]+, 256, 213, 188, 171, 157, 129, 101, 86, 57.
HRMS (EI): m/z [M]+ calcd for C18H30O2N2S: 338.2028; found:
MS (EI): m/z = 354 [M]+, 325, 207, 151, 121, 96, 82, 64, 42.
HRMS (EI): m/z [M]+ calcd for C19H18O3N2S: 354.1038; found:
354.1034.
338.2031.
3-[(3-Chlorophenyl)thio]-4-(dimethylamino)-1-phenyl-1H-pyr-
role-2,5-dione (4o)
3-[(4-Methylphenyl)thio]-4-(phenylamino)-1H-pyrrole-2,5-dione
(5c)
Yield: 0.48 g (67%); yellow crystalline solid; mp 115–117 °C.
IR (KBr): 2942, 1755, 1706, 1610, 1497, 1384, 1247, 1204, 1120, 1068,
Yield: 0.17 g (27%); yellow crystalline solid; mp 233–235 °C.
961, 745, 686, 623 cm–1
.
IR (KBr): 3273, 1772, 1702, 1620, 1588, 1541, 1489, 1446, 1351, 1128,
1H NMR (400 MHz, DMSO-d6): δ = 3.49 (s, 6 H), 7.21 (d, J = 7.7 Hz, 1
H), 7.27 (d, J = 7.8 Hz, 1 H), 7.32–7.40 (m, 5 H), 7.49 (t, J = 7.2 Hz, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 42.60, 83.46, 124.22, 124.84,
125.52, 127.49, 128.01, 129.14, 131.17, 132.63, 134.47, 142.53,
152.78, 164.55, 169.01.
MS (EI): m/z = 358 [M]+, 325, 215, 155, 100, 96, 83, 66.
HRMS (EI): m/z [M]+ calcd for C18H15O2N2SCl: 358.0543; found:
1026, 849, 802, 757, 722, 695, 659 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.20 (s, 3 H), 6.78 (d, J = 7.9 Hz, 2
H), 6.96 (d, J = 7.8 Hz, 2 H), 7.02 (d, J = 7.7 Hz, 2 H), 7.07–7.10 (m, 1 H),
7.16 (t, J = 7.3 Hz, 2 H), 9.87 (s, 1 H), 10.92 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 20.43, 89.36, 124.16, 125.14,
126.37, 127.57, 129.36, 132.41, 134.47, 136.30, 145.97, 167.42,
171.48.
MS (ESI): m/z = 311 [M + H]+.
358.0547.
HRMS (ESI): m/z [M + H]+ calcd for C17H15O2N2S: 311.0849; found:
311.0847.
1-Benzyl-3-(dimethylamino)-4-(phenylthio)-1H-pyrrole-2,5-di-
one (4p)
Yield: 0.48 g (71%); yellow crystalline solid; mp 100–102 °C.
3-(Butylamino)-4-[(2-fluorophenyl)thio]-1-methyl-1H-pyrrole-
IR (KBr): 2932, 1751, 1670, 1608, 1429, 1342, 1246, 1120, 1124, 1068,
2,5-dione (5d)
1026, 849, 743, 695, 625 cm–1
.
Yield: 0.43 g (69%); yellow crystalline solid; mp 98–99 °C.
1H NMR (400 MHz, DMSO-d6): δ = 3.43 (s, 6 H), 4.62 (s, 2 H), 7.13 (t,
J = 7.3 Hz, 1 H), 7.18 (d, J = 7.3 Hz, 2 H), 7.23–7.26 (m, 2 H), 7.26–7.35
(m, 5 H).
IR (KBr): 3311, 2963, 2937, 2879, 1766, 1695, 1613, 1503, 1467, 1448,
1397, 1284, 1258, 1210, 1169, 1101, 1064, 1018, 982, 806, 752, 644
cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 41.51, 42.38, 84.19, 125.49,
125.52, 127.73, 127.75, 128.98, 129.61, 137.41, 139.87, 152.47,
165.50, 169.90.
MS (EI): m/z = 338 [M]+, 227, 177, 121, 91, 77, 51.
HRMS (EI): m/z [M]+ calcd for C19H18O2N2S: 338.1089; found:
1H NMR (400 MHz, DMSO-d6): δ = 0.70 (t, J = 7.3 Hz, 3 H), 1.13–1.10
(m, 2 H), 1.37–1.42 (m, 2 H), 2.90 (d, J = 6.5 Hz, 3 H), 3.50–3.53 (m, 2
H), 7.13–7.22 (m, 4 H), 8.67 (t, J = 5.7 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 13.35, 19.15, 24.09, 31.71, 42.20,
75.88, 115.20 (d, J = 20.5 Hz), 125.15 (d, J = 3.0 Hz), 125.72 (d, J = 16.7
Hz), 126.61 (d, J = 7.4 Hz), 127.15 (d, J = 1.9 Hz), 151.57, 157.89 (d, J =
241.5 Hz), 165.27, 170.92.
338.1093.
MS (ESI): m/z = 309 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
Z.-H. Yang et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C15H18O2N2FS: 309.1068; found:
309.1065.
Yield: 0.06 g (12%); pale yellow solid; mp 48–49 °C.
IR (KBr): 3082, 2366, 1899, 1653, 1574, 1484, 1391, 1388, 1297, 1123,
1073, 1027, 939, 846, 821, 737, 684 cm–1
.
4-[(4-Methylphenyl)thio]-1-phenyl-3-(pyrrolidin-1-yl)-1H-pyr-
role-2,5-dione (5e)
1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 6 H), 7.12 (d, J = 7.6 Hz, 4 H),
7.40 (d, J = 7.5 Hz, 4 H).
13C NMR (101 MHz, CDCl3): δ = 21.08, 128.48, 129.78, 133.85, 137.42.
MS (EI): m/z = 246 [M]+.
Yield: 0.57g (78%); yellow crystalline solid; mp 168–170 °C.
IR (KBr): 2981, 2877, 1759, 1711, 1612, 1506, 1493, 1458, 1392, 1355,
1217, 1155, 1094, 1078, 1012, 943, 812, 776, 762, 693, 649 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 1.84 (t, J = 6.8 Hz, 4 H), 2.24 (s, 3 H),
3.97 (s, 4 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.15–7.16 (m, 2 H), 7.33–7.38 (m,
3 H), 7.45–7.48 (m, 2 H).
13C NMR (151 MHz, DMSO-d6): δ = 21.06, 25.21, 51.79, 84.20, 126.07,
127.52, 128.07, 129.30, 130.38, 132.88, 134.99, 137.13, 150.31,
164.50, 169.65.
3-[(4-Methylphenyl)thio]-1-phenyl-1H-pyrrole-2,5-dione (7a)19
A solution of CuI (0.4 mmol), p-thiocresol (1a) (2.0 mmol), N-phenyl-
maleimide (2b) (2.0 mmol) and 40% HBF4 (2.0 mmol) in DMA (6 mL)
was stirred at 120 °C for 8 h under O2. After cooling to room tempera-
ture, H2O (10 mL) was added and the resulting mixture was extracted
with EtOAc (3 × 10 mL). The combined organic phase was dried over
anhydrous Na2SO4, concentrated and purified by silica gel column
chromatography (eluent: EtOAc/PE, 1:25) to yield the pure product
7a.
MS (ESI): m/z = 365 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H21O2N2S: 365.1318; found:
365.1322.
Yield: 0.38 g (65%); yellow crystalline solid; mp 161–163 °C.
4-[(4-Bromophenyl)thio]-1-phenyl-3-(piperidin-1-yl)-1H-pyrrole-
2,5-dione (5f)
IR (KBr): 2906, 1753, 1685, 1552, 1491, 1387, 1200, 1132, 1051, 1001,
811, 749, 665, 621 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.40 (s, 3 H), 5.94 (s, 1 H), 7.36 (d,
J = 7.5 Hz, 2 H), 7.41 (d, J = 6.9 Hz, 3 H), 7.50 (t, J = 7.2 Hz, 2 H), 7.59 (d,
J = 7.5 Hz, 2 H).
Yield: 0.63 g (71%); yellow crystalline solid; mp 133–135 °C.
IR (KBr): 2938, 2856, 1758, 1706, 1598, 1501, 1470, 1452, 1385, 1269,
1206, 1126, 1081, 1005, 953, 810, 751, 690, 627 cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 21.19, 119.30, 123.36, 127.12,
128.19, 129.20, 131.35, 131.72, 134.11, 140.81, 151.65, 166.86,
168.14.
HRMS (EI): m/z [M]+ calcd for C17H13NO2S: 295.0667; found:
295.0669.
1H NMR (400 MHz, DMSO-d6): δ = 1.61 (s, 6 H), 4.06 (s, 4 H), 7.12–
7.62 (m, 9 H).
13C NMR (101 MHz, DMSO-d6): δ = 23.37, 26.40, 49.47, 84.28, 117.94,
127.04, 127.30, 127.54, 128.64, 131.86, 132.12, 137.67, 151.12,
164.40, 168.36.
MS (ESI): m/z = 443 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H20O2N2BrS: 443.0423; found:
1-Phenyl-3-(pyrrolidin-1-yl)-1H-pyrrole-2,5-dione (8a)20
A solution of CuI (0.4 mmol), N-phenylmaleimide (2b) (2.0 mmol)
and 40% HBF4 (2.0 mmol) in 1-formylpyrrolidine (3b) (6 mL) was
stirred at 120 °C for 8 h under O2. After cooling to room temperature,
H2O (10 mL) was added and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined organic phase was dried over anhy-
drous Na2SO4, concentrated and purified by silica gel column chroma-
tography (eluent: EtOAc/PE, 1:10) to yield the pure product 8a.
443.0420.
1-Benzyl-3-(butylamino)-4-[(4-methoxyphenyl)thio]-1H-pyrrole-
2,5-dione (5g)
Yield: 0.51 g (65%); yellow crystalline solid; mp 149–151 °C.
IR (KBr): 3292, 2925, 1764, 1698, 1620, 1493, 1430, 1406, 1353, 1284,
1239, 1178, 1167, 1120, 1083, 1034, 940, 822, 753, 733, 693, 646 cm–1
.
Yield: 0.38 g (78%); yellow crystalline solid; mp 99–101 °C.
1H NMR (400 MHz, DMSO-d6): δ = 0.77 (t, J = 7.3 Hz, 3 H), 1.16–1.25
(m, 2 H), 1.42–1.50 (m, 2 H), 3.55–3.60 (m, 2 H), 3.71 (s, 3 H), 4.61 (s,
2 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.12 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 7.3 Hz,
2 H), 7.28 (d, J = 7.0 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 2 H), 8.53 (s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 13.53, 19.24, 31.76, 41.05, 42.27,
55.17, 81.09, 114.87, 127.15, 127.31, 127.46, 128.55, 128.98, 136.93,
150.23, 157.52, 165.25, 170.79.
IR (KBr): 3112, 3063, 2994, 2886, 1707, 1635, 1528, 1452, 1395, 1359,
1213, 1137, 1047, 971, 784, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.02 (s, 4 H), 3.35 (s, 2 H), 3.94 (s, 2 H),
4.89 (s, 1 H), 7.30 (d, J = 7.2 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.43 (t, J =
7.5 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 23.60, 25.87, 48.63, 49.98, 85.57,
125.82, 126.70, 128.38, 131.65, 147.70, 165.12, 169.94.
MS (ESI): m/z = 397 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H25O3N2S: 397.1580; found:
HRMS (EI): m/z [M]+ calcd for C14H14N2O2: 242.1055; found:
242.1054.
397.1579.
1-Phenyl-3-(pyrrolidin-1-yl)-pyrrolidine-2,5-dione (9a)
1,2-Di-p-tolyldisulfane (6a)18
A solution of CuI (0.4 mmol), p-thiocresol (1a) (2.0 mmol), N-phenyl-
maleimide (2b) (2.0 mmol) and 40% HBF4 (2.0 mmol) in 1-formylpyr-
rolidine (3b) (6 mL) was stirred at 120 °C for 8 h under O2. After cool-
ing to room temperature, H2O (10 mL) was added and the resulting
mixture was extracted with EtOAc (3 × 10 mL). The combined organic
phase was dried over anhydrous Na2SO4, concentrated and purified by
silica gel column chromatography (eluent: EtOAc/PE, 1:5) to yield the
pure product 9a.
A solution of CuI (0.4 mmol), p-thiocresol (1a) (2.0 mmol), N-phenyl-
maleimide (2b) (2.0 mmol) and 40% HBF4 (2.0 mmol) in DMA (6 mL)
was stirred at 120 °C for 8 h under O2. After cooling to room tempera-
ture, H2O (10 mL) was added and the resulting mixture was extracted
with EtOAc (3 × 10 mL). The combined organic phase was dried over
anhydrous Na2SO4, concentrated and purified by silica gel column
chromatography (eluent: EtOAc/PE, 1:40) to yield the pure product
6a.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
Z.-H. Yang et al.
Paper
Synthesis
Yield: 0.13 g (26%); white crystalline solid; mp 108–110 °C.
References
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963, 902, 770, 743, 687 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 1.71 (s, 4 H), 2.61–2.62 (m, 2 H),
2.81–2.87 (m, 3 H), 3.01 (dd, J = 8.6, 17.9 Hz, 1 H), 3.97 (dd, J = 4.9, 8.6
Hz, 1 H), 7.26–7.27 (m, 2 H), 7.41–7.44 (m, 1 H), 7.50 (dd, J = 4.8, 10.6
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13C NMR (101 MHz, DMSO-d6): δ = 24.54, 34.64, 51.25, 61.14, 128.54,
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245.1284.
3-[(4-Methylphenyl)thio]-1-phenyl-pyrrolidine-2,5-dione (14a)21
A solution of CuI (0.4 mmol), p-thiocresol (1a) (2.0 mmol), N-phenyl-
maleimide (2b) (2.0 mmol) and 40% HBF4 (2.0 mmol) in 1-formylpyr-
rolidine (3b) (6 mL) was stirred at 120 °C for 8 h under N2. After cool-
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mixture was extracted with EtOAc (3 × 10 mL). The combined organic
phase was dried over anhydrous Na2SO4, concentrated and purified by
silica gel column chromatography (eluent: EtOAc/PE, 1:8) to yield the
pure product 14a.
Yield: 0.33 g (55%); pale yellow solid; mp 138–140 °C.
IR (KBr): 1786, 1721, 1665, 1642, 1598, 1564, 1547, 1500, 1467, 1389,
1183, 956, 825, 758, 682, 690 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 2.32 (s, 3 H), 2.79 (dd, J = 3.8, 18.5
Hz, 1 H), 3.41 (dd, J = 9.3, 18.5 Hz, 1 H), 4.43 (dd, J = 3.8, 9.3 Hz, 1 H),
7.01–7.04 (m, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.39–7.41 (m, 1 H), 7.43–
7.47 (m, 4 H).
13C NMR (151 MHz, DMSO-d6): δ = 21.02, 36.61, 44.25, 127.14,
127.34, 128.75, 129.21, 130.34, 132.45, 134.36, 139.21, 174.34,
175.21.
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LC-MS (ESI): m/z = 298 [M + H]+.
Funding Information
The authors acknowledge financial support from Shanghai Municipal
Natural Science Foundation (No. 15ZR1401400), the Fundamental Re-
search Funds for the Central Universities from the Ministry of Educa-
tion of China (CUSF-DH-D-2015048 and CUSF-DH-D-2016028) and
the National Innovation Experiment Program for University Students
(7) Ding, S.; Jiao, N. Angew. Chem. Int. Ed. 2012, 51, 9226; Angew.
Chem. 2012, 124, 9360.
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2009, 48, 9127; Angew. Chem. 2009, 121, 9291. (b) Huang, X.;
Wang, J.; Ni, Z.; Wang, S.; Pan, Y. Chem. Commun. 2014, 50, 4582.
(c) Yang, L.; Lin, J.; Kang, L.; Zhou, W.; Ma, D.-Y. Adv. Synth. Catal.
2018, 360, 485.
(9) (a) Yang, Z.-H.; Tan, H.-R.; Zhu, J.-N.; Zheng, J.; Zhao, S.-Y. Adv.
Synth. Catal. 2018, 360, 1523. (b) Yang, Z.-H.; An, Y.-L.; Chen, Y.;
Shao, Z.-Y.; Zhao, S.-Y. Adv. Synth. Catal. 2016, 358, 3869. (c) An,
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(17T10507) for financial support.
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Acknowledgment
We are grateful to Mr. Christopher Gerry form the Broad Institute of
Harvard and MIT for reviewing and editing this article.
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Supporting information for this article is available online at
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

J
Z.-H. Yang et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J