Three-Component Coupling Reactions of Maleimides, Thiols, and Amines: One-Step Construction of 3,4-Heteroatom-functionalized Maleimides by Copper-Catalyzed C(sp2)?H Thioamination

Article abstract of DOI:10.1002/adsc.201700955

A copper-catalyzed intermolecular thioamination of maleimides with thiols and amines has been developed. A diverse range of 3-amino-4-thiomaleimides and 3,4-dihydropyrrolo[3,4-b][1,4]thiazine-5,7(2H,6H)-diones were obtained with good yields, involving C?N and C?S bond formations. This methodology is very practical and features high atom economy, excellent functional group tolerance. (Figure presented.).

Full text of DOI:10.1002/adsc.201700955

Title: Three-Component Coupling Reactions of Maleimides, Thiols, and
Amines: One-Step Construction of 3,4-Heteroatom-functionalized
Maleimides by Copper-Catalyzed C(sp2)−H Thioamination
Authors: Zhen-Hua Yang, Hong-Ru Tan, Yu-Long An, Yu-Wei Zhao,
Hao-Peng Lin, and Sheng-Yin Zhao
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700955
Link to VoR: http://dx.doi.org/10.1002/adsc.201700955

Advanced Synthesis & Catalysis
10.1002/adsc.201700955
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Three-Component Coupling Reactions of Maleimides, Thiols,
and Amines: One-Step Construction of 3,4-Heteroatom-
2
functionalized Maleimides by Copper-Catalyzed C(sp )−H
Thioamination
a
a
a
a
a
Zhen-Hua Yang, Hong-Ru Tan, Yu-Long An, Yu-Wei Zhao, Hao-Peng Lin, and
a,b*
Sheng-Yin Zhao
a
Department of Chemistry, Donghua University, No. 2999 North Renmin Road, Shanghai 201620, P. R. of China
Fax: (+86)-21-67792608-805; phone: (+86)-21-67792436; e-mail: syzhao8@dhu.edu.cn
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, Shanghai 200032, P. R. of China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A copper-catalyzed intermolecular thioamination
of maleimides with thiols and amines has been developed.
A diverse range of 3-amino-4-thiomaleimides and 3,4-
dihydropyrrolo[3,4-b][1,4]thiazine-5,7(2H,6H)-diones were
obtained with good yields, involving C−N and C−S bond
formations. This methodology is very practical and features
high atom economy, excellent functional group tolerance.
Keywords: copper catalysis; thioamination; maleimides;
thiols; amines
Maleimides are ubiquitous structural motifs found in
a multitude of natural products and drug candidates
[1]
as well as functional materials. Additionally, they
could be transformed into diverse, important hetero-
cyclic frameworks such as succinimides, pyrrolidines,
lactims, and γ-lactams.[ Thus, a great deal of
attention has been focused on the development of
new synthetic routes to access functionalized
maleimides.[ 3-amino-4-thiomaleimides are particu-
larly important organic molecules due to their
antibacterial and antitumor activities.[ Traditionally,
they have been synthesized from the sequential
nucleophilic substitution of 3,4-dichloromaleimides
2]
3]
4]
[4a]
with anilines and benzenethiols (Scheme 1a).
Moreover, the 3,4-dichloromaleic anhydrides have
also served as substrates to build 3-amino-4-thiomal-
eimides in two steps, albeit with low yield (Scheme
1
b).[ However, these methods require the applica-
5]
tion of reactive prefunctionalized materials and
multistep reactions. Hence, the development of novel
and practical methods for one-step synthesis of 3-
amino-4-thiomaleimides using nonfunctionalized rea-
gents remains both a considerable challenge and a
most useful addition to this branch of chemistry.
Scheme 1. Copper-catalyzed intermolecular thioamination
of maleimides.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700955
Table 1. Optimization of the reaction conditions.[a]
Table 2. Cu-catalyzed C-H thioamination of maleimides
with thiols and amines.
[
a,b]
Entry Catalyst
Solvent
Temp.
(℃)
120
120
120
120
120
120
120
120
120
120
reflux
120
120
120
100
140
120
Yield
[
b]
(
equiv.)
[%]
37
52
58
73
36
45
27
78
18
67
25
82
85
57
67
71
0
1[c]
2
3
CuCl (1.0)
CuCl (1.0)
CuBr (1.0)
CuI (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
MCB
DMF
Dioxane
DMA
4
5
6
7
CuCl
Cu(OAc)
2
I (1.0)
2
(1.0)
2
(1.0)
8
9
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)
—
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
DMA
DMA
DMA
DMA
DMA
[
a]
Reaction conditions: 1a (2.1 mmol), 2a (2.0 mmol),
a (2.1 mmol), catalyst, solvent (6 mL), O balloon, 6
3
2
h.
[
[
b]
Isolated yield.
Air condition.
c]
In recent years, there have been significant
[
6]
improvements in the direct thioamination of alkene,
alkyne,[ and aryne
7]
[8]
for C–N and C–S bond
formation. Mizar et al. recently developed efficient
thioamination of alkenes mediated by iodine(III)
reagents.[ Subsequently, highly regio- and stereo-
selective intermolecular seleno- and thioamination of
alkynes was reported by Zheng.[ Yoshida also
described a direct thioamination of arynes via
reaction with sulfilimines and migratory N-arylation
to give o-sulfanylanilines in high yield.[ However,
to the best of our knowledge, an intermolecular
thioamination of maleimides has not yet been
reported. The most likely reason is that the
maleimides are unstable in the presence of strong
acid and alkali, and are apt to polymerize and
decompose. [ Nevertheless, in consideration of our
6a]
7a]
8a]
9]
[10]
previous studies on maleimides and the importance
of the introduction of nitrogen and sulfur functional
groups, we report the first direct copper-catalyzed
intermolecular thioamination of maleimides with
thiols and amines without affecting the olefin bond
[
[
a]
b]
Reaction conditions: 1 (2.1 mmol), 2 (2.0 mmol), 3 (2.1
mmol), CuI (20 mol %), DMA (6 mL), O
Isolated yield.
2
balloon, 6 h.
(
Scheme 1c).
Initially, the reaction of p-thiocresol 1a, maleimide
a and pyrrolidine 3a was chosen as a model system
2
dramatically increased to 52% when the reaction was
conducted under an oxygen atmosphere (entry 2,
Table 1). Clearly, O was beneficial to the efficient
formation of 4a. We next altered several parameters
to identify and optimize reaction parameters (Table 1).
The desired product 4a was obtained in 37% yield in
the presence of CuCl (1 equiv.) in DMSO at 120 ℃
under air for 6 h (entry 1, Table 1). The yield of 4a
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700955
in an attempt to improve the yield of desired product.
First, several catalysts were screened. I and copper
2
salts provided 27-73% isolated yields (entries 2-7,
Table 1). CuI was slightly superior to the others and
proved to be the best catalyst. The solvent also played
a crucial role. Among the solvents tested (DMSO,
DMA, MCB, DMF and Dioxane), DMA was the best
for this transformation (entries 4, 8-11, Table 1).
Subsequent experiments titrating the amount of CuI
showed that 20 mol% CuI loading was appropriate
(
entries 12-14 Table 1). Finally, examination of the
effect of the reaction temperature indicated that
20 ℃ was best for the formation of product in the
1
Figure 1. ORTEP view of the X-ray structure of 6a.
reaction (entries 13, 15-16, Table 1). In addition,
none of the desired product 4a could be obtained in
the absence of catalyst (entry 17, Table 1).
With the optimized reaction conditions identified,
we next turned our attention to explore the scope of
the reaction (Table 2). The reaction is quite general.
A variety of substituted aryl or alkyl amines and
thiols could be employed for the thioamination of
various maleimides. We found that the difference of
nucleophilicity of amines played an important role in
reaction yield. That is, aliphatic amines had a good
yield (4a-h, k-p, 52-85%), and aromatic amines gave
a poor yield (4i-j, 27-39%). Although aliphatic
amines exhibited high reactivity, unfortunately, the
yield of compound (4k and 4n, 52% and 64%) was
low due to steric hindrance. Thiophenols with
electron-deficient nitro (4l) and electron-donating
methoxy (4p) substituents generally delivered the
desired products in comparable yields (71% and 76%,
respectively). Moreover, various halogen functional
groups (4h-j, 4n-o) were also tolerable, providing
useful synthetic handles for further functionalization
to complex molecules. Notably, the substituent (e.g.,
methyl, phenyl, and benzyl) from (NH) maleimides
showed no obvious impact on reaction yields (4l-4p,
6
4-79%). We also tested functional group tolerance
in the reaction. We found that the hydroxyl, ester,
Scheme 2. The reaction of maleimide 2 with 1,2-
diaminoethane, 1,2-ethanedithiol, L-cysteine and L-
cysteine methyl ester hydrochloride.
Table 3. Cu-catalyzed C-H thioamination of maleimides
with 2-aminoethanethiol hydrochloride.[a,b]
ether, and carboxyl groups had no marked effect on
the reaction yields (4d, 4h, 4n, and 4o, 64%-78%).
Since the pyrrolo[3,4-b][1,4]thiazine-5,7(2H,6H)-
diones serve as functional dyes and also show broad
[11]
spectrum antibacterial and antifungal activities, we
next explored the scope of this reaction of
maleimides with 2-aminoethanethiol hydrochloride
under our optimal conditions (Table 3). The results
indicated that maleimides reacted smoothly with 2-
aminoethanethiol hydrochloride and provided the
desired product in good yields (6a-6d, 65%-84%).
The compound 6a was crystallized, and X-ray
analysis unambiguously confirmed the structure of
[12]
thioamination of maleimides (Figure 1). However,
the compound 2a didn’t react with 1,2-diaminoethane
and 1,2-ethanedithiol to yield the corresponding
product 8a and 10a in the protocol (Scheme 2). The
results rule out the possibility of twice Michael
addition and oxidative dehydrogenation processes. In
addition, we also tried to use L-cysteine and L-
[
[
a]
b]
Reaction conditions: 2 (2.0 mmol), 5 (2.1 mmol), CuI
20 mol %), DMA (6 mL), O balloon, 6 h.
Isolated yield.
(
2
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700955
cysteine methyl ester hydrochloride as reaction
materials to explore the scope of the reaction.
Unfortunately, all of the reactions failed. The reaction
results suggested that maleimides could not react with
L-cysteine or L-cysteine methyl ester hydrochloride
to get the desired products 12 and 14. The reaction
systems always became to black mixtures under our
standard reaction condition. The most likely reason is
that the L-cysteine and L-cysteine methyl ester
hydrochloride have strong coordination ability to
cupric ion. They are also easy to be oxidized.
Next, we paid more attention to investigate the
reaction of maleimides with 2-aminothiophenol
(
Scheme 3). The reaction results showed that
maleimide could react with 2-aminothiophenol to
provide a yellow-white solid. We hope the compound
1
6a can be obtained. However, the structure of this
compound was assigned to products 17a by the
1
13
spectral analysis HRMS, H and C NMR. The
analysis of NMR spectral data suggested six
hydrogen and ten carbon signals. Compound 16a and
1
7b have the same amount of hydrogen and carbon.
Luckily, MS spectrum gave us a clue to determine the
structure of product. Furthermore, EI spectrum of this
+
compound showed a molecular ion at 202 (M ).
High-resolution mass spectrum suggested a molecular
formula of C10
H
6
2
N OS. The molecular formula is
consistent with compound 17a. In order to understand
this problem, we used N-methylmaleimide to run this
reaction. Compound 17b was obtained with 35%
yield on the base of spectrum analysis. We believe
the products 17 were synthesized under our standard
condition (see supporting information for details).
Scheme 3. The reaction of maleimide 2 with 2-aminothio-
phenol 15
To acquire insight into the reaction mechanism,
control experiments were conducted. First, a large
amount of bis(4-methylphenyl)disulphide 18a was
obtained in the reaction between p-thiocresol 1a and
N-phenylmaleimide 2b under standard conditions in
addition to the thia-Michael addition product (19a,
1
9
4%) and its oxidative dehydrogenation product (20a,
%) (Scheme 4a). Second, N-phenylmaleimide 2b
Scheme 4. Control experiments.
reacted with pyrrolidine 3a to produce 1-phenyl-3-
nucleophilic substitution (Scheme 4d).[13] The
(
pyrrolidin-1-yl)-1H-pyrrole-2,5-dione (21a, 85%) in
subsequent employment of 21a with bis(4-
methylphenyl)disulfide 18a proved that product 4m
could be obtained with good yield (Scheme 4e).
However, none of target product 4m was detected
one hour (Scheme 4b). We found that the aza-
Michael addition product 22a could be oxidized to
2
(
1a with good yield quickly under optimal conditions
Scheme 4c). At the same time, the product 20a could
under an N atmosphere (Scheme 4f). These results
2
further react with 3a to produce 21a in 76% yield by
show that (i) the compounds 18a, 19a, 20a, 21a and
22a are the intermediates in the reaction, (ii) and that
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700955
oxygen plays an important role in the formation of
product (see supporting information for details).
Based on the above evidence and reported
mechanistic studies on copper chemistry with thiols
products 4 and the copper catalyst is regenerated.[17]
At the same time, the oxidation of the in situ
1
[18]
generated R SH by O reproduces disulphide 18.
2
Oxygen plays an important role in the regeneration of
the catalytically active species as well as the
oxidative dimerization of the thiols.
In summary, we have developed an efficient
2
strategy for direct C(sp )−H difunctionalization of
maleimides with thiols and amines. This metho-
dology is very general, practical, environmentally
friendly and features high atom economy as well as
excellent functional group tolerance. Further bio-
logical activity evaluation of these compounds and
application of this methodology for the preparation of
new potent bioactive molecules are ongoing in our
group.
Experimental Section
General Information
2
All experiments were carried out under O atmosphere. All
chemicals and solvents used in our experiments were
obtained from commercial suppliers and used without
further purification. Melting points were determined with
RY-1 apparatus and uncorrected. IR spectra were recorded
as KBr pellets on a Shimadzu model 470 spectrophoto-
1
13
meter. NMR ( H and C) spectra were recorded using a
Bruker AV 400 or 600 MHz spectrometer in DMSO-d or
CDCl with TMS as internal standard. Chemical shifts (δ)
6
3
were recorded in ppm. Mass spectra were acquired on
Waters micromass GCT premier, Agilent technologies
5
973N and thermo Fisher scientific LTQ FT Ultra.
Typical Procedure for the Synthesis of 3-
Amino-4-thiomaleimides 4
Scheme 5. Proposed reaction mechanism.
and amines, a plausible pathway was proposed as
shown in Scheme 5. On one hand, the amines 3
underwent aza-Michael addition with maleimides 2 to
form 3-aminosuccinimides 22, which produced 3-
aminomaleimides 21 by copper catalyzed aerobic
oxidative dehydrogenation.[14] Because the reaction
A solution of CuI (0.4 mmol), thiols 1 (2.1 mmol),
maleimides 2 (2.0 mmol) and amines 3 (2.1 mmol) in 6 mL
of DMA was stirred at 120 ºC for 6 h under O . After
2
cooling down to room temperature, 10 mL of water were
added, and the resulting mixture was extracted with ethyl
acetate (3 × 10 mL). The organic phases were dried with
was conducted under O , the Cu(I) species in this
2
reaction was easily oxidized to Cu(II), showing that
anhydrous Na
column chromatography (eluent: ethyl acetate-PE, 1:
0~35) to yield the pure product 4.
2 4
SO , concentrated and purified by silica gel
the reaction can be catalyzed by copper catalyst with
as the terminal oxidant.[
15]
Alternatively,
1
O
2
compound 21 also could be obtained via the nucleo-
philic substitution between amines 3 and 3-thio-
maleimides, which have been synthesized by thia-
Michael addition and oxidative dehydrogenation
processes. However, the oxidative dehydrogenation
process of Michael adduct 19 is harder under these
Typical Procedure for the Synthesis of 3,4-Di-
hydropyrrolo[3,4-b][1,4]thiazine-5,7(2H,6H)-
diones 6
[10b]
A solution of CuI (0.4 mmol), maleimides 2 (2.0 mmol)
and 2-aminoethanethiol hydrochloride 5 (2.1 mmol) in 6
conditions according to our previous studies.
Next,
the copper(I) catalyst interacts with disulphide 18 to
generate intermediate I.[
16]
mL of DMA was stirred at 120 ºC for 6 h under O . After
2
cooling down to room temperature, 10 mL of water were
added, and the resulting mixture was extracted with ethyl
acetate (3 × 10 mL). The organic phases were dried with
The region-selective
electrophilic attack of I on 3-aminomaleimides 21 at
the 4-position via its isomeric version 23 results in
the formation of the intermediate II, which
deprotonates to give the corresponding target
anhydrous Na
2
SO
4
, concentrated and purified by silica gel
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201700955
column chromatography (eluent: ethyl acetate-PE, 1: 5~15)
to yield the pure product 6.
Luzikov, M. I. Reznikova, O. Y. Susova, A. A. Shtil,
S. M. Elizarov, V. N. Danilenko, M. N.
Preobrazhens-kaya, Russ. Chem. Bull. 2008, 57,
2
011-2020; c) C. J. Michejda, J. Christopher, W. Yao,
Acknowledgements
B. I. Carr, S. Kar, M. Michejda, US 20080039518
Chem. Abstr. 2008, 148: 239021; d) R. Riggs, J.
Dietz, W. Grammenos, B. Mueller, J. K. Lohmann, N.
Boudet, I. R. Craig, E. Haden, J. Montag, WO
2012143468 Chem. Abstr. 2012, 157: 625845.
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 (CUSF-DH-D-2015048 and
CUSF-DH-D-2016028) and national innovation experiment
program for university students (17T10507) for financial support.
We are grateful to Mr William Alborn for reviewing and editing
this article.
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UPDATE
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