Copper-Catalyzed Oxidative Thioamination of Maleimides with Amines and Bunte Salts

Article abstract of DOI:10.1021/acs.orglett.0c00207

Herein, we describe the first example of copper-catalyzed oxidative thioamination of maleimides with secondary amines and Bunte salts with the achievement of C-N and C-S bonds in a single flask. The protocol showcases a prominently broad substrate scope a

Full text of DOI:10.1021/acs.orglett.0c00207

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Letter
Copper-Catalyzed Oxidative Thioamination of Maleimides with
Amines and Bunte Salts
Shanshan Shi,§ Yunfei Ma,§ Jun Zhou, Jia Li, Luya Chen, and Ge Wu*
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ABSTRACT: Herein, we describe the first example of copper-catalyzed oxidative thioamination of maleimides with secondary
amines and Bunte salts with the achievement of C−N and C−S bonds in a single flask. The protocol showcases a prominently broad
substrate scope and is also efficient for the late-stage modification of an array of pharmaceuticals. Preliminary mechanistic
investigation indicates copper-catalyzed oxidative amination of maleimides with amines to form reactive enaminone and subsequent
intermolecular alkenyl C−H thiolation.
ransition-metal catalyzed vinylic C−H thiolation is one of
electron-deficient alkenes with Bunte salts has never been
Tthe most efficient protocols to synthesize the vinyl reported, because these two coupling partners easily occur in
classical thia-Michael addition7 (Scheme 1A). Ideally, if one
common chemical could be introduced in electron-deficient
alkenes and endowed with new reactivity to achieve a
multicomponent reaction, it would advance synthetic in-
novation and novel drug research. Therefore, we envisioned
developing a copper-catalyzed three-component coupling with
maleimides, Bunte salts, and amines (Scheme 1B). As part of
our design, we assumed that copper-catalyzed oxidative
amination of maleimides with amines to generate enaminone,
in this case, the electrophilic reactivity of maleimides could be
transformed into potent nucleophilicity owing to the strong
electron-donating of an amino group. Then, the intermolecular
oxidative cross-coupling of this key intermediate with Bunte
salts provides a promising route to construct more structurally
diverse thiolated enaminone compounds. As a result, this
transformation not only establishes an efficient protocol to
access thioaminationed maleimides via C−N bond and C−S
bond formation but also provides a complementary protocol
sulfides by the formation of a new C−S bond.1 Although a
variety of methodologies have been made on this avenue, the
sulfurating reagents typically employed are limited to narrow-
ranged diaryl disulfides, ArSO2Cl, and rotten alkyl thiols. Thus,
it would dramatically limit their potential applications for late-
stage modification of bioactive molecules for novel drug
research and development. In contrast, the use of Bunte salts
would be a promising sulfur source in view of its structural
diversity, stability, and no odor.2 As far as we are aware, there
has been no report on such a transformation to construct the
structural diverse vinyl thioethers. In continuation of our
studies on alkene functionalization,3 herein we describe the
development of copper-catalyzed oxidative thioamination of
electron-deficient alkenes with amines and S-alkyl Bunte salts
with the formation of C−N and C−S bonds in a single flask.
In recent years, the oxidative coupling of Bunte salts with a
carbon nucleophile has received increasing attention. Jiang’s
group demonstrated the sulfuration of boronic acids using
copper-catalyzed oxidative coupling under CO2 atmosphere.4
Aryltriethoxysilane could also be converted into thioether
and thioester with a ligand-controlled strategy by the same
group.5 In addition, Yi’s group also developed an efficient
copper-catalyzed decarboxylative sulfuration of alkynyl carbox-
ylic acids with Bunte salts.6 However, oxidative coupling of
Received: January 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00207
© XXXX American Chemical Society
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A

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ineffective (entries 2−4). Furthermore, the addition of a base
inhibited the transformation and the addition of an acid
decreased the yield of 4a to 65% (entries 5 and 6). In addition,
the current reaction was very sensitive to solvent; polar, weak
coordination, and apolar solvents were undesirable (entries 7−
9). When Ag2CO3 was used as the oxidant, although N-methyl
maleimide was fully consumed, 4a was generated in a trace
amount (entry 10). The effect of ligand was next assessed, and
the addition of Phen was detrimental to reaction efficiency
(entry 11). Finally, control experiments demonstrated that a
copper catalyst and oxygen played essential roles in promoting
the three-component tandem reaction (entries 12−13).
Scheme 1. Copper-Catalyzed Thioamination of Maleimides
via Umpolung Strategy
With the optimized reaction conditions in hand, we
examined the scope of amines in the copper-catalyzed three-
component tandem reaction. As shown in Scheme 2, a wide
a
Scheme 2. Secondary Amines Scope
for existing three-component acetamidosulfenylation of alkenes
with Bunte salts and nitriles.
At the outset of our study, we chose sodium S-benzyl
sulfurothioate 1a, N-methyl maleimide 2a, and morpholine 3a
as the model substrate to test the feasibility of copper-catalyzed
thioamination of electron-deficient alkenes. After thorough
optimization of reaction conditions, the reaction was
conducted using CuI as the catalyst, DCE as the solvent,
and oxygen as the green oxidant at 100 °C, the desired product
4a was isolated in 83% yield (Table 1, entry 1). It was
a
Table 1. Reaction Optimization
a
Reaction conditions: Tabel 1, entry 1. Isolated yields after column
chromatography are given.
b
range of cyclic secondary amines could smoothly undergo this
transformation. Morpholine (4a), piperidine (4b−4d), piper-
azine (4e−4f), and pyrrolidine (4g) were suitable substrates,
and the corresponding products were obtained in moderate to
good yields. This reaction showcases good functional group
tolerance, including ester, Boc, phenyl, alkyl, cyano, methoxyl,
and fluoro, thus providing a useful building block for further
transformation of the desired products. Moreover, acyclic
secondary amines (4h and 4i) are also amenable to
vinylthiolation, indicating the versatility and compatibility of
the current catalytic system. In addition, this method was
viable to N-methyl benzylamine substrates (4j−4l), giving the
vinylthiolated products in good yield. However, when primary
alkyl amines, anilines, and amides were used as coupling
partners, no thioaminated product was detected, probably
owing to the poor nucleophilicity of the starting material.
Next, we focused our attention on testing the feasibility of
structurally diverse maleimides reacting under the robust
reaction conditions (Scheme 3). The copper-catalyzed
oxidative thioamination of a variety of maleimides (2a−2l)
exhibited versatility and extensibility, and the predicted
products (5a−5l) were generated in good to excellent yields.
Especially, it was found that free maleimide (5a) also exhibited
high reactivity and afforded the corresponding product in
synthetically useful yield. More generally, N-substituted
maleimides were efficiently thioaminated to give the
entry
variation
yield (%)
1
2
3
4
5
6
7
8
none
83
0
0
0
0
65
0
0
CuCl2 instead of CuI
CuBr2 instead of CuI
Cu(OAc)2 instead of CuI
Na2CO3 (0.4 mmol) as additive
TsOH (0.4 mmol) as additive
DMSO instead of DCE
CH3CN instead of DCE
Toluene instead of DCE
Ag2CO3 (0.4 mmol) as oxidant
Phen (0.02 mmol) as additive
Under N2
9
0
10
11
12
13
trace
44
0
No CuI
0
a
Reaction conditions unless specified otherwise: 1a (0.4 mmol), 2a
(0.2 mmol), 3a (0.4 mmol), CuI (0.02 mmol), DCE (2.0 mL), under
b
O2, 100 °C, 24 h. Isolated yield.
noteworthy that sulfenylation of maleimides,8 thia-Michael
addition of Bunte salt with maleimides,7 and α-amination of
Bunte salt with amines9 were not observed at all during
optimization of the reaction conditions. It was found that the
choice of copper catalyst was a critical success factor for this
reaction. The results suggest that only CuI could provide the
corresponding product; other copper salts were completely
B
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a
Scheme 3. Maleimides Scope
Scheme 5. Late-Stage Modification of Pharmaceuticals
a
Reaction conditions: Tabel 1, entry 1. Isolated yields after column
chromatography are given.
be readily vinylthiolated with high efficiency. The application
of this protocol was demonstrated on Maprotiline11 (7b and
7d), which inhibits neuronal norepinephrine reuptake. The
highly efficient synthesis of thioaminated Cytisine 7e, a drug
more affordable in smoking cessation treatment than nicotine,
was also achieved.12 Meanwhile, common antidepressant drugs
Paroxetine13 (7f) and Fluoxetine14 (7g) were amenable
coupling partners under the current reaction conditions.
Given the versatility of copper-catalyzed thioamination of
maleimides, we conducted some mechanistic investigations to
shed substantial light on the sequence of three-component
coupling (Scheme 6). First, maleimide difunctionalization was
performed in the presence of a frequently used radical inhibitor
affording the expected product with only a minor loss in
efficiency (eq 1), which suggested a radical-based mechanism
could be excluded. Second, when the N-phenyl maleimide and
corresponding products in good yields. Furthermore, many
synthetically important functional groups on the benzene ring
of N-aryl maleimides, including methyl (5f), methoxy (5g),
halogen moiety (5h−5j), and trifluoromethyl (5k), were well
tolerated; these target products could be further modified via
well-developed cross-coupling methodology. To our delight,
maleimide bearing thiophene also reacted smoothly with 1a
and 3a to afford the desired product 5l in 72% yield.
Selected examples of the thioaminated maleimides synthesis
are illustrated in Scheme 4. The current strategy could be
a
Scheme 4. Bunte Salts Scope
Scheme 6. Preliminary Mechanism Investigation
a
Reaction conditions: Tabel 1, entry 1. Isolated yields after column
chromatography are given.
applicable to an array of functionalized S-alkyl Bunte salts
under the optimal reaction conditions, giving the expected
products in satisfactory yields. Alkyl substituted Bunte salts
displayed more reactivity than benzyl substituted ones,
probably due to less steric repulsion between the thiol and
amino groups. It is worth mentioning that sodium S-methyl
sulfurothioate also could be utilized as a methylthio source in
the current three-component reaction and the vinyl methyl
sulfide (6h) was obtained in excellent yield.
Late-stage modification of pharmaceuticals has been become
one of the most efficient gateways for novel compound
discovery and development. As shown in Scheme 5, the
current strategy provides practical evidence for the late-stage
vinylthiolation of secondary amine-containing pharmaceuticals.
Atomoxetine10 (7a and 7c) (marketed as Strattera), a drug
used for treating attention-deficit/hyperactivity disorder, could
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morpholine were subjected to standard reaction conditions,
the oxidative amination product was obtained in 88% yield (eq
2); in comparison, the treatment of maleimide with Bunte salt
did not afford thia-Michael addition and oxidative sulfuration
products (eq 3). To further elucidate the sulfuration of
enaminone, the reaction between 1a and 8a was also
performed, however no desired product was detected.
Interestingly, after the addition of some amount of morpholine,
4a was dramatically generated in 79% yield (eq 4). This result
clearly indicates the amine not only acts as a substrate in the
multicomponent reaction but also functions as an activator of
Bunte salt to promote the enaminone C−H sulfuration. To
examine whether the enaminone 8a is traped by thiolcopper
species, we prepared a (BnS)2Cu complex15 and reacted it with
8a under optimal reaction condition, in both the absence and
presence of an amine. The anticipated product was not
observed, which means thiolcopper was not a key intermediate
under the current reaction system. Finally, 88% deuterium
incorporation of enaminone 8a was confirmed in the presence
of D2O under the standard reaction conditions. In contrast, no
H/D exchange product of simple maleimides was detected by
NMR and GC-MS.16 These results imply that reversibility of
enaminone C−H activation under the current catalytic system
probably may be ascribed to the strong electron-donating
property of the amino group.
introduction of an amino group into the skeleton of
maleimides would endow new reactivity. This approach is
amenable to the late-stage vinylthiolation of secondary amine-
containing pharmaceuticals, which would accelerate the
discovery of new novel drugs. This reaction not only opens a
new door for the synthetic application of S-alkyl Bunte salts as
a sulfuration reagent but also offers new insight into the
oxidative difunctionalization of electron-deficient alkenes.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00207.
1H and 13C NMR spectra of all new compounds and the
experimental procedures (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ge Wu − School of Pharmaceutical Sciences, Wenzhou Medical
University, Wenzhou 325035, People’s Republic of China; State
Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian 350002, China; orcid.org/0000-
0001-8432-5272; Email: wuge@wmu.edu.cn
On the basis of experimental findings and previous literature,
a plausible reaction mechanism for copper-catalyzed thioami-
nation of maleimides is proposed in Scheme 7. First, copper-
Authors
Shanshan Shi − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Scheme 7. Proposed Mechanism
Yunfei Ma − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Jun Zhou − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Jia Li − School of Pharmaceutical Sciences, Wenzhou Medical
University, Wenzhou 325035, People’s Republic of China
Luya Chen − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00207
Author Contributions
§S.S. and Y.M. contributed equally.
Notes
catalyzed oxidative amination of maleimides with secondary
amines form ksey intermediate B via aza-Michael addition/
oxidative dehydrogenation steps.17 Afterward, the reaction of
the Cu(II) salt with B generates vinylcopper complex C via
C−H activation,18 with subsequent ligand exchange between
D and S-alkyl Bunte salt. Disproportionation of D with Cu(II)
forms E,19 which finally undergoes reductive elimination to
afford the corresponding product with the release of SO3.20 It
should be noted that the copper salt played at least three roles
in the whole reaction process.
In summary, we have developed a general and efficient
method of copper-catalyzed thioamination of maleimides with
S-alkyl Bunte salts and secondary amines. The significant
features of this tandem reaction include the use of almost no
odor S-alkyl Bunte salts as the alkylthiol reagent, a simple
catalytic system, a green oxidant, and excellent functional
group tolerance. Preliminary mechanism studies reveal that the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21602158), Zhejiang Provincial Natural
Science Foundation (LY19B020011, LTQ20B010001,
LQ18B010003), State Key Laboratory of Structural Chemistry
(No. 20170037), and Public Welfare Science and Technology
Project of Wenzhou (No. Y20180233, Y20190132) is greatly
appreciated.
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