Oxidative Aminoarylselenation of Maleimides via Copper-Catalyzed Four-Component Cross-Coupling

Article abstract of DOI:10.1021/acs.orglett.8b03980

The first example of copper-catalyzed four-component coupling reaction of aryl iodides, Se powder, secondary amines, and maleimides is developed. This reaction provides an efficient and concise route to access aminoarylselenated maleimides via double C-Se bonds and C-N bond formation. The appealing features of this transformation are the use of Se powder as a selenating reagent, a green catalytic system, a wide range of substrate scope, and late-stage selenation of bioactive compounds.

Full text of DOI:10.1021/acs.orglett.8b03980

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxidative Aminoarylselenation of Maleimides via Copper-Catalyzed
Four-Component Cross-Coupling
Xue Gao,† Liyang Tang,† Lehao Huang,† Zu-Sheng Huang,† Yunfei Ma,† and 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
S
* Supporting Information
ABSTRACT: The first example of copper-catalyzed four-
component coupling reaction of aryl iodides, Se powder,
secondary amines, and maleimides is developed. This reaction
provides an efficient and concise route to access amino-
arylselenated maleimides via double C−Se bonds and C−N
bond formation. The appealing features of this transformation
are the use of Se powder as a selenating reagent, a green
catalytic system, a wide range of substrate scope, and late-stage selenation of bioactive compounds.
selenated enamides remains to be elusive. Only one
intermolecular, three-component aminoselenation of alkynes
has been developed by Zheng.5 Issues associated with prior
preparation of selenating reagent and narrow substrate scope
would dramatically restrict their application on late-stage
transformation of bioactive compounds. Undoubtedly, the use
of elemental selenium as a selenating reagent involved in
transition-metal-catalyzed oxidative selenoamination of alkenes
would be an attractive and promising strategy. To the best of
our knowledge, there is no such report to construct the 2-
amino vinyl selenides.
inyl selenides are of particular importance, due to their
Vreactive handles in further manipulation of complex
compounds and since they are useful building blocks for drug
candidates and agrochemicals.1 To date, transition-metal-
catalyzed alkyne hydroselenation is a practical and efficient
method for vinyl selenide synthesis.2 Palladium-catalyzed
carboselenation of alkynes with sulfenamides and diselenides
to prepare β-selenyl acrylamides has also been reported.3 Most
recently, Baidya developed an efficient Ru-catalyzed C−H
selenylation of maleimides with diselenides via an umpolung
protocol (Scheme 1A).4 However, the use of readily available
starting material for preparation of structurally diverse
In continuing our study toward diverse utility of Se powder,6
we envisaged developing copper-catalyzed four-component
cross-coupling of aryl iodides, Se powder, maleimides, and
amines (Scheme 1B). As part of our design, we speculated that
enamides and arylselenocopper species could be generated on
the basis of distinct mechanisms of copper-catalyzed reactions
in a one-pot manner and then two competent intermediates
undergo selective cross-coupling to afford the corresponding
product. However, a formidable challenge in this approach is
to overcome a number of competitive reactions, including
copper-catalyzed Ullmann amination,7 seleno-Michael addi-
tion,8 selenation of maleimides,9 and homocoupling10 (Scheme
1C). As a result, this transformation establishes a useful
approach to access arylselenoamination of maleimides via one
C−N bond and double C−Se bond formation processes.
Furthermore, this protocol provides a complementary scope
for the existing three-component aminoarylselenation of
alkynes.11
Scheme 1. Copper-Catalyzed Four-Component Cross-
Coupling
We initially chose iodobenzene 1a, Se powder, N-
methylmaleimide 2a, and morpholine 3a as model substrates
to examine the feasibility of copper-catalyzed four-component
Received: December 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03980
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
cross-coupling reactions. To our delight, it was found that the
desired product 4a was isolated in 85% yield along with a small
amount of diphenyl diselenide when the reaction was
performed using Cu(OAc)2 as a catalyst and Na2CO3 as a
base in NMP under an O2 atmosphere at 120 °C (Table 1,
Scheme 2. Secondary Amines Scope
a
Table 1. Reaction Optimization
b
entry
alteration
yield (%)
1
2
3
4
5
6
7
8
none
85
0
0
CuCl2 instead of Cu(OAc)2
CuBr2 instead of Cu(OAc)2
Cu(TFA)2 instead of Cu(OAc)2
CuI instead of Cu(OAc)2
Li2CO3 instead of Na2CO3
K2CO3 instead of Na2CO3
Cs2CO3 instead of Na2CO3
DMSO instead of NMP
CH3CN instead of NMP
toluene instead of NMP
Phen (0.02 mmol) as additive
under N2
0
64
55
trace
0
60
0
0
48
0
a
Reaction conditions: Table 1, entry 1. Isolated yields after column
chromatography are given.
9
substrate and provided the desired product in good yield. We
were pleased to find that unprotected 4-hydroxypiperidine
(4g) could be alkenylarylselenated successfully to access 3-
amino-4-selenomaleimide with high efficiency. Notably, a wide
range of acyclic secondary amines were smoothly accom-
modated; N-methyl cyclohexylamine (4e) and N-methylpen-
tylamine (4i) could be used as aminating reagents. In addition,
N-methyl benzylamines (4j−4l) were feasible in the current
reaction conditions, providing the corresponding products in
excellent yields. However, primary alkyl amines, anilines, and
electron-deficient amide could not take part in this trans-
formation, indicating that the nucleophilicity of amines played
an essential role in promoting the reaction.
10
11
12
13
14
15
no Na2CO3
no Cu(OAc)2
0
0
a
Reaction conditions unless specified otherwise: 1a (0.6 mmol), Se8
(0.6 mmol), 2a (0.2 mmol), 3a (0.3 mmol), catalyst (0.02 mmol),
Na2CO3 (0.8 mmol), NMP (1.0 mL), under O2 atmosphere, 120 °C,
18 h. Isolated yield.
b
entry 1). Remarkably, the Ullmann amination, selenation of
maleimides, and seleno-Michael addition with elemental
selenium were not observed at all under the optimized
reaction conditions. Following encouraging results, a variety of
copper catalysts were examined. Other Cu(II) salts, such as
Cu(TFA)2, CuCl2, and CuBr2, were ineffective; only CuI could
afford a comparable yield (entries 2−5). The influence of base
was next assayed; the desired reactions could be completely
inhibited by switching Na2CO3 to a stronger base, such as
K2CO3 and Cs2CO3 (entries 7 and 8). It is worth noting that
the choice of solvent is critical for the success of trans-
formation. Only polar solvents are beneficial for the reaction
efficiency; other apolar and weak coordination solvents were
unsuitable (entries 9−11). The addition of Phen as a ligand
did not enhance the reaction outcome (entry 12). What is
more, this reaction is very sensitive to N2 atmosphere (entry
13). Furthermore, no product was detected in the absence of
base (entries 14); perhaps base was serving as an activator of
elemental selenium and assisting Michael addition of
secondary amine with maleimide. No desired product was
formed without copper catalyst, thus demonstrating that
copper played an indispensable role in promoting the reaction
(entry 15).
Subsequently, a variety of aryl iodides were examined under
the current copper-catalyzed double C−Se bonds and C−N
bond formation protocol, the results were summarized in
Scheme 3. It was found that aryl iodides bearing electron-
donating substituents (5b−5d, 5h, and 5i) displayed a higher
a
Scheme 3. Aryl Iodides Scope
With the optimal reaction conditions in hand, we set out to
explore the scope of amines which could be employed in this
protocol (Scheme 2). It was found that an array of cyclic
secondary amines were successfully engaged in this trans-
formation, including thiomorpholine (4b), pyrrolidine (4c),
and piperidine (4f−4h). Azepane (4d) was also a viable
a
Reaction conditions: Table 1, entry 1. Isolated yields after column
chromatography are given.
B
DOI: 10.1021/acs.orglett.8b03980
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Letter
reactivity than those with electron-deficient substituents (5e,
5m−5o), implying that the efficiency of transformation is the
hinge on the nature of substituents on the benzene ring. In
addition, 2-iodonaphthalene (5a) proceeded smoothly and
gave the corresponding product in excellent yield. Moreover,
the sterically hindered substrate (5c) also worked well and
produced the anticipated product in satisfactory yield. It is
worth mentioning that typical functional groups, including
methyl (5b−5d), trifluoromethyl (5e, 5n), fluoro (5j), chloro
(5f, 5k), bromo (5g, 5l), nitro (5m), and cyan (5o), were all
well tolerated, providing a good opportunity for further
transformation via well-developed cross-coupling reactions.
Besides aryl iodides, 3-iodothiophene can also be utilized as a
coupling partner for the current four-component cross-
coupling reaction.
Scheme 5. Thioamination of Maleimide and Late-Stage
Alkenylarylselenation of Atomoxetine
Scheme 6. Preliminary Mechanism Investigation
Next, we turned our attention to examining the viability of
various maleimides under the optimal reaction conditions
(Scheme 4). To our delight, free maleimide (6a) was a
a
Scheme 4. Maleimides Scope
a
Reaction conditions: Table 1, entry 1. Isolated yields after column
chromatography are given.
competent substrate and gave the corresponding product in
acceptable yield. Generally, N-substituted maleimides were
readily aminophenylselenated to deliver the corresponding
products in fair to good yields. The copper-catalyzed
aminoarylselenation of maleimides displayed good functional
group tolerance on the benzene ring of N-aryl maleimides,
including methyl (6f), methoxy (6g), fuloro (6h), chloro (6i),
bromo (6j), and trifluoromethyl (6k), providing a useful
synthetic handle for further elaboration of selenium-containing
products. Moreover, thiophene-substituted maleimide was also
amenable to the current reaction conditions and afforded the
target product in 82% yield.
As shown in Scheme 5, the versatile application of the
synthetic protocol was further demonstrated by employing S8
powder as a sulfur source for the corresponding thioamination
of maleimide to provide the corresponding product 7a in 57%
under slightly modified reaction conditions. This strategy
provides additional evidence for the late-stage transformation
of bioactive molecules, such as Atomoxetine,12 a norepinephr-
ine reuptake inhibitor, selectively alkenylarylselenated to give
the expected product 7b in excellent yield, making it of interest
in selenium-containing pharmaceutical research.
affect the efficiency of transformation (eq 1), which indicated a
radical-mediated pathway could be ruled out. Second, oxidative
amination product was isolated in 94% yield when N-
phenylmaleimide was treated with morpholine under the
optimized reaction conditions (eq 2). In contrast, when a
mixture of iodobenzene, Se powder, and maleimide was stirred
for 18 h, there was no seleno-Michael additiion product (eq 3).
To further exclude the possibility of selenation of enami-
none,13 the reaction between Se powder and 8a was also
conducted (eq 4). Moreover, the product 6b was obtained in
79% yield when the iodobenzene, Se powder, and 8a were
subjected to the standard reaction conditions (eq 5). On the
basis of these results, we reasoned that enaminone is involved
in this reaction and ArSeCu species may be the key
intermediate, which was directly supported by the stoichio-
metric reactions between 8a and PhSeCu14 under an O2
atmosphere (eq 6). Furthermore, the use of PhSeCu as
catalyst led to a good yield of 6b (eq 7). These results suggest
that copper plays multiple roles in promoting this reaction.
On the basis of the above experimental observations, a
plausible reaction mechanism for copper-catalyzed four-
component cross-coupling is proposed in Scheme 7. First,
aza-Michael addition and copper-catalyzed dehydrogenation of
maleimides with secondary amines afford intermediate B.15 In
parallel, the oxidative addition of aryl iodides with copper
catalyst to produce C and then species C undergoes ligand
To identify the reaction sequence of the four-component
cross-coupling reaction via copper relay catalysis, some control
experiments were designed, as shown in Scheme 6. First, we
found that the addition of radical inhibitor did not significantly
C
DOI: 10.1021/acs.orglett.8b03980
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Project of Zhejiang Provincial Top Key Discipline of
Pharmaceutical Sciences (201723) is greatly appreciated.
Scheme 7. Proposed Mechanism
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details, see the Supporting Information).
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iodides, Se powder, maleimides, and secondary amines,
providing a concise and efficient pathway to access an array
of difunctionalized maleimides. This protocol enables two C−
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03980.
1H and 13C NMR spectra of all new compounds and the
experimental procedures (PDF)
(14) Taniguchi, N. Synlett 2005, 1687.
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Commun. 2013, 49, 1729.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wuge@wmu.edu.cn.
ORCID
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Ge Wu: 0000-0001-8432-5272
Notes
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), State Key Laboratory of
Structural Chemistry (No. 20170037), and the Opening
D
DOI: 10.1021/acs.orglett.8b03980
Org. Lett. XXXX, XXX, XXX−XXX