Haloamines as Bifunctional Reagents for Oxidative Aminohalogenation of Maleimides

Article abstract of DOI:10.1021/acs.orglett.1c01052

An unprecedented copper-catalyzed oxidative aminohalogenation of electron-deficient maleimides with secondary amines and NXS (X = Cl, Br, I) was developed, in which the N-X bonds generated in situ were used as difunctionalized reagents. The distinctive features of this multicomponent reaction include a simple green catalytic system, a spectral substrate range, and the late-stage modification of drug molecules. Most importantly, this umpolung radical cascade strategy exploits the in situ formation of N-iodoamines that enable efficient alkene aminoiodination.

Full text of DOI:10.1021/acs.orglett.1c01052

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Letter
Haloamines as Bifunctional Reagents for Oxidative
Aminohalogenation of Maleimides
Xueying Zhou, Yujing Yao, Caihong Wang, Yaling Xu, Wenliang Zhang, Yunfei Ma, and Ge Wu*
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ABSTRACT: An unprecedented copper-catalyzed oxidative amino-
halogenation of electron-deficient maleimides with secondary amines
and NXS (X = Cl, Br, I) was developed, in which the N−X bonds
generated in situ were used as difunctionalized reagents. The
distinctive features of this multicomponent reaction include a simple
green catalytic system, a spectral substrate range, and the late-stage
modification of drug molecules. Most importantly, this umpolung
radical cascade strategy exploits the in situ formation of N-
iodoamines that enable efficient alkene aminoiodination.
because of their strong affinity with transition-metal salts, has
not been explored.
rom marine natural products, to candidate pharmaceut-
Ficals, to materials science, β-halogenated enamine scaffolds
have been utilized as both valuable handles and target
compounds.1 Among the developed synthetic approaches,2
the intermolecular catalytic oxidative aminohalogenation of
alkenes is one of the most promising and step-economic
protocols to effectively construct these privileged compounds.
Although a significant number of reports have been made
along this avenue, mainly using palladium as catalysts, the
feasible nitrogen sources are limited to electron-poor anilines
and NH-sulfoximines (Scheme 1A).3 In contrast, the use of
electron-rich alkylamines as coupling partners, which usually
prevents the intermolecular aminofunctionalization reaction
On the contrary, using haloamines as difunctionalized
reagents would be a more attractive strategy. Both halogens
and structurally diverse amine functional groups could be
simultaneously incorporated into organic molecules.4 The Li
group has developed a palladium-catalyzed aminochlorination
of internal alkynes with N,N-dichlorobenzenesulfonamide
(Scheme 1B).5 Terminal alkynes could be converted into
halogenated enamines by DBU-activated N-haloimides.6 It is
indeed supplemental and beyond the scope of the current
pathways for the preparation of β-halogenated enamines;
however, the direct oxidative aminohalogenation of alkenes
with N−X bonds still has not been reported. Herein we
describe the development of the copper-catalyzed oxidative
aminohalogenation of electron-deficient maleimides with full-
spectrum secondary amines and NXS in a single flask (Scheme
1C). Overall, this one-pot multicomponent reaction not only
provides a rapid and efficient method to access the
aminohalogenated maleimides with the formation of C−N
and C−X (X = Cl, Br, I) bonds but also offers a facile approach
to install drug-containing secondary amines into maleimide
skeletons to advance novel drug research. Most importantly,
in-situ-generated N−I bonds were used as difunctionalized
reagents and enabled the synthesis of iodinated enamines that
were difficult to access or inaccessible by previous methods.7
Scheme 1. Motivation and Copper-Catalyzed Oxidative
Aminohalogenation of Maleimides
Received: March 27, 2021
Published: April 12, 2021
https://doi.org/10.1021/acs.orglett.1c01052
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3669−3673
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a
To test the feasibility of the copper-catalyzed radical cascade
strategy for three-component C−N and C−Cl coupling
reactions, N-phenylmaleimide 1a, morpholine 2a, and N-
chlorosuccinimide (NCS) were chosen as the model substrates
in the presence of copper salt (Table 1). A N−Cl bond was
Scheme 2. Scope of Alkylamines
a
Table 1. Reaction Optimization
b
entry
variation
yield %
1
2
3
4
5
6
7
8
none
90
0
75
33
0
CuCl2 instead of CuCl
CuI instead of CuCl
Cu(OAc)2 instead of CuCl
FeCl3 instead of CuCl
Ni(OAc)2·4H2O instead of CuCl
DMSO instead of toluene
CH3CN instead of toluene
DCE instead of toluene
Ag2CO3 (0.4 mmol) as oxidant
Phen (0.02 mmol) as additive
under air
0
0
a
Reaction conditions, unless specified otherwise: 1a (0.2 mmol), 2
(0.6 mmol), NCS (0.6 mmol), and CuCl (0.02 mmol) in toluene (2.0
mL) were stirred at room temperature under O2 for 1 h; then, the
reaction mixture was heated to 100 °C for 24 h. Isolated yields are
given.
22
68
0
38
0
9
10
11
12
13
14
under N2
no CuCl
0
0
secondary amines (2a−2h), and the corresponding products
3a−3h were isolated in excellent yields. Many medically
relevant functional groups, including morpholine (3a),
piperidine (3b, 3c, 3g), piperazine (3d, 3e), and pyrrolidine
(3h), are well accommodated in this transformation. In
addition, the sterically hindered hexamethylenimine also reacts
smoothly with N-phenylmaleimide and NCS to afford the
corresponding product 3f in satisfactory yield. To our delight,
ester and Boc groups, which are usually fragile under strongly
acidic solutions, could be well tolerated, which showcases the
practical application of the current catalytic protocol. In
addition, the acyclic secondary amines (2i−2l) are also
amenable to vinylchlorination, suggesting the versatility and
compatibility of the current reaction conditions. N-Methyl
benzylamine substrates bearing halo groups (3k, 3l) could be
utilized for further transformation via classical cross-coupling
reactions. Regrettably, primary alkylamines, anilines, amides,
and sulfamides were quite unreactive, and no corresponding
products were detected even after extensive optimization of the
reaction parameters. The most likely explanation is the
decomposition of primary alkyl amines under oxidative
reaction conditions and the poor nucleophilicity of electron-
deficient aminating reagents.
Next, we turned our attention to evaluate the feasibility of
N-substituted maleimides by using the optimized reaction
condition (Scheme 3). Overall, the copper-catalyzed oxidative
aminochlorination of structurally diverse N-substituted mal-
eimides (1a−1l) proved to be of good versatility and good
tolerance, and the desired products (4a−4l) were produced in
pleasing yields. It is worth noting that N-methyl maleimides
could take part in this transformation to give the target product
4a in good yield. Importantly, many synthetic useful functional
groups on the aryl ring of N-benzyl maleimides, including
methyl (4d), methoxy (4e), halogen moiety (4f−4h), and
trifluoromethyl (4i), were well tolerated to deliver the
corresponding product. Thus these target products provide a
new opportunity for further derivatization by known cross-
a
Reaction conditions, unless specified otherwise: 1a (0.2 mmol), 2a
(0.6 mmol), NCS (0.6 mmol), and CuCl (0.02 mmol) in toluene (2.0
mL) were stirred at room temperature under O2 for 1 h; then, the
reaction mixture was heated to 100 °C for 24 h. Isolated yield.
b
formed in situ by simply reacting NCS and 2a at room
temperature for 1 h; then, the reaction mixture was heated to
100 °C for 24 h. To our delight, the maleimide amino-
chlorination occurred quite efficiently using CuCl as the
catalyst and toluene as the solvent under an oxygen
atmosphere, and the expected product 3a was isolated in
90% yield (Table 1, entry 1). As shown in Table 1, the
judicious choice of transition-metal catalysts, solvent, additive,
and oxidant was found to be a critical success for this
multicomponent reaction. The use of CuI could provide a
comparable yield, whereas the use of CuCl2 as a catalyst
completely inhibited the reaction (entries 2 and 3). However,
redox metal salts, such as FeCl3 and Ni(OAc)2·4H2O, were
unsuitable for catalyzing the present aminochlorination of
maleimide (entries 5 and 6). It was noteworthy that polar
solvents (such as DMSO and DMF) were unable to promote
the conversion of starting materials. In contrast, other weak
coordination or apolar solvents worked relatively well (entries
7−9). In addition, the use of silver salt as an oxidant almost
inhibited the transformation, and the addition of 1,10-phen as
a ligand drastically decreased the yield of the desired product
(entries 10 and 11). Furthermore, when the reaction was
conducted without a copper catalyst or under N2, 3a could not
be produced, which indicated that the copper catalyst and
oxygen played indispensable roles in promoting the three-
component radical cascade reaction (entries 12−14).
With the robust reaction condition in hand, we examined
the amine scope of the present three-component oxidative
aminohalogenation. As shown in Scheme 2, the reaction
proved to be versatile and amenable to a wide range of cyclic
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a
Scheme 3. Maleimide Scope
Scheme 4. Late-Stage Modification of Pharmaceuticals
a
Reaction conditions, unless specified otherwise: 1 (0.2 mmol), 2a
(0.6 mmol), NCS (0.6 mmol), and CuCl (0.02 mmol) in toluene (2.0
mL) were stirred at room temperature under O2 for 1 h; then, the
reaction mixture was heated to 100 °C for 24 h. Isolated yields are
given.
Scheme 5. Preliminary Mechanism Investigation
coupling methods. Notably, maleimides bearing a thiophene
skeleton (4k) could efficiently participate in aminochlorina-
tion. Shortly afterward, we examined the ability of a series of
alkenes, including styrenes, methyl acrylate, ethene-1,1-
diyldibenzene, and dimethyl maleate. The reaction did not
provide any aminohalogenation products, which clearly
indicated that the unique reactivity of maleimides played a
pivotal role in this transformation.
The practical utility of the current strategy has been
demonstrated in the late-stage functionalization of nitrogen-
containing drugs.8 As shown in Scheme 4A, atomoxetine9
(trade name: Strattera), a selective norepinephrine (NE)
reuptake inhibitor, was selectively vinylchlorinated on a N-Me
group in good yield. Fluoxetine10 is a second-generation
antidepressant that could also undergo the expected trans-
formation to afford the corresponding product with high
efficiency. Encouraged by the versatility of the copper-
catalyzed aminochlorination of maleimides, we then evaluated
the feasibility of intermolecular aminobromination, and we
were glad to obtain the expected product in high yield. Also,
this one-pot, three-component radical chain reaction was
particularly useful because N-iodoamines are too unstable to
be isolated, as illustrated in the aminoiodination of maleimides
(Scheme 4B). The effective installation of iodine atoms on the
maleimide skeleton could be used as a means of further
transformation through matured cross-coupling reactions.
Finally, the practical standpoint of the one-pot, copper-
catalyzed aminohalogenation was applicable to the gram-scale
reaction, as shown in Scheme 4C.
reaction conditions to isolate the expected product in excellent
yield (Scheme 5, entries 1 and 2). This result clearly indicates
that the three-component reaction is initiated by the activation
of amines with NXS.11 Second, we aimed to elucidate the
activation patterns of N−X in the presence of copper salt.
Pathway A involves single-electron transfer between N-
chloroamines and Cu(I) salt to generate N-radical species
and a Cu(II) intermediate.12 Alternatively, the N−X bonds
undergo oxidative addition toward Cu(I) to form the Cu(III)
intermediate (Pathway B).13 To distinguish these possible
pathways in the current reaction, we conducted free-radical
trapping experiments. With the addition of 3.0 equiv of
TEMPO, the aminochlorination of maleimide was completely
Given the generality of the copper-catalyzed, three-
component aminohalogenation of maleimides, some control
experiments were designed to shed substantial light on the
mechanism of one-pot, three-component coupling (Scheme 5).
First, the reactive intermediate N-chloroamine was detected by
1H NMR and cross-coupled to maleimide under the standard
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Letter
suppressed (Scheme 5, entry 3). Meanwhile, the butylated
hydroxytoluene (BHT)-captured product was detected by GC-
MS, and the result showed that under the current reaction
conditions, the N-radical might be generated in the trans-
formation process (Scheme 5, entry 4). Therefore, these
experimental results support the notion that the most likely
reaction mechanism scenario is Pathway A.
On the basis of these experimental findings and the relevant
literature, we proposed a plausible reaction mechanism for the
copper-catalyzed dehydrogenative aminohalogenation of mal-
eimides in Scheme 6. Initially, the electrophilic chlorination of
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
Authors
Xueying Zhou − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Scheme 6. Proposed Mechanism
Yujing Yao − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Caihong Wang − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Yaling Xu − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
Wenliang Zhang − School of Pharmaceutical Sciences,
Wenzhou Medical University, Wenzhou 325035, People’s
Republic of China
Yunfei Ma − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, People’s Republic of
China
secondary amines with NXS provides reactive N-halo amines.
After that, the reaction of N−X bonds with a copper catalyst
forms the N-radical species A and the Cu(II) intermediate
through the single-electron transfer process. The resulting
nucleophilic aminyl radical undergoes the radical nucleophilic
addition14 to maleimide to produce a carbon radical B, then
the recombination of B with the generated key intermediate
Cu(II) to generate the important intermediate C, followed by
reductive elimination to afford the aminohalogenation product
D and the release of the copper center. Finally, substance D
undergoes oxidative dehydrogenation to give the correspond-
ing product.15 However, an alternative pathway is that B reacts
with N−X to produce intermediate D;16 then, copper-
catalyzed oxidative dehydrogenation15a proceeds to provide
the expected product, which also could not be excluded.
In summary, we have developed a direct and efficient
method for the copper-catalyzed aminohalogenation of
maleimides with NXS and secondary amines. The obvious
features of this one-pot, two-step reaction are the use of in-situ-
generated N-haloamines as difunctionalized reagents, the
synthetic simplicity, the excellent functional group tolerance,
the simple and green catalytic system, and the amenability for
the late-stage modification of amine-containing pharmaceut-
icals, which will advance the discovery of novel drugs. This
radical cascade reaction not only opens a new prospect for the
synthetic application of N−X bonds as both aminating and
halogenating reagents but also provides a complement to the
current palladium-catalyzed oxidative aminohalogenation of
electron-deficient alkenes.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01052
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (81803484, 21602158), the Zhejiang
Provincial Natural Science Foundation (LY19B020011,
LTQ20B010001, LQ18B010003), the State Key Laboratory
of Structural Chemistry (no. 20200008), and the Public
Welfare Science and Technology Project of Wenzhou (no.
Y20180233) is greatly appreciated.
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