Mn(ii)-Catalysedortho-alkenylation of aromatic amines and its application in reproductive diseases

Article abstract of DOI:10.1039/d0ra10172a

A Mn(ii)-catalysedortho-alkenylation of aromatic amines and its application in reproductive diseases were developed. The use of MnCl₂was critical for theortho-alkenylation of aromatic amines. The general applicability of this procedure was high

Full text of DOI:10.1039/d0ra10172a

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Mn(II)-Catalysed ortho-alkenylation of aromatic
amines and its application in reproductive diseases†
Cite this: RSC Adv., 2021, 11, 164
Jinfei Yang, ‡* Xiaolong Wu,‡ Banghua Yang, Yirong Liu, Rui Cheng, Zijun Gong
and Fei Sun*
A Mn(II)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases were
2
developed. The use of MnCl was critical for the ortho-alkenylation of aromatic amines. The general
applicability of this procedure was highlighted by the synthesis of 27 vinylanilines, with good
regioselectivities. The value of our approach in practical applications was investigated by studying the
effects of one of the compounds 3m on 8 week-old adult male rats with azoospermia as a mammalian
model. The results show that a small amount of sperm will gradually be produced in the epididymis and
À1
testes by treatment of 8 week-old adult male rats with azoospermia with 1 mg kg 3m after two weeks,
Received 2nd December 2020
Accepted 7th December 2020
À1
while treatment with 10 mg kg 3m led to obvious sperm production. Notably, if we increase the dose
À1
to 100 mg kg , there will be a lot of sperm production in the epididymis and testes after two weeks of
DOI: 10.1039/d0ra10172a
treatment. The results of this study will be of great significance in research on drugs for treating
rsc.li/rsc-advances
azoospermia and oligospermia diseases.
Alkenyl arylamines are very important intermediates for the Ackermann's research group reported several Mn(II)-catalyzed
1
9
synthesis of drug molecules, such as carbamazepine, opipra- ortho-functionalization reactions of arylamides. In addition,
2
3
mol, and indopan (Scheme 1). O-Alkenyl arylamines have a Mn(II)-catalysed dehydrogenative annulation of N-aryl anilines
attracted much attention because of their widespread presence with alkenes or alkynes was reported by our group last year.
in a variety of heterocycles including indoles, quinolines and Herein, we report an example of Mn(II)-catalysed ortho-alke-
10
cinnolines, which are key structural units for many biologically nylation of aromatic amines and its application in reproductive
4
important compounds. Moreover, they have also been used as diseases (Scheme 2). In our previous work, divalent manganese
5
10
synthetic intermediates in several total synthetic methods.
is easily oxidized to tetravalent manganese by K
2
S
2
O
8
.
This
Therefore, it is of great signicance to carry out the ortho-alke- work, we hypothesis the ortho-alkenylation product of aromatic
nylation reaction of aromatic amines. But it is not an easily amine will be generated aer the oxidant was removed in the
accessible process under normal Friedel–Cras conditions due system. Based on this hypothesis, we tried a series of manga-
to the coordination of the Lewis acid with the nitrogen atom of nese catalysts.
amino group, which leads to the deactivation of the aromatic
ring. To overcome this challenge, chemists began to try other with toluene as a solvent. Initially, we attempted using various
We began by treating N-benzylaniline and phenylacetylene
6
methods to achieve ortho-alkenylation of aromatic amines. Mn(II) catalysts to catalyse the ortho-alkenylation of aromatic
ꢀ
Subsequently, several related ortho-alkenylation of aromatic amines at 120 C, i.e., MnO, MnSO
amines with phenylacetylene was reported in the literature.
4
, Mn(OAc)
2
, and Mn(acac)
2
,
4
a,7
as detected by GC analysis, while 73% and 61% yields were
However, the ortho-alkenylation of aromatic amines catalyzed observed when MnBr and MnI were used as catalysts (Table 1,
2
2
by base metals has not yet been developed, especially manga- entries 1–7). Fortunately,
a 80% yield of N-benzyl-2-(1-
nese. Therefore, it is still very important to develop a Mn-
catalyzed ortho-alkenylation reaction of aromatic amines.
Notably, there have been more C–H bond functionalization
reactions catalyzed by monovalent manganese in recent years,
8
but few of them were catalyzed by divalent manganese.
Medical School, Institute of Reproductive Medicine, Nantong University, Nantong
2
†
1
‡
26019, China. E-mail: jfyang@ntu.edu.cn; sunfei@ntu.edu.cn
Electronic supplementary information (ESI) available. See DOI:
0.1039/d0ra10172a
Scheme 1 Drug molecules containing alkenyl arylamine skeleton.
J.-F. Y. and X.-L. W. contributed equally to this work.
164 | RSC Adv., 2021, 11, 164–167
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benzyl-2-(1-phenylvinyl)aniline was obtained the best yield. It is
worth noting that more cyclization products were formed when
ꢀ
the temperature is raised to 130 C. Therefore, temperature is
another key factor that drives the reaction forward. Notably, the
addition of oxidant will terminate this reaction (see the ESI
Table 1† for details). These results therefore support our initial
hypothesis that the ortho-alkenylation product of aromatic
amine will be generated aer the oxidant was removed.
With the optimum reaction conditions in hand, a series of
aromatic amine were investigated for extending the substrate
scope (Scheme 3). This Mn(II)-catalysed ortho-alkenylation of
aromatic amines shows good functional group tolerance.
Scheme 2 Proposed strategy.
2
phenylvinyl)aniline was obtained when using MnCl . To
improve the reaction efficiency, different solvents, including
N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
acetonitrile (CH CN), 1,4-dioxane, tetrahydrofuran (THF), 1,2-
3
dichloroethane (DCE), p-xylene, mesitylene and n-hexane were
tested (Table 1, entries 8–16). The optimal reaction solvent was
found to be toluene. To increase conversion to the N-benzyl-2-
(1-phenylvinyl) aniline, we examined a wide range of reaction
temperatures (Table 1, entries 17–22). The results show that
ꢀ
1
20 C was the optimum temperature, and the corresponding N-
Table 1 Effects of catalyst, temperature, and solvent. N-Benzylaniline
(
(
0.2 mmol), phenylacetylene (0.4 mmol), catalyst (0.04 mmol), solvent
2.0 mL), at 120 C for 24 h
ꢀ
ꢀ
b
Entry
Catalyst
Solvent
T ( C)
Yield 3a (%)
1
2
3
4
5
6
7
8
9
Mn(OAc)
MnO
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
80
20
0
0
50
73
61
80
0
MnSO
Mn(acac)
4
2
MnBr
MnI
2
2
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
MnCl
None
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
DMSO
0
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH
3
CN
Dioxane
THF
DCE
28
14
26
50
52
10
12
29
51
63
70
63
0
p-Xylene
Mesitylene
n-Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
90
100
110
130
140
120
c
a
b
Scheme 3 Reaction conditions: substrate 1 (0.2 mmol), aryl acetylene
The reactions were carried out in sealed tubes. Yields were
c
ꢀ
determined by GC analysis. Without MnCl
2
.
(0.4 mmol), MnCl
2
(0.04 mmol), toluene (2.0 mL), at 120 C for 24 h,
and isolated yields for products.
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2021 The Author(s). Published by the Royal Society of Chemistry
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Aromatic amine with electron-neutral or electron-donating
groups such as alkyl, phenyl, and methoxy on the aryl rings
all gave the corresponding ortho-olenation products with high
selectivities and in good yields. Aryls containing an electron-
withdrawing group such as chloro, and bromo were also toler-
ated and afforded the corresponding ortho-olenation products
3v–3ab in moderate yields with highly ortho-selectivities.
Moreover, the reaction of aromatic amine containing naphthyl
of the aromatic rings also gave the corresponding ortho-ole-
nation products 3k and 3l in good yields. Unfortunately, it does
not give good yields for meta-substituted aromatic amines.
In addition, aryl acetylene with electron-neutral or electron
donating groups such as alkyl and anthryl on the aryl rings all
gave the corresponding ortho-olenation products with high
selectivities and in good yields. Aryls containing an electron-
withdrawing group such as uoro, chloro, bromo and tri-

uoromethyl were also tolerated and afforded the corresponding
ortho olenation products 3b–3e, 3i, 3j, 3l, 3m, 3s–3u, 3w and 3z
in moderate to good yields. More importantly, retention of the Scheme 5 Biological activity evaluation test in spermatogenesis.
uorine, chlorine, and bromine atoms in the products makes the
products of considerable use in organic transformations.

To verify the potential of 3m in promoting spermatogenesis,
The synthetic utility of the current method was tested by we study the effects of 3m, with 8 week-old adult male rats with
performing a gram-scale ortho-alkenylation of aromatic amines azoospermia as a mammalian model (Scheme 5). The test
under the optimum conditions. The target N-benzyl-4-methoxy- results show that a small amount of sperm will gradually be
2
-(1-(4-(triuoromethyl)phenyl)vinyl)aniline 3m was obtained produced in the epididymis and testis by treatment of 8 week-
À1
in 73% yield (Scheme 4).
old adult male rats with azoospermia with 1 mg kg 3m aer
À1
Azoospermia is the medical condition of a man whose semen two weeks later, and treatment with 10 mg kg 3m led to
11
contains no sperm. Pre- and post-testicular azoospermia are obvious sperm production. To our delight, a lot of sperm will be
frequently correctible, while testicular azoospermia is usually produced in the epididymis and testis aer four weeks. Notably,
1
2
À1
permanent. In humans, azoospermia affects about 1% of the if we increase its dose to 100 mg kg , there will be a lot of
male population and may be seen in up to 20% of male infertility sperm production in the epididymis and testis aer two weeks
13
situations in Canada. However, there is no specic drugs for of treatment. In addition, to exclude the inuence of DMSO, we
azoospermia currently on the market. The empirical drug made a group of control test, and the test results showed that
14
commonly used in clinical practice is clomiphene. Clomiphene the sperm number has no change in epididymis and testis. So
is a non-steroidal drug with a chemical structure similar to DMSO has no effect on spermatogenesis. Accordingly, we have
diethylstilbestrol. Its mechanism of action may be that the discovered a drug molecule that can effectively promote sper-
molecule competitively occupies the ER, thereby blocking the matogenesis. The results of this study will be of great signi-
negative feedback effect of circulating endogenous estradiol, cance in research on drugs for treating azoospermia and
leading to increased secretion of GnRH released by the hypo- oligospermia diseases.
thalamus, stimulating the secretion of FSH and LH, and
Additional experiments were performed to gain a better
promoting spermatogenesis. Although it has been widely used by understanding of the roles of MnCl in the ortho-alkenylation of
2
clinicians, clinical studies show that long-term use of clomi- aromatic amines. Control experiments showed that the absence
phene may increase the risk of cancer. Therefore, it is necessary of MnCl2 shut down the reaction (Table 1, entry 23). These
to develop a safer drug that can replace clomiphene. Given that results imply that MnCl2 is essential to this reaction. We
the structure of the 3m is similar to clomiphene, we envision that propose the catalytic cycle shown in the ESI.† Phenylacetylene
3m may also have the effect of promoting spermatogenesis.
and aromatic amine rst undergoes ligand coordination with
the metal center, and subsequent electrophilic addition with
aromatic amine provides an intermediate A. and then the target
product is obtained through proton migration, with regenera-
tion of the catalytic Mn(II) (see the ESI Fig. 1† for details).
Conclusions
In summary, we have developed a highly efficient Mn(II)-cata-
lysed ortho-alkenylation of aromatic amines and its application
in reproductive diseases. This method is safer, more
Scheme 4 Gram-scale synthesis.
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convenient, and more economical than traditional strategies. It
is compatible with a range of functional groups and is suitable
for gram-scale reactions. The value of our approach in practical
applications was shown by studying the effects of treatment
with 3m, with 8 week-old adult male rats with azoospermia as
a mammalian model. The test results show that 3m signicantly
affect spermatogenesis. The results of this study will be of great
signicance in research on drugs for treating azoospermia and
oligospermia diseases. Further investigations of the drug
molecular mechanism of action, and other reaction types are
underway in our laboratory.
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Ethical statement
1
All animal procedures were performed in accordance with the
Guidelines for Care and Use of Laboratory Animals of Nantong
University and Experiments were approved by the Animal Ethics
Committee (approval no. 20171220-005).
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the National Key Research and Development Program
of China (2018YFC1003500 to F. S.), the High Level Talent
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