Al(OTf)3-Catalyzed Tandem Coupling Reaction between N,N-Disubstituted Aminomalonitriles and Substituted Arenes: a Synthesis of 1-Cyano-bisindolylmethane Analogues≠

Article abstract of DOI:10.1002/adsc.202000261

A synthesis of 1-cyano-bisindolylmethane analogues via an Al(OTf)₃-catalyzed tandem coupling reaction between N,N-disubstituted aminomalonitriles and substituted arenes has been developed. This method not only provides an alternative synthetic strategy for the synthesis of corresponding functional molecules, but also enriches the volume of bisarylmethanes library to facilitate related functional studies. (Figure presented.).

Full text of DOI:10.1002/adsc.202000261

Title: Al(OTf)3-Catalyzed Tandem Coupling Reaction between N,N-
Disubstituted Aminomalonitriles and Substituted Arenes: a
Synthesis of 1-Cyano-bisindolylmethane Analogues
Authors: Lin-Sheng Lei, Bo-Wen Wang, Da-Ping Jin, Zhu-Peng Gao,
Huan Liang, Shao-Hua Wang, Xue-Tao Xu, kun zhang, and
Xiao-Yun Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000261
Link to VoR: https://doi.org/10.1002/adsc.202000261

10.1002/adsc.202000261
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Al(OTf)3-Catalyzed Tandem Coupling Reaction between N,N-
Disubstituted Aminomalonitriles and Substituted Arenes: a
‡
Synthesis of 1-Cyano-bisindolylmethane Analogues
Lin-Sheng Lei,a† Bo-Wen Wang,a† Da-Ping Jin,a Zhu-Peng Gao,a Huan-Liang,a Shao-
Hua Wang, ab* Xue-Tao Xu,b Kun Zhang,b Xiao-Yun Zhang a*
a
School of Pharmacy & State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000 (P.
R. China)
Email: wangshh@lzu.edu.cn; zhangxiaoy@lzu.edu.cn
School of Biotechnology and Health Science, Wuyi University, Jiangmen 529020 (P. R. China)
Contribute equally to this work. ‡Patent pending, Chinese patent application (no. 202010218028.8).
b
†
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 synthesis of 1-cyano-bisindolylmethane
analogues via an Al(OTf)3-catalyzed tandem coupling
reaction between N,N-disubstituted aminomalonitriles and
substituted arenes has been developed. This method not
only provides an alternative synthetic strategy for the
synthesis of corresponding functional molecules, but also
enriches the volume of bisarylmethanes library to facilitate
related functional studies.
Keywords: tandem reaction; 1-cyano-bisindolylmethane;
N,N-disubstituted aminomalonitriles; bisarylmethanes;
decyanation
Bis(indolyl)methane (BIM) type of skeleton,[1] as key
structural moiety, broadly exists in a lot of functional
molecules exhibiting a variety of pharmacological
activities such as anti-inflammatory,[2] anti-
oxidation,[3] antibacterial,[4] antihyperlipidemic,[5]
regulating hormone secretion,[6] inducing HL60 cell
differentiation,[7] activating G-protein coupled
receptor--GPR84,[8] and the potential of being
photoelectric material or probe.[9] Selected examples
like (Figure 1): Gelliusine F (I) and 2,2-bis-
Scheme 1. Selected synthetic approaches toward BIMs
(6'-bromo-3'-indolyl)-ethylamine (II) isolated from
the New Caledonian sponge, Orina sp, showing anti-
serotonin activity and
a
strong affinity for
somatostatin and neuropeptide
Y
receptors;[10]
Streptindole (III) isolated from the intestinal
bacterium
demonstrating
Streptococcus
faecium
IB
37,
and
DNA-damaging
activity
genotoxicity;[11] Arsindoline B (IV) obtained from
Xiamen sea bacterium strain CB101 displaying
cytotoxicities against the A-549 cell lines;[12] and
representative laser dye (V) and fluorescent probe
(VI) with a bispyrrol-2-ylmethane or bis(indol-2-
yl)methane skeleton.[13] Accordingly, the construction
of BIM type of skeleton,[14] in particular those with
heteroatom containing substituent on the middle
methylene moiety as shown in Figure 1, has attracted
broad attention of synthetic chemistry community
leading to a series of synthetic methods (Scheme
1).[15]-[25] Despite the achievements above, some of
them still suffer the drawbacks like harsh reaction
Figure 1. Selected functional BIM type of molecules
1
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10.1002/adsc.202000261
Advanced Synthesis & Catalysis
conditions, complex catalyst and multi-step
manipulations. Therefore, it is still necessary to
further explore alternative synthetic method for the
pursuing of new functional utilities of BIM and its
derivatives.
reaction was then investigated. As shown in the Table
2, a series of substituted indoles could be applied to
this reaction affording the desired BIM products in
moderate to good yields. In the case of substituent
type,
Table 1. Optimization of the reaction conditionsa
Scheme 2. The design of the tandem reaction between
indole and N,N-dimethyl aminomalonitrile
Entry 1a
/
Cat.
/equiv.
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
dioxane
THF
T
/°C
80
Yieldb
38%
trace
58%
44%
73%
65%
44%
26%
52%
50%
In the past several years, we have been focusing on
N,N-disubstituted aminomalonitrile related synthetic
methodology investigation, and developed some
efficient strategies for the synthesis of heterocycles
and synthetic intermediates.[26] Based on these results
and the chemical property of N,N-disubstituted
aminomalonitriles, we envisioned that a double
2a
1
2
1:2 Zn(OTf)2
/0.2
1:2 Mg(OTf)2
/0.2
80
80
80
80
80
80
80
80
80
3
1:2
AgOTf
/0.2
decyanation/electrophilic
substitution
reaction
4
1:2 Cu(OTf)2
/0.2
between indole and N,N-dimethylaminomalonitrile
might be possible to give 1,1-di(1H-indol-3-yl)-N,N-
dimethylmethanamine, and accidentally observed the
5
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2:1
1:1
Al(OTf)3
/0.2
Sn(OTf)2
/0.2
Sc(OTf)3
/0.2
In(OTf)3
/0.2
AlCl3
/0.2
Al(OTf)3
/0.1
Al(OTf)3
/0.2
Al(OTf)3
/0.2
Al(OTf)3
/0.2
Al(OTf)3
/0.2
formation
of
2,2-di(1H-indol-3-yl)acetonitrile
6
(Scheme 2). Considering the importance of BIM
analogues and the easy extensibility of the cyano
group toward the synthesis of the functional
molecules shown in Figure 1, we present herein such
an Al(OTf)3-catalyzed tandem coupling reaction for
7
8
the
synthesis
of
1-cyano-bisindolylmethane
9
analogues.
Following the original assumption, we used
compounds 1a and 2a as the model substrates to
verify the feasibility of the expected tandem reaction
for the synthesis of 1,1-di(1H-indol-3-yl)-N,N-
dimethylmethanamine. Under the catalysis of
Zn(OTf)2 in DCE, however, only the unexpected
product 2,2-di(1H-indol-3-yl)acetonitrile 3a was
obtained in 38% yield (Table 1, entry 1). According
to the importance of BIM type of compound, we then
payed our attention to the reaction condition
optimization of product 3a. Subsequently, different
metal catalysts were tested under the same conditions
10
11
12
13
14
15
16
17
18
19
20
100 80%
120 83%
120 67%
120 80%
120 89%
120 85%
120 42%
120 87%
120 36%
120 70%
1:1. Al(OTf)3
/0.2
1:1. Al(OTf)3
/0.2
1:1. Al(OTf)3
/0.2
1:1. Al(OTf)3
/0.2
1:1. Al(OTf)3
/0.2
1:1. Al(OTf)3
/0.2
aReaction conditions: 1a (100 mg, 0.85 mmol,
[27]
with Zn(OTf)2, and the use of Al(OTf)3 gave the
2
best yield of 73% (Table 1, entry 5). Further lowing
the amount of Al(OTf)3 to 0.1 equivalent resulted in a
lower yield of 50% (Table 1, entry 10). In contrast,
increasing the reaction temperature at 120 °C could
improve the yield to 83% (Table 1, entry 12). Next,
the reaction was carried out with different ratio of the
substrates 1a and 2a (Table 1, entries 13 to 16), and
the best result was obtained with the ratio of 1:1.2
(Table 1, entry 15). Afterwards, a series of solvents
was applied to the reaction. Among them, the use of
THF gave 3a in a similar level of 87% yield, and all
other solvents led to lower yield than that in DCE
5
2
2
toluene
CH3CN
2
2
(Table 1, entries 17 to 20). Based on the above results, 1equiv), 2a (indicated amount), solvent (2.0 mL,
anhydrous) in a sealing tube for 8 h; bIsolated
yields of 3a
performing the reaction with Al(OTf)3 as catalyst in
DCE was selected as the optimal reaction conditions
(Table 1, entry 15).
.
With the optimal reaction conditions in hands
(Table 1, entry 15), the substrate scope of this
all the tested alkyl, alkoxy, aryl and halogen groups
were compatible with this reaction. Especially, the
2
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10.1002/adsc.202000261
Advanced Synthesis & Catalysis
presence of a halogen group would provide an
additional reaction site for further derivatization.
Meanwhile, the steric hindrance effect of the
substituent on the indole ring was clearly observed.
Taking methyl as an example, when it was at the 2-
position of the indole ring, the yield of corresponding
product 3c was lower than those of products 3b and
3d, of which the methyl group is at 1-position and 4-
position, respectively. Additionally, changing the
substituent to a larger phenyl group led to product 3i
with a lower yield of 60%. Moreover, the electronic
effect of the substituent on indole ring also exists. For
the indole substrates with a substituent at the 5-
position, those with an electron-donating or neutral
substituent were all converted to expected products in
good yields with substrate 2a. In contrast, substrate
1s and 1t with an electron-withdrawing group at the
same position gave corresponding product 3s and 3t
in lower yields of 26% and 64%, respectively. When
the substituent was a nitro group, only trace amount
of product could be obtained, indicating that strong
electron substituents would hamper the reaction
process. In order to support the potential
practicability of this reaction, a gram scale reaction
between 1a and 2a was carried out affording 3a in
8
4
%
y
i
e
l
d
.
Table 2. Substrate scope investigationa
aUnless specified, all reactions were carried out using 1
(100 mg, 1 equiv), 2a (1.2 equiv), Al(OTf)3 (0.2 equiv) in
DCE (2.0 mL, anhydrous) in a sealing tube at 120 °C for 8
b
c
h; Isolated yields of 3; 1 g of 1a was used; dAnhydrous
e
THF (2 mL) was used as the solvent; The yield is based
on the recovery of 1s.
Furthermore, the structure of the products was
confirmed by the single-crystal X-ray diffraction of
compound 3m.[28] Encouraged by the special function
of 2,2'-bisindolylmethane like anticancer activity,[29]
we further tested the possibility in synthesizing these
molecules via this method. Accordingly, the
regioselectivity of this reaction was adjusted through
the introduction of a substituent at 3-position of the
indole ring. And one representative products 3u could
be obtained in 70% yield.
Following the above results, we further applied
other aromatic substrates to this transformation. As
shown in Table 3, except the indole type of
compound, substrates with other aromatic ring like
pyrrole or benzene were also amenable to this
reaction affording the expected products in moderate
yield. In the case of pyrrole type of substrate, all the
tested compounds led to the desired products with the
coupling bond at 2-position providing an alternative
strategy for the facile synthesis of corresponding
functional molecules,[30] in particular, compound 3y,
the key intermediate of laser dye (V), in a better yield
of 58%.[13a] Besides, aniline type of substrate was also
compatible to this transformation giving the expected
products (3z to 3ab) in good yields. It should also be
noted that no expected product was formed if an
3
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10.1002/adsc.202000261
Advanced Synthesis & Catalysis
electron withdrawing group like Ac or Ts was present
at the 1-position of the indole and pyrrole substrates
(1ac to 1ae). And some other aromatic substrates like
benzimidazole, isoquinoline, furan and thiophene did
not go through this reaction neither.
Table 3. Substrate scope investigationa
Scheme 4. Plausible reaction mechanism
In conclusion, an Al(OTf)3-catalyzed tandem
coupling reaction between N,N-disubstituted
aminomalonitriles and substituted arenes have been
successfully developed, providing an efficient, rapid
and simple strategy for the synthesis of 1-cyano-
substituted BIM and related molecules. Based on the
important biological activity and application of BIM
type of compound, the current method might
facilitate related functional studies. At present,
further application of this method for the pursuing of
more potent bioactive molecules and new fluorescent
probe is ongoing in the same group.
aReaction conditions:
1 (100 mg, 1 equiv.), 2a (1.2
equiv.), Al(OTf)3 (0.2 equiv.) in DCE (2.0 mL,
anhydrous) in a sealing tube at 120 °C for 8 h to give
Experimental Section
corresponding products
3 in isolated yields.
General experimental procedure for products 3a-3ab
(using 3a as an example): To a stirred solution of indole
1a (0.10 g, 0.85 mmol) in DCE (2 mL) were successively
added N,N-dimethylaminomalononitrile 2a (0.11 g, 1.02
mmol) and Al(OTf)3 (0.08 g, 0.17 mmol) at room
temperature under argon atmosphere in a sealing tube (10
mL). Next, the reaction mixture was sealed and heated at
120 °C for 8 h. Then, the solvent of the reaction mixture
was removed in vacuo, and the residue was purified by
column chromatography to afford pure desired product 3a
(103 mg, 89%) as a white solid.
For the sake of possible source for the
cyanomethyl moiety of the products, some control
experiments were carried out between 1a and N,N-
disubstituted aminomalonitriles 2b to 2d. All the
reactions afforded product 3a in good yields under
the optimal reaction conditions (Scheme 3), which
confirmed the cyanomethyl moiety was derived from
the aminomalonitrile substrates.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21472077 and 2177020071), the
Fundamental Research Funds for the Central Universities
(lzujbky-2018-134), and Department of Education of Guangdong
Province (No. 2017KTSCX185, 2017KSYS010, 2016KCXTD005,
2019KZDXM035).
Scheme 3. Control experiments
Based on the above experimental results, a possible
reaction mechanism is proposed using the
transformation between substrates 1a and 2a as an
example. As shown in Scheme 4, under the
promotion of Al(OTf)3 catalyst, decyanation of 2a
would give intermediate A, which could react with
compound 1a to afford intermediate B. A formal 1,3-
proton shift of intermediate B would lead to
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10.1002/adsc.202000261
Advanced Synthesis & Catalysis
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10.1002/adsc.202000261
Advanced Synthesis & Catalysis
COMMUNICATION
Al(OTf)3-Catalyzed Tandem Coupling Reaction
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Adv. Synth. Catal. Year, Volume, Page – Page
Lin-Sheng Lei,a† Bo-Wen Wang,a† Da-Ping Jin,a
ab
Zhu-Peng Gao,a Huan-Liang,a Shao-Hua Wang, *
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7
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