Aniline-initiated and Br?nsted acid-catalyzed one-pot reaction toward 2-aryl-3-sulfenylindoles by using α-aminocarbonyl compounds and primary amines with RSSR

Article abstract of DOI:10.1016/j.catcom.2020.106217

A highly novel method of direct synthesis of 2-aryl-3-sulfenylindoles in moderate to good yields was developed via one-pot tandem reaction of readily available α-aminocarbonyl compounds and catalytic amount of benzenamines with RSSR.

Full text of DOI:10.1016/j.catcom.2020.106217

Catalysis Communications 149 (2021) 106217
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
Aniline-initiated and BrØnsted acid-catalyzed one-pot reaction toward
2-aryl-3-sulfenylindoles by using
amines with RSSR
α
-aminocarbonyl compounds and primary
Yuxuan Liua, De Chena, Chaozhihui Chenga, Wenjian Guana, Yongyue Luob *, Jiajia Zhanga,
,
,
,*
Wei Denga *, Jiannan Xianga
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
b Agricultural Product Processing Research Institute, Chinese Academy of Tropical Agricultural Sciences, Zhanjiang, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A highly novel method of direct synthesis of 2-aryl-3-sulfenylindoles in moderate to good yields was developed
Indole
via one-pot tandem reaction of readily available
amines with RSSR.
α-aminocarbonyl compounds and catalytic amount of benzen-
Acid and aniline catalysis
α
-Aminocarbonyl compound.
1. Introduction
2. Result and discussion
Indole frameworks are known to be widely distributed in diverse
pharmacophores and natural products. Among these, 3-sulfenylindoles
are reported to display important biological activities in the treatment
of cancer, HIV, obesity, allergy, and many common diseases [1–5].
In the past few decades, continuous efforts have been made to search
for efficient methods for the construction of 3-sulfenylindoles [6–9]. The
vast majority of reported transformations are the direct sulfenylation
[10–18] of indoles with disulfide [19], thiol [20–21], N-thioalkyl (aryl)
-phthalimide [22], S-acetaldehyde [23], quinone mono [24], direct
sulfide of thiocyanate or ammonium thiocyanate [25–26], and benze-
nesulfonyl hydrazide [27]. In 2009, Guo (Scheme 1a) reported a novel
and attractive method to construct 3-sulfenylindoles in 92% yields using
2-aminobiphenylacetylene and phenyl sulfide with Palladium catalyst
[28]. However, we also expect a metal-free and efficient method to
obtain such compounds. According to the study of Janakiram Vaitla’s
group for the synthesis of indoles (Scheme 1b) [29] and the experi-
mental research of the previous work (Scheme 1c) [30], we assumed
that the two experiments could be combined to develop a novel one-pot
method to synthesize 3-sulfenylindoles, and thus, we performed a
detailed study (Scheme 1d).
Inspired by these, we envisioned that a free radical reaction of sulfide
and indole which could be generated in situ from α-aminoacet-ophenone
and catalytic amount of aniline might give an approach to the con-
struction of target 3-sulfenylindole.
frameworks. Initially, we commenced our study using
α-amino-
acetophenone (1 equiv) and a catalytic amount of aniline (0.3 equiv) as
the model substrate. Screening of acid catalyst, solvent, and temperature
is shown in the supporting information (Table S1). Under the optimal
reaction condition, we added phenyl disulfide and iodine into the system
to explore the possibility of novel one-pot reaction that we mentioned
above. Interestingly, the desired product was obtained while the yield
was only 32%. Thus, we tested various non-metallic catalysts to promote
this transformation, as shown in Table 1 for acid catalyst, LiClO4, PPA,
and acetic acid had no positive effect in this transformation, while tri-
fluoromethanesulfonic acid and p-toluenesulfonic acid greatly improved
the yield. We chose TfOH as the best catalyst. Then, we studied the effect
of the reaction solvent. We initially believed that the second step of this
reaction was a free radical reaction, so we chose toluene, tri-
fluorotoluene, and dichloroethane as the reaction solvent. Examination
of several solvents (entries 7–12) at the same temperature revealed that
DCE might be the better solvent [31–33]. Additionally, further studies
on increasing or decreasing temperature and reaction time of two steps
did not show any superior result.
* Corresponding authors.
E-mail address: Jnxiang@hnu.edu.cn (J. Xiang).
https://doi.org/10.1016/j.catcom.2020.106217
Received 11 August 2020; Received in revised form 24 October 2020; Accepted 29 October 2020
Available online 2 November 2020
1566-7367/© 2020 The Authors.
Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Y. Liu et al.
Catalysis Communications 149 (2021) 106217
Scheme 1. Various approaches for the synthesis of indoles.
2

Y. Liu et al.
Catalysis Communications 149 (2021) 106217
Table 1
Optimization of the reaction conditions.a
Entry
Catalyst (x mol%)
Solvent
Temperature (T1,T2)
Yield b (%)
1
TFA (20)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
120,80
32
67
15
30
27
71
82
70
42
21
18
65
76
88
57
2
TsOH (20)
LiClO4 (20)
CH3COOH (20)
PPA (20)
3
4
5
6
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (10)
TfOH (20)
7
8
Benzotrifluoride
CH3CN
DMF
9
10
11
12
13
14
15
DMSO
Chlorobenzene
DCE
DCE
DCE
a
All reactions were carried out with 0.3 mmol of 1a, 0.36 mmol of 2a,0.09 mmol aniline, 0.36 mmol I2 in 2.0 mL of the solvent, step1 24 h and
step2 12 h, unless otherwise specified.
b
Isolated yield.
Next, we explored the amount of acid catalyst and found that it was
the best relative to the raw material 10% mol.
react with different disulfides including pyridine disulfide, methyl di-
sulfide, p-toluene disulfide, and p-nitro disulfide, as shown in the
Scheme 2.
Further, lower catalyst loading didn’t achieve better yield (entry 15).
Based on the above research results, the best results were obtained with
Only p-chloro disulfide afforded the corresponding product 3ba in
excellent yield, while p-methyl disulfide gave the desired products 3ea in
74% yield, which may be due to the electronic effect of the substituent in
the aryl ring. Particularly, for p-methyl disulfide, the resulting product
3da was obtained in moderate yield, but for p-benzyl disulfide, the re-
actions failed to work, and only crude mixture was generated (Scheme
3).
α
-aminoacetophenone (1.0 equiv), disulfide (1.2 equiv), aniline (0.3
equiv), and TfOH (10 mol%) in DCE as a solvent at 120 ◦C in step 1 for
24 h and 80 ◦C in step 2 for 12 h, providing the desired sulfenylindole
product in 88% yield (entry 10). We also found that the yield of final
sulfenylindole product was higher than indole intermediate generated in
step 1, which indicated that the second-step thioetherification reaction
promoted the first-step indole synthesis reaction.
To gain insight into the reaction mechanism, control experiments
With the optimization of reaction conditions, the substrate scope was
were conducted. We used 4-methyl α-aminoacetophenone to react with
then examined with various
α
-aminoacetophenones. As shown in
4-methylaniline (1 equiv) and aniline (1 equiv) respectively, and found
that there was a competition between imine formation and Friedel-
Crafts type reaction, the latter usually produces a mixture of
regioisomers, but mainly target compound reacted with aniline (Scheme
4).ith aniline
Scheme 2, this reaction accommodates a broad range of
α-amino-
acetophenones including electron-rich or electron-deficient functional
groups in any position of the aryl rings of acetophenones, yielding the
products 3aa-3 am in moderate to good yields (62–94%). Further, nitro-,
hydroxy-, and amino groups could not be tolerated in this trans-
Treatment of N-methylacetophenone and aniline under our standard
conditions afforded the desired product in 76% yield and no competitive
by-product. This implies that competitive reaction can be prevented
formation, and using amino-substituted α-.
aminoacetophenone as when starting materials, the target product
cannot be detected. We next investigated the substitution effect on the
aryl group of the N-aryl moiety. The electronic effect of the phenyl ring
in substrate 4 had a significant effect on the yields of products. The
yields of product with electron-withdrawing groups (3ao) were better
than those of product with electron-donating groups (3an).
–
when the N H of α-aminoacetophenone was protected, which further
clarified that the N source of final product could be the external aniline.
Based on these results and the reported literature [12,30], a possible
reaction mechanism is proposed in Scheme 5.
α-aminoacetophenone
undergoes acid catalysis and undergoes electrophilic cyclization to
produce 2-phenylindole after a catalytic amount of aniline starts the
Subsequently, these reactions also using α-aminoacetophenone 1a to
3

Y. Liu et al.
Catalysis Communications 149 (2021) 106217
Scheme 2. TfOH-catalyzed annulation of
α
-aminoacetophenones [1] with sulfide (4a) [a]
a Conditions: 1a (0.3 mmol), 2 (0.36 mmol), aniline (0.09 mmol), I2 (0.36 mmol), TfOH (10 mol%), and DCE (2 mL), step1 120 ◦C, 24 h, step2 80 ◦C, 12 h.
4

Y. Liu et al.
Catalysis Communications 149 (2021) 106217
Scheme 3. TfOH-catalyzed annulation of
α
-aminoacetophenone (1a) with sulfides (2) [a]
.
a Conditions: 1a (0.3 mmol), 2 (0.36 mmol), aniline (0.09 mmol), I2 (0.36 mmol), TfOH (10 mol%) and DCE (2 mL), step1 120 ◦C, 24 h, step2 80 ◦C, 12 h.
Scheme 4. Mechanistic investigations
5

Y. Liu et al.
Catalysis Communications 149 (2021) 106217
Scheme 5. Proposed mechanism for the synthesis of 3-sulfenylindoles.
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In summary, we have developed an unprecedented aniline-initiated
one-pot reaction for the synthesis of highly functionalized 3-sulfenylin-
doles in moderate to good yields with TfOH, which is a type of green and
inexpensive non-metallic catalyst.
Declaration of Competing Interest
There are no conflicts to declare.
Acknowledgements
We are grateful for the financial support from the National Natural
Science Foundation of China (Nos. 21502049 and 51573040), Hunan
Provincial Natural Science Foundation of China (Nos.2018JJ2032), and
the Planned Science and Technology Project of Hunan Province, China
(No. 2015WK3003).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.catcom.2020.106217.
[33] C.-R. Liu, L.-H. Ding, Org. Biomol. Chem. 13 (2015) 2251.
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