Recyclable Cellulose-Derived Fe3O4@Pd NPs for Highly Selective C–S Formation by Heterogeneously C–H Sulfenylation of Indoles

Article abstract of DOI:10.1007/s10562-020-03144-9

Abstract: An efficient and convenient method was developed for the preparation of 3-sulfenylindoles via a cellulose-derived Fe₃O₄@Pd NPs catalyzed heterogeneously C–H sulfenylation of indoles. This approach provides an effective synthetic route to an important class of indoles derivatives and features high efficiency, easy operation, good practicality, and environmental friendliness. The recoverable catalyst was separated from the reaction mixture using an outside magnetic field and can be recycled five times without huge loss of catalytic performance. Graphic Abstract: An efficient method was developed for the preparation of 3-sulfenylindoles via cellulose-derived Fe₃O₄@Pd NPs catalyzed heterogeneously C–H sulfenylation of indoles.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-020-03144-9

Catalysis Letters
https://doi.org/10.1007/s10562-020-03144-9
Recyclable Cellulose‑Derived Fe3O4@Pd NPs for Highly Selective C–S
Formation by Heterogeneously C–H Sulfenylation of Indoles
Shengyi Li1 · Jinguo Wang2 · Jianzhong Jin2 · Jianying Tong2 · Chao Shen2
Received: 27 December 2019 / Accepted: 7 February 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
An efcient and convenient method was developed for the preparation of 3-sulfenylindoles via a cellulose-derived Fe3O4@
Pd NPs catalyzed heterogeneously C–H sulfenylation of indoles. This approach provides an efective synthetic route to an
important class of indoles derivatives and features high efciency, easy operation, good practicality, and environmental
friendliness. The recoverable catalyst was separated from the reaction mixture using an outside magnetic feld and can be
recycled fve times without huge loss of catalytic performance.
Graphic Abstract
An efcient method was developed for the preparation of 3-sulfenylindoles via cellulose-derived Fe3O4@Pd NPs catalyzed
heterogeneously C–H sulfenylation of indoles.
1 Introduction
applications in various small-molecule drug discovery pro-
grams [2]. Recently, the functionalization of indole skel-
eton at the C2 or C3 position has attracted much attention
due to the electron-rich nature of indole rings [3–5]. One
of these utilities is the construction of 3-sulfenylindoles
via C–S coupling reaction at the C3 position of the indole
ring, which has various biological activity, including anti-
tumor, anti-HIV, and anti-bacterial properties (Fig. 1).[6]
In recent years, major advances have been achieved in the
C–S coupling reactions for the construction of valuable and
functionalized indoles [7]. Various sulfenylating agents such
as disulfdes [8], thiols [9], sulfonium salts [10], sulfenyl hal-
ides [11], sulfonyl chlorides [12], N-thioimides [13], sulfnic
esters,[14] and sulfonyl hydrazides [15] were successfully
coupled with indoles. Nevertheless, introductions of these
Indoles are privileged structures scafold which plays an
important role in natural and pharmacological compounds
with a broad spectrum of biological and pharmaceuti-
cal activities.[1] Functionalized indoles have found wide
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-020-03144-9) contains
supplementary material, which is available to authorized users.
* Chao Shen
shenchaozju@163.com
1
College of Petroleum Chemical Industry, Changzhou
University, Changzhou 213164, China
2
College of Biology and Environmental Engineering,
Zhejiang Shuren University, Hangzhou 310015, China
Vol.:(0123456789)
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S. Li et al.
supports for metal NPs.[24] In our research group, we have
reported an efcient and eco-friendly protocol that uses cel-
lulose-supported Cu nanoparticles as an efcient catalyst for
the click reaction of glycosyl azides with terminal alkynes
to provide the target glycosyl triazoles in good yields [25].
In view of the importance of 3-sulfenylindoles, and con-
tinuing our longstanding interest in C–S coupling reactions
[26–30], we herein report the synthesis of cellulose-derived
Fe3O4@Pd NPs catalyst and its application for construction
of 3-sulfenylindoles from aryl iodides, thiourea, and indoles.
This protocol provides an efcient route to an important
class of indoles derivatives and features high efciency, easy
operation, good practicality, and environmental friendliness.
O
O
S
O
Cl
S
CONH2
O
N
COCH3
H
N
H
anti-HIV
anti-cancer
O
Cl
Cl
NH
HO
S
Cl
Me
S
O
N
NH2
N
H
2 Results and Discussion
O
respiratory discorders
potent antiviral
2.1 Catalyst Synthesis and Characterization
Fig. 1 Selected examples of biologically 3-sulfenylindoles
The synthesis sketch of the Fe3O4@C/Pd catalyst is depicted
in Scheme 1. The synthesis of Fe3O4@C/Pd nanocatalyst
involved several steps (in supporting information). The mor-
phology of these Fe3O4@C/Pd catalyst was examined by
both XRD, XPS and TEM as demonstrated in Fig. 2. The
XRD pattern of the Fe3O4@C/Pd catalyst and Fe3O4 nano-
particle were shown in Fig. 2(1). The face-centered cubi-
clattice of Fe3O4, which matched well with the standards
of Fe3O4 (JCPDS 65–3107). For the Fe3O4@C/Pd catalyst,
three peaksat 2θ=40°, 47°and 68° were the characteristic
difraction peaks of the face centered cubic crystalline phase
of Pd nanoparticles. The elemental composition of the cata-
lyst was determined by XPS in Fig. 2(2). The Pd (3d5/2) and
Pd (3d3/2) peaks were observed at 337.96 and 343.07 eV,
respectively, which are the characteristic values of the Pd
metal and Pd 3d XPS of Pd nanoparticles suggested the for-
mation of Pd(0) species. The magnetic hysteresis loops of
Fe3O4@C/Pd catalyst was measured and the catalysts satu-
ration magnetization was 27.1 emu/g in Fig. 2(3). There-
fore, the magnetization of cellulose-derived Fe3O4@Pd NPs
was strong enough for magnetic separation by a permanent
magnet. The TEM images shown that the Fe3O4@C/Pd
catalyst was composed of aggregated fne nanoparticles and
had the size distribution mainly between 190 and 210 nm
sulfur segments frequently require multiple experimental
steps, generate wastes, use of toxic reagents, and produce
undesired harmful by-products. Therefore, the development
of convenient and efcient approaches to the sulfenylation
of indoles at the C3-position under mild conditions is still
necessary.
Over the past decade, there has been an increased
focus on the cross coupling reactions that utilize magnetic
shell–core microsphere base catalysts due to their low cost
and high catalytic activities [16]. In recent years, palladium
magnetic shell–core structured catalysts have received sig-
nifcant attention because of their high activity and recy-
clability, which can be applied in many catalytic reactions
such as Sonogashira [17], Suzuki–Miyaura [18], Heck [19],
and hydrogenation [20]. Recently, it has been proved that
the use of biomass on the magnetic Fe3O4 played an major
role in preventing the destruction of magnetic core [21–23].
Generally, cellulose constitutes of the main component of
biomass and is suitable for making cost-competitive carbon
materials. Because of their huge surface area, good water
suspendability and reductive surface functional groups, cel-
lulose has been used as renewable, cheap, and biodegradable
Scheme 1 The large-scale
reaction: 1a (20 mmol), 2a
(20 mmol), 3 (20 mmol), TFA
(30 mL), refux, 3 h. Product 4a
was isolated in 95.3% yield
Br
S
Fe3O4@C/Pd NPs
S
(1 mol%)
+
+
K2CO3 (1 equiv),
TFA, Reflux , 3 h
H2N
NH2
N
H
N
H
4a
3
1a
2a
2.34g, 20.0 mmol
4.29 g (95.3%)
3.14g, 20.0 mmol 1.58g, 20.0 mmol
1 3

Recyclable Cellulose-Derived Fe3O4@Pd NPs for Highly Selective C–S Formation by…
a
b
334
336
338
340
342
20
30
40
50
60
70
80
Binding Energy (eV)
2 Theta (degree)
(1)
(2)
100 nm
(4)
(3)
Fig. 2 Synthesis and characterization of cellulose-derived Fe3O4@C/Pd NPs. 1 XRD patterns of (a) Fe3O4@C/Pd catalyst and (b) Fe3O4 nano-
particles; 2 XPS analysis of Fe3O4@C/Pd catalyst; 3 Hysteresis loops for the Fe3O4@C/Pd catalyst; 4) TEM images of Fe3O4@C/Pd catalyst
in Fig. 2(4). The TEM studies confrmed the incorporated
Pd NPs on the surface of Fe3O4@C nanospheres and also
indicated that the catalyst has a core/shell nanostructure.
The Pd content was determined to be 6.5 wt% by ICP-OES.
To evaluate the catalytic performance of the catalyst, a
reaction of indole 1a (1 mmol), iodobenzene 2a (1 mmol),
thiourea 3a (1 mmol), were carried out as model reaction to
determine the optimized reaction conditions, as summarized
in Table 1. Initially, diferent inorganic sulfur sources were
screened including S8, thiourea, K2S, and Na2S2O3 and the
results indicated that thiourea was the most efective sul-
fur source for this transformation using Na2CO3 as base
(Table 1, entries 1–4). Subsequently, the efect of diferent
base including Cs2CO3, K2CO3, KOH, NaOH, and Et3N was
explored, which reveals that K2CO3 was more appropriate
for the C–S coupling reactions than other base (Table 1,
entries 5–9). Nextly, a number of common solvents such
as DMSO, AcOH, water, ethanol, DMF (3 mL each) were
examined, but no better results were obtained (Table 1,
entries 10–14). As a result, the choice of the solvent is criti-
cal to the success of the reaction. Further increase in the
amount of K2CO3 did not have any signifcant efect on the
product yield (Table 1, entry 15).
When the dosages of catalyst was reduced to 0.5 mol%, a
decreased yield was observed for 3a (Table 1, entry 16). It
was found that the Fe3O4@C shell was not ability to catalyze
1 3

S. Li et al.
Table 1 Optimization of reaction conditions
Table 2 Scope of substituted indoles in the presence of Fe3O4@C/Pd
NPs
Entry
Indoles 1
Proucts 4
Yield b（%）
99 (4a)
Entry “S” source Solvent Base
Temp (℃) Yield (%)a
1
1
2
3
4
5
6
7
8
S8
Thiourea
K2S
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
DMSO
AcOH
H2O
EtOH
DMF
TFA
TFA
TFA
TFA
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
K2CO3
KOH
75
75
75
75
75
75
75
75
75
190
118
100
80
155
75
75
75
60
0
75
0
2
88 (4b)
Na2S3O3
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Thiourea
Trace
81
96
31
25
51
13
21
0
3
4
5
6
7
8
91(4c)
93 (4d)
96 (4e)
95 (4f)
92 (4g)
94 (4h)
NaOH
Et3N
9
10
11
12
13
14
15
16
17
18
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
Trace
96b
77c
0d
53
The reaction conditions: Indole 1a (1 mmol), iodobenzene 2a (1
mmol), ’’S’’ source (1 mmol), 1 mol % catalysts, base (1 mmol) and
solvent (3 mL) under air, 3 h
aIsolated yield
bF1.5 equiv. of K2CO3 was used
c0.5 mol% catalyst was used
dFe3O4@C was used as catalyst.
9
86 (4i)
90(4j)
reaction and Pd nanoparticles was an indispensable com-
position in this reaction (Table 1, entry 17). The efciency
of the reaction was dramatically decreased when lower the
temperature (Table 1, entry 18).
10
aThe reaction conditions: substituted indole 1 (1 mmol), iodoben-
zene 2a (1 mmol), thiourea 3 (1 mmol), 1 mol % Fe3O4@C/Pd NPs,
K2CO3 (1 mmol) and TFA (3 mL) under air
With our optimized reaction conditions in hand, the sub-
strate scope of this transformation was subsequently inves-
tigated, and the results are shown in Table 2. Generally,
indoles with various functional groups can be transformed
smoothly into the desired products. The indoles containing
both electron-donating and electron-withdrawing substitu-
ents in the benzene ring tolerated the reaction conditions
well to aford the target 3-sulfenylindoles in good yields.
As for substitution patterns, 4- or 6-substituted indoles
gave a relatively low yield compared with their 5-analogues
(Table 2, 4b, 4c, 4i). To our delight, substrates possessing
halogens, ester or aldehyde groups were tolerated in this het-
erogeneously C–H sulfenylation, providing an opportunity
bIsolated yield.
for further synthetic transformations. Gratifyingly, a N-het-
eroaryl-bearing indole reacted well in this process, furnish-
ing the desired products with a yield of 90% (Table 2, 4j).
For the generality and scope of this approach to be
explored further, a wide scope of substituted aryl iodides
were examined, and the results are shown in Table 3. In
general, aryl iodides with either an electronwithdrawing or
-donating group on the benzene e ring were able to gen-
erate the corresponding 3-arylthioindoles 4k−4q in good
1 3

Recyclable Cellulose-Derived Fe3O4@Pd NPs for Highly Selective C–S Formation by…
Table 3 Scope of aryl halides in the presence of Fe3O4@C/Pd NPsa
100
90
80
70
60
50
40
30
20
10
0
99
90
97
94
99
0
2
4
6
Runs
Fig. 3 Recycling and reuse of Fe3O4@C/Pd in the C–S coupling reac-
tion
no signifcant decrease in isolated yield, which indicated that
the better stability of the Fe3O4@C/Pd catalyst.
To demonstrate the synthetic utility of the new method,
the reaction was carried out on a gram scale, 20.0 mmol of
indole (1a) with 20.0 mmol of 2a and 3 in the presence of
1 mol% of Fe3O4@C/Pd catalyst and 20 mmol of K2CO3 in
30 mL of TFA. The reaction could aford 4.29 g of 4a in 95.
3% yield (Scheme 1). Therefore, this protocol could be used
as a practical approach to synthesize the precursors of some
important bioactive molecules.
aThe reaction conditions: indole 1a (1 mmol), substituted iodoben-
zene 2 (1 mmol), thiourea 3 (1 mmol), 1 mol % Fe3O4@C/Pd NPs,
K2CO3 (1 mmol) and TFA (3 mL), refux under air
bIsolated yield
c1 equiv. of bromobenzene was used
yields under the optimized conditions. Gratifyingly, a num-
ber of functional groups, such as alkoxyl, alkyl, chloro, and
nitro groups, were compatible with the reaction conditions.
Remarkably, the electronic properties of the substituents on
the benzene ring of aryl iodides did not have a signifcant
infuence on the reaction efciency. Moreover, the NHCOPh
substituted substrate could be converted to the desired
product N-(2-((1H-indol-3-yl)thio)phenyl)benzamide (4q)
in 75% yield. Finally, in the optimized reaction conditions
were quite efective for the C–S coupling reaction of indole
1a, thiourea 3a with bromobenzene and the product was
obtained in 81% yield.
3 Conclusions
In conclusion, an efcient and convenient method was devel-
oped for the preparation of 3-sulfenylindoles via a cellulose-
derived Fe3O4@Pd NPs catalyzed heterogeneously C–H
sulfenylation of indoles. This protocol provides an expe-
ditious route to an important class of indoles derivatives
frequently found in many biologically active compounds
and features high efciency, easy operation, good practical-
ity, and environmental friendliness. The easily recoverable
cellulose-derived Fe3O4@Pd NPs catalysts can be recycled
fve times without huge loss of catalytic performance. Fur-
ther mechanistic studies on this transformation are currently
ongoing in our laboratory.
For practical applications of catalytic systems, the recy-
clability of the catalyst were signifcant factors to evaluate
the heterogeneous catalysts in view of green chemistry and
industrial applications. The recycling experiments for the
Fe3O4@C/Pd catalyst are performed in the coupling reac-
tion of indole, aryl iodide and thiourea. The catalyst was
separated by a permanent magnet after each reaction run,
washed with water and alcohol, dried at 65 ℃ under vacuum,
and reused in a subsequent catalytic run. As shown in Fig. 3,
the magnetic catalyst could be used for at least fve runs with
Acknowledgements This work was supported by the Science and
Technology Plan of Zhejiang Provincial (No. LGG19B060005), and
the National Natural Science Foundation of China (No. 21302171).
We acknowledge the support of the Young and Middle-aged academic
team Project of Zhejiang Shuren University.
1 3

S. Li et al.
15. Yang F, Tian S (2013) Angew Chem Int Ed 52:4929–4932
Compliance with Ethical Standards
16. Biglione C, Cappelletti AL, Strumia MC, Martín SE, Uberman
PM (2018) J Nanopart Res 20:127–142
Conflict of interest The authors declare that they have no confict of
17. Esmaeilpour M, Sardarian AR, Firouzabadi H (2018) J Organomet
Chem 873:22–34
interest.
18. Zheng K, Shen C, Qiao J, Tong J, Jin J, Zhang P (2018) Catalysts
8:443–454
19. Tukhani M, Panahi F, Khalaf-Nezhad A (2018) ACS Sustain
Chem Eng 6:1456–1467
References
20. Kunf A, Szabó V, Mastalir Á, Bucsi I, Mohai M, Németh P,
Bertóti I, London G (2017) ChemCatChem 9:2144–3236
21. Hajipour AR, Rezaei F, Khorsandi Z (2017) Green Chem
19:1353–1361
1. Chinnathambi R, Santhanam V, Vadivelu M, Ramachandran UP,
Hopper W (2017) Asian J. Pharm. Clin Res 10:341–346
2. Funk CD (2005) Nat Rev Drug Discov 4:664–672
3. Song P, Chen Z, Zhou J, Zhang Y (2013) Green Chem
15:2096–2100
22. Kumar BS, Amali AJ, Pitchumani K, Appl ACS (2015) Mater
Interfaces 7:22907–22917
4. Zhiani R, Sadeghzadeh SM, Emrani E, Abasian M (2018) J Orga-
nomet Chem 855:1–6
23. Zhao L, Zheng K, Tong J, Jin J, Shen C (2019) Catal Lett
149:2607–2613
5. Chaudhary B, Diwaker M, Sharma S (2018) Org Chem Front
5:3133–3137
24. Kaushik M, Moores A (2016) Green Chem 18:622–637
25. Yu W, Jiang L, Shen C, Xu W, Zhang P (2016) Catal Commun
79:11–16
6. Ji Y, Li H, Zhang J, Wu Y (2019) Chem Commun 55:11864–11871
7. Wang FX, Zhou SD, Wang C, Tian SK (2017) Org Biomol Chem
15:5284–5288
26. Shen C, Zhang P, Sun Q, Bai S, Hor TSA, Liu X (2015) Chem Soc
Rev 44:291–314
8. Vásquez-Céspedes S, Ferry A, Candish L, Glorius F (2015)
Angew Chem Int Ed 54:5772–5776
27. Shen C, Xu J, Yu W, Zhang P (2014) Green Chem 16:3007–3012
28. Xu J, Shen C, Zhu X, Zhang P, Ajitha MJ, Huang K-W, An Z, Liu
X (2016) Chem -Asian J 11:882–892
9. Ohkado R, Ishikawa T, Iida H (2018) Green Chem 20:984–988
10. Ge X, Sun F, Liu X, Chen X, Qian C, Zhou S (2017) New J Chem
41:13175–13180
29. Yang Y, Wang L, Xia C, Ying B, Shen C, Zhang P (2016) Chem-
CatChem 8:304–307
11. Huang D, Chen J, Dan W, Ding J, Liu M, Wu H (2012) Adv Synth
Catal 354:2123
30. Xia C, Xu J, Shen C, Zhang P (2016) Chem Asian J 11:360–366
12. Zhao X, Wei A, Li T, Su Z, Chen J, Lu K (2017) Org Chem Front
4:232
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
13. Nalbandian CJ, Miller EM, Toenjes ST, Gustafson JL (2017)
Chem Commun 53:1494
14. Yang X, Bao Y, Dai Z, Zhou Q, Yang F (2018) Green Chem
20:3727–3731
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