Mechanistic and experimental study on copper-catalyzed C3-sulfenylation of indoles with sulfur powder and aryl iodides

Article abstract of DOI:10.1016/j.catcom.2019.01.015

The copper-catalyzed sulfenylation of indoles with aryl iodide and sulfur powder has been investigated both experimentally and theoretically. This protocol provides a direct and facile approach to prepare 3-sulfenylindoles with moderate to excellent yields and good functional-group tolerance. The in-situ IR analysis provided evidence for that NaOAc could promote the synthesis of diphenyl disulfide by the coupling of aryl iodide and sulfur powder. According to DFT calculations, the coupling pathway involving the intermediate N-methyl-3-iodoindole is more favored than the direct coupling by the C–H activation of indole. The N-methyl-3-iodoindole was identified as a crucial intermediate in the catalytic cycle.

Full text of DOI:10.1016/j.catcom.2019.01.015

Accepted Manuscript
Mechanistic and experimental study on copper-catalyzed
C3-sulfenylation of indoles with sulfur powder and aryl iodides
Xin Ge, Lin Cheng, Fengli Sun, Xuemin Liu, Xinzhi Chen, Chao
Qian, Shaodong Zhou
PII:
S1566-7367(18)30360-1
DOI:
Reference:
https://doi.org/10.1016/j.catcom.2019.01.015
CATCOM 5599
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
21 August 2018
17 January 2019
20 January 2019
Please cite this article as: X. Ge, L. Cheng, F. Sun, et al., Mechanistic and experimental
study on copper-catalyzed C3-sulfenylation of indoles with sulfur powder and aryl iodides,
Catalysis Communications, https://doi.org/10.1016/j.catcom.2019.01.015
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ACCEPTED MANUSCRIPT
Mechanistic and experimental study on copper-catalyzed C3-sulfenylation of
indoles with sulfur powder and aryl iodides
Xin Ge a, Lin Cheng a, Fengli Sun a, Xuemin Liu a, Xinzhi Chen b,
Chao Qian b* and Shaodong Zhou b*
a School of Chemical and Material Engineering, Jiangnan University, Wuxi, P.R China
b Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College
of Chemical and Biological Engineering, Zhejiang University, Hangzhou, P.R China.
Abstract: The copper-catalyzed sulfenylation of indoles with aryl iodide and
sulfur powder has been investigated both experimentally and theoretically. This
protocol provides a direct and facile approach to prepare 3-sulfenylindoles with
moderate to excellent yields and good functional-group tolerance. The in-situ IR
analysis provided evidence for that NaOAc could promote the synthesis of diphenyl
disulfide by the coupling of aryl iodide and sulfur powder. According to DFT
calculations, the coupling pathway involving the intermediate N-methyl-3-iodoindole
is more favored than the direct coupling by the C-H activation of indole. The N-
methyl-3-iodoindole was identified as a crucial intermediate in the catalytic cycle.
Keywords: sulfur powder; indole; sulfenylation; copper; mechanism
* Corresponding author. Chao Qian, E-mail: qianchao@zju.edu.cn and Shaodong Zhou, E-mail: szhou@zju.edu.cn

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Introduction
Organosulfur compounds play important role in the production of
pharmaceuticals, agrochemicals and functional materials.[1] Up till now, numerous
methods for the construction of C-S bonds to prepare organosulfur compounds have
been developed and continue to attract much attention.[2, 3] Classified by sulfur
sources, there are two general approaches to form the C-S bonds, using organosulfur
substrates and inorganic sulfur reagents, respectively. The first approach relied on
organosulfur substrates is so prevalent that various organosulfur reagents, e.g.
thiols[4], disulfides[5], sulfonyl hydrazides[6], and arylsulfonyl chlorides[7] have
been employed; direct coupling of these reagents with organic halides can be
promoted by a transition metal or metal-free catalysts. However, most organic sulfur
agents suffer from repulsive odors and instability. Thus, the second approach based on
“clean” inorganic sulfur reagents like metal sulfides[8, 9], Na2S2O3[10], and sodium
sulfonates[11, 12], have been exploited. Recently, as a cheap and abundant sulfur
source, sulfur powder (S8) is attracting more and more interest for its high atom
economy in C-S bond formation.[13-19] In general, the substrates with easy leaving
groups, such as Br, I or B(OH)2, could be coupled with elemental sulfur catalyzed by
transition metals. The strategy combing C-H activation and elemental sulfur is a more
atom-economic method to construct a C-S bond whereby great progress has been
achieved. However, the associated mechanism remains a mystery and there are only a
few reports on the coupling of the activated substrates and elemental sulfur[20].
The indole scaffold is a ubiquitous structural motif that exists in bioactive natural

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and pharmacological compounds.[21-24] Among them, 3-thioindole exhibits a broad
range of bioactivities for treating bacterial infection, cancer, and HIV.[25] However,
there are rare efficient methods for the synthesis of 3-thioindole via direct C-H
functionalization of indole and elemental sulfur. Li and Deng[26] found that a double
C-H sulfuration by employing sulfur powder, indoles, and cyclohexanones was
catalyzed by Pd to prepare the benzothieno[2,3-b]indole. Wu and Jiang[27] reported
Pd-catalyzed oxidative sulfenylation of indoles and heteroarenes with aryl boronic
acids and elemental sulfur. In addition, the construction of C-Se bond via direct C-H
functionalization of indole and Se powder has received considerable attention and
copper-catalyzed three-component reactions for arylselenation of aromatic
heterocyclic using Se powder have been reported.[18, 28-31] Thus, it is always
challenging and interesting to probe a green and efficient approach for constructing
the 3-sulfenylindole motif. In this work, we report an eco-friendly and efficient
protocol for the synthesis of copper-catalyzed 3-sulfenylindoles using iodobenzene
and sulfur powder. The mechanistic aspects for the C-S bond formation via three-
component reaction will be revealed upon the comparison of several conceivable
pathways.

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Results and Discussion
The reaction of 1-methyl-1H-indole (1a), iodobenzene (2a) and sulfur powder
(S8) was employed as the model reaction to optimize the reaction conditions, and the
detailed results are shown in Table 1. Initially, several bases including Na2CO3,
K2CO3, Et3N, NaOAc, and KOAc were tested and NaOAc outperformed all the other
bases (Table 1, entries 1-5). Moreover, the base is crucial for this reaction (Table 1,
entry 6). Next, different solvents were screened and DMF was proven to be the most
favorable to this C3-sulfenylation (Table 1, entries 4, 7-10). In comparison of different
copper sources, i.e. CuI, CuBr, CuCl, CuBr2, CuCl2, Cu(OTf)2, CuSO4, Cu(OAc)2 and
CuOAc, Cu(OAc)2 gave the best performance (Table 1, entries 4, 11-18). Without
1,10-phenanthroline or additive KI, this reaction could not occur at all. The presence
of OAc was demonstrated to be crucial, while the addition of the 1,10-phenanthroline
ligand, as well as the additive KI, was indispensable (Table 1, entries 20-25).
Moreover, when the reaction was carried out under a nitrogen atmosphere, the yield
was poor (Table 1, entry 27). Therefore, it indicates that the air is essential for this
model reaction. In contrast, no significant changes were found on the final reaction
yield by changing oxidizers, such as oxygen and Na2S2O8 (Table 1, entries 28 and 29).
A little of water was added into reaction system and it is not moisture sensitive (Table
1, entry 30). Thus, the optimum conditions are obtained: 1,10-phen as the ligand, KI
as an additive, DMF as the solvent, under air atmosphere, the yield of 3-
phenylthioindole is up to 95%. When we found this reaction protocol, the reaction of
1-methyl-1H-indole (1a), iodobenzene (2a) with Se powder instead was immediately

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attempted. To our disappointment, the reaction with Se powder failed (Table 1, entry
26).
Furthermore, an extensive study was performed to examine the applicable scope
of substrates. Detailed results were summarized in Table 2. Aryl iodides with electron-
donating groups like Me, Et, OMe, OEt, and OCF3, on the para-position of benzene
ring can be converted to the corresponding products in excellent yields. When aryl
iodide possessed 4-Cl, 4-NO2 or 3-NO2 groups, the yield of desired product decreased
to 74%, 55%, and 46%, respectively. Unfortunately, aryl iodide with 4-Ac failed to
obtain the final product. Remarkably, the electronic properties of the substituents on
the aryl iodides have a significant influence on the reaction efficiency. Moreover, the
structure of product 3h was further confirmed by single-crystal X-ray diffraction. By
contrast, aryl iodide with F group in the para-position was well tolerated and the
desired product was obtained in 98%. And the electron-withdrawing groups, e.g. Cl,
NO2, substituted on indole resulted in excellent yield. On the other hand, indoles
possessing methyl group in C2, C5, C6, and C7 position, only gave moderate yields.
It may be caused by that the strong electron donor capacity of methyl group makes the
density of aromatic ring electron cloud large, since it is not beneficial to the formation
of iodide intermediates. Finally, the copper-catalyzed sulfenylation of different N-
substituted indoles was studied, demonstrating the high tolerance of this reaction. N-
substituted indoles with methyl, isopropyl, phenyl and benzyl groups can afford the
corresponding products in moderate to excellent yields. Unfortunately, indole failed to
obtain the targeted product. It is suspected to be caused by that the C-N coupling

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reaction of indole with iodobenzene is more likely to occur in this optimized
condition. Moreover, when the substrates have both bromo and iodo groups, they will
be incompatible with this catalytic protocol. The existing of too many byproducts in
this complicated reaction lead to the difficulty for the product purification.
To reveal the mechanism of the above C3-sulfenylation, several controlled
experiments have been carried out (Scheme 1). For example, without iodobenzene
(2a) and sulfur powder (S8), N-methyl-3-iodoindole was detected with 50% yield,
which is due to copper-catalyzed aerobic C-H oxidation of indole under air (Scheme
1a).[11, 32] Subsequently, when iodobenzene (2a) reacted with sulfur powder (S8)
catalyzed by Cu(OAc)2 and NaOAc, diphenyl disulfide was obtained with excellent
yield (Scheme 1b). However, without NaOAc, the yield of diphenyl disulfide was
only 45% (Scheme 1c). This result suggested that NaOAc played a crucial role to
control the selectivity of diphenyl disulfide and phenyl sulfide, which is consistent
with Chen’s report[20]. Furthermore, the desired product can be obtained by copper-
catalyzed Ullmann type C-S coupling reaction of N-methyl-3-iodoindole and diphenyl
disulfide and 1,10-phen (Scheme 1d). In addition, the reaction equivalent of
iodobenzene (2a) and sulfur powder (S8) must be twice as much as that of 1-methyl-
1H-indole(1a) (Table 1, entries 17, 19). It revealed that only one sulfanyl group of
diphenyl disulfide participated in this reaction. Moreover, under the condition without
air, the reaction resulted in poor performance (Scheme 1e), indicating that aerial
oxygen served as an oxidizing agent for this reaction. The desired reaction processes
were not affected when it happened in the presence of radical inhibitor TEMPO

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(Scheme 1f). This result refutes the radical pathway in this reaction pathway.
Subsequently, we used in-situ IR to monitor the stoichiometric reaction of
iodobenzene (2a) and sulfur powder (S8), catalyzed by copper. Initially, sulfur powder
and Cu(OAc)2 were added into DMF at 110 oC. When adding iodobenzene into the
solvent, the peak concerning Ar-I stretch vibration shifted from 731 cm-1 to 742 cm-1
[33] (Figure S1, ESI) and diminishing of the 1062 cm-1 peak is probably due to
cleavage of the C6H5-I bond.[34] After that, a stoichiometric amount of NaOAc was
added to the mixture. As shown in Figure 1, a new peak (1140 cm-1) that belongs to
phenylthiol compound[35] appeared immediately. Based on the controlled
experiments as well as in-situ IR study, it can be concluded that the OAc group is
crucial to the formation of diphenyl disulfide intermediates. Note that the route for
generating C was proposed previously in Scheme 2a.[13, 20]
However, it remains to be uncovered whether or not the formation of N-methyl-3-
iodoindole is dispensable. Thus, two possible mechanisms have been proposed, as
shown in Scheme 2b and Scheme 2c. The reaction mechanisms were further
interrogated by quantum mechanical calculations. The potential energy surfaces
(PESs) and selected structural information for the two possible reaction routes are
shown in Figure 2. As shown in Figure 2a, the intermediate IM1 is formed when N-
methyl-3-iodoindole approaches LCuISC6H5 (L = 1,10-Phenanthroline). Insertion of
the metal center into the C-I bond via TS1 generates IM2, oxidizing CuI to CuIII.
Next, upon liberating an iodide anion in the reductive elimination, the C6H5S group
spontaneously couples with the N-methylindole-3-yl ligand to form an intact 3-

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phenylthioindole ligand; the final product was obtained. On the other hand, the
alternative direct coupling pathway (in Figure 2b), however, is not only energetically
but also entropically much less favored. The transformation starts from an encounter
complex IM4, in which the C6H5S, OAc and 1,10-Phenanthroline ligands are bound
to the CuII center. The C3-H bond of indole is activated by transferring the hydrogen
to an oxygen atom of the OAc ligand via TS2, generating IM5. Subsequently,
coupling of the N-methylindole-3-yl and the C6H5S ligands achieves by surmounting
TS3 and TS4. While TS2 and TS4 possess higher barrier as compared to TS1, the
barrier to generate N-methyl-3-iodoindole is comparative to TS4 as demonstrated in
our previous study.[11] In the process of direct coupling, the OAc group serves as a
hydrogen acceptor. Therefore, compared with the direct coupling pathway, the
coupling reaction involving intermediate N-methyl-3-iodoindole is more favored,
which is consistent with the experimental results that N-methyl-3-iodoindole could be
detected as an intermediate. Finally, by substituting the 1,10-Phenanthroline ligand to
2,2'-Bipyridine, we obtained almost the same PESs as the ones shown in Figure 2
(Figure S2, ESI). Thus, it is not the kinetic hindrance leading to the poor yield (in
Entry 13, Table 1) but most likely due to the lower solubility of CuI(2,2'-Bipyridine)
as compared to CuI(1,10-Phenanthroline).
Conclusion
In summary, we have presented a combined experimental and theoretical study on
C3-sulfenylation of indoles with sulfur powder; this reaction is promoted by 1,10-
phen and Cu(OAc)2. The addition of KI is crucial for the formation of the key

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intermediate N-methyl-3-iodoindole, and the in-situ IR analysis proved that NaOAc
can promote the coupling of aryl iodide and sulfur powder to form diphenyl disulfide.
According to DFT calculations, the coupling pathway involving the intermediate N-
methyl-3-iodoindole is energetically more favorable than the direct coupling route.
These findings provide insight into the course of the reaction and give experimental &
theoretical evidence for the existence of the key intermediate N-methyl-3-iodoindole.
Acknowledgements
The authors are grateful for the financial support from the Natural Science
Foundation of China (21476194, 21606104) and the National Key Research and
Development Program of China (2016YFB0301800).
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Table 1. Screening of Reaction Conditions a
entry
catalyst
CuI
ligand
additive
KI
base
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
1,4-
yield b
30
1
2
3
4
5
6
7
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
Na2CO3
K2CO3
Et3N
CuI
KI
8
CuI
KI
10
CuI
KI
NaOAc
KOAc
-
60
CuI
KI
55
CuI
KI
trace
42
CuI
KI
NaOAc
8
CuI
1,10-phen
KI
NaOAc
25
dioxane
NMP
Xylene
DMF
DMF
DMF
DMF
DMF
DMF
9
CuI
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
KI
KI
KI
KI
KI
KI
KI
KI
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
30
10
11
12
13
14
15
16
CuI
trace
48
CuBr
CuCl
CuBr2
CuCl2
46
49
51
Cu(OTf)2 1,10-phen
CuSO4 1,10-phen
46
34

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17
Cu(OAc)2 1,10-phen
CuOAc 1,10-phen
Cu(OAc)2 1,10-phen
KI
KI
KI
KI
NaOAc
NaOAc
NaOAc
NaOAc
DMF
DMF
DMF
DMF
95
18
91
19 c
20
41
Cu(OAc)2
Cu(OAc)2
-
trace
2,2'-
21
KI
NaOAc
DMF
trace
dipyridyl
22
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
Cu(OAc)2 1,10-phen
-
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
trace
trace
trace
trace
-
23
CuI
NH4I
I2
24
25
26d
27e
28f
29g
30h
KI
KI
KI
KI
KI
5
94
95
95
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), sulfur powder (2 mmol), catalyst
(10 mol%), ligand (10 mol%), additive (1 mmol), base (1 mmol), solvent (5 mL), 110
oC, air, 12 h. b Isolated yield. c 2a (1 mmol) and sulfur powder (1 mmol). d Se powder
(2 mmol) is instead of sulfur powder. e Under nitrogen atmosphere. f Under oxygen
atmosphere. g Using Na2S2O8 as oxidizer. h Adding water (0.1 ml) into the reaction.

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Table 2. Scope for Three-Component Coupling Reactions

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Scheme 1. Control experiments

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Figure 1. Overall three-dimensional Fourier transform IR (3D-FTIR) profile after
adding NaOAc.

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Scheme 2. Proposed mechanism, a): the route for generating diphenyldisulfide, b):
the N-methyl-3-iodoindole involved route, c): the direct coupling by the C-H
activation of indole

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Figure 2. Simplified PESs and selected structural information for a: the pathway
involving N-methyl-3-iodoindole and b: the direct coupling pathway as calculated at
the B97-1/BSII//B97-1/BSI level of theory. Zero-point corrected, relative energies are
given in kJ mol-1 and bond lengths in Å. Charges are omitted for the sake of clarity.

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Graphical Abstract