K2S2O8/arenesulfinate: An unprecedented thiolating system enabling selective sulfenylation of indoles under metal-free conditions

Article abstract of DOI:10.1039/c4ra08669d

An unprecedented thiolating system K₂S₂O₈/arenesulfinate is described for selective sulfenylation of indoles in CH₃CN/H₂O. This metal-free strategy enables a simple, efficient and environment-benign approach to the pharmaceutically important candidates, 3-arylthioindoles. Catalytically reactive halogen and aryl groups are well tolerated. This journal is

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K2S2O8/Arenesulfinate: an Unprecedented Thiolating
System Enabling Selective Sulfenylation of Indoles
under Metal-Free Conditions†
Cite this: DOI: 10.1039/x0xx00000x
Honghua Rao,*a Ping Wang,+b Jianchun Wang,+a Zhongfeng Li,+a Xinzhan Suna and
Shengli Caoa
Received xxth xxxxxxxxx 20xx,
Accepted xxth xxxxxxxxx 20xx
DOI: 10.1039/x0xx00000x
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19
bromosuccinimides,16 carbonates,17 persulfate18 and I2 displayed
An unprecedented thiolating system K2S2O8/arenesulfinate is
described for selective sulfenylation of indoles in
CH3CN/H2O. This metal-free strategy enables a simple,
efficient and environment-benign approach to the
pharmaceutically important candidates, 3-arylthioindoles.
Catalytically reactive halogen and aryl groups are well
tolerated.
efficient reactivities in the absence of any transition metals. Very
recently, sulfonyl hyrazide has been proved to be a successful
sulfenylation agent with catalytic amount of I2 molecule (Scheme
1b).20 Besides, Deng21 and other groups22 found that arenesulfinates
can also undergo sulfenylation reactions with indoles using molecule
I2 as the organocatalyst similarly (Scheme 1c). But it should be noted
that DMSO and phosphite or phosphine are crucial for the
deoxygenation of arylsulfonyl to arylthio group when using
arenesulfinate as the thiolating agent, and thus might give off
unpleasant odors (for dimethyl sulfide was generated from DMSO).
Therefore, it is still desirable to explore cheaper, simpler and more
environment-friendly sulfenylation systems for the syntheses of 3-
sulfanylindoles. It is well known that K2S2O8 can play as a radical
initiator to generate sulfonyl radicals from sulfinates,23 however, to
the best of our knowledge, no examples were given that K2S2O8
acted as promoters for deoxygenation reactions. Herein, we disclose
an unprecedented thiolating system, K2S2O8/arenesulfinate, for the
direct selective sulfenylation of indoles, affording 3-arylthioindoles
in moderate to excellent yields in CH3CN/H2O (v/v ratio 10:1)
without any other additives (Scheme 1d).
Indole scaffold is a prominent and privileged functionality occurring
in many biologically important compounds,1 and consequently, it
has been attracting considerable attentions from synthetic chemists
to develop strategies for the construction and chemical modification
of the indole ring.2 Among these strategies, the sulfenylation of
indoles is particularly attractive owing to the promising therapeutic
applications of the resulting thiolated indoles, in which the 3-
sulfanylindoles could serve as potential candidates for the treatment
of cancer,3 HIV,4 allergies,5 and heart disease (Figure 1).6
Figure 1. Examples of thiolated indoles with biological activities
Conventional methods for the syntheses of 3-sulfanylindoles rely on
the transition-metal-catalyzed cross-couplings between 3-
(pseudo)halogenated indoles and thiols.7 Given the electron-rich
nature of indole rings, direct C-H sulfenylation of indoles with
electrophiles has aroused much more interests in recent years due to
their advantages from both step- and atom-economy points of view
in industrial and green chemistry. In this regard, a variety of
thiolating agents such as thiols, disulfides and activated sulphur
reagents were employed with the C-H sulfenylation occurring
smoothly catalyzed by vanadium,8 magnesium,9 iron,10 cerium,11
copper,12 palladium13 and ruthenium catalysts.14 Some intriguing
achievements via direct C-H sulfenylations to 3-thioindoles were
further developed under metal-free conditions (Scheme 1a).15 For
instance, disulfides as the thiolating agents promoted by N-
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Scheme 1. C3-sulfenylation of indoles with various thiolating systems
Table 1. Optimization of reaction conditions.a
Table 2. Direct C-H sulfenylation of indoles to 3-sulfanylindoles with
K2S2O8/arenesulfinates as the thiolating system.a
Me
Me
Me
Me
Me
S
S
S
Entry Cat. (mol%) [Ox] (equiv.)
Solvent
Temp. (oC) Yieldb (%)
MeO
1
TBAB (10) TBHPdec (2.0)
TBAI (10) TBHPdec (2.0)
TBAI (10) TBHPaq (2.0)
TBAI (10) K2S2O8 (2.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
100
100
100
100
100
100
100
100
100
100
100
100
0
N
N
N
3a, 89%
3b, 80%
3c, 85%
H
H
H
2
Trace
<10
20
Me
Me
Br
3
S
S
S
Cl
4
N
N
N
5
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
K2S2O8 (2.0)
K2S2O8 (1.0)
32
Cl
3d, 69%
3e, 71%
Me
3f, 73%
H
H
H
6
46
Me
Me
S
S
S
7
(NH4)2S2O8 (1.0) CH3CN
37
8
Na2S2O8 (1.0)
Oxone (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (1.0)
K2S2O8 (0.5)
K2S2O8 (1.0)
CH3CN
CH3CN
EtOAc
DMF
41
Me
Ph
N
N
N
F
9
41
3g,78%
3h, 91%
3k, 87%
3i, 74%
3l, 87%
H
H
H
10
11
12
13c
14c
15c
16c,d
17e
18c
19c
a
<10
35
Cl
OMe
S
S
S
p-dioxane
0
N
N
N
3j, 83%
H
CH3CN/H2O 100
CH3CN/H2O 120
CH3CN/H2O 80
CH3CN/H2O 100
CH3CN/H2O 100
CH3CN/H2O 100
CH3CN/H2O 100
89
H
H
81
Cl
S
S
S
74
NO2
Me
70
N
N
N
3m, 88%
3n, 89%
H
3o, 79%
H
71
Me
65
88f, 76g
Me
Me
Cl
S
S
S
Me
Me
3r, 88%
Reaction conditions: indole (0.2 mmol), p-tolylsulfinate (0.3 mmol, 1.5
N
N
N
b
c
equiv.), solvent (1.0 mL), reaction time (24 h), under N2. Isolated yield.
Me
Me
3q, 91%
3p, 80%
Me
Me
d
e
f
CH3CN/H2O 10:1 (v/v ratio). Under air. CH3CN/H2O 1:1 (v/v ratio). p-
g
Tolylsulfinate (0.4 mmol, 2.0 equiv.). p-Tolylsulfinate (0.1 mmol, 0.5
Me
equiv.). cat. = catalyst, [Ox] = oxidant, Temp. = temperature, TBAB = tetra-
n-butylammonium bromide, TBAI = tetra-n-butylammonium iodide, TBHPdec
= tert-butyl hydroperoxide (5.0-6.0 M in decane), TBHPaq = tert-butyl
hydroperoxide (70% aqueous solution).
S
N
3s, 34%
H
a
Reaction conditions: indole (0.2 mmol), arenesulfinate (0.3 mmol, 1.5
equiv.), K2S2O8 (0.2 mmol, 1.0 equiv.), CH3CN/H2O (1.0 mL, v/v ratio 10:1),
o
reaction temperature (100 C), reaction time (24 h), under N2. Isolated yields
were given unless otherwise noted.
Since persulfate could greatly improve the direct C-H sulfenylation
of indole, several persulfates such as (NH4)2S2O8, Na2S2O8 and
oxone were tested and particularly K2S2O8 gave the highest (46%)
yield of product 3a (entries 6-9). In the meanwhile, the efficiency of
the direct sulfenylation shows a strong dependence on solvents. For
example, a sharp decrease was observed when using EtOAc or DMF
as the solvent (entries 10-11). Moreover, even no sulfenylation
product was observed when conducting the reaction in p-dioxane
(entry 12). Fortunately, a small amount of water (v/v ratio to CH3CN
1:10) enhanced the reaction efficiency dramatically, giving 3a in the
highest yield of 89% among all the solvents examined (entry 13).
Other endeavours to improve the yield of 3a were attempted, such as
altering the reaction temperature, reducing the loading of K2S2O8,
running the reaction in air atmosphere or loading different amounts
of reagent p-tolylsulfinate, but none of them could lead to higher
sulfenylation reactivity (entries 14-19).
Figure 2. Structure of compound 3a determined by X-Ray diffraction.
Since ammonium halide/TBHP organocatalytic system has already
been proved to be efficient for C-H functionalizations by our
group,24 the direct C-H sulfenylation of indole (1.0 equiv.) was
o
commenced by testing different ammonium halides at 100 C under
inert atmosphere, with TBHP as the oxidant, p-tolylsulfinate (1.5
equiv.) as the sulfenylation (or sulfonylation) agent, and CH3CN (1.0
mL) as the solvent. As screened in Table 1, either TBAB/TBHP or
TBAI/TBHP as the organocatalytic system afforded nearly full
recovery of indole (Table 1, entries 1-3), while the unexpected
product 3a, 3-p-tolylthioindole (Figure 2), was obtained in 20%
isolated yield if replacing TBHP with K2S2O8 (2.0 equiv.) (entry 4).
Inspiringly, the reaction efficiency increased to 46% when only
subjecting K2S2O8 (1.0 equiv.) to the reaction system (entries 5-6).
With the optimized reaction conditions in hand, the substrate
o
scope was explored at 100 C for 24 h under N2 atmosphere, using
K2S2O8/arenesulfinate as the thiolating system and CH3CN/H2O (v/v
ratio 10:1) as the solvent. As summarized in Table 2, free NH-
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indoles that might exhibit site-selectivity challenges were reacted undesired product 2-p-tosylindole 4 when employing only 1.0
with p-tolylsulfinate to the corresponding 3-arylthioindoles equivalent of p-tolylsulfinate (Scheme 3c). These observations
exclusively in good to excellent yields (Table 2, cf. 3a-g). Indoles suggest that both K2S2O8 and excess amount of arenesulfinates are
with electron-donating substituents such as methyl and methoxyl necessary for the radical sulfenylation reaction, and most
groups (cf. 3b-c) exhibited higher reactivities over that with electron- importantly, arylsulfonyl radical is involved in this process.
withdrawing groups such as fluoro, chloro and bromo groups (cf. 3d- Furthermore, deoxygenation of 3-p-tosylindole (or 2-p-tosylindole)
g). To some extent, the sulfenylation efficiency is affected by steric with K2S2O8 (1.0 equiv.) in CH3CN/H2O (v/v ratio 10:1) or under
hindrance, for example, 4-methylindole as the substrate afforded standard reaction conditions was conducted to explore that whether
slightly lower yield than indole did (cf. 3a-b). Other arylsulfinates 3-arylsulfonylindole (or 2-arylsulfonylindole) is the key intermediate
bearing electron-donating group (e.g. methoxy group) or electron- for this sulfenylation strategy, but unfortunately, full recovery of the
withdrawing groups (e.g. chloro and nitro group) were also tested, starting material was observed (Scheme 3d). This result indicates
and all of them reacted smoothly with indoles, yielding the desired that the tosylated indole is unlikely to serve as the key intermediate
3-arylthioindoles highly efficiently (cf. 3j-n). Besides, N-protected in the sulfenylation pathway, and arylsulfonyl radical most probably
indoles could couple with arenesulfinates effectively as well (cf. 3o- undergoes deoxygenation to arylthio radical (or cation) before finally
r). The availability of 3-substitued indoles for this sulfenylation introduced to indole ring.
strategy was also explored, and the desired 3-methyl-2-(p-
Based on previous work23,27 and the above results, a tentative
tolylthio)indole product from 3-methylindole was obtained, albeit in mechanism for this unprecedented sulfenylation reaction is proposed
a much lower yield (cf. 3s).25 Particularly, it is noteworthy that the in Scheme 4. The reaction is initiated via the homolysis of K2S2O8 to
•
radical anion SO4 - (scheme 4a), which could promote the formation
tolerance of catalytically reactive substituents such as halides and
phenyl groups enables further chemical modifications of the desired
3-arylthioindoles (cf. 3d-g, 3i, 3k-n and 3r), and thus promises the
discovery of various 3-sulfanylindoles with important therapeutic
value. To investigate the practical application of this transformation
in organic synthesis, we conducted gram-scale synthesis of 3a. The
desired product was produced without any significant decrease in
efficiency (86% versus 89% for the reaction on a 0.2 mmol scale for
3a; Scheme 2).
of arylsulfonyl radical A upon reaction with arenesulfinate (Scheme
4b), and the resulting radical A undergoes deoxygenation with
excess amount of arylsulfinate and SO42- to afford arylthio radical B
(Scheme 4c). The radical addition of B to indole ring gives
intermediate C, which is believed to undergo the direct
deprotonation to release the final product 3 (Scheme 4d). (However,
multiple pathways may be involved in this transformation. A
thorough mechanistic study is needed to unravel the mechanistic
intricacies of this process, especially for the generation of arylthio
radical B.)
Scheme 2. Gram-scale synthesis of 3a
Scheme 4. Proposed mechanism
In conclusion, we have developed a cheap, simple and efficient
strategy for direct C3-sulfenylation of indoles. This strategy employs
K2S2O8/arenesulfinate as the unprecedented thiolating system and
CH3CN/H2O as the solvent without any other additives. It shows
good tolerance towards carbon-halogen and aryl functionalities, thus
promises further modifications of the desired 3-arylthioindoles. As
such, the simplicity, high efficiency and environment-friendliness
Scheme 3. Control experiments
To gain some insights into the sulfenylation pathway with this
unprecedented thiolating system, some control experiments were associated with this protocol suggest its potential for widespread use
2-
conducted under various reaction conditions. As S2O8 usually in the construction of pharmaceutically important molecules 3-
serves as a radical initiator at elevated temperature,26 the radical arylthioindols. Further investigations to elucidate the detailed
process is a preferred consideration. Therefore, a radical-trapping mechanism and synthetic applications of this efficient and practical
experiment was carried out by introducing TEMPO into the standard sulfenylation protocol are currently underway in our lab.
conditions (Scheme 3a). And indeed, the desired sulfenylation
reaction did not occur, thus indicating that this transformation is
likely to involve a radical intermediate. Meanwhile, the reaction also
Acknowledgement
We are grateful to the Beijing Natural Science Foundation (Grant No.
2144045), Beijing Municipal Education Commission Foundation
(Grant No. KM201410028007), National Natural Science Foundation
did not take place in the absence of K2S2O8 (Scheme 3b), whereas it
afforded only 52% of the desired product 3a and 29% of the
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DOI: 10.1039/C4RA08669D
23 Z. V. Todres, in Ion-Radical Organic Chemistry: Principles and
Applications, 2nd Ed., CRC Press: New York, 2009.
24 (a) H. H. Rao, X. Y. Ma, Q. Z. Liu, S. L. Cao and C.-J. Li, Adv. Synth.
Catal. 2013, 355, 2191; (b) X. Y. Ma, Z. F. Li, F. J. Liu, S. L. Cao
and H. H. Rao, Adv. Synth. Catal. 2014, 356, 1741.
25 A reaction mixture of 2-methylindole (0.2 mmol), 3-methylindole
(0.2 mmol), K2S2O8 (0.2 mmol, 1.0 equiv.) and
mmol, 1.5 equiv.) in CH3CN/H2O (1.0 mL, v/v ratio 10:1) was stirred
at 100 oC under N2 atmosphere. In 24 h, product 2-methyl-3-
tolylthioindole (3h) was isolated in 87%, while product 3-methyl-2-
-tolylthioindole (3q) in less than 5%.
p-tolylsulfinate (0.3
p
-
p
26 C.-M. Hu and F.-L. Qing, J. Org. Chem. 1991, 56, 6348.
27 F. Freeman, Chem. Rev. 1984, 84, 117.
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DOI: 10.1039/C4RA08669D
One Sentence:
Direct selective sulfenylation of indoles is disclosed via an unprecedented deoxygenation of
arylsulfonyl radical only under K2S2O8/arenesulfinate system in CH3CN/H2O.
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