Iodine-catalyzed regioselective 2-sulfonylation of indoles with sodium sulfinates

Article abstract of DOI:10.1021/ol402987u

Iodine-catalyzed selective 2-arylsulfonyl indole formation from indoles and sodium sulfinates is disclosed. Various substituted 2-arylsulfonyl indoles were obtained in one pot in the absence of metal catalyst at room temperature under air.

Full text of DOI:10.1021/ol402987u

Letter
pubs.acs.org/OrgLett
Iodine-Catalyzed Regioselective 2‑Sulfonylation of Indoles with
Sodium Sulfinates
Fuhong Xiao,† Hui Chen,† Hao Xie,† Shuqing Chen,† Luo Yang,† and Guo-Jun Deng*,†,‡
†Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
‡Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080,
China
S
* Supporting Information
ABSTRACT: Iodine-catalyzed selective 2-arylsulfonyl indole
formation from indoles and sodium sulfinates is disclosed.
Various substituted 2-arylsulfonyl indoles were obtained in one
pot in the absence of metal catalyst at room temperature under
air.
rganosulfones are important intermediates for agro-
Ochemicals, pharmaceuticals, and protecting and activating
groups.1 Among them, aryl sulfones have gained great attention
due to their prominent drug activity, such as anti-HIV-1,
antifungal, antibacterial, and antitumoral.2 As a consequence,
development of facile methods for aryl sulfones has stimulated
considerable interest. The common methods for preparing aryl
sulfones include oxidation of the corresponding aryl sulfides3 or
Figure 1. Structure of SR 33805 oxalate.
Friedel−Crafts sulfonylation of arenes with arenesulfonyl
halides,4 arenesulfonic acids,5 or their derivatives6 in the
presence of a strong acid catalyst. In recent years, many efforts
have been expended on developing sulfonylation reactions in
the absence of strong acid. Among the various methods
developed, palladium- or copper-catalyzed cross-coupling
reaction of sodium arenesulfinates (or arenesulfonyl halides)
with alkyl or aryl halides has proven to be an effective approach
to prepare aryl sulfones, especially for unsymmetrical diaryl
sulfones.7,8 Besides aryl halides, aryl boronic acids9 and
diaryliodonium salts10 also can be used as coupling reagents
with or without metal catalyst. Direct sulfonylation via C−H
functionalization can provide a shortcut for aryl sulfones.11
Dong and co-workers developed a palladium-catalyzed direct
sulfonylation of 2-aryl pyridines with arylsulfonyl chlorides.12
However, direct sulfonylation of an aromatic C−H bond with
less reactive sodium arenesulfinates is rare.
Indolyl aryl sulfones can be found in various drugs, such as
SR 33805 oxalate, a Ca2+ antagonist with length-dependent
Ca2+-sensitizing properties in cardiac myocytes (Figure 1).13
Indolyl aryl sulfones are generally prepared by oxidation of the
corresponding arylthioindoles.14 In recent years, alternative
approaches have been developed for 3-arylsulfonyl indoles
using aryl sulfonyl halides or aryl sulfonic acids as sulfonylation
reagents.15 Driver and co-workers developed an approach for 3-
arylsulfonyl indoles via Rh-catalyzed sulfone group migration.16
Meanwhile, a few approaches have also been developed for 2-
arylsulfonyl indoles. The most used methods are oxidation of
indolyl aryl sulfides or deprotonation and substitution reaction
from indoles and aryl sulfonyl halides in the presence of
butyllithium under anhydrous conditions.17 Obviously, the later
method is not suitable for indoles with active substituents.
Thus, it is highly desirable to develop a general method with
high selectivity and good functional group tolerance for 2-
arylsulfonyl indoles. Herein, we describe an iodine-catalyzed
regioselective sulfonylation of indoles with sodium sulfinates
under mild conditions, affording 2-arylsulfonyl indoles in good
to high yields.18
To achieve the best sulfonylation conditions, the reaction of
indole (1a) with sodium benzenesulfinate (2a) was selected as
the model reaction using tert-butyl hydroperoxide (TBHP, 1.0
equiv) as oxidant in acetic acid. In the absence of metal catalyst,
various iodide-containing additives were investigated at room
temperature under an air atmosphere. The desired product 2-
(phenylsulfonyl)-1H-indole (3a) was obtained in good yield
when 20 mol % of KI, N-iodosuccinimide (NIS), and
tetrabutylammonium iodide (TBAI) were employed (Table 1,
entries 1−3). The use of molecular I2 (10 mol %) could further
improve the reaction yield to 92% (entry 4). Other oxidants
were also investigated and showed less efficiency (entries 5−9).
The product was observed in 15% yield when oxygen was used
as the sole oxidant (entry 9). Other organic solvents such as
TFA, PivOH, toluene, and anisole were less effective for this
Received: October 17, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol402987u | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Table 2. Sulfonylation of Indole (1a) with Sodium
Sulfinates
a
b
entry
catalyst
oxidant
solvent
yield (%)
1
KI
NIS
TBAI
I2
TBHP
TBHP
TBHP
TBHP
TBP
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TFA
68
75
60
92
10
78
54
55
15
4
2
3
4
5
I2
6
I2
H2O2
7
I2
K2S2O8
Oxone
O2
8
I2
9
I2
10
11
12
13
14
15
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
I2
PivOH
toluene
anisole
AcOH
AcOH
50
8
I2
I2
6
0
c
I2
91
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (0.1
mmol, for I2 0.05 mmol), oxidant (0.5 mmol), solvent (1.0 mL), room
b
c
temperature, 4 h under air. GC yield based on 1a. Under Ar.
kind of reaction (entries 10−13). As a control experiment, no
desired product 3a was observed in the absence of I2 catalyst
(entry 14).
The scope of the sodium sulfinate substrates was investigated
under the optimized conditions (Table 2). Various 4-
substituted arylsulfinic acid sodium salts could smoothly react
with 1a to give 2-arylsulfonyl indoles in good to high yields
(entries 2−5). Functional groups such as halogens, trifluor-
omethyl, and trifluoromethoxy could survive well under the
optimized reaction conditions (entries 7−11). It should be
noted that no cleavage of the C−halogen bond was observed. 2-
(Naphthalen-2-ylsulfonyl)-1H-indole (3l) could be obtained in
81% when 2-naphthylsulfinic acid sodium salt (2l) was reacted
with 1a (entry 12). To our delight, besides aromatic sodium
sulfinates, aliphatic sodium methanesulfinate (2m) also could
couple with indole to give 2-(methylsulfonyl)-1H-indole (3m)
in 90% yield (entry 13). It should be noted that the
sulfonylation reaction occurred exclusively at the C-2 position
of the indole ring in all cases.
The influence of the substituents on the indole moiety was
also evaluated (Table 3). Indoles bearing various substituents
could smoothly couple with sodium benzenesulfinate (2a).
When 3-methylindole was employed, the corresponding
product 3n was obtained in 84% yield (entry 1). Slightly
higher yields could be obtained when the methyl group was
located at C-4 and C-7 position in the indole ring (entries 2
and 3). The reaction yields decreased dramatically when 5-
halogen substituted indoles were used as substrates (entries 5
and 6). However, better yields could be obtained when 4-halo
and 5-halo indoles were used (entries 7−9). When the C-2
position of the indole ring was occupied by a methyl group,
only a trace amount of C-3 sulfonylation product was observed
(entry 10). Protected 1-methylindole (1l) also could couple
with 2a and gave lower yield than that of free indole (entry 11).
To gather more information, a control experiment was set up
under the standard conditions. Competition reactions between
styrene and indole with sodium benzenesulfinate were carried
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), I2 (0.05 mmol),
TBHP (0.5 mmol), AcOH (1.0 mL), room temperature, air, 1−4 h.
b
Isolated yield.
out under standard reaction conditions (Scheme 1). Vinyl
sulphone can be obtained in 45% yield as determined by GC
and GC−MS analysis. This means the mechanism might be
similar to Nair’s work, which using CAN as an oxidant.19 Based
on this, a plausible mechanism for the metal-free method to
construct 2-arylsulfonyl indoles is illustrated in Scheme 2. As a
first step, an oxygen-centered radical is generated by oxidation
of sulfinate 1a with TBHP. The oxygen-centered radical can be
resonated to a sulphonyl radical. Addition of the sulphonyl
radical with indole affords an intermediate radical A, which can
be reacted with molecular iodine to form an intermediate B and
an iodide radical. Elimination of intermediate B generates the
desired product 3a and releases HI, which can be reoxidized
into iodide radical by TBHP. Combination of two iodide
radicals regenerates molecular iodine. In the whole process, a
catalytic amount of iodine is enough.
In summary, we have developed a simple method for 2-
arylsulfonyl indoles from indoles and sodium sulfinates in the
absence of metal catalyst. A catalytic amount of iodine acted as
efficient promoter for this transformation, and the reaction
could be finished in a couple of hours at room temperature.
The direct sulfonylation reaction occurred exclusively at the C-
2 position of the indole ring. Halogen other functional groups
were well tolerated. This method afforded a novel alternative
approach for the synthesis of biologically important hetero
diaryl sulfones from sodium sulfinates.
B
dx.doi.org/10.1021/ol402987u | Org. Lett. XXXX, XXX, XXX−XXX

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a
Table 3. Sulfonylation of Various Indoles with 2a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gjdeng@xtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the Hunan
Provincial Natural Science Foundation of China (11JJ1003,
12JJ7002), the New Century Excellent Talents in University
from Ministry of Education of China (NCET-11-0974), and
the Research Fund for the Doctoral Program of Higher
Education of China, Ministry of Education of China
(20124301110005).
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ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and characterization data of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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