A sulfenylation reaction: Direct synthesis of 3-arylsulfinylindoles from arylsulfinic acids and indoles in water

Article abstract of DOI:10.1021/ol503659t

A novel and efficient electrophilic sulfenylation of indoles with arylsulfinic acids is realized. The reaction utilizes readily available starting materials in water under catalyst- and additive-free conditions, providing an alternative and attractive approach to 3-arylsulfinylindoles with high yields. Preliminary mechanistic investigation suggested that the reaction is through an electrophilic substitution process.

Full text of DOI:10.1021/ol503659t

Letter
pubs.acs.org/OrgLett
A Sulfenylation Reaction: Direct Synthesis of 3‑Arylsulfinylindoles
from Arylsulfinic Acids and Indoles in Water
†
†,‡
†
,†,‡
Tao Miao, Pinhua Li, Yicheng Zhang, and Lei Wang*
†
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
‡
State Key Laboratory of Organometallic Chemistry and Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Shanghai 200032, P. R. China
*
S Supporting Information
ABSTRACT: A novel and efficient electrophilic sulfenylation of indoles with arylsulfinic acids is realized. The reaction utilizes
readily available starting materials in water under catalyst- and additive-free conditions, providing an alternative and attractive
approach to 3-arylsulfinylindoles with high yields. Preliminary mechanistic investigation suggested that the reaction is through an
electrophilic substitution process.
ulfoxides, one of the most valuable compounds, constitute
Scheme 1. Synthetic Application of Arylsulfinic Acids (Salts)
1
2
S
the core motif of natural products, materials, and
3
biologically significant molecules, representative examples
3a
3b
being the antiulcer agent esomeprazole and modafinil for
narcolepsy. Furthermore, sulfoxides have been used in
4
5
organocatalysis, and as ligands in organometallic chemistry.
Despite their wide applicability, their direct synthesis remains a
challenge. In general, sulfoxides are prepared by selective
6
oxidation of the parent thioether and the nucleophilic
substitution of sulfinyl derivatives with organometallic
7
reagents. An advance in the synthesis of diaryl sulfoxides is
Pd-catalyzed cross-coupling of sulfenate anions with aryl
8
iodides and bromides. Although some of these methods are
popular and attractive, they still suffer from limitations in
substrate scope, and multistep processes to reactants.
Accordingly, development of straightforward, milder, and
environmentally benign methods for the preparation of
sulfoxides from easily available substrates is highly desirable.
Arylsulfinic acids (salts) are versatile and readily available
9
acids with alkenes leading to β-hydroxysulfones (Scheme 1, eq
intermediates in organic synthesis. In recent years, much effort
11a
2
). Compared to the preparation of functionalized sulfones
has been devoted toward developing sulfonylation reactions
using sulfinic acids (salts) as sulfonylating agents. Among the
reported methods, two different pathways have been developed
to construct sulfones. First, transition-metal-catalyzed cross-
coupling of sodium arenesulfinates with aryl halides and
organoboronic acids has proven to be an effective approach
from arylsulfinic acids via the sulfonyl anions and radicals
process, sulfinyl cations from arylsulfinic acids have never been
used for the synthesis of sulfoxides and sulfones.
Herein, we present a novel strategy for the direct and highly
efficient synthesis of 3-arylsulfinylindoles using arylsulfinic acids
as electrophiles with indoles under metal- and additive-free
conditions at ambient temperature in water (Scheme 1, eq 3).
A preliminary mechanism revealed that an electrophilic
substitution process was involved, and the arylsulfinyl cation
1
0
to sulfones. Arylsulfinic salts as the precursors of the sulfonyl
anion reacted with a metal catalyst to form a key intermediate,
sulfonyl-metal species (Scheme 1, eq 1). Second, addition of
the sulfonyl radical to a carbon−carbon multiple bond provided
an alternative for the preparation of functionalized aryl-
1
1
sulfones. For example, Lei and co-workers described a
Received: December 18, 2014
dioxygen-triggered oxidative radical reaction of aryl-sulfinic
©
XXXX American Chemical Society
A
DOI: 10.1021/ol503659t
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Letter
was found to be a stable and key intermediate by ESI-MS
probe.
Treatment of p-tolylsulfinic acid (1a, 1.0 equiv) with 1-
methylindole (2a, 1.0 equiv) in water at room temperature
under air for 24 h afforded 1-methyl-3-(p-tolylsulfinyl)-indole
tion. An obvious ortho-position effect was observed in the
reaction (3f vs 3g). It should be noted that the trifluoromethyl
group (CF ), as a useful structural motif in many biologically
3
12
active molecules, attached on the arylsulfinic acids afforded
the corresponding product (3i) in excellent yield. More bulky
1,1′-biphenyl-, 1-naphthyl-, and 2-naphthylsulfinic acids also
reacted with 2a smoothly to offer the desired sulfoxides 3j, 3k,
and 3l in good yields.
(
3a) in 45% yield (Table S1, entry 1, Supporting Information).
1
13
The structure of 3a was characterized by H, C NMR
spectroscopy and HRMS and was confirmed by single-crystal
X-ray diffraction analysis (see Supporting Information).
Encouraged by this result, we optimized the reaction conditions
to improve the product yield. To our delight, when the molar
ratio of 1a/2a was increased to 2:1, product 3a was obtained in
To further investigate the scope of indoles, various N-
substituted indoles were treated with p-tolylsulfinic acid and p-
chlorophenylsulfinic acid under optimized reaction conditions,
and the results were summarized in Scheme 3. Both electron-
8
4% yield (Table S1, entry 2). Then, various solvents were
a
examined. The results indicated that organic solvents, such as
tetrahydrofuran (THF), dioxane, ethanol, dimethyl sulfoxide
Scheme 3. Scope of Indoles
(
DMSO), N,N-dimethylformamide (DMF), N,N-dimethyl-
acetamide (DMA), and acetic acid, gave lower yields of 3a
(
(
(
Table S1, entries 3−9). However, acetonitrile, dichloroethane
DCE), and nitromethane prohibited the reaction completely
Table S1, entries 10−12). After extensive additive, reaction
time, and temperature screening, it turned out that the optimal
parameters included being additive-free at room temperature
for 24 h.
Having the optimized reaction conditions, the scope of this
reaction with respect to the arylsulfinic acids was examined,
shown in Scheme 2. The results indicated that the substituted
arylsulfinic acids bearing methyl, tert-butyl, and methoxy on the
aromatic rings reacted with 1-methylindole (2a) to afford the
corresponding sulfenylation products in good yields (3a−d).
Halogens on the arylsulfinic acids were well tolerated, providing
good yields of products (3e−i), which are the potential
substrates for further transition-metal-catalyzed functionaliza-
a
Scheme 2. Scope of Arylsulfinic Acids
a
Reaction conditions: 1 (0.50 mmol), 2 (0.25 mmol), H O (1.0 mL),
2
b
at room temperature, 24 h, isolated yields of the products. The
reaction was performed at 70 °C for 24 h.
donating and -withdrawing groups on the 4−7-positions of
indole cores were tolerated, and the corresponding products
(
3m−3aj) were obtained in 45−98% yields. It is obvious that
the more electron-poor indoles were less reactive and provided
lower yields of the products (3aa, 3ab). It is noteworthy that,
by introducing a methyl group into the 2-position of the indole
nucleus, almost quantitative yields were obtained (3ac, 3ad).
For N-substituted indoles, Et, Bu, and Bn substituents (3ae−
a
Reaction conditions: 1 (0.50 mmol), 2a (0.25 mmol), H O (1.0 mL),
2
b
3
aj) proved to be suitable substrates, while COMe was inert
at room temperature, 24 h, isolated yields of the products. The
reaction was performed at 70 °C for 24 h. The reaction was
c
(3ak and 3al). These results clearly indicated that the sufficient
performed in the mixture of acetic acid and water (1:1, 1.0 mL).
electron density on the pyrrole ring of indole accelerates the
B
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Letter
electrophilic substitution. It is well-known that indoles undergo
electrophilic substitution at the 3-position, whereas pyrroles
results and isotope labeling experiment (see Supporting
Information for detail), which is in agreement with an
electrophilic substitution process. First, the reaction was
initiated by a protonation of arylsulfinic acid (1) to form
species A under acidic conditions. The formed A underwent a
dehydration to release sulfinyl cation B. Subsequently, the
intermediate C could be produced by a direct electrophilic
substitution of an indole (2a) at the C-3 position. Finally, loss
of a proton from C afforded product 3.
13
undergo the reaction at the 2-position. Interesting, the
sulfenylation reaction of electron-rich N-methylpyrrole with p-
tolylsulfinic acid and p-chlorophenylsulfinic acid at 70 °C
generated 3-substituted products 3am and 3an in good yields,
which probably undergo a rearrangement from 2-sulfinyl-
14
pyrroles to isomeric 3-sulfinylpyrroles, and the structure of
3
am was confirmed by X-ray crystallographic analysis
(
Supporting Information).
To understand the reaction process, the model reaction was
In summary, we have developed a highly attractive and
operationally simple method to construct indol-3-yl aryl
sulfoxides from readily available reactants. Notably, various
substrates were employed in the reaction and the correspond-
ing products were obtained in good to excellent yields under
mild conditions. The novel method proceeded without any
additional catalysts and additives and realized direct sulfenyla-
tion of indoles in water, which made this transformation
sustainable and environmentally friendly. The preliminary
mechanism revealed that an electrophilic substitution of the
sulfinyl cation process was involved, determined by ESI-MS
analysis. The unique transformation holds significant potential
for application to a series of new organic reactions. Our further
efforts in this area are currently underway.
performed under an O and Ar atmosphere instead of air.
2
However, no improvement of this transformation was found,
providing 3a in 80% and 82% yields, respectively. The results
demonstrated that a radical process might not be involved in
the reaction, even though O , as a clean and environmental
friendly radical initiator, was used in sulfonylation reactions.
Electrospray ionization mass spectrometry (ESI-MS), as a soft
MS ionization technique, promotes only a few fragmentation
products and is also rapidly becoming the technique of choice
for mechanistic studies and high-throughput screenings of
homogeneous catalysis. Considering the pivotal importance
of characterizing the cationic species, we decided to take
advantage of ESI-MS analysis on the model reaction of 1a and
2
11a,b
15
ASSOCIATED CONTENT
Supporting Information
2
a to further probe the reaction mechanism. After the model
■
reaction was stirred in water at room temperature for 2 h, an
aliquot was withdrawn from the reaction mixture and directly
analyzed by ESI-MS in positive ion mode. Several peaks with
m/z signals characterized for cationic intermediates were
trapped. On the analysis of the present m/z signals in Figure
*
S
Full experimental details and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
, structures of the cationic intermediates were proposed,
AUTHOR INFORMATION
Corresponding Author
■
assigned as A, B, and C.
*
E-mail: leiwang88@hotmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is financially supported by the National Science
Foundation of China (Nos. 21372095, 21172092).
■
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