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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
letter
A
en
C. Xu et al.
Letter
Synlett
Synthesis of 3-Sulfenylindoles from Indoles and Various Sulfenyla-
tion Agents through Aerobic Oxidative C–S Bond Coupling
Chaorong Xu
R
S
KI (20 mol%)
NaNO2 (10 mol%)
R-SSO3Na
or
RSH
Shanli Yi
R1
R2
R1
R2
Meichao Li*
Xinquan Hu
Nan Sun
O2-balloon, AcOH, MeCN
60–80 °C
N
R3
or
N
R3
R-S-S-R
49 examples
Liqun Jin
38–89% isolated yields
Baoxiang Hu
Zhenlu Shen*
College of Chemical Engineering, Zhejiang
University of Technology, Hangzhou 310014,
P. R. of China
Received: 02.06.2018
Accepted after revision: 02.07.2018
Published online: 02.08.2018
fides,1b,11 thiols,12 and Bunte salts (RSSO3Na),13 have been
successfully applied in 3-sulfenylations of indoles. However,
some of these 3-sulfenylation reactions are catalyzed by
transition-metal catalysts whereas others require specific
substrates or moisture-free reaction conditions; moreover,
some of the sulfenylation reagents are difficult to obtain. It
should be noted that thiols and disulfides are attractive
sulfenylation agents because of their ready availability. In
addition, Bunte salts are also good sulfenylation agents that
are stable, odorless, and easy to prepare.14
Molecular iodine is a nontoxic, inexpensive, and readily
available catalyst for various organic transformations. In
particular, the I2–DMSO system is an important catalytic
oxidation system for C–S cross-coupling reactions.11b,13a,15
Although pure DMSO is not considered toxic, solutions of
inorganic salts or organic compounds in DMSO are poten-
tially dangerous because of the high penetrating power of
DMSO and its ability to transport some substances across
skin membranes.16 More importantly, when DMSO is used
as an oxidant, an equal amount of dimethyl sulfide is re-
leased. To meet the requirement for an environmentally be-
nign processes, the use of molecular oxygen as the terminal
oxidant has received great attraction due to its remarkable
advantages, such as its great abundance, its low cost, and
the generation of water as the sole byproduct. Therefore, it
would be ideal if molecular oxygen could serve as the ter-
minal oxidant in iodine-catalyzed reactions.
DOI: 10.1055/s-0037-1610532; Art ID: st-2018-u0335-l
Abstract A novel aerobic catalytic oxidation system for the sulfenyla-
tion of indoles with a variety of sulfenylation agents through oxidative
C–S bond coupling has been successfully developed. The reactions were
performed with potassium iodide as the catalyst, sodium nitrite as the
co-catalyst, and molecular oxygen as the terminal oxidant in the pres-
ence of acetic acid. Under the optimal reaction conditions, a number of
indoles could be sulfenylated with Bunte salts, thiols, or disulfides to
generate 3-sulfenylindoles in good yields. This protocol provided an effi-
cient and environmentally benign strategy for the synthesis of 3-
sulfenylindoles.
Key words indoles, sulfenylation, C–S bond coupling, catalytic oxida-
tion, regioselectivity
The construction of C–S bonds represents an important
step in organic synthesis.1 Consequently, new approaches
for the formation of C–S bonds have long inspired synthetic
organic chemists. In recent years, direct sulfenylation
through C–H functionalization has attracted remarkable at-
tention and has become an efficient strategy for construct-
ing complicated organosulfur compounds.
Substituted indole derivatives are widespread in many
natural products, and are quite significant in medicinal
chemistry.2 The development of general protocols for the
synthesis of 3-sulfenylindoles has received significant in-
terest because some of these compounds can be used to
treat allergies, cancer, HIV, heart disease, and bacterial in-
fections.3 The direct sulfenylation of indoles through C–H
functionalization has emerged as a highly attractive and
powerful strategy for synthesizing 3-sulfenylindoles. Vari-
ous sulfenylation agents, such as arylsulfonium salts,4 sulfe-
nyl halides,5 arylsulfonyl chlorides,6 aryl-N-thioimides,7
O,S-acetals,8 sulfonyl hydrazides,1c,9 sulfinic acids,10 disul-
Our group has reported 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO)/tert-butyl nitrite (TBN)/O2, TEMPO/Na-
NO2/O2,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)/TBN/O2, DDQ/TEMPO/TBN/O2, and 9-azabicy-
clo[3.3.1]nonane N-oxyl (ABNO)/TBN/O2 catalytic oxidation
systems for various oxidation reactions in which TEMPO,
DDQ, or ABNO was employed as the catalyst, TBN or NaNO2
served as the co-catalyst, and molecular oxygen acted as
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G