A novel synthetic route to 3-sulfenyland 3-selenylindoles by n-bu 4ni-induced electrophilic cyclization

Article abstract of DOI:10.1021/ol8021287

3-Sulfenyl-and 3-selenylindoles are prepared in excellent yields by the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by electrophilic cyclization with arylsulfenyl chlorides and arylselenyl chlorides in the presence of a stoichiometric amount of n-Bu₄NI.

Full text of DOI:10.1021/ol8021287

ORGANIC
LETTERS
2009
Vol. 11, No. 1
173-176
A Novel Synthetic Route to 3-Sulfenyl-
and 3-Selenylindoles by n-Bu4NI-Induced
Electrophilic Cyclization
Yu Chen, Chul-Hee Cho, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received September 10, 2008
ABSTRACT
3-Sulfenyl- and 3-selenylindoles are prepared in excellent yields by the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-o-iodoanilines
and terminal alkynes, followed by electrophilic cyclization with arylsulfenyl chlorides and arylselenyl chlorides in the presence of a stoichiometric
amount of n-Bu4NI.
The indole ring is a ubiquitous heterocycle in a wide variety
of biologically important compounds as well as pharmaceuti-
cal agents.1 Among the numerous indole derivatives, 3-thio-
indoles have recently attracted considerable interest from the
pharmaceutical industry due to their therapeutic value in
diseases, such as HIV,2 cancer,3 obesity,4 heart disease,5 and
allergies.6 A number of synthetic routes to 3-sulfenylindoles
have been demonstrated in the literature, including the direct
sulfenylation of indoles by disulfides7 and quinone mono-
O,S-acetals;8 halide-catalyzed sulfenylation by N-thioalkyl-
(aryl)phthalimides;9 sulfenylation using thiols activated in
situ by N-chlorosuccinimide,10 phenyliodine(III) bis(trifluo-
roacetate),11 Selectfluor,12 or transition-metal catalysts;13
oxidant-promoted thiocyanation with ammonium thiocyan-
ate;14 and treatment of 3,3′-dithiobisindoles with metalated
aromatics or heterocycles.15 In general, all these protocols
have focused on direct sulfenylation at the 3-position of the
indole nucleus using different sulfenylating agents.
Recently, our group has shown that the palladium/copper-
catalyzed coupling of functionally substituted aryl halides
and terminal alkynes provides aromatic acetylenes, which
readily undergo electrophilic cyclization in the presence of
halogen, sulfur, and selenium electrophiles to produce an
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W.; Wu, L. Tetrahedron Lett. 2005, 46, 5831. (c) Yadav, J. S.; Reddy,
B. V. S.; Krishna, A. D.; Reddy, C. S.; Narsaiah, A. V. Synthesis 2005,
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10.1021/ol8021287 CCC: $40.75
Published on Web 12/01/2008
2009 American Chemical Society

extraordinary range of medicinally interesting, functionally
substituted heterocycles and carbocycles, including indoles,16
benzofurans,17 benzothiophenes,18 coumestans,19 chromo-
nes,20 isocoumarins,21 isochromenes,22 isoquinolines,23 quin-
olines,24 and isoxazoles.25 Although we have successfully
prepared 3-sulfenylbenzofurans17 and -benzothiophenes18 by
electrophilic cyclization using arylsulfenyl chlorides as the
electrophile, all previous attempts to prepare 3-sulfenylin-
doles using similar methods have thus far been unsuccessful.
The pharmaceutical interest in 3-sulfenylindoles has inspired
us to explore this approach further. In this paper, we report
our preliminary results on the synthesis of 3-sulfenylindoles
using electrophilic sulfur cyclization chemistry. To the best
of our knowledge, this is the first synthetic protocol that
installs the sulfenyl group in the 3-position of an indole ring
while simultaneously constructing the indole nucleus itself.
Our previous results indicated that under common elec-
trophilic cyclization conditions, the reaction between N,N-
dimethyl-(2-phenylethynyl)aniline (1a) and 4-nitrobenzene-
sulfenyl chloride leads predominantly to the simple triple
bond addition product 2. After several unsuccessful trials,
we were pleased to find that in the presence of 1 equiv of
n-Bu4NI the triple bond addition reaction was completely
shut down and the reaction slowly produced the desired
cyclization product 3a solely (Scheme 1).
temperature. Thus, when the reaction is run at 70 °C in
dichloroethane (DCE), instead of room temperature in
dichloromethane (DCM) (Table 1, entries 1 and 2), a 90%
Table 1. n-Bu4NI-Induced Electrophilic Cyclization of
N,N-Dimethyl-(2-phenylethynyl)aniline with
4-Nitrobenzenesulfenyl Chloride
n-Bu4NI
entry (equiv)
solvent T (°C) time (h)
% yielda
1
2
3
1
CH2Cl2
(CH2Cl)2
(CH2Cl)2
rt
70
70
60
5
86 (3a)
1
90 (3a)
0.5
5
48 (3a) + 45 (2)
a Isolated yields after column chromatography.
yield of the desired 3-(arylsulfenyl)indole 3a was obtained
in 5 h. An equimolar amount of n-Bu4NI is found necessary
for exclusive formation of the cyclization product. When 0.5
equiv of n-Bu4NI is used, a mixture of both indole 3a and
triple bond addition products is obtained in approximately a
1:1 ratio (Table 1, entry 3).
Scheme 1. Effect of n-Bu4NI in the Electrophilic Cyclization
The starting N,N-dialkyl-2-(1-alkynyl)anilines 1 are readily
prepared by the Sonogashira coupling26 of N,N-dialkyl-o-
iodoanilines 4 and terminal alkynes (eq 1). The results of
this palladium/copper-catalyzed coupling process are sum-
marized in the Supporting Information.
The cyclization has proved to be a very general route to
a variety of 3-substituted indoles (Table 2). Besides 4-ni-
trobenzenesulfenyl chloride, several other arylsulfenyl chlo-
rides have also been successfully employed as electrophiles
in this cyclization. When electron-deficient pentafluoroben-
zenesulfenyl chloride was employed, an 87% isolated yield
of the corresponding indole was obtained (Table 2, entry
2). The more electron-rich arylsulfenyl chlorides phenyl-
sulfenyl chloride and p-toluenesulfenyl chloride afforded
similar high yields (Table 2, entries 3 and 4). When the more
sterically demanding 2-nitrobenzenesulfenyl chloride was
used, the yield of the cyclization product 3e decreased to
52% (Table 2, entry 5), although the starting material 1a
was completely consumed. However, products of simple
Our preliminary results indicated that the cyclization
reaction can be substantially accelerated at an elevated
(16) (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62.
(b) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037.
(17) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292.
(18) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
(19) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985.
(20) Zhou, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2006,
71, 1626.
(21) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936.
(22) Yue, D.; Della Ca´, N.; Larock, R. C. J. Org. Chem. 2006, 71, 3381.
(23) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437.
(26) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 5,
p 203. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467.
(24) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005,
7, 763.
(25) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643.
174
Org. Lett., Vol. 11, No. 1, 2009

Table 2. Preparation of 3-Sulfenyl- and 3-Selenylindoles by n-Bu4NI-Induced Electrophilic Cyclizationa
a Representative procedure: N,N-dialkyl-2-(1-alkynyl)aniline 1 (0.50 mmol), n-Bu4NI (0.50 mmol), arylsulfenyl/arylselenenyl chloride (1.00 mmol), and
5 mL of DCE were mixed in a sealed 4-dram vial. The reaction was stirred at 70 °C for the indicated time. b Isolated yields after column chromatography.
addition of the 2-nitrobenzenesulfenyl chloride to the triple
bond of 1a were observed. Besides arylsulfenyl chlorides,
an alkylsulfenyl chloride, trichloromethylsulfenyl chloride,
has also been employed in this cyclization; however, this
reagent only afforded a complex reaction mixture under our
current reaction conditions.
Despite our previous lack of success with the synthesis
of 3-selenylindoles via analogous electrophilic cyclization
chemistry,16a the cyclization of aniline 1a by PhSeCl plus
n-Bu4NI was investigated. We were quite pleased to find
that our current reaction conditions were equally suitable for
the synthesis of 3-selenylindoles (Table 2, entry 6).
The electronic effect of the substituents on the aniline
moiety in this electrophilic cyclization process has also been
investigated. It turns out that this process is not particularly
sensitive to electronic effects, which is in a good agreement
with our previous experience with these electrophilic cy-
clization reactions, although the presence of a strong electron-
withdrawing group can significantly reduce the nucleophi-
licity of the dialkylamino group.16 Thus, this cyclization
proceeds nicely in the presence of either electron-withdraw-
ing or electron-releasing groups (Table 2, entries 7-9). In
all cases examined, high yields have been obtained with
reaction times similar to those of the parent system 1a.
Besides 2-(phenylethynyl)anilines, other 2-(arylethynyl)-
anilines have also been successfully employed in this process
(Table 2, entries 10 and 11). In the presence of an electron-
rich thiophene ring, the reaction rate is considerably acceler-
ated (Table 2, entry 11). The same high reaction rate was
observed, when a vinylic moiety, such as a 1-cyclohexenyl
group, was present on the triple bond (Table 2, entry 12).
Interestingly, no product of addition of the 4-nitrobenzene-
sulfenyl chloride to the double bond of the 1-cyclohexenyl
moiety was observed, although such an addition reaction has
previously been reported.27
We have previously shown that o-methoxyaryl alkynes
undergo electrophilic cyclization in the presence of an
arylsulfenyl chloride, without the addition of n-Bu4NI, to
form 3-sulfenylbenzofurans.17 We therefore investigated the
reactivity of substrate 1h under our current cyclization
conditions. Note that this alkyne contains an o-methoxyphe-
nyl group at one end of the ethynyl functionality and an
o-(N,N-dimethylamino)phenyl group at the other end. Thus,
two cyclization paths are possible leading to the formation
of an indole, a benzofuran or possibly a mixture of both. In
practice, the 3-(phenylsulfenyl)indole 3m was generated
exclusively with no benzofuran product being observed
(Table 2, entry 13).
(27) (a) Schmid, G. H.; Strukelj, M.; Dalipi, S.; Ryan, M. D. J. Org.
Chem. 1987, 52, 2403. (b) Akguen, E.; Hartke, K.; Kaempchen, T. Arc.
Pharm. 1981, 314, 72.
Org. Lett., Vol. 11, No. 1, 2009
175

Finally, substrate 1i containing both a methyl and a phenyl
group on the aniline nitrogen was studied in this cyclization.
As expected, the N-phenylindole 3n was produced exclu-
sively in essentially a quantitative yield (Table 2, entry 14).
The role the n-Bu4NI plays in this process is uncertain at
this point. However, we believe that this cyclization involves
an anti addition of the sulfur electrophile and the nitrogen
moiety of the aniline to the alkyne triple bond to form a
transient 3-sulfenylindolium salt 6 via a sulfonium intermedi-
ate 5 (Scheme 2). In the presence of n-Bu4NI, 6 undergoes
the aniline nitrogen atom and the 1 equiv of n-Bu4NI. In
general, delocalization of the lone pair of electrons on the
aniline nitrogen into the aromatic ring π electron system
through orbital overlap dramatically decreases its basicity
and nucleophilicity. However, the steric bulkiness of the two
organic groups on the nitrogen and the ortho-substituted
internal triple bond forces rotation of the aromatic C-N bond
and reduces this orbital overlap, resulting in considerable
enhancement of the nitrogen nucleophilicity. Inductive
electron donation by the two organic groups on nitrogen also
raises the nitrogen nucleophilicity. With respect to n-Bu4NI,
it provides the highly nucleophilic iodide ions needed to
remove the methyl group from the indolium intermediate 6
and thus facilitates construction of the indole nucleus.
Scheme 2
.
Plausible Mechanism for the Electrophilic
Cyclization
In conclusion, we have described a novel synthetic
approach to 3-sulfenylindoles and 3-selenylindoles by the
n-Bu4NI-induced electrophilic cyclization of N,N-dialkyl-2-
(1-alkynyl)anilines and arylsulfenyl chlorides or arylselenyl
chlorides. A wide variety of N,N-dialkyl-2-(1-alkynyl)anilines
undergo this cyclization process in good to excellent yields.
This procedure allows simultaneous construction of the
indole ring system and the installation of a sulfenyl or selenyl
functionality at the 3-position of the indole nucleus, which
is a useful complement to the current synthetic approaches
to 3-sulfenyl- and 3-selenylindoles. The preparation of
biologically active 3-sulfonylindoles and 3-sulfenyl-5-
substituted indoles, as well as a mechanistic study of the
role of n-Bu4NI in this cyclization process, are currently
underway.
methyl group removal via SN2 displacement by the external
iodide to complete indole ring construction, which is possibly
the driving force to shift the equilibrium from the sulfonium
species 5 to the indolium intermediate 6. However, our
attempts to detect MeI and the indolium intermediate28 by
1H NMR spectroscopy in a reaction between 1a and
4-nitrobenzenesulfenyl chloride have been unsuccessful.29
We also cannot rule out activation of the arylsulfenyl chloride
by n-Bu4NI through halogen exchange to form the corre-
sponding arylsulfenyl iodide as the real electrophile.30
The success of this cyclization reaction presumably relies
on two factors: the presence of the two organic groups on
Acknowledgment. We acknowledge the National Institute
of General Medical Sciences (GM070620 and GM079593)
and the National Institutes of Health Kansas University
Center of Excellence for Chemical Methodologies and
Library Development (P50 GM069663) for financial support
of this project. We also thank Johnson Matthey, Inc. and
Kawaken Fine Chemicals Co., Ltd. for donations of pal-
ladium catalysts.
(28) For an example of the preparation and characterization of a
3-iodoindolium triiodide species, see: Ten Hoedt, R. W. M.; Van Koten,
G.; Noltes, J. G. Synth. Commun. 1977, 7, 61.
Supporting Information Available: Experimental pro-
cedures, characterization data of the new compounds, and
(29) We have been able to observe MeBr and the analogous selenium
intermediate in our synthesis of benzoselenophenes. See: Kesharwani, T.;
Worlikar, S. A.; Larock, R. C J. Org. Chem. 2006, 71, 2307.
(30) For a selected example of the synthesis and reactivity of an
arylsulfenyl iodide, see: Goto, K.; Yamamoto, G.; Tan, B.; Okazaki, R.
Tetrahedron Lett. 2001, 42, 4875.
1
copies of H, 13C, and 19F NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8021287
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Org. Lett., Vol. 11, No. 1, 2009