Synthesis of 3-sulfenyl- and 3-selenylindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal alkynes, followed by n-Bu4NI-induced electrophilic cyclization

Article abstract of DOI:10.1021/jo9014003

(Chemical Equation Presented) 3-Sulfenyl- and 3-selenylindoles are readily synthesized by a two-step process involving the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-ortho-iodoanilines and terminal alkynes and subsequent electrophilic cyclization of the resulting N,N-dialkyl-ortho-(1- alkynyl)anilines with arylsulfenyl chlorides or arylselenyl chlorides. The presence of a stoichiometric amount of n-Bu₄NI is crucial to the success of the electrophilic cyclization. A variety of 3-sulfenyl- and 3-selenylindole derivatives bearing alkyl, vinylic, aryl, and heteroaryl substituents have been prepared in good to excellent yields (up to 99%). By employing N,N-dibenzyl-ortho-iodoanilines, a 3-sulfenyl-N-H-indole has been successfully prepared. In addition, 3-sulfonyl- and 3-sulfinylindoles have also been successfully prepared by facile oxidation of the corresponding 3-sulfenylindoles.

Full text of DOI:10.1021/jo9014003

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Synthesis of 3-Sulfenyl- and 3-Selenylindoles by the Pd/Cu-Catalyzed
Coupling of N,N-Dialkyl-2-iodoanilines and Terminal Alkynes, Followed
by n-Bu4NI-Induced Electrophilic Cyclization
Yu Chen, Chul-Hee Cho, Feng Shi, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received July 2, 2009
3-Sulfenyl- and 3-selenylindoles are readily synthesized by a two-step process involving the
palladium/copper-catalyzed crossing coupling of N,N-dialkyl-ortho-iodoanilines and terminal alky-
nes and subsequent electrophilic cyclization of the resulting N,N-dialkyl-ortho-(1-alkynyl)anilines
with arylsulfenyl chlorides or arylselenyl chlorides. The presence of a stoichiometric amount of
n-Bu4NI is crucial to the success of the electrophilic cyclization. A variety of 3-sulfenyl- and
3-selenylindole derivatives bearing alkyl, vinylic, aryl, and heteroaryl substituents have been
prepared in good to excellent yields (up to 99%). By employing N,N-dibenzyl-ortho-iodoanilines,
a 3-sulfenyl-N-H-indole has been successfully prepared. In addition, 3-sulfonyl- and 3-sulfinylindoles
have also been successfully prepared by facile oxidation of the corresponding 3-sulfenylindoles.
Introduction
can augment the antitumor activity of celecoxib in human
colorectal cancer.7 L-737,126 is known to exhibit potent anti-
HIV properties,8 and the 3-(arylsulfenyl)indole 1 is not only an
inhibitor of tubulin polymerization, but also capable of in-
hibiting human breast cancer cell growth.9
Because of their therapeutic potential, there has been
growing interest in developing a general and versatile
synthetic route to 3-thioindole derivatives. As a conse-
quence, a number of synthetic approaches to 3-sulfenyl-
indoles have been developed in the past few years, including
the direct sulfenylation of indoles by disulfides10 or qui-
none mono-O,S-acetals;11 halide-catalyzed sulfenylation
The indole ring is present in a wide variety of biologically
active compounds and pharmaceutical agents.1 Among the
numerous indole derivatives known, 3-thioindoles have re-
cently attracted considerable attention from both industry and
academia due to their therapeutic value in a variety of diseases,
such as HIV,2 cancer,3 obesity,4 heart disease,5 and allergies.6
For instance, MK-886 is an inhibitor of 5-lipoxygenase and
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Published on Web 08/07/2009
DOI: 10.1021/jo9014003
r
2009 American Chemical Society

Chen et al.
JOCArticle
by N-thioalkyl(aryl)phthalimides;12 sulfenylation using
thiols activated in situ by N-chlorosuccinimide,13 phenyl-
iodine(III) bis(trifluoroacetate),14 Selectfluor,15 or transi-
tion-metal catalysts;16 oxidant-promoted thiocyanation
with ammonium thiocyanate;17 and treatment of 3,
30-dithiobisindoles with metalated aromatics or hetero-
cycles.18 In general, all these protocols have focused on
direct sulfenylation at the 3-position of the indole nucleus
by different sulfenylating agents.
benzothiophenes,22 benzoselenophenes,23 benzopyrans,24
furans,25 naphthols,26 naphthalenes,27 isoindolinones,28
coumestans and coumestrols,29 chromones,30 isocoumarins
and R-pyrones,31 isochromenes,32 isoquinolines,33 quino-
lines,34 isoxazoles,35 polycyclic aromatics,36 pyrroles,37 furo-
pyridines,38 furanones,39 and spiro[4,5]trienones.40
Although we had successfully prepared 3-sulfenyl-benzo-
furans21a and -benzothiophenes22b,c by electrophilic cycliza-
tion using arylsulfenyl chlorides as the electrophile, our early
attempts to prepare 3-sulfenylindoles using similar methods
were unsuccessful. The pharmaceutical interest in 3-sulfenyl-
indoles, however, inspired us to explore this approach
further. Our preliminary results have shown that in the
presence of 1 equiv of n-Bu4NI, 3-sulfenylindoles can be
successfully prepared under standard electrophilic cycliza-
tion conditions.41 Herein, we report our detailed results on
the synthesis of 3-sulfenylindoles using this n-Bu4NI-induced
electrophilic sulfur cyclization chemistry.
Results and Discussion
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TABLE 1. Preparation of N,N-Dialkyl-2-(1-alkynyl)anilines by Sonogashira Couplinga
aN,N-Dialkyl-2-iodoaniline (2, 2.0 mmol), terminal acetylene (2.2 mmol), PdCl2(PPh3)2 (0.026 mmol), CuI (0.020 mmol), and 6 mL of Et3N were
mixed in a sealed 4-dram vial. The resulting mixture was flushed with Ar and stirred at room temperature for the indicated time. bIsolated yields after
column chromatography.
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SCHEME 1. Preparation of Intermediate Alkyne 3u
SCHEME 2. Reaction between 3a and 4-Nitrobenzenesulfenyl Chloride under Standard Electrophilic Cyclization Conditions
Alkyne 3u was prepared from N,N-dimethyl-2-iodoaniline
(2a) by a three-step reaction sequence, namely, Sonogashira
coupling, removal of the TMS group, and a second Sono-
gashira coupling (Scheme 1).
TABLE 2. n-Bu4NI-Induced Electrophilic Cyclization of N,N-Dimethyl-(2-
phenylethynyl)aniline with 4-Nitrobenzenesulfenyl Chloridea
Our initial results indicated that under common electro-
philic cyclization conditions, the reaction between N,N-
dimethyl-(2-phenylethynyl)aniline (3a) and 4-nitrobenzene-
sulfenyl chloride leads exclusively to the simple triple bond
addition products 4 (Scheme 2).44 Our previous experience
on the electrophilic cyclization chemistry of functionally
substituted alkynes suggested that the successful cyclization
reactions generally proceed by a stepwise mechanism invol-
ving electrophilic activation of the alkyne C-C triple bond,
intramolecular nucleophilic attack on the cationic intermedi-
ate, and subsequent dealkylation by the in situ generated
halide anion.45 Based on this assumption and careful mecha-
nism analysis, we envisioned that the failure in this electro-
philic sulfur cyclization chemistry could be attributed to the
relatively weak nucleophilicity of the in situ generated chlor-
ide anion, which should play a significant role in removal of
the alkyl group after the intramolecular nucleophilic cycliza-
tion step had taken place. Thus, the nature of the halide
might seriously impact indole ring construction. It is known
that iodide anion is a better nucleophile than chloride anion
due to its greater polarizability. For this reason, 1 equiv of n-
Bu4NI was added to the reaction of 3a and p-O2NC6H4SCl
as an external source of nucleophile. To our delight, in the
presence of 1 equiv of n-Bu4NI, the triple bond addition
reaction was completely shut down and the reaction slowly
produced solely the desired cyclization product 5aa (Table 2,
entry 1).
entry additive (equiv)
solvent
temp (°C) time (h) % yieldb
1
2
3
4
5
6
7
8
9g
n-Bu4NI (1.0)
n-Bu4NI (1.0)
n-Bu4NI (1.0)
n-Bu4NI (1.0)
n-Bu4NCl (1.0) (CH2Cl)2
n-Bu4NBr (1.0) (CH2Cl)2
LiI (1.0)
n-Bu4NI (0.5)
n-Bu4NI (1.0)
CH2Cl2
(CH2Cl)2
CH3CN
toluene
rt
60
5
5
86
90
81
70
70
70
70
70
70
70
70
5
5
5
13c
d
d
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
5
5
5
tracee
48f
72
a4-Nitrobenzenesulfenyl chloride (2.0 equiv) was employed unless
otherwise indicated. bIsolated yield of 5aa after column chromatography
unless otherwise indicated. cYield determined by 1H NMR spectrosco-
py. dNo cyclized product was detected. eOnly a trace amount (<5%) of
the desired cyclized product was detected by 1H NMR spectroscopy.
fApproximately a 40% yield of triple bond addition products 4 was
obtained. g4-Nitrobenzenesulfenyl chloride (1.5 equiv) was employed.
coupling process are summarized in Table 1. In general, this
coupling reaction takes place smoothly between a variety of
functionalized N,N-dialkyl-ortho-iodoanilines and terminal
alkynes, affording high to excellent yields. A longer reaction
time was required when electron-deficient 4-ethynylbenzo-
nitrile was employed (Table 1, entries 11 and 12). Although it
was found that the reaction rate in these cases could be
significantly accelerated by means of either heating or adding
a polar solvent, such as DMF, it is preferred that these
reactions be carried out in Et3N at room temperature to
avoid the generation of cyclized indole byproduct.
Our further study has revealed that this cyclization
reaction can be substantially accelerated at an elevated
temperature. Therefore, several higher boiling solvents were
(44) The 1H NMR spectrum of the reaction mixture indicated that no
cyclized indole product was formed.
(45) Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141.
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TABLE 3. Preparation of 3-Sulfenyl- and 3-Selenylindoles by n-Bu4NI-Induced Electrophilic Cyclizationa
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TABLE 3. Continued
examined. When the reaction is run at 70 °C in dichloro-
ethane (DCE), instead of room temperature in dichloro-
methane (DCM), a 90% yield of the desired 3-(arylsul-
fenyl)indole 5aa was obtained in 5 h (Table 2, entry 2). An
81% yield was obtained when CH3CN was employed
(Table 2, entry 3). On the other hand, only a 13% yield of
the desired indole product was obtained when the cyclization
was carried out in toluene at 70 °C (Table 2, entry 4).
The role of the additive, n-Bu4NI, was then investigated.
None of the desired indole product was observed when either
1 equiv of n-Bu4NCl or n-Bu4NBr was employed (Table 2,
entries 5 and 6). Indole 5aa was generated only in trace
amounts when n-Bu4NI was replaced by LiI (Table 2, entry
7), possibly due to the extremely low solubility of the latter in
DCE. 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 5aa and
the triple bond addition products 4 is obtained in approxi-
mately a 1:1 ratio (Table 2, entry 8). An incomplete reaction
was observed after 5 h when the electrophile 4-nitrobenzene-
sulfenyl chloride was reduced from 2.0 to 1.5 equiv (Table 2,
entry 9).
The reaction scope was then explored under the optimal
reaction conditions (Table 2, entry 2). This cyclization has
proved to be a very general route to a variety of 3-sulfenyl-
indoles (Table 3). Besides 4-nitrobenzenesulfenyl chloride,
several other arylsulfenyl chlorides have also been success-
fully employed as electrophiles in this cyclization. When
electron-deficient pentafluorobenzenesulfenyl chloride was
employed, an 87% isolated yield of the corresponding indole
was obtained (Table 3, entry 2). The more electron-rich
arylsulfenyl chlorides phenylsulfenyl chloride and p-toluene-
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SCHEME 3. Preparation of an N-H3-Sulfenylindole
sulfenyl chloride afforded similar high yields (Table 3, entries
3 and 4). When the more sterically demanding 2-nitrobenze-
nesulfenyl chloride was used, the yield of the cyclization
product 5ae decreased to 52% (Table 3, entry 5), although
the starting material 3a was completely consumed. Products
of simple addition of the 2-nitrobenzenesulfenyl chloride to
the triple bond of 3a were also observed. Besides arylsulfenyl
chlorides, an alkylsulfenyl chloride, trichloromethylsulfenyl
chloride, has also been employed in this cyclization. How-
ever, this reagent only afforded a complex reaction mixture
using our current optimized reaction conditions.
Despite our previous lack of success with the synthesis of
3-selenylindoles via analogous electrophilic cyclization
chemistry,20a the cyclization of aniline 3a 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 3, 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 the electronic effects of the aniline moiety, which
is in good agreement with our previous experience with this
type of electrophilic cyclization reaction, although the pre-
sence of a strong electron-withdrawing group on the aniline
ring can significantly reduce the nucleophilicity of the
dialkylamino group.20a,b Thus, this cyclization proceeds
nicely in the presence of either electron-withdrawing or
electron-releasing groups (Table 3, entries 7-11). In all cases
examined, high yields have been obtained with reaction times
similar to those of the parent system 3a.
Besides 2-(phenylethynyl)anilines, other2-(alkynyl)anilines
have also been successfully employed in this process (Table 3,
entries 12-32). In contrast to the effect of substituents on
the aniline moiety, the substituents on the 2-alkynyl moiety
display a significant electronic effect on this cyclization
process. In general, the reaction is accelerated by the presence
of electron-rich groups situated at the distal end of the 2-
alkynyl triple bond, such as a 4-(N,N-dimethylamino)phenyl
group (Table 3, entries 18 and 19), a thiophene ring (Table 3,
entries 23-25), and a 4-methoxyphenyl group (Table 3,
entries 31 and 32). The same high reaction rate was observed
when a vinylic moiety, such as a 1-cyclohexenyl group, was
present on the distal end of the triple bond (Table 3, entry 26).
In this case, no product of addition of the 4-nitrobenzenesul-
fenyl chloride to the carbon-carbon double bond of the 1-
cyclohexenyl moiety was observed, although such an addition
reaction has previously been reported.46 The same alkyne
substrate 3o also undergoes cyclization smoothly in the pre-
sence of a selenium electrophile leading to the corresponding
3-selenylindole in a 76% yield (Table 3, entry 27). The
cyclization process was, however, significantly slowed by the
presence of electron-withdrawing groups. When an ethoxy-
carbonyl group is situated at the para-position of the aryl
group on the distal end of the alkyne triple bond, the cycliza-
tion takes as long as 18 h (Table 3, entry 20), affording
product 5at in a 66% yield. The effect is even more pro-
nounced when the stronger electron-withdrawing cyano
group is present (Table 3, entries 21 and 22). These cycliza-
tions take more than 50 h and only afford modest yields
(<50%) of the desired indole products. In both cases, a
significant amount of the simple triplebondaddition products
are obtained.
We have previously shown that ortho-methoxyaryl al-
kynes undergo electrophilic cyclization in the presence of
an arylsulfenyl chloride, without the addition of n-Bu4NI, to
form 3-sulfenylbenzofurans.21a We therefore investigated
the reactivity of substrates 3p and 3q under our current
cyclization conditions (Table 3, entries 28-30). Note that
this alkyne contains an ortho-methoxyphenyl group at one
end of the ethynyl functionality and an ortho-(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-sulfenylindoles 5bb, 5bc, and 5bd were generated exclusi-
vely with no benzofuran products being observed.
Substrate 3r containing both a methyl and a phenyl group
on the aniline nitrogen was also studied in this cyclization. As
(46) (a) Schmid, G. H.; Strukelj, M.; Dalipi, S.; Ryan, M. D. J. Org.
Chem. 1987, 52, 2403. (b) Akguen, E.; Hartke, K.; Kaempchen, T. Arch.
Pharm. (Weinheim, Ger.) 1981, 314, 72.
6808 J. Org. Chem. Vol. 74, No. 17, 2009

Chen et al.
JOCArticle
SCHEME 4. Oxidation of a 3-Sulfenylindole
SCHEME 5. Proposed Mechanism and Plausible Effect of n-Bu4NI on the Electrophilic Cyclization
expected, the N-phenylindoles 5be and 5bf were produced
exclusively in essentially quantitative yields (Table 3, entries
31 and 32).
corresponding N-H3-sulfenylindole 6 by employing Dea-
ton-Rewolinski’s debenzylation conditions.48
Although our attempts to prepare 3-sulfonyl- and 3-sul-
finylindoles by direct sulfonyl chloride and sulfinyl chloride
cyclization chemistry were not successful, these compounds
were readily synthesized by simply oxidizing the correspond-
ing 3-sulfenylindoles. Thus, 3-sulfonylindole 7 and 3-sul-
finylindole 8 have been successfully prepared in 83 and 91%
yields, respectively (Scheme 4).
Based on our previous experience with this type of electro-
philic cyclization chemistry, we believe that the current
process 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 10 by a
thiirenium intermediate 9 (Scheme 5, path b). In the presence
of n-Bu4NI, 10 undergoes methyl group removal via SN2
displacement by the external iodide to complete indole ring
construction after the loss of one molecule of MeI, which is
possibly the driving force to shift the equilibrium from the
thiirenium species 9 to the indolium intermediate 10. In the
absence of n-Bu4NI, the harder counterion chloride is less
nucleophilic and prefers trans-addition to the thiirenium
intermediate to form the undesired olefin product
The bromine atom present on the aniline ring of the starting
internal alkynes 3c, 3g, 3i, 3j, 3 L, 3n, and 3q (Table 3) has
proved to be an ideal handle for further chemical elaborations
by palladium-catalyzed coupling processes, after the cycliza-
tion, allowing the efficacious synthesis of a wide variety of
substituted 3-thioindoles. Besides sulfenyl chlorides, sulfonyl
chlorides and sulfinyl chlorides have also been examined in the
current cyclization chemistry. However, none of the desired
3-substituted indole products were observed.
To prepare free N-H 3-thioindoles, we employed 4-bromo-
2-iodoaniline bearing two benzyl groups on the aniline
nitrogen in this cyclization (Scheme 3). The dibenzylated
compound 2g was converted to the internal alkyne 3v by
Sonogashira coupling in the presence of 2 mol % of Pd-
(PPh3)4 and 2 mol % of CuI.47 Subsequent electrophilic
cyclization took place smoothly under our optimal reaction
conditions, affording the N-benzylated indole 5bg in a
71% yield. The latter product was readily converted to the
(47) About 15% of 1-benzyl-5-bromo-2-(4-methoxy-phenyl)indole was
obtained alongside the desired cyclized product 5bg when this Sonogashira
coupling was carried out under the reaction conditions described in Table 1.
(48) Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V.
Tetrahedron Lett. 2002, 43, 399.
J. Org. Chem. Vol. 74, No. 17, 2009 6809

Chen et al.
JOCArticle
(Scheme 5, path a). However, our attempts to detect MeI and
the indolium intermediate 1049 by 1H NMR spectro-
scopy in a reaction between 3a and 4-nitrobenzenesulfenyl
chloride have been unsuccessful. These experiments have
clearly shown the conversion of the starting materials to the
desired 3-sulfenylindole product, but nothing else.50 In
addition, we have also prepared 1-[2-(phenylethynyl)-
phenyl]pyrrolidine and examined its cyclization in the hope
of obtaining the corresponding 3-sulfenylindole with a 4-
iodobutyl chain attached to the nitrogen atom. Unfortunately,
this reaction only afforded a complex reaction mixture with
none of the desired indole product detected.
We cannot rule out activation of the arylsulfenyl chloride
by n-Bu4NI through halogen exchange to form the corre-
sponding arylsulfenyl iodide (ArSI) as the real electrophile.51
In the presence of the softer counterion iodide, the intramole-
cular cyclization (Scheme 5, path b) may take place much
faster than addition to the triple bond (Scheme 5, path a),
thus leading to the indole product.
been proposed and the role of n-Bu4NI has been discussed.
This synthetic approach 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,
and is a useful complement to the known literature protocols
for preparing 3-sulfenyl- and 3-selenylindoles.
Experimental Section
General Procedure for Preparation of the N,N-Dimethyl-o-
iodoanilines. These compounds were prepared according to a
procedure reported by Cadogan.52 To a solution of the corre-
sponding o-iodoaniline (2.0 mmol) and iodomethane (0.85 g,
6.0 mmol) in DMF (10 mL) was added K2CO3 (0.55 g,
4.0 mmol). The resulting mixture was stirred at room tempera-
ture for 48 h. Water (10 mL) was added to the reaction mixture.
The resulting solution was extracted with diethyl ether (3 ꢀ
10 mL). The organic layers were combined and washed with
water to remove any remaining DMF and dried over anhydrous
MgSO4. The solvent was removed under vacuum, and the
residue was purified by flash column chromatography on silica
gel using ethyl acetate/hexanes as the eluent.
The success of this cyclization reaction presumably relies on
two factors, the presence of the two organic groups on 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 or-
ganic 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 enhance-
ment of the nitrogen nucleophilicity. Inductive electron dona-
tion by the two organic groups on nitrogen also raises the
nitrogen nucleophilicity. This hypothesis has been proved by
our experimental data. No cyclization product was obtained
when either the free ortho-amino (NH2) containing alkyne or
the ortho-N-monomethylamino (MeNH) containing alkyne
analogue of 3a was employed. In addition, the Boc-protected
ortho-amino (NHBoc) containing alkyne analogue of 3a has
also been examined in this cyclization. However, no cyclized
product was observed at all. With respect to n-Bu4NI, it
presumably provides the highly nucleophilic iodide ions needed
to remove the methyl group from the indolium intermediate 10
and thus facilitates construction of the indole nucleus.
N,N-Dimethyl-4-bromo-2-iodoaniline (2c). This compound
was obtained as a light red oil in an 81% yield: 1H NMR (400
MHz, CDCl3) δ 2.72 (s, 6H), 6.92 (d, J=8.5 Hz, 1H), 7.40 (dd,
J=8.5, 2.4 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 45.0, 97.6, 116.4, 121.5, 132.0, 142.0, 154.3;
HRMS (EI) calcd for C8H9BrIN, 324.8963; found, 324.8969.
General Procedure for Preparation of the N,N-Dialkyl-2-(1-
alkynyl)anilines. To a 4-dram oven-dried vial was added PdCl2-
(PPh3)2 (18.3 mg, 0.026 mmol), CuI (3.8 mg, 0.020 mmol),
2.0 mmol of the N,N-dialkyl-o-iodoaniline, 2.2 mmol of the
terminal acetylene, and 6 mL of Et3N. The resulting mixture was
flushed with Ar and stirred at room temperature for the desired
time. The reaction mixture was diluted with 15 mL of diethyl ether
and washed with brine (15 mL). The aqueous phase was then
extracted with diethyl ether (2 ꢀ 10 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated under
vacuum to afford the crude product, which was purified by flash
column chromatography on silica gel using ethyl acetate/hexanes
as the eluent.
N,N-Dimethyl-4-bromo-2-(phenylethynyl)aniline (3c). This
compound was obtained as a light yellow oil in a 76% yield:
1H NMR (400 MHz, CDCl3) δ 2.98 (s, 6H), 6.78 (d, J=8.8 Hz,
1H), 7.31-7.37 (m, 4H), 7.51-7.54 (m, 2H), 7.59 (d, J=2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 43.4, 87.7, 95.9, 112.1,
116.7, 118.5, 123.4, 128.4, 128.5, 131.4, 132.0, 136.4, 153.7;
HRMS (EI) calcd for C16H14BrN, 299.0310; found, 299.0314.
General Procedure for Preparation of the 3-Sulfenyl- and 3-
Selenylindoles. To a solution of 0.50 mmol of the N,N-dialkyl-
2-(1-alkynyl)aniline, 0.50 mmol of n-Bu4NI, and 3 mL of 1,2-
dichloroethane (DCE) was gradually added a solution of
1.00 mmol of arylsulfenyl or arylselenyl chloride in 2 mL of
DCE. The resulting mixture was stirred at room temperature for
5 min and then heated to 70 °C for the desired time. The reaction
mixture was cooled to room temperature and diluted with 5 mL
of dichloromethane (DCM). The mixture was then washed with
10 mL of satd aq NH4Cl. The aqueous phase was extracted with
diethyl ether (2 ꢀ 5 mL). The combined organic layers were
dried over anhydrous MgSO4 and concentrated under vacuum
to yield the crude product, which was purified by flash column
chromatography on silica gel using either ethyl acetate/hexanes
or chloroform/hexanes as the eluent.
Conclusions
A synthetic approach to 3-sulfenylindoles and 3-selenyl-
indoles by the n-Bu4NI-induced electrophilic cyclization of
N,N-dialkyl-2-(1-alkynyl)anilines by arylsulfenyl chlorides
or arylselenyl chlorides has been described. A wide variety of
N,N-dialkyl-2-(1-alkynyl)anilines undergo this cyclization
process in good to excellent yields. Free N-H3-thioindoles
have been successfully prepared using the present method
and employing benzyl protecting groups. In addition,
the 3-sulfenylindoles synthesized are readily converted to
the corresponding 3-sulfonyl- and 3-sulfinylindoles by
oxidation. A plausible mechanism for this cyclization has
(49) For an example of the preparation and characterization of a
3-iodoindolium triiodide species, see ref 19d.
1-Benzyl-5-bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)indole
(5bg). This product was obtained as a white solid in a 71% yield:
(50) We have been able to observe MeBr and the analogous selenium
intermediate in our synthesis of benzoselenophenes. See ref 23a.
(51) 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.
(52) Cadogan, J. I. G.; Hickson, C. L.; Husband, J. B.; McNab, H.
J. Chem. Soc., Perkin Trans. 1 1985, 1891.
6810 J. Org. Chem. Vol. 74, No. 17, 2009

Chen et al.
JOCArticle
mp 161-163 °C; 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 5.34
(s, 2H), 6.89 (d, J=8.2 Hz, 2H), 6.99 (d, J=7.0 Hz, 2H), 7.04-7.12
(m, 4H), 7.19 (t, J=7.4 Hz, 2H), 7.25-7.30 (m, 6H), 7.80 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 48.7, 55.5, 99.9, 112.5, 114.1,
114.8, 122.1, 122.4, 124.8, 125.6, 125.96, 126.04, 127.7, 129.0,
129.1, 131.8, 132.1, 135.9, 137.3, 139.6, 147.5, 160.4; HRMS (EI)
calcd for C28H22BrNOS, 499.0605; found, 499.0616.
83% yield: H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 6.48
(d, J=8.2 Hz, 1H), 6.55 (d, J=8.8 Hz, 2H), 6.93 (t, J=7.6 Hz,
1
2H), 7.02-7.14 (m, 4H), 7.79 (d, J=8.8 Hz, 2H), 8.32 (s, 1H); 13
C
NMR (100 MHz, CDCl3) δ 55.6, 112.7, 118.6, 121.29, 121.31,
126.2, 128.2, 128.7, 129.8, 130.6, 131.0, 132.1, 136.1, 139.3, 152.4,
161.4, 175.1; HRMS (EI) calcd for C21H16BrNO3S, 441.0034;
found, 441.0044.
5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)indole (6). This
compound was prepared according to a procedure reported by
Deaton-Rewolinski.48 A solution of 5bg (220 mg, 0.44 mmol) and
KO-t-Bu (345 mg, 3.08 mmol) in DMSO (5 mL) was purged with
O2 at room temperature for 20 min. The reaction mixture was
vigorous stirred at 80 °C for 8 h. The resulting mixturewas diluted
with EtOAc (10 mL) and washed with water (15 mL). The
aqueous layer was extracted with EtOAc (2 ꢀ 10 mL). The
combined organic layers were dried over anhydrous MgSO4
and concentrated under vacuum to afford the crude product,
which was purified by flash column chromatography on silica gel
using ethyl acetate/hexanes as the eluent to afford the corre-
sponding product 6 in an 84% yield as a yellow oil, which
5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfinyl)indole(8). This
compound was prepared according to a modification of a
procedure reported by Xu.54 To a solution of 5-bromo-2-(4-
methoxyphenyl)-3-(phenylsulfenyl)indole (6; 80 mg, 0.195
mmol) and phenol (183.5 mg, 1.95 mmol) in HFIP (2.0 mL)
was added 30% H2O2 (0.05 mL, 0.4 mmol). The reaction
mixture was stirred at room temperature for 5 h. After complete
disappearance of the reactant as monitored by TLC, the excess
H2O2 was quenched with satd aq Na2SO3. Phenol was neutra-
lized with 10% aq NaOH. The aqueous layer was extracted with
EtOAc (2 ꢀ 3 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated under vacuum to afford
the crude product, which was purified by flash column chroma-
tography on silica gel using ethyl acetate/hexanes as the eluent to
afford the corresponding product 8 as a yellow oil in a 91%
yield, which solidified to a yellow solid upon standing: mp 112-
114 °C; 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 6.42 (d, J=
8.6 Hz, 2H), 6.92-7.05 (m, 2H), 7.03 (d, J=8.6 Hz, 2H), 7.45-
7.55 (m, 3H), 7.63-7.72 (m, 2H), 11.22 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 55.6, 109.6, 114.0, 114.4, 114.5, 121.4, 122.2,
125.5, 126.1, 126.5, 129.4, 130.5, 130.6, 135.4, 142.9, 146.5,
160.9; HRMS (EI) calcd for C21H16BrNO2S, 425.0085; found,
425.0089.
1
solidified to a yellow solid upon standing: mp 154-155 °C; H
NMR (400 MHz, CDCl3) δ 3.81 (s, 3H), 6.94 (d, J=8.8 Hz, 2H),
7.02-7.09 (m, 3H), 7.14-7.21 (m, 2H), 7.23-7.34 (m, 2H), 7.74
(d, J=8.8 Hz, 2H), 7.74 (s, 1H), 8.50 (br s, 1H); 13C NMR (100
MHz, CDCl3) δ 55.6, 98.3, 112.7, 114.5, 114.7, 122.4, 123.5,
125.0, 125.6, 126.2, 129.1, 129.6, 133.5, 134.5, 139.1, 143.6, 160.4;
HRMS (EI) calcd for C21H16BrNOS, 409.0136; found, 409.0148.
5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfonyl)indole(7). This
compound was prepared according to a procedure reported
by Shaabani.53 5-Bromo-2-(4-methoxyphenyl)-3-(phenylsulfenyl)-
indole (6; 0.195 mmol, 80 mg) were dissolved in CH2Cl2 (1.0 mL)
and CH3CN (1.0 mL). To the reaction mixture was added
finely ground KMnO4/MnO2 (0.40 g) in portions over a period
of 10 min. The mixture was stirred vigorously at room temperature,
while the progress of the reaction was monitored by TLC. Upon
completion of the reaction, the product was filtered through a
sintered glass funnel to remove the solid precipitate. The pro-
duct (in solution) was then filtered through a Celite pad and the
solid residue was washed with CH2Cl2 (2 ꢀ 3 mL). The organic
layer was washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using ethyl acetate/hexanes as the
eluent to afford the corresponding product 7 as a brown oil in an
Acknowledgment. We thank 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 sup-
port of this project. We also thank Johnson Matthey, Inc.
and Kawaken Fine Chemicals Co., Ltd. for donations of
palladium catalysts.
Supporting Information Available: Experimental proce-
dures, characterization data for the new compounds, and copies
of 1H, 13C, and 19F NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(53) Shaabani, A.; Mirzaei, P.; Naderi, S.; Lee, D. G. Tetrahedron 2004,
60, 11415.
(54) Xu, W.-L.; Li, Y.-Z.; Zhang, Q.-S.; Zhu, H.-S. Synthesis 2004, 227.
J. Org. Chem. Vol. 74, No. 17, 2009 6811